Yogesh A. Kulkarni

Hyperglycemia to Nephropathy via Transforming Growth Factor Beta

Nephropathy is one of the major complications of diabetes which further directs to end stage renal disease. Extensive work has been done to find out the mechanisms involved in pathogenesis of the DN. Now, many researchers have been convinced that almost all of the molecular mediators and intracellular signaling pathways involved in progression of diabetic nephropathy have involvement in transforming growth factor beta (TGF- β) at some stage. In DN, hyperglycemia causes increase in the expression of TGF- β genes, TGF- β proteins and their receptors. Increased glucose level mediates these effects through activation of polyol pathway, protein kinase C pathway, hexosamine pathway, increases advanced glycation end products (AGE) and increases oxidative stress. Hyperglycemia also activates the TGF- β via activation of glucose transporters (GLUT), angiotensine II and platelet derived growth factor (PDGF). Activated TGF-β further leads to glomerular basement membrane (GBM) thickening and glomerulosclerosis through activation of connective tissue growth factor (CDGF) and vascular endothelial growth factor (VEGF). We have discussed the progression of hyperglycemia to DN via TGF- β, whose schematic presentation may serve as an effective way to understand the mechanisms and to find out an effective way for the management of diabetic nephropathy.

Acute and Repeated Dose Toxicity Studies of Different β-Cyclodextrin-Based Nanosponge Formulations

Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

Effects of Gmelina arborea extract on experimentally induced diabetes.

OBJECTIVE To study the effects of aqueous extract of Gmelina arborea bark on normoglycemic levels and streptozotocin (STZ) induced diabetes in rats. METHODS After single administration of the aqueous extract, plasma glucose level was determined up to 6 h. In subacute study, the aqueous extract was administered for 28 d and plasma glucose level was determined weekly. The diabetes was induced in rats by the intraperitoneal injection of STZ at a dose of 55 mg/kg body weight. The diabetic animals were divided into four groups containing six in each: Group I diabetic control, Group II and III treated with the aqueous extract respectively at a dose of 250 and 500 mg/kg body weight once daily and Group IV treated with glibenclamide at a dose of 0.6 mg/kg body weight once daily. In acute study, the aqueous extract and glibenclamide were administered orally to rats. Plasma glucose levels were determined at 30, 60, 120, 240 and 360 min after the administration of the test samples. To study subacute effects, test samples (the aqueous extract and glibenclamide) were administered for 28 d consecutively. The effects of each test sample on plasma glucose level, body weight as well as food and water intake were also monitored weekly. The oral glucose tolerance test and biochemical indicators were estimated on day 28. RESULTS The aqueous extract did not significantly decrease the plasma glucose level in the normoglycemic rats as shown by the acute and subacute assays. However, after oral administration of the aqueous extract, the plasma glucose level was significantly (P<0.001) decreased in the diabetic rats in the acute study. The long-term administration of the aqueous extract significantly (P<0.001) reduced plasma glucose levels of the diabetic rats. Additionally, the aqueous extract also reduced loss of body weight and significantly decreased food and water intake in the diabetic animals. Nevertheless, no effects on biochemical indicators were observed at the selected doses. CONCLUSIONS The aqueous extract of Gmelina arborea bark had antihyperglycemic activity against STZ induced diabetes in rats, after single and subacute oral administration. Moreover, it did not show significant glucose lowering effect in normoglycemic rats.

NF-κβ: A Potential Target in the Management of Vascular Complications of Diabetes

Diabetes is a metabolic disorder affecting large percentage of population worldwide. NF-κβ plays key role in pathogenesis of vascular complications of diabetes. Persistent hyperglycemia activates NF-κβ that triggers expression of various cytokines, chemokines and cell adhesion molecules. Over-expression of TNF-α, interleukins, TGF-β, Bcl2 and other pro-inflammatory proteins and pro-apoptotic genes by NF-κβ is key risk factor in vascular dysfunction. NF-κβ over-expression also triggers calcification of endothelial cells leading to endothelial dysfunction and further vascular complications. Inhibition of NF-κβ pro-inflammatory pathway is upcoming novel target for management of vascular complications of diabetes. Various natural and synthetic inhibitors of NF-κβ have been studied in management of diabetic complications. Recent preclinical and clinical studies validate NF-κβ as promising target in the management of vascular complications of diabetes.

Effect of Gmelina arborea Roxb in experimentally induced inflammation and nociception

Background: Gmelina arborea Roxb (Verbenaceae), also known as “Gambhari”, is an important medicinal plant in the Ayurveda. There are no meticulous scientific reports on effect of the plant on inflammation and pain. Objective: To study the anti-inflammatory and anti-nociceptive properties of aqueous extracts (AE) and methanol extracts (ME) of G. arborea. Materials and Methods: The AE and ME of stembark of G. arborea was prepared by cold maceration and Soxhlet extraction technique respectively. Anti-inflammatory activity was determined in Wistar albino rats in a model of acute plantar inflammation induced by carrageenan. The anti-nociceptive activity was evaluated by using hot plate test and writhing test in Swiss albino mice. Significant differences between the experimental groups were assessed by analysis of variance. Results: AE and ME at dose of 500 mg/kg showed maximum inhibition in carrageenan induced inflammation up to 30.15 and 31.21% respectively. In hot plate test, the AE and ME showed the maximum response of 8.8 ± 0.97 (P < 0.01) and 8.2 ± 1.24 (P < 0.01) respectively at dose of 500 mg/kg when compared with control. AE showed maximum inhibition of writhing response (84.3%) as compared to ME (77.9%) in writhing test at a dose of 500 mg/kg. Conclusion: The findings suggested that G. arborea possess significant anti-inflammatory and anti-nociceptive activities.

