Bhoomika M. Patel

Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases.

The present review shall familiarize the readers with the role of renin-angiotensin aldosterone system (RAAS), which regulates blood pressure, electrolyte and fluid homeostasis. The local RAAS operates in an autocrine, paracrine and/or intracrine manner and exhibits multiple physiological effects at the cellular level. In addition to local RAAS, there exists a complete pancreatic RAAS which has multi-facet role in diabetes and cardiovascular diseases. Aldosterone is known to mediate hyperinsulinemia, hypertension, cardiac failure and myocardial fibrosis while angiotensin II mediates diabetes, endothelial dysfunction, vascular inflammation, hypertrophy and remodeling. As the understanding of this biology of RAAS increases, it serves to exploit this for the pharmacotherapy of diabetes and cardiovascular diseases.

TNF-α and cancer cachexia: Molecular insights and clinical implications.

Abstract Cancer cachexia characterized by a chronic wasting syndrome, involves skeletal muscle loss and adipose tissue loss and resistance to conventional nutritional support. Cachexia is responsible for the reduction in quality and length of life of cancer patients. It also decreases the muscle strength of the patients. The pro‐inflammatory and pro‐cachectic factors produced by the tumor cells have important role in genesis of cachexia. A number of pro‐inflammatory cytokines, like interleukin‐1 (IL‐1), IL‐6, tumor necrosis factor‐ alpha (TNF‐&agr;) may have important role in the pathological mechanisms of cachexia in cancer. Particularly, TNF‐&agr; has a direct catabolic effect on skeletal muscle and causes wasting of muscle by the induction of the ubiquitin‐proteasome system (UPS). In cancer cachexia condition, there is alteration in carbohydrate, protein and fat metabolism. TNF‐&agr; is responsible for the increase in gluconeogenesis, loss of adipose tissue and proteolysis, while causing decrease in protein, lipid and glycogen synthesis. It has been associated with the formation of IL‐1 and increases the uncoupling protein‐2 (UCP2) and UCP3 expression in skeletal muscle in cachectic state. The main aim of the present review is to evaluate and discuss the role of TNF‐&agr; in different metabolic alterations and muscle wasting in cancer cachexia.

Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood–brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

Cardioprotective effects of magnesium valproate in type 2 diabetes mellitus.

We have evaluated the effect of magnesium valproate (210 mg/kg/day, p.o.) in type 2 diabetes induced cardiovascular complications induced by streptozotocin (STZ, 90 mg/kg, i.p.) in neonatal wistar rats. Various biochemical, cardiovascular and hemodynamic parameters were measured at the end of 8 weeks of treatment. STZ produced significant hyperglycaemia, hypoinsulinemia and dyslipidemia, which was prevented by magnesium valproate treatment. STZ produced increase in Creatinine Kinase, C-reactive protein and lactate dehydrogenase levels and treatment with magnesium valproate produced reduction in these levels. STZ produced increase in cardiac and LV hypertrophy index, LV/RV ratio, LV collagen deposition and LV cardiomyocyte diameter which were decreased by magnesium valproate treatment. Magnesium valproate also prevented STZ induced hemodynamic alterations and oxidative stress. These results were further supported by histopathological studies in which magnesium valproate showed marked reduction in fibrosis and cardiac fiber disarray. In conclusion, our data suggests that magnesium valproate is beneficial as an anti-diabetic agent in type-2 diabetes mellitus and also prevents its cardiac complications.

Therapeutic implications of small interfering RNA in cardiovascular diseases.

Cardiovascular diseases (CVDs) place a heavy burden on the economies of low‐ and middle‐income countries. Comprehensive action requires combining approaches that seek to reduce the risks throughout the entire population with strategies that target individuals at high risk or with established disease. Small interfering RNA (siRNA) as a functional mediator for regulation of gene expression has been evaluated for potential therapeutic targets for the treatment of various cardiovascular diseases such as hypertension, atherosclerosis, heart failure etc. The present review attempts have been made to provide a brief outline of the current understanding of the mechanism of RNAi and the delivery system and describe the therapeutic application of siRNAs and their potential for treating CVDs which are taking a heavy toll on human life.

