Metabolomics Study of Type 2 Diabetes Mellitus and the AntiDiabetic Effect of Berberine in Zucker Diabetic Fatty Rats Using Uplc-ESI-Hdms. Dong Yu,Chen Yi-Tao,Yang Yuan-Xiao,Zhou Xiao-Jie,Dai Shi-Jie,Tong Jun-Feng,Shou Dan,Li Changyu Phytotherapy research : PTR The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd. 10.1002/ptr.5587
    Activation of AMPK by Medicinal Plants and Natural Products: Its Role in Type 2 Diabetes Mellitus. Francini Flavio,Schinella Guillermo R,Ríos José-Luis Mini reviews in medicinal chemistry Type-2 diabetes (T2D) is a metabolic disease characterized by permanent hyperglycemia, whose development can be prevented or delayed by using therapeutic agents and implementing lifestyle changes. Some therapeutic alternatives include regulation of glycemia through modulation of different mediators and enzymes, such as AMP-activated protein kinase (AMPK), a highly relevant cellular energy sensor for metabolic homeostasis regulation, with particular relevance in the modulation of liver and muscle insulin sensitivity. This makes it a potential therapeutic target for antidiabetic drugs. In fact, some of them are standard drugs used for treatment of T2D, such as biguanides and thiazolidindiones. In this review, we compile the principal natural products that are activators of AMPK and their effect on glucose metabolism, which could make them candidates as future antidiabetic agents. Phenolics such as flavonoids and resveratrol, alkaloids such as berberine, and some saponins are potential natural activators of AMPK with a potential future as antidiabetic drugs. 10.2174/1389557519666181128120726
    Antidiabetic activity of the chemical constituents of Combretum dolichopetalum root in mice. Uzor Philip F,Osadebe Patience O EXCLI journal The root of Combretum dolichopetalum (Combreatacea) is used in ethnomedicine for the management of diabetes mellitus. Though some compounds have been isolated from it, the antidiabetic principles have not been identified. The present study was designed to evaluate the chemical constituents from the root of C. dolichopetalum with a view to identifying the antidiabetic principles. The constituents include the alkaloids, echinulin (1) and arestrictin B (2), the terpenoids, arjunolic acid (3) and 4'-dihydrophaseic acid (4) as well as the phenolic acids, ellagic acid (5) and 3, 4, 3'-tri-O-methylellagic acid (6). Twenty eight mice (in seven groups, n = 4) were made diabetic using alloxan monohydrate (i.p., 120 mg/kg) and treated orally with either the vehicle (control group), any of the constituents or glibenclamide (standard drug). The fasting blood glucose of the diabetic animals was monitored for nine hours. Results showed that all the chemical constituents (1-6) exhibited significant (p < 0.05) antidiabetic activity comparable to glibenclamide. The alkaloids exhibited the most profound antidiabetic activity. The present study has thus identified the antidiabetic principles of C. dolichopetalum root as echinulin, arestrictin B, arjunolic acid, 4'-dihydrophaseic acid, ellagic acid and 3, 4, 3'-tri-O-methylellagic acid. The study has further validated the ethnomedicinal use of the root of C. dolichopetalum in diabetes. 10.17179/excli2016-252
    Mulberry latex rich in antidiabetic sugar-mimic alkaloids forces dieting on caterpillars. Konno Kotaro,Ono Hiroshi,Nakamura Masatoshi,Tateishi Ken,Hirayama Chikara,Tamura Yasumori,Hattori Makoto,Koyama Akio,Kohno Katsuyuki Proceedings of the National Academy of Sciences of the United States of America Since ancient times, mulberry leaves (Morus spp.) have been used to rear the silkworm Bombyx mori. Because the silkworm grows well on mulberry leaves, the toxicities and defensive activities of these leaves against herbivorous insects have been overlooked. Here we show that mulberry leaves are highly toxic to caterpillars other than the silkworm B. mori, because of the ingredients of the latex, a milky sap exuded from mulberry leaf veins. The toxicity of mulberry leaves was lost when the latex was eliminated from the leaves, and artificial diets containing latex showed toxicity. Mulberry latex contained very high concentrations of alkaloidal sugar-mimic glycosidase inhibitors reported to have antidiabetic activities, such as 1,4-dideoxy-1,4-imino-D-arabinitol, 1-deoxynojirimycin, and 1,4-dideoxy-1,4-imino-D-ribitol. The overall concentrations of these inhibitors in latex reached 1.5-2.5% (8-18% dry weight) in several mulberry varieties, which were approximately 100 times the concentrations previously reported from whole mulberry leaves. These sugar-mimic alkaloids were toxic to caterpillars but not to the silkworm B. mori, indicating that the silkworm can circumvent the mulberry tree's defense. Our results suggest that latex ingredients play key roles in defense of this tree and of other plants against insect herbivory, and they imply that plant latexes are treasuries of bioactive substances useful as medicines and pesticides. 10.1073/pnas.0506944103
