Incretin hormones receptor signaling plays the key role in antidiabetic potential of PTY-2 against STZ-induced pancreatitis.
TL;DR: In addition to previously studied DPPIV inhibitor, PTY-2 also acts as incretin receptors agonist and protects against STZ-induced diabetes by down regulating β cells apoptosis.
About: This article is published in Biomedicine & Pharmacotherapy.The article was published on 2018-01-01. It has received 21 citations till now. The article focuses on the topics: Incretin & GPR119.
Citations
More filters
TL;DR: The results suggest that SA ameliorates the development of STZ-induced DN in rats via NRF2/HO-1 mediated pathways and proposes that the nephroprotective mechanism of SA is due to its antioxidant and anti-inflammatory activity.
Abstract: Diabetic neuropathy (DN) is a complicated inauspicious outcome of diabetes, like other abnormalities of diabetes the cause of DN is still vague and it may be the result of various pathological conditions leading up to end-stage renal failure. The present study examines the efficacy of sinapic acid (SA) in streptozotocin (STZ)-induced DN nephropathy and the linked pathway. Twenty-four rats were equally divided randomly into four categories: Normal control (NC), STZ, STZ + SA 20 mg/kg bw, and STZ + SA 40 mg/kg bw. After 8 weeks they were evaluated for ratio of renal index, the fasting blood glucose (FBG), blood urea nitrogen (BUN), 24 h urea protein, serum creatinine (SCr), reduced glutathione peroxidase (GPx), superoxide dismutase (SOD), lipid peroxidation (MDA), tumor necrosis factor α (TNFα), interleukin (IL)-6, as well as lipid profile total cholesterol (TC), total triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) levels. Additionally, histomorphology and ultrastructure of the kidneys were also assessed. Protein expression levels of transforming growth factor-β1 (TGF-β1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), IκBα protein (IkBα), anti-apoptotic protein BCl2, nuclear factor kappa B (NF-kB), and Bax were examined. We observed that SA 20 mg/kg bw and 40 mg/kg bw pretreatment significantly and dose-dependently upregulated the protein expression of HO-1, Nrf2, IKBα, and Bcl-2 but downregulated the protein expression of NF-κB, proposing that the nephroprotective mechanism of SA is due to its antioxidant and anti-inflammatory activity; SA prevents the release of cytokines and inflammatory markers (TNFα and IL-6), upregulates antioxidant defense enzymes, and reduces lipid peroxidation, as well as nitric oxide, and anti-apoptotic activity, which may be influenced by the regulation of TNF-α, IL-6, Bcl-2, NF-kB, and BaX via the Nrf2/HO-1 pathway in STZ induced DN. Thus, our results suggest that SA ameliorates the development of STZ-induced DN in rats via NRF2/HO-1 mediated pathways. Further comprehensive studies are required for complete elucidation of the fundamental mechanisms.
56 citations
TL;DR: The findings suggest that PTY-2r exerted the nephroprotective potential against STZ induced DN rats via suppressing oxidative stress and apoptosis due to the presence of different bioactive compounds.
Abstract: Oxidative stress and renal apoptosis play a significant role in the progression of diabetic nephropathy. The tubers of Pueraria tuberosa (Roxb. ex Willd.) DC. has been traditionally used as anti-ageing and health promotive tonic. The purpose of this study was to investigate its nephroprotective effect and mechanism via antioxidant and antiapoptotic potential in Streptozotocin-induced diabetic nephropathy (DN) in rats. The chemical composition of aqueous extract of Pueraria tuberosa (PTY-2r) was analyzed by gas chromatography-mass spectrometry (GC-MS). Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (55 mg/kg body weight) in rats. After 60 days, the rats were randomly divided into 3 groups (n = 6/each group), namely DN control (DN) group-2, DN rats treated with PTY-2r at the dose of 50 mg/100 g, group-3 and 100 mg/100 g, group-4 p.o. for 20 days. The normal rats were chosen as a normal control (NC) group-1. PTY-2r was orally given to the rats for 20 days. Reactive oxygen species (ROS), lipid peroxidation (LPO) and the activity of ROS-scavenging enzymes – superoxide dismutase (SOD), catalase (CAT) & glutathione peroxidase (GPx) were determined in the kidney tissue of DN rats. The expression of apoptosis-related proteins was measured by immunofluorescence. GC-MS analysis of PTY-2r indicated the presence of 37 compounds among them 5-Hydroxymethylfurfural (17.80%), 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (17.03%), n-Hexadecanoic acid (5.18%) and 9-Octadecenoic acid (Z) - (6.69%) were found in the higher amount. A significant increase in ROS and LPO was observed along with the decreased activity of antioxidant enzymes, responsible for oxidative stress in the kidney of DN rats. Since, high oxidative stress induces apoptosis in target cells, as shown by significantly decreased expression of Bcl-2 along with increased expression of Bax, active Caspase-3 & cleaved PARP-1 in DN control rats, suggesting apoptosis. The PTY-2r treatment significantly raised the activity of antioxidant enzymes, suppressed oxidative stress and apoptosis thus, prevented urinary albumin excretion in a dose-dependent manner. The findings suggest that PTY-2r exerted the nephroprotective potential against STZ induced DN rats via suppressing oxidative stress and apoptosis due to the presence of different bioactive compounds. ᅟ
33 citations
Cites background from "Incretin hormones receptor signalin..."
