Alpha lipoic acid prevents doxorubicin‐induced nephrotoxicity by mitigation of oxidative stress,inflammation, and apoptosis in rats

This study aimed to evaluate the protective effects of alpha lipoic acid (ALA) against doxorubicin (DOX)‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg i.v.) induced nephrotoxicity evidenced by significant elevations in kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha, and renal contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3. Also, it causes significant reduction in final body weight, serum albumin, renal contents of reduced glutathione and superoxide dismutase activity. Histopathological changes in the kidney tissue confirmed the nephrotoxic effect. In contrast, pretreatment with ALA (50 mg/kg, orally) for 14 days before DOX and for 7 days after DOX administration mitigated renal toxicity evidenced by greater improvement in the examined oxidative stress, inflammation, and apoptosis parameters. In conclusion, ALA had promising protective effects against DOX‐induced nephrotoxicity that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Palliative effect of curcumin on doxorubicin‐induced testicular damage in male rats

This study aimed to investigate the effect of curcumin (CUR) on doxorubicin (DOX)‐induced testicular damage in male rats. Thirty‐five adult male Wistar rats were used. Control group was received saline for 7 days. CUR group received CUR for 7 days. DOX group received single dose DOX on the 5th day. DOX+ CUR‐100 group received 100 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX + CUR‐200 group received 200 mg/kg/day CUR for 7 days and DOX injection on the 5th day. DOX treatment decreased in sperm motility rate, live sperm percentages, cellular antioxidants, and increased malondialdehyde (MDA) levels, necrosis, degenerations, and slimming in seminiferous tubules, and DNA damages in testes by inducing oxidative stress. CUR treatment mitigated significantly these side effects when compared with DOX group in a dose‐dependent manner. In conclusion, CUR treatment can be used in the mitigation of DOX‐induced testicular toxicity.     

Nimbolide prevents myocardial damage by regulating cardiac biomarkers,antioxidant level,and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)‐treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione‐S‐transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX‐treated animals. DOX‐treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein‐1, interferon‐gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase‐muscle/brain, heart‐type fatty acid‐binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor‐β, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX‐induced cardiotoxicity. Furthermore, DOX‐induced rats showed augmented inflammatory mediators (nuclear factor‐κB [NF‐kB], tumor necrosis factor‐α [TNF‐α], and interleukin‐1β [IL‐1β]) and increased PI3K/Akt signaling proteins (PI3K, p‐Bad/Bad, caspase‐3, and p‐Akt), whereas decreased oxidative markers (HO‐1 and NQO‐1) and p‐PTEN were observed. Nimbolide‐supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide‐supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p‐Bad/Bad, caspase‐3, PI3K, p‐Akt, TNF‐α, NF‐kB, IL‐1β, HO‐1, NQO‐1, and p‐PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX‐induced cardiac tissue damage.     

TLR9 deficiency alleviates doxorubicin‐induced cardiotoxicity via the regulation of autophagy

Doxorubicin is a commonly used anthracycline chemotherapeutic drug. Its application for treatment has been impeded by its cardiotoxicity as it is detrimental and fatal. DNA damage, cardiac inflammation, oxidative stress and cell death are the critical links in DOX‐induced myocardial injury. Previous studies found that TLR9‐related signalling pathways are associated with the inflammatory response of cardiac myocytes, mitochondrial dysfunction and cardiomyocyte death, but it remains unclear whether TLR9 could influence DOX‐induced heart injury. Our current data imply that DOX‐induced cardiotoxicity is ameliorated by TLR9 deficiency both in vivo and in vitro, manifested as improved cardiac function and reduced cardiomyocyte apoptosis and oxidative stress. Furthermore, the deletion of TLR9 rescued DOX‐induced abnormal autophagy flux in vivo and in vitro. However, the inhibition of autophagy by 3‐MA abolished the protective effects of TLR9 deletion on DOX‐induced cardiotoxicity. Moreover, TLR9 ablation suppressed the activation of p38 MAPK during DOX administration and may promote autophagy via the TLR9‐p38 MAPK signalling pathway. Our study suggests that the deletion of TLR9 exhibits a protective effect on doxorubicin‐induced cardiotoxicity by enhancing p38‐dependent autophagy. This finding could be used as a basis for the development of a prospective therapy against DOX‐induced cardiotoxicity.     

