Metformin strengthens uroepithelial immunity against E. coli infection.
Majhi Rakesh Kumar,Mohanty Soumitra,Kamolvit Witchuda,White John Kerr,Scheffschick Andrea,Brauner Hanna,Brauner Annelie
Urinary tract infection frequently caused by E. coli is one of the most common bacterial infections. Increasing antibiotic resistance jeopardizes successful treatment and alternative treatment strategies are therefore mandatory. Metformin, an oral antidiabetic drug, has been shown to activate macrophages in the protection against certain infecting microorganisms. Since epithelial cells often form the first line of defense, we here investigated the effect on uroepithelial cells during E. coli infection. Metformin upregulated the human antimicrobial peptides cathelicidin LL-37 and RNase7 via modulation of the TRPA1 channel and AMPK pathway. Interestingly, metformin stimulation enriched both LL-37 and TRPA1 in lysosomes. In addition, metformin specifically increased nitric oxide and mitochondrial, but not cytosolic ROS. Moreover, metformin also triggered mRNA expression of the proinflammatory cytokines IL1B, CXCL8 and growth factor GDF15 in human uroepithelial cells. The GDF15 peptide stimulated macrophages increased LL-37 expression, with increased bacterial killing. In conclusion, metformin stimulation strengthened the innate immunity of uroepithelial cells inducing enhanced extracellular and intracellular bacterial killing suggesting a favorable role of metformin in the host defense.
Conjugating berberine to a multidrug efflux pump inhibitor creates an effective antimicrobial.
Ball Anthony R,Casadei Gabriele,Samosorn Siritron,Bremner John B,Ausubel Frederick M,Moy Terence I,Lewis Kim
ACS chemical biology
In bacteria, multidrug-resistance pumps (MDRs) confer resistance to chemically unrelated amphipathic toxins. A major challenge in developing efficacious antibiotics is identifying antimicrobial compounds that are not rapidly pumped out of bacterial cells. The plant antimicrobial berberine, the active component of the medicinal plants echinacea and golden seal, is a cation that is readily extruded by bacterial MDRs, thereby rendering it relatively ineffective as a therapeutic agent. However, inhibition of MDR efflux causes a substantial increase in berberine antimicrobial activity, suggesting that berberine and potentially many other compounds could be more efficacious if an effective MDR pump inhibitor could be identified. Here we show that covalently linking berberine to INF 55 , an inhibitor of Major Facilitator MDRs, results in a highly effective antimicrobial that readily accumulates in bacteria. The hybrid molecule showed good efficacy in a Caenorhabditis elegans model of enterococcal infection, curing worms of the pathogen.
Study on the anti-inflammatory action of Berberis vulgaris root extract, alkaloid fractions and pure alkaloids.
Ivanovska N,Philipov S
International journal of immunopharmacology
Extracts obtained from the roots of Berberidaceae species have been used in Eastern and Bulgarian folk medicine in rheumatic and other chronic inflammatory disorders. The investigations of the chemical composition and immunological properties show that their activity is mainly due to the alkaloid constituents. In the present study the anti-inflammatory properties of total ethanol extract (TEE), three alkaloid fractions, a major alkaloid berberine and oxyacanthine isolated from Berberis vulgaris roots were compared. All these were applied in acute inflammation (carrageenan- and zymosan-induced paw oedema), as the TEE showed the highest reducing effect. Their ability to alter in vivo and in vitro complement activity was determined. Also, the TEE was most effective in a chronic inflammatory model of adjuvant arthritis. The protoberberine fractions Bv2, Bv3 and berberine suppressed a delayed type hypersensitivity (DTH) reaction. Fraction Bv1 and berberine diminished antibody response against SRBC in vivo. The in vitro treatment of splenocytes with berberine showed that the anti-SRBC antibody synthesis was influenced in a different manner depending on the time course of its application. Oxyacanthine was less effective than berberine in the tests used.
Antimicrobial properties of alkaloids from Xanthorhiza simplicissima.
Okunade A L,Hufford C D,Richardson M D,Peterson J R,Clark A M
Journal of pharmaceutical sciences
The organic extract of the whole plant Xanthorhiza simplicissima was found to exhibit good activity against the AIDS-related opportunistic pathogens Candida albicans, Cryptococcus neoformans, and Mycobacterium intracellularae. Bioassay-directed fractionation of the extract led to the isolation of the known alkaloid berberine as the major active component. A second alkaloid of the isohomoprotoberberine family, puntarenine, was isolated from this plant family for the first time. Puntarenine also showed marginal activity against the dermatophytic fungus Trichophyton mentagrophytes and the yeast Saccharomyces cerevisiae.
A patent review of berberine and its derivatives with various pharmacological activities (2016-2020).
Expert opinion on therapeutic patents
INTRODUCTION:Berberine (BBR), as one of the outstanding representatives of isoquinoline alkaloids, has been used as an antibacterial drug for a long time in China since ancient times. Currently, a large number of studies have been reported that berberine has a wide spectrum of pharmacological activities, such as anti-tumor, anti-inflammatory, hypoglycemic, hypolipidemic, anti-obesity, and the like. AREAS COVERED:This review systematically discussed important patents on berberine and berberine derivatives in terms of pharmacological activity between 2016 and 2020. These patents were mainly searched through the European Patent Office database and Web of Science. These berberine patents (~41) cover a wide range of applications, mainly including antitumor, anti-inflammatory, antibacterial, anti-metabolic disorder, and other newly reported pharmacological activities. EXPERT OPINION:Berberine is an important lead compound with great potential for optimization in drug development. However, there is a lack of research related to the biomolecular targets of BBR, which directly restricts the development of berberine in the pharmaceutical field. The problems involved with poor bioavailability and cytotoxicity are also worth considering in the development of berberine-based drugs. Accordingly, the increasing number of patents involving biomolecular targets in BBR's patent applications will be published as its related pharmacological mechanisms are further deciphered.
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.
An insight into the medicinal attributes of berberine derivatives: A review.
Gaba Sobhi,Saini Anjali,Singh Gurpreet,Monga Vikramdeep
Bioorganic & medicinal chemistry
In the last few decades, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding perpetually. Berberine, with remarkable therapeutic diversity, is a plant derived isoquinoline alkaloid which is widely used as a traditional medicine in China. Berberine has been tackled as a fascinating pharmacophore to make great contributions to the discovery and development of new therapeutic agents against variegated diseases. Despite its tremendous therapeutic potential, clinical utility of this alkaloid was significantly compromised due to undesirable pharmacokinetic properties. To overcome this limitation, several structural modifications were performed on this scaffold to improve its therapeutic efficacy. The collective efforts of the community have achieved the tremendous advancements, bringing berberine to clinical use and discovering new therapeutic opportunities by structural modifications on the berberine scaffold. In this review, recent advancements in the medicinal chemistry of berberine and its derivatives in the last few years (2016-2020) have been compiled to represent inclusive data associated with various biological activities of this alkaloid. The comprehensive structure-activity relationship studies along with molecular modelling and mechanistic studies have also been summarized. This article would be highly helpful for the scientific community to get better insight into medicinal research of berberine and become a compelling guide for the rational design of berberine based compounds.
A small molecule compound berberine as an orally active therapeutic candidate against COVID-19 and SARS: A computational and mechanistic study.
Wang Zhen-Zhen,Li Kun,Maskey Anish R,Huang Weihua,Toutov Anton A,Yang Nan,Srivastava Kamal,Geliebter Jan,Tiwari Raj,Miao Mingsan,Li Xiu-Min
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.
Enhanced in vitro antimicrobial activity of amphotericin B with berberine against dual-species biofilms of Candida albicans and Staphylococcus aureus.
Gao S,Zhang S,Zhang S
Journal of applied microbiology
AIMS:Multi-species biofilms formed by fungi and bacteria are clinically common and confer the commensal micro-organisms with protection against antimicrobial therapies. Previously, the plant alkaloid berberine was reported to show antimicrobial efficacy to eliminate bacterial and fungal biofilms. In this study, the combination of berberine and amphotericin B, an antifungal agent, was evaluated against dual-species Candida albicans/Staphylococcus aureus biofilms. METHODS AND RESULTS:Combinatorial treatment by berberine and amphotericin B significantly reduced the biomass and viability of residing species in biofilms. Moreover, morphological examination revealed hyphal filamentation of C. albicans and coadhesion between C. albicans/S. aureus were considerably impaired by the treatment. These effects coincided with the reduced expression of cell surface components and quorum-sensing-related genes in both C. albicans and S. aureus. Additionally, in C. albicans, the core transcription factors for controlling biofilm formation together with a crucial component of dual-species biofilms were also downregulated. CONCLUSIONS:These results demonstrated synergistic effects of berberine and amphotericin B against C. albicans/S. aureus dual-species biofilms. SIGNIFICANCE AND IMPACT OF THE STUDY:This study confirms the potential of berberine and amphotericin B for treating the C. albicans/S. aureus biofilms related infections and reveals molecular basis for the efficacy of combinatorial treatment.
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.
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.
The use of predictive scores in the management of patients with carbapenem-resistant Klebsiella pneumoniae infection.
Giannella Maddalena,Pascale Renato,Gutiérrez-Gutiérrez Belén,Cano Angela,Viale Pierluigi
Expert review of anti-infective therapy
INTRODUCTION:Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections are associated with high morbidity and mortality rates. A therapeutic approach based on the patient risk stratification could improve outcome and avoid antibiotic misuse. Areas covered: English literature search, from 2008 to 2018, was done using PubMed database. Risk factors for developing CR-KP infection in several settings were reviewed. Since, rectal carriage was a main risk factor for developing infection, we revised in deep clinical score to predict infection among colonized patients. Furthermore, we investigated overall and treatment-related risk factors for poor outcome in patients with CR-KP infection, in particular the carbapenem producing Enterobacteriacieae (CPE)-INCREMENT score. Finally, an algorithm, based on such scores, for the therapeutic management of patients with CR-KP colonization was commented. Expert opinion: The therapeutic approach analyzed in this review could help physicians to avoid antibiotic overuse as well as to start promptly with the most appropriate antibiotic regimen. However, it has to be validated in further studies, mainly among special population such as immunocompromised patients. The availability of new drugs, fast microbiology, and analysis of gut microbiome could significantly improve the management of CR-KP colonized and/or infected patients.
Gold Nanoparticles Cure Bacterial Infection with Benefit to Intestinal Microflora.
Li Juanjuan,Cha Ruitao,Zhao Xiaohui,Guo Hongbo,Luo Huize,Wang Mingzheng,Zhou Fengshan,Jiang Xingyu
Antibiotics that are most used to cure bacterial infections in the clinic result in the imbalance of intestinal microflora, destroy the intestinal barrier, and induce bacterial resistance. There is an urgent need for antibacterial agent therapy for bacterial infections that does not destroy intestinal microflora. Herein, we applied 4,6-diamino-2-pyrimidinethiol (DAPT)-coated Au nanoparticles (D-Au NPs) for therapy of bacterial infection induced by Escherichia coli ( E. coli) in the gut. We cultured D-Au NPs and E. coli in an anaerobic atmosphere to evaluate their bactericidal effect. We studied the microflora, distribution of Au, and biomarkers in mice after a 28-day oral administration to analyze the effect of Au NPs on mice. D-Au NPs cured bacterial infections more effectively than levofloxacin without harming intestinal microflora. D-Au NPs showed great potential as alternatives to oral antibiotics.
Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats.
Zhang Xu,Zhao Yufeng,Xu Jia,Xue Zhengsheng,Zhang Menghui,Pang Xiaoyan,Zhang Xiaojun,Zhao Liping
Accumulating evidence suggests that the gut microbiota is an important factor in mediating the development of obesity-related metabolic disorders, including type 2 diabetes. Metformin and berberine, two clinically effective drugs for treating diabetes, have recently been shown to exert their actions through modulating the gut microbiota. In this study, we demonstrated that metformin and berberine similarly shifted the overall structure of the gut microbiota in rats. Both drugs showed reverting effects on the high-fat diet-induced structural changes of gut microbiota. The diversity of gut microbiota was significantly reduced by both berberine- and metformin-treatments. Nearest shrunken centroids analysis identified 134 operational taxonomic units (OTUs) responding to the treatments, which showed close associations with the changes of obese phenotypes. Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteriodes, Blautia, Butyricoccus, and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin. Taken together, our findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.
