Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation

Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose‐limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin‐induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey‐treated group as compared to the cisplatin alone‐treated group. Interestingly, honey feeding significantly reduced cisplatin‐induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin‐induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation.     

Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines

Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated.Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.     

Protective role of silymarin against manganese‐induced nephrotoxicity and oxidative stress in rat

Metal toxicity may occur after exposure from many sources. Oxidative stress is thought to be involved in manganese‐induced toxicity and leads to various health disorders. Silymarin (SIL), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of this study was to assess the toxicity of manganese (Mn) on oxidative stress and DNA damage in the kidney of rats and its alleviation by SIL. Manganese was given orally in drinking water (20 mg MnCl₂/mL) with or without SIL administration (100 mg /kg intraperitoneally) for 30 days. Our data showed that SIL significantly prevented Mn induced nephrotoxicity, indicated by both diagnostic indicators of kidney injury like plasma urea, uric acid and creatinine and urinary electrolyte levels and by histopathological analysis. Moreover, Mn‐induced profound elevation of the production of reactive oxygen species (ROS) and altered the levels of oxidative stress related biomarkers in kidney tissue. This is evidenced by the increase of lipid peroxidation, protein carbonylation, DNA fragmentation and urinary hydrogen peroxide, while, the activities of enzymatic antioxidant and glutathione level were decreased. Treatment with SIL reduced the alterations in the renal and urine markers, decreasing lipid peroxidation markers, increasing the antioxidant cascade and decreasing the Mn‐induced damage. All these changes were supported by histopathological observations. These findings suggested that the inhibition of Mn‐induced damage by SIL was due at least in part to its antioxidant activity and its capacity to modulate the oxidative damage. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1147–1154, 2014.     

Pre-treatment with cardamonin protects against cisplatin-induced nephrotoxicity in rats: Impact on NOX-1, inflammation and apoptosis

Cisplatin is an effective anti-cancer drug; however, its clinical use is usually associated with nephrotoxicity as a dose-limiting side effect. Several molecular mechanisms have been found to be involved in this nephrotoxicity such as oxidative stress, inflammation and apoptosis. The aim of this study was to explore the potential nephroprotective effect of cardamonin, a flavone found in Alpinia plant, in a rat model of cisplatin-induced nephrotoxicity. The possible mechanisms underlying this nephroprotective effect were investigated. Cardamonin was given at two different doses; 10 and 30 mg/kg orally for two weeks, starting one week before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Acute nephrtoxicity was evident by significantly increased blood urea nitrogen and serum creatinine levels. Also, cisplatin increased lipid peroxidation and depleted reduced glutathione level and superoxide dismutase. Additionally, cisplatin showed a marked pro-inflammatory response as evidenced by significant increase in tissue levels of IL-1β, TNF-α, NF-kB, iNOS, ICAM-1 and MCP-1. Pre-treatment with cardamonin significantly attenuated the nephrotoxic effects, oxidative stress and inflammation induced by cisplatin, in a dose-dependent manner. Also, cardamonin decreased caspase-3 expression and Bax/Bcl-2 ratio as compared to cisplatin group. Besides, cradamonin reversed cisplatin-induced decrease in EGF. Furthermore, up-regulation of NOX-1 was found to be involved in cisplatin-induced nephrotoxicity and its expression was significantly reduced by cardamonin. Histopathological examination further confirmed the nephroprotective effect of cardamonin. Moreover, pre-treatment with subtoxic concentration of cardamonin has significantly enhanced cisplatin cytotoxic activity in four different human cancer cell lines; hela, hepG2, PC3 and HCT116 cancer cell lines. In conclusion, these findings suggest that cardamonin improves therapeutic index of cisplatin and that NOX-1 is partially involved in the pathogenesis of cispaltin-induced nephrotoxicity.     

Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (-/-) mice and corresponding wild-type (WT) mice. After LPS (1 mg/kg) challenge, UTI (-/-) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (-/-) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1beta, macrophage inflammatory protein-2, MCP-1, and KC in the liver, were significantly greater in UTI (-/-) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.     

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate

Background and Purpose

Recently, two phase‐II trials demonstrated improved renal function in critically ill patients with sepsis‐associated acute kidney injury treated with the enzyme alkaline phosphatase. Here, we elucidated the dual active effect on renal protection of alkaline phosphatase.

Experimental Approach

The effect of human recombinant alkaline phosphatase (recAP) on LPS‐induced renal injury was studied in Sprague–Dawley rats. Renal function was assessed by transcutaneous measurement of FITC‐sinistrin elimination in freely moving, awake rats. The mechanism of action of recAP was further investigated in vitro using conditionally immortalized human proximal tubular epithelial cells (ciPTEC).

Key Results

In vivo, LPS administration significantly prolonged FITC‐sinistrin half‐life and increased fractional urea excretion, which was prevented by recAP co‐administration. Moreover, recAP prevented LPS‐induced increase in proximal tubule injury marker, kidney injury molecule‐1 expression and excretion. In vitro, LPS‐induced production of TNF‐α, IL‐6 and IL‐8 was significantly attenuated by recAP. This effect was linked to dephosphorylation, as enzymatically inactive recAP had no effect on LPS‐induced cytokine production. RecAP‐mediated protection resulted in increased adenosine levels through dephosphorylation of LPS‐induced extracellular ADP and ATP. Also, recAP attenuated LPS‐induced increased expression of adenosine A_2A receptor. However, the A_2A receptor antagonist ZM‐241385 did not diminish the effects of recAP.

Conclusions and Implications

These results indicate that the ability of recAP to reduce renal inflammation may account for the beneficial effect observed in septic acute kidney injury patients, and that dephosphorylation of ATP and LPS are responsible for this protective effect.

Abbreviations

AKI

acute kidney injury

ciPTEC

conditionally immortalized proximal tubular epithelial cells

dLPS

detoxified LPS

IAP

intestinal alkaline phosphatase

KIM‐1

kidney injury molecule‐1

NGAL

neutrophil gelatinase‐associated lipocalin

PBMCs

peripheral blood mononuclear cells

PFA

paraformaldehyde

recAP

human recombinant alkaline phosphatase

TLR4

toll‐like receptor 4

     

Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: Role of oxidative stress and caspase-3

Cadmium (Cd) is an environmental and industrial pollutant that can induce a broad spectrum of toxicological effects that affect various organs in humans and experimental animals. This study aims to investigate the effect of betaine supplementation on cadmium-induced oxidative impairment in rat kidney. The animals were divided into four groups (n = 10 per group): control, cadmium, betaine and betaine + cadmium (1) saline control group; (2) cadmium group in which cadmium chloride (CdCl₂) was given orally at a daily dose of 5 mg/kg body weight for four weeks; (3) betaine group, in which betaine was given to rats at a dose of 250 mg/kg/day, orally via gavage for six weeks; (4) cadmium + betaine group in which betaine was given at a dose of 250 mg/kg/day, orally via gavage for two weeks prior to cadmium administration and concurrently during cadmium administration for four weeks. Cadmium nephrotoxicity was indicated by elevated blood urea nitrogen (BUN) and serum creatinine levels. Kidneys from cadmium-treated rats showed an increase in lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) concentration and reductions in total antioxidant status (TAS), reduced glutathione (GSH) content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase concentration (SOD) and catalase activity. Caspase-3 activity, a marker of DNA damage was also elevated in renal tissues of cadmium-treated rats. Pre-treatment of rats with betaine substantially attenuated the increase in BUN and serum creatinine levels. Betaine also inhibited the increase in TBARS concentration and reversed the cadmium-induced depletion in total antioxidant status, GSH, GSH-Px, SOD and catalase concentrations in renal tissues. Renal caspase-3 activity was also reduced with betaine supplementation. These data emphasize the importance of oxidative stress and caspase signaling cascade in cadmium nephrotoxicity and suggest that betaine pretreatment reduces severity of cadmium nephrotoxicity probably via antioxidant action and suppression of apoptosis.     

Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats

The aim of this work was to test whether consumption with hydrogen-rich water (HW) alleviated renal injury and inhibited early tumor promotional events in Ferric nitrilotriacetate (Fe-NTA)-treated rats. Rats were injected with Fe-NTA solution (7.5 mg Fe/kg body weight) intraperitoneally to induce renal injury and simultaneously treated with HW (1.3 ± 0.2 mg/l). We found that consumption with HW ameliorated Fe-NTA-induced renal injuries including suppressing elevation of serum creatinine and blood urea nitrogen and inhibited early tumor promotional events including decreasing ornithine decarboxylase activity and incorporation of [3H]thymidine into renal DNA. Consumption with HW suppressed Fe-NTA-induced oxidative stress through decreasing formation of lipid peroxidation and peroxynitrite and activities of NADPH oxidase and xanthine oxidase, increasing activity of catalase, and restoring mitochondrial function in kidneys. Consumption with HW suppressed Fe-NTA-induced inflammation marked by reduced NF-κB, IL-6, and MCP-1 expression and macrophage accumulating in kidneys. In addition, consumption with HW suppressed VEGF expression, STAT3 phosphorylation and PCNA expression in kidneys of Fe-NTA-treated rats. Consumption with HW decreased the incidence of renal cell carcinoma and suppressed tumor growth in Fe-NTA-treated in rats. In conclusion, drinking with HW attenuated Fe-NTA-induced renal injury and inhibited early tumor promotional events in rats.     

Dietary fish oil protects against lung and liver inflammation and fibrosis in monocrotaline treated rats

The purpose of the present study was to evaluate the effectiveness of fish oil in preventing tissue pathologies associated with monocrotaline (MCT) toxicity. Twenty-four weanling rats were randomly assigned to one of two groups: (1) 12 to a group fed a diet containing 15% (w/w) corn oil (control) and (2) 12 to a group fed a diet containing fish oil (13%) and corn oil (2%) as the source of fat. Rats were fed for 4 weeks prior to MCT treatment. Six rats in each group were subcutaneously injected with MCT and six injected with its vehicle (water) and all were continued on their respective diets. All rats were sacrificed 3 weeks after injection. In rats receiving MCT, we observed severe interstitial pneumonia, septal fibrosis, vasculitis with virtual obliteration of the lumen of the small arteries and arterioles, right ventricular hypertrophy (RVH), and hepatomegaly and hepatocyte vacuole formation. Dietary fish oil significantly reduced septal fibrosis and development of pneumonia. There was a slight, but statistically insignificant decrease in vasculitis and fish oil did not prevent RVH (pulmonary hypertension). In addition, fish oil effectively protected the MCT-treated rats from development of hepatocyte vacuoles (steatosis), hepatic inflammation and vasculitis, increased presence of fibroblasts and collagen deposition in the centrilobular and, to a lesser extent, in the periportal spaces. These results suggest that lung parenchymal inflammation can be attenuated without altering the course of development of pulmonary hypertension in the MCT model. These results also indicate that fish oil protects against inflammation and fibrosis in the lung and liver, and against hepatocyte vacuole formation in MCT-treated rats.     

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters (OATs)

Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC₅₀ values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.     

