Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management.

Synergistic physiologic mechanisms involving the renin-angiotensin system (RAS), the sympathetic nervous system, and the arginine-vasopressin system play an integral role in blood pressure homeostasis. A subset of patients with sepsis experience septic shock with attendant circulatory, cellular, and metabolic abnormalities. Septic shock is associated with increased mortality because of an inadequacy to maintain mean arterial blood pressure (MAP) despite volume resuscitation and the use of vasopressors. Vasodilatory shock raises the dose of vasopressors required to maintain a MAP of > 65 mm Hg. The diminished response to endogenous angiotensin II in sepsis-induced vasoplegia may be related to the aberrant RAS activation that stimulates a proinflammatory beneficial antibacterial response, increasing the secretion of proinflammatory cytokines that downregulate AT-1 receptors expression. Moreover, excessive systemic upregulation of nitric oxide synthase, stimulation of prostaglandin synthesis, and activation of ATP-sensitive potassium channels followed by reduced vascular entry of calcium ions are putative mechanisms in the reduced responsiveness to vasopressors. However, intravenous angiotensin II in catecholamine-resistant septic shock patients showed substantial evidence of raising the MAP to target hemodynamic levels, thus allowing time to treat underlying conditions. Nevertheless, evidence of catecholamine-sparing effect by adding angiotensin II, aimed at increasing the therapeutic index of vasopressor therapy, does not show an attenuation of end-organ damage. The use of angiotensin II in septic shock has not been evaluated in patients who are not catecholamine resistant. This, in conjunction with an evolving definition of catecholamine resistance, provides an opportunity for further evaluation of exogenous angiotensin II in septic shock.

The physiologic and physiopathologic roles of perivascular adipose tissue and its interactions with blood vessels and the renin-angiotensin system.

The perivascular adipose tissue (PVAT) refers to an ectopic local deposit of connective tissue that anatomically surrounds most of the blood vessels. While it was initially known only as a structural support for vasculature, the landmark findings of Soltis and Cassis (1991), first demonstrating that PVAT reduces the contractions of norepinephrine in the isolated rat aorta, brought the potential vascular role of PVAT into the limelight. This seminal work implied the potential ability of PVAT to influence vascular responsiveness. Several vasoactive/vasocrine substances influencing vascular homeostasis were successively shown to be released from PVAT that include both adipocyte-derived relaxing and contracting factors. The PVAT is currently recognized as a metabolically active endocrine organ and is eventually considered as the 'protagonist' in vascular homeostasis. It plays prominent defending and opposing roles in vascular function, while the actual vascular influences of PVAT vary with an increase in adiposity. Recent studies have presented compelling evidence implicating the pivotal role of PVAT in the local activation of the renin-angiotensin system (RAS), which substantially impacts vascular physiology and physiopathology. Current findings have advanced our understanding of the role of PVAT in favorably or adversely modulating the vascular function through differential RAS activation. Given that adipocytes also produce major RAS components locally to influence vascular function, this review provides a scientific basis to distinctly understand the key role of PVAT in regulating the autocrine and paracrine functions of vascular RAS components and its potential as an emerging therapeutic target for mitigating cardiovascular complications.

Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: Pathologic implications and putative pharmacologic targets.

Though the pathogenesis of hyperuricemia-induced renal complications is not precisely known, hyperuricemia has been recognized as an independent risk factor for renal disease. While the clinical implication of hyperuricemia in renal disease has been a contemporary topic of debate, growing body of bench and clinical evidences certainly suggest a causative role of high uric acid in renal abnormalities by implicating diverse pathologic and molecular mechanisms. Urate crystals after having deposited in the kidney could cause hyperuricemia nephropathy leading to glomerular hypertrophy and tubulointerstitial fibrosis, while high serum uric acid might predict progressive renal damage and dysfunction. Hyperuricemia could be associated with manifestation of tubular injury and macrophage infiltration as well as an increased expression of inflammatory mediators. This review sheds light on the mechanistic aspects pertaining to hyperuricemia-associated renal abnormalities. Besides, the renal detrimental actions of high uric acid possibly mediated through its potential role on oxidative stress, renal inflammation, endothelial dysfunction, glycocalyx shedding, endothelial-to-mesenchymal transition and more specifically on the renal epithelial-to-mesenchymal transition have been addressed. Moreover, this review discusses a number of potential targets such as endothelin-1, TLR4/NF-kB, PI3K/p-Akt, Wnt5a/Ror2, NLRP3 inflammasome, NADPH oxidase, ERK1/2, enhancer of zeste homolog 2, serum response factor and Smad3/TGF-ß signalling pathways, among others, implicated in hyperuricemia-associated renal abnormalities. This review finally apprises a number of bench and clinical studies which supporting a notion that the pharmacologic reduction of high uric acid might have a therapeutic value in the management of renal abnormalities, with an emphasis on febuxostat and its renal pleiotropic actions.

