Synthesis,in-vivo anti-diabetic & anticancer activities and molecular modelling studies of tetrahydrobenzo[d]thiazole tethered nicotinohydrazide derivatives

A series of thirty new thiazole-pyridine derivatives were synthesized by reaction of 4,4,7,7-tetra-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine with 6-chloronicotinate followed by condensing with benzaldehydes and screened for their anti-diabetic activity by in vivo housing Swiss albino mice. All synthesized compounds resulted in reducing the glucose level when compared with reference standard drug glibenclamide. In specific, compound 7 exhibited significant activity in terms of fasting blood glucose level reduction. In addition, the in-silico binding studies of the potential compounds 11f and 11g with human PPAR-γ protein complexed with Retinoid X Receptor (RXR) alpha Nuclear Receptor showed good interactions when compared to the standard drug Rosiglitazone. The newly synthesized drugs may be potential anti-diabetic drugs with possible specific actions.     

Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKα activation

We found compound 12N-p-trifluoromethylbenzenesulfonyl matrinane (1) was a potent anti-diabetic agent. Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes, taking 1 as the lead. In high-fat diet (HFD) and STZ induced diabetic mice, 9a significantly lowers blood glucose, improves glucose tolerance, and especially alleviates diabetic nephropathy and islet damage. Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio, as well as liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase (CaMKK), which synergistically activates AMPKα and then stimulates glucose transporter 4 (GLUT4) membrane translocation and 2-deoxyglucose (2-DG) uptake to exert anti-diabetic efficacy. Therefore, compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism, worthy of further investigation.     

Anti-diabetic Effects of Polysaccharides from Ethanol-insoluble Residue of Schisandra chinensis(Turcz.) Baill on Alloxan-induced Diabetic Mice

The ethanol-insoluble residue of Schisandra generated during lignans industrial production is usually treated as solid waste. However, there is active polysaccharide which could be used in it. In this work, the water-soluble polysaccharides from the ethanol-insoluble residue of Schisandra(ESCP) were obtained and their anti-diabetic effect was evaluated. The results indicate that ESCP could significantly reduce the blood glucose level in alloxan-induced diabetic mice. Moreover, the ESCP could significantly improve the lipid metabolism and increase the content of liver glycogen in alloxan-induced diabetic mice. The results indicate that ESCP could be developed into a potential natural hypoglycemic agent.     

Hypoglycaemic activity of saponin fraction extracted from Momordica charantia in PEG/salt aqueous two-phase systems

Momordica charantia (family, Cucurbitaceae), commonly known as karela or bitter melon (Japanese name 'Tsurureishi'), is used as a folk medicine in China, the Indian subcontinent and South America. In Chinese traditional medicine, the plant is usually used as a hypoglycaemic and anti-diabetic agent. The hypoglycaemic activity of saponin fraction (SF) extracted from M. charantia in PEG/salt aqueous two-phase systems was studied in this article. Alloxan-induced hyperglycaemic mice were used in the study. The blood glucose, insulin secretion, glycogen synthesis and the body weight of the mice were analysed. At the same time, the sugar tolerance of the normal mice was also determined. After the mice were administered (i.g.) with SF (500 mg kg(-1)), the blood glucose of alloxan-induced hyperglycaemic mice decreased (p < 0.05), the level of insulin secretion and glycogen synthesis of alloxan-induced hyperglycaemic mice elevated (p < 0.05, p < 0.01) and the sugar tolerance of the normal mice was improved. Also, the body weight of the alloxan-induced hyperglycaemic mice was increased gradually. The saponin constituents extracted from M. charantia in an aqueous two-phase extraction system induced significant hypoglycaemic activity in hyperglycaemic and normal mice.     

