双(2-取代-3-羟基-4-吡喃酮)合铜(II)配合物的合成和降血糖作用

合成了双(2-取代-3-羟基-4-吡喃酮)合铜(II)配合物, 采用元素分析、质谱、红外光谱、电子光谱、电子自旋共振谱表征了它们为平面正方型配合物, 中心离子和配体的物质的量比为1∶2. 在STZ-糖尿病小鼠模型上, 其中双(2-乙基-3-羟基-4-吡喃酮)合铜(II)在10 mg/kg的剂量下灌胃给药, 能增加血清胰岛素的合成和分泌、降低糖尿病小鼠的血糖水平, 显示出良好的抗糖尿病的作用. 该配合物毒性低, 对正常小鼠灌胃给药的半数致死量LD₅₀是855.9 mg/kg.     

Synthesis,anti-hyperglycaemic activity,and in-silico studies of N-substituted 5-(furan-2-ylmethylene)thiazolidine-2,4-dione derivatives

Thiazolidinedione derivatives have been used as anti-hyperglycemic agents in diabetic patients since last decade. In the present study, a series of N-substituted-5-(furan-2-ylmethylene)thiazolidine-2,4-dione derivatives were synthesized and characterized by ¹H-NMR, ¹³C-NMR and mass spectra. The introduction of the alkyl/haloalkyl moiety onto the amidic nitrogen of the thiazolidine-2,4-dione ring was intended to enhance the anti-hyperglycaemic activity, which was further tested in vivo by using alloxan-induced diabetic laca mice. Molecular docking simulation studies further helped in understanding the nature of the interactions and the binding mode of ligands inside the active site of the protein tyrosine phosphatase 1B enzyme, which negatively regulates the insulin signaling pathway. The compounds were screened for in-vivo anti-hyperglycaemic activity in which compounds 9 and 10 have exhibited significant decreases in blood glucose level comparable to that of pioglitazone.

     

Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.     

Anti-Hyperglycemic Effects of Refined Fractions from Cyclocarya paliurus Leaves on Streptozotocin-Induced Diabetic Mice

To identify the chemical components responsible for the anti-hyperglycemic effect of Cyclocarya paliurus (Batal.) Iljinsk (Juglandaceae) leaves, an ethanol extract (CPE) and a water extract (CPW) of C. paliurus leaves, as well as their total flavonoids (CPF), triterpenoids (CPT) and crude polysaccharides (CPP), were prepared and assessed on streptozotocin (STZ)-induced diabetic mice. After being orally administrated once a day for 24 days, CPF (300 mg/kg), CPP (180 mg/kg), or CPF+CPP (300 mg/kg CPF + 180 mg/kg CPP) treatment reversed STZ-induced body weight and muscle mass losses. The glucose tolerance tests and insulin tolerance tests suggested that CPF, CPP, and CPF+CPP showed anti-hyperglycemic effect in STZ-induced diabetic mice. Furthermore, CPF enhances glucose-stimulated insulin secretion in MIN6 cells and insulin-stimulated glucose uptake in C2C12 myotubes. CPF and CPP suppressed inflammatory cytokine levels in STZ-induced diabetic mice. Additionally, CPF and CPP improved STZ-induced diabetic nephropathy assessed by H&E staining, blood urea nitrogen content, and urine creatinine level. The molecular networking and Emperor analysis results indicated that CPF showed potential anti-hyperglycemic effects, and HPLC–MS/MS analysis indicated that CPF contains 3 phenolic acids and 9 flavonoids. In contrast, CPT (650 mg/kg) and CPC (300 mg/kg CPF + 180 mg/kg CPP + 650 mg/kg CPT) did not show anti-hyperglycemic effect. Taken together, polysaccharides and flavonoids are responsible for the anti-hyperglycemic effect of C. paliurus leaves, and the clinical application of C. paliurus need to be refined.     