Radioprotective effect of silymarin against radiation induced hepatotoxicity

The radioprotective effect of silymarin using different modes of treatment against radiation (3 or 6 Gy) induced hepatotoxicity 1, 3 and 7 days post-irradiation was studied. Whole-body gamma-irradiation revealed an increase in serum alkaline phosphatase (AP) activity as well as liver glutathione reductase (GR) and glutathione peroxidase (GSH-PX) activities on the first post-exposure day with respect to the control value. However, 3 days after radiation exposure, these parameters showed a significant decrease below the control level which persisted till the end of the experimental time except for serum AP activity that showed another increase on the seventh post-exposure day at 3 Gy dose of radiation. A gradual increase in serum alanine and aspartate aminotransferase (ALT&AST) as well as gamma glutamyl transpeptidase activities were observed due to irradiation throughout the experimental time. Administration of silymarin as single (70 mg kg (-1)), fractionated (490 mg kg (-1)) oral doses or as intravenous (i.v.) injection (50 mg kg (-1)), caused significant protection. Intravenous treatment showed the most pronounced protection. The protective effect of silymarin was attributed to its antioxidant and free radicals scavenging properties.     

Dietary supplementation with laminarin, a fermentable marine beta (1-3) glucan, protects against hepatotoxicity induced by LPS in rat by modulating immune response in the hepatic tissue

We tested the hypothesis that laminarin (LAM), a beta (1-3) polysaccharide extracted from brown algae, can modulate the response to a systemic inflammation. Male Wistar rats (n=7 per group) were fed a standard diet (control) or a diet supplemented with LAM for 25 days (5% during 4 days followed by 10% during 21 days). Thereafter, Escherichia coli lipopolysaccharides (LPS; 10 mg/kg i.p.) were injected and the animals were sacrificed 24 h after LPS challenge. The hypothermia, hyperglycemia and hypertriglyceridemia occurring early after LPS administration were less pronounced in LAM-treated rats than in controls. The increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities - reflecting hepatic alterations - was lessened after LPS injection in LAM-treated rats compared to control rats. LAM treatment decreased serum monocytes number, nitrite (NO2) and tumor necrosis factor-alpha (TNF-alpha). LAM also modulated intra-hepatic immune cells: it lowered the occurrence of peroxidase-positive cells (corresponding to monocytes/neutrophils) and, in contrast, it increased the number of ED2-positive cells, corresponding to resident hepatic macrophages, i.e. Kupffer cells. In conclusion, the hepatoprotective effect of marine beta (1-3) glucan during endotoxic shock may be linked to its immunomodulatory properties. We propose that both lower recruitment of inflammatory cells inside the liver tissue and lower secretion of inflammatory mediators play a role in the tissue protective effect of LAM. These effects could be due to a direct effect of beta-glucan on immune cells, or to an indirect effect through their dietary fibre properties (fermentation in the gut).     

Dietary inclusion of sorghum (Sorghum bicolour) straw dye protects against cisplatin-induced nephrotoxicity and oxidative stress in rats

Context: Sorghum straw (dried leaves and stem fiber) extracts and infusion are employed in the management of several ailments in folklore, and it is also a natural dye source used in food preparation.

Objective: This study sought to investigate the modulatory effect of dietary inclusion of Sorghum straw dye on cisplatin-induced nephrotoxicity and antioxidant status in rats.

Materials and methods: Adult male rats were randomly divided into four groups of six animals each. Groups I (normal rats) and II (control rats) were fed with basal diet while Groups III and IV were fed with diets containing 0.5% and 1% sorghum straw dye, respectively. Nephrotoxicity was induced in Groups I–IV on the 20th day by the administration of a single dose of cisplatin solution (7?mg/kg body weight, i.p.) and the experiment was terminated 3?d after. Thereafter, the kidney and plasma of the rats were analyzed for kidney function (creatinine, urea, uric acid, and blood urea nitrogen) and antioxidant indices [superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), malondialdehyde (MDA), vitamin C, and reduced glutathione (GSH)].

Results: The average feed intake of the rats in all the groups ranged from 9.0 to 9.5 (g/rat/day). Furthermore, the result indicated that administration of cisplatin caused significant (p?Discussion and conclusion: The study suggests that dietary inclusion of sorghum straw dye as colorants could protect against oxidative stress and cisplatin-induced nephrotoxicity.     