双（α－呋喃甲酸）氧钒的合成和抗糖尿病活性研究

设计和合成了一种新型的有机羧酸氧钒配合物双（α－呋喃甲酸）氧钒。运用 元素分析、红外光谱、紫外光谱、质谱和核磁共振氢谱对配合物的结构进行了初步 确证。在实验性动物模型上研究了这个配合物的初步毒性和降血糖作用。结果表明 ：双（α－呋喃甲酸）氧钒具有活性高，安全性好的优点，对糖尿病的治疗显示出 潜在的开发应用前景。     

Structure analysis and anti-fatigue activity of a polysaccharide from Lepidium meyenii Walp

A polysaccharide was obtained from Lepidium meyenii Walp by hot water extraction and purification by Millipore (100 kD) and Sephadex G-200. The content of polysaccharide was examined to be 89.9% with phenol-sulfuric acid method. Its average molecular weight was estimated to be 2.213 × 10⁶ Da by High Performance Gel Permeation Chromatography (HPGPC). Monosaccharide analysis showed that the polysaccharide was composed of arabinose, mannose, glucose and galactose with the molar ratio of 2.134: 1: 2.78: 2.82. After Smith degradation, methylation, infrared spectroscopy and NMR, the primary structure of the polysaccharide was identified. The backbone of the polysaccharide was composed of →4)-β-D-Galp-(1→ and →4)-α-D-Galp-(1→, while the branches were comprised of →6)-β-D-Glup-(1→, →5)- β-D-Araf-(1→, →3,6)-α-D-Manp-(1→, →3)-α-D-Galp-(1→, and α-D-Glup-(1→. The anti-fatigue effect of the polysaccharide was evaluated using exhaustive swimming test and biochemical indexes. The results indicated the polysaccharide has anti-fatigue effect.     

1H NMR-based metabonomics of the hypoglycemic effect of polysaccharides from Cordyceps militaris on streptozotocin-induced diabetes in mice

Abstract

The crude polysaccharide was extracted from Cordyceps militaris. Material ratio of powder and water was 1:10. The polysaccharide was successively purified by Sevag and chromatography on Sephadex G-100 column to produce a polysaccharide fraction termed CBPS-II. The average molecular weight of CBPS-II was 1.273?×?10³ kDa. The study was conducted to investigate the hypoglycemic effect of Cordyceps militaris polysaccharide on diabetic mice. Analysis of the clinical chemistry of the serum samples included serum creatinine (CRE), urea nitrogen (BUN), triglyceride (TG) and total cholesterol (TC). Results revealed that a certain dose of polysaccharide can alleviate the symptoms of metabolic disorders of diabetes, contributing to the body to restore the normal levels. The metabolic profiling method was adopted to find the related biomarkers and the metabolic pathway of diabetes. Moreover, results showed that 100?mg·kg^?1 of Cordyceps polysaccharides can effectively reduce the blood glucose level of diabetic mice, thus regulating the metabolism of their energy, amino acids and intestinal microbes. The biomarkers noted in their metabolism were glucose, lactic acid, 3-hydroxy butyric acid, creatine, glutamate, valine, leucine, isoleucine and very low density lipoprotein (VLDL).     

网络结构对多层聚乙烯共混物界面扩散行为的影响

通过溶液法制备超高分子量聚乙烯(UHMWPE)/乙烯-己烯共聚物(PEH)共混物,采用动态流变学方法研究了UHMWPE/PEH共混物多层膜在熔点以上的界面扩散行为,结合Double-Reptation理论计算得到了UHMWPE/PEH共混物多层膜的自扩散系数.研究表明UHMWPE在浓度c=1.0 wt%以上可以在PEH基体中形成网络结构.UHMWPE/PEH共混物多层膜界面扩散不符合严格的菲克扩散定律,扩散系数具有时间依赖性.扩散曲线显示扩散过程在到达平台值之前分为2个区域,区域I接近于菲克扩散;然而由于引入UHMWPE,区域II扩散显著偏离菲克扩散行为,特别是当UHMWPE在PEH基体中形成网络结构以后,偏离菲克扩散行为更加显著.     

