Pitchai Balakumar

Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it?

Aminoglycoside antibiotics are employed clinically because of their potent bactericidal activities, less bacterial resistance, post-antibiotic effects and low cost. However, drugs belong to this class are well-known to cause nephrotoxicity, which limits their frequent clinical exploitation. Gentamicin, a commonly used aminoglycoside, is associated with an induction of tubular necrosis, epithelial oedema of proximal tubules, cellular desquamation, tubular fibrosis, glomerular congestion, perivascular edema and inflammation, which ultimately show the way to renal dysfunction. It is a matter of debate whether we have promising agents to prevent the incidence of gentamicin-induced nephrotoxicity. The present review critically discussed the pathogenesis of gentamicin-induced nephrotoxicity. In addition, based on the experimental and clinical studies, the possible therapeutic approach to prevent gentamicin-induced nephrotoxicity has been discussed.

A century old renin–angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology

Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.

Multifarious molecular signaling cascades of cardiac hypertrophy: Can the muddy waters be cleared?

The mammalian heart during its development and in response to physiological or pathological stimuli undergoes hypertrophic enlargement, a consequence of an increase in cardiac myocyte size. Cardiac hypertrophy in response to biomechanical stress stimuli may be initially a compensatory event, but gradually becomes a pathological event if the mechanical stress on the myocardium persists. In fact, studies have shown cardiac hypertrophy as a dominant risk factor for the development of heart failure and coronary artery disease. A number of complex signaling cascades were identified that regulate the cardiac hypertrophic response. Much progress has been made previously in identifying various target sites and understanding the molecular and cellular processes that are involved in the development of cardiac hypertrophy and heart failure. This has led drug discovery research in developing effective therapies to treat various cardiovascular diseases. However, the available therapeutic agents for the treatment of heart failure have limited effectiveness in halting the progression of the disease. Therefore, novel therapeutic strategies are being identified to inhibit the development of cardiac hypertrophy before heart failure develops. In this review, we describe multifarious molecular signaling mechanisms involved in the pathogenesis of cardiac hypertrophy, including tumor necrosis factor-α, Wnt/Frizzled signals, calcineurin, mitofusin-2, mitogen-activated protein kinases, Janus kinase, Rho kinase, poly (ADP-ribose) polymerase, transcription factors, oxidative signals and G-protein-coupled-receptor-associated signaling system. Elucidation of signaling cascades that initiate cardiac hypertrophy will open up a new area of research in developing innovative therapeutics for the treatment of pathological cardiac hypertrophy.

Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions

Chronic diabetes mellitus is associated with various complications such as retinopathy, neuropathy, nephropathy, cardiomyopathy, vasculopathy, dermatopathy and encephalopathy. Nephropathy is one of the major complications of diabetes mellitus, and the morbidity and mortality due to diabetic nephropathy is constantly progressing in industrialized nations. No satisfactory therapeutic option is currently available to treat patients with nephropathy except for fewer agents like angiotensin converting enzyme inhibitors, angiotensin AT(1) receptor blockers and few antioxidants, which have been shown to improve the function of diabetic kidney to some extent. Thus, tremendous efforts are being made to explore promising therapeutic interventions to treat diabetic nephropathy. This review discussed various presently employed and recently developed pharmacological interventions to treat diabetic nephropathy and to improve the function of diabetic kidney. In addition, the recently identified potential target sites involved in the pathogenesis of diabetic nephropathy have been delineated.

Vascular endothelial dysfunction: a tug of war in diabetic nephropathy?

Vascular endothelium regulates vascular tone and maintains free flow of blood in vessels. Vascular endothelial dysfunction (VED) results in reduced activation of endothelial nitric oxide synthase (eNOS), reduced generation and bioavailability of nitric oxide (NO) and increased production of reactive oxygen species (ROS). The eNOS uncoupling in VED leads to eNOS mediated production of ROS that further damage the endothelial cells by upregulating the proinflammatory mediators and adhesion molecules. VED has been associated in the pathogenesis of hypertension, atherosclerosis, coronary artery diseases, diabetes mellitus and nephropathy. Diabetes is a chronic metabolic disorder characterized by hyperglycemia followed by micro and macrovascular complications. A correlation between diabetes and VED has been demonstrated in various studies. The downregulation of eNOS in diabetes has been noted to accelerate diabetic nephropathy. Moreover, various endogenous vasoconstrictors are also upregulated in diabetic nephropathy. VED has been shown to be involved in diabetic nephropathy by inducing nodular glomerulosclerosis followed by glomerular basement membrane thickness and mesangial expansion, which ultimately decline glomerular filtration rate (GFR). Thus it is suggested that diabetes-induced VED could be one of the culprits involved in the pathogenesis of diabetic nephropathy.