Fecal Microbiota of Diarrhea-Predominant Irritable Bowel Syndrome Patients Causes Hepatic Inflammation of Germ-Free Rats and Berberine Reverses It Partially.
Jia Qiong,Zhang Lu,Zhang Jindong,Pei Fei,Zhu Shiwei,Sun Qinghua,Duan Liping
BioMed research international
Effects of the microbiome associated with diarrhea-predominant irritable bowel syndrome (IBS-D) on the gut have been reported, but no study has reported the effects of the IBS-D gut microbiome on the liver. We transplanted the fecal microbiota from an IBS-D patient and from a healthy volunteer to GF rats. The hepatic inflammation, serum biochemical parameters and metabolome, fecal microbiota profile, fecal short-chain fatty acids (SCFAs), and correlations among them before and after berberine intervention were assessed. Compared with the healthy control fecal microbiome transplantation (FMT) rats, the fecal microbiota of IBS-D patients induces significant Kupffer cell hyperplasia, hepatic sinusoid hypertrophy, and elevated levels of hepatic tumor necrosis factor- and interferon- and decreases the synthesis of ALB in GF rats. This is possibly related to and attributable to fecal formate, acetate, and propionate levels, which are associated with the host linoleic acid pathway. Berberine can partially reverse the Kupffer cell hyperplasia, , fecal formate, acetate, and propionate by modulating the gut microbiome composition. These results may imply that IBS-D not only is an intestinal functional disorder but can cause liver inflammation, thus providing some implications regarding the clinical cognition and treatment of IBS-D.
The antibacterial mechanism of berberine against Actinobacillus pleuropneumoniae.
Kang Shuai,Li Zhengwen,Yin Zhongqiong,Jia Renyong,Song Xu,Li Li,Chen Zhenzhen,Peng Lianci,Qu Jing,Hu Zhiqiang,Lai Xin,Wang Guangxi,Liang Xiaoxia,He Changliang,Yin Lizi
Natural product research
This study demonstrated berberine to be a potential natural compound against Actinobacillus pleuropneumoniae. Liquid doubling dilution, transmission electron microscopy (TEM), SDS-PAGE and 4',6-diamidino-2-phenylindole (DAPI) staining were employed to elucidate the antibacterial activity and mechanism of berberine. The minimal inhibitory concentration of berberine was 0.3125 mg/mL, and time-kill curves showed concentration and time dependence. The TEM micrographs displayed damaged cell wall, concentrated cytoplasm, cytoplasmic content leakage and cell death. SDS-PAGE and DAPI assays revealed that berberine can restrain DNA and protein syntheses. Berberine inhibited the synthesis of proteins associated with the growth and cleavage of bacteria and then blocked the division and development of bacteria. The compound ultimately induced cytoplasm pyknosis and bacterial death.
Advances in the study of berberine and its derivatives: a focus on anti-inflammatory and anti-tumor effects in the digestive system.
Zou Kun,Li Zhao,Zhang Yong,Zhang Hao-Yue,Li Bo,Zhu Wei-Liang,Shi Ji-Ye,Jia Qi,Li Yi-Ming
Acta pharmacologica Sinica
It has been widely recognized that inflammation, particularly chronic inflammation, can increase the risk of cancer and that the simultaneous treatment of inflammation and cancer may produce excellent therapeutic effects. Berberine, an alkaloid isolated from Rhizoma coptidis, has broad applications, particularly as an antibacterial agent in the clinic with a long history. Over the past decade, many reports have demonstrated that this natural product and its derivatives have high activity against both cancer and inflammation. In this review, we summarize the advances in studing berberine and its derivatives as anti-inflammatory and anti-tumor agents in the digestive system; we also discuss their structure-activity relationship. These data should be useful for the development of this natural product as novel anticancer drugs with anti-inflammation activity.
Comprehensive evaluation of SCFA production in the intestinal bacteria regulated by berberine using gas-chromatography combined with polymerase chain reaction.
Wang Lu-Lu,Guo Hui-Hui,Huang Shuai,Feng Chen-Lin,Han Yan-Xing,Jiang Jian-Dong
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Short-chain fatty acids (SCFAs) of intestine microbial have caught accumulating attention for their beneficial effects on human health. Botanic compounds with low bioavailability such as berberine (BBR) and resveratrol might interact with intestinal microbial ecosystem and promote gut bacteria to produce SCFA, which contribute to their biological effects. In the present study, a comprehensive assay system was built to detect SCFAs production in intestinal bacteria, in which stringent anaerobic culture was applied for in vitro bacterial fermentation, followed by direct-injection GC detection (chemical detection) in combination with real time polymerase chain reaction (RT-PCR, biological detection). BBR was used as positive reference. The direct injection GC method was calibrated and successfully applied to analyze the concentration of SCFAs in gut microbiota and BBR was proved to be effective in the dose- and time-dependent up-regulation of SCFAs production. As compared to the saline group, the concentration of acetic acid, propionate acid and butyric acid (the main SCFAs in gut microbiota) were increased by 17.7%, 11.1% and 30.5%, respectively, after incubating intestinal bacteria with 20μg/mL BBR for 24h. The increase reached to 34.9%, 22.4% and 51.6%, respectively when the BBR was 50μg/mL. Additionally, consensus-degenerate hybrid oligonucleotide primers (CODEHOPs) were designed for the detection of acetate kinase (ACK), Methylmalonyl-CoA decarboxylase (MMD) and butyryl-CoA: acetate-CoA transferase (BUT), as they are the key enzymes in the synthetic pathway for acetic acid, propionate acid and butyric acid, respectively. After 24hr's incubation, BBR was shown to promote the gene expression of ACK, MMD and BUT significantly (86.5%, 27.2% and 60.4%, respectively, with 20μg/mL BBR; 130.2%, 84.2% and 98.4%, respectively, with 50μg/mL BBR), showing a solid biological support for the chemical detection. This comprehensive assay system might be useful in identifying SCFAs promoting agents with information on their mechanism.
Berberine for Appetite Suppressant and Prevention of Obesity.
Park Hyun-Jung,Jung EunYee,Shim Insop
BioMed research international
Berberine (BBR), a natural plant product, has been shown to have antidiabetic, cholesterol-reducing effects. To investigate the action of BBR as appetite suppressants, two experimental protocols were performed. In the first experiment, the mice were fed either a normal-chow diet or a high-fat diet (HF). The mice received daily intraperitoneal injections of BBR (10 mg/kg or saline at 1 ml/kg) for 3 weeks. To determine the antiobesity effects of BBR, the food consumption, body weight, fat contents, serum leptin, and glucose level were investigated. In the second experiment, we set out to validate the effect of BBR on central neuropeptide Y (NPY) stimulated rats. Experiments were carried out in 24-hour fasted rats, and then food intake and glucose level were subsequently recorded for 1 hour. The experimental groups were subdivided into the intra-3rd ventricular microinjections of ACSF (artificial cerebrospinal fluid), neuropeptide Y (NPY; 100 nM), NPY+BBR (10 nM), and NPY+BBR (100 nM) group. And then the blood glucose level was examined. In the first experiment, treatment with BBR in the HF diet mice reduced food intake, body weight, fat contents, serum leptin, and glucose level. In the second experiment, the NPY-injected group increased food intake by 39.3%, and food intake was reduced in the BBR group by 47.5%, compared with the ACSF-injected group. Also, the serum glucose level in the NPY+BBR (100 nM) group was significantly lower than that in the NPY (100 nM) group. The results suggest that BBR improved lipid dysregulation in obesity by controlling the central obesity related pathway.
Berberine inhibits Chlamydia pneumoniae infection-induced vascular smooth muscle cell migration through downregulating MMP3 and MMP9 via PI3K.
Ma Lu,Zhang Lijun,Wang Beibei,Wei Junyan,Liu Jingya,Zhang Lijun
European journal of pharmacology
The mechanisms by which Chlamydia pneumoniae infection promote vascular smooth muscle cell (VSMC) migration required in the development of atherosclerosis have not yet been fully clarified. Matrix metalloproteinases (MMPs) have important roles in VSMC migration. However, it is still unknown whether MMPs are involved in C. pneumoniae infection-induced VSMC migration. In addition, whether berberine can exert its inhibitory effects on the infection-induced VSMC migration also remains unclear. Accordingly, we investigated the effects of berberine on C. pneumoniae infection-induced VSMC migration and explored the possible mechanisms involved in this process. Herein, we found that C. pneumoniae infection could induce VSMC migration through Matrigel-coated membrane (P<0.05), which can be significantly inhibited by the broad-spectrum MMP inhibitor GM6001 (P<0.05). Our results also showed that C. pneumoniae infection upregulated both mRNA and protein expressions of MMP3 and MMP9 (P<0.05). The specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 significantly suppressed the increases in MMP3 and MMP9 protein expressions induced by C. pneumoniae infection (P<0.05). Further experiments showed that berberine significantly attenuated C. pneumoniae infection-induced VSMC migration (P<0.05). Moreover, berberine suppressed the protein expressions of MMP3 and MMP9 caused by C. pneumoniae infection in a dose-dependent manner (P<0.05). C. pneumoniae infection-induced increase in the phosphorylation level of Akt at Ser473 was inhibited by the treatment with berberine (P<0.05). Taken together, our data suggest that berberine inhibits C. pneumoniae infection-induced VSMC migration by downregulating the expressions of MMP3 and MMP9 via PI3K.
In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumoniae.
Zhou Xiao-Yuan,Ye Xiao-Guang,He Li-Ting,Zhang Su-Rong,Wang Ruo-Lun,Zhou Jun,He Zhuo-Shan
The Journal of antibiotics
Ciprofloxacin is a quinolone antibiotic used to treat Klebsiella pneumoniae infections in the clinic. Previous studies have demonstrated that berberine exhibits antibacterial activity and less acquired resistance related to efflux pumps. The multidrug efflux pump acrAB-tolC can be stimulated to expel as much toxic material as possible from the cells, but a detrimental effect can be produced owing to an overcrowded periplasm with excess expression products, which inhibits bacterial growth. In this study, the in vitro antibacterial activities of ciprofloxacin in combination with berberine were evaluated and compared with those of ciprofloxacin and berberine alone by evaluating the MIC, MBC and summation fractional IC against 20 clinical multidrug-resistant K. pneumoniae isolates, 1 quality control bacterium and 1 induced-resistance bacterium. Susceptibility tests showed that the MIC for the combination of berberine and ciprofloxacin was 1/2 that of the individual agents or less. Antimicrobial activities of 18.18% synergy and 77.27% additivity were found. Furthermore, synergism was verified through a time-kill assay, which suggested that the synergistic antibacterial effect of the two-drug combination may, to some extent, be related to the high expression of the acrAB-tolC and acrR multidrug efflux pumps. Indeed, the expression of these genes was increased >14-fold in the isolates affected by ciprofloxacin-berberine combination synergism.
Role of Berberine in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections.
Chu Ming,Zhang Ming-Bo,Liu Yan-Chen,Kang Jia-Rui,Chu Zheng-Yun,Yin Kai-Lin,Ding Ling-Yu,Ding Ran,Xiao Rong-Xin,Yin Yi-Nan,Liu Xiao-Yan,Wang Yue-Dan
Berberine is an isoquinoline alkaloid widely used in the treatment of microbial infections. Recent studies have shown that berberine can enhance the inhibitory efficacy of antibiotics against clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA). However, the underlying mechanisms are poorly understood. Here, we demonstrated that sub-minimum inhibitory concentrations (MICs) of berberine exhibited no bactericidal activity against MRSA, but affected MRSA biofilm development in a dose dependent manner within the concentration ranging from 1 to 64 μg/mL. Further study indicated that berberine inhibited MRSA amyloid fibrils formation, which consist of phenol-soluble modulins (PSMs). Molecular dynamics simulation revealed that berberine could bind with the phenyl ring of Phe19 in PSMα2 through hydrophobic interaction. Collectively, berberine can inhibit MRSA biofilm formation via affecting PSMs' aggregation into amyloid fibrils, and thereby enhance bactericidal activity of antibiotics. These findings will provide new insights into the multiple pharmacological properties of berberine in the treatment of microbial-generated amyloid involved diseases.