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.

Effects of pre and post-treatments with dipyridamole in gentamicin-induced acute nephrotoxicity in the rat.

This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.

Prevalence and prevention of cardiovascular disease and diabetes mellitus.

Noncommunicable diseases (NCDs) have become important causes of mortality on a global scale. According to the report of World Health Organization (WHO), NCDs killed 38 million people (out of 56 million deaths that occurred worldwide) during 2012. Cardiovascular diseases accounted for most NCD deaths (17.5 million NCD deaths), followed by cancers (8.2 million NCD deaths), respiratory diseases (4.0 million NCD deaths) and diabetes mellitus (1.5 million NCD deaths). Globally, the leading cause of death is cardiovascular diseases; their prevalence is incessantly progressing in both developed and developing nations. Diabetic patients with insulin resistance are even at a greater risk of cardiovascular disease. Obesity, high cholesterol, hypertriglyceridemia and elevated blood pressure are mainly considered as major risk factors for diabetic patients afflicted with cardiovascular disease. The present review sheds light on the global incidence of cardiovascular disease and diabetes mellitus. Additionally, measures to be taken to reduce the global encumbrance of cardiovascular disease and diabetes mellitus are highlighted.

Effect of edaravone in diabetes mellitus-induced nephropathy in rats.

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.

Cardiovascular drugs-induced oral toxicities: A murky area to be revisited and illuminated.

Oral health is an imperative part of overall human health. Oral disorders are often unreported, but are highly troublesome to human health in a long-standing situation. A strong association exists between cardiovascular drugs and oral adverse effects. Indeed, several cardiovascular drugs employed clinically have been reported to cause oral adverse effects such as xerostomia, oral lichen planus, angioedema, aphthae, dysgeusia, gingival enlargement, scalded mouth syndrome, cheilitis, glossitis and so forth. Oral complications might in turn worsen the cardiovascular disease condition as some reports suggest an adverse correlation between periodontal oral disease pathogenesis and cardiovascular disease. These are certainly important to be understood for a better use of cardiovascular medicines and control of associated oral adverse effects. This review sheds lights on the oral adverse effects pertaining to the clinical use of cardiovascular drugs. Above and beyond, an adverse correlation between oral disease and cardiovascular disease has been discussed.

Nephroprotective effect of catechin on gentamicin-induced experimental nephrotoxicity.

BACKGROUND: Gentamicin is an effective aminoglycoside antibiotic employed against severe Gram-negative bacterial infections, but induction of nephrotoxicity limits its frequent clinical use. This study was undertaken to investigate the effect of catechin hydrate on gentamicin-induced nephrotoxicity in rats. METHODS: Rats were administered nephrotoxic dose of gentamicin (100 mg/kg/day, i.p.) once daily for 14 days. Gentamicin-administered rats were treated with catechin hydrate (50 mg/kg/day, per os), the treatment was started 3 days before the administration of gentamicin while it was continued for 14 days from the day of gentamicin administration. RESULTS: Two weeks administration of gentamicin significantly increased the serum creatinine and blood urea nitrogen levels. Renal histopathological examination of gentamicin-administered rats revealed degenerative changes in glomeruli and tubules after 2 weeks. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with renal oxidative stress as assessed in terms of marked decrease in renal-reduced glutathione (GSH). However, catechin hydrate treatment showed considerably nephroprotective action against gentamicin-induced nephrotoxicity in rats by preventing aforementioned renal structural and functional abnormalities and oxidative stress. CONCLUSION: Catechin hydrate has a potential to prevent gentamicin-induced experimental nephrotoxicity. The renoprotective effect of catechin hydrate against gentamicin-induced nephrotoxicity might be mediated through its antioxidant and possible direct nephroprotective actions.