    Potential Antidiabetic Fumiquinazoline Alkaloids from the Marine-Derived Fungus F41-1. Li Chan-Juan,Chen Pei-Nan,Li Hou-Jin,Mahmud Taifo,Wu Dong-Lan,Xu Jun,Lan Wen-Jian Journal of natural products Fumiquinazoline alkaloids have attracted much attention from medicinal and natural product chemists due to their interesting structures and biological potential. In this study, three new and 12 known fumiquinazoline alkaloids were isolated and characterized from the marine fungus F41-1. The structures of the new compounds and their absolute configurations were determined using NMR spectroscopy, ECD, and OR calculations. The compounds were evaluated for their antidiabetic potential by determining their triglyceride-promoting activity using 3T3-L1 adipocytes. One of the new compounds, scequinadoline J (), as well as scequinadolines D () and E (), was found to promote triglyceride accumulation in 3T3-L1 cells. Scequinadoline D () demonstrated the most potent activity, with an EC value of 0.27 ± 0.03 μM. Quantitative polymerase chain reaction experiments suggested that scequinadoline D () acts through activation of the PPARγ pathway. It stimulated the mRNA expression of PPARγ, AMPKα, C/EBPα, LXRα, SCD-1, and FABP4. In addition, its triglyceride-promoting efficacy could be blocked by a double dose of the PPARγ antagonist GW9662. These results indicated that scequinadoline D () is a potent insulin sensitizer that targets adipocytes and may be useful for the treatment of type 2 diabetes mellitus after further investigation. 10.1021/acs.jnatprod.9b01096
    Anti-hyperglycemic and anti-hyperlipidemia effects of the alkaloid-rich extract from barks of Litsea glutinosa in ob/ob mice. Zhang Xiaopo,Jin Yan,Wu Younan,Zhang Caiyun,Jin Dejun,Zheng Qingxia,Li Youbin Scientific reports The present study investigated the anti-hyperglycemic and anti-hyperlipidemia effects of the alkaloid-rich extract from Litsea glutinosa barks (CG) in ob/ob mice. CG was orally administrated (50, 100 and 200 mg/kg) to ob/ob mice for 4 weeks. Parameters of glucose metabolism, hepatotoxicity, hyperlipidemia and inflammation were measured. CG was chemically characterized using UPLC-QTOF-MS. CG dose-dependently decreased body and fat weights without reducing average food intake. CG (100-200 mg/kg) significantly reduced the serum levels of fasting glucose, glycosylated hemoglobin (HbAlc) and glycosylated serum protein (GSP). CG increased insulin sensitivity as manifested by decreased fasting serum insulin, reduced homeostasis model assessment-estimated insulin resistance (HOMA-IR) and improved oral glucose tolerance. CG also alleviated dyslipidemia, ameliorated liver steatosis, increased the activity of serum lipase and alleviated inflammation. The activities of liver pyruvate kinase and glucokinase as well as liver content of glycogen were increased after CG treatment. CG was rich in alkaloids and eight main alkaloids were identified, many of which had been demonstrated to possess adequate anti-diabetic activities. These results suggest that the alkaloid-rich extract of CG possesses potential anti-hyperglycemic and anti-hyperlipidemic effects and can be utilized as an effective agent for the treatment of type 2 diabetes. 10.1038/s41598-018-30823-w
    Marine Natural Product Bis-indole Alkaloid Caulerpin: Chemistry and Biology. Lunagariya Jignesh,Bhadja Poonam,Zhong Shenghui,Vekariya Rohit,Xu Shihai Mini reviews in medicinal chemistry Marine bis-indole alkaloids comprise a large and increasingly growing class of secondary metabolites, and continue to deliver a great variety of structural templates for diverse biological targets. The alkaloids derived from marine resources play a crucial role in medicinal chemistry and as chemical agents. In particular, bis-indole alkaloid caulerpin which has been isolated from marine green algae Caulerpa and a red algae Chondria armata at various places around the world, was tested for several therapeutic potentials such as anti-diabetic, antinociceptive, anti-inflammatory, anti-tumor, anti- larvicidal, anti-herpes, anti-tubercular, anti-microbial and immunostimulating activities as well as a means of other chemical agents. Herein, we summarized the discovery and isolation of caulerpin, and its potential medicinal and chemical applications in chronological order with various aspects. Additionally, synthesis of caulerpin and its functional analogues have also been reviewed. 10.2174/1389557517666170927154231
