ACTION OF VITAMIN C AGAINST ACETAMINOPHEN-INDUCED HEPATORENAL TOXICITY IN RATS

Effects of different doses of vitamin C against acetaminophen (APAP)-induced hepatorenal toxicity was investigated in male rats. The experimental groups included, a control group which received vehicle, a group intraperitoneally injected with a single dose of vitamin C (320 mg/kg body weight (b.wt.)), a group which received an oral overdose of APAP (1 g / kg b.wt.), as well as three groups administered the APAP overdose followed by a single dose of vitamin C (80, 160 or 320 mg/kg b.wt). All animals were watched for 24 hours, after which the mortality rate and serum levels of the hepatorenal indices were measured. Liver glutathione level and the ultrastructure of hepatic and renal tissues were also studied.

Administration of APAP overdose induced a high mortality rate and hepatorenal toxicity as indicated by significantly higher levels of hepatorenal indices and decreased liver glutathione. It also caused cellular alterations and necrosis of hepatocytes and some renal cortical cells. However, injection of vitamin C alone caused no abnormalities. The injection of vitamin C after APAP administration decreased the hepatorenal toxicity in a dose-dependent manner. The highest dose of vitamin C normalized the levels of liver glutathione and serum hepatorenal indices except for bilirubin. It also protected hepatic and renal cells except for slight dilatation of rough endoplasmic reticulum and glycogen depletion in some hepatocytes, as well as the presence of lysosomal structures in cortical tubular epithelia. No fatalities were seen in rats treated with the highest two doses of vitamin C. It could be concluded that the highest dose of vitamin C prevented against the lethal effect of APAP overdose, although it incompletely protected against hepatorenal toxicity.     

Allicin modulates diclofenac sodium induced hepatonephro toxicity in rats via reducing oxidative stress and caspase 3 protein expression

PurposeThis study was designed to evaluate the protective effects of allicin against diclofenac sodium induced hepatonephro toxicity in rats.MethodsSixty male Wister albino rats were assigned into six groups. The control group received calcium carbonate and corn starch. 2^nd group received diclofenac sodium (2 mg/kg bw orally) for 30 days. 3^rd group received allicin (45 mg/kg bw orally) for 30 days. 4^th group administrated diclofenac sodium as in the 2^nd group and allicin (15 mg/kg bw orally) for 30 days. 5^th group received diclofenac sodium as in the 2^nd group and allicin (30 mg/kg bw orally) for 30 days. 6^th group received diclofenac sodium as 2^nd and allicin (45 mg/kg bw orally) for 30 days.ResultsDiclofenac sodium significantly elevated activities of serum aspartate aminotransferase and alanine aminotransferase and serum levels of creatinine and urea. In addition, it induced hyperglycemia, lipid peroxidation, pathological alteration and caspase 3 protein expression in hepatic and renal tissues. However, it decreased reduced glutathione concentration and proliferating cell nuclear antigen protein expression in hepatic tissues. In contrast, allicin modulated the diclofenac sodium induced alteration in liver and kidney functions and structures dose dependently.ConclusionThis study indicated that allicin had potential preventive effects against diclofenac sodium induced hepatonephro toxicity in rats.     

Cadmium and nickel co‐exposure exacerbates genotoxicity and not oxido‐inflammatory stress in liver and kidney of rats: Protective role of omega‐3 fatty acid