Protective effect of miR378* on doxorubicin‐induced cardiomyocyte injury via calumenin

Doxorubicin (Dox) is a highly effective antitumor antibiotic, however myocardial toxicity severely limits its use clinically. The pathogenesis of doxorubicin‐induced cardiomyopathy is unclear. In Dox cardiomyopathy mice, there is a decline in cardiac function, a change in myocardial pathology and a reduction in miR378* expression. Expression changes in calumenin, an endoplasmic reticulum stress (ERS) chaperone protein and pathway factor, as well as apoptosis, were observed in cardiomyocytes after doxorubicin‐induced injury. However, miR378* increased calumenin expression, eased ERS, and reduced cardiomyocyte apoptosis, while, silencing miR378* reduced calumenin expression, aggravated ERS, and increased cardiomyocyte apoptosis. The above results indicate that miR378* alleviates ERS and inhibits the activation of the ERS‐mediated apoptosis signaling pathway in cardiomyocytes via regulating calumenin expression, thereby reducing cardiomyocyte apoptosis after doxorubicin‐induced injury. Increasing miR378* expression may be a new way to improve cardiac function and quality of life in patients with Dox cardiomyopathy.     

Curcumin ameliorates doxorubicin‐induced cardiotoxicity by abrogation of inflammation,apoptosis, oxidative DNA damage,and protein oxidation in rats

Doxorubicin (DXR) is a highly effective drug for chemotherapy. However, cardiotoxicity reduces its clinical utility in humans. The present study aimed to assess the ameliorative effect of curcumin against DXR‐induced cardiotoxicity in rats. Rats were subjected to oral treatment of curcumin (100 and 200 mg/kg body weight) for 7 days. Cardiotoxicity was induced by single intraperitoneal injection of DXR (40 mg/kg body weight) on the 5th day and the rats sacrificed on 8th day. Curcumin ameliorated DXR‐induced lipid peroxidation, glutathione depletion, decrease in antioxidant (superoxide dismutase, catalase, and glutathione peroxidase) enzyme activities, and cardiac toxicity markers (CK‐MB, LDH, and cTn‐I). Curcumin also attenuated activities of Caspase‐3, cyclooxygenase‐2, inducible nitric oxide synthase, and levels of nuclear factor kappa‐B, tumor necrosis factor‐α, and interleukin‐1β, and cardiac tissue damages that were induced by DXR. Moreover, curcumin decreased the expression of 8‐OHdG and 3,3′‐dityrosine. This study demonstrated that curcumin has a multi‐cardioprotective effect due to its antioxidant, anti‐inflammatory, and antiapoptotic properties.     

The dietary isoflavone daidzein mitigates oxidative stress,apoptosis, and inflammation in CDDP‐induced kidney injury in rats: Impact of the MAPK signaling pathway

Cisplatin‐induced nephrotoxicity persists as a clinical problem despite several supportive measures to alleviate renal damage. Daidzein (DZ), a dietary isoflavone having antioxidant and anti‐inflammatory activity, is investigated in this study for protective effects against cisplatin‐induced renal injury in rats. DZ (25, 50, or 100 mg/kg; intraperitoneally; 10 days) was administered along with Cisplatin, single dose, on the 7th day of the experiment. On the 11th day, the rats were euthanized, and different samples were collected for analysis. Biochemical, histopathological, and molecular parameters were assessed to evaluate the effect of daidzein. Cisplatin injection resulted in renal dysfunction, lipid peroxidation that led to consumption of antioxidants, exaggerated apoptosis, and inflammation. These changes were associated with increase in the signaling proteins. DZ attenuated the toxic effects of cisplatin on the kidney at 100 mg/kg dose. The study concludes with the finding that daidzein imparts protection against the nephrotoxic effect of Cisplatin and can be considered as a novel, potential therapy.     

