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Effects of combination treatment with metformin and berberine on hypoglycemic activity and gut microbiota modulation in db/db mice. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Gut microbiota alterations could influence the metabolism of administered drugs, leading to their altered pharmacokinetics and pharmacodynamics. Despite that metformin and berberine has individually demonstrated their impacts on hypoglycemic activities and gut microbiota alterations in diabetic mice, investigation regarding the impact of their combination treatment in diabetic treatment has never been conducted. PURPOSE:Our current study was proposed aiming to investigate the effect of combination use of metformin with berberine on hypoglycemic activity and identify the possible intestinal bacteria involved in their microbiota-medicated drug-drug interactions in db/db mice. STUDY DESIGN:Pharmacodynamics interactions between metformin and berberine were evaluated in six groups of db/db mice (db, M250, B250, B125, B250+M250, and B125+M250) with its wild type (WT) as control to receive 14 days treatment of vehicle, metformin at 250 mg/kg, berberine at 250/125 mg/kg, and metformin (250 mg/kg) 2 h after dosing berberine (250/125 mg/kg). METHODS:On day 13, insulin tolerance test (ITT) was conducted. On day 15, fasting serum samples were obtained for insulin concentration determination followed by intraperitoneal glucose tolerance test (ipGTT), homeostatic model assessment for insulin resistance (HOMA-IR) calculation, and feces collection for microbial 16S rRNA sequencing analyses. In addition, metformin steady state plasma concentrations on day 15 were measured by validated LC-MS/MS method. RESULTS:Combination treatment of metformin with berberine could further reduce in blood glucose in comparison to that of db/db diabetic control. Further microbial 16S rRNA sequencing analyses revealed that gut microbiota compositions were significantly changed with the abundance of Proteobacteria and Verrucomicrobia altered the most after metformin and berberine co-treatment compared to their monotherapy. In addition, steady state metformin concentrations in their combination treatment were significantly higher than that from metformin monotherapy. CONCLUSION:Co-administration of metformin (250 mg/kg) with berberine (125 mg/kg) could not only further improve insulin sensitivity, but also demonstrate different alterations on gut microbial communities than that of their individual treatment in db/db mice. 10.1016/j.phymed.2022.154099
Supplemental Berberine in a High-Fat Diet Reduces Adiposity and Cardiac Dysfunction in Offspring of Mouse Dams with Gestational Diabetes Mellitus. The Journal of nutrition BACKGROUND:There are few evidence-based strategies to attenuate the risk of metabolic syndrome in offspring exposed to gestational diabetes mellitus (GDM). Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese herbs and exhibits glucose lowering properties. OBJECTIVES:We hypothesized that dietary BBR would improve health outcomes in the mouse offspring of GDM dams. METHODS:Wild-type C57BL/6 female mice were fed either a Lean-inducing low-fat diet (L-LF,10% kcal fat, 35% kcal sucrose) or a GDM-inducing high-fat diet (GDM-HF, 45% kcal fat, 17.5% sucrose) for 6 wk prior to breeding with wild-type C57BL/6 male mice throughout pregnancy and the suckling period. The resulting Lean and GDM-exposed male and female offspring were randomly assigned an LF (10% kcal fat, 35% kcal sucrose), HF (45% kcal fat, 17.5% sucrose), or high-fat berberine (HFB) (45% kcal fat, 17.5% sucrose diet) containing BBR (160 mg/kg/d, HFB) at weaning for 12 wk. The main outcome was to evaluate the effects of BBR on obesity, pancreatic islet function, and cardiac contractility in GDM-exposed HF-fed offspring. Significance between measurements was determined using a 2 (gestational exposure) × 3 (diet) factorial design by a 2- way ANOVA using Tukey post-hoc analysis. RESULTS:In the GDM-HF group, body weights were significantly increased (16%) compared with those in baseline (L-LF) animals (P < 0.05). Compared with the L-LF animals, the GDM-HF group had a reduction in pancreatic insulin glucose-stimulated insulin secretion (74%) and increased cardiac isovolumetric contraction time (IVCT; ∼150%) (P < 0.05). Compared with GDM-HF animals, the GDM-HFB group with the dietary addition of BBR had significantly reduced body weight (16%), increased glucose-stimulated insulin secretion from pancreatic islets (254%), and reduced systolic heart function (46% IVCT) (P < 0.05). CONCLUSIONS:In a mouse model of GDM, dietary BBR treatment provided protection from obesity and the development of pancreatic islet and cardiac dysfunction. 10.1093/jn/nxaa408
Berberine is an insulin secretagogue targeting the KCNH6 potassium channel. Nature communications Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels. 10.1038/s41467-021-25952-2
Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study. Wang Shujie,Ren Huahui,Zhong Huanzi,Zhao Xinjie,Li Changkun,Ma Jing,Gu Xuejiang,Xue Yaoming,Huang Shan,Yang Jialin,Chen Li,Chen Gang,Qu Shen,Liang Jun,Qin Li,Huang Qin,Peng Yongde,Li Qi,Wang Xiaolin,Zou Yuanqiang,Shi Zhun,Li Xuelin,Li Tingting,Yang Huanming,Lai Shenghan,Xu Guowang,Li Junhua,Zhang Yifei,Gu Yanyun,Wang Weiqing Gut microbes Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal level responding to BBR alone or Prob+BBR treatment. Four genes encoding long-chain acyl-CoA synthetase were identified in the genome of this strain, and transcriptionally activated by BBR. BBR treatment further decreased the concentration of FFA in the culture medium of compared to vehicle. Thus, the activation of by BBR could enhance FFA import and mobilization in and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob () could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D. 10.1080/19490976.2021.2003176
Berberine Improves TNF-α-Induced Hepatic Insulin Resistance by Targeting MEKK1/MEK Pathway. Inflammation Berberine (BBR), a natural isoquinoline alkaloid exhibiting insulin sensitizing activity, has been applicated in the treatment of diabetes. However, until now, the exact target of BBR has not been well investigated. Here, primary hepatocytes pre-treated with TNF-α were used to evaluate the role of BBR on hepatic insulin sensitivity. Western blot and immunoprecipitation were used to investigate the effect of BBR on the crosstalk between TNF-α pathway and insulin signaling pathway. Molecular docking was used to verify the interactions between BBR and its potential targets. BBR inhibits the MEKK1 and MEK1/2, and thus suppresses the activation of their downstream ERK1/2. It attenuates the ERK1/2-induced serine phosphorylation of IRS-1 and thus enhances IRS-1 tyrosine phosphorylation and Akt activation. By molecular docking, BBR is proved to efficiently bind MEK1/2. MEKK1 is also considered as BBR target for its similarity in primary structure with MEK1/2. In conclusion, BBR ameliorates TNF-α-induced hepatic insulin resistance by targeting MEKK1 and MEK1/2. 10.1007/s10753-022-01671-8
Acetylation of p65 by p300 in macrophages mediates anti-inflammatory property of berberine. Redox biology Nuclear factor (NF)-κB plays a pivotal role in the regulation of inflammatory response in macrophages. Berberine (BBR), which is an active constituent isolated from Coptis rhizome, possesses a prominent anti-inflammatory activity. Here we show that BBR changes the global acetylation landscape in LPS-induced protein acetylation of macrophages and reduces the acetylation of NF-κB subunit p65 at site Lys310(p65), leading to the inhibition of NF-κB translocation and transcriptional activity to suppress the expressions of inflammatory factors. BBR resists the inflammatory response in acute LPS-stimulated mice through downregulation of p65 acetylation in peritoneal macrophages. In obese mice, BBR alleviates the metabolic disorder and inflammation with the reduced acetylation of p65 in white adipose tissue. Furthermore, we demonstrate that BBR acts as a regulator of p65 by inhibiting the expression of p300 in macrophages. Our findings elucidate a new molecular mechanism for the anti-inflammatory effect of BBR via the p300/p65 axis. 10.1016/j.redox.2023.102704
The short-term effects of berberine in the liver: Narrow margins between benefits and toxicity. Toxicology letters Berberine is a plant alkaloid to which antihyperglycemic properties have been attributed. It is also known as an inhibitor of mitochondrial functions. In this work short-term translation of the latter effects on hepatic metabolism were investigated using the isolated perfused rat liver. Once-through perfusion with a buffered saline solution was done. At low portal concentrations berberine modified several metabolic pathways. It inhibited hepatic gluconeogenesis, increased glycolysis, inhibited ammonia detoxification, increased the cytosolic NADH/NAD ratio and diminished the ATP levels. Respiration of intact mitochondria was impaired as well as the mitochondrial pyruvate carboxylation activity. These results can be regarded as evidence that the direct inhibitory effects of berberine on gluconeogenesis, mediated by both energy metabolism and pyruvate carboxylation inhibition, represent most likely a significant contribution to its clinical efficacy as an antihyperglycemic agent. However, safety concerns also arise because all effects occur at similar concentrations and there is a narrow margin between the expected benefits and toxicity. Even mild inhibition of gluconeogenesis is accompanied by diminutions in oxygen uptake and ammonia detoxification and increases in the NADH/NAD ratio. All combined, desired and undesired effects could well in the end represent a deleterious combination of events leading to disruption of cellular homeostasis. 10.1016/j.toxlet.2022.08.005
Berberine combined with stachyose improves glycometabolism and gut microbiota through regulating colonic microRNA and gene expression in diabetic rats. Life sciences AIMS:Berberine is effective for type 2 diabetes mellitus (T2DM), but has limited use in clinic. This study aims to evaluate the effect of berberine combined with stachyose on glycolipid metabolism and gut microbiota and to explore the underlying mechanisms in diabetic rats. MAIN METHODS:Zucker diabetic fatty (ZDF) rats were orally administered berberine, stachyose and berberine combined with stachyose once daily for 69 days. The oral glucose tolerance and levels of blood glucose, insulin, triglyceride and total cholesterol were determined. The gut microbial profile, colonic miRNA and gene expression were assayed using Illumina sequencing. The quantitative polymerase chain reaction was used to verify the expression of differentially expressed miRNAs and genes. KEY FINDINGS:Repeated treatments with berberine alone and combined with stachyose significantly reduced the blood glucose, improved the impaired glucose tolerance, and increased the abundance of beneficial Akkermansiaceae, decreased that of pathogenic Enterobacteriaceae in ZDF rats. Furthermore, combined treatment remarkably decreased the abundances of Desulfovibrionaceae and Proteobacteria in comparison to berberine. Combined treatment evidently decreased the expression of intestinal early growth response protein 1 (Egr1) and heparin-binding EGF-like growth factor (Hbegf), and significantly increased the expression of miR-10a-5p, but berberine alone not. SIGNIFICANCE:Berberine combined with stachyose significantly improved glucose metabolism and reshaped gut microbiota in ZDF rats, especially decreased the abundance of pathogenic Desulfovibrionaceae and Proteobacteria compared to berberine alone, providing a novel strategy for treating T2DM. The underlying mechanisms may be associated with regulating the expression of intestinal Egr1, Hbegf and miR-10a-5p, but remains further elucidation. 10.1016/j.lfs.2021.119928
Plant isoquinoline alkaloids: Advances in the chemistry and biology of berberine. Singh Sneha,Pathak Nandini,Fatima Eram,Negi Arvind Singh European journal of medicinal chemistry Alkaloids are one of the most important classes of plant bioactives. Among these isoquinoline alkaloids possess varied structures and exhibit numerous biological activities. Basically these are biosynthetically produced via phenylpropanoid pathway. However, occasionally some mixed pathways may also occur to provide structural divergence. Among the various biological activities anticancer, antidiabetic, antiinflammatory, and antimicrobial are important. A few notable bioactive isoquinoline alkaloids are antidiabetic berberine, anti-tussive codeine, analgesic morphine, and muscle relaxant papaverine etc. Berberine is one of the most discussed bioactives from this class possessing broad-spectrum pharmacological activities. Present review aims at recent updates of isoquinoline alkaloids with major emphasis on berberine, its detailed chemistry, important biological activities, structure activity relationship and implementation in future research. 10.1016/j.ejmech.2021.113839
Berberine alleviates myocardial ischemia-reperfusion injury by inhibiting inflammatory response and oxidative stress: the key function of miR-26b-5p-mediated PTGS2/MAPK signal transduction. Jia Xiaojing,Shao Wei,Tian Suqing Pharmaceutical biology CONTEXT:Berberine has myocardial protective effects. OBJECTIVES:The protective effects of berberine on heart ischemia-reperfusion (I/R) injury were explored. MATERIALS AND METHODS:Human cardiomyocytes were divided into control group, oxygen-glucose deprivation/re-oxygen (OGD/R) (2 h OGD with 24 h reoxygenation) group, OGD/R + low group (5 μM berberine for 24 h) and OGD/R + high group (10 μM berberine for 24 h). Twenty-four Wistar rats were divided into sham group, I/R group (45 min occlusion with 2 h reperfusion), I/R + berberine group (50 mg/kg berberine 1 h before I/R surgery) and I/R + berberine + antagomir (intraperitoneally injected with miR-26b-5p antagomir). MicroRNA profile, effects of berberine on I/R or OGD/R-induced injuries, and the role of miR-26b-5p in the function of berberine were explored. RESULTS:OGD/R treatment suppressed viability (0.41 ± 0.05 vs. 0.87 ± 0.13, < 0.05), while induced apoptosis (6.6 ± 1.0% vs. 26.3 ± 4.8%, < 0.05) in cardiomyocytes, which was restored by berberine (viability: 0.64 ± 0.01 for 5 μM and 0.72 ± 0.01 for 10 μM, < 0.05; apoptosis: 10.9 ± 2.2 for 5 μM and 7.9 ± 1.3 for 10 μM). Berberine induced miR-26b-5p and inhibited PTGS2/MAPK pathway. MiR-26b-5p inhibition counteracted the protective function of berberine. In rats, berberine (50 mg/kg) improved heart histological structure and suppressed inflammatory response, which was impaired by miR-26b-5p inhibition. DISCUSSION AND CONCLUSIONS:Berberine exerted anti-I/R function in heart by inducing miR-26b-5p and suppressing the PTGS2/MAPK pathway. These data promote the application of berberine as an anti-I/R agent. 10.1080/13880209.2022.2048029
Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Zhang Yifei,Gu Yanyun,Ren Huahui,Wang Shujie,Zhong Huanzi,Zhao Xinjie,Ma Jing,Gu Xuejiang,Xue Yaoming,Huang Shan,Yang Jialin,Chen Li,Chen Gang,Qu Shen,Liang Jun,Qin Li,Huang Qin,Peng Yongde,Li Qi,Wang Xiaolin,Kong Ping,Hou Guixue,Gao Mengyu,Shi Zhun,Li Xuelin,Qiu Yixuan,Zou Yuanqiang,Yang Huanming,Wang Jian,Xu Guowang,Lai Shenghan,Li Junhua,Ning Guang,Wang Weiqing Nature communications Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261). 10.1038/s41467-020-18414-8
Cellular and Molecular Mechanisms and Effects of Berberine on Obesity-Induced Inflammation. Biomedicines Obesity represents chronic low-grade inflammation that precipitates type 2 diabetes, cardiovascular disease, and cancer. Berberine (BBR) has been reported to exert anti-obesity and anti-inflammatory benefits. We aimed to demonstrate the underlying immune-modulating mechanisms of anti-obesity effects of BBR. First, we performed in silico study to identify therapeutic targets, describe potential pathways, and simulate BBR docking at M1 and M2 adipose tissue macrophages (ATMs), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4 (CXCR4). Next, in vivo, we divided 20 C58BL/6 mice into four groups: normal chow, control (high fat diet (HFD)), HFD + BBR 100 mg/kg, and HFD + metformin (MET) 200 mg/kg. We evaluated body weight, organ weight, fat area in tissues, oral glucose and fat tolerance tests, HOMA-IR, serum lipids levels, population changes in ATMs, M1 and M2 subsets, and gene expression of TNF-α, CCL2, CCL3, CCL5, and CXCR4. BBR significantly reduced body weight, adipocyte size, fat deposition in the liver, HOMA-IR, triglycerides, free fatty acids, ATM infiltration, all assessed gene expression, and enhanced the CD206+ M2 ATMs population. In conclusion, BBR treats obesity and its associated metabolic dysfunctions, by modulating ATM recruitment and polarization via chemotaxis inhibition. 10.3390/biomedicines10071739
Berberine enhances the function of db/db mice islet β cell through GLP-1/GLP-1R/PKA signaling pathway in intestinal L cell and islet α cell. Frontiers in pharmacology The evidence on berberine stimulating the secretion of GLP-1 in intestinal L cell has been studied. However, few research has explored its role on generating GLP-1 of islet α cell. Our experiment aims to clarify the mechanism of berberine promoting the secretion of GLP-1 in intestinal L cell and islet α cell, activating GLP-1R and its downstream molecules through endocrine and paracrine ways, thus improving the function of islet β cell and treating T2DM. After confirming that berberine can lower blood glucose and improve insulin resistance in db/db mice, the identity maintenance, proliferation and apoptosis of islet cells were detected by immunohistochemistry and immunofluorescence. Then, the activation of berberine on GLP-1/GLP-1R/PKA signaling pathway was evaluated by Elisa, Western blot and PCR. Finally, this mechanism was verified by experiments on Min6 cells, STC-1 cells and aTC1/6 cells. Berberine ameliorates glucose metabolism in db/db mice. Additionally, it also increases the number and enhances the function of islet β cell. This process is closely related to improve the secretion of intestinal L cell and islet α cell, activate GLP-1R/PKA signaling pathway through autocrine and paracrine, and increase the expression of its related molecule such as GLP-1, GLP-1R, PC1/3, PC2, PKA, Pdx1. , the phenomenon that berberine enhanced the GLP-1/GLP-1R/PKA signal pathway had also been observed, which confirmed the results of animal experiments. Berberine can maintain the identity and normal function of islet β cell, and its mechanism is related to the activation of GLP-1/GLP-1R/PKA signal pathway in intestinal L cell and islet α cell. 10.3389/fphar.2023.1228722
Berberine protects against palmitate induced beta cell injury via promoting mitophagy. Genes & genomics BACKGROUND:Destruction of pancreatic beta cells is the most typical characteristic of diabetes. OBJECTIVE:We aimed to evaluate the effect of berberine (BBR), a bioactive isoquinoline derivative alkaloid, on beta cell injury. METHODS:Rodent pancreatic beta cell line INS-1 was treated with 0.5 mM palmitate (PA) for 24 h to establish an in vitro beta cell injury model. RESULTS:BBR at 5 µM promoted cell viability, inhibited cell apoptosis and enhanced insulin secretion in PA-induced INS-1 cells. BBR treatment also suppressed PA-induced oxidative stress in INS-1 cells, as evidenced by the decreased ROS production and increased activities of antioxidant enzymes. In addition, suppressed ATP production and reduced mitochondrial membrane potential were restored by BBR in PA-treated INS-1 cells. It was further determined that BBR affected the expressions of mitophagy-associated proteins, suggesting that BBR promoted mitophagy in PA-exposed INS-1 cells. Meanwhile, we found that BBR facilitated nuclear expression and DNA-binding activity of Nrf2, an antioxidative protein that can regulate mitophagy. Finally, a rescue experiment was performed and the results demonstrated that the effect of BBR on cell viability, apoptosis and mitochondrial function in PA-induced INS-1 cells were cancelled by PINK1 knockdown. CONCLUSIONS:BBR protects islet β cells from PA-induced injury, and this protective effect may be achieved by regulating mitophagy. The present study may provide a novel therapeutic strategy for β cell injury in diabetes mellitus. 10.1007/s13258-022-01250-z
The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches. Habtemariam Solomon Biomedicines Berberine is a quaternary isoquinoline alkaloid that has been isolated from numerous plants which are still in use today as medicine and herbal supplements. The great deal of enthusiasm for intense research on berberine to date is based on its diverse pharmacological effects via action on multiple biological targets. Its poor bioavailability resulting from low intestinal absorption coupled with its efflux by the action of P-glycoprotein is, however, the major limitation. In this communication, the chemical approach of improving berberine's bioavailability and pharmacological efficacy is scrutinised with specific reference to type-2 diabetes and associated diseases such as hyperlipidaemia and obesity. The application of modern delivery systems, research from combination studies to preparation of berberine structural hybrids with known biologically active compounds (antidiabetic, antihyperlipidaemic and antioxidant), as well as synthesis approaches of berberine derivative are presented. Improvement of bioavailability and efficacy through in vitro and ex vivo transport studies, as well as animal models of bioavailability/efficacy in lipid metabolism and diabetes targets are discussed. 10.3390/biomedicines8040090