The present study examined the influence of co‐exposure to cadmium (Cd) and nickel (Ni) on hepatorenal function as well as the protective role of omega‐3 polyunsaturated fatty acids (ω‐3FA) in rats. The animals were exposed to Cd (5 mg/kg) and Ni (150 μg/L in drinking water) singly or co‐exposed to both metals and ω‐3FA at 20 mg/kg for 14 consecutive days. Results showed that hepatorenal injury resulting from individual exposure to Cd or Ni was not aggravated in the co‐exposure group. Moreover, ω‐3FA markedly abrogated the reduction in the antioxidant enzyme activities, the increase in reactive oxygen and nitrogen species, and lipid peroxidation induced by Cd and Ni co‐exposure. Additionally, ω‐3FA administration markedly suppressed the increase in hepatic and renal myeloperoxidase activity, nitric oxide, tumor necrosis factor alpha, and interleukin‐1 β levels in the co‐exposure group. Genotoxicity resulting from individual exposure to Cd or Ni was intensified in the co‐exposure group. However, ω‐3FA administration markedly ameliorated the genotoxicity and histological lesions in the co‐exposure group. Taken together, co‐exposure to Cd and Ni aggravated genotoxicity and not oxido‐inflammatory stress in the liver and kidney of rats. ω‐3FA abated hepatorenal injury and genotoxicity induced by Cd and Ni co‐exposure in rats.     

薄荷油致大鼠肝毒性时量关系及对肝细胞超微结构的影响

目的研究薄荷油致大鼠肝毒性的时效、量效关系以及对肝细胞超微结构的影响。方法大鼠按不同时间点或不同剂量分组,口服给药后检查血清ALT等肝功能指标,光镜或电镜下观察肝组织形态及肝细胞超微结构变化。结果与正常组相比,薄荷油组大鼠血清ALT等肝功能数值升高,于给药后24～48h达到高峰;随着剂量增大,ALT等肝功能指标相应升高(P<0.01)。薄荷油高剂量组对肝组织损伤明显,出现肝细胞核溶解等超微结构变化,与CCl4组相似。结论大鼠一次性口服大剂量薄荷油可造成急性肝脏毒性,并显示一定的毒性时效、量效关系;肝细胞损伤可出现脂肪变性、坏死等结构变化。     

Subacute toxicity assessment of diflubenzuron,an insect growth regulator,in adult male rats

Diflubenzuron (DFB), an insecticide and acaricide insect growth regulator, can be used in agriculture against insect predators and in public health programs, to control insects and vectors, mainly Aedes aegypti larvae. Due to the lack of toxicological assessments of this compound, the objective of the present study was to evaluate the toxicological effects of subacute exposure to the DFB insecticide in adult male rats. Adult male rats were exposed (gavage) to 0, 2, 4, or 8 mg/kg of DFB for 28 days. No clinical signs of toxicity were observed in the DFB‐treated animals of the experimental groups. However, there was an increase in serum levels of alanine aminotransferase in the group that received 8 mg/kg/DFB/day and urea at doses of 4 and 8 mg/kg/DFB/day, without altering other biochemical or hematological parameters. The subacute exposure to the lowest dose of DFB caused significant decrease in testis weight, daily sperm production, and in number of sperm in the epididymis in relation to the control group. However, no alterations were observed in the sperm morphology, testicular, epididymis, liver and kidney histology, or testosterone levels. These findings unveiled the hazardous effects of DFB on male reproduction after the subacute exposure and special attention should be addressed to the effects of low doses of this pesticide. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 407–414, 2016.     

Gallic acid prevents 1, 2‐Dimethylhydrazine induced colon inflammation,toxicity, mucin depletion,and goblet cell disintegration

1,2‐Dimethylhydrazine (DMH), an environmental toxicant specifically targets the colon. The present study was aimed to evaluate the efficacy of gallic acid (GA) against colon toxicity induced by DMH in Wistar rats. GA, a phenolic acid has numerous beneficial properties, which include antiviral, antifungal and antioxidant properties which help cells to overcome oxidative stress and balance the redox homeostasis. GA was administered orally at two doses (25 and 50 mg/kg body weight) once daily for 14 days and a single dose (40 mg/kg body weight) of DMH was administered subcutaneously on 14th day. Animals were sacrificed on the 15th day and we could find that GA at both the doses significantly ameliorates DMH‐induced increased toxicity markers and also substantially increases the glutathione content level and activities of detoxifying enzymes. It also ameliorates the expression of proliferation, inflammation, apoptosis, goblet cell disintegration, and mucin depletion in the colon that was elevated upon administration of DMH. Histological alterations provide further confirmation of the protective role of GA against DMH‐induced colon toxicity. The results of this study clearly indicate supplementation of GA is beneficial in ameliorating DMH‐induced oxidative stress, inflammation, proliferation, apoptosis, mucin depletion, and goblet cell disintegration in colon of Wistar rats.     