Effect of spironolactone on cardiovascular complications associated with type-2 diabetes in rats.

We have studied the effect spironolactone (20 mg/kg/day) on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2 day old rats. Diabetes was checked after 12 weeks. At the end of 8 weeks of treatment, various biochemical and cardiac parameters were measured. STZ produced hyperglycemia, hyperinsulinemia, dyslipidemia, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, worsened hemodynamic parameters, cardiac hypertrophy and oxidative stress. Chronic treatment with spironolactone significantly reduced serum glucose levels but did not alter insulin levels. It also significantly prevented the dyslipidemia and reduced elevated Lactate de-hydrogenase, creatinine kinase, CRP and creatinine levels. Chronic treatment with spironolactone prevented STZ-induced hypertension, tachycardia and elevated rate of pressure development and decay. Spironolactone also produced beneficial effect by preventing cardiac hypertrophy as evident from left ventricular collagen levels, cardiac and left ventricular hypertrophic indices and prevented oxidative stress. In conclusion, our data suggests that spironolactone prevents STZ induced metabolic abnormalities and cardiovascular complications in animal model of type 2 diabetes.

Choice of anti-hypertensive agents in diabetic subjects.

Hypertension is an extremely common co-morbid condition in diabetes leading to acceleration in micro-vascular and macro-vascular complications. The use of anti-hypertensives in diabetic patients should be considered in the context of preventing the development of complications. Various factors contribute to the pathophysiology of diabetes in hypertension. With the advancements in technology, the understanding of the pathophysiological mechanisms has increased, and this can contribute in providing evidence for beneficial role of certain anti-hypertensives. Many clinical trials have been carried out for use of diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The present review gives an overview of pathophysiological mechanisms of hypertension and diabetes in addition to the details of clinical trials of anti-hypertensives in diabetic patients. This is an attempt to provide some evidences for the clinicians, which may serve as a guide for use of anti-hypertensives in clinical practice.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

BACKGROUND Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. METHODS The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. RESULTS Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. CONCLUSION The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice.

Evaluation of Buspirone on Streptozotocin Induced Type 1 Diabetes and Its Associated Complications

We have evaluated the effect of buspirone (1.5 mg/kg/day, p.o.) type 1 diabetes induced cardiovascular complications induced by streptozotocin (STZ, 45 mg/kg, i.v.) in Wistar rats. Various biochemical, cardiovascular, and hemodynamic parameters were measured at the end of 8 weeks of treatment. STZ produced significant hyperglycaemia, hypoinsulinemia, and dyslipidemia, which was prevented by buspirone treatment. STZ produced increase in serum creatinine, urea, lactate dehydrogenase, creatinine kinase, and C-reactive protein levels and treatment with buspirone produced reduction in these levels. STZ produced increase in cardiac and LV hypertrophy index, LV/RV ratio, and LV collagen, which were decreased by buspirone treatment. Buspirone also prevented STZ induced hemodynamic alterations and oxidative stress. These results were further supported by histopathological studies in which buspirone showed marked reduction in fibrosis and cardiac fiber disarray. In conclusion, our data suggests that buspirone is beneficial as an antidiabetic agent in type 1 diabetes mellitus and also prevents its cardiac complications.

Type 2 diabetes-induced cardiovascular complications: comparative evaluation of spironolactone, atenolol, metoprolol, ramipril and perindopril.

Abstract The present study was carried out to study the effect of spironolactone, atenolol, metoprolol, ramipril and perindopril on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2-day-old rats. Our data suggest that spironolactone, metoprolol and perindopril prevent not only the STZ-induced metabolic abnormalities but also cardiovascular complications as evident from the reduction in cholesterol, triglyceride and decrease in cardiac hypertrophy which are the initial symptoms of congestive heart failure. Metoprolol and perindopril appears to be beneficial agents as compared to atenolol and ramipril.