Evaluation of berberine as a natural fungicide: biodegradation and antimicrobial mechanism.
Li Ying,Yin Yi-Ming,Wang Xin-Yue,Wu Hao,Ge Xi-Zhen
Journal of Asian natural products research
Berberine (BBR) is a traditional Chinese medicine which recently was applied as a biological pesticide. Here, we studied the antimicrobial mode of BBR and its impact on soil bacterial diversity. BBR was more effective against fungi than bacteria due to the specific interaction between BBR and glucan. Also, BBR was degraded rapidly in soil, leading to the limited effect on soil bacterial diversity. Collectively, BBR is an environment-friendly pesticide and it is promising in dealing with fungal plant diseases.
Uptake and levels of the antibiotic berberine in individual dormant and germinating Clostridium difficile and Bacillus cereus spores as measured by laser tweezers Raman spectroscopy.
Wang Shiwei,Setlow Barbara,Setlow Peter,Li Yong-Qing
The Journal of antimicrobial chemotherapy
OBJECTIVES:Spores of Clostridium difficile and Bacillus cereus are major causes of nosocomial diarrhoea and foodborne disease. Our aim was to measure the dynamics of the uptake of the antibiotic berberine by individual germinating spores and the levels of berberine accumulated in germinated spores. METHODS:Laser tweezers Raman spectroscopy (LTRS) and differential interference contrast microscopy were used to measure levels of berberine accumulated in single germinating spores and to monitor berberine uptake and germination of individual C. difficile and B. cereus spores. RESULTS:MIC values of berberine for C. difficile and B. cereus spores were 640 and 256 mg/L, respectively. Levels of berberine accumulated at the berberine MICs in individual germinated spores were heterogeneous, with values of 17.1 ± 5.4 and 12.7 ± 5.5 g/L for C. difficile and B. cereus spores, respectively. These values were 25-50-fold higher than the MIC values. However, berberine did not affect the germination of C. difficile and B. cereus spores, but did block germinated spores' outgrowth. Berberine uptake kinetics were similar for these two kinds of spores. After the addition of germinants, berberine began to enter germinating spores at the time (Tlag) when rapid release of the spore core's large depot of the 1:1 chelate of Ca(2+) with dipicolinic acid began, and the level of berberine taken up was maximal shortly after spore cortex lysis was completed (Tlysis). CONCLUSIONS:LTRS can be used to measure uptake and levels of berberine in single cells. High levels of berberine can enter spores of C. difficile and B. cereus soon after germination is initiated, thus inhibiting spore outgrowth and minimizing hazards posed by germinated spores.
Berberine Antifungal Activity in Fluconazole-Resistant Pathogenic Yeasts: Action Mechanism Evaluated by Flow Cytometry and Biofilm Growth Inhibition in Candida spp.
da Silva Anderson Ramos,de Andrade Neto João Batista,da Silva Cecília Rocha,Campos Rosana de Sousa,Costa Silva Rose Anny,Freitas Daniel Domingues,do Nascimento Francisca Bruna Stefany Aires,de Andrade Larissa Nara Dantas,Sampaio Letícia Serpa,Grangeiro Thalles Barbosa,Magalhães Hemerson Iury Ferreira,Cavalcanti Bruno Coêlho,de Moraes Manoel Odorico,Nobre Júnior Hélio Vitoriano
Antimicrobial agents and chemotherapy
The incidence of fungal infections and, in particular, the incidence of fungal antibiotic resistance, which is associated with biofilm formation, have significantly increased, contributing to morbidity and mortality. Thus, new therapeutic strategies need to be developed. In this context, natural products have emerged as a major source of possible antifungal agents. Berberine is a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, and Hydrastis canadensis, and of Phellodendron amurense Berberine has been proven to have broad antibacterial and antifungal activity. In the present study, the potential antifungal effect of berberine against fluconazole-resistant Candida and Cryptococcus neoformans strains, as well as against the biofilm form of Candida spp., was assessed. The antifungal effect of berberine was determined by a broth microdilution method (the M27-A3 method of the Clinical and Laboratory Standards Institute) and flow cytometry techniques, in which the probable mechanism of action of the compound was also assessed. For biofilm assessment, a colorimetric 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to determine the susceptibility of sessile cells. The isolates used in the study belonged to the Laboratory of Bioprospection and Experiments in Yeast (LABEL) of the Federal University of Ceará. After 24 and 72 h, fluconazole-resistant Candida and Cryptococcus neoformans strains showed berberine MICs equal to 8 μg/ml and 16 μg/ml, respectively. Cytometric analysis showed that treatment with berberine caused alterations to the integrity of the plasma and mitochondrial membranes and DNA damage, which led to cell death, probably by apoptosis. Assessment of biofilm-forming isolates after treatment showed statistically significant reductions in biofilm cell activity (P < 0.001).
Inhibitory effect of berberine hydrochloride against Candida albicans and the role of the HOG-MAPK pathway.
Huang Xiaoxue,Yi Yuling,Yong Jiangyan,Sun Jiayi,Song Zhen,Li Dongmei,Li Yan
The Journal of antibiotics
Berberine hydrochloride (BH), an active component of Coptis chinensis and other plant taxa, has broad antimicrobial activity and may be useful for the treatment of Candida infections. In this study, the mechanisms underlying the inhibitory effect of BH against Candida albicans were evaluated, with a focus on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway, which regulates multiple physiological functions. BH (256 and 64 μg ml) significantly increased intracellular glycerol and ROS levels in C. albicans, inhibited germ tube and hyphal formation, and increased chitin and β-1,3-glucan exposure on the cell wall. The inhibitory effect of BH was positively correlated with its concentration, and the inhibitory effect of 256 μg ml BH was greater than that of 4 μg ml fluconazole (FLC). Furthermore, RT-PCR analysis showed that 256 and 64 μg ml BH altered the HOG-MAPK pathway in C. albicans. In particular, the upregulation of the core genes, SLN1, SSK2, HOG1, and PBS2 may affect the expression of key downstream factors related to glycerol synthesis and osmotic pressure (GPD1), ROS accumulation (ATP11 and SOD2), germ tube and hyphal formation (HWP1), and cell wall integrity (CHS3 and GSC1). BH affects multiple biological processes in C. albicans; thus, it can be an effective alternative to conventional azole antifungal agents.
Berberine treatment-emergent mild diarrhea associated with gut microbiota dysbiosis.
Yue Shi-Jun,Liu Juan,Wang Wen-Xiao,Wang Ai-Ting,Yang Xin-Yu,Guan Hua-Shi,Wang Chang-Yun,Yan Dan
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman's correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.
Pharmacological effects of berberine and its derivatives: a patent update.
Jin Yifeng,Khadka Daulat B,Cho Won-Jea
Expert opinion on therapeutic patents
INTRODUCTION:A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms. AREAS COVERED:This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer's disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed. EXPERT OPINION:Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine-based drugs in clinical settings.
The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling.
Varghese Finny S,Thaa Bastian,Amrun Siti Naqiah,Simarmata Diane,Rausalu Kai,Nyman Tuula A,Merits Andres,McInerney Gerald M,Ng Lisa F P,Ahola Tero
Journal of virology
Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a high-throughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH-terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCE:Chikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections.
Preparation of novel berberine nano-colloids for improving wound healing of diabetic rats by acting Sirt1/NF-κB pathway.
Zhang Peng,He Libang,Zhang Jie,Mei Xifan,Zhang Yiyao,Tian He,Chen Zhenhua
Colloids and surfaces. B, Biointerfaces
In the present work, novel berberine nano-colloids hydrogel (BNH) was prepared for improving wound healing of diabetic rats. Polyvinyl alcohol (PVA), sodium alginate (Alg) were adopted as building blocks to form BNH. Calcium ions was used as crosslink agent to construct BNH. The skin injury model of diabetic rats was successfully established, and the prepared hydrogel was applied to the wound. Animal experiments proved that BNH could promote wound healing of diabetic rats. Further molecular mechanism research revealed that BNH could inhibit the expression of NF-κB, TNF-a and IL-6, but increase the expression of F VEGF, CD 31 and SMA by activating Sirt 1 which were benefit for wound healing of diabetic rats.
Berberine regulates fecal metabolites to ameliorate 5-fluorouracil induced intestinal mucositis through modulating gut microbiota.
Chen Haitao,Zhang Fan,Li Rongrong,Liu Yu,Wang Xuanying,Zhang Xinjie,Xu Chao,Li Yan,Guo Yong,Yao Qinghua
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Berberine (BBR) is an isoquinoline alkaloid, which has been used in the treatment of intestinal mucositis. However, BBR on chemotherapy-induced mucositis in cancer patients remains largely unknown. Here, we investigated the effect of BBR on intestinal mucositis induced by 5-fluorouracil (5-Fu) using rat model. We detected the degree of intestinal mucosal damage and inflammatory response in 5-Fu treated rats with or without BBR administration, and investigated the changes of fecal metabolites and gut microbiota using H NMR spectroscopy and 16S rRNA. The mechanism was further explored by fecal microbiota transplantation (FMT). Results showed that BBR treated rats displayed less weight loss, lower diarrhea score and longer colon length in 5-Fu treated rats. Meanwhile, BBR treatment significantly increased the expression of Occludin in ileum and decreased the d-lactate content in serum. Moreover, the expression of IL-1β, IL-6 and TNF-α in ileum were suppressed by BBR treatment. The pattern of fecal metabolism changed obviously after treated with 5-Fu, which was reversed by BBR. Importantly, BBR significantly increased the levels of butyrate and glutamine in feces from 5-Fu treated rats. In terms of gut microbiota, BBR enriched the relative abundance of Firmicutes and decreased Proteobacteria at the phylum level. Meanwhile, BBR increased the propotion of unclassified_f_ Porphyromonadaceae, unclassified_f_ Lachnospiraceae, Lactobacillus, unclassified_o_ Clostridiales, Ruminococcus, Prevotella, Clostridium IV, and decreased Escherichia/Shigella at the genera level. Furthermore, principal component analysis (PCA) showed that fecal transplantation led to changes in fecal metabolites. Fecal transplantation from BBR treated rats had low diarrhea score, reduced inflammatory response in ileum, and relieved intestinal mucosal injury, which may be caused by the increased of butyrate level in fecal metabolites. In conclusion, our study provides evidence that BBR regulates fecal metabolites to ameliorate 5-Fu induced intestinal mucositis by modifying gut microbiota.
Berberine Hampers Influenza A Replication through Inhibition of MAPK/ERK Pathway.
Botwina Paweł,Owczarek Katarzyna,Rajfur Zenon,Ochman Marek,Urlik Maciej,Nowakowska Maria,Szczubiałka Krzysztof,Pyrc Krzysztof
BACKGROUND:Berberine (BBR) is an isoquinoline alkaloid which exhibits a variety of biological and therapeutic properties, and has been reported by some to block replication of the influenza virus. However, contradictory results have also been presented, and the mechanistic explanation is lacking. METHODS:A panel of cell lines (Madin-Darby canine kidney (MDCK), adenocarcinoma human alveolar basal epithelial cells (A549), lung epithelial type I (LET1)) and primary human airway epithelial cells (HAE) susceptible to influenza virus infection were infected with a seasonal influenza A virus in the presence or absence of BBR. Cytotoxicity towards cell lines was measured using XTT assay. The yield of the virus was analyzed using RT-qPCR. To study the molecular mechanism of BBR, confocal microscopy and Western blot analyses of cellular fractions were applied. RESULTS AND CONCLUSIONS:Our results show cell-type-dependent anti-influenza properties of BBR in vitro which suggests that the compound acts on the cell and not the virus. Importantly, BBR hampers influenza replication in primary human airway epithelium 3D cultures that mimic the natural replication site of the virus. Studies show that the influenza A virus upregulates the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathway and hijacks this pathway for nucleolar export of the viral ribonucleoprotein. Our results suggest that BBR interferes with this process and hampers influenza A replication.