Geranylgeranylacetone preconditioning may attenuate heat‐induced inflammation and multiorgan dysfunction in rats

Objectives Geranylgeranylacetone, an acyclic isoprenoid, is a non‐toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat‐induced inflammation and multiple organ dysfunction. Methods Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43°C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls. Key findings Vehicle‐treated rats all succumbed to heat stress; their survival time was 25 ± 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 ± 15 min. Compared with normothermic controls, all vehicle‐treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin‐1β, tumour necrosis factor‐α and interleukin‐6). These heat‐stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin‐10 (an anti‐inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke. Conclusions Geranylgeranylacetone preconditioning attenuates heat‐induced inflammation and multiorgan dysfunction in rats.     

Thymoquinone ameliorates the immunological and histological changes induced by exposure to imidacloprid insecticide

Previous studies have shown that thymoquinone (TQ) exerts protective effects in some models of pesticide-induced immunotoxicity. However, no data exist regarding its possible modulatory effect during imidacloprid (IC)-induced toxicity. Therefore, the aim of this study was to investigate the impact of TQ on IC-induced immunotoxicity. Sixty adult male albino rats were divided into three groups of twenty animals each. The control group was given distilled water orally, while the IC-treated group was orally administered 0.01 LD(50 )(0.21 mg/kg body weight) of IC insecticide daily for 28 days. The animals in the third group (IC/TQ group) received the same IC dose as the IC-treated group for 28 days in addition to an intraperitoneal (I.P.) injection of TQ (1 mg/kg) once every 7 days. We found that IC induced significant increases (P < 0.05) in total leukocyte counts, total immunoglobulins (Igs) (especially IgGs), the hemagglutination of antibodies, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and malondialdehyde (MDA) compared to the control group. In contrast, significant decreases (P < 0.05) in phagocytic activity, chemokine expression and chemotaxis were observed in the IC-treated group, as were severe histopathological lesions in the liver, spleen and thymus. Notably, TQ supplementation ameliorated the biochemical, histopathological, and immunological changes induced by IC by increasing phagocytic activity, chemokinesis, chemotaxis, immunoglobulin levels, and the hemagglutination of antibodies, as well as by decreasing hepatic enzymes and serum MDA levels. Taken together, our data reveal the benefits of TQ supplementation for ameliorating IC toxicity by decreasing oxidative stress and enhancing immune efficiency.     

Effects of quercetin and chrysin on 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin induced hepatotoxicity in rats

The objective of current study is to investigate the effects of the administration of chrysin (CH) and quercetin (Q) on rat liver in which oxidative and histological damage had been induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). Rats were randomly divided into six equal groups. TCDD was orally administered at the dose of 2 μg/kg/week, and Q and CH were orally administered at the doses of 20 mg/kg day and 50 mg/kg/day, respectively, by gavages dissolved in corn oil. The liver samples to be analyzed for the determination of oxidative and histological alternations were taken from rats at 60 days. The results indicated that although 2,3,7,8‐TCDD significantly induced (P ≤ 0.01) lipid peroxidation (increase of MDA levels), it positively affected oxidant/antioxidant system (a decline in the levels of GSH, CAT, GSH‐Px, and CuZn‐SOD) in rats significantly. The histological changes observed in the liver correlated with the biochemical findings. However, these effects of TCDD on oxidative and histological changes were eliminated by Q and CH treatment. In conclusion, TCDD caused an adverse effect on rat's liver. When Q and CH were given together with TCDD, they prevented hepatotoxicty induced by TCDD. Thus, it is thought that Q and CH may be useful as a new category of anti‐TCDD toxicity agent. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.     