Mitochondria‐mediated mitigatory role of curcumin in cisplatin‐induced nephrotoxicity

Cisplatin (CP) is one of the most potent chemotherapeutic anti‐tumour drugs, and it has been implicated in renal toxicity. Oxidative stress has been proven to be involved in CP‐induced toxicity including nephrotoxicity. However, there is paucity of literature involving role of mitochondria in mediating CP‐induced renal toxicity, and its underlying mechanism remains unclear. Therefore, the present study was undertaken to examine the antioxidant potential of curcumin (CMN; a natural polyphenolic compound) against the mitochondrial toxicity of CP in kidneys of male rats. Acute toxicity was induced by a single intra‐peritoneal injection of CP (6 mg kg^?1). We studied the ameliorative effect of CMN pre‐treatment (200 mg kg^?1) on the toxicity of CP in rat kidney mitochondria. CP caused a significant elevation in the mitochondrial lipid peroxidation (LPO) levels and protein carbonyl (PC) content. Pre‐treatment of rat with CMN significantly replenished the mitochondrial LPO levels and PC content. It also restored the CP‐induced modulatory effects on altered enzymatic and non‐enzymatic antioxidants in kidney mitochondria. We hypothesize that the reno‐protective effects of CMN may be related to its predisposition to scavenge free radicals, and upregulate antioxidant machinery in kidney mitochondria. Copyright © 2013 John Wiley & Sons, Ltd.     

Oxidative stress‐induced renal telomere shortening as a mechanism of cyclosporine‐induced nephrotoxicity

Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine‐A exerts its nephrotoxic side effects via induction of oxidative stress‐induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8‐hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine‐A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8‐hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine‐A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine‐induced oxidative stress, indicating the potential mechanism of cyclosporine‐induced nephrotoxicity.     

Thymoquinone attenuates doxorubicin‐cardiotoxicity in rats

Contrary to the fact that doxorubicin is a powerful chemotherapeutic agent for the treatment of neoplastic diseases, cardiotoxicity is too important to be ignored. Thymoquinone serves as a powerful free radical scavenger. In the study, the effects of thymoquinone against doxorubicin‐cardiotoxicity will be evaluated. Forty rats were divided into five groups. Group I: control group (n = 8); group II: olive oil group (n = 8); group III: thymoquinone group (n = 8); given 10 mg/kg thymoquinone intraperitoneally per day throughout the experiment; group IV: doxorubicin group (n = 8); injected with a single dose of 15 mg/kg ip doxorubicin on the 7th day of the experiment; group V: doxorubicin + thymoquinone group (n = 8); administered with 10 mg/kg thymoquinone per day during the experiment and 15 mg/kg doxorubicin ip on the 7th day. The experiment was planned for 14 days. Immunohistochemically, heat shock protein (HSP) 70 and HSP90, glucose‐regulated protein 78 (GRP78), caspase‐3 were stained. We made terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptotic evaluation. Total oxidant status (TOS) levels and total antioxidant status (TAS) were measured in the heart tissue. Atrial natriuretic peptide (ANP) and pro‐B type natriuretic peptide (proBNP) were evaluated. In the study, HSP70, HSP90, GRP78, and caspase‐3 levels increased in group IV. TOS and TAS levels were significant compared to group I. Doxorubicin significantly increased ANP and NT‐proBNP levels. Thymoquinone revealed significant differences in these values. Thymoquinone can be an important cardioprotective agent against doxorubicin‐cardiotoxicity.     

