Withania somnifera (L.) Dunal: Phytochemistry, structure-activity relationship, and anticancer potential.

BACKGROUND: Ayurveda is a highly recognized, well-documented, and well-accepted traditional medicine system. This system utilizes many natural products in various forms for therapeutic purposes. Thousands of plants mentioned in the Ayurvedic system are useful in disease mitigation and health preservation. One potential plant of the Ayurvedic system is "Ashwagandha" [Withania somnifera (L.) Dunal], commonly regarded as Indian Ginseng. It possesses various therapeutic activities, such as neuroprotective, hypoglycemic, hepatoprotective, antiarthritic, and anticancer effects. PURPOSE: Here we present a comprehensive insight on the anticancer effects of W. somnifera and mechanistic attributes of its bioactive phytocompounds. This review also provides updated information on the clinical studies pertaining to cancer, safety evaluation and opportunities for chemical modifications of withanolides, a group of specialized phytochemicals of W. somnifera. METHODS: The present study was performed in accordance with the guidelines of the Preferred Reporting Items for Systemic Reviews and Meta-Analysis. Various scientific databases, such as PubMed, Science Direct, Scopus, Google Scholar, were explored for related studies published up to May 2021. RESULTS: An updated review on the anticancer potential and mechanisms of action of the major bioactive components of W. somnifera, including withanolides, withaferin A and withanone, is presented. Comprehensive information on clinical attributes of W. somnifera and its active components are presented with the structure-activity relationship (SAR) and toxicity evaluation. CONCLUSION: The outcome of the work clearly indicates that W. somnifera has a significant potential for cancer therapy. The SAR revealed that various withanolides in general and withaferin A in particular have binding energies against various proteins and tremendous potential to serve as the lead for new chemical entities. Nevertheless, additional studies, particularly well-designed clinical trials are required before therapeutic application of withanolides for cancer treatment.

Structural characterization of Himalayan black rock salt by SEM, XRD and in-vitro antioxidant activity.

Salt is an essential component of daily life that balances the physiological functions of the human body as well as other living systems. Different varieties of salts are available in the global market. Out of many salt varieties, Himalayan rock salts have gained tremendous importance among consumers due to its diverse nutritional and medicinal properties. There are two types of Himalayan rock salts. One is the Himalayan pink salt and the other one is Himalayan black salt. Out of the two, the Himalayan pink salt is studied extensively but the black salt is underexplored. In the present study, the Himalayan black rock salt was explored to generate more scientific evidence in terms of its geochemical characterization using FE-SEM, X-ray diffractometry (XRD), elemental content using atomic absorption spectrophotometry (AAS) and in vitro antioxidant activity by different methods for the first time. The study revealed that Himalayan black salt was irregular in shape with a quadrilateral, cubic, irregular crystalline structure. The Himalayan black salt exhibited antioxidant effect and interestingly showed low Na levels than common sea salt and Himalayan pink salt. The Himalayan black salt also contained important minerals like iron, calcium and magnesium which are beneficial to human health thus exhibiting superior characteristics over other conventional table salts.

Emerging strategies for enhancing the homing of hematopoietic stem cells to the bone marrow after transplantation.

Bone marrow failure is the primary cause of death after nuclear accidents or intentional exposure to high or low doses of ionizing radiation. Hematopoietic stem cell transplantation is the most potent treatment procedure for patients suffering from several hematopoietic malignancies arising after radiation injuries. Successful hematopoietic recovery after transplantation depends on efficient homing and subsequent engraftment of hematopoietic stem cells in specific niches within the bone marrow. It is a rapid and coordinated process in which circulating cells actively enter the bone marrow through the process known as transvascular migration, which involves the tightly regulated relay of events that finally leads to homing of cells in the bone marrow. Various adhesion molecules, chemokines, glycoproteins, integrins, present both on the surface of stem cells and sinusoidal endothelium plays a critical role in transvascular migration. But despite having an in-depth knowledge of homing and engraftment and the key events that regulate it, we are still not completely able to avoid graft failures and post-transplant mortalities. This deems it necessary to design a flawless plan for successful transplantation. Here, in this review, we will discuss the current clinical methods used to overcome graft failures and their flaws. We will also discuss, what are the new approaches developed in the past 10-12 years to selectively deliver the hematopoietic stem cells in the bone marrow by adopting proper targeting strategies that can help revolutionize the field of regenerative and translational medicine.