Effect of acute hepatic failure on the hepatic first‐pass effect of 5‐fluorouracil in rats

Objectives In cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil is widely used and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver and so the hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil may be lower in patients with hepatic failure, and systemic toxicity may not be reduced. In this study, we have investigated the effect of acute hepatic failure on the first‐pass effect of 5‐fluorouracil in rats. Methods Experimental acute hepatic failure was induced by treatment with carbon tetrachloride (CCl₄). 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of rats at a dose of 1.25 mg/kg. Key findings Hepatic availability in 50% CCl₄‐treated (severe hepatic failure) rats was higher than in controls. Conclusions The hepatic first‐pass effect after intrahepatic arterial administration of 5‐fluorouracil was lower in severe hepatic failure. Therefore, the reducing effect of the systemic toxicity after intrahepatic arterial administration may be lower in severe hepatic failure.     

Investigational New Drug‐Directed, 5‐Day Repeat Dose Toxicity Study of 4‐[3‐(2‐Nitro‐1‐Imidazolyl)‐Propylamino]‐7‐Chloroquinoline Hydrochloride (NLCQ‐1, NSC 709257) Administered with or without Taxol® in Sprague–Dawley Rats

Abstract: In pre‐clinical studies, 4‐[3‐(2‐nitro‐1‐imidazolyl)‐propylamino]‐7‐chloroquinoline hydrochloride (NLCQ‐1, NSC 709257) is a weak DNA‐intercalating, hypoxia‐selective cytotoxin with a promising profile as an adjuvant to radio/chemotherapy and it is about to enter phase I clinical trials. The present investigation was undertaken to further evaluate potential systemic toxicity induced by i.v. doses of NLCQ‐1 alone or in combination with Taxol ^® in Sprague–Dawley rats, in support of an investigational new drug application. Doses of NLCQ‐1 were based on previous range‐finding studies. In the present study, NLCQ‐1 was administered either alone, at 0, 6, 9 or 12 mg/kg/dose to male rats and 8, 12 or 16 mg/kg/dose to female rats or, at 9 (male rats) and 12 (female rats) mg/kg/dose, in combination with Taxol^®, on a qd × 5 schedule. Taxol^® was administered i.v. at 3.5 mg/kg/dose 1 hr before NLCQ‐1. Observations were recorded for mortality/moribundity, clinical signs of toxicity, body weights, food consumption, haematology, clinical chemistry, gross lesions at necropsy and histopathology. Blood samples were taken from 10 animals from each dose group on each of 2 days (days 8 and prior to scheduled necropsy on day 33). Administration of i.v. doses of NLCQ‐1 alone, on a qdx5 schedule, resulted in no signs of toxicity over the 33‐day study. Taxol^®‐induced toxicity included minimal decreases in the group mean RBC, haemoglobin and haematocrit values, minimal increases in group mean reticulocyte counts (females), marked decreases in group mean neutrophil counts and minimal decreases in group mean monocyte and eosinophil counts. Lymphoid atrophy of thymus, atrophy of bone marrow and atrophy of the germinal epithelium of the testis were also associated with the administration of Taxol^®. There was no additional toxicity associated with the co‐administration of NLCQ‐1 and Taxol^®. In the present study, the ‘no observable adverse effect level’ for NLCQ‐1, when administered on a qdx5 schedule, was >12 and >16 mg/kg/dose in male and female rats respectively. Daily administration of 9 (male rats) or 12 (female rats) mg/kg of NLCQ‐1 1 hr after i.v. administration of Taxol^® (3.5 mg/kg) had no effect on Taxol^®‐induced toxicity.     

