Mohammad Shamsul Ola

Role of Bcl-2 family proteins and caspases in the regulation of apoptosis

Apoptosis, or programmed cell death, plays a pivotal role in the elimination of unwanted, damaged, or infected cells in multicellular organisms and also in diverse biological processes, including development, cell differentiation, and proliferation. Apoptosis is a highly regulated form of cell death, and dysregulation of apoptosis results in pathological conditions including cancer, autoimmune and neurodegenerative diseases. The Bcl-2 family proteins are key regulators of apoptosis, which include both anti- and pro-apoptotic proteins, and a slight change in the dynamic balance of these proteins may result either in inhibition or promotion of cell death. Execution of apoptosis by various stimuli is initiated by activating either intrinsic or extrinsic pathways which lead to a series of downstream cascade of events, releasing of various apoptotic mediators from mitochondria and activation of caspases, important for the cell fate. In view of recent research advances about underlying mechanism of apoptosis, this review highlights the basics concept of apoptosis and its regulation by Bcl-2 family of protein. Furthermore, this review discusses the interplay of various apoptotic mediators and caspases to decide the fate of the cell. We expect that this review will add to the pool of basic information necessary to understand the mechanism of apoptosis which may implicate in designing better strategy to develop biomedical therapy to control apoptosis.

Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy

One of the major complications in patients with diabetes is diabetic retinopathy (DR), a leading cause of blindness worldwide. It takes several years before any clinical signs of retinopathy appear in diabetic patients, which gives an ample opportunity for scientists to uncover biochemical and molecular mechanism implicated early in the development and progression of the disease. During the past few decades, research progress has been made in investigating the pathophysiology of the disease; however, due to nonavailability of human retinal samples at different stages of the disease and also due to lack of a proper animal model of DR, the exact molecular mechanism has not been elucidated, making therapeutic a difficult task. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, lipids, amino acids, and other related factors and molecules that are implicated in the pathophysiology of the DR. Furthermore, we have highlighted neurodegeneration and regulation of neurotrophic factors, being recognized as early events that may be involved in the pathology of the disease in the course of DR. An understanding of the biochemical and molecular changes especially early in the diabetic retina may lead to new and effective therapies towards prevention and amelioration of DR, which is important for the millions of individuals who already have or are likely to develop the disease before a cure becomes available.

Neurodegeneration and Neuroprotection in Diabetic Retinopathy

Diabetic retinopathy is widely considered to be a neurovascular disease. This is in contrast to its previous identity as solely a vascular disease. Early in the disease progression of diabetes, the major cells in the neuronal component of the retina consist of retinal ganglion cells and glial cells, both of which have been found to be compromised. A number of retinal function tests also indicated a functional deficit in diabetic retina, which further supports dysfunction of neuronal cells. As an endocrinological disorder, diabetes alters metabolism both systemically and locally in several body organs, including the retina. A growing body of evidences indicates increased levels of excitotoxic metabolites, including glutamate, branched chain amino acids and homocysteine in cases of diabetic retinopathy. Also present, early in the disease, are decreased levels of folic acid and vitamin-B12, which are potential metabolites capable of damaging neurons. These altered levels of metabolites are found to activate several metabolic pathways, leading to increases in oxidative stress and decreases in the level of neurotrophic factors. As a consequence, they may damage retinal neurons in diabetic patients. In this review, we have discussed those potential excitotoxic metabolites and their implications in neuronal damage. Possible therapeutic targets to protect neurons are also discussed. However, further research is needed to understand the exact molecular mechanism of neurodegeneration so that effective neuroprotection strategies can be developed. By protecting retinal neurons early in diabetic retinopathy cases, damage of retinal vessels can be protected, thereby helping to ameliorate the progression of diabetic retinopathy, a leading cause of blindness worldwide.

Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy

Abstract Objectives: Present study aims to investigate the ameliorative effects of naringenin (NG) on experimentally induced diabetic neuropathy (DN) in rats. Methods: Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ, 60 mg/kg). Naringenin (25 and 50 mg/kg/day) treatment was started 2 weeks after the diabetes induction and continued for five consecutive weeks. Pain threshold behaviour tests were performed at the end of the treatment. Serum levels of glucose, insulin and pro-inflammatory cytokines were assessed. In sciatic tissues, markers oxidative stress, cytokines and neurotrophic factors were measured. Results: NG treatments showed significant decrease in paw-withdrawal (P < 0.01) and tail-flick latency (P < 0.01). The drug attenuated the diabetic-induced changes in serum glucose, insulin and pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In sciatic nerve, the diabetic-induced alterations in interleukins and oxidative stress biomarkers were significantly attenuated by NG. Decreased sciatic expressions of insulin growth factor (IGF) and nerve growth factor (NGF) in diabetic rats were also ameliorated by NG. Diabetes-induced dysregulated levels of nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were ameliorated by NG. Histological analysis showed that NG corrected the altered sciatic changes in diabetic animals. Discussion: We suggest that neuro-protective effect of NG molecules in sciatic nerve of diabetic rats, through its anti-diabetic as well as antioxidant and anti-inflammatory properties.

Pathophysiology and management of diabetic retinopathy

Diabetic retinopathy remains a major cause of worldwide preventable blindness. In this review, we evaluate the recent advances in understanding the molecular mechanisms of diabetic retinopathy, highlight the current management of diabetic retinopathy and new therapeutic approaches, and discuss the range of potential future therapeutic strategies in order to combat the disease. The microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, including the activation of PKC, increased advanced glycation end-products formation, polyol pathway and oxidative stress, and activation of the renin–angiotensin system. There is an accumulating body of evidence that inflammation and neurodegeneration play a prominent role in the pathogenesis of diabetic retinopathy. Strict metabolic control, tight blood pressure control, laser photocoagulation and vitrectomy remain the standard care for diabetic retinopathy. Emerging therapies include intravitreal triamcinolone or anti-VEGF agents, ruboxistaurin, renin–angiotensin system blockers, fenofibrate, islet cell transplantation, PPAR-γ agonists and intravitreal hyaluronidase. However, more randomized, controlled clinical trials are required to clarify their role alone or in combination.

