Tapan Behl

Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy.

Diabetic retinopathy, a sight-threatening microvascular complication of diabetes mellitus, is initiated by retinal endothelial dysfunction and succeeded by various pathological events, eventually resulting in vision-loss. These events are regulated by numerous mediators, including vascular endothelial growth factor (VEGF), which induces the progression of various events characterizing diabetic retinopathy, such as neovascularization and macular edema. VEGF is physiologically required for regulating proliferation and assembling of endothelial cells, during vasculogenesis, as well as for their maintenance and survival throughout the lifetime of blood vessels. However, various pathological conditions are induced in the body during diabetes (such as ischemia, oxidative stress and overactivation of protein kinase C), which upregulate the expression of VEGF, thereby deviating it from its physiological role and leading to various pathological demonstrations such as angiogenesis, increased permeability of endothelium, decreased inhibition of pro-apoptotic proteins and activation of various other inflammatory mediators. Such events disrupt vascular homeostasis and play key roles in the pathophysiology of diabetic retinopathy. Hence, acknowledging various VEGF-mediated pathways helps in understanding the deeper aspects related to progression of this disorder. Targeting and inhibiting VEGF-mediated disease progression might provide an effective alternative therapy and hence prove beneficial in the treatment of diabetic retinopathy.

Implication of oxidative stress in progression of diabetic retinopathy

Diabetic retinopathy, a severe sight-threatening complication of diabetes mellitus, accounts for a large number of cases of acquired, yet potentially avoidable, blindness. The principal mechanism of its pathogenesis appears to be alterations in the microvasculature of retina as the result of hyperglycemia. The elevated concentration of blood glucose is a harbinger of numerous molecular changes. These lead to various responses that result in microangiopathy. Oxidative stress, one such response, is attributed to disruption in the homeostasis of free radical production during the various vital processes such as the electron transport chain reaction and the scavenging mechanisms designed to neutralize these damaging molecules. This imbalance has been linked to the pathophysiology of diabetic retinopathy. Excessive formation of free radicals influences almost all pathways involved in normal human physiology. Thus, hyperglycemia-induced oxidative stress is one of the factors associated with biochemical changes. These changes are further responsible for the various structural and functional abnormalities seen in diabetic retinopathy.

Possible role of endostatin in the antiangiogenic therapy of diabetic retinopathy.

Diabetic retinopathy is one of various complications of diabetes mellitus, which is one of the most prevalent chronic disorders in the modern world. Diabetic retinopathy is one of the secondary complications encountered by the patients suffering from chronic diabetes mellitus. Two major characterizing features of diabetic retinopathy are - macular edema and angiogenesis. It has been noted in the past few years that by controlling or completely inhibiting the factors contributing to the progression of events leading to angiogenesis, there is a noticeable amount of progress seen in the prevention and cure of the animal models of diabetic retinopathy. Endostatin is one such antiangiogenic agent being studied at present. It is a carbon terminal protein fragment obtained after cleavage from the carbon terminus of collagen XVIII. It is one of the most potent inhibitors of angiogenesis known at present and is currently undergoing clinical trials. Although the exact mechanism of action of endostatin is not completely known, various factors which are altered/influenced by the action of endostatin are being studied. These include the downregulation and activation/inactivation of various factors which have been proven to have some role in the progression of angiogenesis. Endostatin could be well exploited as a durable agent in the antiangiogenic therapy, once the clinical trials show positive results.

Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy

Diabetic retinopathy is an ocular complication associated with the chronic endocrine disorder of diabetes mellitus. Angiogenesis is adjudged as a prime modulatory event in this complication. The formation of new blood vessels on the pre-existing vasculature gives rise to an abundance of anatomical and physiological alterations which ultimately results in vision loss. The drastic consequences of this complication prompt the obligation of developing effective therapies for its cure. The existing therapy mainly includes destructive techniques such as laser photocoagulation. Owing to the various drawbacks associated with this technique, there is a need to develop alternative therapies which could halt the progression of diabetic retinopathy without causing considerable damage to the retinal cells. One such possible alternative treatment being researched upon is the antiangiogenic therapy. Since angiogenesis is a critical event during the progression of this disorder, targeting this event may perhaps prove effective in its treatment. Amongst several antiangiogenic agents, thalidomide holds a reputable position due to its effectiveness in terminating angiogenesis during various pathological conditions. This review focuses on the diverse molecular mechanisms proposed to explain the antiangiogenic properties of thalidomide and their applicability in diabetic retinopathy.