Tiopronin protects against the nephrotoxicity of cisplatin in the rat

1. Tiopronin (N-(2-mercaptopropionyl)-glycine) is a drug with a free thiol (sulphydryl) group that is used clinically. We have reported previously that tiopronin protects rat kidney slices in vitro from the nephrotoxic effects of cisplatin and does not reduce the antitumour activity of cisplatin. Tiopronin has been investigated therefore for its protective effects in rats in vivo. 2. The extent of kidney damage was studied 5 days after the administration of cisplatin. A single injection (i.p.) of cisplatin (6 mg/kg; 20 micromol/kg) to female Wistar albino rats caused a sustained decrease in body weight and, after 5 days, plasma urea, creatinine and kidney weight were increased. Tiopronin (2.5 mmol/kg, p.o.) ameliorated cisplatin nephrotoxicity when given 1 h before cisplatin. Tiopronin provided marked protection against cisplatin-induced increases in urea (from 237+/-19 mg to 48+/-23 mg/100 ml; control: 17+/-1) and creatinine (from 6.5+/-0.5 to 1.7+/-0.5 mg/100 ml control: 1.0+/-0.1). Tiopronin did not, prevent the body weight loss caused by cisplatin. In addition, an intraperitoneal dose (1 mmol/kg) of tiopronin afforded similar protection to that of an oral dose. Rats that received an i.p. mixture of cisplatin (6 mg/kg) and tiopronin (65 mg/kg) displayed generally less toxicity, as indicated by a small fall in body weight and smaller increases in urea and creatinine and kidney weight. 3. The results show that tiopronin protects against cisplatin-induced nephrotoxicity. Oral administration of tiopronin may be a clinically useful way to prevent cisplatin nephrotoxicity.     

水飞蓟素和维生素E对维持性血液透析患者氧化应激、炎症反应及血红蛋白的影响

目的探讨水飞蓟素和维生素E对维持性血液透析(MHD)患者氧化应激、炎症反应及血红蛋白的影响。方法选择80例维持性血液透析的患者,随机分为水飞蓟素组、维生素E组、联合组和对照组。水飞蓟素组口服水飞蓟素140 mg,3次/d;维生素E组口服维生素E软胶囊400 mg,1次/d;联合用药组口服水飞蓟素140 mg,3次/d,维生素E胶囊400 mg,1次/d;对照组予以安慰剂治疗。治疗前及治疗4周后,采血检测血清丙二醛(MDA)、C反应蛋白(CRP)、红细胞沉降率(ESR)及血红蛋白(HGB)水平。结果与对照组比较,治疗4周后,水飞蓟素组和联合组血清MDA、CRP和ESR水平明显降低,HGB水平明显上升(P<0.05)。结论水飞蓟素或水飞蓟素联合维生素E可以减轻MHD患者体内氧化应激及炎症反应水平,提高血红蛋白浓度。     

Antileukoproteinase protects against hepatic inflammation, but not apoptosis in the response of D-galactosamine-sensitized mice to lipopolysaccharide