Toxicological studies on aqueous extract of Gmelina arborea in rodents

Context: Gmelina arborea Roxb. (Verbenaceae) is an important medicinal plant in the traditional system of medicine of India. The plant is used in the treatment of snake-bites, fever, piles, and diabetes. However, there is little toxicological information available regarding its safety after exposure. The present study was designed to evaluate acute and repeated dose toxicity of the aqueous extract of Gmelina arborea stem bark. Materials and methods: In the acute toxicity test, Swiss albino mice were treated with aqueous extract (300, 2000, and 5000 mg/kg), orally. Animals were observed periodically during the first 24 h after administration of the extract, and daily thereafter for 14 days. In the repeated dose toxicity study, the aqueous extract of Gmelina arborea (300, 1000, and 2000 mg/kg per day) was administered orally for a period of 28 days in Wistar rats. The effects on body weight, food and water consumption, organ weight, hematology, clinical biochemistry, as well as histology, were studied. Results and conclusion: Aqueous extract did not produce mortality, changes in behavior or any other physiological activities in mice, for any of the selected doses. There were no significant differences in the body weight, organ weights and feeding habits between control and treated animals. Hematological and biochemical analysis showed no marked differences in any of the parameters examined in either the control or treated groups. Pathologically, neither gross abnormalities nor histopathological changes were observed. The aqueous extract of Gmelina arborea was found safe in acute and repeated dose toxicity studies when tested in rodents.

Gallic acid attenuates type I diabetic nephropathy in rats

Literature suggests that TGF-β1 has a central role in the progression of diabetic nephropathy and its down regulation can improve the disease condition. Oxidative stress, generation of advanced glycation end products and activation of renin angiotensin system are the connecting links between hyperglycemia and TGF-β1 over expression. Gallic acid is a phytochemical having wide range of biological activities. Gallic acid is reported to have antioxidant and advanced glycation inhibitory activity. It has also shown inhibitory effects on angiotensin converting enzyme. Gallic acid qualifies as a drug candidate to be tested in the diabetic nephropathy, one of the important complication of diabetes. Streptozotocin (55 mg/kg body weight, i.p.) induced diabetic nephropathy was used as an experimental model. Gallic acid was evaluated for its possible effect at the dose of 20 and 40 mg/kg body weight. Gallic acid treatment significantly lowered plasma levels of the creatinine and blood urea nitrogen and elevated the levels of the protein and albumin. Gallic acid also improved creatinine clearance. Determination of oxidative stress parameters showed that the oxidative stress in kidney tissues was reduced significantly in gallic acid treated animals. Results of the plasma, urine and oxidative stress parameters were also reflected in the histopathological evaluation showing improvement in kidney pathophysiology. ELISA assay for circulating TGF-β1 evaluation and immunohistochemical study for determination of kidney expression of TGF-β1 revealed that gallic acid significantly lowered both the circulating and tissue levels of TGF-β1. Results support the hypothesis that gallic acid can be effectively used in the treatment of diabetic nephropathy.

Traditional uses, phytochemistry and pharmacology of the medicinal species of the genus Cordia (Boraginaceae)

Cordia (family Boraginaceae) is a genus of deciduous flowering trees or shrubs comprising more than 300 species distributed widely in the tropical regions. The aim of this review was to provide exhaustive scientific information on traditional uses, phytochemistry and pharmacological activities of the 36 important species with medicinal value from the genus Cordia, to divulge prospects for further research on its therapeutic potential.

Bauhinia variegata (Caesalpiniaceae) leaf extract: An effective treatment option in type I and type II diabetes.

Among various metabolic disorders, diabetes mellitus is one of the most common disorder. Present study was designed to evaluate the effectiveness of aqueous extract of Bauhinia variegata leaves (AE) in animal models of type I and type II diabetes. Type I diabetes was induced by streptozotocin at the dose of 55mg/kg (i.p.) in male Sprague Dawley rats while type II diabetes was induced by high fat diet and streptozotocin at the dose of 35mg/kg (i.p.). Diabetic animals were treated with AE at the dose of 250, 500 and 1000mg/kg. Glipizide (5mg/kg) was used as standard treatment drug. Treatment was given for 28days. Parameters evaluated were body weight, plasma glucose, cholesterol, triglyceride, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total proteins, albumin, creatinine and bun urea nitrogen. In type II diabetes, high density lipoprotein levels in plasma and plasma insulin level were also evaluated. Histopathological study of pancreases were carried out in type I study. AE showed significant decrease in plasma glucose significantly. AE was also found to decrease cholesterol, triglyceride, creatinine and blood urea nitrogen level in both types of diabetes. AE did not show any significant effect on plasma levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase. AE was found to increase the albumin and total protein levels. Histopathological study showed that AE decreases the necrotic changes in the pancreatic tissue. Aqueous extract of B. variegata leaves was found effective in treatment of both type I and type II diabetes.

Synthesis and evaluation of novel marine bromopyrrole alkaloid-based derivatives as potential antidepressant agents.

Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAOs inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50–70% at 30 mg/kg dose levels in FST. Further, derivative 5b, 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO‐A potency and selectivity (Ki MAO‐A (μm) = 2.4 ± 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho‐ and/or para‐position of phenyl ring and N‐alkylation of pyrrole core is favored features for antidepressant activity.