Bioassay-guided antidiabetic study of Phaleria macrocarpa fruit extract

An earlier anti-hyperglycemic study with serial crude extracts of Phaleria macrocarpa (PM) fruit indicated methanol extract (ME) as the most effective. In the present investigation, the methanol extract was further fractionated to obtain chloroform (CF), ethyl acetate (EAF), n-butanol (NBF) and aqueous (AF) fractions, which were tested for antidiabetic activity. The NBF reduced blood glucose (p < 0.05) 15 min after administration, in an intraperitoneal glucose tolerance test (IPGTT) similar to metformin. Moreover, it lowered blood glucose in diabetic rats by 66.67% (p < 0.05), similar to metformin (51.11%), glibenclamide (66.67%) and insulin (71.43%) after a 12-day treatment, hence considered to be the most active fraction. Further fractionation of NBF yielded sub-fractions I (SFI) and II (SFII), and only SFI lowered blood glucose (p < 0.05), in IPGTT similar to glibenclamide. The ME, NBF, and SFI correspondingly lowered plasma insulin (p < 0.05) and dose-dependently inhibited glucose transport across isolated rat jejunum implying an extra-pancreatic mechanism. Phytochemical screening showed the presence of flavonoids, terpenes and tannins, in ME, NBF and SFI, and LC-MS analyses revealed 9.52%, 33.30% and 22.50% mangiferin respectively. PM fruit possesses anti-hyperglycemic effect, exerted probably through extra-pancreatic action. Magniferin, contained therein may be responsible for this reported activity.     

Facile green synthesis of gold nanoparticles using leaf extract of antidiabetic potent Cassia auriculata

A simple biological method for the synthesis of gold nanoparticles (AuNPs) using Cassia auriculata aqueous leaf extract has been carried out in the present study. The reduction of auric chloride led to the formation of AuNPs within 10 min at room temperature (28°C), suggesting a higher reaction rate than chemical methods involved in the synthesis. The size, shape and elemental analysis were carried out using X-ray diffraction, TEM, SEM-EDAX, FT-IR and visible absorption spectroscopy. Stable, triangular and spherical crystalline AuNPs with well-defined dimensions of average size of 15-25 nm were synthesized using C. auriculata. Effect of pH was also studied to check the stability of AuNPs. The main aim of the investigation is to synthesize AuNPs using antidiabetic potent medicinal plant. The stabilizing and reducing molecules of nanoparticles may promote anti-hyperglycemic if tested further.     

Application of a Stability-Indicating Densitometric RP-TLC Method for Analysis of Pioglitazone Hydrochloride in the Bulk Material and in Pharmaceutical Formulations

JPC – Journal of Planar Chromatography – Modern TLC - Pioglitazone hydrochloride is an oral anti-hyperglycemic agent used for treatment of type-II diabetes. This paper reports a...     

Inhibitory effect of eleven herbal extracts on advanced glycation end-products formation and aldose reductase activity

The formation of advanced glycation end-products(AGEs) and aldose reductase(AR) activity have been implicated in the development of diabetic complications. Our study sought to characterize the capacities of eleven herbal extracts against the formation of AGEs and the AR activity. An ultrahigh performance liquid chromatography and tandem mass spectrometry(UPLC–MS/MS) method was used for the detection of AR activity and the screening of AR inhibitors in this research. The amount of sorbitol from each analyte was directly detected using the multiple reaction monitoring mode and the sorbitol level could be reduced via the addition of an inhibitor. Moreover, the BSA/glucose(fructose) system was applied to investigate their inhibitory activities of AGEs formation in glycation model reactions.Compared with other screened herbs used in our study, Flos Sophorae Immaturus and Radix Scutellariae seemed to be more effective on inhibiting the formation of AGEs and AR activity. The inhibiting capacities of herbal extracts against AR activity and AGEs formation may be correlated with the bioactive components of the herbal extracts. The differences were correlated with the amount of polyphenol and flavonoid components. In the study, we have investigated the potential anti-hyperglycemic bioactivity of eleven herbal extracts in vitro, which could provide a reference for further in vivo research in the prevention and treatment of diabetic complications.     

Three new phenylacetamide glycosides from Dracocephalum tanguticum Maxim and their anti-hyperglycemic activity

Abstract

Three new phenylacetamide glycosides (1–3) together with one known phenylacetamide glycoside (4) and two known flavonoid glycosides (5–6) were isolated from whole plants of Dracocephalum tanguticum. The structure of all compounds were elucidated based on spectroscopic data analysis and comparison with data reported in related literature. Compounds (1–3) were evaluated for their anti-hyperglycemic and anti-fungal (Candida albicans) activities, the results revealed that all of them showed moderate activity with 3T3-L1 adipocytes glucose consumption rate of 20.80?±?1.47%, 21.48?±?2.44%, and 21.57?±?1.35%, respectively at the final concentration of 25?μM. However, none of them showed obvious Candida albicans inhibitory activity.     

