A potential role of the renin-angiotensin-aldosterone system in epithelial-to-mesenchymal transition-induced renal abnormalities: Mechanisms and therapeutic implications.

Epithelial-to-mesenchymal transition (EMT) is an orchestrated event where epithelial cells progressively undergo biochemical changes and transition into mesenchymal-like cells by gradually losing their epithelial characteristics. EMT plays a crucial pathologic role in renal abnormalities, especially renal fibrosis. A number of bench studies suggest the potential involvement of renin-angiotensin-aldosterone system (RAAS) in renal EMT process and associated renal abnormalities. EMT appears to be an important pathologic mechanism for the deleterious renal effects of angiotensin II and aldosterone, the two major RAAS components. Mechanistically, the renal RAAS-TGF-ß-Smad3 signalling pathway plays an important pathologic role in EMT-associated renal abnormalities. Intriguingly, the RAAS antagonists such as losartan, telmisartan, eplerenone, and spironolactone have the potential to prevent renal EMT in bench studies. This review describes the key mechanistic role of RAAS overactivation in EMT-induced renal abnormalities. Moreover, drugs interrupting the RAAS at different levels in the cascade ameliorating the EMT-associated renal abnormalities are described.

Molecular targets of fenofibrate in the cardiovascular-renal axis: A unifying perspective of its pleiotropic benefits.

The activation of peroxisome proliferator-activated receptor α (PPARα) is a key pharmacological drug target for dyslipidemic management. Dyslipidemia is associated with abnormal serum lipid profiles viz. elevated total cholesterol, high triglyceride, elevated low-density lipoprotein cholesterol, and reduced high-density lipoprotein cholesterol levels. Fenofibrate, a third-generation fibric acid derivative, is an activator of PPARα indicated for the treatment of mixed dyslipidemia and hypertriglyceridemia in adults. Fenofibrate is considered an important lipid-lowering medication employed in patients afflicted with atherogenic dyslipidemia. Intriguingly, recent bench studies have demonstrated an array of cardiovascular and renal pleiotropic beneficial activities of fenofibrate, besides its foremost lipid-lowering action. The activation of PPARα by fenofibrate could negatively regulate the cardiomyocyte hypertrophy. In addition, fenofibrate has been suggested to have a protective effect against experimental ischemia/reperfusion injury in the myocardium in part via endoplasmic reticulum stress inhibition. Fenofibrate has also been shown to suppress arrhythmias in isolated rat hearts subjected to ischemic/reperfusion-induced cardiac injury. Moreover, in a rat model of metabolic syndrome and myocardial ischemia, fenofibrate therapy has been shown to restore antioxidant protection and improve myocardial insulin resistance. Furthermore, studies have highlighted the pleiotropic vascular endothelial protective and antihypertensive actions of fenofibrate. Interestingly, recent bench studies have demonstrated renoprotective actions of fenofibrate by implicating diverse mechanisms. This review sheds light on the current perspectives and molecular mechanistic aspects pertaining to the cardiovascular pleiotropic actions of fenofibrate. Additionally, the renal pleiotropic actions of fenofibrate by focusing its possible modulatory role on renal fibrosis, inflammation and renal epithelial-to-mesenchymal transition have been enlightened.

A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia.

BACKGROUND: Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. CONCLUSION: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

Evaluation of anti-inflammatory activity of chloroform extract of Bryonia laciniosa in experimental animal models.

The anti-inflammatory effect of the leaves of Bryonia laciniosa was evaluated using carrageenan, dextran, histamine, serotonin induced rat paw oedema and cotton pellet induced granuloma (chronic) models in rats. In mice, carrageenan peritonitis test was performed for the extract by oral administration. The chloroform extract of Bryonia laciniosa (CEBL) exhibited significant anti-inflammatory effect at the dose 50, 100 and 200 mg/kg. Maximum inhibition (52.4%) was noted at the dose of 200 mg/kg after 3 h of drug treatment in carrageenan induced paw oedema, whereas the indomethacin (standard drug) produced 62.1% of inhibition. The extract exhibited significant anti-inflammatory activity in dextran induced paw oedema in a dose dependent manner. The extract also exhibited significant inhibition on the hind paw oedema in rats caused by histamine and serotonin respectively. In the chronic model (cotton pellet induced granuloma) the CEBL (200 mg/kg) and standard drug showed decreased formation of granuloma tissue by 50.1 and 57.3% (p<0.001) respectively. The extract also inhibited peritoneal leukocyte migration in mice. Thus, the present study revealed that the chloroform extract of Bryonia laciniosa exhibited significant anti-inflammatory activity in the tested models.