Mechanism of Action of Natural Dipeptidyl Peptidase-IV Inhibitors (Berberine and Mangiferin) in Experimentally Induced Diabetes with Metabolic Syndrome. International journal of applied & basic medical research Background:Berberine (BER) and mangiferin are known natural dipeptidyl peptidase (DPP-IV) inhibitors. Hence, the study was designed to elucidate the mechanism of action of natural DPP-IV inhibitors (BER and MNG) in experimentally induced diabetes with metabolic syndrome. Aim:The aim of this study was to observe mechanism through which natural DPP-IV inhibitor works in diabetes with metabolic syndrome rat model. Materials and Methods:Wistar rats were fed high-fat diet for 10 weeks and challenged with streptozotocin (STZ) (40 mg/kg) at the 3 week (high-fat diabetic control [HF-DC] group). After the confirmation of metabolic syndrome in the setting of diabetes, monotherapy (metformin [MET], vildagliptin [VIL], BER, and MNG) and combination (MET + VIL, MET + BER, and MET + MNG) therapy was orally fed to these rats from the 4 to 10 weeks. Results:Insulin resistance (IR) was seen in the HF-DC group as indicated by raised homeostasis model assessment of IR (HOMA-IR) in HF-DC group as compared with normal control (NC) groups. The treatment groups reduced IR as shown by a decrease in HOMA-IR as compared with HF-DC group rats. The marked reduction ( < 0.001) of beta-cell function was observed in the HF-DC group as a reduced level of HOMA for beta-cell function (HOMA-β) was found as compared with the NC group. Increases in HOMA-β as compared to the HFDC group were observed in the therapy groups. The treatment group significantly reduced cholesterol and atherogenic index. The treatment group showed significant preservation of beta-cell mass as per immunohistochemistry and significant anti-apoptotic activity as per Terminal Deoxyribonucleotidyl Transferase-Mediated dUTP Nick End Labeling assay report. The treated rats significantly ( < 0.05) reduced high-sensitivity C-reactive protein. Lipid peroxidation (thiobarbituric acid reactive substances) marker ( < 0.001) was significantly reduced in the treatment group. Conclusion:The natural DPP-IV inhibitors BER and MNG treatment showed beneficial effects on various components of metabolic syndrome. 10.4103/ijabmr.ijabmr_115_23
Berberine and Ginsenoside Rb1 Ameliorate Depression-Like Behavior in Diabetic Rats. Zhang Jing-Hua,Yang Hui-Zeng,Su Hao,Song Jun,Bai Yu,Deng Lan,Feng Chun-Peng,Guo Hong-Xia,Wang Yi,Gao Xin,Gu Yan,Zhen Zhong,Lu Yao The American journal of Chinese medicine (Huang-lian) and Asian have been widely used in the treatment of diabetes and other concurrent diseases with apparent effects. This study investigated the effects of the active ingredients of and , berberine and ginsenoside Rb1, on depression-like behavior in a rat diabetes model. The animal model was established via a high-fat diet and intraperitoneal injection of streptozotocin, while the animal's depression-like behavior was induced via chronic unpredictable mild stress. These experimental rats were divided into four groups: control, depression-like behavior (DLB), metformin plus fluoxetine hydrochloride (M+FH), and berberine plus ginsenoside Rb1 (B+GRb1) groups. Glucose metabolism and insulin resistance were evaluated by oral glucose test and glucose clamp study. Depression-like behavior was evaluated via behavioral analyses, including forced swim, sucrose preference, elevated plus maze, and open-field tests. HE and Nissl staining, plasma cortisol expression of adrenocorticotropic hormone, and brain-derived neurotrophic factor (BDNF) levels were assayed to explore the mechanisms of action. Compared with the control, rats in the DLB group had a significant increase in the levels of blood glucose and depression-like behavior. The B+GRb1 group significantly improved glucose metabolism and insulin resistance, reduced depression-like behavior, downregulated levels of plasma cortisol and adrenocorticotropic hormone under stress, and upregulated BDNF protein expression compared to the DLB rats. HE and Nissl staining data revealed that B+GRb1 protected neurons from pathological and morphological changes. Thus, berberine and ginsenoside Rb1 not only improved glucose metabolism in diabetic rats but also ameliorated their depression-like behavior under chronic unpredictable stress. Mechanistically, studied data with plasma hormonal levels and brain neuronal pathological/morphological changes supported the observed effects. The combination of berberine and ginsenoside Rb1 may have a clinical value in the management of diabetic patients with depression. 10.1142/S0192415X21500579
Berberine improves insulin-induced diabetic retinopathy through exclusively suppressing Akt/mTOR-mediated HIF-1α/VEGF activation in retina endothelial cells. Wang Ning,Zhang Cheng,Xu Yu,Tan Hor-Yue,Chen Haiyong,Feng Yibin International journal of biological sciences Insulin therapy is the major treatment of glycaemic control in type I diabetes mellitus (DM) and advanced type II DM patients who fail to respond to oral hypoglycemic agents. Nonetheless, insulin therapy is deemed unsuccessful in controlling the incidence of diabetic retinopathy (DR) and is likely a risk factor. Berberine, an isoquinoline alkaloid, has caught great attention towards its anti-diabetic mechanisms. This study aims to investigate the effect of berberine in decelerating DR progression in insulin-treated DM. To better understand the therapeutic potential of berberine in the presence of insulin, we elaborated the action of mechanism whether berberine inhibited retinal expression of HIF-1α and VEGF through regulating AKT/mTOR pathway. Suppression of insulin-induced neovasculature of retina endothelial cells by berberine was also studied. Lastly, the efficacy and safety of berberine as adjuvant therapy for the treatment of DR were systemically investigated in experimental type I and type II DM mice with insulin treatment. Among various types of retinal cells, the activity of HIF-1α and VEGF in retinal endothelial cells could be particularly and exclusively stimulated by insulin intervention, which could be inhibited by berberine treatment in a dose- and time-dependent manner. Berberine suppressed Akt/mTOR activity in these cells, and restoration of Akt/mTOR signalling attenuated berberine's inhibition on HIF-1α and VEGF expression. Berberine suppressed the progression of DR in experimental type I and type II diabetic mice receiving insulin therapy. Berberine improves insulin-induced diabetic retinopathy in type I and II diabetes through inhibiting insulin-induced activation of retinal endotheliocytes via Akt/mTOR/ HIF-1α/VEGF pathway. 10.7150/ijbs.62868
Exploring the synergistic and complementary effects of berberine and paeoniflorin in the treatment of type 2 diabetes mellitus by network pharmacology. Zhang Lili,Han Lin,Ma Jiang,Wu Tingchao,Wei Yu,Zhao Linhua,Tong Xiaolin European journal of pharmacology Investigation of the synergistic and complementary effects is vital but difficult for Chinese herbal medicine. We explored the synergistic and complementary mechanisms of berberine (BBR) and paeoniflorin (PF) in the treatment of type 2 diabetes mellitus (T2DM) through network pharmacology and molecular docking. We identified putative targets of BBR, PF, and T2DM, and constructed a protein-protein interaction (PPI) network. Gene ontology and Kyoto encyclopedia of gene and genomes pathway enrichment analysis and molecular docking were used to predict the molecular mechanisms. A diabetes model was induced by a high-fat diet to verify the therapeutic effect. Ninety-two targets of BBR + PF in the treatment of T2DM were identified, which were considered as synergistic targets. Fifty-nine complementary targets of BBR-T2DM and 47 of PF-T2DM were identified. PPI network analysis showed that JAK2, ESR1, IFG1R, STAT3, EGFR, MAPK1, and AKT1 are closely related to T2DM. The enrichment analysis further showed that the synergistic targets mainly involved the AGE-RAGE signaling pathway in diabetic complications, FOXO, AMPK, and VEGF signaling pathways, and glycolysis/gluconeogenesis. AKT1, JAK2, and STAT3, which are common targets of the AGE-RAGE signaling pathway in diabetic complications and the FOXO signaling pathway, were chosen for docking with BBR and PF, respectively, and showed good binding activities. BBR + PF significantly reduced weight and fasting blood glucose, and alleviated insulin resistance. Moreover, BBR + PF promoted the phosphorylation of AKT1, JAK2, and STAT3. This study provides information to understand the synergistic and complementary mechanism of BBR + PF against T2DM, and may facilitate the development of new anti-T2DM drugs. 10.1016/j.ejphar.2022.174769
Exploring the molecular mechanism of berberine for treating diabetic nephropathy based on network pharmacology. International immunopharmacology BACKGROUND AND PURPOSE:Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus characterized by hyperglycemia, hyperlipidemia, albuminuria and edema. Increasing evidence indicated that berberine (BBR) could alleviate the occurrence and development of DN. However, the molecular mechanism underlying the beneficial effects of BBR in the treatment of DN remains unclear. METHODS:The online public databases were chosen to screen the relevant targets of BBR and DN and the screened overlapped targets were analyzed by GO enrichment analysis, KEGG enrichment analysis and protein-protein interaction network analysis. The interaction between BBR and the key proteinwas verified by molecular docking and cellularthermalshiftassay. Additionally, the expression of key proteins and related indicators of DN were verified by immunofluorescence and western blot in vitro and in vivo. RESULTS:We successfully identified 92 overlapped targets of BBR and DN based on network pharmacology. Notably, VEGFR2 was identified to be the main target of BBR. Meanwhile, we found that BBR exhibited a high binding affinity to VEGFR2 protein, as confirmed by molecular docking and CETSA. This binding led to interfering with the PI3K/AKT/mTOR signaling pathway. In addition, we found that BBR could inhibit the abnormal proliferation of mesangial cells and reduce the expression of downstream pathway protein in vitro and in vivo. Finally, BBR was found to effectively lower the level of blood glucose and improve kidney function in mice, highlighting its potential as a therapeutic agent for the treatment of DN. CONCLUSION:Berberine interfered the PI3K/AKT/mTOR signaling pathway via targeting VEGFR2 protein, further led to the inhibition of abnormal proliferation of mesangial cells and ultimately resulted in improved renal function. 10.1016/j.intimp.2023.111237
Berberine alleviates diabetic retinopathy by regulating the Th17/Treg ratio. Immunology letters BACKGROUND:Diabetic retinopathy (DR) stands as a prominent complication of diabetes. Berberine (BBR) has reported to be effective to ameliorate the retinal damage of DR. Studying the potential immunological mechanisms of BBR on the streptozotocin (STZ) induced DR mouse model will explain the therapeutic mechanisms of BBR and provide theoretical basis for the clinical application of this drug. METHODS:C57BL/6 J mice were induced into a diabetic state using a 50 mg/(kg·d) dose of STZ over a 5-day period. Subsequently, they were subjected to a high-fat diet (HFD) for one month. Following a 5-week treatment with 100 mg/(kg·d) BBR, the concentrations of inflammatory factors in the mice's peripheral blood were determined using an enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin staining was employed to scrutinize pathological changes in the mice's retinas, while flow cytometry assessed the proportions of T-lymphocyte subsets and the activation status of dendritic cells (DCs) in the spleen and lymph nodes. CD4T cells and DC2.4 cell lines were utilized to investigate the direct and indirect effects of BBR on T cells under high glucose conditions in vitro. RESULTS:Following 5 weeks of BBR treatment in the streptozotocin (STZ) mouse model of DR, we observed alleviation of retinal lesions and a down-regulation in the secretion of inflammatory cytokines, namely TNF-α, IL-1β, and IL-6, in the serum of these mice. And in the spleen and lymph nodes of these mice, BBR inhibited the proportion of Th17 cells and promoted the proportion of Treg cells, thereby down-regulating the Th17/Treg ratio. Additionally, in vitro experiments, BBR directly inhibited the expression of the transcription factor RORγt and promoted the expression of the transcription factor Foxp3 in T cells, resulting in a down-regulation of the Th17/Treg ratio. Furthermore, BBR indirectly modulated the Th17/Treg ratio by suppressing the secretion of TNF-α, IL-1β, and IL-6 by DCs and enhancing the secretion of indoleamine 2,3-dioxygenase (IDO) and transforming growth factor-beta (TGF-β) by DCs. This dual action inhibited Th17 cell differentiation while promoting Treg cells. CONCLUSION:Our findings indicate that BBR regulate T cell subpopulation differentiation, reducing the Th17/Treg ratio by directly or indirectly pathway. This represents a potential therapeutic avenue of BBR for improving diabetic retinopathy. 10.1016/j.imlet.2024.106862
Berberine Ameliorates Hepatic Insulin Resistance by Regulating microRNA-146b/SIRT1 Pathway. Diabetes, metabolic syndrome and obesity : targets and therapy OBJECTIVE:Hepatic insulin resistance is a major initiating factor for type 2 diabetes mellitus. In previous study, Gegen Qinlian Decoction containing berberine could enhance hepatic insulin sensitivity by SIRT1-dependent deacetylation of FOXO1. However, it is not clear whether berberine also can improve hepatic insulin sensitivity by SIRT1/FOXO1 pathway. This study aimed to evaluate the efficacy of berberine for improving hepatic insulin resistance and the possible molecular mechanisms involved. METHODS:In vitro, HepG2 cells were induced with palmitic acid, and glycogen synthesis was examined. In vivo, a high-fat diet (HFD)-fed mouse model was established, and metabolic parameters were assessed. The expressions of miR-146b and sirtuin 1 (SIRT1) in liver were also examined. The relationship between miR-146b and SIRT1 was examined by the dual-luciferase reporter gene assay. RESULTS:Serum biochemical parameters, such as glucose and HOMA-IR index, were increased in HFD mice; miR-146b and SIRT1 were abnormally expressed in HFD mice and palmitic acid-treated HepG2 cells. Interestingly, berberine reduced body weight and caused a significant improvement in glucose tolerance and HOMA-IR index without altering food intake in mice. Overexpression of miR-146b abolished the protective effect of berberine on palmitic acid-induced impaired glycogen synthesis in HepG2 cells. Luciferase assay showed that miR-146b directly targeted SIRT1. CONCLUSION:The present findings suggest that berberine could attenuate hepatic insulin resistance through the miR-146b/SIRT1 pathway, which may represent a potential therapeutic target for the prevention and treatment of metabolic diseases, particularly diabetes. 10.2147/DMSO.S313068
Berberine protects diabetic nephropathy by suppressing epithelial-to-mesenchymal transition involving the inactivation of the NLRP3 inflammasome. Renal failure Accumulating evidence has implicated that berberine (BBR) has a beneficial effect on diabetic kidney disease (DKD), but its mechanism is not clear. The aim of this study was to assess whether berberine could alleviate tubulointerstitial fibrosis and attenuate epithelial-to-mesenchymal transition (EMT) and its possible molecular mechanism. High-fat diet (HFD) followed by injection of STZ was used to induce diabetic rats . After the onset of diabetes, rats were treated with either BBR or saline for 12 weeks. , the human renal proximal tubular epithelial cell line (HK-2) was exposed to high glucose, with or without BBR. The influence of berberine on renal tubulointerstitial histological changes, markers of epithelial-to-mesenchymal transition (EMT) and (NOD-like receptor pyrin domain-containing protein 3) NLRP3 inflammasome expression were examined. Results showed that , BBR could significantly ameliorate microalbumin and renal pathologic changes in diabetic rats. Immunofluorescence showed that BBR could inhibit EMT. Furthermore, BBR could down-regulate the level of the NLRP3 inflammasome in diabetic rats. Consistently, , BBR suppressed high glucose-induced EMT and activation of NLRP3 inflammasome in HK-2. Our study demonstrated that BBR could inhibit high glucose-induced EMT and renal interstitial fibrosis by suppressing the NLRP3 inflammasome. BBR might be used as a novel drug to ameliorate tubulointerstitial fibrosis in DKD. 10.1080/0886022X.2022.2079525
Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction. The American journal of Chinese medicine Berberine (BBR) is a principal component of known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM. 10.1142/S0192415X24500113
Neuroprotective Properties of Berberine: Molecular Mechanisms and Clinical Implications. Antioxidants (Basel, Switzerland) Berberine (BBR), an isoquinoline alkaloid natural product, is isolated primarily from and other plants. BBR possesses various bioactivities, including antioxidant, anti-inflammation, anticancer, immune-regulation, and antimicrobial activities. Growing scientific evidence underscores BBR's substantial neuroprotective potential, prompting increased interest and scrutiny. In this comprehensive review, we elucidate the neuroprotective attributes of BBR, delineate the underlying molecular mechanisms, and assess its clinical safety and efficacy. The multifaceted molecular mechanisms responsible for BBR's neuroprotection encompass the attenuation of oxidative stress, mitigation of inflammatory responses, inhibition of apoptotic pathways, facilitation of autophagic processes, and modulation of CYP450 enzyme activities, neurotransmitter levels, and gut microbiota composition. Furthermore, BBR engages numerous signaling pathways, including the PI3K/Akt, NF-κB, AMPK, CREB, Nrf2, and MAPK pathways, to confer its neuroprotective effects. This comprehensive review aims to provide a substantial knowledge base, stimulate broader scientific discourse, and facilitate advancements in the application of BBR for neuroprotection. 10.3390/antiox12101883
High fructose-induced skeletal muscle insulin resistance could be alleviated by berberine via AMPD1 and ADSL. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis that is activated in response to an elevated intracellular AMP/ATP ratio. Although many studies have shown berberine is an AMPK activator widely used in metabolic syndrome, how to properly control AMPK activity remains obscure. Our present study aimed to examine the protective effect of berberine against fructose-induced insulin resistance in rats and L6 cells, as well as its potential activation mechanism on AMPK. The results showed that berberine effectively reversed body weight gain, Lee's index, dyslipidemia and insulin intolerance. Moreover, berberine alleviated inflammatory response, antioxidant capacity and promoted glucose uptake in vivo and in vitro. The beneficial effect was associated with upregulation of both Nrf2 and AKT/GLUT4 pathways, which were regulated by AMPK. Notably, berberine could increase the level of AMP and the ratio of AMP/ATP, then further activate AMPK. Mechanistic experiments revealed that berberine suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and promoted the expression of adenylosuccinate synthetase (ADSL). Taken together, berberine exerted excellent therapeutic effect on insulin resistance. And its mode of action may be related to the AMP-AMPK pathway by regulating AMPD1 and ADSL. 10.1016/j.fct.2023.113731
Treatment of berberine alleviates diabetic nephropathy by reducing iron overload and inhibiting oxidative stress. Histology and histopathology Diabetic nephropathy (DN) has become one of the major fatal factors in diabetic patients. The aim of this study was to elucidate the function and mechanism by which berberine exerts renoprotective effects in DN. In this work, we first demonstrated that urinary iron concentration, serum ferritin and hepcidin levels were increased and total antioxidant capacity was significantly decreased in DN rats, while these changes could be partially reversed by berberine treatment. Berberine treatment also alleviated DN-induced changes in the expression of proteins involved in iron transport or iron uptake. In addition, berberine treatment also partially blocked the expression of renal fibrosis markers induced by DN, including MMP2, MMP9, TIMP3, β-arrestin-1, and TGF-β1. In conclusion, the results of this study suggest that berberine may exert renoprotective effects by ameliorating iron overload and oxidative stress and reducing DN. 10.14670/HH-18-599
Berberine attenuates brain aging via stabilizing redox homeostasis and inflammation in an accelerated senescence model of Wistar rats. Metabolic brain disease Aging is a multifaceted and progressive physiological change of the organism categorized by the accumulation of deteriorating processes, which ultimately compromise the biological functions. The objective of this study was to investigate the anti-aging potential of berberine (BBR) in D-galactose (D-Gal) induced aging in rat models. In this study, male Wistar rats were divided into four groups: The control group was given only vehicle, the BBR group was treated with berberine orally, the D-Gal group was treated with D-galactose subcutaneously and the BBR + D-Gal group was treated with D-galactose and berberine simultaneously. D-galactose exposure elevated the pro-oxidants such as malondialdehyde (MDA) level, protein carbonyl and advanced oxidation protein products (AOPP) in the brain. It decreased the anti-oxidants such as reduced glutathione (GSH) and ferric reducing antioxidant potential (FRAP) in the brain. D-galactose treatment also reduced the mitochondrial complexes (I, II, III and IV) activities and elevated the inflammatory markers such as interleukine-6 (IL-6), tumor necrosis factor- α (TNF-α) and C-reactive protein (CRP). The mRNA expressions of IL-6 and TNF-α in the brain were upregulated following D-galactose exposure. Berberine co-treatment in D-galactose induced aging rat model prevented the alteration of pro-oxidant and anti-oxidant in the brain. Berberine treatment restored the mitochondrial complex activities in the brain and also normalized the inflammatory markers. Based on these findings we conclude that berberine treatment has the potential to mitigate brain aging in rats via stabilizing the redox equilibrium and neuroinflammation. 10.1007/s11011-024-01350-7
The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway. Phytotherapy research : PTR The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases. 10.1002/ptr.8040
Huangbai liniment and berberine promoted wound healing in high-fat diet/Streptozotocin-induced diabetic rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Diabetic ulcer is a challenging complication of diabetes mellitus but current treatments cannot achieve satisfactory results. In this study, the effect of Huangbai liniment (HB) and berberine on the wound healing in high fat diet/streptozotocin injection induced diabetic rats was investigated by RNA-seq technology. HB topical treatment promoted wound healing in the diabetic patients and diabetic rats, and it affected multiple processes, of which IL-17 signalling pathway was of importance. Inhibiting IL-17a by its inhibitor or antibody remarkably facilitated wound healing and HB significantly repressed the high IL-17 expression and its downstream targets, including Cxcl1, Ccl2, Mmp3, Mmp9, G-CSF, IL1B and IL6, in diabetic wounds, promoted T-AOC, SOD activity and GSH levels; decreased the levels of nitrotyrosine and 8-OHdG; enhanced angiogenesis-related CD31, PDGF-BB and ANG1 expression; inhibited cleaved caspase-3 levels and promoted TIMP1 and TGFB1. Moreover, berberine (a major component in HB) repressed the IL-17 signalling pathway, and promoted wound healing in diabetes mellitus. This study highlights the strategy of targeting IL-17a in diabetic wounds, deepens the understanding of wound healing in diabetes mellitus in a dynamic way and reveals the characteristics of HB and berberine in promoting wound healing of type 2 diabetes mellitus. 10.1016/j.biopha.2022.112948