In vitro α-glucosidase and α-amylase inhibition,and in vivo anti-hyperglycemic effects of <Emphasis Type="Italic">Psidium littorale</Emphasis> Raddi leaf extract

Guava, belonging to family Myrtaceae, is widely grown in tropical countries. Different parts of guava are reported to have long been used in folk medicine. In this study, the in vitro and in vivo anti-hyperglycemic activities of Psidium littorale Raddi leaves extract were investigated. The results indicated that the leaf extract demonstrates relatively high intestinal α-glucosidase inhibitory activity in rats, twice as high as acarbose. In addition, the extract also induced lowering fasting blood glucose levels in streptozotocin- induced diabetic rats at the dose of 150 mg/kg body weight, and without any effect on normal rats. Moreover, the extract did not significantly induce body weight loss in rats. The results suggest that P. littorale Raddi may prove to be useful in treating diabetes in humans.     

Determination of Metformin in Human Plasma by Liquid Chromatography-tandem Mass Spectrometric Assay

Introduction Metformin (1,1-dimethylbiguanide) (Fig. 1) is an oral anti-hyperglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus (type Ⅱ). Owing to its weight-decreasing and serum lipid-normalizing effects, it is especially recommended for obese patients[1,2] Various analytical methods have been described for the measurement of metformin in biological fluids, including gas chromatography(GC)[3-5], capillary electrophoresis (CE)[6] and HPLC[7～16]with UV detection[7-12,17] HPLC-Mass spectrometry (LC/APCIMS/MS ) offers an attractive alternative to HPLC[18].     

Antioxidant and α-Glucosidase Inhibitory Compounds of Centella Asiatica

Centella asiatica, as known as Pegagan was previously reported to have anti-hyperglycemic effects in animal diabetic model rats. However, its α-glucosidase activity in vitro assay not yet reported. Our goal in this study is to isolate and identify active compounds as α-glucosidase inhibitor and antioxidant from aqueous ethanol 70% (v/v) extract of C. asiatica. The extract was partitioned by n-hexane, EtOAc, and n-butanol sequentially. Among the fractions tested, EtOAc fraction was showed the highest antioxidant and α-glucosidase inhibitory activities with an IC₅₀ values of 45.42 and 73.17 μg/mL, respectively. The antioxidant activity was conducted by determination of DPPH radical scavenging activity, whereas α-glucosidase inhibitory activity was determined against yeast α-glucosidase. Furthermore, isolation of the ethyl acetate extract yielded two active compounds, which were identified as kaempferol (1) and quercetin (2). Both of the compounds showed good yeast α-glucosidase inhibitory activity with IC₅₀ values of 16.50 and 21.61 μg/mL, respectively. In addition those compounds also could scavenge DPPH radical activity with IC₅₀ values of 9.64 and 11.97 μg/mL, respectively. Due to its ability in reducing α-glucosidase activity and scavenging free radical activity, the C. asiatica appears to be a potential as a good resource for future development of antioxidant and antidiabetic drug.     

Liquid chromatography-diode array detection-electrospray ionisation mass spectrometry/nuclear magnetic resonance analyses of the anti-hyperglycemic flavonoid extract of Genista tenera. Structure elucidation of a flavonoid-C-glycoside

The anti-hyperglycemic flavonoid extract obtained from Genista tenera was first studied by liquid chromatography (LC)-diode array detection (DAD) which showed the presence of two major compounds. One of them was identified as genistein-7-O-glucoside. Luteolin-7-O-glucoside was detected as a minor constituent, while luteolin-7,3'-di-O-glucoside and rutin were found in trace amounts. LC-DAD-ESI-MS and NMR were used to confirm the structure of these compounds and allowed the elucidation of the structure of the unknown major compound, which is the flavonoid 5,7,4'-trihydroxyisoflavone-8-C-glucoside.     

Synthesis and pharmacological activity evaluation of curcumin derivatives

Curcumin 3,4-dihydropyrimidinones/thiones/imines have been synthesized using one-pot cyclocondensation of curcumin with substituted aromatic aldehydes and urea/thiourea/guanidine in the presence of chitosamine hydrochloride as a biodegradable and nontoxic catalyst under solvent-free microwave irradiation. The synthesized product was purified by crystallization from ethanol and the process does not involve any hazardous solvent. All the synthesized curcumin derivatives 4a-o were screened for antioxidant and anti-inflammatory activity. Biological activity data of the synthesized showed that most of the synthesized compounds exhibited greater antioxidant and anti-inflammatory activity than curcumin.     