Berberine inhibits hepatitis C virus entry by targeting the viral E2 glycoprotein.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Despite the advent of direct-acting antivirals (DAAs), HCV remains an important public health problem globally. There is at present no effective vaccine against the virus, and the DAAs in current use cannot prevent de novo infection, including in liver transplant setting wherein donor livers inevitably become re-infected. Developing inhibitors to HCV entry using nature-derived small molecules may help to expand/complement the current treatment options. PURPOSE:In this study, we explored the effect of the plant alkaloid berberine (BBR) on HCV early viral entry. METHODS:Cell culture-derived HCV (HCVcc), viral pseudoparticles bearing HCV glycoproteins (HCVpp), and entry-related assays were employed to assess BBR's bioactivity. Molecular docking was used to predict BBR-HCV glycoproteins interaction, and the compound's antiviral activity was confirmed against HCVcc infection of primary human hepatocytes (PHHs). RESULTS:BBR specifically impeded HCVcc attachment and entry/fusion steps without inactivating the free virus particles or affecting the expression of host cell entry factors and post-entry viral replication. BBR also effectively inhibited infection by viral pseudoparticles expressing HCV E1/E2 glycoproteins and molecular docking analysis pointed at potential interaction with HCV E2. Finally, BBR could suppress HCVcc infection of PHHs. CONCLUSIONS:We identified BBR as a potent HCV entry inhibitor, which merits further evaluation particularly for use in transplant setting against graft re-infection by HCV.
Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS.
Liu Hui,You Leiming,Wu Jun,Zhao Mengfan,Guo Rui,Zhang Haili,Su Rina,Mao Qin,Deng Di,Hao Yu
Journal of leukocyte biology
Berberine (BBR) is an isoquinoline alkaloid extracted from several commonly used Chinese herbs. Our previous studies demonstrated BBR-mediated alleviation of lung injury due to inflammation and decrease in the mortality of mice with influenza viral pneumonia. The recent argument of autophagy against inflammatory responses has aroused wide concerns. This study focuses on the reactive oxygen species-Nod-like receptor protein 3 (ROS-NLRP3) pathway to investigate whether BBR inhibits NLRP3 inflammasome activation by inducing mitophagy. Our results demonstrate that BBR and mitochondrion-targeted superoxide dismutase mimetic (Mito-TEMPO; a specific mitochondrial ROS scavenger) significantly restricted NLRP3 inflammasome activation, increased mitochondrial membrane potential (MMP), and decreased mitochondrial ROS (mtROS) generation in J774A.1 macrophages infected with PR8 influenza virus. These observations suggest that the inhibitory effects of BBR on NLRP3 inflammasome activation were associated with the amelioration of mtROS generation. BBR treatment induced regular mitophagy, as evident from the increase in microtubule-associated protein 1 light chain 3 II, decrease in p62, colocalization of LC3 and mitochondria, and formation of autophagosomes. However, 3-methyladenine, an autophagy inhibitor, reversed the inhibitory effects of BBR on mitochondrial damage and NLRP3 inflammasome activation in influenza virus-infected macrophages, indicating the involvement of mitophagy in mediating the inhibitory effects of BBR on NLRP3 inflammasome activation. Furthermore, the knockdown of Bcl-2/adenovirus E18-19-kDa interacting protein 3 (BNIP3) expression attenuated the effects of BBR on mitophagy induction to some extent, suggesting that the BBR-induced mitophagy may be, at least in part, mediated in a BNIP3-dependent manner. Similar results were obtained in vivo using a mouse model of influenza viral pneumonia that was administered with BBR. Taken together, these findings suggest that restricting NLRP3 inflammasome activation by decreasing ROS generation through mitophagy induction may be crucial for the BBR-mediated alleviation of influenza virus-induced inflammatory lesions.
Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels.
Xu Jian Hui,Liu Xing Zhen,Pan Wei,Zou Da Jin
Molecular medicine reports
Systemic inflammation, which can be induced by metabolic endotoxemia, and corresponding high‑fat diet‑mediated metabolic disorders are associated with gut microbiota. In the present study reverse transcription-polymerase chain reaction, immunofluorescence, pyrosequencing, ELISA and Oil Red O staining were performed to assess whether berberine can protect against diet-induced obesity, through modulating the gut microbiota and consequently improving metabolic endotoxemia and gastrointestinal hormone levels. Alterations in the gut microbiota induced by berberine resulted in a significant reduction in bacterial lipopolysaccharide levels in portal plasma. Levels of inflammatory and oxidative stress markers, as well as the mRNA expression levels of macrophage infiltration markers in visceral adipose tissue, were also reduced by berberine. Inhibition of the inflammatory response was associated with a reduction in intestinal permeability and an increase in the expression of tight junction proteins. In addition, berberine was reported to restore aberrant levels of gut hormones in the portal plasma, such as glucagon‑like peptide‑1 and ‑2, peptide YY, glucose‑dependent insulinotropic polypeptide and pancreatic polypeptide. The present findings indicated that berberine, through modulating gut microbiota, restored the gut barrier, reduced metabolic endotoxemia and systemic inflammation, and improved gut peptide levels in high‑fat diet‑fed rats. The present study suggests that berberine may be an effective therapeutic strategy for the treatment of obesity and insulin resistance.
Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway.
Li Cailan,Ai Gaoxiang,Wang Yongfu,Lu Qiang,Luo Chaodan,Tan Lihua,Lin Guosheng,Liu Yuhong,Li Yucui,Zeng Huifang,Chen Jiannan,Lin Zhixiu,Xian Yanfang,Huang Xiaoqi,Xie Jianhui,Su Ziren
Berberine (BBR), a naturally-occurring isoquinoline alkaloid isolated from several Chinese herbal medicines, has been widely used for the treatment of dysentery and colitis. However, its blood concentration was less than 1 %, and intestinal microflora-mediated metabolites of BBR were considered to be the important material basis for the bioactivities of BBR. Here, we investigated the anti-colitis activity and potential mechanism of oxyberberine (OBB), a novel gut microbiota metabolite of BBR, in DSS-induced colitis mice. Balb/C mice treated with 3 % DSS in drinking water to induce acute colitis were orally administrated with OBB once daily for 8 days. Clinical symptoms were analyzed, and biological samples were collected for microscopic, immune-inflammation, intestinal barrier function, and gut microbiota analysis. Results showed that OBB significantly attenuated DSS-induced clinical manifestations, colon shortening and histological injury in the mice with colitis, which achieved similar therapeutic effect to azathioprine (AZA) and was superior to BBR. Furthermore, OBB remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. OBB appreciably inhibited TLR4-MyD88-NF-κB signaling pathway through down-regulating the protein expressions of TLR4 and MyD88, inhibiting the phosphorylation of IκBα, and the translocation of NF-κB p65 from cytoplasm to nucleus. Moreover, OBB markedly modulated the gut dysbiosis induced by DSS and restored the dysbacteria to normal level. Taken together, the result for the first time revealed that OBB effectively improved DSS-induced experimental colitis, at least partly through maintaining the colonic integrity, inhibiting inflammation response, and modulating gut microflora profile.
A review on pain-relieving activity of berberine.
Hashemzaei Mahmoud,Rezaee Ramin
Phytotherapy research : PTR
As isoquinoline alkaloid naturally occurs in Coptis and Berberis species, berberine (BER) has shown anti-oxidant, anti-tumour, anti-bacterial and hepatoprotective activities and beneficial effects against digestive, cardiovascular and neurological conditions. Also, BER antiinflammatory, pain-relieving and anti-cholinesterase activities were widely studied. The present overview discusses the analgesic effects of BER. Based on the literature, BER exerted pain-relieving activity against diabetic and chemotherapy-induced neuropathy, and sciatic nerve injury-induced pain via down-regulation of transient receptor potential vanilloid 1, suppression of NF-κB and modulation of μ and δ opioid receptors. Besides, BER could repress inflammatory markers tumour necrosis factor-α, interleukin-6 and IL-1β, as well as prostaglandin E2, inducible nitric oxide synthase and cyclooxygenase-2. The modulatory effects of BER on dopamine and N-methyl d-aspartate systems were also noted. Moreover, BER could induce Nrf2 expression but inhibits p38-MAPK and STAT3 phosphorylation. Noteworthy, anti-cholinesterase activity, which may potentially contribute to BER analgesic properties, warrants particular attention.
The combined antibacterial effects of sodium new houttuyfonate and berberine chloride against growing and persistent methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.
Li Xue,Wang Penghe,Hu Xinxin,Zhang Youwen,Lu Xi,Li Congran,Nie Tongying,Li Guoqing,Wang Xiukun,Pang Jing,Lu Yun,Yang Xinyi,You Xuefu
BACKGROUND:Infections caused by drug-resistant Staphylococcus aureus, especially vancomycin-intermediate Staphylococcus aureus (VISA), leave clinicians with limited therapeutic options for treatment. Persister cells is a leading cause of recalcitrant infection and antibiotic treatment failure, and there is no drug in clinical use that specifically targets persister cells currently. Here, we report a promising combination therapy of sodium new houttuyfonate (SNH) and berberine chloride (BBR) which is able to eradicate both growing and persistent drug-resistant Staphylococcus aureus. RESULTS:The susceptibility test showed SNH exhibited anti-MRSA activity with MIC at 64 μg/mL, while BBR showed weak anti-MRSA activity with MIC at 512 μg/mL. MICs of BBR in combination with 1/2 MIC SNH decreased by 4 to 64 folds compared with MICs of BBR alone. The results of time-killing assays revealed that the combined use of sub-MIC SNH and BBR offered an in vitro synergistic action against growing MRSA (including pathogenic MRSA) and VISA strains. More importantly, the combination of SNH and BBR was able to eradicate VISA Mu50 and pathogenic MRSA persister cells. The synergistic effect is likely related to the interruption of the cell membrane caused by SNH, which is confirmed by scanning electron microscope and membrane potential and permeability analysis. CONCLUSIONS:Our study provide a promising clinical curative strategy for combating drug-resistant S. aureus infections, especially for recalcitrant infections caused by persister cells.
The metabolism of berberine and its contribution to the pharmacological effects.
Wang Kun,Feng Xinchi,Chai Liwei,Cao Shijie,Qiu Feng
Drug metabolism reviews
Berberine, a bioactive alkaloid isolated from several herbal substances, possesses multiple pharmacological effects, including antimicrobial, antidiabetic, anticancer activities. Meanwhile, berberine undergoes extensive metabolism after oral administration which results in its extremely low plasma exposure. Therefore, it is believed that the metabolites of berberine also contribute a lot to its pharmacological effects. Along these lines, this review covers the metabolism studies of berberine in terms of its metabolic pathways and metabolic organs based on the identified metabolites, and it also covers the pharmacological activities of its active metabolites. In brief, the predominant metabolic pathways of berberine are demethylation, demethylenation, reduction, hydroxylation and subsequent conjugation in vivo. Active metabolites such as columbamine, berberrubine and demethyleneberberine also exhibit similar pharmacological effects by comparison with berberine, such as antioxidant, anti-inflammatory, antitumor, antimicrobial, hepatoprotective, neuroprotective, hypolipidemic and hypoglycemic effects. Overall, berberine together with its metabolites formed the material basis of berberine in vivo.
Nanocellulose hyperfine network achieves sustained release of berberine hydrochloride solubilized with β-cyclodextrin for potential anti-infection oral administration.
Xiao Lin,Poudel Abishek Jung,Huang Lixia,Wang Yang,Abdalla Ahmed M E,Yang Guang
International journal of biological macromolecules
Berberine hydrochloride (BBH) has been used to treat diarrhea and other gastrointestinal diseases, however its therapeutic efficacy is compromised because of poor aqueous solubility and dissolution. In this work, BBH was solubilized with β-cyclodextrin (β-CD) in aqueous solution through formation of the BBH/β-CD inclusion complex (IC), which was confirmed by the combination of different techniques including FT-IR, XRD, DSC, H NMR and H NOESY. The aqueous solubility of BBH at 25 °C was increased by ca. 102% in the presence of 16 mM β-CD. BBH/β-CD IC-loaded bacterial cellulose (BC) hydrogels (denoted as BC/IC) were prepared by physical absorption method, resulting in higher drug loading capacity (DLC) than BC/BBH hydrogels. In vitro drug release showed that sustained drug release was achieved at different pH conditions simulating the gastrointestinal fluids by BC/IC hydrogels due to the hyperfine network of BC matrix. Furthermore, in vitro anti-bacterial test demonstrated the BC/IC hydrogels induced effective bacterial inhibition. Together with the good biocompatibility and edibility of the BC matrix, these BC/IC hydrogels appear to be promising candidates of oral administration medicine against gastrointestinal infections.