Effects of Berberine on the Gastrointestinal Microbiota. Zhang Lichao,Wu Xiaoying,Yang Ruibing,Chen Fang,Liao Yao,Zhu Zifeng,Wu Zhongdao,Sun Xi,Wang Lifu Frontiers in cellular and infection microbiology The gastrointestinal microbiota is a multi-faceted system that is unraveling novel contributors to the development and progression of several diseases. Berberine has been used to treat obesity, diabetes mellitus, atherosclerosis, and metabolic diseases in China. There are also clinical trials regarding berberine use in cardiovascular, gastrointestinal, and endocrine diseases. Berberine elicits clinical benefits at standard doses and has low toxicity. The mechanism underlying the role of berberine in lipid-lowering and insulin resistance is incompletely understood, but one of the possible mechanisms is related to its effect on the gastrointestinal microbiota. An extensive search in electronic databases (PubMed, Scopus, Embase, Web of Sciences, Science Direct) was used to identify the role of the gastrointestinal microbiota in the berberine treatment. The aim of this review was to summarize the pharmacologic effects of berberine on animals and humans by regulation of the gastrointestinal microbiota. 10.3389/fcimb.2020.588517
Berberine ameliorates glucocorticoid-induced hyperglycemia: an in vitro and in vivo study. Naunyn-Schmiedeberg's archives of pharmacology Berberine (BBR), a bioactive compound isolated from Coptidis Rhizoma, possesses diverse pharmacological activities including anti-bacterial, anti-inflammatory, antitumor, hypolipidemic, and anti-diabetic. However, its role as an anti-diabetic agent in animal models of dexamethasone (Dex)-induced diabetes remains unknown. Studies have shown that natural compounds including aloe, caper, cinnamon, cocoa, green and black tea, and turmeric can be used for treating Type 2 diabetes mellitus (DM). Compared to conventional drugs, natural compounds have less side effects and are easily available. Herein, we studied the anti-diabetic effects of BBR in a mice model of Dex-induced diabetes. HepG2 cell line was used for glucose release and glycogen synthesis studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. For animal studies, mice were treated with Dex (2 mg/kg, i.m.) for 30 days and effect of BBR at the doses 100, 200, and 500 mg/kg (p.o.) was analyzed. Glucose, insulin, and pyruvate tests were performed for evaluating the development of the diabetic model. Echo MRI was performed to assess the fat mass. Further, to elucidate the mechanism of action of BBR, mRNA expression of genes regulating gluconeogenesis, glucose uptake, and glycolysis was analyzed. In vitro BBR had no impact on cell viability up to a concentration of 50 μM. Moreover, BBR suppressed the hepatic glucose release and improved glucose tolerance in HepG2 cells. In vivo, BBR improved glucose homeostasis in diabetic mice as evidenced by enhanced glucose clearance, increased glycolysis, elevated glucose uptake, and decreased gluconeogenesis. Further, Dex treatment increased the total fat mass in mice, which was ameliorated by BBR treatment. BBR improves glucose tolerance by increasing glucose clearance, inhibiting hepatic glucose release, and decreasing obesity. Thus, BBR may become a potential therapeutic agent for treating glucocorticoid-induced diabetes and obesity in the future. 10.1007/s00210-023-02703-2
A Descriptive Review of the Action Mechanisms of Berberine, Quercetin and Silymarin on Insulin Resistance/Hyperinsulinemia and Cardiovascular Prevention. Molecules (Basel, Switzerland) Insulin resistance (IR) and the associated hyperinsulinemia are early pathophysiological changes which, if not well treated, can lead to type 2 diabetes, endothelial dysfunction and cardiovascular disease. While diabetes care is fairly well standardized, the prevention and treatment of IR lacks a single pharmaceutical approach and many lifestyle and dietary interventions have been proposed, including a wide range of food supplements. Among the most interesting and well-known natural remedies, alkaloid berberine and the flavonol quercetin have particular relevance in the literature, while silymarin-the active principle of the thistle-was traditionally used for lipid metabolism disorders and to sustain liver function. This review describes the major defects of insulin signaling leading to IR and the main properties of the three mentioned natural substances, their molecular targets and synergistic action mechanisms. The actions of berberine, quercetin and silymarin are partially superimposable as remedies against reactive oxygen intermediates generated by a high-lipid diet and by NADPH oxidase, which is triggered by phagocyte activation. Furthermore, these compounds inhibit the secretion of a battery of pro-inflammatory cytokines, modulate intestinal microbiota and are especially able to control the various disorders of the insulin receptor and post-receptor signaling systems. Although most of the evidence on the effects of berberine, quercetin and silymarin in modulating insulin resistance and preventing cardiovascular disease derive from experimental studies on animals, the amount of pre-clinical knowledge strongly suggests the need to investigate the therapeutic potential of these substances in human pathology. 10.3390/molecules28114491
Berberine Modulates Macrophage Activation by Inducing Glycolysis. Journal of immunology (Baltimore, Md. : 1950) Classical activation of macrophage and monocyte differentiation induced by β-glucan is accompanied with metabolic change in glucose. However, the role of the metabolic rewiring in monocyte/macrophage activation remains elusive. In this study, we show that berberine induces aerobic glycolysis by blocking the tricarboxylic acid cycle and modulates cytokine responses in bone marrow-derived macrophages (BMDMs) from mice and human PBMC. 13-Methyberberine had activities on glucose metabolism and BMDM activation similar to those of berberine, whereas other tested derivatives lost both activities. Glucose transporter (GLUT)1 expression and total cellular hexokinase activity increased gradually in BMDMs in the presence of berberine. In the contrast, LPS upregulated GLUT1 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) levels in 6 h. Extracellular glucose levels and replacing glucose with galactose in culture medium affected the cytokine secretion of BMDMs. Berberine alleviated enteritis of infection and protected mice against endotoxic shock. In mice i.p. injected with LPS, the increase of serum TNF-α and the drop of blood glucose were attenuated by berberine treatment. These data together demonstrated that macrophage activation was closely related with glucose metabolism. 10.4049/jimmunol.2100716
Berberine attenuates diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα in ApoE mice. Biochemical and biophysical research communications Cardiovascular disease caused by atherosclerosis is a leading cause of morbidity and mortality worldwide. Diabetes is a major independent risk factor for the development of atherosclerotic cardiovascular diseases. Diabetic atherosclerosis is characterized by hyperglycemia, hyperinsulinemia, and dyslipidemia. These multiple pathological factors can induce oxidative stress, inflammation, and vascular dysfunction, which can initiate and accelerate atherogenesis. Therefore, the strategy to control the development of diabetic atherosclerosis is beneficial to the patients. Berberine is one of the most promising natural products that feature significant beneficial properties on lipid and glucose metabolism, indicating the potential to improve diabetic atherosclerosis. However, the effect and underlying mechanism against diabetic atherosclerosis remain unclear. In this study, HFD and STZ were used to induce diabetic atherosclerosis in apoE mice, which was followed by berberine administration. Subsequently, the degree of atherosclerotic plaque, plaque stability, and lipid and glucose metabolism were determined. In addition, the underlying mechanism was revealed by in vitro and in vivo experiments. We observed that berberine improved the dysfunction of lipid and glucose metabolism, and inhibited vascular inflammation, which reduced atherogenesis and plaque vulnerability. Mechanistically, berberine stimulated KLF16 and PPARα expression in vivo and in vitro, and activation of PPARα by berberine was through enhancing KLF16 expression and nuclear translocation. Collectively, berberine can attenuate diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα, suggesting that KLF16 is a new target of berberine and enhancing KLF16 by berberine is an efficient strategy for alleviating diabetic atherosclerosis. 10.1016/j.bbrc.2022.07.072
Macrovascular Protecting Effects of Berberine through Anti-inflammation and Intervention of BKCa in Type 2 Diabetes Mellitus Rats. Endocrine, metabolic & immune disorders drug targets OBJECTIVE:The aim of this study was to examine the effect of berberine on diabetes mellitus in vivo and in vitro, and elucidate the underlying mechanisms. METHODS:Rat models of type 2 diabetes mellitus (T2DM) were established and were treated with berberine. Pathological changes in the thoracic aorta, and inflammatory factor and adiponectin levels were investigated. Vascular smooth muscle cells (VSMCs) of the thoracic aorta were cultured and treated with berberine. Cellular proliferation, migration, and inflammatory factor levels were investigated. Responses of vascular rings to phenylephrine (PE) and sodium nitroprusside (SNP) after berberine intervention and the changes of relaxation responses to SNP after adding Iberiotoxin (IbTX) were investigated. RESULTS:Berberine ameliorated the pathological status of the thoracic aorta in the T2DM rats. Berberine significantly inhibited the C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) production, and increased the adiponectin level compared with the model group. Compared with the model group, berberine inhibited the proliferation and migration of VSMCs in vitro, and reduced tumor growth factor-β1 (TGF-β1), IL-6, and TNF-α levels. Furthermore, the contraction of thoracic aorta to PE was reduced, while the relaxation response of thoracic aorta to SNP was increased, after the berberine intervention in the T2DM rats. The relaxation response of thoracic aorta to SNP in the model and berberine groups decreased after the IbTX treatment. CONCLUSION:Protective effects of berberine against macrovascular complications induced by diabetes mellitus may be attributed to inhibiting of the inflammation and intervening of the calcium- activated potassium (BK). 10.2174/1871530320999200904123618
Berberine Decreases Thrombosis Potential Induced by a High-choline Diet by Inhibiting CutC Enzyme. Current medicinal chemistry INTRODUCTION:Gut microbes influence thrombosis potential by generating trimethylamine N-oxide (TMAO). However, whether the antithrombotic effect of berberine is associated with TMAO generation remains unclear. OBJECTIVE:The present study was designed to explore whether berberine decreases the TMAO-induced thrombosis potential and the possible mechanism underneath it. METHODS:C57BL/6J female mice under a high-choline diet or standard diet were treated with/without berberine for 6 weeks. The TMAO level, carotid artery occlusion time following FeCl3 injury and platelet responsiveness were measured. The binding of berberine to the CutC enzyme was analysed with molecular docking, and molecular dynamics simulations were verified with enzyme activity assays. Results:The results showed that berberine increased the carotid artery occlusion time following FeCl3 injury and decreased the platelet hyperresponsiveness induced by a high-choline diet, both offset by intraperitoneal injection of TMAO. The effect of berberine on thrombosis potential was associated with decreasing the generation of TMAO by inhibiting the CutC enzyme. CONCLUSION:Targeting TMAO generation with berberine might be a promising therapy for ischaemic cardiac-cerebral vascular diseases. 10.2174/0929867330666230524142632
Berberine-microbiota interplay: orchestrating gut health through modulation of the gut microbiota and metabolic transformation into bioactive metabolites. Frontiers in pharmacology Berberine is an isoquinoline alkaloid found in plants. It presents a wide range of pharmacological activities, including anti-inflammatory and antioxidant properties, despite a low oral bioavailability. Growing evidence suggests that the gut microbiota is the target of berberine, and that the microbiota metabolizes berberine to active metabolites, although little evidence exists in the specific species involved in its therapeutic effects. This study was performed to detail the bidirectional interactions of berberine with the broiler chicken gut microbiota, including the regulation of gut microbiota composition and metabolism by berberine and metabolization of berberine by the gut microbiota, and how they contribute to berberine-mediated effects on gut health. As previous evidence showed that high concentrations of berberine may induce dysbiosis, low (0.1 g/kg feed), middle (0.5 g/kg feed) and high (1 g/kg feed) doses were here investigated. Low and middle doses of in-feed berberine stimulated potent beneficial bacteria from the Lachnospiraceae family in the large intestine of chickens, while middle and high doses tended to increase villus length in the small intestine. Plasma levels of the berberine-derived metabolites berberrubine, thalifendine and demethyleneberberine were positively correlated with the villus length of chickens. Berberrubine and thalifendine were the main metabolites of berberine in the caecum, and they were produced by the caecal microbiota, confirming their microbial origin. We show that members of the genus could demethylate berberine into mainly thalifendine, and that this reaction may stimulate the production of short-chain fatty acids (SCFAs) acetate and butyrate, via acetogenesis and cross-feeding respectively. We hypothesize that acetogens such as spp. are key bacteria in the metabolization of berberine, and that berberrubine, thalifendine and SCFAs play a significant role in the biological effect of berberine. 10.3389/fphar.2023.1281090
Liposome-Encapsulated Berberine Alleviates Liver Injury in Type 2 Diabetes via Promoting AMPK/mTOR-Mediated Autophagy and Reducing ER Stress: Morphometric and Immunohistochemical Scoring. Antioxidants (Basel, Switzerland) In the advanced stages of type 2 diabetes mellitus (T2DM), diabetic liver damage is a common complication that can devastate a patient's quality of life. The present study investigated the ability of liposomal berberine (Lip-BBR) to aid in ameliorating hepatic damage and steatosis, insulin homeostasis, and regulating lipid metabolism in type 2 diabetes (T2DM) and the possible pathways by which it does so. Liver tissue microarchitectures and immunohistochemical staining were applied during the study. The rats were divided into a control non-diabetic group and four diabetic groups, which are the T2DM, T2DM-Lip-BBR (10 mg/kg b.wt), T2DM-Vildagliptin (Vild) (10 mg/kg b.wt), and T2DM-BBR-Vild (10 mg/kg b.wt + Vild (5 mg/kg b.wt) groups. The findings demonstrated that Lip-BBR treatment could restore liver tissue microarchitectures, reduce steatosis and liver function, and regulate lipid metabolism. Moreover, Lip-BBR treatment promoted autophagy via the activation of LC3-II and Bclin-1 proteins and activated the AMPK/mTOR pathway in the liver tissue of T2DM rats. Lip-BBR also activated the GLP-1 expression, which stimulated insulin biosynthesis. It decreased the endoplasmic reticulum stress by limiting the CHOP, JNK expression, oxidative stress, and inflammation. Collectively, Lip-BBR ameliorated diabetic liver injury in a T2DM rat model with its promotion activity of AMPK/mTOR-mediated autophagy and limiting ER stress. 10.3390/antiox12061220
The effect of berberine and fenugreek seed co-supplementation on inflammatory factor, lipid and glycemic profile in patients with type 2 diabetes mellitus: a double-blind controlled randomized clinical trial. Diabetology & metabolic syndrome BACKGROUND:Type 2 Diabetes mellitus is one of the most common chronic diseases in the world and has many complications. Due to the importance of using alternative therapies in managing symptoms of this disease, the present study was designed and conducted to investigate the effect of co-supplementation of berberine and fenugreek in patients with type 2 diabetes mellitus. METHODS:A randomized controlled clinical trial was conducted on 50 patients with type 2 diabetes mellitus. Participants were randomized in the intervention group, which received 3 capsules/day of 500 mg (300 mg of berberine + 200 mg of fenugreek seed powder) or placebo for 12 weeks. Biochemical and anthropometric variables were measured at the beginning and end of the study. RESULTS:We observed that fasting insulin, HbA1C, and hs-CRP significantly decreased in the intervention group compared to the baseline. The mean difference in insulin resistance (-0.32 vs. 0.15), fasting blood sugar (-14.40 vs. 1.68), and fasting insulin (- 2.18 vs. 1.34) were clinically significant in comparison to the control group. Almost all domains of SF-12 scores were significantly higher in the intervention group than in the placebo group. CONCLUSIONS:The combination of berberine and fenugreek seed can improve cardio-metabolic status in patients with diabetes and support the anti-diabetic and anti-inflammatory role of herb in the improvement of quality of life. 10.1186/s13098-022-00888-9
Berberine: A Promising Treatment for Neurodegenerative Diseases. Frontiers in pharmacology Berberine, as a natural alkaloid compound, is characterized by a diversity of pharmacological effects. In recent years, many researches focused on the role of berberine in central nervous system diseases. Among them, the effect of berberine on neurodegenerative diseases has received widespread attention, for example Alzheimer's disease, Parkinson's disease, Huntington's disease, and so on. Recent evidence suggests that berberine inhibits the production of neuroinflammation, oxidative, and endoplasmic reticulum stress. These effects can further reduce neuron damage and apoptosis. Although the current research has made some progress, its specific mechanism still needs to be further explored. This review provides an overview of berberine in neurodegenerative diseases and its related mechanisms, and also provides new ideas for future research on berberine. 10.3389/fphar.2022.845591
A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Inflammation and insulin resistance play important roles in the development and progression of type 2 diabetes mellitus. The enhancement of adipocyte differentiation can improve insulin sensitivity by increasing glucose uptake, improving insulin signaling, and reducing inflammation. However, only a few adipogenic agents have shown clinical success in patients with type 2 diabetes mellitus. The therapeutic potential of berberine in type 2 diabetes mellitus was confirmed in terms of the target gene-disease relationship using a network pharmacology database prior to synthesizing the derivatives. Novel berberine derivatives were synthesized, and compound 3b promoted adipocyte differentiation and improvement of insulin resistance in OP9 cells. Compound 3b significantly increased the expression of key adipogenic markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein β (C/EBPβ) and promoted lipid accumulation without cytotoxicity. Furthermore, tumor necrosis factor α (TNF-α)-induced inhibition of adipocyte differentiation and the elevation of inflammatory responses were reversed by compound 3b. Subsequently glucose uptake level through insulin sensitivity improvement was enhanced by compound 3b. Mechanistically, TNF-α activated mitogen-activated protein kinases (MAPKs): ERK, JNK, and p38, whereas compound 3b attenuated phosphorylation of three MAPKs. Finally, in silico molecular docking suggested the possible binding sites of compound 3b on PPARγ. Collectively, the adipogenic and glucose uptake effects of compound 3b were associated with its anti-inflammatory effects and reduced phosphorylation of MAPKs. These findings suggest that the berberine derivative compound 3b may be a potent antidiabetic agent. 10.1016/j.biopha.2023.115433
Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action. Zhang Jing-Hua,Zhang Jin-Feng,Song Jun,Bai Yu,Deng Lan,Feng Chun-Peng,Xu Xin-Yao,Guo Hong-Xia,Wang Yi,Gao Xin,Gu Yan,Jin Chuan,Zheng Jun-Fu,Zhen Zhong,Su Hao The American journal of Chinese medicine Diabetes is a group of metabolic disorders with an increased risk of developing cognitive impairment and dementia. The hippocampus in the forebrain contains an abundance of insulin receptors related to cognitive function and plays an important role in the pathophysiology of neurodegenerative disorders. Berberine from traditional Chinese medicine has been used to treat diabetes and diabetic cognitive impairment, although its related mechanisms are largely unknown. In this study, a STZ diabetes rat model feeding with a high-fat diet was used to test the effects of berberine compared with metformin. Oral glucose tolerance and hyperinsulinemic-euglycemic clamp were used for glucose metabolism and insulin resistance. The Morris water maze was used to observe the compound effects on cognitive impairment. Serum and hippocampal [Formula: see text]-amyloid peptide (A[Formula: see text], Tau and phosphorylated Tau protein deposition in the hippocampi were measured. The TUNEL assay was used to detect the neuronal apoptosis, supported by histomorphological changes and transmissional electron microscopy (TEM) image. Our data showed that the diabetic rats had a significantly cognitive impairment. In addition to improving glucose metabolism and reducing insulin resistance, berberine significantly improved the cognitive function in the rat. Berberine also effectively decreased the expression of hippocampal tau protein, phosphorylated Tau, and increased insulin receptor antibodies. Moreover, berberine downregulated the abnormal phosphorylation of A[Formula: see text] and Tau protein and improved hippocampal insulin signaling. The TUNEL assay confirmed that berberine reduced hippocampal neuronal apoptosis supported by TEM. Thus, berberine significantly improved the cognitive function in diabetic rats by changing the peripheral and central insulin resistance. The reduction of neuronal injury, A[Formula: see text] deposition, abnormal phosphorylation of Tau protein, and neuronal apoptosis in the hippocampus were observed as the related mechanisms of action. 10.1142/S0192415X21500658
Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis. Biochemical pharmacology Type 2 diabetes (T2D) is a chronic, burdensome disease that is characterized by disordered insulin sensitivity and disturbed glucose/lipid homeostasis. Berberine (BBR) has multiple therapeutic actions on T2D, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity and energy expenditure. Recently, the function of BBR on fibroblast growth factor 21 (FGF21) has been identified. However, if BBR ameliorates T2D through FGF21, the underlying mechanisms remain unknown. Herein, we used T2D wild type (WT) and FGF21 global knockout (FKO) mice [mouse T2D model: established by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection], and hepatocyte-specific peroxisome proliferator activated receptor γ (PPARγ) deficient (PPARγ) mice, and cultured human liver carcinoma cells line, HepG2 cells, to characterize the role of BBR in glucose/lipid metabolism and insulin sensitivity. We found that BBR activated FGF21 expression by up-regulating PPARγ expression at the cellular level. Meanwhile, BBR ameliorated glucosamine hydrochloride (Glcn)-induced insulin resistance and increased glucose transporter 2 (GLUT2) expression in a PPARγ/FGF21-dependent manner. In T2D mice, BBR up-regulated the expression of PPARγ, FGF21 and GLUT2 in the liver, and GLUT2 in the pancreas. BBR also reversed T2D-induced insulin resistance, liver lipid accumulation, and damage in liver and pancreas. However, FGF21 deficiency diminished these effects of BBR on diabetic mice. Altogether, our study demonstrates that the therapeutic effects of BBR on T2D were partly accomplished by activating PPARγ-FGF21-GLUT2 signaling pathway. The discovery of this new pathway provides a deeper understanding of the mechanism of BBR for T2D treatment. 10.1016/j.bcp.2023.115928
Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy. Open life sciences Abnormal mitochondrial function resulting in inadequate energy supply leads to sarcopenia and IR, suggesting that maintaining mitochondrial homeostasis by regulating mitophagy may be a promising strategy for sarcopenia IR therapy. Herein, we constructed sarcopenia mice model, which was treated with berberine and/or SIRT1/mitophagy inhibitors, and the activity of SIRT1/mitophagy signaling pathway was identified. Then, muscle tissue, blood biochemical index, inflammatory factors, GTT, and ITT were detected. We found that berberine treatment increased the body weight and alleviated d-galactose-induced weight loss in mice. SIRT1/mitophagy inhibitors suppressed the effects of berberine in the treatment of sarcopenia. The effect of berberine on the increase of muscle tissue, improving metabolic disorders, reducing the expression of inflammatory factors, and suppressing sarcopenia insulin resistance (IR) were reversed by SIRT1/mitophagy inhibitors. Our study establishes proof-of-concept to distinct the effect of berberine in sarcopenia IR, and provides strong evidence to support the hypothesis that berberine-induced SIRT1 triggers mitochondrial autophagy pathway and suppresses IR in sarcopenia. 10.1515/biol-2022-0648
Neuroprotective Effect and Possible Mechanisms of Berberine in Diabetes-Related Cognitive Impairment: A Systematic Review and Meta-Analysis of Animal Studies. Frontiers in pharmacology Berberine, the main bioactive component of Franch., is widely used in the treatment of diabetes. Previous studies have reported that berberine supplementation may play a multitarget therapeutic role in diabetes-related cognitive impairment (DCI). This systematic review and meta-analysis evaluated the effect and possible mechanisms of berberine in animal models of DCI. Relevant studies were searched through PubMed, Web of Science, Embase, and three Chinese databases (CNKI, Wanfang, and VIP) until March 2022. Twenty studies involving 442 animals were included, and SYRCLE's risk of bias tool was used to assess methodological quality. The statistical analysis was performed using STATA 15.0 to calculate the weighted standard mean difference (SMD) with a 95% confidence interval (CI). The fasting blood glucose (FBG) and Morris water maze test (MWM) were the main outcomes to be analyzed. The overall results showed that berberine could significantly improve FBG, escape latency, the times of crossing the platform, the time spent in the target quadrant, serum insulin, 2hBG of oral glucose tolerance test (OGTT), amyloid β (Aβ), acetylcholinesterase (AChE), oxidative stress, and inflammation levels. The present meta-analysis demonstrated that berberine could not only lower blood glucose levels but also improve learning and memory in DCI animal models, which might involve regulating glucose and lipid metabolism, improving insulin resistance, anti-oxidation, anti-neuroinflammation, inhibiting endoplasmic reticulum (ER) stress; and improving the cholinergic system. However, additional attention should be paid to these outcomes due to the significant heterogeneity. 10.3389/fphar.2022.917375
Berberine-induced glucagon-like peptide-1 and its mechanism for controlling type 2 diabetes mellitus: a comprehensive pathway review. Archives of physiology and biochemistry A growing number of studies have thus far showed the association between type 2 diabetes mellitus (DM) and the intestinal microbiome homoeostasis. As reported, the gut microflora can be significantly different in patients with type 2 DM (T2DM) compared to those in healthy individuals. The authors collected the relevant articles published until 2022 and these are carefully selected from three scientific databases based on keywords. This review highlights research on the anti-diabetic properties of berberine (BBR)-induced glucagon-like peptide-1 (GLP-1), as a glucose-lowering factor and a balance regulator in the microbial flora of the intestines, which plays an important role in adjusting the signalling pathways affecting insulin secretion. Considering the anti-diabetic characteristics of the BBR-induced GLP-1, BBR makes a promising complementary treatment for reducing the clinical symptoms of DM by reducing the hyperglycaemia. Berberin might be a safe and effective drug for T2DM with little or no adverse effects.HighlightsBerberine induces GLP-1 insulin secretion by PLC2 pathway in the intestinalBerberine-induced GLP-1 decreases mitochondrial stress and relocates cytochrome c out of the mitochondria.Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptomsBerberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell.Preventing mitochondrial damage, reducing adipose tissue fat, and reducing oxidative stress are thus among the results of BBR-induced GLP-1.The lower costs of BBR, and its limited side effects and higher availability, make it a promising supplementary medicine for DM. 10.1080/13813455.2023.2258559
Berberine Ameliorates Insulin Resistance by Inhibiting IKK/NF-κB, JNK, and IRS-1/AKT Signaling Pathway in Liver of Gestational Diabetes Mellitus Rats. Metabolic syndrome and related disorders Berberine is derived from rhizoma coptidis, a well-known Traditional Chinese herbal Medicine that has been found to be effective in the treatment of type 2 diabetes mellitus in recent years. The aim of the present study was to investigate the effects of berberine on a gestational diabetes mellitus (GDM) rat model and the related mechanisms. GDM was induced in Sprague-Dawley rats using a high-fat diet before and during pregnancy. Berberine (100 mg/kg/day) was administered from the 7th to 20th day of pregnancy. Insulin resistance (IR), glucose tolerance, and maternal, fetal, and placental weight were determined. Liver histopathological analysis, as well as analysis of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), inhibitor kappa B kinaseβ (IKKβ), nuclear factor kappa-B (NF-κB), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1), and protein kinase B (AKT), was performed at the end of pregnancy. Treatment of GDM rats with berberine markedly decreased IR, the number of dead and absorptive fetuses, maternal body weight gain, and fetal and placental weight compared with GDM without berberine. Furthermore, berberine decreased CRP and TNF-α levels, IKKβ expression, NF-κB P65 nuclear translocation, and changed the phosphorylation of JNK, IRS-1, and AKT in the liver of GDM rats. Berberine improved IR and maternal-fetal outcomes of GDM rats, possibly through modulation of IKK/NF-κB, JNK, and IRS-1/AKT signaling pathways in the liver. Therefore, berberine may be a potential GDM treatment. 10.1089/met.2022.0017
Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment. Han Yunfeng,Xiang Yunan,Shi Yi,Tang Xi,Pan Lin,Gao Jie,Bi Ruohong,Lai Xianrong Evidence-based complementary and alternative medicine : eCAM Traditional Chinese medicine (TCM) has good clinical application prospects in diabetes treatment. In addition, TCM is less toxic and/or has fewer side effects and provides various therapeutic effects. Berberine (BBR) is isolated as the main component in many TCM kinds (e.g., and ). Furthermore, BBR can reduce blood sugar and blood fat, alleviate inflammation, and improve the state of patients. Based on the recent study results of BBR in diabetes treatment, the BBR pharmacokinetics and mechanism on diabetes are mainly studied, and the specific molecular mechanism of related experimental BBR is systematically summarized and analyzed. Clinical studies have proved that BBR has a good therapeutic effect on diabetes, suggesting that BBR may be a promising drug candidate for diabetes. More detailed BBR mechanisms and pathways of BBR need to be studied further in depth, which will help understand the BBR pharmacology in diabetes treatment. 10.1155/2021/9987097
Effects of Berberine Plus Inulin on Diabetes Care in Patients With Latent Autoimmune Diabetes in Adults: Protocol for a Randomized Controlled Trial. Frontiers in endocrinology Background:Latent autoimmune diabetes in adults (LADA) is a heterogeneous form of diabetes, characterized by autoimmune destruction of pancreatic β-cells as well as insulin resistance and is triggered by environmental factors in the context of genetic susceptibility. Berberine (BBR), a small alkaloid isolated from medicinal plants, has antidiabetic, anti-inflammatory, and antibacterial effects. Inulin is a common prebiotic that has been shown to improve glycemic control, alter the gut microbiota and suppress inflammation. The primary purpose of this study was to evaluate the effects of oral BBR and inulin combined with insulin therapy on diabetes care in patients with LADA. Methods and Analysis:We will conduct a single-center, prospective, randomized, double-blind, placebo-controlled trial. A total of 240 patients with LADA who have started insulin therapy will be randomly allocated either to the intervention or control group. After a 1-week run-in period, they will complete a 3-month treatment of BBR alone, inulin plus BBR, inulin alone, or placebo. Anthropometric and clinical data will be collected at five time points: baseline, 3 months, 6 months, 9 months, and 12 months from baseline. The primary outcome was the change in glycated hemoglobin levels. Dynamic blood glucose parameters, β-cell function, and gut microbiota, as well as adverse events and quality of life will be monitored. Discussion:Glycemic control is critical for preventing the progression of diabetes. Although insulin is a recommended treatment for patients with LADA, there are currently no drugs that can effectively prevent the progressive destruction of pancreatic β-cells or maintain their function. Several studies have found that when berberine and prebiotics are used alone, they have beneficial metabolic effects. This clinical research protocol will assess the efficacy of the combined treatment of berberine plus inulin and provide new ideas for future pharmacological research and clinical practices in diabetes care and glycemic control for LADA patients. Ethics and Dissemination:This study has been approved by the Ethics Committee of National Clinical Research Center of the Second Xiangya Hospital of Central South University (approval number: 2021-046). Clinical Trial Registration:ClinicalTrials.gov, identifier NCT04698330. 10.3389/fendo.2022.876657
Potential role of Akt in the regulation of fibroblast growth factor 21 by berberine. Journal of natural medicines Fibroblast growth factor 21 (FGF21) is expressed in several organs, including the liver, adipose tissue, and cardiovascular system, and plays an important role in cross-talk with other organs by binding to specific FGF receptors and their co-receptors. FGF21 represents a potential target for the treatment of obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH). The production of FGF21 in skeletal muscle was recently suggested to be beneficial for metabolic health through its autocrine and paracrine effects. However, the regulatory mechanisms of FGF21 in skeletal muscle remain unclear. In the present study, we showed that berberine regulated FGF21 production in C2C12 myotubes in a dose-dependent manner. We also examined the effects of A-674563, a selective Akt1 inhibitor, on the berberine-mediated regulation of FGF21 expression in C2C12 myotubes. Berberine significantly increased the secretion of FGF21 in C2C12 myotubes, while A-674563 attenuated this effect. Moreover, a pre-treatment with A-674563 effectively suppressed berberine-induced increases in Bmal1 expression in C2C12 myotubes, indicating that the up-regulation of Bmal1 after the berberine treatment was dependent on Akt1. Additionally, berberine-induced increases in FGF21 secretion were significantly attenuated in C2C12 cells transfected with Bmal1 siRNA, indicating the contribution of the core clock transcription factor BMAL1 to Akt-regulated FGF21 in response to berberine. Collectively, these results indicate that berberine regulates the expression of FGF21 through the Akt1 pathway in C2C12 myotubes. Moreover, the core clock gene Bmal1 may participate in the control of the myokine FGF21. Berberine stimulated Akt1-dependent FGF21 expression in C2C12 myotubes. The up-regulation of FGF21 through the modulation of PI3K/AKT1/BMAL1 in response to berberine may be involved in the regulation of cellular function (such as Glut1 expression) by acting in an autocrine and/or paracrine manner in skeletal muscle. 10.1007/s11418-023-01755-1
Antioxidant and antiarthritic potential of berberine: and studies. Chinese herbal medicines Objective:To extract and isolate berberine from (Berberidaceae). Isolated berberine was characterised using spectroscopy and its antioxidant and antiarthritic activity was analyzed. Methods:The berberine was isolated from using microwave-assisted extraction (MAE) and characterised by a spectroscopic technique. The isolated berberine was evaluated for its antioxidant activity in DPPH, nitric oxide, and superoxide scavenging assays, while antiarthritic activity was evaluated in the complete freund's adjuvant (CFA)-induced arthritis rat model. Results:The antioxidant activity of berberine revealed potent antioxidant activity in DPPH, nitric oxide, and superoxide scavenging assays. The antiarthritic activity of berberine in the CFA-induced arthritis rat model showed a significant reduction in paw diameter, arthritic score, and an increase in body weight. Furthermore, a concentration-dependent ameliorating action of berberine on haematological parameters was noticed. Proinflammatory biomarkers, including IL-6, IL-10, and TGF-b in serum were reported, and histopathology examination revealed that berberine decreased pannus formation, synovial hyperplasia, and bone erosion. Radiographic investigation showed soft tissue inflammation, bone resorption and erosion, joint gap reduction, and substantial connective tissue expansion after treatment with berberine. Conclusion:The ameliorating action on haematological parameters and proinflammatory biomarkers of berberine makes them a suitable remedy for the treatment of arthritis. 10.1016/j.chmed.2023.02.007
A Mechanistic Review on How Berberine Use Combats Diabetes and Related Complications: Molecular, Cellular, and Metabolic Effects. Pharmaceuticals (Basel, Switzerland) Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to treat various disorders. It is a multi-target drug with multiple mechanisms. Studies have shown that it has antioxidant and anti-inflammatory properties and can also adjust intestinal microbial flora. This review focused on the promising antidiabetic effects of BBR in several cellular, animal, and clinical studies. Based on previous research, BBR significantly reduced levels of fasting blood glucose, hemoglobin A1C, inflammatory cytokines, and oxidative stress markers. Furthermore, BBR stimulated insulin secretion and improved insulin resistance through different pathways, including up-regulation of protein expression of proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT) 4, PI3K/AKT, and AMP-activated protein kinase (AMPK) activation. Interestingly, it was demonstrated that BBR has protective effects against diabetes complications, such as diabetic-induced hepatic damage, cardiovascular disorders, nephropathy, and neuropathy. Furthermore, multiple clinical trial studies have emphasized the ameliorative effects of BBR in type 2 diabetic patients. 10.3390/ph17010007
Berberine influences multiple diseases by modifying gut microbiota. Frontiers in nutrition Berberine (BBR) is an isoquinoline alkaloid that is widely distributed in the plant kingdom and is commonly found in Franch. It has low bioavailability, but it can interact with gut microbiota and affect a variety of diseases. The effects of BBR in diabetes, hyperlipidemia, atherosclerosis, liver diseases, intestinal diseases, mental disorders, autoimmune diseases, and other diseases are all thought to be related to gut microbiota. This review systematically and comprehensively summarize these interactions and their effects, and describes the changes of gut microbiota after the intervention of different doses of berberine and its potential clinical consequences, in order to provide a basis for the rational application of BBR in the future clinical treatment. 10.3389/fnut.2023.1187718
Berberine and Its Study as an Antidiabetic Compound. Biology Diabetes mellitus (DM) is a metabolic disorder that causes hyperglycemia conditions and leads to various chronic complications that causes death. The prevalence of diabetes is predicted to continue to increase, and with the high toxicity levels of current diabetes drugs, the exploration of natural compounds as alternative diabetes treatment has been widely carried out, one of which is berberine. Berberine and several other alkaloid compounds, including some of its derivatives, have shown many bioactivities, such as neuraminidase and hepatoprotective activity. Berberine also exhibits antidiabetic activity. As an antidiabetic compound, berberine is known to reduce blood glucose levels, increase insulin secretion, and weaken glucose tolerance and insulin resistance by activating the AMPK pathway. Apart from being an antidiabetic compound, berberine also exhibits various other activities such as being anti-adipogenic, anti-hyperlipidemic, anti-inflammatory, and antioxidant. Many studies have been conducted on berberine, but its exact mechanism still needs to be clarified and requires further investigation. This review will discuss berberine and its mechanism as a natural compound with various activities, mainly as an antidiabetic. 10.3390/biology12070973
Addressing the preventive and therapeutic perspective of berberine against diabetes. Heliyon Diabetes has emerged as one the leading detrimental factors for human life expectancy worldwide. The disease is mainly considered as outcome of dysregulation in glucose metabolism, resulting in consistent high glucose concentration in blood. At initial stages, the diabetes particularly type 2 diabetes, is manageable by lifestyle interventions such as regular physical activity and diet with less carbohydrates. However, in advance stage, regular intake of external insulin dose and medicines like metformin are recommended. The long-term consumption of metformin is associated with several side effects such as nausea, vomiting, diarrhoea, lectic acidosis etc., In this scenario, several plant-based medicines have shown promising potential for the prevention and treatment of diabetes. Berberine is the bioactive compound present in the different plant parts of berberis family. Biochemical studies have shown that berberine improve insulin sensitivity and insulin secretion. Additionally, berberine induces glucose metabolism by activating AMPK signaling and inhibition of inflammation. A series of studies have demonstrated the antidiabetic potential of berberine at , pre-clinical and clinical trials. This review provides comprehensive details of preventive and therapeutic potential of berberine against diabetes. 10.1016/j.heliyon.2023.e21233
Molecular Mechanism of Berberine in the Treatment of Calcified Aortic Valve Disease Based on AGE-RAGE Signal Pathway. Alternative therapies in health and medicine Objective:We aimed to explore the molecular mechanism of berberine in the treatment of calcified aortic valve disease through the network pharmacology-molecular docking method. Methods:The targets of berberine and calcified aortic valve disease were retrieved, the interactions between the targets were analyzed, Cytoscape software was used to build a "target-path" network, R language was used to conduct enrichment analysis of GO and KEGG pathways, and AutoDock Vina was used to verify the binding force of the target protein and small molecules. Results:96 targets for berberine and 4293 disease targets were screened through multiple databases, and 56 targets were identified through veen analysis. The enrichment of PPI, GO, and KEGG pathways suggests that berberine may act on PIK3CD, PIK3CB, PIK3R1, MAPK14, MAPK10, and other targets, and regulate the role of calcified aortic valve disease through AGE-RAGE signaling pathway, Chemokine signaling pathway, Lipid and atherosclerosis, and other pathways. The docking results showed that berberine has good binding activity with the target on the key pathway AGE-RAGE signaling pathway. Conclusion:The network pharmacology preliminarily revealed the mechanism of berberine in the treatment of calcified aortic valve disease by regulating vascular calcification, inflammatory reaction, oxidative stress, and other effects, providing the basis for follow-up experimental research, and also providing the basis for clinical medication.
