Appraisal of Pancreatic Lipase Inhibitory Potential of Ziziphus oenoplia (L.)Mill. Leaves by In Vitro and In Silico Approaches.

Pancreatic lipase is one of the crucial lipolytic enzymes of the gut that actively facilitates the digestion and absorption of the dietary triglycerides and cholesteryl esters. Although it has been deemed as one of the most reliable targets for the treatment of obesity and/or dyslipidemia, to date, orlistat is the only known FDA-approved, effective, oral pancreatic lipase inhibitor available for clinical use apart from the centrally acting antiobesity agents. However, it is known to be associated with adverse gastrointestinal and renal complications. In this study, we attempted to assess the antioxidant and porcine pancreatic lipase inhibitory potentials of Ziziphus oenoplia (L.)Mill. leaves through a systematic combination of in vitro and in silico approaches. Among the four different extracts including petroleum ether extract, ethyl acetate extract, ethanolic extract, and aqueous extract obtained through successive solvent extraction, the ethyl acetate extract has outperformed the other extracts and orderly displayed competent peroxide scavenging (IC50 value: 267.30 µg/mL) and porcine pancreatic lipase inhibitory (IC50 value: 444.44 µg/mL) potentials compared to the selected reference compounds: ascorbic acid (IC50 value: 251.50 µg/mL) and orlistat (IC50 value: 502.51 µg/mL) in the selected in vitro assay models. In addition, based on the molecular docking simulations of the six essential phytoconstituents of the leaves of Ziziphus oenoplia (L.)Mill. and their respective chemical analogues against the crystal structure of pancreatic lipase-colipase complex (PDB ID: 1LPB), four best-ranked molecules (PubChem CIDs: 15515703, 132582306, 11260294, and 44440845) have been proposed. Further, among these, the interaction potentials of the two top-ranked molecules (PubChem CIDs: 132582306 and 15515703) were analyzed through molecular dynamics (MD) simulations at a trajectory of 100 ns. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were theoretically predicted for all of the molecules using Swiss ADME and ADMET lab2.0. In conclusion, Ziziphus oenoplia (L.)Mill. leaves could become a prominent source for various potent bioactive compounds that may serve as prospective leads for the development of clinically cognizable pancreatic lipase inhibitors, provided their pharmacokinetic and in particular toxicity properties are thoroughly optimized.

Nephroprotective Effects of Mycophenolate Mofetil and Glibenclamide on Streptozotocin-induced Diabetic Renal Injury in Rats: An Experimental Study.

Diabetic renal injury is a microvascular complication associated with inflammation and oxidative stress, culminating in renal dysfunction. Conventionally, it is treated with hypoglycemic agents to address metabolic perturbations. However, the way to mitigate immunological, inflammation, and oxidative stress have seldom been studied. Hence, in the present study, the nephroprotective role of immunosuppressive and anti-inflammatory drugs, mycophenolate mofetil (MMF) in combination with the oral hypoglycemic agent glibenclamide, on streptozotocin (STZ)- induced diabetic renal damage was studied. Bodyweight, fasting blood glucose, and glycosylated hemoglobin levels were altered in the diabetic rats. Furthermore, renal injury was indicated by abnormal levels of urinary protein and creatinine and serum markers of renal function in diabetic rats. Hyperglycemia-induced oxidative stress and inflammation were also observed in the diabetic rats. The combination of MMF and glibenclamide treatment significantly attenuated the abnormal effects of hyperglycemia, oxidative stress, and inflammation-induced renal injury in diabetic rats. Histopathological studies confirmed the nephroprotective role of MMF and glibenclamide by reversing renal injury in diabetic rats. The present study suggests that MMF and glibenclamide have a protective role in STZ-induced diabetic renal damage.

Type-2 diabetes mellitus-associated cancer risk: In pursuit of understanding the possible link.

BACKGROUND AND AIM: The insulin resistance-mediated abnormal gluconeogenesis when exceeds a given threshold culminates in type 2 diabetes mellitus (T2DM). This induces severe cellular oxidative stress that may eventually facilitate typical neoplastic transformations. This narrative review aims to portray some of the plausible key mechanistic links bridging T2DM and specific cancers. METHODS: A thorough literature search was conducted in the PubMedCentral database to retrieve information from various reputed biomedical reports/articles published from the year 2000. The information regarding the key biochemical signaling pathways mediating the carcinogenic transformation, especially in T2DM patients, was extensively excavated to systematically compile and present a narrative review. RESULTS: T2DM-associated insulin resistance is known to negatively influence certain crucial genetic and metabolic components (such as insulin/IGFs, PI-3K/Akt, AMPK, and AGEs/RAGE) that may eventually lead to neoplastic transformation. In particular, the risk of developing cancers like pancreatic, colorectal, breast, liver, endometrial, and bladder seems to be more significant in T2DM patients. CONCLUSION: Despite the fact that several studies have suggested a possible correlation between T2DM and cancer mortality, a more detailed research at both pre-clinical and clinical levels is still required so as to fully understand the intricate relationship and make a precise conclusion.

