Design and synthesis of novel N-[3-(benzimidazol-2-ylamino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives as potential anticancer agents.

In this contribution, we report the design, synthesis and cytotoxicity studies of a series of N-[3-(benzimidazol-2-yl-amino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives. In vitro cytotoxicity assay of 26 selected compounds was carried out at National Cancer Institute (NCI), USA. Out of them, compounds 10e (NSC D-762842/1) and 11s (NSC D-764942/1) have shown remarkable cytotoxicity with GI50 values ranging between "0.589-14.3 µM" and "0.276-12.3 µM," respectively, in the representative nine subpanels of human tumor cell lines. Further, flow cytometry analysis demonstrated that compound 10e exerted cell cycle arrest at G2/M phase and showed dose-dependent enhancement in apoptosis in K-562 leukemia cancer cells.

Curriculum for pharmacology in pharmacy institutions in India: opportunities and challenges.

The curriculum of pharmacy institutions in India is regulated by the All India Council for Technical Education (AICTE) and the Pharmacy Council of India (PCI) at degree and diploma levels. However, it has been over two decades that the syllabi have been revised by these regulatory agencies. Considering the dynamic character of pharmacology, it is essential to prepare a syllabus that caters to the contemporary needs of the academic institutions and pharmaceutical industry, the community. Pharmacists are also witnessing a greater role in community pharmacy practice as well as in several healthcare sectors. Considering these facts, a panel discussion was held at IPSCON 2013, (the Annual Conference of Indian Pharmacological Society) at Bangalore. The discussion saw several recommendations for syllabi for institutions offering various pharmacy courses to meet the objectives of teaching, learning and research in Pharmacology. This article documents a summary of the discussion. For B. Pharm. course, a balance between industry-oriented pharmacology and clinical pharmacy has been recommended. Redundant animal experiments should be replaced with the simulation experiments or those which are feasible in the light of stringent regulations of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). It is recommended that the M. Pharm curriculum should focus on preclinical research with the inclusion of molecular biology and experiments on gene expression, proteomics, pharmacogenomics, cell culture and tissue culture. In general, at all levels, exposure of students to hospitals and clinicians is needed. Pharm. D., syllabus too should lay lesser emphasis on experimental pharmacology. Present experiments in the D. Pharm. course have no relevance to the program objectives and hence, only experiments through demonstrations or simulated preparations or interactive videos maybe undertaken. Regulatory bodies as well as universities should design a comprehensive syllabus and plan an effective pedagogy to prepare graduates who are competent and capable of bringing positive changes in the community and healthcare in India.

Effects of Trigonella foenum-graecum (L.) on retinal oxidative stress, and proinflammatory and angiogenic molecular biomarkers in streptozotocin-induced diabetic rats.

The aim of the present study was to investigate the protective effects of Trigonella foenum-graecum Linn. (fenugreek) in Streptozotocin-induced diabetic rat retina. Fenugreek (100 and 200 mg/kg body weights) treatment was carried out for 24 weeks and evaluated for inflammatory [tumor necrosis factor (TNF)-α and interleukin (IL)-1ß] and angiogenic [vascular endothelial growth factor (VEGF) and protein kinase C (PKC)-ß] molecular biomarkers. Retinal oxidative stress was evaluated by estimating antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Fluorescein angiography was performed to detect retinal vascular leakage. Electron microscopy was performed to determine basement membrane thickness. In the present study, significant rises in the expressions of retinal inflammatory (TNF-α and IL-1ß) and angiogenic (VEGF and PKC-ß) molecular biomarkers were observed in diabetic retinae compared with normal retinae. However, fenugreek-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic molecular biomarkers. Moreover, results from the present study showed positive modulatory effects of fenugreek on retinal oxidative stress. Fluorescein angiograms and fundus photographs obtained from diabetic retinae showed retinal vascular leakage. On the other hand, fenugreek-treated retinae did not show vascular leakage. Further, thickened BM was recorded in diabetic retina compared with normal retinae. However, fenugreek-treated retinae showed relatively lesser thickening of capillary BM. In conclusion, it may be postulated that fenugreek has great potential in preventing diabetes-induced retinal degeneration in humans after regular consumption in the specified dosage.

An experimental assessment of toxic potential of nanoparticle preparation of heavy metals in streptozotocin induced diabetes.