...We have already reported its anti-inflammatory [16], antioxidant [17] and anti-diabetic properties [18, 19]....
[...]
TL;DR: Pueraria tuberosa (Roxb. ex Willd.) DC. as mentioned in this paper is a perennial herb distributed throughout India and other Asian countries, and its extracts have been reported for nutritional and medicinal properties in Ayurveda as well as in Chinese traditional practices.
Abstract: Pueraria tuberosa (Roxb. ex Willd.) DC. (Fabaceae), also known as Indian Kudzu (vidari kand), is a perennial herb distributed throughout India and other Asian countries. Traditionally, tuber and leaves of this plant have extensively been reported for nutritional and medicinal properties in Ayurveda as well as in Chinese traditional practices. The objective of the present review is to compile and update the published data on traditional uses, pharmacological potential, and phytochemistry of compounds isolated from the plant Pueraria tuberosa. P. tuberosa extracts and its purified compounds possess multiple activities such as anticancer, anticonvulsant, antidiabetic, antifertility, anti-inflammatory, antioxidant, anti-stress, antiulcerogenic, cardioprotective, hypolipidemic, hepatoprotective, immunomodulatory, nephroprotective, nootropic, neuroprotective, and wound healing. Tuber and leaf extracts of P. tuberosa contain several bioactive constituents such as puerarin, daidzein, genistein, quercetin, irisolidone, biochanin A, biochanin B, isoorientin, and mangiferin, which possess an extensive range of pharmacological activities. The extensive range of pharmacological properties of P. tuberosa provides opportunities for further investigation and presents a new approach for the treatment of ailments. Many phytochemicals have been identified and characterized from P. tuberosa; however, some of them are still unexplored, and there is no supporting data for their activities and exact mechanisms of action. Therefore, further investigations are warranted to unravel the mechanisms of action of individual constituents of this plant.
22 citations
TL;DR: Findings from related studies in T1DM and T2DM are included to highlight potential pathological mechanisms involved in initiation and progression of DEP, and to provide directions for future research studies.
Abstract: The clinical significance of diabetes arising in the setting of pancreatic disease (also known as diabetes of the exocrine pancreas, DEP) has drawn more attention in recent years. However, significant improvements still need to be made in the recognition, diagnosis and treatment of the disorder, and in the knowledge of the pathological mechanisms. The clinical course of DEP is different from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DEP develops in patients with previous existing exocrine pancreatic disorders which damage both exocrine and endocrine parts of pancreas, and lead to pancreas exocrine insufficiency (PEI) and malnutrition. Therefore, damage in various exocrine and endocrine cell types participating in glucose metabolism regulation likely contribute to the development of DEP. Due to the limited amount of clinical and experimental studies, the pathological mechanism of DEP is poorly defined. In fact, it still not entirely clear whether DEP represents a distinct pathologic entity or is a form of T2DM arising when β cell failure is accelerated by pancreatic disease. In this review, we include findings from related studies in T1DM and T2DM to highlight potential pathological mechanisms involved in initiation and progression of DEP, and to provide directions for future research studies.
20 citations
TL;DR: The aim of this study was to explore the anti‐inflammatory role of PTY‐2r (extracted from Pueraria tuberosa), on streptozotocin (STZ)‐induced DN rats.