Pre-conditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury: what could be the next footstep?

Myocardial ischemia is a condition in which the coronary blood flow to the heart is reduced, which results in deficient oxygen and nutrients supply to the heart. Reperfusion to an ischemic myocardium often results in lethal myocardial injury. The brief episodes of ischemia and reperfusion given before prolonged ischemia and reperfusion denote pre-conditioning. On the other hand, brief episodes of ischemia and reperfusion given after prolonged ischemia and at the onset of reperfusion denotes postconditioning. Pre- and postconditioning are anti-jeopardized phenomenons in which both forms have been shown to protect the myocardium from lethal ischemia-reperfusion injury. However, numerous experimental studies reveal that the cardioprotective effects of these phenomenons have been suppressed in presence of some pathological factors such as hyperglycemia, obesity, hypercholesterolemia, etc. In this review, we have critically discussed the mechanisms involved in the cardioprotective effects of pre- and postconditioning to limit ischemia-reperfusion-induced myocardial injury. Moreover, the clinical relevance and factors affecting the cardioprotective potentials of pre- and postconditioning have been delineated.

PPAR Ligands: Are They Potential Agents for Cardiovascular Disorders?

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPARα, PPARγ, and PPARβ/δ. Fibrates are acting via PPARα, and they are used as lipid-lowering agents. PPARγ agonists reduce insulin resistance and have been used in the treatment of type 2 diabetes. As the knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including a novel role in the management of cardiovascular disorders (CVD). PPARα/γ dual agonists are currently under development and hold considerable promise in the management of type 2 diabetes and provide an effective therapeutic option for treating the multifactorial components of CVD. Several experimental and clinical evidences elucidated the beneficial effects of PPAR ligands in prevention and treatment of various CVD. However, PPARα and PPARγ agonists have been shown to be proinflammatory and proatherogenic in a few studies. Further, PPARγ ligands have been noted to be involved in the pathogenesis of congestive heart failure. These controversial results obtained from a few studies created further complication in understanding the role of PPARs. The function of PPARδ and its potential as a cardiovascular therapeutic target are currently under investigation. The present review focuses on the merits and limitations of PPAR agonists with regard to their use in CVD.

The multifaceted therapeutic potential of benfotiamine

Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.

Pathophysiology of Diabetic Nephropathy: Involvement of Multifaceted Signalling Mechanism

Diabetic nephropathy is a major cause of end-stage renal failure and the mortality rate due to this disease is continuously progressing worldwide. The multifaceted signalling mechanisms have been identified to be involved in the pathogenesis of diabetic nephropathy. Despite the modern therapies like antidiabetics, antihypertensives, and antioxidants available to treat diabetic nephropathy; most of patients continue to show progressive renal damage. It suggests that the key pathogenic mechanism involved in the induction and progression of diabetic nephropathy is still remaining active and unmodified by the present therapies. The purpose of this review is to bring together the current information concerning the signalling systems involved in the pathogenesis of diabetic nephropathy.

Potential target sites to modulate vascular endothelial dysfunction : Current perspectives and future directions

Endothelium is innermost lining of the blood vessel and it regulates the vascular tone. It plays a critical role in the mechanics of blood flow, regulation of coagulation, leukocyte adhesion, vascular smooth muscle cell (VSMC) growth and immune function. Endothelial dysfunction results in reduced vasodilatation, proinflammatory state and prothrombotic properties. Various experimental evidences revealed that reduced nitric oxide production and increased oxidative stress lead to vascular endothelial dysfunction (VED). Environmental factors such as cigarette smoking, alcohol consumption and exposure to arsenic play a critical role in the development of endothelial dysfunction. Vascular endothelial dysfunction is a hallmark for various cardiovascular disorders such as hypertension, atherosclerosis, heart failure, myocardial infarction and stroke. However, the pathological mechanism involved in the vascular endothelial dysfunction is poorly understood. The present review delineates various potential target sites for vascular endothelial dysfunction, which may open a new vista for exploring novel pharmacological agents to treat various cardiovascular disorders.