Pluronic-F127/Platelet Microvesicles nanocomplex delivers stem cells in high doses to the bone marrow and confers post-irradiation survival.

Platelet microvesicles (pMVs) are submicron-sized heterogeneous vesicles released upon activation and contain several membrane receptors and proteins (CD41, CD61, CD62, CXCR4, PAR-1, etc.). We have revealed their ability to adhere to the triblock copolymer pluronic-F127 (PF127) and form a platelet microvesicular nanocloud which has the potential to enhance the transvascular migration of hematopoietic stem cells across the sinusoidal endothelium to the bone marrow. Besides, the pMVs nanoclouds bestow survival benefits when present on the cells used for infusion, particularly with PF127-stabilized with chitosan-alginate (PF127-CA HSCs). The vesicles were found to be firmly associated with PF127 in the nanocloud, which was detected by confocal laser scanning microscopy. The abrogation of CXCR4/SDF-1 axis regulating the transmigration of the cells by antagonist AMD3100 revealed that the enriched CXCR4 receptors on pMVs robustize the transmigration of the infused cells. The homing of the cells led to effective engraftment and faster regeneration of the critical blood lineages, which elicited 100% survival of the mice receiving lethal doses of radiation. The Human Long-Term Culture Initiating Cells (LTC-ICs), Severe Combined Immunodeficient (SCID) - Repopulating Cells (SRCs) and Colony Forming Cells (CFCs) responsible for the regeneration, but present in extremely low numbers in the infused cell dose, have enabled the cells to reach the bone marrow in high numbers. This potential of the PF127 to sequester the pMVs and its application to achieve over 10-fold delivery of HSCs across the trans-endothelial checkpoint has so far not been reported. Thus, this mechanistic innovation is a potential post-exposure life-saving regimen capable of circumventing the irreparable damage to the bone marrow caused by lethal doses of radiation.

Cell encapsulation potential of chitosan-alginate electrostatic complex in preventing natural killer and CD8+ cell-mediated cytotoxicity: an in vitro experimental study.

Natural killer and cytotoxic CD8+ T cells are involved in the rapid clearance of cells which express foreign antigens. Hence, these cells are crucial elements of the vertebrate immune system. However, these benefits turn problematic when they cause transplant rejection through their direct cytotoxic effects on donor organs/cells, which is attributed to the human leukocyte antigen disparity. To overcome these limitations, a strategy has been devised wherein the above effects can be minimised by shielding the cells through encapsulation. The layer-by-layer approach was employed for encapsulation using chitosan and alginate. Confocal microscopy, scanning electron microscopy confirmed the complete shielding of cells. Encapsulation did not affect cell viability as no toxicity was discerned. Calcein release assay was applied for assessing cell-mediated cytotoxicity. It was observed that the encapsulated cells underwent lesser lysis, thereby revealing the potential that this approach offers in reducing conditions such as graft failure and hypersensitivity.

Pharmaceutical Compounds in Drinking Water.

Pharmaceutical products and their wastes play a major role in the degradation of environment. These drugs have positive as well as negative consequences on different environmental components including biota in different ways. Many types of pharmaceutical substances have been detected with significant concentrations through various advanced instrumental techniques in surface water, subsurface water, ground water, domestic waste water, municipal waste water and industrial effluents. The central as well as state governments in India are providing supports by creating excise duty free zones to promote the pharmaceutical manufacturers for their production. As a result, pharmaceutical companies are producing different types of pharmaceutical products at large scale and also producing complex non-biodegradable toxic wastes byproducts and releasing untreated or partially treated wastes in the environment in absence of strong regulations. These waste pollutants are contaminating all types of drinking water sources. The present paper focuses on water quality pollution by pharmaceutical pollutants, their occurrences, nature, metabolites and their fate in the environment.