Antioxidant and antiapoptotic effects of proanthocyanidin and ginkgo biloba extract against doxorubicin‐induced cardiac injury in rats

Grape seed proanthocyanidins (GSPE) and ginkgo biloba extract (EGb761) are considered to have protective effects against several diseases. The cardiotoxicity of doxorubicin (DOX) has been reported to be associated with oxidative damage. This study was conducted to evaluate the cardioprotective effects of GSPE and EGb761 against DOX‐induced heart injury in rats. DOX was administered as a single i.p. dose (20 mg kg^–1) to adult male rats. DOX‐intoxicated rats were orally administered GSPE (200 mg kg^–1 day^–1) or EGb761 (100 mg kg^–1 day^–1) for 15 consecutive days, starting 10 days prior DOX injection. DOX‐induced cardiotoxicity was evidenced by a significant increase in serum aspartate transaminase (AST), creatine phosphokinase isoenzyme (CK‐MB), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) activities and levels. Increased oxidative damage was expressed by the depletion of cardiac reduced glutathione (GSH), elevation of cardiac total antioxidant (TAO) level and accumulation of the lipid peroxidation product, malondialdehyde (MDA). Significant rises in cardiac tumour necrosis factor‐alpha (TNF‐α) and caspase‐3 levels were noticed in DOX‐intoxicated rats. These changes were ameliorated in the GSPE and EGb761‐treated groups. Histopathological analysis confirmed the cardioprotective effects of GSPE and EGb761. In conclusion, GSPE and EGb761 mediate their protective effect against DOX‐induced cardiac injury through antioxidant, anti‐inflammatory and antiapoptotic mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.     

Resveratrol,a polyphenol phytoalexin,protects against doxorubicin‐induced cardiotoxicity

Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose‐dependent cardiotoxicity. The mechanism of doxorubicin‐induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin‐induced cardiotoxicity.     

Curcumin synergistically potentiates the protective effect of sitagliptin against chronic deltamethrin nephrotoxicity in rats: Impact on pro‐inflammatory cytokines and Nrf2/Ho‐1 pathway

Deltamethrin (DLM) is a synthesized organophosphorus acaricide and bug spray, broadly utilized for veterinary and farming purposes. Although its exposure to humans and animals causes toxicity in the kidney and other primary organs, our objective was to assess the defensive effects of sitagliptin (Sita) and additionally curcumin (Cur) in the DLM‐intoxicated rats’ kidney. DLM‐intoxicated rats revealed a huge increase of various biochemical parameters in serum identified with kidney damage: uric acid, urea, and creatinine. DLM intoxication altogether increased renal lipid peroxidation, and critically restrained antioxidative biomarkers including superoxide dismutase, glutathione, and glutathione peroxidase. Likewise, it increased the tumor necrosis factor‐α, interleukin 6 (IL‐6) and IL‐1β level in serum. Additionally, DLM intoxication diminished the outflow of the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2)/heme oxygenase‐1 (HO‐1) pathway in rats. Both Sita and Cur act against DLM‐prompted serum along with renal tissue biochemical parameters when utilized alone or in a mix alongside DLM intoxication. Besides this, both Sita and Cur delivered synergetic nephroprotective, antioxidative, and anti‐inflammatory impacts. Consequently, it could be presumed that Sita as well as Cur administration can limit the poisonous impacts of DLM by their free radical‐scavenging, strong antioxidant, and Nrf2/HO‐1 pathway upregulation activity.     

Hydrogen‐rich water alleviates cyclosporine A‐induced nephrotoxicity via the Keap1/Nrf2 signaling pathway

Oxidative stress induced by long‐term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation. Although hydrogen‐rich water (HRW) has been used to prevent various oxidative stress‐related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA‐induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick‐end labeling stains. Oxidative stress markers and the activation of the Kelch‐like ECH‐associated protein 1 (Keap1)/nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway.     