Implications of the endogenous PPAR-gamma ligand, 15-deoxy-delta-12, 14-prostaglandin J2, in diabetic retinopathy

Diabetic retinopathy, a common secondary complication of diabetes mellitus, involves extensive damage to the retinal microvasculature. Retina, being a susceptible target, is highly prone to hyperglycemia-induced molecular damages. PPAR receptor, chiefly gamma subtype, mediates numerous responses related to glucose metabolism and hence is utilized, through its agonism, for the restoration of normal insulin sensitivity and glucose homeostasis in the body. Although a number of synthetic PPAR-gamma receptor agonists have been developed and are being employed for treatment purposes, the role of its endogenous ligand in the prevention of diabetic retinopathy is poorly acknowledged. Activation of PPAR-gamma receptor, via endogenous agents, provides a natural defensive shield against various hyperglycemia-induced pathological conditions. Although the biological levels of 15d-PGJ2 (an endogenous agonist of PPAR-gamma receptor) are found to be below the concentration required to trigger PPAR-gamma-mediated actions, employment of several advanced methods for the exogenous administration of this ligand might provide a beneficial option. Besides, 15d-PGJ2-induced defense is better than any of the newly developed alternative therapies, such as anti-inflammatory, anti-angiogenic or anti-apoptotic agents, of diabetic retinopathy, since it singularly provides, virtually, a complete protection package against all these pathological eventualities. Therefore, the physiology of this endogenous PPAR-gamma ligand might, possibly, be exploited to a great extent for the development of prophylactic agents, in order to restrict the progression of diabetic retinopathy.

Chinese herbal drugs for the treatment of diabetic retinopathy

To explore the various pharmacological actions and the molecular mechanisms behind them by which Chinese herbs tend to lower the risk of developing microvascular diabetic complications in retina and prevent its further progression.

Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium-mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body.

Role of leukotrienes in diabetic retinopathy.

The pathophysiology of diabetic retinopathy is highly complex and encompasses the detrimental roles of numerous factors/mediators in inducing various molecular pathological alterations. Although the roles of many inflammatory mediators, involved in the progression of this complication, have been thoroughly researched and studied, the part played by leukotrienes remains widely neglected. This review focuses on leukotrienes-induced mediation and aggravation of the pathological pathways, such as inflammation, oxidative stress and retinal angiogenesis, responsible for exhibition of various characteristic events including leukostasis, macular edema, retinal neovascularization and vitreous hemorrhages, hence, marking the advent of diabetic retinopathy. Acknowledging these roles, it might be possible to potentially utilize leukotrienes antagonists for suppressing or reducing the intensity of the mentioned pathological alterations. Hence, leukotrienes antagonists may act as an effective adjuvant therapy either along with other developing novel therapies (such as anti-VEGF or anti-TNF-α therapy), or with the established conventional laser photocoagulation treatment, to provide additional symptomatic relief or, possibly prevent the progression of diabetic retinopathy.

Omega‐3 fatty acids in prevention of diabetic retinopathy

To review the competence of Omega‐3 fatty acids in restricting the progression, thereby leading to prevention of diabetic retinopathy.

Role of endocannabinoids in the progression of diabetic retinopathy.

In the past decades, the role of numerous factors in the pathophysiology of diabetic retinopathy has been explored, following which marked progress has been made in developing several novel therapeutic options, such as anti‐vascular endothelial growth factor, anti‐tumor necrosis factor‐alpha and various other anti‐inflammatory and anti‐angiogenic agents, for the treatment of diabetic retinopathy. However, the involvement of endocannabinoid system in its pathogenesis has not been much explored. This review aims at unveiling every aspect of association of the endocannabinoid system and its interactions with various physiological and pathological pathways to induce disease progression. The various alterations induced by endocannabinoids, such as anandamide and 2‐arachidonylglycerol, in retina during hyperglycaemia clearly demonstrate and verify their involvement in aggravating the pathological conditions, hence leading to the progression of diabetic retinopathy. Exploring this involvement furthermore, in greater depths, might be beneficial in acknowledging and understanding the hidden aspects of the pathogenesis of this complication even better and might provide a therapeutically beneficial alternative target to combat and restrict its progression amongst diabetic patients. Copyright