Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes.

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.

Adverse Effects of Subchronic Dose of Aspirin on Reproductive Profile of Male Rats.

Aspirin (acetylsalicylic acid) is widely used for cardiovascular prophylaxis and as anti-inflammatory pharmaceutical. An investigation was carried out to evaluate the influence of subchronic dose of aspirin on reproductive profile of male rats, if any. Experimental animals were divided into three groups: control and aspirin subchronic dose of 12.5 mg/kg for 30 days and 60 days, respectively, while alterations in sperm dynamics, testicular histopathological and planimetric investigations, body and organs weights, lipid profiles, and hematology were performed as per aimed objectives. Subchronic dose of aspirin reduced sperm density, count, and mobility in cauda epididymis and testis; histopathology and developing primary spermatogonial cells (primary spermatogonia, secondary spermatogonia, and mature spermatocyte) count were also significantly decreased in rats. Hematological investigations revealed hemopoietic abnormalities in 60-day-treated animals along with dysfunctions in hepatic and renal functions. The findings of the present study revealed that administration with subchronic dose of aspirin to male rats resulted in altered reproductive profiles and serum biochemistry.

Oral cysticercosis: a diagnostic difficulty.

Cysticercosis is a rare disease caused by the ingestion of the parasite Cysticercus cellulosae, a larval stage of Taenia solium. The definitive host is human who harbors the adult worm and may accidentally or incidentally become the host. The larval form of cyst is commonly seen in the brain, meninges and eyes. Cases in the maxillofacial region including oral cavity and cheek muscles are rarely reported. Cysticercosis is not commonly considered in the diagnosis of swellings of the head and neck and a diagnostic and therapeutic dilemma for clinicians. Hence, they are of utmost interest to the practitioner and have to be studied. We present an unusual case of cysticercosis presenting as a solitary cystic nodule in the upper left vestibule of the oral cavity in an 18 year male and the diagnosis was made on histopathological examination.

Antiatherosclerotic and Cardioprotective Potential of Acacia senegal Seeds in Diet-Induced Atherosclerosis in Rabbits.

Acacia senegal L. (Fabaceae) seeds are essential ingredient of "Pachkutta," a specific Rajasthani traditional food. The present study explored antiatherosclerotic and cardioprotective potential of Acacia senegal seed extract, if any, in hypercholesterolemic diet-induced atherosclerosis in rabbits. Atherosclerosis in rabbits was induced by feeding normal diet supplemented with oral administration of cholesterol (500 mg/kg body weight/day mixed with coconut oil) for 15 days. Circulating total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), triglycerides, and VLDL-cholesterol (VLDL-C) levels; atherogenic index (AI); cardiac lipid peroxidation (LPO); planimetric studies of aortal wall; and histopathological studies of heart, aorta, kidney, and liver were performed. Apart from reduced atherosclerotic plaques in aorta (6.34 ± 0.72) and increased lumen volume (51.65 ± 3.66), administration with ethanolic extract of Acacia senegal seeds (500 mg/kg/day, p.o.) for 45 days to atherosclerotic rabbits significantly lowered serum TC, LDL-C, triglyceride, and VLDL-C levels and atherogenic index as compared to control. Atherogenic diet-induced cardiac LPO and histopathological abnormalities in aorta wall, heart, kidney, and liver were reverted to normalcy by Acacia senegal seed extract administration. The findings of the present study reveal that Acacia senegal seed extract ameliorated diet-induced atherosclerosis and could be considered as lead in the development of novel therapeutics.

Study on gluco-regulatory potential of glimepiride sulfonamide using in silico, in vitro and in vivo approaches.

Glimepiride sulfonamide (GS) is a drug intermediate to synthesize glimepiride (antidiabetic drug). We hypothesized that GS exerts gluco-regulatory effect because GS is comprised of the structural components of dipeptidyl peptidase-IV (DPP-IV) inhibitors sitagliptin and DPP-728and glimepiride (sulfonylurea based antidiabetic drug).We analyzed the drug-likeness and docking efficiency of GS with DPP-IV using in silico tools. Also DPP-IV inhibition assays were conducted in vitro. Gluco-regulatory potential and parameters of drug safety were evaluated on normal euglycemic and streptozotocin (STZ) induced diabetic rats. We observed strong drug-likeness and DPP-IV binding efficiency of GS. Similarly, profound DPP-IV inhibition was also observed in vitro. Studies on euglycemic and STZ induced diabetic rats revealed antidiabetic potential for GS without significant change in the studied toxicological parameters. Glimepiride sulfonamide has antidiabetic potential mainly through DPP-IV inhibition, but also through insulin stimulation and alpha-amylase inhibition.