Dapagliflozin: glucuretic action and beyond.

Diabetes mellitus is a greatly challenging disease of the 21 century, and the mortality rate due to this insidious disease is increasing worldwide in spite of availability of effective oral hypoglycemic agents. Satisfactory management of glycemic control in patients afflicted with type 2 diabetes mellitus (T2DM) remains a major clinical challenge. Identification of potential pharmacological target sites is therefore continuing as an integral part of the diabetic research. The sodium-glucose co-transporter type 2 (SGLT2) expressed in the renal proximal tubule plays an essential role in glucose reabsorption. Pharmacological blockade of SGLT2 prevents glucose reabsorption and subsequently induces the elimination of filtered glucose via urine, the process is known as 'glucuresis'. Dapagliflozin is a selective inhibitor of SGLT2. The US FDA approved dapagliflozin in January 2014 to improve glycemic control along with diet and exercise in adult patients afflicted with T2DM. It has a potential to decrease glycated hemoglobin and to promote weight loss. Although the mechanism of action of dapagliflozin is not directly linked with insulin or insulin sensitivity, reduction of plasma glucose by dapagliflozin via induction of glucosuria could improve muscle insulin sensitivity. Moreover, dapagliflozin could cause diuresis and subsequently fall in blood pressure. In addition to general discussion on the pharmacology of dapagliflozin, we propose in this review the possibilities of dual antidiabetic effect of dapagliflozin and its possible additional beneficial actions in hypertensive-obese-T2DM patients through its indirect blood pressure-lowering action and reduction of body calories and weight. Long-term clinical studies are however needed to clarify this contention.

Classical and pleiotropic actions of dipyridamole: Not enough light to illuminate the dark tunnel?

Dipyridamole is a platelet inhibitor indicated for the secondary prevention of transient ischemic attack. It inhibits the enzyme phosphodiesterase, elevates cAMP and cGMP levels and prevents platelet aggregation. Dipyridamole inhibits the cellular uptake of adenosine into red blood cells, platelets and endothelial cells that results in increased extracellular availability of adenosine, leading to modulation of cardiovascular function. The antiplatelet action of dipyridamole might offer therapeutic benefits in secondary stroke prevention in combination with aspirin. Inflammation and oxidative stress play an important role in atherosclerosis and thrombosis development, leading to stroke progression. Studies demonstrated anti-inflammatory, anti-oxidant and anti-proliferative actions of dipyridamole. These pleiotropic potentials of dipyridamole might contribute to improved therapeutic outcomes when used with aspirin in preventing secondary stroke. Dipyridamole was documented as a coronary vasodilator 5 decades ago. The therapeutic failure of dipyridamole as a coronary vasodilator is linked with induction of 'coronary steal' phenomenon in which by dilating resistance vessels in non-ischemic zone, dipyridamole diverts the already reduced blood flow away from the area of ischemic myocardium. Dipyridamole at high-dose could cause a marked 'coronary steal' effect. Dipyridamole, however, at low-dose could have a minimal hemodynamic effect. Low-dose dipyridamole treatment has a therapeutic potential in partially preventing diabetes mellitus-induced experimental vascular endothelial and renal abnormalities by enhancing endothelial nitric oxide signals and inducing renovascular reduction of oxidative stress. In spite of plenteous research on dipyridamole's use in clinics, its precise clinical application is still obscure. This review sheds lights on pleiotropic pharmacological actions and therapeutic potentials of dipyridamole.

Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats.

Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin-eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.

Implications of fundamental signalling alterations in diabetes mellitus-associated cardiovascular disease .

The chronic diabetes mellitus (DM) is a major risk factor for cardiovascular disease. The incidence of cardiovascular disease might be a foremost cause of morbidity and mortality in patients afflicted with DM. In fact, DM is associated with multi-factorial cardiovascular signalling alterations via significant modulation of expression pattern, activation or release of PI3K, PKB, eNOS, EDRF, NADPH oxidase, EDHF, CGRP, adenosine, iNOS, ROCK, PKC-ß2, CaMKII, microRNA (miR)-126 and miR-130a, which could result in inadequate maintenance of cardiovascular physiology and subsequent development of cardiovascular pathology. This review highlights the possible adverse implications of fundamental cardiovascular signalling alteration in DM-associated cardiovascular disease pathology.