Preparation,structure elucidation,and antioxidant activity of new bis(thiosemicarbazone) derivatives

Schiff-base–bearing new bis(thiosemicarbazone) derivatives were prepared from terephthalaldehyde and various thiosemicarbazides. FT–IR, ¹H NMR, ¹³C NMR, and UV–Vis spectroscopic methods and elemental analysis were used to elucidate the identification of the synthesized molecules. The in vitro antioxidant activity of the synthesized compounds was analysed with the 1,1-diphenyl-2-picryl hydrazyl free-radical–trapping process. The synthesized compounds exhibited lower antioxidant activity than the standard ascorbic acid. IC₅₀ values of the synthesized molecules measured from 3.81 ± 0.01 to 29.05 ± 0.11 μM. Among the synthesized compounds, compound 3 had the best antioxidant activity. Moreover, this study explained the structure–activity relationship of the synthesized molecules with different substituents in radical trapping reactions.     

Synthesis and biological activity of novel phenyltriazolinone derivatives

Phenyltriazolinones are one of the most important classes of herbicides targeting the protoporphyrinogen oxidase enzyme. A series of triazolinone derivatives containing a strobilurin pharmacophore were designed and synthesized with the aim of discovering new phenyltriazolinone analogues with high activity. The herbicidal activity of the synthesized compounds was assayed and some of the test compounds displayed moderate herbicidal activity at 150 g ai/ha.     

A FACTOR FROM GRANULOSA CELLS CAN STIMULATE OOCYTE TISSUE PLASMINOGEN ACTIVATOR ACTIVITY

Several studies indicate that substances synthesized by granulosa cells are capableof regulating oocyte activity. We have studied the effect of factors synthesized by gran-ulosa cells on tPA activity of denuded oocytes using a co- culture system. The resultsshow that an FSH- dependent factor(s) synthesized by granulosa cells (but not by theca-interstitial cells) is capable of stimulating tPA activity of denuded oocytes. This findingis important for understanding hormonal regulation of oocyte tPA activity by mediatorssynthesized in granulosa cells.     

Malaysian Propolis and Metformin Synergistically Mitigate Kidney Oxidative Stress and Inflammation in Streptozotocin-Induced Diabetic Rats

Diabetic nephropathy is reported to occur as a result of the interactions between several pathophysiological disturbances, as well as renal oxidative stress and inflammation. We examined the effect of Malaysian propolis (MP), which has anti-hyperglycemic, antioxidant and anti-inflammatory properties, on diabetes-induced nephropathy. Diabetic rats were either treated with distilled water (diabetic control (DC) group), MP (300 mg/kg b.w./day), metformin (300 mg/kg b.w./day) or MP + metformin for four weeks. We found significant increases in serum creatinine, urea and uric acid levels, decreases in serum sodium and chloride levels, and increase in kidney lactate dehydrogenase activity in DC group. Furthermore, malondialdehyde level increased significantly, while kidney antioxidant enzymes activities, glutathione level and total antioxidant capacity decreased significantly in DC group. Similarly, kidney immunoexpression of nuclear factor kappa B, tumor necrosis factor-α, interleukin (IL)-1β and caspase-3 increased significantly, while IL-10 immunoexpression decreased significantly in DC group relative to normal control group. Histopathological observations for DC group corroborated the biochemical data. Intervention with MP, metformin or both significantly mitigated these effects and improved renal function, with the best outcome following the combined therapy. MP attenuates diabetic nephropathy and exhibits combined beneficial effect with metformin.     

Formulation and Optimization of Alogliptin-Loaded Polymeric Nanoparticles: In Vitro to In Vivo Assessment

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box–Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity.     

A factor from granulosa cells can stimulate oocyte tissue plasminogen activator activity

Several studies indicate that substances synthesized by granulosa cells are capable of regulating oocyte activity. We have studied the effect of factors synthesized by granulosa cells on tPA activity of denuded oocytes using a co-culture system. The results show that an FSH-dependent factor(s) synthesized by granulosa cells (but not by theca-interstitial cells) is capable of stimulating tPA activity of denuded oocytes. This finding is important for understanding hormonal regulation of oocyte tPA activity by mediators synthesized in granulosa cells.