Efficacy of Cyanotis tuberosa (Roxb.) Schult. &Schult. f. root tubers' active fraction as anti-diabetic, antihyperlipidemic and antioxidant in Streptozotocin-induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyanotis tuberosa (Roxb.) Schult. &Schult.f. is traditionally used as ethnomedicine for curing several ailments like diabetes, liver problems, ulcers, etc. OBJECTIVE: The present study was designed to evaluate the anti-diabetic potential of Cyanotis tuberosa root tubers (CTRT)in Streptozotocin (STZ) induced diabetic rats. MATERIALS AND METHODS: Anti-hyperglycemic activity of hexane extract of CTRT was investigated in diabetic rats. Silica gel chromatography was used to fractionate the hexane extract and the fraction's antihyperglycemic activity was checked in diabetic rats. Effects of long-term (30 days) treatment with an active fraction (CTAF) were evaluated in diabetic rats for 30 days by measurement of body weights, glycemic control, insulin levels, HbA1c, and serum and tissue lipid profiles. Lipid peroxide levels and antioxidant status were measured in the liver and kidney. Hepatic and Renal functional markers were also measured. Phytochemical characterization of CTAF was carried out by LC-ESI-MS/MS analysis. RESULTS: Hexane extract of CTRT at a dose of 750 mg/kg b.w produced significant antihyperglycemic activity in diabetic rats whereas CTAF has produced maximum antihyperglycemic activity at the dose of 75 mg/kg b.w. Following long-term treatment with CTAF in diabetic rats, significant improvement in glycemic control, (HbA1c) along with decreased insulin resistance (HOMA-IR), increase in body weights, and plasma insulin were observed. Also, CTAF ameliorated the serum and tissue lipid profiles. In addition, CTAF suppressed lipid peroxidation and restored the activities of antioxidant enzymes in the liver and kidney to normal levels. Further, CTAF reversed the liver and kidney functional markers to normalcy. LC-ESI-MS/MS analysis revealed the presence of 7 different phytoconstituents. CONCLUSION: This study confirmed that CTAF exerts antidiabetic effects in diabetic rats by improving insulin secretion, glycemic control, and restoring functional activities of the liver and kidney. Our results suggest that root tubers of Cyanotis tuberosa can be used as a complementary or alternative agent for the treatment of diabetes mellitus.

A bioactive fraction of Pterocarpus santalinus inhibits adipogenesis and inflammation in 3T3-L1 cells via modulation of PPAR-γ/SREBP-1c and TNF-α/IL-6.

Pterocarpus santalinus has huge demand owing to its commercial and medicinal value. However, there are limited research studies on its therapeutic activity against obesity and obesity-induced inflammation and underlying mechanism of action. Therefore, in the present study, chloroform bioactive fraction of P. santalinus (CFP) was isolated and evaluated for its activity against adipogenesis and adipogenesis-induced inflammation in 3T3-L1 cell culture model. LC-MS/MS analysis of CFP was performed to identify the compounds present. CFP-treated 3T3-L1 cells (50, 100 and 200 µg/ml) have significantly (p < 0.01 or < 0.05) enhanced glycerol release and adiponectin level, but reduced lipid accumulation and leptin, and MTT assay demonstrated CFP was non-toxic till a dose of 300 µg/ml at 24 and 48 h. A considerable reduction in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels was witnessed in lipopolysaccharide (LPS)-induced 3T3-L1 cells with CFP treatment in dose-dependent manner. Gene expression studies demonstrated down-regulation of mRNA expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), sterol regulatory element-binding protein-1c (SREBP-1c), leptin, TNF-α and IL-6 but up-regulation of adiponectin and uncoupling protein-1 (UCP-1) and the same trend was observed in protein expression also. In conclusion, it is suggested that CFP could be beneficial to treat obesity and associated inflammation.