Insulin-like antigen of mangrove leaves and its anti-diabetic activity in alloxan-induced diabetic rats

The objective of this study was to evaluate the anti-diabetic potential of three mangrove plants, Rhizophora mucronata, Rhizophora apiculata and Rhizophora annamalayana, and to detect the presence of their insulin-like protein. The in?vivo anti-diabetic experiment was done on male albino Wister rats. Oral administration of 60?mg?kg(-1) leaf powder extract of the three different mangrove plants for 30 days modulated the parameters such as blood glucose, plasma insulin, body weight, total haemoglobin, glycosylated haemoglobin, liver glycogen, plasma and tissue lipids, cholesterol, triglycerides, free fatty acids and phospholipids to normal levels in the alloxan-induced diabetic rats. The anti-diabetic activity of R.?apiculata was more pronounced than that of the other mangrove extracts, but it was on a par with the commercial drug glibenclamide. The presence of an insulin-like protein in the mangrove extracts was detected by SDS-PAGE analysis and confirmed through ELISA. Hence, the anti-diabetic activity and the presence of an insulin-like protein in Rhizophora species were proved scientifically.     

The Effect of Chrysin-Loaded Phytosomes on Insulin Resistance and Blood Sugar Control in Type 2 Diabetic db/db Mice

Although a variety of beneficial health effects of natural flavonoids, including chrysin, has been suggested, poor solubility and bioavailability limit their practical use. As a promising delivery system, chrysin-loaded phytosomes (CPs) were prepared using egg phospholipid (EPL) at a 1:3 molar ratio and its antidiabetic effects were assessed in db/db diabetic mice. Male C57BLKS/J-db/db mice were fed a normal diet (control), chrysin diet (100 mg chrysin/kg), CP diet (100 mg chrysin equivalent/kg), metformin diet (200 mg/kg) or EPL diet (vehicle, the same amount of EPL used for CP preparation) for 9 weeks. Administration of CP significantly decreased fasting blood glucose and insulin levels in db/db mice compared with the control. An oral glucose tolerance test and homeostatic model assessment for insulin resistance were significantly improved in the CP group (p < 0.05). CP treatment suppressed gluconeogenesis via downregulation of phosphoenolpyruvate carboxykinase while it promoted glucose uptake in the skeletal muscle and liver of db/db mice (p < 0.05). The CP-mediated improved glucose utilization in the muscle was confirmed by upregulation of glucose transporter type 4, hexokinase2 and peroxisome proliferator-activated receptor γ during treatment (p < 0.05). The CP-induced promotion of GLUT4 plasma translocation was confirmed in the skeletal muscle of db/db mice (p < 0.05). Based on the results, CP showed greater antidiabetic performance compared to the control by ameliorating insulin resistance in db/db mice and phytosome can be used as an effective antidiabetic agent.     

Fructose production

Amyloglucosidase, pullulanase, and glucose isomerase were coimmobilized onto granular chicken bone (BIOBONE^TM). Enzyme ratios showing optimum glucose and fructose production (0.7:10:22.3 U amyloglucosidase: pullulanase: glucose isomerase) resulted in 14.4±1.9% of activity bound relative to an equal amount of free enzyme. The estimated specific activity for these enzymes decreased 4.6-fold with immobilization. Reaction_pH strongly influenced the yield and ratio of glucose and fructose produced. Net hexose production from the immobilized system was optimal at_pH 6.5 and 55°C with a fructose yield of about 20%.     