Effect of metformin on renal microsomal proteins, lipid peroxidation and antioxidant status in dexamethasone-induced type-2 diabetic mice.

An SDS-PAGE analysis of renal microsomal fraction of albino mice was performed to study the involvement of proteins in dexamethasone-induced type-2 diabetes mellitus (DM) and their alterations by metformin, a widely accepted oral antidiabetic drug. In addition, changes in renal lipid peroxidation (LPO), activities of superoxide dismutase (SOD) and catalase (CAT), reduced glutathione (GSH) content, as well as renal somatic index (RSI) and daily rate of water consumption were also investigated. While dexamethasone administration (1.0 mg/kg for 21 days) expressed two renal proteins (43 kDa and 63.23 kDa), in addition to the increased fasting serum levels of glucose and insulin, renal LPO, RSI and daily rate of water consumption, a parallel decrease in renal SOD, CAT and GSH was also observed. Treatment with metformin normalized these alterations including the renal proteins and LPO, confirming its efficacy in ameliorating dexamethasone-induced type-2 DM and also the association of two proteins with type-2 DM.

Anti-inflammatory and anti-peroxidative roles of diacerein are possibly mediated through an alteration in thyroid functions in animal model of inflammation.

This study was designed to reveal the possible involvement of thyroid hormones, if any, in diacerein induced alterations in glucose metabolism and tissue lipid peroxidation (LPO) in the animal model of carrageenan-induced inflammation. We studied the influence of diacerein administration on the changes in carrageenan-induced thyroid dysfunction; hepatic, renal and cardiac LPO as well as serum glucose, thyroid hormones and insulin concentrations in Wistar rats. Alterations in paw volume, serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides as well as hepatic, renal and cardiac reduced glutathione (GSH) contents were also studied as supporting parameters. While a decrease in the level of serum thyroid hormones and HDL-C and in tissue GSH content was observed in carrageenan-treated animals, it increased paw volume, the concentration of other serum lipids, glucose and insulin as well as tissue LPO. However, following diacerein administration for 21 days to carrageenan-treated animals, level of thyroid hormones and all other thyroid dependent parameters were reversed suggesting that the drug might be acting through stimulation in the thyroid functions.

Amelioration of metformin-induced hypothyroidism by Withania somnifera and Bauhinia purpurea extracts in Type 2 diabetic mice.

An investigation was carried out to reveal the possible ameliorative role of two plant extracts on an antidiabetic drug-induced hypothyroidism in Type 2 diabetic animals. Dexamethasone (1.0 mg/kg, i.m.) administration caused hyperglycemia with a parallel increase in renal lipid peroxidation (LPO), relative risk ratio (RR), and the concentrations of serum insulin; total cholesterol (TC); low-density lipoprotein cholesterol (LDL-C); very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG). It decreased serum triiodothyronine (T3), thyroxine (T4) and high-density lipoprotein cholesterol (HDL-C) levels as well as renal superoxide dismutase (SOD); catalase (CAT) and reduced glutathione (GSH) content. Administration with metformin (150 mg/kg, orally) to diabetic animals further reduced circulating T4 level and caused severe hypothyroidism. It also reduced renal LPO, RR, serum concentrations of insulin; glucose and LDL-C with a parallel increase in cellular antioxidants. While oral administration with either Withania somnifera (1.4 g/kg) or Bauhinia purpurea (2.5 mg/kg) extract along with dexamethasone and metformin elevated the concentrations of circulating T3 and T4 to euthyroid level. The plant extracts also corrected RR ratio and serum concentration of lipids. The findings of the present study, for the first time, reveal that the evaluated plant extracts have a potential to ameliorate metformin-induced hypothyroidism in Type 2 diabetic subjects.

Positive influence of Centchroman on cardiovascular system and tissue lipid peroxidation in rats.