Protective effects of garlic extract and vitamin C against in vivo cypermethrin-induced teratogenic effects in rat offspring

Exposure of male (55.1 mg/kg b.wt. orally for 60 days) and/or pregnant female Wistar rats (55.1 mg/kg b.wt. orally at days 6–15 of gestation), to the insecticide cypermethrin (CYP); resulted in the development of a lot of external morphological deformities and visceral malformations in their offspring pubs, which signify the potential of such insecticide to induce reproductive toxicity and teratogenesis. Data cleared that CYP treatment induced significant increase in the percentages of post-implantation deaths, dwarf foeti and subcutaneous oedema beside significant decrease in percentages of live borne foeti and uterine implants. CYP also caused many visceral malformations among different treated groups including nasal, ophthalmic, cerebral, pulmonary, cardiac and renal malformations. Concomitant oral administration of garlic extract or vitamin C (5 days/week) to treated fathers and/or pregnant mothers with CYP provided significant reduction in the percentage of the foetal malformations induced by the insecticide, when compared with the control. The current study proves that garlic and ascorbic acid dampen the reproductive toxicity and/or teratogenicity of cypermethrin toxicity in rats; therefore might prove to be effective dietary supplements in developing countries where pesticide pollution is high.     

Effects of nanoparticle‐encapsulated curcumin on arsenic‐induced liver toxicity in rats

We investigated the therapeutic effectiveness of the nanoparticle‐encapsulated curcumin (CUR‐NP) against sodium arsenite‐induced hepatic oxidative damage in rats. The CUR‐NP prepared by emulsion technique was spherical in shape with an encapsulation efficiency of 86.5%. The particle size ranged between 120 and 140 nm with the mean particle size being 130.8 nm. Rats were divided into five groups of six each. Group 1 served as control. Group 2 rats were exposed to sodium arsenite (25 ppm) daily through drinking water for 42 days. Groups 3, 4, and 5 were treated with arsenic as in group 2, however, they were administered, empty nanoparticles, curcumin (100 mg/kg bw) and CUR‐NP (100 mg/kg bw), respectively, by oral gavage during the last 14 days of arsenic exposure. Arsenic increased the activities of serum alanine aminotransferase and aspartate aminotransferase and caused histological alterations in liver indicating hepatotoxicity. Arsenic increased lipid peroxidation, depleted reduced glutathione and decreased the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in liver. All these effects of arsenic were attenuated with both curcumin and CUR‐NP. However, the magnitude of amelioration was more pronounced with CUR‐NP. The results indicate that curcumin given in nano‐encapsulated form caused better amelioration than free curcumin. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 628–637, 2015.     

Protective role of zinc during aluminum‐induced hepatotoxicity

The study was carried out to assess the role of zinc (Zn) in mitigating the biochemical alterations induced by aluminum (Al) in rat liver. Rats were divided into four groups: normal control, Al treated (AlCl₃, 100 mg/kg b.wt./day), Zn treated (ZnSO₄, 227 mg/L drinking water), and combined Al + Zn treated. Al and zinc treatments were given for a total duration of 2 months. Al treatment caused a significant increase in the activity of alkaline phosphatase (ALP), but decreased aspartate aminotransferase (AST) and alanine aminotranferase (ALT) activities, which showed the reverse trend following Zn supplementation. Levels of lipid peroxidation (LPx) and activities of catalase and glutathione‐S‐transferase (GST) were significantly decreased following Al treatment, which, however, were increased significantly in Zn co‐treated rats. Further Al exposure showed a significant increase in reduced glutathione (GSH) content as well as activities, of superoxide dismutase (SOD) and glutathione reductase (GR). However, Zn supplementation to Al‐treated rats brought down the raised levels of reduced (GSH) and SOD to within normal limits, but caused no effect on GR activity. Furthermore, Al treatment also resulted in alterations in liver histoarchitecture with disruption of hepatic cords and increased vacuolization, which were close to normal following Zn supplementation. The present study reveals that Zn is effective in attenuating the liver damage inflicted by Al toxicity. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 320–327, 2014.     