Renoprotective effects of montelukast in an experimental model of cisplatin nephrotoxicity in rats

Renal toxicity is one of the most severe complications that can occur with cisplatin (CIS) administration in cancer patients. Montelukast (ML) renoprotective outcome contrary to CIS‐drawn nephrotoxicity remains obscure. Therefore, adult male Sprague–Dawley rats were orally given ML (10 and 20 mg/kg/day) 5 days before and after single CIS (5 mg/kg; i.p.) treatment. ML returned blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase that were elevated by CIS to normal level. The improved kidney function tests corroborated the attenuation of CIS renal injury at the microscopical level. It also reduced serum/renal nitric oxide and renal hemeoxygenase‐1. Meanwhile, ML hindered the raised levels of serum endothelin‐1, serum and renal tumor necrosis factor‐α, and monocyte chemoattractant protein‐1. These effects were associated by deceased caspase‐3 expression in kidney after ML treatment. In conclusion, ML guards against CIS‐induced nephrotoxicity via anti‐inflammatory and antiapoptotic properties.     

Melatonin attenuates methotrexate‐induced oxidative stress and renal damage in rats

Nephrotoxicity is an adverse side effect of methotrexate (MTX) chemotherapy. The present study verifies whether melatonin, an endogenous antioxidant prevents MTX‐induced renal damage. Adult rats were administered 7 mg/kg body weight MTX intraperitoneally for 3 days. In the melatonin pretreated rats, 40 mg/ kg body weight melatonin was administered daily intraperitoneally 1 h before the administration of MTX. The rats were killed 12 h after the final dose of MTX/vehicle. The kidneys were used for light microscopic and biochemical studies. The markers of oxidative stress were measured along with the activities of the antioxidant enzymes and myeloperoxidase activity in the kidney homogenates. Pretreatment with melatonin reduced MTX induced renal damage both histologically and biochemically as revealed by normal plasma creatinine levels. Melatonin pretreatment reduced MTX induced oxidative stress, alteration in the activity of antioxidant enzymes as well as elevation in myeloperoxidase activity. The results suggest that melatonin has the potential to reduce MTX induced oxidative stress, neutrophil infiltration as well as renal damage. As melatonin is an endogenous antioxidant and is non‐toxic even in high doses it is suggested that melatonin may be beneficial in minimizing MTX induced renal damage in humans. Copyright © 2010 John Wiley & Sons, Ltd.     

The effects of mesenchymal stem cell mitochondrial transplantation on doxorubicin‐mediated nephrotoxicity in rats

The effect of dysfunctional mitochondria in several cell pathologies has been reported in renal diseases, including diabetic nephropathy and acute kidney injury. Previous studies have reported that mitochondrial transplantation provided surprising results in myocardial and liver ischemia, as well as in Parkinson's disease. We aimed to investigate the beneficial effects of isolated mitochondria transplantation from mesenchymal stem cells (MSCs) in vivo, to mitigate renal damage that arises from doxorubicin‐mediated nephrotoxicity and its action mechanism. In this study, a kidney model of doxorubicin‐mediated nephrotoxicity was used and isolated mitochondria from MSCs were transferred to the renal cortex of rats. The findings showed that the rate of isolated mitochondria from MSCs maintains sufficient membrane integrity, and was associated with a beneficial renal therapeutic effect. Following doxorubicin‐mediated renal injury, isolated mitochondria or vehicle infused into the renal cortex and rats were monitored for five days. This study found that mitochondrial transplantation decreased cellular oxidative stress and promoted regeneration of tubular cells after renal injury (P < .001, P = .009). Moreover, mitochondrial transplantation reduced protein accumulation of tubular cells and reversed renal deficits (P = .01, P < .001). Mitochondrial transplantation increased Bcl‐2 levels, and caspase‐3 levels decreased in injured renal cells (P < .015, P < .001). Our results provide a direct link between mitochondria dysfunction and doxorubicin‐mediated nephrotoxicity and suggest a therapeutic effect of transferring isolated mitochondria obtained from MSCs against renal injury. To our knowledge, this study is the first study in the literature that showed good therapeutic effects of mitochondrial transplantation in a nephrotoxicity model, which is under‐researched.     