Sodium nitroprusside and L-arginine attenuates ferric nitrilotriacetate-induced oxidative renal injury in rats.

The role of nitric oxide (NO) in acute renal failure (ARF) is debatable. In the present study, we investigated the effect of acute administration of NO donor, Sodium nitroprusside (SNP), L-Arginine (L-Arg) and NO synthase inhibitor, N(omega)-L-arginine methyl ester (L-NAME) in Fe-NTA induced renal toxicity. Rats were pretreated with SNP (2.5 mg/kg i.p), L-Arg (125 mg/kg, i.p.) and L-NAME (10 mg/kg, i.p.) prior to administration of Fe-NTA (8 mg iron/kg body weight, i.p.) to determine the urea and creatinine levels along with biochemical analysis of oxidative stress. Fe-NTA administration markedly increased the BUN and serum creatinine level which was coupled with a marked lipid peroxidation, decreased levels of reduced glutathione and total nitric oxide levels of rat kidneys coupled with significant morphological alterations. It also resulted in the significant increase in tumor necrosis factor-alpha (TNF-alpha) in serum. Concomitant treatment with SNP and L-Arg significantly reduced the serum creatinine and BUN levels, reduced lipid peroxidation in a significant manner, restored levels of reduced glutathione, increased total nitric oxide levels and restored the normal morphology. Pretreatment with SNP and L-Arg attenuated the levels of TNF-alpha in serum in a significant manner. Prior administration of L-NAME reversed the protective effects produced by SNP and L-Arg. Present findings strongly suggest that nitric oxide plays a significant role in the pathophysiology of iron-induced renal failure and administration of NO donors can be valuable in the treatment of ARF.

Protective effect of resveratrol, a polyphenolic phytoalexin on glycerol-induced acute renal failure in rat kidney.

Rhabdomyolysis-induced myoglobinuric acute renal failure (ARF) accounts for about 10% to 40% of all cases of ARF. Reactive oxygen intermediates have been demonstrated to play an etiologic role in myoglobinuric renal failure. This study was designed to investigate the effect of resveratrol, a polyphenolic phytoalexin in glycerol-induced ARF in rats. Seven groups of rats were employed in this study, group I served as control; group II was given 50% glycerol (8 mL/kg, intramuscularly); groups III IV, and V were given glycerol plus resveratrol (2 mg/kg, 5 mg/kg, and 10 mg/kg p.o. route, respectively) 60 min prior to the glycerol injection; group VI received L-NAME (10 mg/kg, i.p.) along with glycerol and resveratrol (5 mg/kg), group VII animals received L-NAME (10 mg/kg) 30 min prior to glycerol administration. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine, and urea clearance. The oxidative stress was measured by renal malondialdehyde levels and reduced glutathione levels, and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Tissue and urine nitrite levels were measured as an index of total nitric oxide levels. Glycero treatment resulted in a marked decrease in tissue and urine nitric oxide levels, renal oxidative stress, and significantly deranged the renal functions along with deterioration of renal morphology. Pre treatment of animals with resveratrol (5 and 10 mg/kg) 60 min prior to glycerol injection markedly attenuated the fall in nitric oxide levels, renal dysfunction, morphologic alterations, reduced elevated thiobarbituric acid reacting substances, and restored the depleted renal antioxidant enzymes. This protection afforded by resveratrol was significantly reversed by cotreatment of L-NAME along with resveratrol, clearly indicating that resveratrol exerts its protective effect through nitric oxide release along with the antioxidative effect in glycerol-induced ARF.

Antioxidants in the prevention of renal disease.

Reactive oxygen species (ROS) play a key role in the pathophysiological processes of renal diseases. The cellular damage is mediated by an alteration in the antioxidant status, which increases the concentration of ROS in the stationary state (oxidative stress). Oxidative stress mediates a wide range of renal impairments, from acute renal failure, rhabdomyolysis, obstructive nephropathy, hyperlipidemia, and glomerular damage to chronic renal failure and hemodialysis. Therefore, interventions favoring the scavenging and/or depuration of ROS (dietary and pharmacological antioxidants) should attenuate or prevent the oxidative stress, thereby mitigating against the subsequent renal damage.