Antidiabetic activity of root tubers of Asparagus gonoclados Baker in streptozotocin induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Asparagus gonoclados Baker is a traditional folk remedy used for diabetes, diuretic, galactogogue, gastric ulcer activities etc. AIM: The present investigation was intended to evaluate the beneficial effect of the A.gonoclados (Lilliaceae) root tubers against diabetes mellitus. MATERIALS AND METHODS: Different solvent extracts of root tubers of A. gonoclados were used to study the antihyperglycemic activity in streptozotocin (45 mg/kg.wt) induced diabetic rats. Oral glucose tolerance test was performed in diabetic and normal rats treated with A.gonoclados. Total phenolic content (TPC), total flavanoid content (TFC) and total steroidal saponins content (TSSC) were measured in different solvent extracts. Following bioassay guided fractionation method antihyperglycemic active fraction of A. gonoclados (AGAF) was isolated from the ethanol extract (AGEE) by silica gel column chromatography. We further tested relationship between insulin stimulation effect and the influence of active fraction on K+-ATP and Ca2+ channels opening in normal and diabetic rats. The characterization of AGAF was carried out by LC-ESI-MS/MS. RESULTS: Among the different solvent extracts, the ethanol extract (AGEE) at a dose of 500 mg/kg b.wt has produced maximum (67%) reduction in fasting blood glucose levels (FBG) in diabetic treated rats after 6 h of oral administration when compared to the standard drug glibenclamide (40%). AGEE also showed dose-dependent inhibitory effect on the activities of α-glucosidase (74.73%) and α-amylase (76.47%), which is comparable to the activity of standard drug acarbose (88.42%). AGEE was found to have the richest quantity of TPCs (138.4 ±â€¯0.39 µg/mg gallic acid equivalents), TFCs (64.8 ±â€¯0.54 µg/mg quercetin equivalents) and TSSCs (12.9 ±â€¯0.11µg/mg sarasapogenin equivalents). We identified 8 potential antihyperglycemic compounds in AGAF by LC-ESI-MS/MS analysis. CONCLUSION: From our current study we confirm that A. gonoclados root tubers have potent antihyperglycemic activity and it can be a unique drug/formulation for the management of diabetes mellitus.

Evaluation of biochemical mechanisms of anti-diabetic functions of Anisomeles malabarica.

Anisomeles malabarica (AM) is an aromatic plant traditionally used for the treatment of diabetes mellitus in India. Following bioassay guided fractionation, we recently identified an active fraction of AM (AMAF, with potential mix of active principles) that showed significant antihyperglycemic and antihyperlipidemic activities. In addition, AMAF treatment improved insulin levels. However, the biochemical mechanism/s through which AMAF demonstrates the antidiabetic effects is largely unknown. Based on its beneficial effects we investigated the biochemical mechanism of the anti-diabetic activity of A.malabarica active fraction (AMAF) in streptozotocin (STZ) induced diabetic rats. Streptozotocin induced diabetic rats were treated with AMAF (50 mg AMAF/kg/day) for 30 days and alterations in the body weights, glycogen and protein content of tissues, functional markers of hepatic and renal tissues, carbohydrate metabolic enzymes and their genes expression were evaluated. Lipid peroxides levels and activities of antioxidant enzymes of hepatic and renal tissues were also measured. The AMAF treatment resulted in increase in body weights, hepatic and renal protein and tissue glycogen levels in diabetic treated rats compared to diabetic rats. In addition, the treatment improved activities of carbohydrate metabolic enzymes, antioxidant enzymes and, liver and renal functional markers in the AMAF treated diabetic rats. Gene expressions of key carbohydrate metabolic enzymes/factors glucokinase, glucose transporter protein (GLUT-2) and phosphoenolpyruvate carboxykinase (PEPCK) were also normalized up on AMAF treatment in diabetic rats. Our studies indicate that the isolated active fraction of AM (AMAF) from the leaves of A.malabarica positively regulated the glucose homeostasis and oxidative stress through carbohydrate metabolism and antioxidant enzyme activities respectively in hepatic and renal tissues.

Anti-Diabetic Potential of the Leaves of Anisomeles malabarica in Streptozotocin Induced Diabetic Rats.