BACKGROUND: Centchroman, a nonsteroidal oral contraceptive, was evaluated for its hitherto unstudied effect on cardiovascular system, thyroid function and tissue lipid peroxidation in rats. STUDY DESIGN: Wistar sperm-positive female rats were treated with Centchroman (1.5 mg/kg per day, po) for 10 days and the alterations in serum concentration of thyroid hormones [triiodothyronine (T(3)) and thyroxine (T(4))], insulin, glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phospahatase (ALP) activity, hepatic type-1 iodothyronine 5'-monodeiodinase (5'D) enzyme activity and hepatic, renal, cardiac and serum lipid peroxidation (LPO) were studied. Simultaneously, alterations in endogenous antioxidants [superoxide dismutase (SOD); catalase (CAT) and reduced glutathione (GSH)], relative risk ratio (RR), atherogenic index (AI) and daily rate of food and water consumption were also investigated as supportive parameters. RESULTS: Centchroman administration resulted in the complete inhibition of pregnancy. It increased serum T(4) marginally and HDL-C levels, hepatic SOD, CAT and GSH; cardiac SOD and GSH and renal SOD and CAT activity significantly. However, it reduced LPO in all tissues; concentrations of other serum lipids; AI; RR and activity of ALP. CONCLUSIONS: As Centchroman administration did not alter the concentrations of most active thyroid hormone, T(3), serum insulin and glucose, it appears that the drug has no side effect on thyroid function and glucose metabolism. Rather, it possesses cardiovascular and anti-peroxidative benefits.

Amelioration of corticosteroid-induced type 2 diabetes mellitus by rosiglitazone is possibly mediated through stimulation of thyroid function and inhibition of tissue lipid peroxidation in mice.

We investigated the possible involvement of thyroid hormones and lipid peroxidation in the antidiabetic potential of rosiglitazone (a peroxisome proliferator-activated receptors gamma-agonist) on corticosteroid-induced type 2 diabetes mellitus. Rosiglitazone was administered to dexamethasone-induced hyperglycaemic male mice and the alterations in serum concentrations of thyroid hormones insulin, total cholesterol, triglycerides and fasting glucose were studied. Simultaneously changes in lipid peroxidation, reduced glutathione (GSH) content, superoxide dismutase and catalase activities in renal and cardiac tissues (which are commonly affected in diabetes mellitus), were also investigated. Administration of dexamethasone (1.0 mg/kg/day intramuscularly for 28 days) caused hyperglycaemia with a parallel increase in serum insulin, total cholesterol, triglycerides and tissue lipid peroxidation with a decrease in serum levels of both the thyroid hormones (triiodothyronine, T(3) and thyroxine, T(4)) and in the activity of associated tissue antioxidants such as superoxide, catalase and glutathione. However, rosiglitazone administration (3.2 mg/kg/day orally for 21 days) along with an equivalent amount of dexamethasone reverted most of these changes, including a marked inhibition of tissue lipid peroxidation and an increase in the serum levels of both thyroid hormones. The present findings reveal that the test drug ameliorates corticosteroid-induced type 2 diabetes mellitus through an increase in serum thyroid hormone concentrations and inhibition in tissue lipid peroxidation.

Cardio-protective role of terazosin is possibly mediated through alteration in thyroid function.

An investigation was made to reveal the possible involvement of thyroid hormones, if any, in terazosin (an alfa-1 adrenergic receptor blocker) induced alterations in tissue lipid peroxidation (LPO) and in the concentration of different serum lipids. We determined the impact of terazosin on the changes in hypercholesterolemic (CCT) diet induced thyroid dysfunction; cardiac, renal and hepatic LPO and on serum glucose concentration in female Wister rats. Simultaneously levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), creatinine, alkaline phosphatase (ALP) activity, hepatic glycogen synthesis and total daily food consumption were studied as supporting parameters. While a decrease in the level of serum thyroid hormones, HDL-C and in hepatic glycogen content, was observed in CCT diet fed animals; it increased the concentration of other serum lipids, glucose and creatinine; ALP activity; tissue and serum LPO. However, following terazosin administration for 15 days to CCT diet fed animals, status of thyroid hormones and all other thyroid dependent parameters were reversed suggesting that the drug might be acting through an alteration in the thyroid functions.