Protective effect of nitric oxide pathway in resveratrol renal ischemia-reperfusion injury in rats.

BACKGROUND: Nitric oxide (NO), synthesized from L-arginine by the enzyme nitric oxide synthase (NOS), seems to play an ambiguous role during tissue ischemia-reperfusion (I/R) injury. This study was designed to investigate the effects of resveratrol, a polyphenolic phytoalexin, in renal ischemia reperfusion (RIR) injury in rats. METHODS: Forty-eight rats were randomized into six groups. Group 1: sham operated (C); group 2: right nephrectomy (UNI); group 3: UNI + 45 min of ischemia and 24 h of reperfusion in the contralateral kidney; group 4: UNI + RIR + L-NAME (10 mg/kg, i.p.); group 5: UNI + RIR + resveratrol (5 mg/kg, p.o.); group 6: UNI + RIR + resveratrol + L-NAME. At the end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, catalase (CAT), and superoxide dismutase (SOD) activities were determined in renal tissue. Serum creatinine and blood urea nitrogen (BUN) were measured for the evaluation of renal function. Tissue and urine nitrite levels were measured to assess total nitric oxide levels. RESULTS: Ischemic control animals demonstrated severe deterioration of renal function, altered renal morphology, reduced total nitric oxide levels and a marked renal oxidative stress. CONCLUSIONS: Pretreatment of animals with resveratrol markedly attenuated renal dysfunction, morphological alterations, improved nitric oxide levels, reduced elevated TBARS levels and restored the depleted renal antioxidant enzymes, However, treatment with L-NAME attenuated this protection afforded by resveratrol indicating that resveratrol exerts its protective effect through NO release.

Possible role of nitric oxide in the protective effect of resveratrol in 5/6th nephrectomized rats.

BACKGROUND: Nitric oxide (NO) plays an important role in the modulation of glomerular disease. The renal protective effect of resveratrol (RVT), a polyphenolic phytoalexin, was investigated in the 5/6th nephrectomized rats. MATERIALS AND METHODS: Resveratrol (5 mg/kg, PO) was administered for 12 weeks to 5/6th nephrectomized (NX) rats together with and without nitro L-arginine methyl ester (L-NAME) (10 mg/kg, IP). We evaluated the effect of these agents on proteinuria, hypertension, renal function, glomerulosclerosis, and urinary excretion of nitric oxide metabolites. RESULTS: 5/6th NX resulted in elevation in systolic blood pressure (SBP), reduced the urinary excretion of NO metabolites, increased urinary protein excretion, and deranged renal function and glomerulosclerosis. Treatment of animals with resveratrol significantly attenuated the increase in SBP, preserved the normal renal function, reduced the urinary protein excretion, increased the urinary excretion of NO metabolites, and prevented the glomerulosclerosis. Co-administration of animals with L-NAME along with resveratrol prevented the protection observed with resveratrol. CONCLUSION: These findings indicate that resveratrol exerts its protective effect in 5/6 NX rats through a nitric oxide pathway.

Role of nitric oxide in resveratrol-induced renal protective effects of ischemic preconditioning.