The effect of berberine chloride and/or its combination with vancomycin on the growth, biofilm formation, and motility of Clostridioides difficile.
Wultańska Dorota,Piotrowski Michał,Pituch Hanna
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology
This study aims to investigate the antimicrobial and antibiofilm activity of berberine chloride (BBR) and vancomycin (VAN) as well as synergistic combinations of BBR with VAN against Clostridioides difficile strains. The effect of different concentrations of BBR on strain motility was also assessed. Twelve C. difficile strains (two reference C. difficile 630, ATCC 9689, and one control M120, and 9 clinical C. difficile strains belonging to the PCR-ribotype (RT027)) were collected and investigated for their susceptibility to BBR and VAN in planktonic and biofilm forms. Both the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of BBR for the C. difficile strains were found to vary over a broad range (256-1.024 mg/L and 256-16.384 mg/L, respectively). The MIC and MBC of VAN also varied greatly, ranging from 0.25 to 4.0 mg/L for MIC and 0.25 to 64.0 mg/L for MBC. The synergistic effect of the sub-MIC (1/2 MIC) BBR with VAN reduced of MICs of VAN against the planktonic forms of ten C. difficile strains. The sub-MIC of BBR enhanced the biofilm formation of one strain and was found to be statistically significant. In addition, the sub-MIC of BBR with VAN surprisingly enhanced the biofilm formation of one C. difficile strain. The effect of inhibition of motility in the presence of BBR was statistically significant for 3 clinical strains (p < 0.05). Altogether, BBR exhibited strong antimicrobial activity against C. difficile, and the analysis of the combination of BBR with VAN showed a synergistic effect.
Natural Berberine-Based Chinese Herb Medicine Assembled Nanostructures with Modified Antibacterial Application.
Li Tong,Wang Penglong,Guo Wenbo,Huang Xuemei,Tian Xuehao,Wu Gaorong,Xu Bing,Li Feifei,Yan Cong,Liang Xing-Jie,Lei Haimin
The abuse of traditional antibiotics has caused a series of health problems including antimicrobial resistance, which threatens human health. Therefore, searching for broad sources of antimicrobial agents and developing multidimensional strategies to combat bacterial infections are urgent. Here, we reported two natural self-assembling modes between berberine (BBR) and flavonoid glycosides: nanoparticles (NPs) and nanofibers (NFs), which were both mainly governed by electrostatic and hydrophobic interactions. These two nanostructures exhibited different antibacterial properties from BBR. NPs showed significantly enhanced bacteriostatic activity, whereas NFs displayed a much weaker effect than BBR. The distinguishing properties can be attributed to the different spatial configurations and self-assembly processes of NPs and NFs. Flavonoid glycosides and BBR first formed a one-dimensional complex unit and subsequently self-assembled into three-dimensional nanostructures. With the hydrophilic glucuronic acid toward the outside, NPs exhibited stronger affinity to bacteria, thereby inducing the collapse of the bacteria population and the decrease in biofilm. In addition, in vitro hemolysis tests, cytotoxicity tests, and in vivo zebrafish toxicity evaluation showed that the obtained self-assemblies had good biocompatibility. This supramolecular self-assembly strategy can be applied to construct other nanoscale antibacterial drugs and thus provides weapons for the development of self-delivering drugs in bacterial infection treatment.
An Updated Review on Therapeutic Potential and Recent Advances in Drug Delivery of Berberine: Current Status and Future Prospect.
Mujtaba Md Ali,Akhter Md Habban,Alam Md Sarfaraz,Ali Mohammad Daud,Hussain Afzal
Current pharmaceutical biotechnology
Natural products are well known for their high potency with minimum side effects. Plant extracts are the most commonly used natural products because of their ease of availability and relatively low production cost. Berberine (BBR), a phytochemical component of some Chinese medicinal herbs (most commonly Berberis vulgaris), is an isoquinoline alkaloid with several biological and pharmacological effects including antioxidant, anti-inflammatory, antitumour, antimicrobial, antidepressant, hepatoprotective, hypolipidemic, and hypoglycemic actions. Interestingly, multiple studies have shown that BBR is a potential drug candidate with a multi-spectrum therapeutic application. However, the oral delivery of BBR is challenged owing to its poor bioavailability. Therefore, its oral bioavailability needs to be enhanced before it can be used in many clinical applications. This review provides an overview of the various studies that support the broad range of pharmacological activities of BBR. Also, it includes a section to address the issues and challenges related to the drug and methods to improve the properties of BBR, such as solubility, stability and bioavailability that may be explored to help patients reap the maximum benefit from this potentially useful drug.
Mechanism of berberine hydrochloride interfering with biofilm formation of Hafnia alvei.
Pang Yuesheng,Wang Sha,Tao Jiayue,Wang Jing,Xue Zhe,Wang Rufeng
Archives of microbiology
The mechanism of berberine hydrochloride (BBH) inhibiting the biofilm formation of Hafnia alvei was investigated in this study. The antibiofilm potential of BBH was evaluated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) as well as crystal violet staining. The quorum-sensing (QS) inhibition was revealed by determination of QS-related genes expression and related signal molecules production using real-time quantitative PCR (RT-qPCR) and high performance liquid chromatography (HPLC). The binding of BBH to receptor proteins was simulated by molecular docking and molecular dynamics simulations. It was found that BBH at sub-minimum inhibitory concentrations (sub-MICs) significantly reduced the biofilm formation of H. alvei in a dose dependent manner. BBH inhibited the bacterial swimming motility, decreased the transcription of halI and halR genes, and reduced the production of signal molecule C14-HSL. It bound to HalR protein mainly through Van der Waals force and electrostatic interaction force. Based on these results, it was concluded that BBH inhibits the biofilm formation of H. alvei and the mechanism is related to its interference with QS through down-regulating the expression of halI and halR genes.
Berberine nanoparticles with enhanced in vitro bioavailability: characterization and antimicrobial activity.
Sahibzada Muhammad Umar Khayam,Sadiq Abdul,Faidah Hani S,Khurram Muhammad,Amin Muhammad Usman,Haseeb Abdul,Kakar Maria
Drug design, development and therapy
BACKGROUND:Berberine is an isoquinoline alkaloid widely used in Ayurveda and traditional Chinese medicine to treat illnesses such as hypertension and inflammatory conditions, and as an anticancer and hepato-protective agent. Berberine has low oral bioavailability due to poor aqueous solubility and insufficient dissolution rate, which can reduce the efficacy of drugs taken orally. In this study, evaporative precipitation of nanosuspension (EPN) and anti-solvent precipitation with a syringe pump (APSP) were used to address the problems of solubility, dissolution rate and bioavailability of berberine. METHODS:Semi-crystalline nanoparticles (NPs) of 90-110 nm diameter for APSP and 65-75 nm diameter for EPN were prepared and then characterized using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Thereafter, drug content solubility and dissolution studies were undertaken. Berberine and its NPs were evaluated for their antibacterial activity. RESULTS:The results indicate that the NPs have significantly increased solubility and dissolution rate due to conversion of the crystalline structure to a semi-crystalline form. CONCLUSION:Berberine NPs produced by both APSP and EPN methods have shown promising activities against Gram-positive and Gram-negative bacteria, and yeasts, with NPs prepared through the EPN method showing superior results compared to those made with the APSP method and the unprocessed drug.
Berberine-piperazine conjugates as potent influenza neuraminidase blocker.
Enkhtaivan Ganuskh,Kim Doo Hwan,Park Gyun Seok,Pandurangan Muthuraman,Nicholas Daniel A,Moon So Hyun,Kadam Avinash A,Patel Rahul V,Shin Han-Seung,Mistry Bhupendra M
International journal of biological macromolecules
In these studies, we analyzed substituted piperazine based berberine analogs conjugated through a pentyloxy side chain for their in vitro and in silico biological effects. All the final analogs were screened for their in vitro antiviral action against a collection of different influenza virus strains using the CPE assay and SRB assay. Moreover, their cytotoxicity towards non-cancer cell lines was examined employing Madin-Darby canine kidney (MDCK) cell lines. The anti-influenza activities of berberine-piperazine derivatives (BPD) were evaluated in the range from 35.16 μg/mL to 90.25 μg/mL of the ICs along with cytotoxicity level which was observed in the range 44.8 μg/mL to 3890.6 μg/mL of CCs towards MDCK cells. In an effort to know the mechanism of action of BPD1-BPD23, results of Neuraminidase inhibition assay and Molecular docking studies carried out against neuraminidase as the target enzyme revealed that titled compounds are potential neuraminidase inhibitors that merge to the active site of neuraminidase, with moderate to high binding energy.
Alginate-based composite microspheres coated by berberine simultaneously improve hemostatic and antibacterial efficacy.
Jin Jia,Xu Ming,Liu Yixuan,Ji Zhixiao,Dai Kaili,Zhang Lun,Wang Lei,Ye Fei,Chen Gang,Lv Zhengbing
Colloids and surfaces. B, Biointerfaces
It is important to develop effective, biocompatible, easily stored and affordable hemostats for controlling bleeding and preventing infection in prehospital trauma. In this study, we synthesized a series of alginate-based composite microspheres coated by different amounts of berberine (SCC-1B, SCC-5B and SCC-10B), which were further characterized using scanning electron microscopy (SEM), viscometer, particle analyzer and Fourier transform infrared (FT-IR) spectroscopy. The in vitro and vivo results demonstrated that compared to control group (SCC, Composite polysaccharide microspheres without berberine, and CMPHP, Commercial hemostatic agent), SCC-10B with proper content berberine (7%), not only exhibited inherent excellent antibacterial activity, but also enhanced hemostatic effect by increasing adhesion and aggregation of blood cells, which could be considered as synergistic effects. More importantly, through inserting berberine into the cross-linked network, biodegradability and biocompatibility of SCC-10B were also improved. Taken together, SCC-10B could be a candidate for emergency hemostatic and antibacterial treatment in prehospital trauma.
Natural Berberine-derived Azolyl Ethanols as New Structural Antibacterial Agents against Drug-Resistant .
Sun Hang,Huang Shi-Yu,Jeyakkumar Ponmani,Cai Gui-Xin,Fang Bo,Zhou Cheng-He
Journal of medicinal chemistry
Natural berberine-derived azolyl ethanols as new structural antibacterial agents were designed and synthesized for fighting with dreadful bacterial resistance. Partial target molecules exhibited potent activity against the tested strains, particularly, nitroimidazole derivative and benzothiazole-2-thoil compound , with low cytotoxicity both exerted strong antibacterial activities against multidrug-resistant at low concentrations as 0.007 and 0.006 mM, respectively. Meanwhile, the active compounds and possessed the ability to rapidly kill bacteria and observably eradicate the biofilm by reducing exopolysaccharide content to prevent bacterial adhesion, which was conducive to alleviating the development of resistance. Preliminary mechanistic explorations suggested that the excellent antibacterial potential of molecules and might be attributed to their ability to disintegrate membrane, accelerate ROS accumulation, reduce bacterial metabolism, and intercalate into DNA groove. These results provided powerful information for the further exploitation of natural berberine derivatives against bacterial pathogens.
Nano strategies for berberine delivery, a natural alkaloid of Berberis.
Mirhadi Elaheh,Rezaee Mehdi,Malaekeh-Nikouei Bizhan
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Berberine, as a phytochemical component of some medicinal Chinese herbs (most frequently Berberis vulgaris), is an isoquinoline alkaloid with many therapeutic effects including anti-viral, anti-microbial, anti-diarrhea, anti-inflammatory and anti-tumor effects. Berberine has some significant effects on type 2 diabetes through adenosine monophosphate-activated protein kinase activation, glycolysis stimulation, and mitochondrial function inhibition which subsequently improves both lipid and glucose metabolism. Some other effects of berberine on congestive heart failure, cardiac arrhythmia and hypertension have been reported. Beside the beneficial effects of berberine, some limitations including poor aqueous solubility, slight absorption, and low bioavailability have hindered its applications. To overcome these limitations, nanotechnology has been considered as main strategy. This review describes different types of nanocarriers (polymeric based, magnetic mesoporous silica based, lipid based, dendrimer based, graphene based, silver and gold nanoparticles) have been used for encapsulation of berberine.