Nanoparticle preparations of heavy metals have attracted enormous scientific and technological interest. Biologically produced nanoparticle preparations of heavy metals are elaborately described in traditional texts and being widely prescribed. The underlying interactions of nano preparations within the physiological fluids are key feature to understand their biological impact. In this perspective, we performed an experimental assessment of the toxicity potential of a marketed metallic preparation named Vasant Kusumakar Ras (VKR), wherein different heavy metals in composite form are reduced to nanoparticle size to produce the desired effect in diabetes and its complications. VKR (50mg/kg) was administered to Albino Wistar rats rendered diabetic using streptozotocin (90mg/kg) in 2 days old neonates. Anti-hyperglycemic effect was observed with VKR along with increased levels of plasma insulin. Renal variables including total proteins and albumin along with glomerular filtration rate were found to improve biochemically. The results were supplemented by effects on different inflammatory and growth factors like TNF-α, nitric oxide, TGF-ß and VEGF. However, the results observed in kidney histopathology were not in accordance with the biochemical parameters. Inflammation observed in kidney was confirmed by immunostaining metallothionein, which was due to the accumulation of heavy metals. Furthermore, mercury accumulation in kidney further confirmed by autometallography, which activated mononuclear phagocyte system, which generated an immune response. This was further supported by increase in the extent of apoptosis in kidney tissues. In conclusion, nanoparticle preparations of heavy metals can be toxic to kidney if it is not regulated with respect to its surface chemistry and dosage.

Potential nephrotoxic effects produced by steroidal saponins from hydro alcoholic extract of Tribulus terrestris in STZ-induced diabetic rats.

Chronic hyperglycemia leads to the development of microvascular complications like diabetic nephropathy. The present study investigated the potential effects of the hydroalcoholic extract of Tribulus terrestris, a plant of Zygophyllaceae family, on the renal complications in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by administering STZ (90 mg/kg) to the 2-days old neonates. After 6 weeks of induction, diabetic rats were treated with 50 mg/kg hydroalcoholic extract of T. terrestris for 8 weeks. The anti-hyperglycaemic nature was confirmed by reduction in blood glucose and improvement in insulin levels. Diabetic renal injury associated with decrease in total proteins and albumin levels was observed to be improved by T. terrestris extract. Glomerular filtration rate along with inflammatory and growth factors, adiponectin and erythropoietin were also improved by the treatment, though the findings were not significant. However, the beneficial antidiabetic effects of T. terrestris extract in plasma were not observed in kidney histopathology. This was confirmed by the quantitative estimation of unhydrolyzed fraction of saponins (major component: protodioscin) in plasma and kidney samples of normal and diabetic rats. Hence, it can be concluded that 8 weeks treatment with T. terrestris extract produces potential toxic effects in kidney, which are independent of its anti-diabetic action.

Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats.

The purpose of the study was to evaluate the effects of hesperetin (Hsp) on diabetes-induced retinal oxidative stress, neuroinflammation and apoptosis in rats. The Hsp treatment (100 mg/kg body weight) was carried for twenty four weeks in STZ-induced diabetic rats and evaluated for antioxidant (Superoxide dismutase; SOD, Catalase; CAT and glutathione; GSH) enzymes, inflammatory cytokines (TNF-α, IL-1ß), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4(AQP4) expression. Histological changes were evaluated by light and transmission electron microscopic (LM and TEM) studies. Retinal GSH levels and anti-oxidant enzymes (SOD and CAT) activity were significantly decreased in diabetic group as compared to normal group. However, in Hsp-treated rats, retinal GSH levels were restored close to normal levels and positive modulation of anti-oxidant enzyme activity was observed. Diabetic retinae showed significantly increased expression of Pro-inflammatory cytokines (TNF-α and IL-1ß) as compared to normal retinae. While Hsp-treated retinae showed significantly lower levels of cytokines as compared to diabetic retinae. Diabetic retinae showed increased caspase-3, GFAP and AQP4 expression. However, Hsp-treated retinae showed inhibitory effect on caspase-3, GFAP and AQP4 expression. LM images showed edematous Müller cell endfeet, and also degenerated photoreceptor layer; however, protective effect of Hsp was seen on Müller cell processes and photoreceptors. TEM study showed increased basement membrane (BM) thickness in diabetic retina, while relatively thin BM was recorded in Hsp-treated retina. It can be postulated that dietary flavanoids, like Hsp, can be effective for the prevention of diabetes induced neurovascular complications such as diabetic retinopathy.

Retinoprotective effects of Moringa oleifera via antioxidant, anti-inflammatory, and anti-angiogenic mechanisms in streptozotocin-induced diabetic rats.