BACKGROUND: Resveratrol, a natural antioxidant and polyphenol found in red wine and grapes, has been found to pharmacologically precondition the heart through upregulation of nitric oxide (NO). This study was designed to explore the involvement of NO in the renoprotective effect of resveratrol in renal ischemic preconditioning in rat kidney. METHODS: Ischemic preconditioning was induced by three cycles 2-minutes of ischemia followed by 5 minutes of reperfusion before 45 minutes of prolonged ischemia. Resveratrol was given 1 hour before the surgical procedures. RESULTS: Ischemic preconditioning and resveratrol treatment significantly improved the renal dysfunction, decrease in total NO levels, and oxidative stress induced by 45 minutes of ischemia followed by 24 hours of reperfusion. Histopatholgic examination of the kidneys of ischemic/reperfusion rats revealed severe renal damage, which was attenuated in both preconditioned and resveratrol-treated animals. Preconditioning and resveratrol administration led to a marked increase in NO levels in kidney. Renoprotective effects of resveratrol were abolished when animals were pretreated with NG-nitro-L-arginine methyl ester, a nonspecific NO synthase inhibitor. CONCLUSIONS: These findings demonstrate an important contributory role of NO in the protection afforded by resveratrol in renal ischemic preconditioning. CLINICAL RELEVANCE: It is now well established that brief periods of ischemia followed by reperfusion render a variety of tissues tolerant to subsequent ischemia/reperfusion-induced injury. This phenomenon, referred to as ischemic preconditioning, was first demonstrated in the dog myocardium. The potential for clinical application of such a powerful protective phenomenon has generated enormous interest in identifying the underlying intracellular signaling pathways, with the ultimate aim of pharmacologically exploiting these mechanisms to develop therapeutic strategies that can enhance tolerance to ischemia/reperfusion injury in patients. This study explored the possible involvement of nitric oxide in renal ischemic preconditioning.

Nifedipine attenuates changes in nitric oxide levels, renal oxidative stress, and nephrotoxicity induced by cyclosporine.

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. The causes for the nephrotoxicity of CsA have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. To determine if the renal alterations are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if nifedipine prevents these alterations. Eight groups of rats were employed in this study, group 1 served as control, group 2 rats were treated with CsA (20 mg/mL, s.c. for 21 days), groups 3, 4, and 5 received CsA along with various doses of nifedipine (5, 10, and 20 mg/kg, p.o.) 24 h before and 21 days concurrently, groups 6, 7, and 8 received L-NAME (10 mg/kg i.p.), propranolol (10 mg/kg i.p.), and aminoguanidine (100 mg/kg p.o.), respectively, along with CsA. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, and urea clearance. Tissue and urine nitrite and nitrate levels were measured to estimate the total nitric oxide levels. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels, and enzymatic activity of catalase and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress, and significantly deranged the renal functions as well as renal morphology. Treatment with nifedipine (10, 20 mg/kg) significantly improved the renal dysfunction, tissue and urine total nitric oxide levels, and renal oxidative stress and prevented the alterations in renal morphology. These results clearly demonstrate that nifedipine is beneficial as a protective agent against nephrotoxicity induced by CsA, and the protection afforded by nifedipine appears to be mediated by an increase in endothelial nitric oxide release.

Renal protective effect of molsidomine and L-arginine in ischemia-reperfusion induced injury in rats.

BACKGROUND: Nitric oxide (NO), synthesized from L-arginine by the enzyme NO synthase (NOS) seems to play an ambiguous role during tissue ischemia-reperfusion (I/R) injury. This study was designed to investigate the effects of molsidomine, a NO donor and L-arginine in I/R induced renal failure in rats METHODS: The protective effect of molsidomine and L-arginine against the damage inflicted by I/R was investigated in Sprague-Dawley rats. In one set of experiments animals were unilaterally nephrectomized, and subjected to 45 min of left renal pedicle occlusion and in another set both the renal pedicles were occluded for 45 min followed by 24 h of reperfusion. Molsidomine (10 mg/kg, p.o.) was administered twice, 30 min before ischemia and 12 h after the reperfusion period, while L-arginine was administered once, 30 min before ischemia. At the end of the reperfusion period, rats were sacrificed. Tissue and urine nitrite levels were measured to assess the total NO levels. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, catalase (CAT), and superoxide dismutase (SOD) activities were determined in renal tissue. Serum creatinine and BUN concentrations were measured for the evaluation of renal function. RESULTS: Ischemic control animals demonstrated severe deterioration of renal function, renal morphology, reduced levels of tissue, and urine NO levels and a significant renal oxidative stress. Pretreatment of animals with molsidomine and L-arginine markedly attenuated renal dysfunction, morphological alterations, improved the tissue as well as urine NO contents, reduced elevated TBAR levels and restored the depleted renal antioxidant enzymes. CONCLUSIONS: The findings imply that NO play a causal role in I/R induced renal injury.