Combination of berberine and ciprofloxacin reduces multi-resistant strain biofilm formation by depressing mRNA expressions of , , and .
Shi Chenxi,Li Minmin,Muhammad Ishfaq,Ma Xin,Chang Yicong,Li Rui,Li Changwen,He Jingshan,Liu Fangping
Journal of veterinary science
Bacterial biofilms have been demonstrated to be closely related to clinical infections and contribute to drug resistance. Berberine, which is the main component of , has been reported to have efficient antibacterial activity. This study aimed to investigate the potential effect of a combination of berberine with ciprofloxacin (CIP) to inhibit biofilm formation and its effect on expressions of related genes (, , and ). The fractional inhibitory concentration (FIC) index of the combination of berberine with CIP is 0.75 showing a synergistic antibacterial effect. The biofilm's adhesion rate and growth curve showed that the multi-resistant strain had the potential to form a biofilm relative to that of strain CVCC528, and the antibiofilm effects were in a dose-dependent manner. Biofilm microstructures were rarely observed at 1/2 × MIC/FIC concentrations (MIC, minimal inhibition concentration), and the combination had a stronger antibiofilm effect than each of the antimicrobial agents used alone at 1/4 × FIC concentration. , , and mRNA expressions were significantly repressed ( ＜ 0.01) at 1/2 × MIC/FIC concentrations, and the berberine and CIP combination repressed mRNA expressions more strongly at the 1/4 × FIC concentration. The results indicate that the combination of berberine and CIP has a synergistic effect and is effective in inhibiting biofilm formation via repression of , , and mRNA expressions.
Berberine-Loaded Nanostructured Lipid Carriers Enhance the Treatment of Ulcerative Colitis.
International journal of nanomedicine
PURPOSE:Berberine (BBR), a major ingredient extracted from , is a natural drug with limited oral bioavailability. We developed nanostructured lipid carriers (NLCs) as a delivery system for enhanced anti-inflammatory activity of BBR against ulcerative colitis (UC). METHODS:BBR-loaded nanostructured lipid carriers (BBR-NLCs) prepared via high-pressure homogenization were evaluated for particle size, zeta potential, drug entrapment efficiency, drug loading, drug release, toxicity, and cellular uptake. The anti-UC activities of free and encapsulated BBR were evaluated in a DSS-induced acute model of UC in mice. RESULTS:Spherical BBR-NLCs were prepared with a particle size of 63.96± 0.31 nm, a zeta potential of +3.16 ± 0.05 mV, an entrapment efficiency of 101.97±6.34%, and a drug loading of 6.00±0.09%. BBR-NLCs showed excellent biocompatibility in vivo. Cellular uptake experiments showed that BBR-NLCs improved uptake of BBR by RAW 264.7 cells and Caco-2 cells. Oral administration of BBR-NLCs significantly alleviated colitis symptoms (DAI, colon length, spleen swelling, MPO activity) through inhibition of NF-κB nuclear translocation, decreased expression of pro-inflammatory cytokines (IL-1β, IL-6, MMP-9, CX3CR1, COX-2, TERT), and increased expression of the tight junction protein ZO-1. CONCLUSION:BBR-loaded NLCs improved colitis symptoms, which suggested that this may be a novel formulation for treatment of UC.
Berberine and its structural analogs have differing effects on functional profiles of individual gut microbiomes.
Li Leyuan,Chang Lu,Zhang Xu,Ning Zhibin,Mayne Janice,Ye Yang,Stintzi Alain,Liu Jia,Figeys Daniel
The understanding of the effects of compounds on the gut microbiome is limited. In particular, it is unclear whether structurally similar compounds would have similar or distinct effects on the gut microbiome. Here, we selected berberine (BBR), an isoquinoline quaternary alkaloid, and 16 structural analogs and evaluated their effects on seven individual gut microbiomes cultured . The responses of the individual microbiomes were evaluated by metaproteomic profiles and by assessing butyrate production. We show that both interindividual differences and compound treatments significantly contributed to the variance of metaproteomic profiles. BBR and eight analogs led to changes in proteins involved in microbial defense and stress responses and enrichment of proteins from Verrucomicrobia, Proteobacteria, and Bacteroidetes phyla. It also led to a decrease in proteins from the Firmicutes phylum and its Clostridiales order which correlated to decrease proteins involved in the butyrate production pathway and butyrate concentration. Three of the compounds, sanguinarine, chelerythrine, and ethoxysanguinarine, activated bacterial protective mechanisms, enriched Proteobacteria, increased opacity proteins, and markedly reduced butyrate production. Dihydroberberine had a similar function to BBR in enriching the genus. In addition, it showed less overall adverse impacts on the functionality of the gut microbiome, including a better maintenance of the butyrate level. Our study shows that microbiome assay can assess differential regulating effects of compounds with subtle differences and reveals that compound analogs can have distinct effects on the microbiome.
Berberine and barberry (Berberis vulgaris): A clinical review.
Imenshahidi Mohsen,Hosseinzadeh Hossein
Phytotherapy research : PTR
Barberry (Berberis vulgaris L.) has different medicinal applications in folk medicine of Iran. Berberine, an alkaloid constituent of this plant, is present in the roots, rhizomes, stem, and bark of B. vulgaris and many other plants. There have been many clinical trials conducted that suggested a wide range of therapeutic applications. Here, we investigated the clinical uses of berberine and B. vulgaris in the treatment of different diseases in humans. An extensive search in electronic databases (PubMed, Scopus, Embase, Web of Sciences and Science Direct) was used to identify the clinical trials on B. vulgaris and berberine. Lipid-lowering and insulin-resistance improving actions are the most studied properties of berberine in numerous randomized clinical trials. There are also clinical trials regarding cardiovascular, anticancer, gastrointestinal, CNS, endocrine, and so on. Berberine has very low toxicity in usual doses and reveals clinical benefits without major side effects. Only mild gastrointestinal reactions may occur in some patients. The purpose of this review is to provide a summary concerning the clinical trials conducted on berberine to improve the clinical application of this nutraceutical in different diseases. In this review article, we used 77 clinical studies on human subjects.
Efficacy and safety of berberine in preventing recurrence of colorectal adenomas: A systematic review and meta-analysis.
Fang ShuangShuang,Guo Song,Du SiJing,Cao Zeng,Yang Yang,Su XiaoLan,Wei Wei
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Berberine(BBR) is a kind of isoquinoline alkaloids extracted from the rhizomes of Coptis chinensis Franch., which was the main active ingredient. Accumulating evidence has shown that it has potential pharmacological effects in preventing the recurrence of colorectal adenomas. AIM OF THE STUDY:The roles of BBR in the overall recurrence of colorectal adenoma have still not been assessed because of the limitations of the available data and the restriction of a single study. Therefore, we evaluated the effectiveness and safety of BBR in preventing the recurrence of colorectal adenomas through a systematic review and meta-analysis of available data. MATERIALS AND METHODS:We searched four English databases (PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Web of Science) and four Chinese language databases (Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) and the WanFang Database) from their inception through October 2020. Meta-analysis was performed with RevMan5.3 software after data extraction and the quality of studies assessment. RESULTS:Three randomized controlled clinical trials were included with 1076 patients. Our results illustrated that 1-year and 2-year supplementation with BBR was associated with lower recurrence rate of colorectal adenoma (RR 0.69, 95% CI 0.57 to 0.84, p=0.0001; RR 0.75, 95% CI 0.64 to 0.88, p=0.0004). The relative risk of oral BBR for 1 year and 2 years is not comparable, for 2-year efficacy outcomes were assessed in all participants who had at least one colonoscopy with pathological evaluation after baseline (lots of participants completed the first colonoscopy but discontinued during the second follow-up interval.). Moreover, the results also suggest that BBR had more adverse events than placebo (RR 2.91, 95% CI 1.24 to 6.85, p=0.01). Through the full-text reading, no serious adverse events were observed, and constipation was the most common event which disappears once the drug is discontinued. CONCLUSION:Generally, the present study indicated that BBR has a comparable therapeutic effect on the prevention of colorectal adenomas recurrence. Adverse reactions are worthy of attention which requires additional studies to obtain a precise conclusion. PROSPERO REGISTRATION NO:CRD42020209135.
New Development of Novel Berberine Derivatives against Bacteria.
Jamshaid Faisal,Dai Jun,Yang Li Xi
Mini reviews in medicinal chemistry
Many berberine derivatives have been synthesized for their antibacterial activity in the past years. In order to elucidate their new Structural Activity Relationship (SAR), the recently synthesized berberine derivatives are reviewed. The newly synthesized berberine derivatives are reported in this review with novel modifications on the berberine structure at various positions. It is hoped that this article would help scientists to design and synthesize new berberine derivatives with high potency and a broad spectrum of antimicrobial activities, more effectiveness and lower toxicity for improved antimicrobial therapy. These berberine derivatives could be developed as novel antibacterial agents to treat patients with infectious diseases, especially caused by resistant bacteria.
Effects of berberine and metformin on intestinal inflammation and gut microbiome composition in db/db mice.
Zhang Wang,Xu Ji-Hao,Yu Tao,Chen Qi-Kui
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Berberine and metformin, both established pharmaceutical agents with herbal origins, have incidental beneficial effects on multiple diseases, including diabetes. These effects have been speculated to occur via the gut microbiome. In this study, we administered either berberine or metformin to db/db mice and investigated changes in body weight, food intake, and blood glucose levels. Fresh stool samples were analyzed using 16 s rDNA high-throughput sequencing to evaluate the gut microbiome. Short-chain fatty acids (SCFA) in the stool were quantified using gas chromatography. The expression of NF-κB signaling pathway and tight junction (ZO1 and occludin) proteins in the intestinal epithelium was determined using qPCR and western blotting. The intestinal barrier structure was examined using transmission electron microscopy and serum lipopolysaccharide (LPS) was measured using a commercial kit. Both berberine and metformin reduced food intake, body weight, and blood glucose and HbA1c levels. Both treatments effectively restored the intestinal SCFA content, reduced the level of serum LPS, relieved intestinal inflammation, and repaired intestinal barrier structure. Intervention with metformin or berberine modified the gut microbiome in db/db mice, increasing the number of SCFA-producing bacteria (e.g., Butyricimonas, Coprococcus, Ruminococcus) and reducing opportunistic pathogens (e.g., Prevotella, Proteus). An increased abundance of other probiotics including Lactobacillus and Akkermansia was also observed. Berberine and metformin can modulate the composition of the gut microbiome and reduce body weight, blood glucose levels, and intestinal inflammation in db/db mice, which demonstrates their effectiveness in the reduction of diabetic complications in this model.
In vitro Antifungal Effects of Berberine Against spp. In Planktonic and Biofilm Conditions.
Drug design, development and therapy
PURPOSE:Antifungal resistance associated with the extensive use of antifungals and biofilm formation presents major clinical challenges. Thus, new therapeutic strategies for fungal infections are urgently required. This study aimed to evaluate the in vitro antifungal effects of the natural bioactive alkaloid berberine against spp. in planktonic and biofilm conditions. METHODS:Using the CLSI M27-A3 reference method for broth dilution antifungal susceptibility testing of yeasts, the MICs for five standard strains comprised of (ATCC 10231, ATCC 90028), (ATCC 6258), (ATCC 90030), (MYA 646), and six clinical isolates (CLC1-CLC6) were tested. The 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay was used to evaluate the inhibitory effects of berberine against biofilms. The optical density value at 490 nm was measured and illustrated using concentration-absorbance curves. Finally, the effects were quantified by confocal laser scanning microscopy (CLSM), and 3-dimensional reconstruction was performed. The viability inhibition rates, biofilm formation, and thickness decrease rates were tested and analyzed using independent-samples -test. The differences among the five strains were analyzed using one way ANOVA. RESULTS:The MICs for the five standard strains described above were 80, 160, 10, 20, and 40 μg/mL, respectively, which was similar to that of the clinical isolates, suggesting the stable, broad-spectrum antifungal activity of berberine. Berberine exerted concentration-dependent inhibitory effects against biofilms, which were enhanced with the maturation of biofilms. Berberine decreased the viability of biofilms, with inhibition rates by CLSM ranging from 19.89 ± 0.57% to 96.93 ± 1.37%. Following 3-dimensional reconstruction, the biofilms of the berberine-treated group displayed a poorly developed architecture, and the biofilm thickness decrease rates ranged from 15.49 ± 8.45% to 30.30 ± 15.48%. CONCLUSION:Berberine exhibited significant antifungal activity in spp. The results provide a useful reference for multiple infections and biofilm infections associated with antifungal resistance. Therefore, berberine might have novel therapeutic potential as an antifungal agent or a major active component of antifungal drugs.