PURPOSE: The present study was aimed to evaluate the retinoprotective effects of Moringa oleifera (MO) in Streptozotocin-induced diabetic rats. METHODS: The study was continued for 24 weeks and evaluated for inflammatory (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß, angiogenic (vascular endothelial growth factor [VEGF] and protein kinase C [PKC]-ß) and antioxidant (Glutathione, Superoxide dismutase, and Catalase) parameters. Retinal leakage was checked by Fluorescein angiography (FA) and fundus photographs were evaluated for retinal vessel caliber (arteriolar and venular). Transmission electron microscopy was done to determine basement membrane (BM) thickness. RESULTS: The results of the present study showed potential hypoglycemic and retinal antioxidant effects of MO. In the present study, a significant rise in the expression of retinal inflammatory (TNF-α and IL-1ß) and angiogenic (VEGF and PKC-ß) parameters was observed in diabetic retinae as compared to normal retinae. However, MO-treated retinae showed marked inhibition in the expression of inflammatory and angiogenic parameters. Further, in the present study, diabetic retinae showed dilated retinal vessels as compared to normal. However, MO-treated retinae showed marked prevention in the dilatation of retinal vessels. Fluorescein angiograms obtained from diabetic retinae showed leaky and diffused retinal vasculature. On the other hand, MO-treated retinae showed intact retinal vasculature. Further, results of the transmission electron microscopy study showed thickened capillary BM in the diabetic retina as compared to normal retinae. However, treatment with MO prevented thickening of capillary BM. CONCLUSION: Our result suggests that MO may be useful in preventing diabetes induced retinal dysfunction.

Anti-inflammatory action of Tamarind seeds reduces hyperglycemic excursion by repressing pancreatic ß-cell damage and normalizing SREBP-1c concentration.

CONTEXT: Tamarindus indica L. (Leguminosae) is widely used as a traditional medicine for the management of diabetes mellitus (DM) in India, in addition to its anti-inflammatory activity. The present study has been designed to understand the correlation involved between antidiabetic and anti-inflammatory action of aqueous seed extract of T. indica (TSE) in diabetic rats. OBJECTIVE: In view of the fact that fatty acid synthesis and insulin release from islets of pancreas are regulated by sterol regulatory element-binding proteins (SREBP-1c) and cytosolic calcium, respectively, the objectives of present study were to determine the influence of TSE on SREBP-1c mRNA and to investigate the intracellular islets calcium [Ca²âº](I) involvement and ß-cell mass preservation in insulin secretagogue action of TSE. MATERIALS AND METHODS: The effect of 4 weeks oral treatment (120 and 240 mg/kg) of high-performance liquid chromatography (HPLC) standardized TSE was studied in streptozotocin (STZ)-induced diabetic male Wistar rats. Reverse transcription-PCR (RT-PCR) and a spectrofluorometer were used for mRNA concentration and islets [Ca²âº](I) determination, respectively. The TUNEL assay was followed to study the pancreatic apoptosis. RESULTS: TSE (120 and 240 mg/kg) showed positive correlation with [Ca²âº](I) and insulin release. The anti-inflammatory action of TSE was significant on nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in addition to a favorable effect on ß-cell neogenesis and improved mRNA concentration of SREBP-1c. DISCUSSION AND CONCLUSION: The results suggest that anti-inflammatory action of Tamarind seeds on ß-cell cells of islets and cytokines contribute toward its antidiabetic activity by way of complex mechanisms of [Ca²âº](I) handling and through SREBP-1c gene in liver.

Aqueous extract of tamarind seeds selectively increases glucose transporter-2, glucose transporter-4, and islets' intracellular calcium levels and stimulates ß-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes mellitus.