BACKGROUND/AIMS: Diabetes mellitus is a pandemic metabolic disorder that is affecting a majority of populations in recent years. There is a requirement for new drugs that are safer and cheaper due to the side effects associated with the available medications. METHODS: We investigated the anti-diabetic activity of leaves of Anisomeles malabarica following bioactivity guided fractionation. The different solvent (hexane, ethyl acetate, methanol and water) extracts of A. malabarica leaves were used in acute treatment studies to evaluate and identify the active fraction. The ethyl acetate extract was subjected to further fractionation using silica gel column chromatography and the compounds were identified by LC-SRM/MS and GC-MS. Additional chronic treatment studies were carried out using this active fraction (AMAF) for 30 days in experimental diabetic rats. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), plasma insulin levels and glucose tolerance were measured along with insulin resistance/sensitivity indicators (HOMA-IR, HOMA-ß and QUICKI) to assess the beneficial effects of A. malabarica in the management of diabetes mellitus. RESULTS: Among the different solvent extracts tested, ethyl acetate extract showed maximum (66%) anti-hyperglycemic activity. The hexane and ethyl acetate (1: 1) fraction that has maximum anti-diabetic activity was identified as active fraction of A. malabarica (AMAF). The FBG, HbA1c, plasma insulin levels and insulin sensitivity/resistance indicators such as glucose tolerance, HOMA-IR, HOMA-ß and QUICKI were significantly improved to near normal in diabetic rats treated with AMAF. Further, we identified key flavonoids and fatty acids as the anti-diabetic active principles from the AMAF of A. malabarica leaves. CONCLUSION: The results of our study suggest that Anisomeles malabarica has potential anti-diabetic activity in STZ induced diabetic rats.

Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents.

BACKGROUND: Chronic and oral administration of benzylamine improves glucose tolerance. Picolylamine is a selective functional antagonist of the human adenosine A2B receptor. Phosphonic diamide derivatives enhance the cellular permeability and in turn their biological activities. METHODS: A series of heteroaryl phosphonicdiamide derivatives were designed as therapeutics to control and manage type2 diabetes. Initially defined Lipinski parameters encouraged them as safer drugs. Molecular docking of these compounds against Protein tyrosine phosphatase (PTP), the potential therapeutic target of type 2 diabetes, revealed their potential binding ability explaining their anti-diabetic activity in terms of PTP inhibition. Human intestinal absorption, Caco-2 cell permeability, MDCK cell permeability, BBB penetration, skin permeability and plasma protein binding abilities of the title compounds were calculated by PreADMET server. A convenient method has been developed for the synthesis of title compounds through the formation of 1-ethoxy-N,N'-bis(4-fluorobenzyl/pyridin-3-ylmethyl)phosphinediamine by the reaction of 4-fluorobenzylamine/ 3-picolylamine with ethyldichlorophosphite, subsequently reacted with heteroaryl halides using lanthanum(III) chloride as a catalyst. RESULTS: All the compounds exhibited significant in vitro anti-oxidant activity and in vivo evaluation in streptozotocin induced diabetic rat models revealed that the normal glycemic levels were observed on 12(th) day by 9a and 20(th) day by 5b, 5c, 9e and 9f. The remaining compounds also exhibited normal glycemic levels by 25(th) day. CONCLUSION: The results from molecular modeling, in vitro and in vivo studies are suggesting them as safer and effective therapeutic agents against type2 diabetes. Graphical Abstract Development of PTPs inhibitors.

Antihyperglycemic and antioxidant activities of alcoholic extract of Commiphora mukul gum resin in streptozotocin induced diabetic rats.

BACKGROUND AND OBJECTIVES: The present study investigated the effect of Commiphora mukul ethanol extract gum resin (CMEEt) on streptozotocin (STZ) induced diabetic rats by measuring fasting blood glucose, plasma insulin, plasma lipid profile, atherogenic index, hepatic lipid peroxidation (LPO), protein oxidation (PO) and activities of enzymatic antioxidants. METHODS: Wistar albino rats were divided into 4 groups, normal control group, CM-treated control group, diabetic control group and CM-treated diabetic group. For induction of diabetes, STZ was administered at a dose of 55mg/kg body weight, meanwhile CM-treated groups were administered CMEEt at a dose of 200mg/kg body weight for 60 days. Body weight, plasma glucose and insulin levels were determined in different experimental days, after end of the experimental period the plasma lipid profile and antioxidant enzymes were determined in hepatic tissue. RESULTS: Increase in plasma glucose, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), hepatic LPO and PO levels with decrease in plasma high density lipoprotein cholesterol (HDL-C), insulin, hepatic reduced glutathione (GSH) content and activities of antioxidant enzymes namely, glutathione peroxidase (GPX), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) were the salient features observed in diabetic rats. On the other hand, oral administration of CMEEt at a dose of 200mg/kg for 60 days resulted in the prevention of above mentioned abnormalities. CONCLUSION: The results suggest that CMEEt could be beneficial in the treatment of diabetes, characterized by atherogenous lipoprotein profile, aggravated antioxidant status and impaired glucose metabolism and in their prevention.