Glucocorticoid receptor-mediated alleviation of inflammation by berberine: , and investigations. Liang Yuan,Zhang Tiehua,Zhao Jingqi,Li Chenfei,Zou Haoyang,Li Fangyu,Zhang Jie,Ren Li Food & function As a natural dietary ingredient, berberine possesses multiple biological activities including anti-inflammatory effects. In this work, glucocorticoid receptor (GR)-mediated alleviation of inflammation by berberine was investigated by a combination of , , and approaches. The fluorescence polarization assay showed that berberine bound to GR with an IC value of 9.14 ± 0.16 pM. Molecular docking and molecular dynamics simulation suggested that berberine bound stably to the active site of GR hydrogen bonding and hydrophobic interactions. Berberine induced GR nuclear translocation but did not activate the glucocorticoid response element in HeLa cells. Furthermore, both gene and protein expressions of PEPCK were significantly attenuated by berberine in HepG2 cells. Interestingly, berberine downregulated CBG mRNA and protein levels without up-regulating TAT mRNA and protein levels in HepG2 cells, demonstrating its dissociated characteristics that could separate transrepression from transactivation. In addition, the and anti-inflammatory effects of berberine were confirmed in lipopolysaccharide-induced RAW 264.7 cells and in a mouse model of allergic contact dermatitis, respectively. In conclusion, berberine might serve as a potential selective GR modulator. 10.1039/d1fo01612a
Efficacy and Underlying Mechanism of Berberine Against Atherosclerosis: A Meta-Analysis in Preclinical Animal Studies. Journal of cardiovascular pharmacology ABSTRACT:Atherosclerosis is the primary cause of many cardiovascular diseases, and an increasing number of studies have shown that berberine could delay plaque formation and development. Therefore, we aimed to evaluate its effects and explore its mechanisms in this meta-analysis. We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP databases for original preclinical studies to conduct meta-analysis. Twelve articles (16 studies; 312 ApoE -/- mice) were included, and all the studies scored 3-5 points according to SYRCLE's risk of bias tool. Berberine could significantly decrease plaque area and plaque macrophage content (plaque area, SMD = -2.02, 95% CI: -2.80 to -1.24, P = 0.000; plaque macrophage content, SMD = -4.28, 95% CI: -7.67 to -0.88, P = 0.013); lower the levels of TC, triglyceride, and low-density lipoprotein (TC, SMD = -1.47, 95% CI: -2.20 to -0.74, P = 0.000; triglyceride, SMD = -0.77, 95% CI: -1.21 to -0.33, P = 0.000; low-density lipoprotein, SMD = -0.61, 95% CI: -1.11 to -0.11, P = 0.000), and change the secretion of inflammatory cytokines (IL-1β, SMD = -2.29, 95% CI: -3.40 to -1.18, P = 0.000; interleukin-6, SMD = -1.48, 95% CI: -2.11 to -0.85, P = 0.008; tumor necrosis factor-α, SMD = -1.98, 95% CI: -3.01 to -0.94, P = 0.000; interleukin-10, SMD = 1.78, 95% CI: 0.76 to 2.80, P = 0.015), but there were no significant differences in high-density lipoprotein levels and plaque lipid content (high-density lipoprotein, SMD = 0.02, 95% CI: -0.35 to 0.40, P = 0.021; plaque lipid content, SMD = -6.85, 95% CI: -21.09 to 7.39, P = 0.007). The results were robust across a range of sensitivity analyses. Therefore, the results indicate that berberine is a promising drug for the treatment of atherosclerosis through regulating lipid metabolism, inflammation, and plaque composition. However, some potential mechanisms remain to be further elucidated. 10.1097/FJC.0000000000001308
Effect of berberine on hyperglycaemia and gut microbiota composition in type 2 diabetic Goto-Kakizaki rats. Zhao Jin-Dong,Li Yan,Sun Min,Yu Chan-Juan,Li Jia-Yun,Wang Si-Hai,Yang Di,Guo Cheng-Lin,Du Xue,Zhang Wen-Jin,Cheng Ruo-Dong,Diao Xiao-Chuan,Fang Zhao-Hui World journal of gastroenterology BACKGROUND:A recent investigation showed that the prevalence of type 2 diabetes mellitus (T2DM) is 12.8% among individuals of Han ethnicity. Gut microbiota has been reported to play a central role in T2DM. Goto-Kakizaki (GK) rats show differences in gut microbiota compared to non-diabetic rats. Previous studies have indicated that berberine could be successfully used to manage T2DM. We sought to understand its hypoglycaemic effect and role in the regulation of the gut microbiota. AIM:To determine whether berberine can regulate glucose metabolism in GK rats the gut microbiota. METHODS:GK rats were acclimatized for 1 wk. The GK rats were randomly divided into three groups and administered saline (Mo), metformin (Me), or berberine (Be). The observation time was 8 wk, and weight, fasting blood glucose (FBG), insulin, and glucagon-like peptide-1 (GLP-1) were measured. Pancreatic tissue was observed for pathological changes. Additionally, we sequenced the 16S rRNA V3-V4 region of the gut microbiota and analysed the structure. RESULTS:Compared with the Mo group, the Me and Be groups displayed significant differences in FBG ( < 0.01) and GLP-1 ( < 0.05). A significant decrease in weight and homeostatic model assessment-insulin resistance was noted in the Be group compared with those in the Me group ( < 0.01). The pancreatic islets of the Me- and Be-treated rats showed improvement in number, shape, and necrosis compared with those of Mo-treated rats. A total of 580 operational taxonomic units were obtained in the three groups. Compared to the Mo group, the Me and Be groups showed a shift in the structure of the gut microbiota. Correlation analysis indicated that FBG was strongly positively correlated with Clostridia_UCG-014 ( < 0.01) and negatively correlated with ( < 0.01). Body weight showed a positive correlation with ( < 0.01) and a negative correlation with ( < 0.01). Importantly, our results demonstrated that Me and Be could significantly decrease ( < 0.01) and the / ratio ( < 0.01). Furthermore, ( < 0.01; < 0.05) was significantly decreased in the Me and Be groups, and ( < 0.01) was significantly increased. CONCLUSION:Berberine has a substantial effect in improving metabolic parameters and modulating the gut microbiota composition in T2DM rats. 10.3748/wjg.v27.i8.708
Evaluation of anti-inflammatory response of berberine-loaded gum nanocomplexes in carrageenan-induced acute paw edema in rats. Bakshi Jyoti,Lathar Prity,Mehra Meenakshi,Grewal Sapna,Dhingra Dinesh,Kumari Santosh Pharmacological reports : PR BACKGROUND:Berberine is a natural plant alkaloid and has been reported to possess anti-inflammatory activity. However, berberine's poor bioavailability and low solubility have limited its clinical applicability. Nanoencapsulation of berberine using a suitable carrier can be a promising strategy to improve its efficacy. Therefore, this study aimed to produce berberine-loaded gum nanocomplexes to evaluate their therapeutic effects in a carrageenan-induced rat model. METHODS:Berberine-loaded gum nanocomplexes were prepared by the ionic complexation between the negative charges of the gums (tragacanth and acacia gum) using a cross-linker for loading cationic berberine and their anti-inflammatory activity was evaluated against carrageenan-induced paw edema in rats. ELISA and qRT-PCR were employed to measure the concentration and mRNA expression level of inflammatory mediators in plasma and paw tissue, respectively. RESULTS:Berberine nanocomplexes were characterized for particle size (219.5 nm), zeta potential by the dynamic light scattering (DLS), and for entrapment efficiency (93.2%) Infrared spectroscopy affirmed the loading of berberine in gum nanocomplexes. Transmission electron microscopy of formulation showed the spherical shape of nanocomplexes and small particle size (100-150 nm). Pretreatment of rats with berberine nanocomplexes significantly reduced the paw edema in inflamed rat paws, decreased the production of nitrite and TNF-α in plasma and repressed the mRNA expression levels of TNF-α and IL-1β in paw tissue in comparison to berberine per se treated rats. CONCLUSION:The obtained berberine-loaded gum nanocomplexes produced a better anti-inflammatory effect as compared to berberine alone and hence can be used as an efficient candidate in the treatment of inflammation. The schematic representation of the preparation of the preparation of berberine-loaded tragacanth/acacia gum nanocomplexes and the evaluation in vivo for anti-inflammatory effects. 10.1007/s43440-021-00350-z
Discovery of C-9 Modified Berberine Derivatives as Novel Lipid-Lowering Agents. Li Dong-Dong,Yu Pan,Xu Hui,Wang Zhen-Zhong,Xiao Wei,Zhao Lin-Guo Chemical & pharmaceutical bulletin Berberine (BBR), a kind of quaternary ammonium benzylisoquinoline alkaloids with multiple pharmacological activities, has been regarded as a promising lipid-lowering agent in the field of drug repurposing. Particularly, the chemical modification at the C-9 position of BBR can remarkably improve its lipid-lowering efficacy. In this study, thirteen novel BBR derivatives were rationally designed, synthesized, and evaluated by preliminary pharmacological tests. The results showed that most compounds exhibited more potent hypolipidemic activities when compared with BBR and simvastatin. Among these compounds, compound 2h-1 and 2h-2 exhibited better activity profiling in these four tests involving with inhibition of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) and the increase of high-density lipoprotein cholesterol (HDLC). Correspondingly, the BBR analogs with 9-O-cinnamic moiety probably exhibited potent lipid-lowering activity, and should be exploited as an important versatile template for the development of BBR-like lipid-lowering agents. 10.1248/cpb.c20-00453
Berberine alleviates intestinal barrier dysfunction in glucolipid metabolism disorder hamsters by modulating gut microbiota and gut-microbiota-related tryptophan metabolites. Journal of the science of food and agriculture BACKGROUND:Barberry plants can be considered as useful additives and functional compounds in various industries, especially in the food industry. Berberine (BBR), the most important functional compound in the barberry roots, has recently been used to treat obesity, diabetes, and atherosclerosis. Gut microbiota and the intestinal barrier play an important role in the development of glucolipid metabolism disorders (GLMDs). However, the association of gut microbiota metabolism disorder and the intestinal barrier dysfunction effect of BBR in GLMDs remains elusive. RESULTS:The results showed that administration of BBR could increase the number of colonic glands and goblet cell mucus secretion, improve the intestinal barrier function, and reduce the serum glycolipid level in GLMD hamsters. Interestingly, BBR was metabolized into 12 metabolites by gut microbiota, and the main metabolic pathways were oxidation, demethylation, and hydrogenation. In addition, BBR significantly improved the species diversity and uniformity of gut microbiota and promoted the proliferation of beneficial microbiota. Furthermore, the levels of tryptophan metabolites, such as indole, indole-3-acetamide, indole-3-acetaldehyde, indole-3-pyruvic acid, and indole-3-acetic acid were significantly altered by BBR. Both the intestinal tight junction proteins and intestinal immune factors were altered by BBR. CONCLUSION:BBR could alleviate intestinal barrier dysfunction of GLMDs by modulating gut microbiota and gut-microbiota-related tryptophan metabolites, which may be one of the pharmacological mechanisms for the treatment of GLMDs. © 2022 Society of Chemical Industry. 10.1002/jsfa.12242
Protective effects of berberine against MPTP-induced dopaminergic neuron injury through promoting autophagy in mice. Deng Han,Ma ZeGang Food & function Berberine, an isoquinoline alkaloid isolated from , has been widely studied for its efficacy in the treatment of neurodegenerative diseases. However, the detailed mechanisms are unknown. In this study, the effects of berberine on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease were investigated. We showed that treatment with berberine significantly ameliorates the degeneration of dopaminergic neurons in (SNc) and improves motor impairment in MPTP-treated mice. Berberine also significantly decreased the level of α-synuclein and enhanced the microtubule-associated protein light chain 3 (LC3-II)-associated autophagy in the SN of MPTP-treated mice. Furthermore, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was activated by berberine. Berberine's actions were abolished by pre-treatment with 3-methyladenine (an autophagy inhibitor) or compound c (an AMPK inhibitor) in the MPP-treated SH-SY5Y cells. These results suggested that the protective effects of berberine on the toxicity of MPTP could be attributed to berberine-enhanced autophagy the AMPK dependent pathway. 10.1039/d1fo01360b
Berberine attenuates cognitive dysfunction and hippocampal apoptosis in rats with prediabetes. Chemical biology & drug design The cognitive dysfunction caused by prediabetes causes great difficulties in human life, and the terrible thing is that the means to prevent the occurrence of this disease are very limited at present, Berberine has shown the potential to treat diabetes and cognitive dysfunction, but it still needs to be further explored to clarify the mechanism of its therapeutic effect. Therefore, the aim of this study was to investigate the effects and mechanisms of Berberine on prediabetes-induced cognitive dysfunction. Prediabetes rat model was induced by a high-fat diet and a normal diet was used as a control. They were fed for 20 weeks. At week 13, the model rats were given 100 mg/kg Berberine by gavage for 7 weeks. The cognitive function of rats was observed. At the same time, OGTT, fasting blood glucose, blood lipids, insulin and other metabolic parameters, oxidative stress, and apoptosis levels were measured. The results showed that the model rats showed obvious glucose intolerance, elevated blood lipids, and insulin resistance, and the levels of oxidative stress and apoptosis were significantly increased. However, after the administration of Berberine, the blood glucose and lipid metabolism of prediabetic rats were significantly improved, and the oxidative stress level and apoptosis level of hippocampal tissue were significantly reduced. In conclusion, Berberine can alleviate the further development of diabetes in prediabetic rats, reduce oxidative stress and apoptosis in hippocampal tissue, and improve cognitive impairment in prediabetic rats. 10.1111/cbdd.14420
Inhibition of inflammation by berberine: Molecular mechanism and network pharmacology analysis. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Traditional Chinese Medicine (TCM), renowned for its holistic approach with a 2000-year history of utilizing natural remedies, offers unique advantages in disease prevention and treatment. Berberine, found in various Chinese herbs, has been employed for many years, primarily for addressing conditions such as diarrhea and dysentery. Berberine has recently become a research focus owing to its pharmacological activities and benefits to human bodies. However, little is known about the anti-inflammatory mechanism of berberine. PURPOSE:To summarize recent findings regarding the pharmacological effects and mechanisms of berberine anti-inflammation and highlight and predict the potential therapeutic effects and systematic mechanism of berberine. METHODS:Recent studies (2013-2023) on the pharmacological effects and mechanisms of berberine anti-inflammation were retrieved from Web of Science, PubMed, Google Scholar, and Scopus up to July 2023 using relevant keywords. Network pharmacology and bioinformatics analysis were employed to predict the therapeutic effects and mechanisms of berberine against potential diseases. RESULTS:The related pharmacological mechanisms of berberine anti-inflammation include the inhibition of inflammatory cytokine production (e.g., IL-1β, IL-6, TNF-α), thereby attenuating the inflammatory response; Inhibiting the activation of NF-κB signaling pathway and IκBα degradation; Inhibiting the activation of MAPK signaling pathway; Enhancing the activation of the STAT1 signaling pathway; Berberine interacts directly with cell membranes through a variety of pathways, thereby influencing cellular physiological activities. Berberine enhances human immunity and modulates immune system function, which is integral to addressing certain autoimmune and tumour-related health concerns. CONCLUSION:This study expounds on the correlation between berberine and inflammatory diseases, encapsulating the mechanisms through which berberine treats select typical inflammatory ailments. Furthermore, it delves into a deeper understanding of berberine's effectiveness by integrating network pharmacology and molecular docking techniques in the context of treating inflammatory diseases. It provides guidance and reference for berberine's subsequent revelation of the modern scientific connotation of Chinese medicine. 10.1016/j.phymed.2023.155258
Berberine Protests the Heart from Ischemic Reperfusion Injury via Interference with Oxidative and Inflammatory Pathways. Medical archives (Sarajevo, Bosnia and Herzegovina) BACKGROUND:Ischemia and reperfusion (I/R) is a pathological condition characterized by an initial restriction of blood supply to an organ followed by the subsequent restoration of perfusion and concomitant reoxygenation. OBJECTIVE:The aim of the study is to assess the possible cardioprotective potential effect of berberine in myocardial ischemia reperfusion injury induced by ligation of coronary artery in a male rat model. METHODS:Total amount of 28 adult male albino rats were randomized into 4 equal groups: 1) Sham group, rats underwent the same anesthetic and surgical procedure as the control group except for LAD ligation; 2), Active control group, rats subjected to regional ischemia for 30 min by ligation of LAD coronary artery and reperfusion for 2 hours, 3), Control vehicle group, rats received dimethyl sulphoxide (DMSO) (vehicle of berberine) via IP route and subjected to ischemia for 30 minutes before ligation of LAD coronary artery & reperfusion for 2 hr; 4), Berberine treated group, rats pretreated with berberine10 mg/kg via IP injection 30minutes before ligation of LAD coronary artery & then subjected to reperfusion for 2 hr. RESULTS:In the control group, as compared with sham, tissue TNF-α, IL-6, IL-10, caspase-3 and BAX, plasma cTn-T and serum MDA significantly increased (P<0.05), while serum GSH significantly decreased (P<0.05). The histopathological control group showed a significant cardiac injury (P<0.05) compared with the sham group. Berberine significantly counteracted (P<0.05) the increase of TNF-α, IL-6, caspase-3 and BAX and counteracted the increase in plasma cTn-T and serum MDA. Berberine produces a significant elevation (P<0.05) in cardiac IL-10 and serum GSH with a significant reduction in (P<0.05) cardiac injury. CONCLUSION:Berberine attenuates myocardial I/R injury in male rats via interfering with inflammatory reactions and apoptosis which were induced by I/R injury. 10.5455/medarh.2021.75.174-179
Berberine suppresses cecal ligation and puncture induced intestinal injury by enhancing Treg cell function. Qiu Dongze,Zhang Wen,Song Zhenju,Xue Mingming,Zhang Yazhen,Yang Yunke,Tong Chaoyang,Cai Dingfang International immunopharmacology The gut is hypothesized to be the "motor" of critical illness and plays an important role in the development of sepsis. Berberine (BBR) is an alkaloid compound extracted from herbs, which has anti-inflammatory, anti-oxidative effects and can be used in intestinal infectious diseases and inflammatory bowel disease (IBD). BBR could promote differentiation of Treg cells which play a key role in maintaining intestinal immune homeostasis. However, its effect on sepsis-induced intestinal injury remains poorly understood. This study investigated the effect of BBR on cecal ligation and puncture (CLP)-induced intestinal injury and explained the underlying mechanism. These results showed that BBR treatment decreased the mortality of septic mice, alleviated intestinal injury and reduced serum endotoxin level; at the same time, BBR had a protective effect on CLP-induced lung and liver apoptosis. Meanwhile, BBR treatment increased the proportion of Treg cells and CTLA-4 in Treg cells. Treg cells from BBR treatment mice could decrease the pro-inflammatory response by inhibiting the activation of macrophages, thus exerting a protective effect on CLP-induced intestinal injury, and CTLA-4 mediated cell-cell contact pathway is required for this protective effect. 10.1016/j.intimp.2022.108564
Berberine Regulates the Metabolism of Uric Acid and Modulates Intestinal Flora in Hyperuricemia Rats Model. Combinatorial chemistry & high throughput screening BACKGROUND:Intestinal microbiota is the primary target for the multifunctional nature of berberine. Berberine can reverse the structure and composition of gut microbiota under pathological conditions. This study aimed to investigate the effects of berberine on uric acid (UA) metabolism and gut microbiota in a hyperuricemia rat model established using potassium oxonate. METHODS:Sprague-Dawley (SD) male rats were divided into a normal control group (n= 10), a hyperuricemia group (n = 12) and a berberine-treated group (n = 11). The UA level in serum, urine and fecal, blood xanthine oxidase (XOD), and urate transports ABCG2 and Galectin-9 in the liver and colon, were evaluated using ELISA kits. The alterations in gut microbiota were investigated using 16S rRNA sequencing. RESULTS:The UA level in the hyperuricemia group was significantly elevated (p<0.001), suggesting that the model was successfully established. After treatment with berberine, levels of blood and fecal UA significantly decreased (p<0.001), but not uric UA. The blood XOD level decreased, urate transport ABCG2 in the colon increased, and urate transport Galectin-9 in the colon decreased after berberine treatment (p<0.05). Further 16S sequencing revealed that berberine affected the gut microbiota composition and diversity in hyperuricemia rats. Berberine treatment reduced the relative abundance of Bacteroidetes, and increased the relative abundance of Lactobacillus. The gut microbiota were predicted to be involved in multiple metabolic pathways, such as sphingolipid metabolism, starch and sucrose metabolism and N-glycans. CONCLUSION:Berberine might be a possible therapeutic candidate in hyperuricemia, which could regulate UA metabolism by affecting XOD, and urate transports and partly by regulating gut microbiota. 10.2174/1386207326666221124093228
Anti-inflammatory, antioxidant, and immunomodulatory effects of Berberis vulgaris and its constituent berberine, experimental and clinical, a review. Phytotherapy research : PTR Berberis vulgaris (B. vulgaris or barberry) is a medicinal plant that has been used for various purposes in traditional medicine. Berberine is one of the main alkaloids isolated from B. vulgaris and other plants. Both B. vulgaris and berberine have shown anti-inflammatory, antioxidant, and immunomodulatory effects in different experimental models and clinical trials. This review aims to summarize the current evidence on the mechanisms and applications of B. vulgaris and berberine in modulating inflammation, oxidative stress, and immune responses. The literature search was performed using PubMed, Scopus, and Google Scholar databases until August 2023. The results indicated that B. vulgaris and berberine could inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin-17 (IL-17), and enhance the expression of anti-inflammatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor-β (TGF-β), in various cell types and tissues. B. vulgaris and berberine can also scavenge free radicals, increase antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduce lipid peroxidation and DNA damage. B. vulgaris and berberine have been reported to exert beneficial effects in several inflammatory, oxidative, and immune-related diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, allergic diseases, and infections. However, more studies are needed to elucidate the optimal doses, safety profiles, and potential interactions of B. vulgaris and berberine with other drugs or natural compounds. 10.1002/ptr.8077
Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy. 10.1016/j.biopha.2022.112955