Nelumbo nucifera leaf extract treatment attenuated preneoplastic lesions and oxidative stress in the livers of diethylnitrosamine‐treated rats

Lotus (Nelumbo nucifera Gaertn) possesses antioxidant, hepatoprotective, and anticancer potential. This study determined the protective role of aqueous extract from Nelumbo nucifera leaves (NLE) against N‐diethylnitrosamine (DEN)‐induced oxidative stress and hepatocellular carcinogenesis in a sample of Sprague–Dawley rats. NLE was fed orally to rats in which hepatic carcinoma was induced with DEN for 12 weeks. Five groups of 12 rats each were used for the study: Group I (control group) rats received distilled water; Group II rats were induced with DEN; Group III rats were induced with DEN and cotreated with 0.5% NLE; Group IV rats were induced with DEN and cotreated with 1.0% NLE; and Group V rats were induced with DEN and cotreated with 2.0% NLE. Clinical chemistry, organ weight, inflammatory marker, protein expression, enzyme, and antioxidant analyses were conducted. NLE administration to rats resulted in significantly decreased levels of serum alanine aminotransferase, aspartate aminotransferase, and albumin, which is indicative of hepatocellular damage, compared with the control group. DEN‐induced oxidative stress was inhibited by NLE and this inhibition was paralleled by decreased lipid peroxides and increased glutathione transferase, superoxide dismutase, catalase, and glutathione peroxidase activity in liver tissues. The status of nonenzymatic antioxidants, such as reduced glutathione, was also found to be increased in NLE‐administered rats. Furthermore, NLE decreased tumor size, hepatic Rac1, PKCα, and GSTπ expressions compared with the DEN‐only group. Thus, supplementation of NLE reduced the adverse changes that occur because of liver cancer. These results prove that NLE protects against liver carcinogenesis induced because of treatment with DEN through blocking lipid peroxidation, hepatic cell damage, and enhancing the antioxidant defense system.     

Effect of dimethylnitrosamine‐induced liver dysfunction on the pharmacokinetics of 5‐fluorouracil after administration of S‐1, an antitumour drug,to rats

Objectives The anti‐tumour agent S‐1 comprises tegafur (a prodrug of 5‐fluorouracil; 5‐FU), gimeracil (2‐chloro‐2,4‐dihydroxypyridine (CDHP); a competitive inhibitor of 5‐FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5‐FU after administration of S‐1 to rats was investigated. Methods S‐1 (5 mg/kg) was administered intravenously and orally to rats with DMN‐induced liver dysfunction. Plasma concentrations of S‐1 components and 5‐FU were measured by HPLC and LC/MS‐MS. Blood tests and in‐vitro enzymatic investigations were also conducted. Key findings DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5‐FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S‐1, the blood concentration‐time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half‐life of tegafur was significantly prolonged. The maximum plasma concentration (C_max) of 5‐FU was significantly reduced and the area under the blood concentration‐time curve (AUC) was reduced by 22%. Following oral administration, the C_max of tegafur, 5‐FU and CDHP were significantly decreased and half‐lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5‐FU (13.6% reduction). Conclusions The pharmacokinetic profiles of tegafur, 5‐FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5‐FU. However, hepatic dysfunction had less of an effect on the AUC of 5‐FU, which correlates with anti‐tumour effect, after the oral administration of S‐1.     

Acute and subacute oral toxicity of copper oxide nanoparticles in female albino Wistar rats

The extensive use of copper oxide nanoparticles (CuO‐NPs) in various industries and their wide range of applications have led to their accumulation in different ecological niches of the environment. This excess exposure raises the concern about its potential toxic effects on various organisms including humans. However, the hazardous potential of CuO‐NPs in the literature is elusive, and it is essential to study its toxicity in different biological models. Hence, we have conducted single acute dose (2000 mg/kg) and multiple dose subacute (30, 300 and 1000 mg/kg daily for 28 days) oral toxicity studies of CuO‐NPs in female albino Wistar rats following OECD guidelines 420 and 407 respectively. Blood analysis, tissue aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and acetylcholinesterase, superoxide dismutase, catalase, lipid malondialdehyde and reduced glutathione assays, and histopathology of the tissues were carried out. The higher dose treatments of the acute and subacute study caused significant alterations in biochemical and antioxidant parameters of the liver, kidney and brain tissues of the rat. In addition, histopathological evaluation of these three organs of treated rats showed significantly high abnormalities in their histoarchitecture when compared to control rats. We infer from the results that the toxicity observed in the liver, kidney and brain of treated rats could be due to the increased generation of reactive oxygen species by CuO‐NPs.     