Influence of kolaviron and vitamin E on ethylene glycol monoethyl ether‐induced haematotoxicity and renal apoptosis in rats

The present study investigated the protective effects of kolaviron, a biflavonoid from the seed of Garcinia kola, and vitamin E on ethylene glycol monoethyl ether (EGEE)‐induced haematotoxicity and renal apoptosis in male rats. EGEE was administered at a dose of 200 mg kg^?1 alone or simultaneously administered with kolaviron (100 and 200 mg kg^?1) and vitamin E (50 mg kg^?1) for 14 days. Results of haematological examination showed that white blood cells, platelets, neutrophils and mean corpuscular haemoglobin concentration were significantly lower, whereas lymphocytes were increased in EGEE‐exposed rats compared with those in the control. Administration of EGEE caused a significant decrease in the superoxide dismutase and catalase activities as well as in the glutathione level but significantly increased glutathione Stransferase activity and levels of hydrogen peroxide and lipid peroxidation in kidneys of rats compared with those in the control. Also, EGEE‐treated rats showed significant elevation in the serum urea and creatinine with marked increase in the frequency of terminal deoxynucleotidyl transferase‐mediated dUTP nick end labelling assay‐positive apoptotic cells in the tubular epithelial cells in comparison with the control. Co‐administration with kolaviron or vitamin E exhibited chemoprotective effects against EGEE‐mediated haematotoxicity, augmented renal antioxidant status and prevented the induction of renal apoptosis. Copyright © 2013 John Wiley & Sons, Ltd.     

基于氧化应激与细胞凋亡探究双酚A慢性暴露致小鼠肾毒性作用机制

双酚A (bisphenol A, BPA)被广泛应用于生产环氧树脂和聚碳酸酯塑料等制品,在强酸、强碱或高温条件下,BPA被释放出来,然后渗入环境中。在大多数生物液体中都检测到了不同浓度的BPA,BPA的存在已被证明与许多慢性疾病密切相关,包括慢性肾病(chronic kidney disease,CKD)。然而,关于BPA的有害作用及其对CKD的不良影响知之甚少。为了探讨BPA对动物肾毒性的作用机制,本研究通过向饮水中加入0.01、0.1和1 mg/L的BPA,暴露于雌性小鼠4周后,交配和怀孕的雌性小鼠持续接触BPA,直到断奶;F1代3周龄雄性仔鼠继续口服相同剂量的BPA,持续10周。结果表明,0.1mg/L和1mg/LBPA处理组小鼠的肾脏损伤严重,血清中肾脏功能指标尿素氮(urea nitrogen,UN)、肌酐(creatinine,CR)和尿酸(uric acid,UA)的含量均发生显著升高(P<0.05);肾脏组织形态结构被损害;肾脏抗氧化相关基因在mRNA和蛋白水平上的表达显著降低(P<0.05),包括谷胱甘肽硫转移酶(glutathione-S-transf...     

Ameliorative effect of carnosine and N-acetylcysteine against sodium nitrite induced nephrotoxicity in rats

The widespread use of sodium nitrite (NaNO₂) for various industrial purposes has increased human exposure to alarmingly high levels of nitrate/nitrite. Because NaNO ₂ is a strong oxidizing agent, induction of oxidative stress is one of the mechanisms by which it can exert toxicity in humans and animals. We have investigated the possible protection offered by carnosine (CAR) and N-acetylcysteine (NAC) against NaNO ₂-induced nephrotoxicity in rats. Animals orally received CAR at 100 mg/kg body weight/d for seven days or NAC at 100 mg/kg body weight/d for five days followed by a single oral dose of NaNO ₂ at 60 mg/kg body weight. The rats were killed after 24 hours, and the kidneys were removed and processed for various analyses. NaNO ₂ induced oxidative stress in kidneys, as shown by the decreased activities of antioxidant defense, brush border membrane, and metabolic enzymes. DNA-protein crosslinking and DNA fragmentation were also observed. CAR/NAC pretreatment significantly protected the kidney against these biochemical alterations. Histological studies supported these findings, showing kidney damage in NaNO ₂-treated animals and reduced tissue impairment in the combination groups. The protection offered by CAR and NAC against NaNO ₂-induced damage, and their nontoxic nature, makes them potential therapeutic agents against nitrite-induced nephrotoxicity.