The art and science of research methodology, biostatistics, manuscript writing, and publication ethics: An invigorating training for improving research aptitudes in southern Indian biomedical institutions.

The basic concepts of research are learned through systematic literature searches which form the basis of a research statement and research topic. Then the research question, hypothesis, aim, and objectives, as well as the experimental design, are developed. Given the context provided, the primary focus is on the importance of adequately training postgraduates and young research investigators in research methodology and project development. It is evident that there is a lack of proper training in these areas, and the rapid expansion of colleges in India exacerbates this issue. To address this, research students must receive comprehensive instruction in scientific research methodology, experimental design, statistics, scientific writing, publishing, and research ethics. Our team has been conducting workshops and symposia for more than two decades to improve the current teaching methods in these areas. Most recently, we organized a series of national and international workshops and seminars in multiple states across India to fortify the core concepts of scientific research for students and faculty members. This report highlights the key aspects of these workshops and the positive outcomes experienced by participants.

Possible involvement of PPARγ-associated eNOS signaling activation in rosuvastatin-mediated prevention of nicotine-induced experimental vascular endothelial abnormalities.

Nicotine exposure via cigarette smoking and tobacco chewing is associated with vascular complications. The present study investigated the effect of rosuvastatin in nicotine (2 mg/kg/day, i.p., 4 weeks)-induced vascular endothelial dysfunction (VED) in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating aortic and serum nitrite/nitrate concentration. Further, scanning electron microscopy and hematoxylin-eosin staining of thoracic aorta were performed to assess the vascular endothelial integrity. Moreover, oxidative stress was assessed by estimating aortic superoxide anion generation and serum thiobarbituric acid-reactive substances. The nicotine administration produced VED by markedly reducing acetylcholine-induced endothelium-dependent relaxation, impairing the integrity of vascular endothelium, decreasing aortic and serum nitrite/nitrate concentration, increasing oxidative stress, and inducing lipid alteration. However, treatment with rosuvastatin (10 mg/kg/day, i.p., 4 weeks) markedly attenuated nicotine-induced vascular endothelial abnormalities, oxidative stress, and lipid alteration. Interestingly, the co-administration of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 (1 mg/kg/day, i.p., 2 weeks) submaximally, significantly prevented rosuvastatin-induced improvement in vascular endothelial integrity, endothelium-dependent relaxation, and nitrite/nitrate concentration in rats administered nicotine. However, GW9662 co-administration did not affect rosuvastatin-associated vascular anti-oxidant and lipid-lowering effects. The incubation of aortic ring, isolated from rosuvastatin-treated nicotine-administered rats, with L-NAME (100 µM), an inhibitor of nitric oxide synthase (NOS), significantly attenuated rosuvastatin-induced improvement in acetylcholine-induced endothelium-dependent relaxation. Rosuvastatin prevents nicotine-induced vascular endothelial abnormalities by activating PPARγ and endothelial NOS signaling pathways. Moreover, the PPARγ-independent anti-oxidant and lipid-lowering effects of rosuvastatin might additionally play a role in the improvement of vascular endothelial function.

Mechanistic insights into the beneficial effects of curcumin on insulin resistance: Opportunities and challenges.

The past couple of decades in particular have seen a rapid increase in the prevalence of type 2 diabetes mellitus (T2DM), a debilitating metabolic disorder characterised by insulin resistance. The insufficient efficacy of current management strategies for insulin resistance calls for additional therapeutic options. The preponderance of evidence suggests potential beneficial effects of curcumin on insulin resistance, while modern science provides a scientific basis for its potential applications against the disease. Curcumin combats insulin resistance by increasing the levels of circulating irisin and adiponectin, activating PPARγ, suppressing Notch1 signalling, and regulating SREBP target genes, among others. In this review, we bring together the diverse areas pertaining to our current understanding of the potential benefits of curcumin on insulin resistance, associated mechanistic insights, and new therapeutic possibilities.