Abstract: Objectives Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to explore the anti-inflammatory role of PTY-2r (extracted from Pueraria tuberosa), on streptozotocin (STZ)-induced DN rats. Methods Diabetes was induced by intraperitoneal injection of STZ (55mg/kg) in rats. After 60 days, the rats were randomly divided into three groups (n = 6/each group), namely DN control group 2, DN rats treated with PTY-2r at dose of 100 mg/100 g, group 3 and 50 mg/100 g, group 4, p.o for 20 days. The normal rats were chosen as a normal control (NC) group 1. Key findings In DN rats, the expression of iNOS and inflammatory cytokines (IL-6 and TNF-α) was significantly increased. Raised expression of PKC-α was also found. As NF-kB is the main transcription factor for the inflammatory response-mediated progression of DN, variation in NF-kB expression and its activated phosphorylated derivative (pNF-kB) were also evaluated and increase in expression was obtained in the kidney of DN rats. PTY-2r treatment significantly reversed these changes in dose-dependent manner. Conclusions This study suggested that the nephroprotective effect of PTY-2r is possibly due to downregulation of PKC-α and NF-kB pathway and normalizing the expression of inflammatory cytokines and iNOS in the kidney of DN rats.
17 citations
References
More filters
TL;DR: Whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies are discussed.
1,068 citations
TL;DR: A new approach to solve the ‘molecular graphics problem’ is described, which shares the work between GPU and multiple CPU cores, generates high-quality results with perfectly round spheres, shadows and ambient lighting and requires only OpenGL 1.0 functionality.
Abstract: SUMMARY: Today's graphics processing units (GPUs) compose the scene from individual triangles. As about 320 triangles are needed to approximate a single sphere-an atom-in a convincing way, visualizing larger proteins with atomic details requires tens of millions of triangles, far too many for smooth interactive frame rates. We describe a new approach to solve this 'molecular graphics problem', which shares the work between GPU and multiple CPU cores, generates high-quality results with perfectly round spheres, shadows and ambient lighting and requires only OpenGL 1.0 functionality, without any pixel shader Z-buffer access (a feature which is missing in most mobile devices). AVAILABILITY AND IMPLEMENTATION: YASARA View, a molecular modeling program built around the visualization algorithm described here, is freely available (including commercial use) for Linux, MacOS, Windows and Android (Intel) from www.YASARA.org. CONTACT: elmar@yasara.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
1,026 citations
TL;DR: Evidence is provided that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis, and better-preserved three-dimensional islet morphology in the GLp-1-treated islets, compared with controls.
Abstract: The peptide hormone, glucagon-like peptide 1 (GLP-1), has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass, and inhibit -cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured fo r5di n thepresence, or absence, of GLP-1 (10 nM, added every 12 h) and studied for viability and expression of proapoptotic (caspase-3) and antiapoptotic factors (bcl-2) as well as glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1-treated islets, compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1-treated islets was particularly evident at d 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at d 5 (8.9 vs. 18.9%; P < 0.01). The antiapoptotic effect of GLP-1 was associated with the downregulation of active caspase-3 (P < 0.001) and the up-regulation of bcl-2 (P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control (P < 0.001, at d 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion (P < 0.01 at d 3; P < 0.05 at d 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis. (Endocrinology 144: 5149 –5158, 2003)
645 citations
TL;DR: The similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non‐insulinotropic effects are summarized and their potential in treatment of type 2 diabetes is discussed.
Abstract: Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic b cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic b cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP-1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP-1 together promote b cell proliferation and inhibit apoptosis, thereby expanding pancreatic b cell mass, while GIP enhances postprandial glucagon response and GLP-1 suppresses it. In adipose tissues, GIP but not GLP-1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP-1 inhibits bone absorption. In the brain, both GIP and GLP-1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP-1 and their insulinotropic effects on b cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic b cells, and their non-insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00022.x, 2010)
484 citations
TL;DR: A consensus method metaPocket is presented, in which the predicted sites from four methods: LIGSITE(cs), PASS, Q-SiteFinder, and SURFNET are combined together to improve the prediction success rate.
Abstract: The identification of ligand-binding sites is often the starting point for protein function annotation and structure-based drug design. Many computational methods for the prediction of ligand-binding sites have been developed in recent decades. Here we present a consensus method metaPocket, in which the predicted sites from four methods: LIGSITE(cs), PASS, Q-SiteFinder, and SURFNET are combined together to improve the prediction success rate. All these methods are evaluated on two datasets of 48 unbound/bound structures and 210 bound structures. The comparison results show that metaPocket improves the success rate from approximately 70 to 75% at the top 1 prediction. MetaPocket is available at http://metapocket.eml.org .
347 citations