Neurodegeneration in diabetic retina and its potential drug targets.

Diabetic retinopathy (DR) is one of the major complications of diabetes causing vision loss and blindness worldwide. DR is widely recognized as a neurodegenerative disease as evidenced from early changes at cellular and molecular levels in the neuronal component of the diabetic retina, which is further supported by various retinal functional tests indicating functional deficits in the retina soon after diabetes progression. Diabetes alters the level of a number of neurodegenerative metabolites, which increases influx through several metabolic pathways which in turn induce an increase in oxidative stress and a decrease in neurotrophic factors, thereby damage retinal neurons. Loss of neurons may implicate in vascular pathology, a clinical signs of DR observed at later stages of the disease. Here, we discuss diabetes-induced potential metabolites known to be detrimental to neuronal damage and their mechanism of action. In addition, we highlight important neurotrophic factors, whose level have been found to be dysregulated in diabetic retina and may damage neurons. Furthermore, we discuss potential drugs and strategies based on targeting diabetes-induced metabolites, metabolic pathways, oxidative stress, and neurotrophins to protect retinal neurons, which may ameliorate vision loss and vascular damage in DR.

Changing paradigms in the treatment of diabetic retinopathy.

Purpose of review To review current treatment approaches in diabetic retinopathy. Recent findings Diabetic retinopathy remains one of the leading causes of blindness worldwide. Strict metabolic control, tight blood pressure control, laser photocoagulation, and vitrectomy remain the standard care for diabetic retinopathy. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with diabetic macular edema. The current evidence suggests that intravitreal triamcinolone acetonide or antivascular endothelial growth factor agents are effective adjunctive treatment to laser photocoagulation or vitrectomy. However, triamcinolone is associated with risks of elevated intraocular pressure and cataract. Vitrectomy with removal of the posterior hyaloid without internal limiting membrane peeling seems to be effective in eyes with persistent diffuse diabetic macular edema, particularly in eyes with associated vitreomacular traction. Emerging therapies include islet cell transplantation, fenofibrate, ruboxistaurin, and intravitreal hyaluronidase. Summary A variety of promising new medical and surgical therapies are emerging, but more randomized controlled clinical trials are required to clarify their role alone or in combination.

Novel drugs and their targets in the potential treatment of diabetic retinopathy

Diabetic retinopathy (DR) is the most common complication of diabetes. It causes vision loss, and the incidence is increasing with the growth of the diabetes epidemic worldwide. Over the past few decades a number of clinical trials have confirmed that careful control of glycemia and blood pressure can reduce the risk of developing DR and control its progression. In recent years, many treatment options have been developed for clinical management of the complications of DR (e.g., proliferative DR and macular edema) using laser-based therapies, intravitreal corticosteroids and anti-vascular endothelial growth factors, and vitrectomy to remove scarring and hemorrhage, but all these have limited benefits. In this review, we highlight and discuss potential molecular targets and new approaches that have shown great promise for the treatment of DR. New drugs and strategies are based on targeting a number of hyperglycemia-induced metabolic stress pathways, oxidative stress and inflammatory pathways, the renin-angiotensin system, and neurodegeneration, in addition to the use of stem cells and ribonucleic acid interference (RNAi) technologies. At present, clinical trials of some of these newer drugs in humans are yet to begin or are in early stages. Together, the new therapeutic drugs and approaches discussed may control the incidence and progression of DR with greater efficacy and safety.

Expression of thrombospondin-2 as a marker in proliferative diabetic retinopathy.

Purpose:  To determine the expression of the endogenous anti‐angiogenic and pro‐fibrotic matricellular protein thrombospondin (TSP)‐2 and its receptors CD36 and CD47 in proliferative diabetic retinopathy (PDR). In addition, we examined the expression of TSP‐2 in the retinas of diabetic rats.

Influence of insulin on glutamine synthetase in the Müller glial cells of retina

Glutamine synthetase (GS), a Müller cell specific enzyme in the retina, is the key enzyme involve in glutamate metabolism. The goal of this study was to investigate the expression and regulation of GS by insulin in the cultured rat retinal Müller cells. Immunocytochemical and immunoblotting experiments showed that the cultured Müller cells express GS protein under normal cell culture conditions. Insulin treatments decreased the GS expression both in a time and dose dependent manner. Insulin also decreased the hydrocortisone induced GS expression. Furthermore, we investigated the expression and regulation of two other Müller cell specific enzymes known to be involved in glutamate metabolism, the mitochondrial branched chain aminotransferase (BCATm) and pyruvate carboxylase (PC). Immunoblotting experiments showed that Müller cells expressed both BCATm and PC. Treatments of cells with hydrocortisone or insulin did not influence the BCATm expression level. Hydrocortisone treatment of cells increased the PC expression but this induced expression was suppressed by insulin treatment. Müller cells expressed insulin receptor proteins (IRβ and IRS-1) and insulin activation induced the phosphotyrosine level of insulin receptor proteins. Moreover, hydrocortisone did not influence the expression or activation of these receptor proteins. The data suggests that insulin modulates the GS synthesis and may influence glutamate metabolism in the cultured retinal Müller cells but not by influencing the insulin signaling pathway.