Kolaviron ameliorates hepatic and renal dysfunction associated with multiwalled carbon nanotubes in rats

The increase in the exposure to carbon nanotubes (CNTs) and their incorporation into industrial, electronic, and biomedical products have required several scientific investigations into the toxicity associated with CNTs. Studies have shown that the metabolism and clearance of multiwalled CNTs (MWCNTs) from the body involve biotransformation in the liver and its excretion via the kidney. Since oxidative stress and inflammation underlines the toxicity of MWCNT, we investigated the ameliorative effect of kolaviron (KV), a natural antioxidant and anti‐inflammatory agent, on hepatorenal damage in rats. Exposure to MWCNTs for 15 days significantly increased serum activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase thereby suggesting hepatic dysfunction. Kidney function, which was monitored by urea and creatinine levels, was also impaired by MWCNTs. Additionally, MWCNTs markedly increased myeloperoxidase activity, nitric oxide level, reactive oxygen and nitrogen species, and tumor necrosis factor level in both tissues. However, KV in a dose‐dependent manner markedly attenuated MWCNT‐induced markers of hepatorenal function in the serum and MWCNT‐associated inflammation in the liver and kidney. Also, MWCNTs elicited significant inhibition of superoxide dismutase, catalase, glutathione peroxidase, and glutathione‐S‐transferase activities. There was a significant diminution in glutathione level (GSH) and enhanced production of malondialdehyde (MDA) in MWCNTs‐exposed rats. KV treatment was able to significantly increase the antioxidant enzymes and enhance the GSH level with a subsequent reduction in the MDA level. Taken together, KV elicited ameliorative effects against hepatorenal damage via its anti‐inflammatory and antioxidant properties. Thus, KV could be an important intervention strategy for the hepatorenal damage associated with MWCNTs exposure.     

Diallyl sulfide alleviates cisplatin‐induced nephrotoxicity in rats via suppressing NF‐κB downstream inflammatory proteins and p53/Puma signalling pathway

Despite being a potent anticancer drug, nephrotoxicity is an adverse effect which renders the clinical use of cisplatin (Cis) limited. The protective role of diallyl sulfide (DAS); a naturally occurring organo‐sulfide, present in garlic, in cisplatin‐induced nephrotoxicity has been reported earlier. However, the mechanism through which DAS exerts its nephroprotective activity remains elusive. The aim of the current study was to elucidate the possible mechanisms underlying the reno‐protective effect of DAS in cisplatin‐induced nephrotoxicity in rats. DAS was given at 2 dose levels; 50 and 100 mg/kg, orally for 4 consecutive days, starting 1 hour after administration of single dose of cisplatin (3.5 mg/kg, intraperitoneally [i.p.]). The Cis‐induced elevation in serum urea and creatinine, degree of histopathological alterations was significantly ameliorated in cisplatin groups co‐treated with DAS. In addition, DAS significantly restored Cis‐depleted glutathione (GSH) content and superoxide dismutase (SOD) activity and attenuated Cis‐elevated Malondialdehyde (MDA) level. Also, DAS significantly reduced Cis‐increased renal expression of nuclear factor kappa B (NF‐κB) and subsequent pro‐inflammatory mediators; tumour necrosis factor alpha (TNF‐α), interleukin‐1β (IL‐1β), intercellular adhesion molecule‐1 (ICAM‐1) and inducible nitric oxide synthase (iNOS) in kidney tissues. Moreover, co‐treatment with DAS significantly inhibited Cis‐increased caspase‐8 and ‐9 levels. Additionally, DAS significantly mitigated Cis‐induced protein expression of p53, Puma, and Bax while, it significantly restored Cis‐reduced protein expression of Bcl‐xL compared to the Cis group. In conclusion, these results demonstrate that DAS ameliorates cisplatin‐induced nephrotoxicity in rats through enhancement of antioxidant defense, reduction of inflammatory cytokine tissue levels as well as inhibition of apoptosis via p53/Puma signalling pathway.