Protective effect of catechin on ischemia-reperfusion-induced renal injury in rats.

There is increasing evidence to suggest that toxic oxygen radicals play a role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of catechin, a bioflavonoid, in I/R-induced renal failure in rats. The protective effect of catechin against the damage inflicted by reactive oxygen species (ROS) during renal I/R was investigated in Sprague Dawley rats using histopathological and biochemical parameters. In one set of experiments, animals were unilaterally nephrectomized, and subjected to 45 min of left renal pedicle occlusion, and in another set both the renal pedicles were occluded for 45 min followed by 24 h of reperfusion. Catechin (40 mg/kg, po) was administered twice daily for 4 days and 2 h prior to ischemia. At the end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive substances (TBARS), reduced glutathione levels, glutathione reductase, catalase, and superoxide dismutase activities were determined in renal tissue. Serum creatinine and blood urea nitrogen concentrations were measured for the evaluation of renal function. Ischemic control animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with catechin markedly attenuated renal dysfunction, morphological alterations, reduced elevated TBARS levels and restored the depleted renal antioxidant enzymes. The findings imply that ROS play a causal role in I/R-induced renal injury, and catechin exerts renoprotective effects probably by the radical scavenging and antioxidant activities.

Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism.

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its use is frequently accompanied by severe renal toxicity. The causes for the nephrotoxicity of CsA have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals have been proposed. The present study was designed to investigate the possible protective effect of resveratrol on CsA-induced nephrotoxicity and to explore the possible mechanism involved in resveratrol's effect. Eight groups of rats were employed in this study, group 1 served as control, group 2 rats were treated with olive oil (vehicle for CsA), group 3 rats were treated with CsA (20 mg/kg, s.c. for 21 days), groups 4, 5 and 6 received CsA along with resveratrol (2, 5 and 10 mg/kg, p.o. 24 h before and 21 days concurrently), respectively, group 7 rats were treated with NOS inhibitor, L-NAME (10 mg/kg) along with resveratrol and CsA and group 8 rats received L-NAME along with CsA. CsA administration for 21 days resulted in a marked renal oxidative stress, significantly deranged the renal functions, reduced the tissue and urine nitrite levels and markedly altered the renal morphology. Treatment with resveratrol (5 and 10 mg/kg) significantly improved the renal dysfunction; tissue and urine total nitric oxide levels, renal oxidative stress and prevented the alterations in renal morphology. Concurrent administration of L-NAME blocked the protective effect of resveratrol indicating that resveratrol exerts its protective effect by releasing nitric oxide. These results clearly demonstrate the pivotal role of nitric oxide in etiology of CsA nephrotoxicity and indicate the renoprotective potential of resveratrol in CsA nephrotoxicity.

Molsidomine, a nitric oxide donor and L-arginine protects against rhabdomyolysis-induced myoglobinuric acute renal failure.

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Nitric oxide and reactive oxygen intermediates play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). This study was designed to investigate the effect of molsidomine and L-arginine in glycerol induced ARF in rats. Six groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), groups III and IV were given glycerol plus molsidomine (5 mg/kg, and 10 mg/kg p.o. route respectively) 60 min prior to the glycerol injection, group V animals were given glycerol plus L-arginine (125 mg/kg, p.o.) 60 min prior to the glycerol injection, and group VI received L-NAME (10 mg/kg, i.p.) along with glycerol 30 min prior to glycerol administration. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, reduced glutathione and superoxide dismutase. Tissue and urine nitrite levels were measured as an index of total nitric oxide levels. Glycerol treatment resulted in a marked decrease in tissue and urine nitric oxide levels, renal oxidative stress and significantly deranged the renal functions along with deterioration of renal morphology. Pre-treatment of animals with molsidomine (10 mg/kg) and L-arginine 60 min prior to glycerol injection markedly attenuated fall in nitric oxide levels, renal dysfunction, morphological alterations, reduced elevated TBARS and restored the depleted renal antioxidant enzymes. The animals treated with L-NAME along with glycerol further worsened the renal damage observed with glycerol. As a result, our results indicate that molsidomine and L-arginine may have beneficial effects in myoglobinuric ARF.