Natural Berberine-Hybridized Benzimidazoles as Novel Unique Bactericides against .
Sun Hang,Ansari Mohammad Fawad,Fang Bo,Zhou Cheng-He
Journal of agricultural and food chemistry
Natural berberine-hybridized benzimidazoles as potential antibacterial agents were constructed to treat infection in the livestock industry. Bioassay showed that some new berberine-benzimidazole hybrids exhibited potent antibacterial efficacies, especially, the 2,4-dichlorobenzyl derivative not only showed strong activity against ATCC 29213 with the MIC value of 0.006 mM but also effectively eradicated bacterial biofilm and exhibited low toxicity toward mammalian cells. The drug combination experiments showed that compound together with norfloxacin could enhance the antibacterial efficacy. Moreover, the 2,4-dichlorobenzyl derivative did not show obvious propensity to develop bacterial resistance. Preliminary mechanism studies revealed that the active molecule could damage the membrane integrity, stimulate ROS generation, and bind with DNA as well as sortase A, thus exerting powerful antibacterial ability. In light of these facts, berberine-benzimidazole hybrid showed a large potentiality as a new bactericide for treating in the livestock industry.
Berberine ameliorates colonic damage accompanied with the modulation of dysfunctional bacteria and functions in ulcerative colitis rats.
Liao Ziqiong,Xie Yuzhen,Zhou Benjie,Zou Baorong,Xiao Dan,Liu Wen,Cai Ying,Liu Deliang,Liao Qiongfeng,Xie Zhiyong
Applied microbiology and biotechnology
Intestinal flora imbalance is one of the potential pathogenesis of inflammatory bowel diseases, and the study aims to discover the effect of berberine on the composition and function of gut microbiota in ulcerative colitis (UC) rats. UC rats were induced by dextran sulfate sodium (DSS) and administrated with berberine. Colonic morphological changes and claudin-1 protein of colon tissues were primarily examined to validate the protective effects brought by berberine treatment. Then the composition and function of gut microbiota were analyzed, accompanied with quantitative analysis of serum amino acids. The results showed that berberine could not only ameliorate the colonic damages in DSS-induced UC rats but also regulate the gut microbiota by increasing lactic acid-producing bacteria and carbohydrate hydrolysis bacteria as well as decreasing conditional pathogenic bacteria. Accordingly, the relevant functions of above bacteria were improved, including the metabolism and biosynthesis of amino acids, capability of DNA replication and repair, carbohydrate digestion and absorption and glycolysis/gluconeogenesis. Furthermore, the serum amino acids were regulated and showed high correlation with the gut microbiota after berberine treatment. In conclusion, the study confirms the effect of berberine on ameliorating the colonic damage and highlights some specific bacteria and relevant functions linked with berberine treatment, exploring the potential of gut microbiota as a diagnostic biomarker or a therapeutic target in UC treatment.
In Vitro and In Vivo Biological Activity of Berberine Chloride against Uropathogenic Strains Using as a Host Model.
Petronio Petronio Giulio,Cutuli Marco Alfio,Magnifico Irene,Venditti Noemi,Pietrangelo Laura,Vergalito Franca,Pane Antonella,Scapagnini Giovanni,Di Marco Roberto
Molecules (Basel, Switzerland)
Berberine is an alkaloid of the protoberberine type used in traditional oriental medicine. Its biological activities include documented antibacterial properties against a wide variety of microorganisms; nonetheless, its use against strains isolated from urinary infections has not yet been widely investigated in vivo. The emergence of antimicrobial resistance requires new therapeutic approaches to ensure the continued effectiveness of antibiotics for the treatment and prevention of urinary infections. Moreover, uropathogenic (UPEC) has developed several virulence factors and resistance to routine antibiotic therapy. To this end, several in vitro and in vivo tests were conducted to assess the activity of berberine on uropathogenic strains. as an infection model was employed to confirm the in vivo translatability of in vitro data on berberine activity and its influence on adhesion and invasion proprieties of on human bladder cells. In vitro pre-treatment with berberine was able to decrease the adhesive and invasive UPEC ability. In vivo treatment increased the larvae survival infected with UPEC strains and reduced the number of circulating pathogens in larvae hemolymph. These preliminary findings demonstrated the efficacy and reliability of as in vivo model for pre-clinical studies of natural substances.
Proteomic investigation into the action mechanism of berberine against Streptococcus pyogenes.
Du Gao-Fei,Le Yao-Jin,Sun Xuesong,Yang Xiao-Yan,He Qing-Yu
Journal of proteomics
Berberine is an isoquinoline alkaloid found in many plants. Although berberine is known to possess the antibacterial activity against Streptococcus pyogenes, the mechanism underlying it is not fully understood. In the current study, to investigate the molecular mechanism how berberine exerts its antibacterial effects, quantitative proteomics was conducted to investigate differential expressed proteins in S. pyogenes in response to berberine treatment. KEGG pathways analysis revealed that berberine regulated proteins were mainly involved in carbohydrate metabolism, fatty acid biosynthesis, pyrimidine metabolism, RNA degradation, ribosome, purine metabolism, DNA replication and repair and oxidative phosphorylation pathways. Moreover, we found that berberine induced the accumulation of reactive oxygen species (ROS), whereas inhibition of ROS generation with antioxidant N-acetyl L-cysteine could block the berberine induced antibacterial effects. Collectively, we demonstrated that berberine exerts its antibacterial effects by perturbing carbohydrate metabolism, which therefore generate ROS to damage the DNA, protein and lipids biosynthesis, ultimately trigger cell lethality. These findings provide novel insights into the mechanism of berberine as an antimicrobial drug to control diseases caused by S. pyogenes. SIGNIFICANCE: Streptococcus pyogenes is the major cause of invasive bacterial disease in human, which leads to hundreds of million cases annually and over 500,000 deaths due to severe infections. Berberine is an isoquinoline alkaloid from medicinal plants, which possesses a variety of pharmacological effects including antibacterial. In this work, proteomic analysis revealed that berberine affected carbohydrate metabolism, DNA, protein and fatty acid biosynthesis and oxidative phosphorylation pathways in S. pyogenes. And further experimental results showed that berberine exerts its antibacterial effects against Streptococcus pyogenes by stimulated the generation of reactive oxygen species (ROS). These data provide novel insights into the effect of berberine on oxidative stress as an antimicrobial drug.
Potential application of berberine in the treatment of sepsis.
Pierpaoli Elisa,Cirioni Oscar,Simonetti Oriana,Orlando Fiorenza,Giacometti Andrea,Lombardi Paolo,Provinciali Mauro
Natural product research
Gram-negative sepsis ranks as the leading cause of death in intensive care units. Despite the development of new antibiotics, mortality from gram-negative sepsis remains high. The present study aims to investigate the effects of berberine (BBR) administration on septic death induced by intraperitoneal injection. The results showed that (i) single 5 mg/kg dose of BBR increases the survival of septic mice, (ii) BBR administration improves the antimicrobial efficacy of antibiotic drug, (iii) BBR pre-treatment prevents improvements of BBR therapy without affecting the pro-survival effects of antibiotic drug. The effects of BBR administration were associated with immunological alterations represented by changes in CD4+ and CD8+ lymphocytes population and IL-6 and TNF-α production. This study highlighted the benefits of berberine administration as antibiotic adjuvant in sepsis. Furthermore, information about berberine-induced immunological perturbations and their influence on host response to infection and therapy has been shown.
Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization.
Molecules (Basel, Switzerland)
Berberine is multifunctional natural product with potential to treat diverse pathological conditions. Its broad-spectrum anticancer effect through direct effect on cancer cell growth and metastasis have been established both in vitro and in vivo. The cellular targets that account to the anticancer effect of berberine are incredibly large and range from kinases (protein kinase B (Akt), mitogen activated protein kinases (MAPKs), cell cycle checkpoint kinases, etc.) and transcription factors to genes and protein regulators of cell survival, motility and death. The direct effect of berberine in cancer cells is however relatively weak and occur at moderate concentration range (10-100 µM) in most cancer cells. The poor pharmacokinetics profile resulting from poor absorption, efflux by permeability-glycoprotein (P-gc) and extensive metabolism in intestinal and hepatic cells are other dimensions of berberine's limitation as anticancer agent. This communication addresses the research efforts during the last two decades that were devoted to enhancing the anticancer potential of berberine. Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.
Berberine pharmacology and the gut microbiota: A hidden therapeutic link.
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.
[Research progress of effect of berberine in treatment of ulcerative colitis based on cell signaling pathway].
Wang Jia-Jun,Wang Jian,Li Yong,Ren Mi-Hong,Fu Yin,Yang Xian-Juan,Wang Li-Ying
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Berberine is the main extract of Coptis chinensis, and its anti-inflammatory, antioxidant, antibacterial and immunomodulatory effects have been confirmed by modern studies. Ulcerative colitis(UC) is a chronic, idiopathic inflammatory bowel disease with unknown etiology. Its causes involve genetics, intestinal microecology and mucosal immune system disorders. In this paper, literatures on relevant pathways and mechanism of berberine on ulcerative colitis in recent years were consulted and summarized to provide me-thods and ideas for developing berberine in the treatment of UC and exploring the mechanisms. The results showed that berberine protects the intestinal mucosal barrier, restores the body's normal immune response, and improves oxidative stress by regulating multiple signaling pathways, such as JAK-STAT, NK-κB, PI3 K-AKT, MAPK, Nrf2, ERS, and MLCK-MLC, so as to treat UC.
The effect of Berberine on weight loss in order to prevent obesity: A systematic review.
Ilyas Zahra,Perna Simone,Al-Thawadi Salwa,Alalwan Tariq A,Riva Antonella,Petrangolini Giovanna,Gasparri Clara,Infantino Vittoria,Peroni Gabriella,Rondanelli Mariangela
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
This study provides a critical overview of experimental studies in vitro, in humans, and in animals that evaluated the efficacy of Berberine and its effect on management of obesity and the related metabolic consequences. As a result of this review, we summarized the effects of Berberine in different models and the related mechanism of actions. In preclinical models, Berberine demonstrates that it affects gut microbiota by reducing diversity of microbes starting at a dosage of 100 mg/kg/day. Moreover, in animal models, Berberine explicates an action on glucose through the inhibition of α-glycosidase at a dose of 200 mh/kg/day. Berberine is also known to be effective against differentiation of adipocytes through a decrease in LXRs, PPARs, and SREBPs expression at 150 mg/kg/day. Other mechanism ascribed to Berberine are related to its inhibition of hepatic gluconeogenesis through the Phospheoenolpyruvate carboxykinase (PEPCK), Glucose-6-phosphate (G6Pase) and AMP-activated protein kinase (AMPK). Furthermore, Berberine (associated to Red Yeast Rice) is effective in decreasing lipid levels in rats, which consequently lowers the change of weight gain at dosage of 40 mg/kg to 380 mg/kg/day. All the above preclinical data are confirmed in human studies where Berberine can modulate the diversity of gut microbes at the dose of 500 mg/day. In addition, Berberine is found to have a beneficial impact on gene regulation for the absorption of cholesterol at a daily dose of 300 mg in humans, an amelioration on glucose accumulation at 1.0 g daily dose was also observed. For all these reasons, this review gives an important good account of the impact of Berberine in obesity treatment and prevention.
Prebiotic Effect of Berberine and Curcumin Is Associated with the Improvement of Obesity in Mice.