Berberine Protects against High-Energy and Low-Protein Diet-Induced Hepatic Steatosis: Modulation of Gut Microbiota and Bile Acid Metabolism in Laying Hens. International journal of molecular sciences Berberine (BBR) is a natural alkaloid with multiple biotical effects that has potential as a treatment for fatty liver hemorrhagic syndrome (FLHS). However, the mechanism underlying the protective effect of BBR against FLHS remains unclear. The present study aimed to investigate the effect of BBR on FLHS induced by a high-energy, low-protein (HELP) diet and explore the involvement of the gut microbiota and bile acid metabolism in the protective effects. A total of 90 healthy 140-day-old Hy-line laying hens were randomly divided into three groups, including a control group (fed a basic diet), a HELP group (fed a HELP diet), and a HELP+BBR group (high-energy, high-protein diet supplemented with BBR instead of maize). Our results show that BBR supplementation alleviated liver injury and hepatic steatosis in laying hens. Moreover, BBR supplementation could significantly regulate the gut's microbial composition, increasing the abundance of Actinobacteria and Romboutsia. In addition, the BBR supplement altered the profile of bile acid. Furthermore, the gut microbiota participates in bile acid metabolism, especially taurochenodeoxycholic acid and α-muricholic acid. BBR supplementation could regulate the expression of genes and proteins related to glucose metabolism, lipid synthesis (FAS, SREBP-1c), and bile acid synthesis (FXR, CYP27a1). Collectively, our findings demonstrate that BBR might be a potential feed additive for preventing FLHS by regulating the gut microbiota and bile acid metabolism. 10.3390/ijms242417304
Berberine promotes the degradation of phenylacetic acid to prevent thrombosis by modulating gut microbiota. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Berberine is the main bioactive constituent of Coptis chinensis, a quaternary ammonium alkaloid. While berberine's cardiovascular benefits are well-documented, its impact on thrombosis remains not fully understood. PURPOSE:This study investigates the potential of intestinal microbiota as a novel target for preventing thrombosis, with a focus on berberine, a natural compound known for its effectiveness in managing cardiovascular conditions. METHODS:Intraperitoneal injection of carrageenan induces the secretion of chemical mediators such as histamine and serotonin from mast cells to promote thrombosis. This model can directly and visually observe the progression of thrombosis in a time-dependent manner. Thrombosis was induced by intravenous injection of 1 % carrageenan solution (20 mg/kg) to all mice except the vehicle control group. Quantitative analysis of gut microbiota metabolites through LC/MS. Then, the gut microbiota of mice was analyzed using 16S rRNA sequencing to assess the changes. Finally, the effects of gut microbiota on thrombosis were explored by fecal microbiota transplantation. RESULTS:Our research shows that berberine inhibits thrombosis by altering intestinal microbiota composition and related metabolites. Notably, berberine curtails the biosynthesis of phenylacetylglycine, a thrombosis-promoting coproduct of the host-intestinal microbiota, by promoting phenylacetic acid degradation. This research underscores the significance of phenylacetylglycine as a thrombosis-promoting risk factor, as evidenced by the ability of intraperitoneal phenylacetylglycine injection to reverse berberine's efficacy. Fecal microbiota transplantation experiment confirms the crucial role of intestinal microbiota in thrombus formation. CONCLUSION:Initiating our investigation from the perspective of the gut microbiota, we have, for the first time, unveiled that berberine inhibits thrombus formation by promoting the degradation of phenylacetic acid, consequently suppressing the biosynthesis of PAG. This discovery further substantiates the intricate interplay between the gut microbiota and thrombosis. Our study advances the understanding that intestinal microbiota plays a crucial role in thrombosis development and highlights berberine-mediated intestinal microbiota modulation as a promising therapeutic approach for thrombosis prevention. 10.1016/j.phymed.2024.155517
Berberine regulates intestinal microbiome and metabolism homeostasis to treat ulcerative colitis. Life sciences AIMS:This study aims to investigate the effects of berberine (BBR) on the intestinal microbiome (IM) and serum metabolome in ulcerative colitis (UC). Furthermore, the underlying molecular mechanisms of BBR in treating UC also will be explored systematically. MATERIALS AND METHODS:A multi-omics approach that integrates the 16s rDNA, serum metabolome, transcriptomics and bioinformatics was profiled to investigate the potential effects of BBR on the IM, serum metabolites and metabolic pathways, and gene expression. In addition, BBR-induced fecal microbiota transplantation (BBR_FMT) was conducted in pseudo germ-free mice combined with the UC model to explore the effects of the IM on metabolic pathways and gene expression. The results of the transcriptomics and metabolic pathway-related genes were further examined by real-time PCR and western blot. KEY FINDINGS:BBR ameliorated the community of IM and significantly promoted the abundance of f__Muribaculaceae, Bacteroides, Dubosiella, Allobaculum and Akkermansia. The metabolic profiles in UC mice were significantly modulated by BBR treatment. Furthermore, the inflammation-related metabolites and metabolic pathways in serum were negatively correlated with the abundance of Bacteroides and Akkermansia, which were induced by BBR treatment. BBR_FMT significantly inhibited the arachidonic acid (AA) metabolism pathway and its multiple markers with the mediation of the IM. SIGNIFICANCE:BBR ameliorated serum metabolic homeostasis by regulating the IM. The inhibition of the AA metabolism pathway and its multiple markers was one of the mechanisms of BBR in the treatment of UC. 10.1016/j.lfs.2023.122385
Modulating gut microbiota as an anti-diabetic mechanism of berberine. Han Junling,Lin Huiling,Huang Weiping Medical science monitor : international medical journal of experimental and clinical research Berberine, one of the main constituents of a Chinese traditional herb used to treat bacterial diarrhea, has an effect of lowering glucose, which has been recently confirmed by many studies. However, the mechanism of berberine's antidiabetic effect has not yet been well explained. Recent evidence suggests that the gut microbiota composition is associated with obesity and type 2 diabetes, which are closely associated with a low-grade inflammatory state. The protective effect against diabetes of gut microbiota modulation with probiotics or antibiotics has been confirmed in recent observations. Berberine has significant antimicrobial activity against several microbes through inhibiting the assembly function of FtsZ and halting the bacteria cell division. Because berberine acts topically in the gastrointestinal tract and it is poorly absorbed, berberine might modulate gut microbiota without systemic anti-infective activity. Our hypothesis is that gut microbiota modulation may be one mechanism of the antidiabetic effect of berberine. Our hypothesis may provide a novel explanation for berberine's therapeutic effect in patients with diabetes mellitus. 10.12659/msm.881842
Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential. Fan Dahua,Liu Liping,Wu Zhengzhi,Cao Meiqun Current neuropharmacology Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide. Such diseases are characterized by a progressive degeneration and / or death of neurons in the central nervous system. Currently, there are no therapeutic approaches to cure or even halt the progression of neurodegenerative diseases. During the last two decades, much attention has been paid to the neuroprotective and anti-neurodegenerative activities of compounds isolated from natural products with high efficacy and low toxicity. Accumulating evidence indicates that berberine, an isoquinoline alkaloid isolated from traditional Chinese medicinal herbs, may act as a promising anti-neurodegenerative agent by inhibiting the activity of the most important pathogenic enzymes, ameliorating intracellular oxidative stress, attenuating neuroinflammation, triggering autophagy and protecting neurons against apoptotic cell death. This review attempts to summarize the current state of knowledge regarding the therapeutic potential of berberine against neurodegenerative diseases, with a focus on the molecular mechanisms that underlie its effects on Alzheimer's, Parkinson's and Huntington's diseases. 10.2174/1570159X16666180419141613
The Effect of Berberine Supplementation on Glycemic Control and Inflammatory Biomarkers in Metabolic Disorders: An Umbrella Meta-analysis of Randomized Controlled Trials. Clinical therapeutics PURPOSE:Several meta-analyses reported berberine (BBR) supplementation improves glycemic parameters and inflammatory marker, but findings remain inconsistent. Therefore, this study was conducted. METHODS:We systematically searched PubMed, Embase, Web of Science, Scopus, and Google Scholar to identify the relevant meta-analyses up to April 2023. FINDINGS:BBR supplementation was effective in reducing fasting blood glucose (FBG) (ES: -0.77; 95% CI: -0.90 to -0.63, and ES: -0.65; 95% CI: -0.83 to -0.47), hemoglobin A1C (HbA1C) (ES: -0.57; 95% CI: -0.68 to -0.46), homeostasis model assessment for insulin resistance (HOMA-IR) (ES: -1.04; 95% CI: -1.66 to -0.42, and ES: -0.71; 95% CI: -0.97 to -0.46), insulin (ES: -1.00; 95% CI: -1.70 to -0.30, and ES: -0.63; 95% CI: -0.94 to -0.32), interleukin (IL)-6 (ES: -1.23; 95% CI: -1.61 to -0.85), tumor necrosis factor-α (TNF-α) (ES: -1.04; 95% CI: -1.28 to -0.79), and C-reactive protein (CRP) (ES: -0.62; 95% CI: -0.74 to -0.50, and ES: -1.70; 95% CI: -2.21 to -1.19). IMPLICATIONS:The finding of our umbrella showed that the supplementation of BBR could be effective in improving glycemic parameters and inflammatory marker in adults. 10.1016/j.clinthera.2023.10.019
Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties. Expert opinion on drug metabolism & toxicology INTRODUCTION:Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability. AREAS COVERED:Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed. EXPERT OPINION:Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR. 10.1080/17425255.2023.2203857
Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy. European journal of pharmacology Diabetes cardiomyopathy (DCM) refers to myocardial dysfunction and disorganization resulting from diabetes. In this study, we investigated the effects of berberine on cardiac function in male db/db mice with metformin as a positive control. After treatment for 8 weeks, significant improvements in cardiac function and a reduction in collagen deposition were observed in db/db mice. Furthermore, inflammation and pyroptosis were seen to decrease in these mice, as evidenced by decreased expressions of p-mTOR, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), IL-1β, IL-18, caspase-1, and gasdermin D (GSDMD). In vitro experiments on H9C2 cells showed that glucose exposure at 33 mmol/L induced pyroptosis, whereas berberine treatment reduced the expression of p-mTOR and NLRP3 inflammasome components. Moreover, berberine treatment was seen to inhibit the generation of mitochondrial reactive oxygen species (mtROS) and effectively improve cell damage in high glucose-induced H9C2 cells. The mTOR inhibitor, Torin-1, showed a therapeutic effect similar to that of berberine, by reducing the expression of NLRP3 inflammasome components and inhibiting mtROS generation. However, the activation of mTOR by MHY1485 partially nullified berberine's protective effects during high glucose stress. Collectively, our study reveals the mechanism that berberine regulates the mTOR/mtROS axis to inhibit pyroptosis induced by NLRP3 inflammasome activation, thereby alleviating DCM. 10.1016/j.ejphar.2023.176253
Nanocarrier Based Delivery of Berberine: A Critical Review on Pharmaceutical and Preclinical Characteristics of the Bioactive. Current pharmaceutical biotechnology Berberine (BBR) is an isoquinoline alkaloid with several therapeutic properties, including anti-microbial, anti-diarrhea, anti-viral, anti-inflammatory, antihypertensive, anti-tumor, and anti-diabetes. However, its low water solubility, low absorption, first-pass metabolism, nontargeting, and poor bioavailability represent major hurdles to its successful therapeutic applications. Hence, researchers have attempted to enhance the biological and pharmacological activity of BBR to overcome its drawbacks by encapsulation of BBR in micro and nano delivery systems. For the preparation of nanostructured carrier systems of BBR, a range of methods has been developed, and each method has its benefits and characteristics. This review critically describes different types of nanocarriers like liposomes, niosomes, ethosomes, nanoemulsions, polymeric nanoparticles, micelles, dendrimers, and silver and gold nanoparticles that have been used for encapsulation of BBR for different therapeutic applications. The various pharmaceutical characteristics (size, shape, entrapment efficiency, zeta potential, drug release, and drug permeation) of these BBR-loaded nanocarriers have been discussed systematically. Preclinical studies of BBR nanoformulations involving animal models are also discussed. 10.2174/1389201024666230112141330
Berberine alleviates myocardial diastolic dysfunction by modulating Drp1-mediated mitochondrial fission and Ca homeostasis in a murine model of HFpEF. Frontiers of medicine Heart failure with preserved ejection fraction (HFpEF) displays normal or near-normal left ventricular ejection fraction, diastolic dysfunction, cardiac hypertrophy, and poor exercise capacity. Berberine, an isoquinoline alkaloid, possesses cardiovascular benefits. Adult male mice were assigned to chow or high-fat diet with L-NAME ("two-hit" model) for 15 weeks. Diastolic function was assessed using echocardiography and noninvasive Doppler technique. Myocardial morphology, mitochondrial ultrastructure, and cardiomyocyte mechanical properties were evaluated. Proteomics analysis, autophagic flux, and intracellular Ca were also assessed in chow and HFpEF mice. The results show exercise intolerance and cardiac diastolic dysfunction in "two-hit"-induced HFpEF model, in which unfavorable geometric changes such as increased cell size, interstitial fibrosis, and mitochondrial swelling occurred in the myocardium. Diastolic dysfunction was indicated by the elevated E value, mitral E/A ratio, and E/e' ratio, decreased e' value and maximal velocity of re-lengthening (-dL/dt), and prolonged re-lengthening in HFpEF mice. The effects of these processes were alleviated by berberine. Moreover, berberine ameliorated autophagic flux, alleviated Drp1 mitochondrial localization, mitochondrial Ca overload and fragmentation, and promoted intracellular Ca reuptake into sarcoplasmic reticulum by regulating phospholamban and SERCA2a. Finally, berberine alleviated diastolic dysfunction in "two-hit" diet-induced HFpEF model possibly because of the promotion of autophagic flux, inhibition of mitochondrial fragmentation, and cytosolic Ca overload. 10.1007/s11684-023-0983-0
Multi-target regulation of intestinal microbiota by berberine to improve type 2 diabetes mellitus. Frontiers in endocrinology Type 2 diabetes mellitus (T2DM) and its complications are major public health problems that seriously affect the quality of human life. The modification of intestinal microbiota has been widely recognized for the management of diabetes. The relationship between T2DM, intestinal microbiota, and active ingredient berberine (BBR) in intestinal microbiota was reviewed in this paper. First of all, the richness and functional changes of intestinal microbiota disrupt the intestinal environment through the destruction of the intestinal barrier and fermentation/degradation of pathogenic/protective metabolites, targeting the liver, pancreas, visceral adipose tissue (VAT), etc., to affect intestinal health, blood glucose, and lipids, insulin resistance and inflammation. Then, we focus on BBR, which protects the composition of intestinal microbiota, the changes of intestinal metabolites, and immune regulation disorder of the intestinal environment as the therapeutic mechanism as well as its current clinical trials. Further research can analyze the mechanism network of BBR to exert its therapeutic effect according to its multi-target compound action, to provide a theoretical basis for the use of different phytochemical components alone or in combination to prevent and treat T2DM or other metabolic diseases by regulating intestinal microbiota. 10.3389/fendo.2022.1074348
Anti-inflammatory potential of berberine-rich extract via modulation of inflammation biomarkers. Journal of food biochemistry Berberine-rich extract (BRE) prepared from Berberis lycium root bark using green extraction approach and its marker compound berberine has a broad spectrum of clinical applications. Berberine's potential pharmacological effects include anticancer, antidiarrheal, antidiabetic, antimicrobial and anti-inflammatory activities. In current work, BRE and berberine were evaluated for their therapeutic prospects in inflammation models. The comparative effect of BRE and berberine against inflammation was determined through in vitro chemiluminescence technique. The in vivo anti-inflammatory evaluation of BRE and berberine (25, 75, and 125 mg/kg) compared to diclofenac (10 mg/kg) was performed in carrageenan and formaldehyde-induced inflammation in Wistar rats. Histopathological and biochemical studies were conducted to find the comparative anti-inflammatory potential of BRE and berberine on pathological hallmarks induced by formaldehyde. Moreover, the modulatory effects on inflammatory biomarkers were also investigated through qPCR. ELISA (enzyme-linked immunoassay test assay) was performed to investigate the expression of pathological protein biomarkers like TNF-α and IL-6 and levels of antioxidant enzymes were estimated in liver homogenates. Both BRE and berberine markedly (p < .001) reduced paw diameter and inflammation in carrageenan and formaldehyde-induced inflammation. The levels of antioxidant enzymes were recovered (p < .001) by BRE and berberine treatments, and compared to the formaldehyde-treated inflammation model. Both BRE and berberine remarkably downregulated the mRNA and protein expression of inflammatory biomarkers. BRE similar to berberine mitigated the level of antioxidant enzymes in liver homogenate. The undertaken study suggests that BRE, a natural, green, and therapeutically bioequivalent to berberine could be used as an economical phytomedicine in the treatment of inflammatory disorders. PRACTICAL APPLICATIONS: Anti-inflammatory drugs like NSAIDS are associated with serious adverse effects like gastrointestinal ulcer, worsening of preexisting cardiovascular disorders, and renal failure. Therefore, there is a constant demand to develop novel, inexpensive therapeutic strategies to treat the inflammatory disorder with the least harmful effects. Pure phytochemicals with anti-inflammatory potential are costly and hard to isolate, therefore green microwave-assisted extraction technique is developed to get the rich bioequivalent extract. Berberis lycium a medicinal plant with berberine as a major bioactive constituent, has wide acceptance in traditionally used medicine and as food. Pharmacological studies revealed its hepatoprotective, anticancer, antidiabetic, and antihypertensive activities. BRE was prepared by green microwave-assisted extraction and enrichment by resin column to get a higher yield of berberine. The comparative anti-inflammatory effect of BRE and berberine was determined by in vitro and in vivo studies. Results obtained from this experimental work contribute beneficial guidance that reinforces the use of the BRE to treat inflammatory disorders. 10.1111/jfbc.14389
Promising Anti-atherosclerotic Effect of Berberine: Evidence from In Vitro, In Vivo, and Clinical Studies. Reviews of physiology, biochemistry and pharmacology Elevated levels of plasma cholesterol, impaired vascular wall, and presence of inflammatory macrophages are important atherogenic risk factors contributing to atherosclerotic plaque formation and progression. The interventions modulating these risk factors have been found to protect against atherosclerosis development and to decrease atherosclerosis-related cardiovascular disorders. Nutritional approaches involving supplements followed by improving dietary habits and lifestyle have become growingly attractive and acceptable methods used to control atherosclerosis risk factors, mainly high levels of plasma cholesterol. There are a large number of studies that show berberine, a plant bioactive compound, could ameliorate atherosclerosis-related risk factors. In the present literature review, we put together this studies and provide integrated evidence that exhibits berberine has the potential atheroprotective effect through reducing increased levels of plasma cholesterol, particularly low-density lipoprotein (LDL) cholesterol (LDL-C) via LDL receptor (LDLR)-dependent and LDL receptor-independent mechanisms, inhibiting migration and inflammatory activity of macrophages, improving the functionality of endothelial cells via anti-oxidant activities, and suppressing proliferation of vascular smooth muscle cells. In conclusion, berberine can exert inhibitory effects on the atherosclerotic plaque development mainly through LDL-lowering activity and suppressing atherogenic functions of mentioned cells. As the second achievement of this review, among the signaling pathways through which berberine regulates intracellular processes, AMP-activated protein kinase (AMPK) has a central and critical role, showing that enhancing activity of AMPK pathway can be considered as a promising therapeutic approach for atherosclerosis treatment. 10.1007/112_2020_42
A Review on the Neuroprotective Effect of Berberine against Chemotherapy- induced Cognitive Impairment. Current drug targets Chemobrain is one of the major side effects of chemotherapy; despite increased research, the mechanisms underlying chemotherapy-induced cognitive changes remain unknown. Several possibly important candidate mechanisms have been identified and will be studied further in the future. Chemobrain is characterized by memory loss, cognitive impairment, difficulty in language, concentration, acceleration, and learning. The major characteristic of chemobrain is oxidative stress, mitochondrial dysfunction, immune dysregulation, hormonal alteration, white matter abnormalities, and DNA damage. Berberine (BBR) is an isoquinoline alkaloid extracted from various berberine species. BBR is a small chemical that easily passes the blood-brain barrier (BBB), making it useful for treating neurodegenerative diseases. Many studies on the pharmacology of BBR have been reported in the past. Furthermore, several clinical and experimental research indicates that BBR has a variety of pharmacological effects. So, in this review, we explore the pathogenesis of chemobrain and the neuroprotective potential of BBR against chemobrain. We also introduced the therapeutic role of BBR in various neurodegenerative and neurological diseases such as Alzheimer's, Parkinson's disease, mental depression, schizophrenia, anxiety, and also some stroke. 10.2174/1389450123666220303094752
Berberine-containing natural-medicine with boiled peanut-OIT induces sustained peanut-tolerance associated with distinct microbiota signature. Frontiers in immunology Background:Gut microbiota influence food allergy. We showed that the natural compound berberine reduces IgE and others reported that BBR alters gut microbiota implying a potential role for microbiota changes in BBR function. Objective:We sought to evaluate an oral Berberine-containing natural medicine with a boiled peanut oral immunotherapy (BNP) regimen as a treatment for food allergy using a murine model and to explore the correlation of treatment-induced changes in gut microbiota with therapeutic outcomes. Methods:Peanut-allergic (PA) mice, orally sensitized with roasted peanut and cholera toxin, received oral BNP or control treatments. PA mice received periodic post-therapy roasted peanut exposures. Anaphylaxis was assessed by visualization of symptoms and measurement of body temperature. Histamine and serum peanut-specific IgE levels were measured by ELISA. Splenic IgEB cells were assessed by flow cytometry. Fecal pellets were used for sequencing of bacterial 16S rDNA by Illumina MiSeq. Sequencing data were analyzed using built-in analysis platforms. Results:BNP treatment regimen induced long-term tolerance to peanut accompanied by profound and sustained reduction of IgE, symptom scores, plasma histamine, body temperature, and number of IgE B cells (0.001 vs Sham for all). Significant differences were observed for / ratio across treatment groups. Bacterial genera positively correlated with post-challenge histamine and PN-IgE included , , and (all ) while . , , and were negatively correlated. Conclusions:BNP is a promising regimen for food allergy treatment and its benefits in a murine model are associated with a distinct microbiota signature. 10.3389/fimmu.2023.1174907