Chemical Profile of Launaea nudicaulis Ethanolic Extract and Its Antidiabetic Effect in Streptozotocin-Induced Rats

Launaea nudicaulis is used in folk medicine worldwide to treat several diseases. The present study aimed to assess the antidiabetic activity of L. nudicaulis ethanolic extract and its effect on diabetic complications in streptozotocin-induced hyperglycemic rats. The extract was orally administrated at 250 and 500 mg/kg/day for 5-weeks and compared to glibenclamide as a reference drug at a dose of 5 mg/kg/day. Administration of the extract exhibited a potential hypoglycemic effect manifested by a significant depletion of serum blood glucose concurrent with a significant elevation in serum insulin secretion. After 5-weeks, extract at 250 and 500 mg/kg/day decreased blood glucose levels by about 53.8 and 68.1%, respectively, compared to the initial values (p ≤ 0.05). The extract at the two dosages prevented weight loss of rats from the 2nd week till the end of the experiment, compared to diabetic control rats. The extract further exhibited marked improvement in diabetic complications including liver, kidney and testis performance, oxidative stress, and relative weight of vital organs, with respect to diabetic control. Histopathological examinations confirmed the previous biochemical analysis, where the extract showed a protective effect on the pancreas, liver, kidney, and testis that degenerated in diabetic control rats. To characterize extract composition, UPLC-ESI–qTOF-MS identified 85 chromatographic peaks belonging to flavonoids, phenolics, acyl glycerols, nitrogenous compounds, and fatty acids, with four novel phenolics reported. The potential anti-diabetic effect warrants its inclusion in further studies and or isolation of the main bioactive agent(s).     

Extraction, Purification and Anti-tumor Activity of Polysaccharide from Mycelium of Mutant Cordyceps Militaris

A water-soluble polysaccharide(named MCMP) was isolated from the mycelium with high yield mutation Cordyceps militaris by hot-water extraction, deproteinization by sevage, alcohol precipitation, anion-exchange and gel filtration chromatography CL-6B. The polysaccharide contained mannose, rhamnose, galactose and glucose in a molar ratio of 59.36:1:8.31:39.50, of which the average molecular weight is 8100. In our research, Hep-G2 cells, Hela cells and mesangial cells were chosen to determine the anti-tumor activity of the polysaccharide. The results of MTT assay show that polysaccharides of the mutant strain presented inhibitory activity on the cells proliferation after 48 h incubation.     

Naringenin and Phytoestrogen 8-Prenylnaringenin Protect against Islet Dysfunction and Inhibit Apoptotic Signaling in Insulin-Deficient Diabetic Mice

It has been shown that citrus flavanone naringenin and its prenyl derivative 8-prenylnaringenin (8-PN) possess various pharmacological activities in in vitro and in vivo models. Interestingly, it has been proposed that prenylation can enhance biological potentials, including the estrogen-like activities of flavonoids. The objective of this study was to investigate the anti-diabetic potential and molecular mechanism of 8-PN in streptozotocin (STZ)-induced insulin-deficient diabetic mice in comparison with naringenin reported to exhibit hypoglycemic effects. The oral administration of naringenin and 8-PN ameliorated impaired glucose homeostasis and islet dysfunction induced by STZ treatment. These protective effects were associated with the suppression of pancreatic β-cell apoptosis and inflammatory responses in mice. Moreover, both naringenin and 8-PN normalized STZ-induced insulin-signaling defects in skeletal muscles and apoptotic protein expression in the liver. Importantly, 8-PN increased the protein expression levels of estrogen receptor-α (ERα) in the pancreas and liver and of fibroblast growth factor 21 in the liver, suggesting that 8-PN could act as an ERα agonist in the regulation of glucose homeostasis. This study provides novel insights into the mechanisms underlying preventive effects of naringenin and 8-PN on the impairment of glucose homeostasis in insulin-deficient diabetic mice.     