Neyrinck Audrey M,Sánchez Cándido Robles,Rodriguez Julie,Cani Patrice D,Bindels Laure B,Delzenne Nathalie M
Berberine and curcumin, used as food additives or food supplements, possess interesting anti-inflammatory and antioxidant properties. We tested the potential protective effect of both phytochemicals in genetically obese mice and we determined whether these effects can be related to the modulation of gut functions and microbiota. mice were fed a standard diet supplemented with or without 0.1% berberine and/or 0.3% curcumin for 4 weeks. By using targeted qPCR, we found that cecal content of spp. and spp. increased mainly upon berberine supplementation. Genes involved in innate immunity (), mucus production () and satietogenic peptide production ( and were upregulated in the colon of mice treated with both phytochemicals. Berberine supplementation alone reduced food intake, body weight gain, hypertriglyceridemia and hepatic inflammatory and oxidative stress markers, thus lessening hepatic injury. The increase in spp. and spp. was correlated with the improvement of gut barrier function and with the improvement of hepatic inflammatory and oxidative stresses in obese mice. These data support the fact that non-carbohydrate phytochemicals may modulate the gut microbiota in obesity and related gut and hepatic alterations.
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.
Regulation of MFN2 by berberine alleviates obesity exacerbated colitis.
Chen Youlan,Zheng Yiyuan,Wen Shuting,Liu Fengbin
Biochemical and biophysical research communications
Obesity has become a global health issue, which can cause metabolic abnormalities systemically leading to increased morbidity of series diseases. At present, researches have presented obesity is a high-risk factor for colitis, and berberine shows positive therapeutic effect on colitis. Thus, we explored the beneficial effects and potential mechanisms of berberine on obesity-exacerbated colitis in this article. High-fat diet (HFD) exacerbated dextran sulfate sodium (DSS) induced colitis mice model was applied, the results showed that HFD promoted DSS-induced weight loss and inflammatory manifestations in intestine. The results of cytokines in serum and mRNA expression of inflammatory indicators in colon showed that HFD increased all their levels evidently, and the outcomes of Western blot analyses presented that HFD downregulated the MFN2 expression, inhibited the phosphorylation of AMPK as well as upregulated the BIP/Grp78 expression, while berberine could significantly reverse all these situations. In vitro, we stimulated Caco-2 cells with palmitic acid (PA) to replicate the lipotoxicity damage in the intestine, and the results presented that intervention therapy of berberine effectively enhanced the MFN2 expression, inhibited the mRNA levels of inflammatory factors, and reversed the PA induced protein level changes of AMPK and BIP/Grp78. In general, we proposed that berberine could regulate MFN2 to alleviate obesity exacerbated colitis.
Berberine reduces gut-vascular barrier permeability via modulation of ApoM/S1P pathway in a model of polymicrobial sepsis.
Li Yanning,Zhou Jun,Qiu Jiasheng,Huang Zudong,Wang Weiwei,Wu Ping,Feng Aiwen
AIMS:The hyperpermeability of gut-vascular barrier (GVB) plays a role in gut-derived sepsis. The goal of this study was to evaluate if berberine might improve hepatic apolipoprotein M (ApoM) generation and raise plasma ApoM level to protect the compromised GVB. MATERIALS AND METHODS:The compromised GVB was induced by sepsis. Hepatic ApoM mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA and plasma ApoM level were assayed by qRT-PCR and ELISA, respectively. The permeability of intestinal capillary in vivo and of rat intestinal microvascular endothelial cells (RIMECs) in vitro was assayed by FITC-dextran. The blood glucose was detected by a glucometer. Plasma insulin, TNF-α and IL-1β were assayed by ELISA. The plasmalemma vesicle-associated protein-1 (PV1), β-catenin and occludin in RIMECs were assayed by Western blot. KEY FINDINGS:Sepsis decreased hepatic ApoM mRNA and plasma ApoM level, but raised hepatic PEPCK mRNA and plasma glucose, insulin, TNF-α, and IL-1β levels. The increased vascular endothelial permeability was abrogated by recombinant rat ApoM in vivo or ApoM-bound S1P in vitro. ApoM-bound S1P decreased PV1 but increased occludin and β-catenin expression in LPS-treated RIMECs. Berberine in a dose-dependent manner raised hepatic ApoM mRNA and plasma ApoM level, but decreased septic hyperglycemia, insulin resistance and plasma TNF-α and IL-1β levels. Berberine reduced sepsis-induced PEPCK and TLR4 mRNA overexpression in the liver. SIGNIFICANCE:This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.
Berberine functions as a negative regulator in lipopolysaccharide -induced sepsis by suppressing NF-κB and IL-6 mediated STAT3 activation.
Wang Yin,Du Pengfei,Jiang Donghui
Pathogens and disease
Sepsis is a deadly complication raised by bacterial pathogens-induced dysregulated innate inflammatory response. Thus, anti-inflammatory is a potential therapeutic treatment for septic patients. Numerous evidence exhibited that berberine possesses potent anti-inflammatory, anti-apoptotic and anti-oxidative activities. However, the effect of berberine on sepsis is not fully understood. The anti-inflammatory effect of berberine was evaluated using lipopolysaccharide (LPS)-induced macrophages differentiation model in vitro and using LPS/D-galactosamine-challenged septic mice model in vivo. The secreted protein levels were determined by ELISA assay. The multiple targets mRNA and protein levels were measured by quantitative RT-PCR and western blot assay, respectively. Our study demonstrated that administration of berberine significantly attenuated lung tissue injury, and potently increased the survival rate of septic mice by modulating excessive inflammatory response with negligible side-effects. We further found that berberine inhibited the expression of tumor necrosis factor (TNF)-α, interleukin-(IL)-1β and IL-6 via suppressing nuclear factor kappa B subunit 1 (NF-κB) signaling activation. Our study strongly supported the concept that berberine may serve as a single drug or a promising adjuvant that can be used in conjunction with other medications for the treatment of septic patients.
Biological Activity of Berberine-A Summary Update.
Och Anna,Podgórski Rafał,Nowak Renata
Berberine is a plant metabolite belonging to the group of isoquinoline alkaloids with strong biological and pharmacological activity. Currently, berberine is receiving considerable interest due to its anticancer activity based on many biochemical pathways, especially its proapoptotic and anti-inflammatory activity. Therefore, the growing number of papers on berberine demands summarizing the knowledge and research trends. The efficacy of berberine in breast and colon cancers seems to be the most promising aspect. Many papers focus on novel therapeutic strategies based on new formulations or search for new active derivatives. The activity of berberine is very important as regards sensitization and support of anticancer therapy in combination with well-known but in some cases inefficient therapeutics. Currently, the compound is being assessed in many important clinical trials and is one of the most promising and intensively examined natural agents.
Potentiating the activity of berberine for Staphylococcus aureus in a combinatorial treatment with thymol.
Aksoy Cemile Selin,Avci Fatma Gizem,Ugurel Osman Mutluhan,Atas Basak,Sayar Nihat Alpagu,Sariyar Akbulut Berna
A plethora of natural products emerges as attractive molecules in the struggle against antibiotic resistance. These molecules impose their bioactivities not only alone but also in combinations as well, which further enhances their effects. Berberine is a well-known isoquinoline alkaloid with antibacterial activity. Unfortunately, it is readily extruded, which significantly reduces its efficacy and restricts its potential. Thymol is a monoterpenic phenol that exhibits different biological activities but its major effect is observed only at relatively high concentrations, which raises concern on cytotoxicity. The aim of the study was to potentiate the antibacterial activity of berberine, in a combination treatment with thymol in the opportunistic pathogen Staphylococcus aureus and understand the antibacterial mechanism of the combination treatment. The synergism of berberine and thymol was first established by the checkerboard assay. Then the antibacterial mechanism of the synergistic combination was explored by growth curves, biofilm formation assay, SEM observation, and RNA-Seq based transcriptomic profiling. Checkerboard assay showed that 32 μg mL berberine and 64 μg mL thymol was a synergistic combination, both concentrations below their cytotoxicity limits for many cells. 32 μg mL berberine and 32 μg mL thymol was sufficient to inhibit biofilm formation. SEM images confirmed the morphological changes on the structure of combination treated cells. The major finding of the combination treatment from the transcriptomic analysis was the repression in the expression of virulence factors or genes related to virulence factors. Apart from the particular changes related to the cell envelope, the majority of expressional changes seemed to be similar to berberine-treated cells or to be resulting from general stress conditions. The findings of this work showed that when thymol was used in combination with berberine, it enhanced the antibacterial activity of berberine in a synergistic manner. Furthermore, thymol could be considered as an antivirulence agent, disarming S. aureus cells.
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.
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.
Targeting effect of berberine on type I fimbriae of Salmonella Typhimurium and its effective inhibition of biofilm.
Xu Chenran,Wang Feiying,Huang Fangfang,Yang Min,He Dinggeng,Deng Le
Applied microbiology and biotechnology
As a primary cause of food contamination and human diseases, Salmonella Typhimurium can easily form a biofilm that is difficult to remove from food surfaces, and often causes significant invisible threats to food safety. Although berberine has been widely used as an anti-infective drug in traditional medicine, some basic principles underlying its mechanism, especially the interaction between berberine and type I fimbriae genes, has not been verified yet. In this study, two strains of major fimbrial gene mutants (ΔfimA and ΔfimH) were constructed to demonstrate the possible action of berberine on type I fimbriae genes. The broth microdilution method was used to determine the antibacterial activity of berberine against selected strains (WT, ΔfimA, and ΔfimH). Cell agglutination experiments revealed that the number of S. Typhimurium type I fimbriae reduced after berberine treatment, which was consistent with transmission electron microscopy results. Quantitative real-time PCR experiments also confirmed that berberine reduced fimA gene expression, indicating a certain interaction between berberine and fimA gene. Furthermore, confocal laser scanning microscopy imaging of biofilm clearly revealed that berberine prevents biofilm formation by reducing the number of type I fimbriae. Overall, it is well speculated for us that berberine could be an excellent combating-biofilm drug in clinical microbiology and food preservation. KEY POINTS: • Reduce the number of fimbriae. • Berberine targeting fimA. • Effective biofilm inhibitor.
Berberine Promotes Induction of Immunological Tolerance to an Allograft via Downregulating Memory CD8 T-Cells Through Altering the Gut Microbiota.
Qiu Feifei,Lu Weihui,Ye Shulin,Liu Huazhen,Zeng Qiaohuang,Huang Haiding,Liang Chun-Ling,Chen Yuchao,Zheng Fang,Zhang Qunfang,Lu Chuan-Jian,Dai Zhenhua
Frontiers in immunology
Emerging evidence has linked the gut microbiota dysbiosis to transplant rejection while memory T-cells pose a threat to long-term transplant survival. However, it's unclear if the gut microbiome alters the formation and function of alloreactive memory T-cells. Here we studied the effects of berberine, a narrow-spectrum antibiotic that is barely absorbed when orally administered, on the gut microbiota, memory T-cells, and allograft survival. In this study, C57BL/6 mice transplanted with islets or a heart from BALB/c mice were treated orally with berberine. Allograft survival was observed, while spleen, and lymph node T-cells from recipient mice were analyzed using a flow cytometer. High-throughput sequencing and qPCR were performed to analyze the gut microbiota. CD8 T-cells from recipients were cultured with the bacteria to determine potential T-cell memory cross-reactivity to a specific pathogen. We found that berberine suppressed islet allograft rejection, reduced effector CD8CD44CD62L and central memory CD8CD44CD62L T-cells (T), altered the gut microbiota composition and specifically lowered abundance. Further, berberine promoted long-term islet allograft survival induced by conventional costimulatory blockade and induced cardiac allograft tolerance as well. Re-colonization of upregulated CD8 T cells and reversed long-term islet allograft survival induced by berberine plus the conventional costimulatory blockade. Finally, alloantigen-experienced memory CD8 T-cells from transplanted recipients rapidly responded to . Thus, berberine prolonged allograft survival by repressing CD8 T through regulating the gut microbiota. We have provided the first evidence that donor-specific memory T-cell generation is linked to a specific microbe and uncovered a novel mechanism underlying the therapeutic effects of berberine. This study may be implicated for suppressing human transplant rejection since berberine is already used in clinic to treat intestinal infections.
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.