Berberine attenuates depression-like behavior by modulating the hippocampal NLRP3 ubiquitination signaling pathway through Trim65. International immunopharmacology OBJECTIVE:Increasing evidence suggests that inflammation appears to play a role in the genesis of depression. Berberine has potent anti-inflammatory effects and potential antidepressant activity, although the mechanism by which it works is yet unclear. Our study aimed to investigate the molecular mechanisms through which berberine treats depression and reduces inflammation. METHODS:The CUMS model and behavioral evaluation were utilized in this study to evaluate the efficacy of berberine in the treatment of depression. Berberine's effect on the inflammatory response in CUMS mice was evaluated via ELISA assays and western blotting. Nissl staining was used to observe hippocampal neuronal functional damage. Western blotting, ELISA, ubiquitination tests, and immunoprecipitation were utilized in conjunction with in vitro experiments to study the involvement of Trim65 in the antidepressant effects of berberine. RESULTS:The results suggest that berberine effectively alleviates depressive symptoms, suppresses the expression of genes associated with the NLRP3 inflammasome (NLRP3, cleaved caspase-1, ASC, GSDMD-N, Pro-IL-1β, IL-1β, Pro-IL-18, and IL-18), and reduces hippocampal neuronal functional damage in CUMS mice. Further studies showed that knockdown of Trim65 reversed the effects of berberine and increased NLRP3 inflammasome activity. Finally, K285, an important site for Trim65 binding to NLRP3, was identified. CONCLUSION:Our study describes the mechanism of berberine limiting NLRP3 inflammasome activity by promoting the conjugation of Trim65 to NLRP3 and NLRP3 ubiquitination, and suggests NLRP3 inflammasome activation as a prospective target for treating inflammation-associated disorders such as depression. 10.1016/j.intimp.2023.110808
Berberine modulates gut microbiota to attenuate cerebral ferroptosis induced by ischemia-reperfusion in mice. European journal of pharmacology Ferroptosis was reported to be involved in cerebral ischemia-reperfusion injury (CIRI), on which the effects of berberine (BBR) remain unclear. Moreover, based on the critical role of gut microbiota in pleiotropic actions of BBR, we hypothesized that BBR can suppress CIRI-induced ferroptosis by modulating the gut microbiota. In this study, the results showed that BBR obviously attenuated the behavioral deficits of CIRI mice, accompanied with the improved survival rate and neuron damages, as phenocopied by dirty cage experiment. The typical morphological changes in ferroptotic cells and biomarkers of ferroptosis were attenuated in BBR- and its fecal microbiota-treated mice, accompanied by reduced malondialdehyde and reactive oxygen species, and the increased glutathione (GSH). BBR was found to alter the gut microbiota of CIRI mice with decreased abundance of Muribaculaceae, Erysipelotrichaceae, Helicobacteraceae, Streptococcaceae and Tannerellaceae, but elevated Bacteroidaceae and Enterobacteriaceae. KEGG analysis based on the 16S rRNA results indicated that multiple metabolic pathways including ferroptosis and GSH metabolism, were altered by BBR. Oppositely, the antibiotics administration counteracted the protective properties of BBR. Summarily, this study revealed the therapeutic potential of BBR on CIRI via inhibiting neuronal ferroptosis, in which upregulated glutathione peroxidase 1 (GPX1) was possibly involved. Moreover, the BBR-modulated gut microbiota was shown to play the critical role in the underlying mechanism. 10.1016/j.ejphar.2023.175782
Immunomodulatory and Anti-Inflammatory Effects of Berberine in Lung Tissue and its Potential Application in Prophylaxis and Treatment of COVID-19. Frontiers in bioscience (Landmark edition) Natural products with known safety profiles are a promising source for the discovery of new drug leads. Berberine presents an example of one such phytochemical that has been extensively studied for its anti-inflammatory and immunomodulatory properties against myriads of diseases, ranging from respiratory disorders to viral infections. A growing body of research supports the pluripotent therapeutic role berberine may play against the dreaded disease COVID-19. The exact pathophysiological features of COVID-19 are yet to be elucidated. However, compelling evidence suggests inflammation and immune dysregulations as major features of this disease. Being a potent immunomodulatory and anti-inflammatory agent, berberine may prove to be useful for the prevention and treatment of COVID-19. This review aims to revisit the pharmacological anti-inflammatory and immunomodulatory benefits of berberine on a multitude of respiratory infections, which like COVID-19, are known to adversely affect the airways and lungs. We speculate that berberine may help alleviate COVID-19 via preventing cytokine storm, restoring Th1/Th2 balance, and enhancing cell-mediated immunity. Furthermore, the role this promising phytochemical plays on other important inflammatory mediators involved in respiratory disorders will be underscored. We further highlight the role of berberine against COVID-19 by underscoring direct evidence from , , and studies suggesting the inhibitory potential berberine may play against three critical SARS-CoV-2 targets, namely main protease, spike protein, and angiotensin-converting enzyme 2 receptor. Further preclinical and clinical trials are certainly required to further substantiate the efficacy and potency of berberine against COVID-19 in humans. 10.31083/j.fbl2705166
Berberine for the treatment of hypertension: A systematic review. Complementary therapies in clinical practice BACKGROUND:Hypertension is the highest risk factor for disease globally. When prescription of drug therapy is recommended, patients might decline treatment due to hypertension asymptomatic nature, sometimes turning to alternative therapies. One popular therapy is berberine, a plant alkaloid that has been used in eastern medicine for millennia to treat several ailments, including cardiovascular diseases and their risk factors. AIMS:Through a transparent and pragmatic approach towards searching, synthesising, assessing, and reporting the available clinical evidence, the present review aimed to investigate berberine effect on blood pressure and cardiovascular disease risk. It also intended to provide guidance for clinician when advising their patients, and to highlight gaps in the research along offering suggestions to fill them. METHODS:The review was conducted following the protocol PRISMA-P, and reported according to the related PRISMA statement. The PICO framework was used to define the scope of the review, and to arrive at a database search strategy. The strategy was run on the databases Medline, CINAHL, AMED, Embase, and Cochrane Library through the platforms EBSCOhost and Ovid. Citations were exported to Mendeley citation manger for screening. Relevant studies were selected based on specified inclusion and exclusion criteria. Data from included studies was extracted in the form of a detailed table of characteristics of studies, and summarised in an evidence table. Quality of studies was assessed using the SIGN methodology checklist for controlled trials. The results from the quality assessment were summarised through an adaptation of the Robvis tool software package output. Effect estimates and their precision were calculated with RevMan 5 computer program from the extracted study outcomes. RESULTS:Five randomised controlled trials and two non-randomised controlled trials were included with 614 participants. All provided data on blood pressure, but none measured cardiovascular events or long-term adverse events. The group of studies was highly heterogeneous in terms of experimental intervention, comparator intervention, length to follow-up, participants' diagnosis, and setting. The heterogeneity prevented a meaningful meta-analysis. Berberine plus amlodipine was not significantly better than amlodipine alone at reducing systolic and diastolic blood pressure. Compared to metformin, berberine provided a statistically significant moderate reduction effect on systolic blood pressure (-11.87 [-16.64, -7.10] mmHg). A proprietary nutraceutical containing berberine as one of its ingredients was in one study significantly effective at reducing blood pressure compared to placebo (-11.80 [-18.73, -4.87] mmHg systolic, and -11.10 [-15.17, -7.43] mmHg diastolic), and also effective in another study compared to dietary advice (-3.40 [-5.48, -1.32] mmHg for systolic 24 h ambulatory blood pressure), although effects could not be reliably attributed to berberine alone. The herbal extract Chunghyul-dan, which contains berberine, showed a significant beneficial moderate effect compared to no treatment on systolic 24 h ambulatory blood pressure (-7.34 [-13.14, -1.54] mmHg) in one study, but in another study employing higher dose and longer treatment duration, no effects were detected. Again, the effects could not be attributed to berberine alone. The quality of the body of evidence was low, especially due to lack of trial design details and presence of outcome reporting bias. CONCLUSIONS:The evidence around berberine effect on blood pressure is limited, of low quality, and ultimately inconclusive. Clinicians should be aware that the evidence from randomised trials is not sufficient to establish berberine effectiveness and safety in the treatment of hypertension, and they should balance these findings with the long history of berberine use in the Eastern world. Researchers should aim at improving quality of studies, by raising the standard of designing and reporting them, e.g., by following the CONSORT guidelines, and strive to measure meaningful clinical endpoints, such as cardiovascular events, mortality, and adverse outcomes. 10.1016/j.ctcp.2020.101287
The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress. Phytotherapy research : PTR Various factors interfere with the endoplasmic reticulum (ER) function, which is involved in protein folding and calcium homeostasis. ER dysfunction referred to as ER stress triggers cell death by apoptosis and inflammation. Berberine (BBR) is an alkaloid extracted from the family Berberidacea. It has shown multiple pharmacological activities, including anti-inflammatory, antioxidative, anti-apoptotic, antiproliferative, and antihypertensive. It has been reported that BBR can decrease apoptosis and inflammation following different pathological conditions, which might be mediated by targeting ER stress pathways. In this manuscript, we reviewed the protective potential of BBR against several diseases, such as metabolic disorders, cancer, intestinal diseases, cardiovascular, liver, kidney, and central nervous system diseases, in both in vivo and in vitro studies. 10.1002/ptr.7539
Efficacy of berberine in treatment of rheumatoid arthritis: From multiple targets to therapeutic potential. Huang Dan-Na,Wu Fang-Fang,Zhang Ai-Hua,Sun Hui,Wang Xi-Jun Pharmacological research Rheumatoid arthritis is a systemic autoimmune disorder involved in persistent synovial inflammation. Berberine is a nature-derived alkaloid compound with multiple pharmacological activities in different pathologies, including RA. Recent experimental studies have clarified several determinant cellular and molecular targets of BBR in RA, and provided novel evidence supporting the promising therapeutic potential of BBR to combat RA. In this review, we recapitulate the therapeutic potential of BBR and its mechanism of action in ameliorating RA, and discuss the modulation of gut microbiota by BBR during RA. Collectively, BBR might be a promising lead drug with multi-functional activities for the therapeutic strategy of RA. 10.1016/j.phrs.2021.105667
Berberine as a natural modulator of inflammatory signaling pathways in the immune system: Focus on NF-κB, JAK/STAT, and MAPK signaling pathways. Haftcheshmeh Saeed Mohammadian,Abedi Maliheh,Mashayekhi Kazem,Mousavi Mohammad Javad,Navashenaq Jamshid Gholizadeh,Mohammadi Asadollah,Momtazi-Borojeni Amir Abbas Phytotherapy research : PTR Three main inflammatory signaling pathways include nuclear factor-κB (NF-κB), Janus kinases/Signal transducer and activator of transcriptions (JAKs/STATs), and mitogen-activated protein kinases (MAPKs) play crucial roles in inducing, promoting, and regulating inflammatory responses in the immune system. Importantly, the breakdown of mechanisms that tightly regulate inflammatory signaling pathways can be the underlying cause of uncontrolled inflammatory responses and be associated with the generation and development of several inflammatory diseases. Hence, therapeutic strategies targeting inflammatory signaling pathways and their downstream components may promise to treat inflammatory diseases. Studies over the past two decades have provided important information on the polytrophic pharmacological and biochemical properties of berberine (BBR) as a naturally occurring compound, such as antioxidant, antitumor, antimicrobial, and antiinflammatory activates. Interestingly, the modulatory effects of BBR on inflammatory signaling cascades, which lead to the inhibition of inflammation, have been widely investigated in several in vitro and in vivo studies. For the first time, herein, this comprehensive review attempts to put together these studies and provide important insight into the modulatory effects of BBR on NF-κB, JAKs/STATs, and MAPKs signaling pathways in vitro in various types of immune cells and in vivo in several experimental inflammatory diseases. As the second achievement of this review, we also explore the therapeutic efficacy and antiinflammatory effects of BBR regarding its modulatory action. 10.1002/ptr.7407
Therapeutic Efficacies of Berberine against Neurological Disorders: An Update of Pharmacological Effects and Mechanisms. Cells Neurological disorders are ranked as the leading cause of disability and the second leading cause of death worldwide, underscoring an urgent necessity to develop novel pharmacotherapies. Berberine (BBR) is a well-known phytochemical isolated from a number of medicinal herbs. BBR has attracted much interest for its broad range of pharmacological actions in treating and/or managing neurological disorders. The discoveries in basic and clinical studies of the effects of BBR on neurological disorders in the last decade have provided novel evidence to support the potential therapeutical efficacies of BBR in treating neurological diseases. In this review, we summarized the pharmacological properties and therapeutic applications of BBR against neurological disorders in the last decade. We also emphasized the major pathways modulated by BBR, which provides firm evidence for BBR as a promising drug candidate for neurological disorders. 10.3390/cells11050796
Molecular updates on berberine in liver diseases: Bench to bedside. Bansod Sapana,Saifi Mohd Aslam,Godugu Chandraiah Phytotherapy research : PTR Liver diseases are life-threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug-induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR-γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation-based novel approaches are also summarized to overcome the clinical hurdles for BBR. 10.1002/ptr.7181
AMPK and its Activator Berberine in the Treatment of Neurodegenerative Diseases. Qin Siru,Tang Huiling,Li Wei,Gong Yinan,Li Shanshan,Huang Jin,Fang Yuxin,Yuan Wenjuan,Liu Yangyang,Wang Shenjun,Guo Yongming,Guo Yi,Xu Zhifang Current pharmaceutical design Neurodegenerative disorders are heterogeneous diseases associated with either acute or progressive neurodegeneration, causing the loss of neurons and axons in the central nervous system (CNS), showing high morbidity and mortality, and there are only a few effective therapies. Here, we summarized that the energy sensor adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and its agonist berberine can combat the common underlying pathological events of neurodegeneration, including oxidative stress, neuroinflammation, mitochondrial disorder, glutamate excitotoxicity, apoptosis, autophagy disorder, and disruption of neurovascular units. The abovementioned effects of berberine may primarily depend on activating AMPK and its downstream targets, such as the mammalian target of rapamycin (mTOR), sirtuin1 (SIRT1), nuclear factor erythroid-2 related factor-2 (Nrf2), nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), nicotinamide adenine dinucleotide (NAD+), and p38 mitogen-activated protein kinase (p38 MAPK). It is hoped that this review will provide a strong basis for further scientific exploration and development of berberine's therapeutic potential against neurodegeneration. 10.2174/1381612826666200523172334
Berberine inhibits breast carcinoma proliferation and metastasis under hypoxic microenvironment involving gut microbiota and endogenous metabolites. Pharmacological research A potential role of berberine, a benzyl isoquinoline alkaloid, in cancer therapy is apparent. Its underlying mechanisms of berberine against breast carcinoma under hypoxia have not been elucidated. We focused on the doubt how berberine restrains breast carcinoma under hypoxia in vitro and in vivo. A molecular analysis of the microbiome via 16 S rDNA gene sequencing of DNA from mouse faeces confirmed that the abundances and diversity of gut microbiota were significantly altered in 4T1/Luc mice with higher survival rate following berberine treatment. A metabolome analysis liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS) revealed that berberine regulated various endogenous metabolites, especially L-palmitoylcarnitine. Furthermore, the cytotoxicity of berberine was investigated in MDA-MB-231, MCF-7, and 4T1 cells. In vitro to simulate under hypoxic environment, MTT assay showed that berberine inhibited the proliferation of MDA-MB-231, MCF-7, and 4T1 cells with IC values of 4.14 ± 0.35 μM, 26.53 ± 3.12 μM and 11.62 ± 1.44 μM, respectively. Wound healing and trans-well invasion studies revealed that berberine inhibited the invasion and migration of breast cancer cells. RT-qPCR analysis shed light that berberine reduced the expression of hypoxia-inducible factor-1α (HIF-1α) gene. Immunofluorescence and western blot demonstrated that berberine decreased the expression of E-cadherin and HIF-1α protein. Taken together, these results provide evidence that berberine efficiently suppresses breast carcinoma growth and metastasis in a hypoxic microenvironment, highlighting the potential of berberine as a promising anti-neoplastic agent to combat breast carcinoma. 10.1016/j.phrs.2023.106817
Research progress on the pharmacological effects of berberine targeting mitochondria. Frontiers in endocrinology Berberine is a natural active ingredient extracted from the rhizome of , which interacts with multiple intracellular targets and exhibits a wide range of pharmacological activities. Previous studies have preliminarily confirmed that the regulation of mitochondrial activity is related to various pharmacological actions of berberine, such as regulating blood sugar and lipid and inhibiting tumor progression. However, the mechanism of berberine's regulation of mitochondrial activity remains to be further studied. This paper summarizes the molecular mechanism of the mitochondrial quality control system and briefly reviews the targets of berberine in regulating mitochondrial activity. It is proposed that berberine mainly regulates glycolipid metabolism by regulating mitochondrial respiratory chain function, promotes tumor cell apoptosis by regulating mitochondrial apoptosis pathway, and protects cardiac function by promoting mitophagy to alleviate mitochondrial dysfunction. It reveals the mechanism of berberine's pharmacological effects from the perspective of mitochondria and provides a scientific basis for the application of berberine in the clinical treatment of diseases. 10.3389/fendo.2022.982145
The pharmacological activity of berberine, a review for liver protection. Zhou Mengting,Deng Ying,Liu Meichen,Liao Li,Dai Xuyang,Guo Chaocheng,Zhao Xingtao,He Linfeng,Peng Cheng,Li Yunxia European journal of pharmacology Liver plays an important role in bile synthesis, metabolic function, degradation of toxins, new substances synthesis in body. However, hepatopathy morbidity and mortality are increasing year by year around the world, which become a major public health problem. Traditional Chinese medicine (TCM) has a prominent role in the treatment of liver diseases due to its definite curative effect and small side effects. The hepatoprotective effect of berberine has been extensively studied, so we comprehensively summarize the pharmacological activities of lipid metabolism regulation, bile acid adjustment, anti-inflammation, oxidation resistance, anti-fibrosis and anti-cancer and so on. Besides, the metabolism and toxicity of berberine and its new formulations to improve its effectiveness are expounded, providing a reference for the safe and effective clinical use of berberine. 10.1016/j.ejphar.2020.173655
The mechanism of berberine alleviating metabolic disorder based on gut microbiome. Frontiers in cellular and infection microbiology With socioeconomic advances and improved living standards, metabolic syndrome has increasingly come into the attention. In recent decades, a growing number of studies have shown that the gut microbiome and its metabolites are closely related to the occurrence and development of many metabolic diseases, and play an important role that cannot be ignored, for instance, obesity, type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease and others. The correlation between gut microbiota and metabolic disorder has been widely recognized. Metabolic disorder could cause imbalance in gut microbiota, and disturbance of gut microbiota could aggravate metabolic disorder as well. Berberine (BBR), as a natural ingredient, plays an important role in the treatment of metabolic disorder. Studies have shown that BBR can alleviate the pathological conditions of metabolic disorders, and the mechanism is related to the regulation of gut microbiota: gut microbiota could regulate the absorption and utilization of berberine in the body; meanwhile, the structure and function of gut microbiota also changed after intervention by berberine. Therefore, we summarize relevant mechanism research, including the expressions of nitroreductases-producing bacteria to promote the absorption and utilization of berberine, strengthening intestinal barrier function, ameliorating inflammation regulating bile acid signal pathway and axis of bacteria-gut-brain. The aim of our study is to clarify the therapeutic characteristics of berberine further and provide the theoretical basis for the regulation of metabolic disorder from the perspective of gut microbiota. 10.3389/fcimb.2022.854885
Neuroprotective potential of berberine in modulating Alzheimer's disease via multiple signaling pathways. Akbar Moazzama,Shabbir Anam,Rehman Kanwal,Akash Muhammad Sajid Hamid,Shah Muhammad Ajmal Journal of food biochemistry Berberine is one of the most important quinoline alkaloids, which has shown numerous pharmacological activities. There are pieces of evidence that berberine serves as a promising substance for treating Alzheimer's disease (AD). Recently, numerous studies on animal models have shown the neuroprotective role of berberine. AD is a complex disease having multiple pathological factors. Berberine restrains the deposition of amyloid plaques and neurofibrillary tangles. Substantial studies have demonstrated that berberine may also exhibit the protective effect against the risk factors associated with AD. This review illustrates the role of berberine in neuroinflammation, oxidative stress and its activity against acetylcholinesterase enzyme. It also focuses on the bioavailability and safety of berberine in AD. However, more investigations are required to explore the bioavailability and safety assessment of berberine and its new perspectives in limiting the AD-related pathogenesis and risk factors. PRACTICAL APPLICATIONS: Current therapeutic measures only provide symptomatic relief against AD by slowing memory loss, resolving thinking problems and behavioral issues. In recent past years, many biological actions and potential therapeutic applications have been observed by berberine particularly in neurological diseases. Berberine has been investigated by various researchers for its activity against AD. This review demonstrates a variety of mechanisms by which berberine imparts its neuroprotective roles and provides the possible mechanism of action of berberine by which it prevents the formation of neurofibrillary tangles and disaggregation of amyloid beta plaques in AD. It also focuses that berberine limits the neuroinflammation and oxidative stress in AD. Pre-clinical aspects of berberine against AD are also discussed. Eventually, a prospect is formulated that berberine might be a therapeutically significant agent for treating and preventing AD. 10.1111/jfbc.13936