Tamarindus indica Linn. has been in use for a long time in Asian food and traditional medicine for different diseases including diabetes and obesity. However, the molecular mechanisms of these effects have not been fully understood. In view of the multidimensional activity of tamarind seeds due to their having high levels of polyphenols and flavonoids, we hypothesized that the insulin mimetic effect of aqueous tamarind seed extract (TSE) might increase glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family and sterol regulatory element-binding proteins (SREBP) 1c messenger RNA (mRNA) in the liver. Daily oral administration of TSE to streptozotocin (STZ)-induced (90 mg/kg intraperitoneally) type 2 diabetic male Wistar rats at different doses (120 and 240 mg/kg body weight) for 4 weeks showed positive correlation with intracellular calcium and insulin release in isolated islets of Langerhans. Tamarind seed extract supplementation significantly improved the GLUT-2 protein and SREBP-1c mRNA expression in the liver and GLUT-4 protein and mRNA expression in the skeletal muscles of diabetic rats. The elevated levels of serum nitric oxide (NO), glycosylated hemoglobin level (hemoglobin (A1c)) and tumor necrosis factor α (TNF-α) decreased after TSE administration. Immunohistochemical findings revealed that TSE abrogated STZ-induced apoptosis and increased ß-cell neogenesis, indicating its effect on islets and ß-cell mass. In conclusion, it was found that the antidiabetic effect of TSE on STZ-induced diabetes resulted from complex mechanisms of ß-cell neogenesis, calcium handling, GLUT-2, GLUT-4, and SREBP-1c. These findings show the scope for formulating a new herbal drug for diabetes therapy.

Hesperetin ameliorates hyperglycemia induced retinal vasculopathy via anti-angiogenic effects in experimental diabetic rats.

The purpose of the study was to evaluate vasculoprotective effects of Hesperetin (Hsp) in Streptozotocin induced diabetic rats. The study was carried out for a period of 24weeks and evaluated for angiogenic parameters (VEGF and PKC-ß), retinal vascular leakage by fluorescein angiography and, vessel (arteriolar and venular) diameters and any morphological abnormality through fundus photographs. Apart from this, transmission electron microscopy (TEM) was done to determine capillary basement membrane (BM) thickness. The results of the present study showed a significant increase in the expression of VEGF and PKC-ß in diabetic retinae as compared to normal retinae. On the other hand, Hsp-treated retinae showed marked inhibition in the expression of VEGF and PKC-ß. In the present study, diabetic retinae showed increase vascular permeability and leakage as compared to normal retinae. However, Hsp-treated retinae have not shown any such vascular dysfunctions. Moreover, there was significant increase in vessel caliber recorded in diabetic retinae compared to normal retinae, on the contrary Hsp-treated retinae showed lesser dilated vessels. Further, TEM study showed thickened BM in diabetic group as compared to normal group. However, Hsp-treated retinae showed marked prevention in BM thickness. In conclusion, it can be sated that Hsp has potential vasoprotective effects and can be useful in preventing diabetes induced vasculopathy.

Chronic DPP-IV inhibition with PKF-275-055 attenuates inflammation and improves gene expressions responsible for insulin secretion in streptozotocin induced diabetic rats.

Inhibitors of dipeptidyl peptidase-4 (DPP-IV), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major question concerns the potential ability of long term DPP-IV inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ß-cell mass due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of vildagliptin (PKF-275-055), on glycemic control, pancreatic ß-cell mass, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. To induce NIDDM, streptozotocin (STZ) 90 mg/kg was administered i.p. to a group of 2 days old pups. Diabetic rats were administered orally with vildagliptin analog PKF-275-055. Saline treated animals served as diabetic control. Significant and dose-dependent correction of postprandial hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with PKF-275-055 showed increased the number of insulin-positive ß-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with PKF-275-055 significantly increased insulin content, glycogen content and total proteins content; and decreased the inflammatory markers i.e. nitric oxide and TNF-alpha. The present studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor having potential to reduce inflammation that might be a potential agent for type 2 diabetes.

Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension.

Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20 mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO(x)) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15 mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME-induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3 µM) and high K(+) (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS.

16,17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and ß-cell proliferation in diabetic rat.

Reduces levels of intact GLP-1 and inhibition of DPPIV augments levels of intact GLP-1 improves glycemic control in type 2 diabetes patients and diabetic animal model. Although, GLP-1 is known to stimulate insulin secretion, insulin biosynthesis and dose insulin gene transcription, augmented supplies of insulin for secretion. DHIM is an indole alkaloid, isolated from Mitragyna parvifolia. In the present in vitro study, we investigated the inhibitor activity of novel alkaloid on DPP IV. DHIM produced marked inhibition of DPP IV. Accordingly, we used 5, 10 and 20 µg DHIM alkaloids in DPPIV assay, and then found 18%, 56%, and 68% inhibition activity. In the present in vivo study, we examined the 16,17-dihydro-17b-hydroxy (DHIM) effect on neonatal Wistar albino rats treated with streptozotocin, an established model of type 2 diabetes. Diabetic rats, 8 weeks chronic administered with DHIM (100mg/kg) markedly reduced plasma glucose concentration, increased glucose tolerance in response to glucose loading. Consequently, GLP-1 and IL-10 levels were also significantly increased in treated diabetic rats. Despite, body weight was not found changed significantly; the insulin content and ß-cell mass at 2 months were significantly increased by DHIM. Immunostaining and Confocal image of TUNEL assay showed that DHIM stimulates ß-cell proliferation and reduced pancreatic cell apoptosis in diabetic treated rats. These results suggest that DHIM induces proliferation of pancreatic cells and increases the formation of ß-cells.