    Antidiabetic activity of alkaloids of Aerva lanata roots on streptozotocin-nicotinamide induced type-II diabetes in rats. Agrawal Ritesh,Sethiya Neeraj K,Mishra S H Pharmaceutical biology CONTEXT:The roots of Aerva lanata Linn. (Amaranthaceae) (AL) are employed traditionally as an antihyperglycaemic in the Ayurvedic system of medicine. OBJECTIVE:The present investigation is focus for identification and isolation of the bioactive compound from methanol roots extract of AL against streptozocin-nicotinamide induced elevated serum glucose level in rats. MATERIALS AND METHODS:The methanol extract of the roots was fractionated using different solvents. The partially purified alkaloid basified toluene fraction (PPABTF) showed the presence of alkaloids. The fraction (10 and 20 mg/kg) was tested for oral glucose tolerance test (OGTT) and in non-insulin-dependent diabetes mellitus (NIDDM)-induced elevated serum glucose level in rats. The fraction was also subjected to high performance thin layer chromatography (HPTLC) for the determination of content of individual alkaloids. RESULTS:Single oral administration of PPABTF (10 and 20 mg/kg) after 20 h caused a significant (p < 0.01) reduction in the serum glucose level (mg/dl). On other hand, PPABTF normalised plasma glucose levels after 2 weeks of repeated oral administration in diabetic rats (p < 0.01). HPTLC analysis on PPABTF showed the presence of three known alkaloids. The fraction was further subjected to column chromatography and the compounds identified by ultraviolet, infrared, mass spectroscopy and nuclear magnetic resonance, as canthin-6-one derivatives. CONCLUSION AND DISCUSSION:The PPABTF in the dose of 20 mg/kg showed significant effects on streptozotocin-nicotinamide induced type-II NIDDM in rats. The activity may be due to the presence of alkaloids like canthin-6-one derivatives. 10.3109/13880209.2012.761244
    Pharmacokinetics, Tissue Distribution, and Elimination of Three Active Alkaloids in Rats after Oral Administration of the Effective Fraction of Alkaloids from Ramulus Mori, an Innovative Hypoglycemic Agent. Yang Shuang,Mi Jiaqi,Liu Zhihao,Wang Baolian,Xia Xuejun,Wang Renyun,Liu Yuling,Li Yan Molecules (Basel, Switzerland) In this study, we systematically investigated the plasma pharmacokinetics, tissue distribution, and elimination of three active alkaloids after oral administration of the effective fraction of alkaloids from (SZ-A)-an innovative hypoglycemic agent-in rats. Moreover, the influences of other components in SZ-A on dynamic process of alkaloids were explored for the first time. The results showed that 1-deoxynojirimycin (DNJ), fagomine (FGM) and 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) exhibited nonlinear pharmacokinetics following oral administration of SZ-A (40-1000 mg/kg). The prolonged t and greater area under concentration-time curve (AUC) versus time (AUC) of DNJ for SZ-A than for purified DNJ has been observed after both oral and intravenous administration. It was found that other components in SZ-A could enhance the absorption of DNJ through the intestinal barrier. The major distribution tissues of DNJ, FGM, and DAB were the gastrointestinal tract, liver, and kidney. Three alkaloids were mainly excreted into urine and feces, but less into bile. Interestingly, the excess excretion of FGM was revealed to be partly due to the biotransformation of other components in SZ-A via gut microbiota. These information provide a rational basis for the use of SZ-A in clinical practice. 10.3390/molecules22101616
    Vindogentianine, a hypoglycemic alkaloid from Catharanthus roseus (L.) G. Don (Apocynaceae). Tiong Soon Huat,Looi Chung Yeng,Arya Aditya,Wong Won Fen,Hazni Hazrina,Mustafa Mohd Rais,Awang Khalijah Fitoterapia Vindogentianine, a new indole alkaloid together with six known alkaloids, vindoline, vindolidine, vindolicine, vindolinine, perivine and serpentine were isolated from leaf extract (DA) of Catharanthus roseus (L.) G. Don. Their structures were elucidated by spectroscopic methods; NMR, MS, UV and IR. Vindogentianine is a dimer containing a vindoline moiety coupled to a gentianine moiety. After 24h incubation, vindogentianine exhibited no cytotoxic effect in C2C12 mouse myoblast and β-TC6 mouse pancreatic cells (IC50>50μg/mL). Real-time cell proliferation monitoring also indicated vindogentianine had little or no effect on C2C12 mouse myoblast cell growth at the highest dose tested (200μg/mL), without inducing cell death. Vindogentianine exhibited potential hypoglycemic activity in β-TC6 and C2C12 cells by inducing higher glucose uptake and significant in vitro PTP-1B inhibition. However, in vitro α-amylase and α-glucosidase inhibition assay showed low inhibition under treatment of vindogentianine. This suggests that hypoglycemic activity of vindogentianine may be due to the enhancement of glucose uptake and PTP-1B inhibition, implying its therapeutic potential against type 2 diabetes. 10.1016/j.fitote.2015.01.019
    Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents. Patel Om P S,Mishra Akansha,Maurya Ranjani,Saini Deepika,Pandey Jyotsana,Taneja Isha,Raju Kanumuri S R,Kanojiya Sanjeev,Shukla Sanjeev K,Srivastava Mahendra N,Wahajuddin M,Tamrakar Akhilesh K,Srivastava Arvind K,Yadav Prem P Journal of natural products This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes. 10.1021/acs.jnatprod.5b00883
    Evaluation of antidiabetic potential of steroidal alkaloid of Sarcococca saligna. Ullah Jan Naeem,Ali Amjad,Ahmad Bashir,Iqbal Naveed,Adhikari Achyut,Inayat-Ur-Rehman ,Ali Abid,Ali Safdar,Jahan Azra,Ali Hamid,Ali Ijaz,Ullah Anwar,Musharraf Syed Ghulam Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie The demand for natural medicines has increased because of their limited adverse effects. The aim of study is to explore the antidiabetic potential of isolated steroidal alkaloid from Sarcococca saligna in streptozotocin induced diabetic rats. To determine the antidiabetic activity of steroidal alkaloids, diabetes was induced in rats by injecting streptozotocin intraperitoneally at a dose of 40 mg/Kg. After a week of STZ injection the treatment were started and the 8th day was considered as the 1st day of treatment and up to four weeks the rats were treated with steroidal alkaloids. Animals were divided into five groups, group 1 considered as a control group by receiving normal saline (1 ml/Kg) twice daily and group 2, 3, 4 were treated with active compound sarcovagine-D, saracodine and holaphylline at the dose of 5 mg/Kg subcutaneously twice a day while group 5 was treated with a standard drug glibenclamide at a dose of 1 mg/Kg/day. The result showed that treated group 2 and 4 reduced the glucose level in blood significantly while group 3 showed moderate glucose reduction. The fructosamine level reduced significantly in treating group 4 from the 2nd week of treatment while group 2 and 3 decreased the level significantly in week 4 in diabetic rats. The treated groups showed gradual decreases the glucose level in 1st and 2nd week of oral glucose tolerance test compared to control group. The group receiving holaphylline (4) and sarcovagine-D (2) showed good improvements in blood lipids while the effect of compound on body weight showed less significant improvement. The present study concluded that steroid alkaloids from isolated Sarcococca saligna possess hypoglycemic effect and improve others diabetes associated complications. Together these finding further research is needed using a range of doses to explore the other possible beneficial effects in diabetes mellitus and its molecular mechanism. 10.1016/j.biopha.2018.01.008
    Antidiabetic and antioxidant properties of alkaloids from Catharanthus roseus (L.) G. Don. Tiong Soon Huat,Looi Chung Yeng,Hazni Hazrina,Arya Aditya,Paydar Mohammadjavad,Wong Won Fen,Cheah Shiau-Chuen,Mustafa Mohd Rais,Awang Khalijah Molecules (Basel, Switzerland) Catharanthus roseus (L.) G. Don is a herbal plant traditionally used by local populations in India, South Africa, China and Malaysia to treat diabetes. The present study reports the in vitro antioxidant and antidiabetic activities of the major alkaloids isolated from Catharanthus roseus (L.) G. Don leaves extract. Four alkaloids--vindoline I, vindolidine II, vindolicine III and vindolinine IV--were isolated and identified from the dichloromethane extract (DE) of this plant's leaves. DE and compounds I-III were not cytotoxic towards pancreatic β-TC6 cells at the highest dosage tested (25.0 µg/mL). All four alkaloids induced relatively high glucose uptake in pancreatic β-TC6 or myoblast C2C12 cells, with III showing the highest activity. In addition, compounds II-IV demonstrated good protein tyrosine phosphatase-1B (PTP-1B) inhibition activity, implying their therapeutic potential against type 2 diabetes. III showed the highest antioxidant potential in ORAC and DPPH assays and it also alleviated H₂O₂-induced oxidative damage in β-TC6 cells at 12.5 µg/mL and 25.0 µg/mL. 10.3390/molecules18089770