Cyclosporine protects against ischemia/reperfusion injury in rat kidneys.

Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allografts. Cyclosporine A (CsA) has been used as an immunosuppressive agent in organ transplantation. In the present study, the effect of CsA on ischemia/reperfusion (I/R)-induced injury in the kidney was investigated. Ischemia/reperfusion injury caused a significant deterioration in the renal function, morphology and gave rise to a severe oxidative stress in the kidney. At 3 mg/kg i.v., CsA significantly improved the functional and histological parameters and attenuated the oxidative stress induced by renal ischemia/reperfusion. From the results of our study, it can be concluded that low-dose CsA pretreatment preconditions the rat kidneys against subsequent ischemia/reperfusion injury.

Effect of molsidomine and L-arginine in cyclosporine nephrotoxicity: role of nitric oxide.

Cyclosporine A (CsA) is a potent and effective immunosuppressive agent, but its action is frequently accompanied by severe renal toxicity. To determine if the renal alterations are mediated directly by cyclosporine or by secondary homodynamic alterations induced by cyclosporine, we evaluated if L-arginine and a nitric oxide donor, molsidomine could prevent these alterations. Eight groups of rats were employed in this study, group 1 served as control, group 2 rats were treated with CsA (20 mg/kg, s.c. for 21 days), group 3 received CsA along with L-arginine (125 mg/kg in drinking water concurrently with CsA), groups 4 and 5 received CsA along with molsidomine (5 and 10 mg/kg, p.o. 24 h before and 21 days concurrently with CsA), group 6 received CsA along with L-arginine (125 mg/l in drinking water concurrently with CsA) and L-NAME (10 mg/kg), groups 7 and 8 received L-NAME (10 mg/kg) along with CsA and molsidomine (5 and 10 mg/kg), respectively. Renal function was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance. Tissue and urine nitrite and nitrate levels were measured to estimate the total nitric oxide levels. The renal oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase and superoxide dismutase. Renal morphological alterations were assessed by histopathological examination. CsA administration for 21 days resulted in a marked renal oxidative stress, significantly deranged the renal functions as well as renal morphology. Treatment with L-arginine as well as with molsidomine significantly improved the renal dysfunction; tissue and urine total nitric oxide levels, renal oxidative stress and prevented the alterations in renal morphology. This protection against CsA nephrotoxicity was attenuated by treatment with L-NAME, clearly indicating that NO plays a pivotal role in renoprotective effect of L-arginine and molsidomine against cyclosporine nephrotoxicity.

Reversal of experimental myoglobinuric acute renal failure in rats by quercetin, a bioflavonoid.

The occurrence of acute renal failure (ARF) following rhabdomyolysis has been put at between 10 and 40% of cases, and accounts for between 3 and 15% of all cases of ARF. Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was performed to explore the protective effect of quercetin, a bioflavonoid, in an experimental model of myoglobinuric ARF in rats. Four groups of rats were employed in this study: group 1 served as control, group 2 was given 50% glycerol (8 ml/kg, i.m.), group 3 was given glycerol + quercetin (2 mg/kg, i.p.), and group 4 was given glycerol + DMSO (the solvent for quercetin, 5 ml/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol administration resulted in a marked renal oxidative stress, significantly deranged the renal functions as well as renal cytoarchitecture. All these factors were significantly improved by quercetin treatment. Because of its radical-scavenging and iron-chelating properties, quercetin protected the kidney against the glycerol-induced oxidative stress and resultant renal dysfunction. Based on these results, this study confirms the role of oxidative stress and demonstrates the renoprotective potential of quercetin in this rhabdomyolysis-mimicking model.