Vildagliptin selectively ameliorates GLP-1, GLUT4, SREBP-1c mRNA levels and stimulates ß-cell proliferation resulting in improved glucose homeostasis in rats with streptozotocin-induced diabetes.

OBJECTIVE: Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ß-cell mass and function due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor vildagliptin on glycemic control, pancreatic ß-cell mass and function, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. METHOD: To induce NIDDM, STZ (sigma chemicals, USA) (90 mg/kg) was administered i.p. to a group of 2 days old pups. Another group of pups received only saline. The pups were weaned for 21 days, and 6 weeks after the injection of STZ, the animals were checked for fasting glucose level (FPG) ≥160 mg/dl were considered as diabetic. RESULTS: Significant and dose-dependent correction of postprandial and fasting hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with vildagliptin showed increase in the number of insulin-positive ß-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with vildagliptin significantly increased insulin content; and decreased the nitric oxide and TNF-alpha concentration. CONCLUSION: These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of diabetes mellitus by modifying the courses of the disease.

Effective blockade of RAAS by combination of aliskiren and olmesartan improves glucose homeostasis, glomerular filtration rate along with renal variables in streptozotocin induced diabetic rats.

The present study aims to investigate the combined and individual treatment of aliskiren and olmesartan for 8 weeks in streptozotocin induced diabetic rats provide an effective blockade of RAAS by improving glucose homeostasis, glomerular filtration rate along with renal variables thereby delaying the progression of the disease. Streptozotocin induced diabetic rats were administered with aliskiren (10mg/kg/day), olmesartan (6mg/kg/day) alone and in combination. To identify the glucose homeostasis, translocation of glucose transporter proteins in liver and muscle was observed by their expression after treatment. Glomerular filtration rate is estimated using serum creatinine, cystatin C and beta 2 microglobulin. This study also examined the effects of combination and monotherapy on various renal variables viz. albumin, total proteins, TGF-ß, TNF-α, VEGF, nitric oxide, adiponectin and erythropoeitin. In addition, histopathological and anti-apoptotic profile of kidney was also investigated. The present study indicates that dual blockade of RAAS improved glucose homeostasis and confirms the nephroprotective effects of the combined treatment of aliskiren and olmesartan independent of their antihypertensive property in the STZ induced diabetes. In addition, its antifibrotic, antiproteinuric effects indicate that combination treatment might be potential as an important therapeutic option for chronic fibrotic diseases in renal complications.

A novel long acting DPP-IV inhibitor PKF-275-055 stimulates ß-cell proliferation resulting in improved glucose homeostasis in diabetic rats.

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10mg/kg) on ß-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2h and 10h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1-10mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1mg/kg or higher. Immunological staining showed PKF-275-055 stimulates ß-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.

Relationships between the islets blood flow, nitric oxide, insulin, and cytosolic calcium in rat pancreatic islets: effects of DPP-IV inhibitor vildagliptin.

The aim of the present study was to evaluate the relationships between the islets blood flow, nitric oxide, insulin, and cytosolic calcium in rat pancreatic islets, using dipeptidyl peptidase-IV (DPP-IV) inhibitor vildagliptin. For measuring pancreatic and islets blood a non-radioactive microsphere technique was used. Vehicle pre-treatment of glucose administered diabetic rats had decrease pancreatic and islets blood flow as compared with glucose administered normal rats. Blood glucose concentrations were not affected after vildagliptin administration in either diabetic or normal rats (10 min after glucose administration). Vildagliptin had no effects on baseline pancreatic or islets blood flow in glucose administered normal rats. Administration of vildagliptin increased both pancreatic and islets blood flow as compared with vehicle treated diabetic rats. Furthermore, diabetic rats showed significant increase in NO and decrease in insulin secretions and vice versa in normal rats. Vildagliptin pre-treatment to both normal and diabetic rats had shown mild decrease in NO, but significantly increased insulin secretions. In addition, vildagliptin itself is able to mobilize intracellular Ca(2+) in pancreatic islets both in absence and presence of glucose. From the present study, we conclude following points (A) administration of vildagliptin augmented the blood flow seen in islets of diabetic rats, (B) islets insulin secretions are independent of islets blood flow and NO, (C) vildagliptin inhibited excessive NO production in diabetic rats that prevents the damage to ß-cells due to excessive production of peroxynitrite (ONOO(-)) ions and protects from cytokine-induced suppression of insulin release.