BACKGROUND AND PURPOSE: There is major evidence for the strong bi-directional interrelation of parenchymal cell apoptosis and leukocyte accumulation and inflammation in acute liver injury. Therefore, the aim of this in vivo study was to investigate the anti-apoptotic and anti-inflammatory potential of antileukoproteinase (ALP) in a murine model of acute liver failure. EXPERIMENTAL APPROACH: C57BL/6J mice were given galactosamine (D-GalN) and E. coli lipopolysaccharide (LPS) followed by administration of saline or ALP. Besides survival rate, hepatic tissue damage and inflammatory response were analyzed by intravital fluorescence microscopy 6 hours after treatment. In addition, immunohistochemical analysis of NFkappaB-p65 and hepatocellular apoptosis, plasma levels of AST/ALT, TNF-alpha and IL-10 were determined. KEY RESULTS: Administration of D-GalN/LPS provoked hepatic damage, including marked leukocyte recruitment and microvascular perfusion failure, as well as hepatocellular apoptosis and enzyme release. NFkappaB-p65 became increasingly detectable in hepatocellular nuclei, accompanied by a rise of TNF-alpha and IL-10 plasma levels. ALP markedly reduced intrahepatic leukocyte accumulation, nuclear translocation of NFkappaB and plasma levels of TNF-alpha and IL-10. Moreover, liver enzyme levels indicated the absence of necrotic parenchymal cell death. In contrast, ALP failed to block both apoptosis and caspase-3 levels and the mortality rate of ALP-treated animals was comparable to that of saline-treated mice. CONCLUSIONS AND IMPLICATIONS: ALP could effectively prevent D-GalN/LPS-associated intrahepatic inflammatory responses by inhibition of NFkappaB activity, but not apoptosis-driven mortality. Thus, a protease-inactivating approach such as application of ALP seems to be inadequate in damaged liver where apoptosis represents the predominant mode of cell death.     

Diphenyl diselenide protects against glycerol‐induced renal damage in rats

In this study we evaluated the effect of diphenyl diselenide (PhSe)₂ on glycerol‐induced acute renal failure in rats. Rats were pre‐treated by gavage every day with (PhSe)₂ (7.14 mg kg^?1) for 7 days. On the eighth day, rats received an intramuscular injection of glycerol (8 mL kg^?1). Twenty‐four hours afterwards, rats were euthanized and the levels of urea and creatinine were measured in plasma. Catalase (CAT), glutathione peroxidase (GPx), glutathione S‐transferase (GST), δ‐aminolevulinate dehydratase (δ‐ALA‐D) and Na⁺, K⁺‐ATPase activities and ascorbic acid levels were evaluated in renal homogenates. Histopathological evaluations were also performed. The results demonstrated that (PhSe)₂ was able to protect against the increase in urea and creatinine levels and histological alterations in kidney induced by glycerol. (PhSe)₂ protected against the inhibition in δ‐ALA‐D, CAT and GPx activities and the reduction in ascorbic acid levels induced by glycerol in kidneys of rats. In conclusion, the present results indicate that (PhSe)₂ was effective in protecting against acute renal failure induced by glycerol. Copyright © 2009 John Wiley & Sons, Ltd.     

The nitric oxide donor,V-PYRRO/NO,protects against acetaminophen-induced nephrotoxicity in mice

The nitric oxide (NO) donor, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P450 enzymes to release NO in the liver and possibly other tissues. V-PYRRO/NO has been shown to be hepatoprotective, but little is known about its effect in the kidney, another organ rich in P450s. Thus, mice were given V-PYRRO/NO (0.4-5.4 mg/ml, 8 microl/h) before and/or after a nephrotoxic dose of acetaminophen (APAP; 600 mg/kg, i.p.) to examine its nephroprotective effects. V-PYRRO/NO administration significantly reduced APAP-induced nephrotoxicity in a dose- and time-dependent manner, as evidenced by mitigation of increased blood urea nitrogen levels and by amelioration of renal pathology, specifically interstitial congestion, proximal tubular cell degeneration and necrosis. The best protection was observed at the highest dose (5.4 mg/ml) and with V-PYRRO/NO pretreatment (4-16 h). Implanting V-PYRRO/NO pumps simultaneously with APAP also attenuated APAP nephrotoxicity. The protection is probably not due to a decreased APAP toxication metabolism, as similar depletion of renal glutathione levels was observed regardless of V-PYRRO/NO treatment. APAP-induced renal lipid peroxidation was reduced by V-PYRRO/NO, as determined by the concentrations of hydroxynonenals and malondialdehyde. In summary, this study demonstrates that the NO donor V-PYRRO/NO is effective in blocking APAP-induced nephrotoxicity in mice. The protection is probably due to multiple mechanisms involving attenuation of APAP-induced congestion and lipid peroxidation in the kidney.