Size,surface charge and flexibility of vinegar-baked Radix Bupleuri polysaccharide affecting the immune response

Remarkably, nanomaterials can interact with the cells of immune system and either enhance or inhibit its function in many ways. Unfortunately, such valuable information has been overlooked in studies of polysaccharide immune activity. This study isolated a nano-polysaccharide from vinegar-baked Radix Bupleuri by membrane separation system, DEAE-52 and Sephadex-G200. The physicochemical characterization and immunoregulatory activity were studied through DLS, Congo red, Scanning Electron Microscope, UV–Vis, HPGPC, FT-IR, Methylation, NMR, MTT, neutral red and enzyme linked immunosorbent assay. Results showed that VBCP2.5 was an acidic polysaccharide with a molecular weight of 674 kDa. Its monosaccharides composed of mannose, rhamnose, galacturonic acid, glucose, galactose and arabinose at a molar ratio of 1.72: 9.59: 57.63: 5.37: 6.71: 18.99. VBCP2.5 possessed micelle forming ability at 52.574 µg/mL and flexible chain conformation, as well as with a small size distribution ～ 84.99 nm and positive charge in stimulated blood fluid and different from that in deionized water. The microtopography was characterized by irregular lamellar, dendritic, cylindrical or spherical aggregates, with folds and cracks on the surface. Structure analyses showed that VBCP2.5 characterized by high proportion of 1,4 linked-α-D-GalpA and a small fraction of RG-I, some other glycosidic linkages included 1,5 linked-α-L-Araf, 1,3,5 linked-α-L-Araf, 1,3,4 linked-Galp, 1,4,6 linked-Manp, t-α-L-Araf, t-β-D-Glcp and t-α-D-Galp were also comprised. VBCP2.5 exhibited immunomodulatory potential which included the promotion of phagocytosis, the release of NO and the secretion of TNF-α and IL-6 of RAW264.7 cells. The possible activation of macrophages by VBCP2.5 may be mediated through endocytosis pathway. Small size, positive charge, shape and flexible conformation may accelerate this process. The information gathered here could lead to new platform for comprehensive understand included primary structure, properties of nanoscale, and correlation with immunoregulation of polysaccharides.     

Gundelia tournefortii: Fractionation,Chemical Composition and GLUT4 Translocation Enhancement in Muscle Cell Line

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 μg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography–mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.     

A new anti-diabetic sesquiterpenoid from Acorus calamus

A new sesquiterpenoid,1β,5α-guaiane-4β,10α-diol-6-one(1),was isolated from 70%EtOH extract of the rhizomes of Acorus calamus.The structure was determined on spectroscopic methods,especially 2D NMR techniques.The absolute configuration of 1 was confirmed by TDDFT quantum chemical calculation of its ECD spectrum.Compound 1 showed promising anti-diabetic activity on a insulin-mediated glucose consumption model of HepG2 cells.     

Antihyperglycaemic mechanisms of an aceteoside polymer from rose flowers and a polysaccharide–protein complex from abalone mushroom

Oral administration of an aceteoside polymer from rose Rosa rugosa (P_1-b) and a polysaccharide–peptide complex from abalone mushroom Pleurotus abalonus (LB-1b), both with antioxidant activity, produced antihyperglycaemic effects in alloxan-induced diabetic mice. The expression of insulin, superoxide dismutase and pancreas duodenum homeobox factor-1 essential for pancreatic islet function as estimated by real-time PCR was augmented. The reactive oxygen species-scavenging ability of the rose constituent was notably stronger than the mushroom constituent. Thus, the two biomolecules protected the pancreas from oxidative stress, elevated pancreatic insulin expression and lowered circulating glucose level.     

An eco-friendly technology for polysaccharide production from logging and sawing waste

A polysaccharide recovery technology was developed with intent to be used in integrated processing of larch biomass waste into practically significant arabinogalactan, pectin, and crystalline glucose suitable for medicinal, food-industry, and agricultural applications. Theoretical aspects were considered for arabinogalactan extraction from larch wood, in which procedure some of individual stages and the entire process cycle of arabinogalactan recovery on a pilot installation were optimized. The possibility of saccharification of larch wood-derived lignocellulosic residue into crystalline glucose was demonstrated. The results of a technological study on pectin polysaccharide isolation from larch bark were reported along with the findings concerning the membrane tropic activity of pectin and ability to form nanobiocomposites via interaction with transition and noble metal ions.