Berberine on the Prevention and Management of Cardiometabolic Disease: Clinical Applications and Mechanisms of Action. Cao Richard Y,Zheng Yuntao,Zhang Ying,Jiang Lingling,Li Qing,Sun Wanqun,Gu Wenqin,Cao Weifeng,Zhou Linyan,Zheng Hongchao,Yang Jian The American journal of Chinese medicine Berberine is an alkaloid from several medicinal plants originally used to treat diarrhea and dysentery as a traditional Chinese herbal medicine. In recent years, berberine has been discovered to exhibit a wide spectrum of biological activities in the treatment of diverse diseases ranging from cancer and neurological dysfunctions to metabolic disorders and heart diseases. This review article summarizes the clinical practice and laboratory exploration of berberine for the treatment of cardiometabolic and heart diseases, with a focus on the novel insights and recent advances of the underlying mechanisms recognized in the past decade. Berberine was found to display pleiotropic therapeutic effects against dyslipidemia, hyperglycemia, hypertension, arrhythmia, and heart failure. The mechanisms of berberine for the treatment of cardiometabolic disease involve combating inflammation and oxidative stress such as inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9) activation, regulating electrical signals and ionic channels such as targeting human ether-a-go-go related gene (hERG) currents, promoting energy metabolism such as activating adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, modifying gut microbiota to promote transforming of berberine into its intestine-absorbable form, and interacting with non-coding RNAs via targeting multiple signaling pathways such as AMPK, mechanistic target of rapamycin (mTOR), etc. Collectively, berberine appears to be safe and well-tolerated in clinical practice, especially for those who are intolerant to statins. Knowledge from this field may pave the way for future development of more effective pharmaceutical approaches for managing cardiometabolic risk factors and preventing heart diseases. 10.1142/S0192415X21500762
The effect of berberine supplementation on obesity parameters, inflammation and liver function enzymes: A systematic review and meta-analysis of randomized controlled trials. Asbaghi Omid,Ghanbari Niloofar,Shekari Mahdi,Reiner Željko,Amirani Elaheh,Hallajzadeh Jamal,Mirsafaei Liaosadat,Asemi Zatollah Clinical nutrition ESPEN INTRODUCTION:So far, no study has summarized the findings on the effects of berberine intake on anthropometric parameters, C-reactive protein (CRP) and liver enzymes. This systematic review and meta-analysis were done based upon randomized controlled trials (RCTs) to analyze the effects of berberine on anthropometric parameters, CRP and liver enzymes. METHOD:Following databases were searched for eligible studies published from inception to 30 July 2019: MEDLINE, EMBASE, Web of Science, Cochrane Library, PubMed and Google scholar. Necessary data were extracted. Data were pooled by the inverse variance method and expressed as mean difference with 95% Confidence Intervals (95% CI). RESULT:12 studies were included. Berberine treatment moderately but significantly decreased body weight (WMD = -2.07 kg, 95% CI -3.09, -1.05, P < 0.001), body mass index (BMI) (WMD = -0.47 kg/m, 95% CI -0.70, -0.23, P < 0.001), waist circumference (WC) (WMD = -1.08 cm, 95% CI -1.97, -0.19, P = 0.018) and C-reactive protein (CRP) concentrations (WMD = -0.42 mg/L, 95% CI -0.82, -0.03, P = 0.034). However, berberine intake did not affect liver enzymes, including alanine aminotransferase (ALT) (WMD = -1.66 I/U, 95% CI -3.98, 0.65, P = 0.160) and aspartate aminotransferase (AST) (WMD = -0.87 I/U, 95% CI -2.56, 0.82, P = 0.311). CONCLUSION:This meta-analysis found a significant reduction of body weight, BMI, WC and CRP levels associated with berberine intake which may have played an indirect role in improved clinical symptoms in diseases with metabolic disorders. Berberine administration had no significant effect on ALT and AST levels. 10.1016/j.clnesp.2020.04.010
Berberine in the Treatment of Neurodegenerative Diseases and Nanotechnology Enabled Targeted Delivery. Mohi-Ud-Din Roohi,Mir Reyaz Hassan,Wani Taha Umair,Shah Abdul Jalil,Banday Nazia,Pottoo Faheem Hyder Combinatorial chemistry & high throughput screening BACKGROUND:Berberine (BBR), an alkaloidal compound found in many plants, is widely used for hundreds of years in the traditional system of Chinese medicine. OBJECTIVE/AIM:The present review is aimed to summarize the potential of Berberine in the amelioration of various neurological disorders. METHODS:The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Of late, researchers are more focused on its beneficial role in neurodegenerative diseases. RESULTS:BBR has proven its protective role in numerous neurotoxicity models including, oxygen-glucose deprivation, mercury-induced, neurodegenerative model by ibotenic acid, and hypoxia caused by COCl2. BBR treatment averts the generation of reactive oxygen species in the oxygen-glucose deprivation model. Further, it subdues cytochrome c along with the divulge of apoptosis-inducing factors that indicate its beneficial action in the management of stroke. BBR diminished hydrogen peroxide-induced neuronal damage by enhancing the PI3k / Akt / Nrf-2 based pathway and showed a preventive impact on neurites of SH-SY5Y cells by averting the formation of ROS and inhibiting apoptosis. The impact of BBR on neurological disorder using a transgenic AD type mouse strain (TgCRND8) showed a reduction in the piling up of amyloid-β plaque. In mice, administration of BBR in the dose range of 5-10m/kg has been reported to raise the levels of serotonin (47%), dopamine (31%), and norepinephrine (29%) in CNS to allay depression. CONCLUSION:The present review is aimed to summarize the potential of Berberine in the amelioration of various neurological disorders. 10.2174/1386207324666210804122539
Berberine protects against ischemia-reperfusion injury: A review of evidence from animal models and clinical studies. Liu Dai-Qiang,Chen Shu-Ping,Sun Jia,Wang Xiao-Mei,Chen Nan,Zhou Ya-Qun,Tian Yu-Ke,Ye Da-Wei Pharmacological research Ischemia-reperfusion (I/R) injury is accompanied with high morbidity and mortality and has seriously negative social and economic influences. Unfortunately, few effective therapeutic strategies are available to improve its outcome. Berberine is a natural medicine possessing multiple beneficial biological activities. Emerging evidence indicates that berberine has potential protective effects against I/R injury in brain, heart, kidney, liver, intestine and testis. However, up-to-date review focusing on the beneficial role of berberine against I/R injury is not yet available. In this paper, results from animal models and clinical studies are concisely presented and its mechanisms are discussed. We found that berberine ameliorates I/R injury in animal models via its anti-oxidant, anti-apoptotic and anti-inflammatory effects. Moreover, berberine also attenuates I/R injury by suppressing endoplasmic reticulum stress and promoting autophagy. Additionally, regulation of periphery immune system may also contributes to the beneficial effect of berberine against I/R injury. Although clinical evidence is limited, the current studies indicate that berberine may attenuate I/R injury via inhibiting excessive inflammatory response in patients. Collectively, berberine might be used as an alternative therapeutic strategy for the management of I/R injury. 10.1016/j.phrs.2019.104385
Berberine: Pharmacological Features in Health, Disease and Aging. Current medicinal chemistry BACKGROUND:Berberine is the main active compound of different herbs and is defined as an isoquinoline quaternary botanical alkaloid found in barks and roots of numerous plants. It exhibits a wide range of pharmacological effects, such as anti-obesity and antidiabetic effects. Berberine has antibacterial activity against a variety of microbiota, including many bacterial species, protozoa, plasmodia, fungi, and trypanosomes. OBJECTIVE:This review describes the role of berberine and its metabolic effects. It also discusses how it plays a role in glucose metabolism, fat metabolism, weight loss, how it modulates the gut microbiota, and what are its antimicrobial properties along with its potential side effects with maximal tolerable dosage. METHODS:Representative studies were considered and analyzed from different scientific databases, including PubMed and Web of Science, for the years 1982-2022. RESULTS:Literature analysis shows that berberine affects many biochemical and pharmacological pathways that theoretically yield a positive effect on health and disease. Berberine exhibits neuroprotective properties in various neurodegenerative and neuropsychological ailments. Despite its low bioavailability after oral administration, berberine is a promising tool for several disorders. A possible hypothesis would be the modulation of the gut microbiome. While the evidence concerning the aging process in humans is more limited, preliminary studies have shown positive effects in several models. CONCLUSION:Berberine could serve as a potential candidate for the treatment of several diseases. Previous literature has provided a basis for scientists to establish clinical trials in humans. However, for obesity, the evidence appears to be sufficient for hands-on use. 10.2174/0929867330666230207112539
Berberine: A Promising Natural Isoquinoline Alkaloid for the Development of Hypolipidemic Drugs. Li Dong-Dong,Yu Pan,Xiao Wei,Wang Zhen-Zhong,Zhao Lin-Guo Current topics in medicinal chemistry Berberine, as a representative isoquinoline alkaloid, exhibits significant hypolipidemic activity in both animal models and clinical trials. Recently, a large number of studies on the lipid-lowering mechanism of berberine and studies for improving its hypolipidemic activity have been reported, but for the most part, they have been either incomplete or not comprehensive. In addition, there have been a few specific reviews on the lipid-reducing effect of berberine. In this paper, the physicochemical properties, the lipid-lowering mechanism, and studies of the modification of berberine all are discussed to promote the development of berberine as a lipid-lowering agent. Subsequently, this paper provides some insights into the deficiencies of berberine in the study of lipid-lowering drug, and based on the situation, some proposals are put forward. 10.2174/1568026620666200908165913
Berberine and its derivatives represent as the promising therapeutic agents for inflammatory disorders. Lu Qiukai,Fu Yifan,Li Heng Pharmacological reports : PR Berberine, with the skeleton of quaternary ammonium, has been considered as the well-defined natural product in treating multiple diseases, including inflammation, acute and chronic infection, autoimmune diseases, and diabetes. However, due to the low bioavailability and systemic exposure, broad clinical applications of berberine have been largely impeded. Numerous studies have been conducted to further explore the therapeutic capacities of berberine in preclinical and clinical trials. Over the past, berberine and its derivatives have been shown to possess numerous pharmacological activities, as evidenced in intestinal, pulmonary, skin, and bone inflammatory disorders. In the present review, the pharmacological impact of berberine on inflammatory diseases are fully discussed, with indication that berberine and its potential derivatives represent promising natural therapeutic agents with anti-inflammatory properties. 10.1007/s43440-021-00348-7
Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence. Xu Xinmei,Yi Huan,Wu Jiasi,Kuang Tingting,Zhang Jing,Li Qi,Du Huan,Xu Tong,Jiang Guihua,Fan Gang Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The increased incidence of metabolic diseases (e.g., diabetes and obesity) has seriously affected human health and life safety worldwide. It is of great significance to find effective drugs from natural compounds to treat metabolic diseases. Berberine (BBR), an important quaternary benzylisoquinoline alkaloid, exists in many traditional medicinal plants. In recent years, BBR has received widespread attention due to its good potential in the treatment of metabolic diseases. In order to promote the basic research and clinical application of BBR, this review provides a timely and comprehensive summary of the pharmacological and clinical advances of BBR in the treatment of five metabolic diseases, including type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, hyperlipidemia, and gout. Both animal and clinical studies have proved that BBR has good therapeutic effects on these five metabolic diseases. The therapeutic effects of BBR are based on regulating various metabolic aspects and pathophysiological procedures. For example, it can promote insulin secretion, improve insulin resistance, inhibit lipogenesis, alleviate adipose tissue fibrosis, reduce hepatic steatosis, and improve gut microbiota disorders. Collectively, BBR may be a good and promising drug candidate for the treatment of metabolic diseases. More studies, especially clinical trials, are needed to further confirm its molecular mechanisms and targets. In addition, large-scale, long-term and multi-center clinical trials are necessary to evaluate the efficacy and safety of BBR in the treatment of these metabolic diseases. 10.1016/j.biopha.2020.110984
Berberine for bone regeneration: Therapeutic potential and molecular mechanisms. Zhang Yuhan,Ma Jinlong,Zhang Weifen Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Berberine is a quaternary ammonium isoquinoline alkaloid, mainly extracted from plants berberaceae, papaveraceae, ranunculaceae and rutaceae such as coptis chinensis Franch, Phellodendron chinense, and berberis pruinosa. The plants are extensively used in traditional medicine for treating infection, diabetes, arrhythmia, tumor, osteoporosis et al. Pharmacological studies showed berberine has effects of anti-inflammation, anti-tumor, lower blood lipid, lower blood glucose, anti-osteoporosis, anti-osteoarthritis et al. AIM OF THE STUDY: This review aims to summarize the application of natural herbs that contain berberine, the further use and development of berberine, the effects as well as mechanism of berberine on osteoblasts and osteoclasts, the recent advances of in vivo studies, in order to provide a scientific basis for its traditional uses and to prospect of the potential applications of berberine in clinics. METHOD:The research was achieved by retrieving from the online electronic database, including PubMed, Web of Science, Google Scholar and China national knowledge infrastructure (CNKI). Patents, doctoral dissertations and master dissertations are also searched. RESULTS:Berberine has a long history of medicinal use to treat various diseases including bone disease in China. Recent studies have defined its function in promoting bone regeneration and great potential in developing new drugs. But the systemic mechanism of berberine on bone regeneration still needs more research to clarify. CONCLUSION:This review has systematically summarized the application, pharmacological effects, mechanism as well as in vivo studies of berberine and herbs which contain berberine. Berberine has a definite effect in promoting the proliferation and differentiation of osteoblasts as well as inhibiting the production of osteoclasts to promote bone regeneration. However, the present studies about the system mechanisms and pharmacological activity of berberine were incomplete. Applying berberine for new drug development remains an exciting and promising alternative to bone regeneration engineering, with broad potential for therapeutic and clinical practice. 10.1016/j.jep.2021.114249
Berberine: A Traditional Natural Product With Novel Biological Activities. Alternative therapies in health and medicine CONTEXT:Having been used for thousands of years to treat gastrointestinal diseases, the natural isoquinoline alkaloid, berberine, has exhibited a wide spectrum of biochemical and pharmacological effects in studies of recent years. OBJECTIVE:The review intended to examine the many novel bioactivities of berberine, including antidiabetic, anticancer, neuroprotective, anti-inflammatory, and anti-atherosclerotic actions. DESIGN:The research team searched the MEDLINE database using PubMed, using different keyword combinations, including berberine AND diabetes, berberine AND cancer, berberine AND (neuron OR brain), berberine AND inflammation, and "berberine AND atherosclerosis to find studies evaluating the various effects exerted berberine. CONCLUSION:Berberine is a promising multipotent agent to combat diabetes, cancer, Alzheimer's disease, and other diseases.
Integrated lipidomics and network pharmacology analysis to reveal the mechanisms of berberine in the treatment of hyperlipidemia. Journal of translational medicine BACKGROUND:Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma Coptis, is widely used in the treatment of hyperlipidemia (HLP) in China. At present, the efficacy of BBR against HLP is relatively clear, but there are few researches on its mechanism. The purpose of this study was to evaluate the potentially beneficial role of BBR in HLP hamster models, as well as investigate its possible mechanisms and potential lipid biomarkers in combination with network pharmacology. METHODS:HLP hamster model was induced by high-fat diet. Hematoxylin-eosin (HE) staining was used to determine the degree of hepatic pathological injury. Liquid chromatography-mass spectrometry was used to analyze lipid metabolism profiles of liver samples, and multiple statistical analysis methods were used to screen and identify lipid biomarkers. The possible molecular mechanism was unraveled by network pharmacology. RESULTS:The results showed that 13 metabolites, including CE (16:1), HexCer (D18:1/19:0) and LPC (O-22:0) were biomarkers of BBR regulation. CHPT1, PLA2G4A, LCAT and UGCG were predicted as the lipid-linked targets of BBR against HLP, whilst glycerophospholipid and sphingolipid metabolism were the key pathways of BBR against HLP. CONCLUSIONS:In summary, this study provides new insights into the protective mechanism of BBR against HLP through network pharmacology and lipidomic approaches. 10.1186/s12967-022-03623-0
Protective effect of berberine in diabetic nephropathy: A systematic review and meta-analysis revealing the mechanism of action. Pharmacological research Coptis Chinensis Franch is widely used in the treatment of diabetes, and berberine is the primary bioactive component in it. Evidence from previous studies has shown that berberine supplementation is effective for treating diabetic nephropathy (DN) in animal models. In this systematic review and meta-analysis, we evaluated the effects and potential mechanisms of action of berberine in animal models of DN. Relevant studies were searched from the English language databases PubMed, Web of Science, and Embase starting from the establishment of the database till June 2022. Twenty-five studies were included, and the risk of bias tool from SYRCLE was used to assess the methodological quality. Statistical analysis was conducted using STATA 15.1. Fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (SCR), and the kidney index (KI) were the primary outcomes to be analyzed. The overall results showed that berberine improves the indicators of renal function, such as BUN, SCR, proteinuria, and KI. Meanwhile, berberine also improved inflammatory indicators, such as IL-6 and TNF-α, and oxidative stress indicators, such as the superoxide dismutase activity and malondialdehyde content. Additionally, berberine lowered the levels of known risk factors, including triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL). These beneficial effects of berberine in DN may be related to its anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. However, to assess the anti-diabetic nephropathy effects and safety of berberine in a more accurate manner, additional large-scale, long-term, and high-quality preclinical trials are needed to confirm these findings before clinical application. 10.1016/j.phrs.2022.106481
Berberine as a Potential Anticancer Agent: A Comprehensive Review. Rauf Abdur,Abu-Izneid Tareq,Khalil Anees Ahmed,Imran Muhammad,Shah Zafar Ali,Emran Talha Bin,Mitra Saikat,Khan Zidan,Alhumaydhi Fahad A,Aljohani Abdullah S M,Khan Ishaq,Rahman Md Mominur,Jeandet Philippe,Gondal Tanweer Aslam Molecules (Basel, Switzerland) Berberine (BBR), a potential bioactive agent, has remarkable health benefits. A substantial amount of research has been conducted to date to establish the anticancer potential of BBR. The present review consolidates salient information concerning the promising anticancer activity of this compound. The therapeutic efficacy of BBR has been reported in several studies regarding colon, breast, pancreatic, liver, oral, bone, cutaneous, prostate, intestine, and thyroid cancers. BBR prevents cancer cell proliferation by inducing apoptosis and controlling the cell cycle as well as autophagy. BBR also hinders tumor cell invasion and metastasis by down-regulating metastasis-related proteins. Moreover, BBR is also beneficial in the early stages of cancer development by lowering epithelial-mesenchymal transition protein expression. Despite its significance as a potentially promising drug candidate, there are currently no pure berberine preparations approved to treat specific ailments. Hence, this review highlights our current comprehensive knowledge of sources, extraction methods, pharmacokinetic, and pharmacodynamic profiles of berberine, as well as the proposed mechanisms of action associated with its anticancer potential. The information presented here will help provide a baseline for researchers, scientists, and drug developers regarding the use of berberine as a promising candidate in treating different types of cancers. 10.3390/molecules26237368
Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics. Feng Xiaojun,Sureda Antoni,Jafari Samineh,Memariani Zahra,Tewari Devesh,Annunziata Giuseppe,Barrea Luigi,Hassan Sherif T S,Šmejkal Karel,Malaník Milan,Sychrová Alice,Barreca Davide,Ziberna Lovro,Mahomoodally Mohamad Fawzi,Zengin Gokhan,Xu Suowen,Nabavi Seyed Mohammad,Shen Ai-Zong Theranostics Cardiovascular and metabolic diseases (CVMD) are the leading causes of death worldwide, underscoring the urgent necessity to develop new pharmacotherapies. Berberine (BBR) is an eminent component of traditional Chinese and Ayurvedic medicine for more than 2000 years. Recently, BBR has attracted much interest for its pharmacological actions in treating and/or managing CVMD. Recent discoveries of basic, translational and clinical studies have identified many novel molecular targets of BBR (such as AMPK, SIRT1, LDLR, PCSK9, and PTP1B) and provided novel evidences supporting the promising therapeutic potential of BBR to combat CVMD. Thus, this review provides a timely overview of the pharmacological properties and therapeutic application of BBR in CVMD, and underlines recent pharmacological advances which validate BBR as a promising lead drug against CVMD. 10.7150/thno.30787
Berberine pharmacology and the gut microbiota: A hidden therapeutic link. Habtemariam Solomon Pharmacological research Berberine is a natural pentacyclic isoquinoline alkaloid that has been isolated as the principal component of many popular medicinal plants such as the genus Berberis, Coptis and Hydrastis. The multifunctional nature of berberine as a therapeutic agent is an attribute of its diverse effects on enzymes, receptors and cell signalling pathways. Through specific and general antioxidant and anti-inflammatory mechanisms, its polypharmacology has been established. Intriguingly, this is despite the poor bioavailability of berberine in animal models and hence begging the question how it induces its reputed effects in vivo. A growing evidence now suggest the role of the gut microbiota, the so-called the hidden organ, as targets for the multifunctional role of berberine. Evidences are herein scrutinised to show that the structural and numerical changes in the gut microbiota under pathological conditions are reversed by berberine. Examples in the pharmacokinetics field, obesity, hyperlipidaemia, diabetes, cancer, inflammatory disease conditions, etc. are used to show the link between the gut microbiota and the polypharmacology of berberine. 10.1016/j.phrs.2020.104722
Biological properties and clinical applications of berberine. Song Danyang,Hao Jianyu,Fan Daiming Frontiers of medicine Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases. 10.1007/s11684-019-0724-6