The study of aqueous extract of Ficus religiosa Linn. on cytokine TNF-α in type 2 diabetic rats.

BACKGROUND: Chronic systemic inflammation is an early process in pathogenesis of type 2 diabetes. Hence the present study was aimed to investigate the effect of traditionally known plant Ficus religiosa on elevated glucose and inflammatory marker namely tumor necrosis factor (TNF)-α in type 2 diabetic rats. METHODS: Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rat model. Aqueous extract of F. religiosa at a dose of 100 and 200 mg/kg was given orally to desired group of animals for a period of 4 weeks. After 4 weeks of drug treatment, parameters such as fasting blood glucose, postprandial blood glucose and TNF-α in serum were analyzed. RESULTS: Aqueous extract of F. religiosa at both dose levels i.e., 100 and 200 mg/kg decreased the elevated glucose and TNF-α in type 2 diabetic rats. The extract at 200 mg/kg had more pronounced effect. CONCLUSION: Modulation of cytokine TNF-α by the aqueous extract of F. religiosa indicates that the anti-inflammatory and immunomodulatory property of the plant is related with its potential anti-diabetic activity.

Cardioprotective activity of alcoholic extract of Tinospora cordifolia (Willd.) Miers in calcium chloride-induced cardiac arrhythmia in rats.

The present study investigated the antiarrhythmic activity of alcoholic extract of Tinospora cordifolia (T. cordifolia) in CaCl2 induced arrhythmia. CaCl2 (25 mg/kg) was administered by intravenous infusion (iv) to produce arrhythmia in rats. The animals were then treated with T. cordifolia extract (150, 250, and 450 mg/kg) and verapamil (5 mg/kg,iv). Lead II electrocardiogram was monitored. Plasma calcium, sodium and potassium levels were measured. In CaCl2 induced arrhythmia, heart rate was decreased by 41.10%, T. cordifolia at 150, 300, and 450 mg/kg decreased the heart rate by 26.30%, 29.16%, and 38.29%, respectively, and verapamil reduced the heart rate by 9.70% compared to the normal group. The PQRST waves were normalized and atrial and ventricular fibrillation was controlled in rats treated with verapamil and T. cordifolia. CaCl2 increased calcium and sodium levels and decreased potassium levels in blood. T. cordifolia dose-dependently decreased calcium and sodium levels and increased potassium levels. Hence, T. cordifolia can be used in antiarrhythmic clinical settings and beneficial in atrial and ventricular fibrillation and flutter and may be indicated in ventricular tachyarrhythmia.

The study of aqueous extract of Pterocarpus marsupium Roxb. on cytokine TNF-α in type 2 diabetic rats.

OBJECTIVE: This study was designed to investigate the effect of aqueous extract of Pterocarpus marsupium Roxb. on elevated inflammatory cytokine, tumor necrosis factor (TNF)-α in type 2 diabetic rats. MATERIALS AND METHODS: Type 2 diabetes was induced by administering streptozotocin (90 mg/kg, i.p.) in a neonatal rat model. Aqueous extract of P. marsupium at a dose of 100 and 200 mg/kg was given orally to desired group of animals for a period of 4 weeks. After 4 weeks of drug treatment, parameters such as fasting blood glucose, postprandial blood glucose, and TNF-α in serum were analyzed. RESULTS: Aqueous extract of P. marsupium at both doses, i.e., 100 and 200 mg/kg, decreased the fasting and postprandial blood glucose in type 2 diabetic rats. The 200 mg/kg had more pronounced effect on postprandial hyperglycemia. The drug also improved the body weight of diabetic animals. Cytokine TNF-α was found to be elevated in untreated diabetic rats due to chronic systemic inflammation. The aqueous extract at both doses significantly (P < 0.001) decreased the elevated TNF-α level in type 2 diabetic rats. CONCLUSION: Modulation of cytokine TNF-α by the rasayana drug P. marsupium is related with its potential anti-diabetic activity.