Gold Nanoparticles Perturb Drug-Metabolizing Enzymes and Antioxidants in the Livers of Male Rats: Potential Impact on Drug Interactions.

BACKGROUND AND AIM: With the wide applications of chitosan and gold nanoparticles in drug delivery and many consumer products, there is limited available information about their effects on drug-metabolizing enzymes (DMEs). Changes in DMEs could result in serious drug interactions. Therefore, this study aimed to investigate the effects of exposure to chitosan or gold nanoparticles on hepatic Phase I and II DMEs, liver function and integrity, oxidative damage and liver architecture in male rats. METHODS: Animals were divided into three equal groups: a control group, a group treated with chitosan nanoparticles (200 mg/kg, 50±5 nm) and a group treated with gold nanoparticles (4 mg/kg, 15±5 nm). Rats were orally administered their respective doses daily for 10 days. RESULTS: Both chitosan and gold nanoparticles decreased the body weights by more than 10%. Gold nanoparticles reduced the activities of antioxidants (superoxide dismutase and catalase), and reduced glutathione level and elevated the malondialdehyde level in the liver. Gold nanoparticles caused significant reductions in CYP1A1, CYP2E1, quinone oxidoreductase1, and glutathione S-transferase and elevated CYP2D6 and N-acetyl transferase2. Chitosan elevated CYP2E1 and CYP2D6 and reduced UDP-glucuronosyltransferase 1A1. Both nanoparticles disturbed the architecture of the liver, but the deleterious effects after gold nanoparticles treatment were more prominent. CONCLUSION: Taken together, gold nanoparticles severely perturbed the DMEs and would result in serious interactions with many drugs, herbs, and foods.

Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats.

The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone.

Ameliorative effects of docosahexaenoic acid on the toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cultured rat hepatocytes.

The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant toxicant that mediates carcinogenic effects associated with oxidative DNA damage. Docosahexaenoic acid (DHA) with antioxidant functions has many biochemical, cellular, and physiological functions for cells. The present study assessed, for the first time, the ameliorative effect of DHA in alleviating the toxicity of TCDD on primary cultured rat hepatocytes (HEPs). In vitro, isolated HEPs were incubated with TCDD (5 and 10 µM) in the presence and absence of DHA (5, 10, and 20 µM) for 48 h. The cell viability was detected by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) release. DNA damage was analyzed by liver micronucleus assay and 8-oxo-2-deoxyguanosine (8-OH-dG) level. In addition, total antioxidant capacity (TAC) and total oxidative stress (TOS) were assessed to determine the oxidative injury in HEPs. The results of MTT and LDH assays showed that TCDD decreased cell viability but not DHA. On the basis of increasing treatment concentrations, the dioxin caused significant increases of micronucleated HEPs and 8-OH-dG as compared to control culture. TCDD also led to significant increases in TOS content. On the contrary, in cultures treated with DHA, the level of TAC was significantly increased during treatment in a concentration-dependent fashion. DHA showed therapeutic potential against TCDD-mediated cell viability and DNA damages. As conclusion, this study provides the first evidence that DHA has protective effects against TCDD toxicity on primary cultured rat hepatocytes.

Cisplatin-induced renal toxicity via tumor necrosis factor-α, interleukin 6, tumor suppressor P53, DNA damage, xanthine oxidase, histological changes, oxidative stress and nitric oxide in rats: protective effect of ginseng.

Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of solid tumors, while its usage is limited due to its nephrotoxicity. The present study was undertaken to examine the effectiveness of ginseng to ameliorate the renal nephrotoxicity, damage in kidney genomic DNA, tumor necrosis factor-α, interleukin 6, tumor suppressor P53, histological changes and oxidative stress induced by cisplatin in rats. Cisplatin caused renal damage, including DNA fragmentation, upregulates gene expression of tumor suppressor protein p53 and tumor necrosis factor-α and IL-6. Cisplatin increased the levels of kidney TBARS, xanthine oxidase, nitric oxide, serum urea and creatinine. Cisplatin decreased the activities of antioxidant enzymes (GST, GPX, CAT and SOD), ATPase and the levels of GSH. A microscopic examination showed that cisplatin caused kidney damage including vacuolization, severe necrosis and degenerative changes. Ginseng co-treatment with cisplatin reduced its renal damage, oxidative stress, DNA fragmentation and induced DNA repair processes. Also, ginseng diminished p53 activation and improved renal cell apoptosis and nephrotoxicity. It can be concluded that, the protective effects of ginseng against cisplatin induced-renal damage was associated with the attenuation of oxidative stress and the preservation of antioxidant enzymes.

Cypermethrin induced damage in genomic DNA and histopathological changes in brain and haematotoxicity in rats: the protective effect of sesame oil.

The protective effect of sesame oil against cypermethrin-induced brain toxicity was studied. Female rats were orally treated with cypermethrin, sesame oil and their combination for 30 consecutive days. The results showed that cypermethrin increased thiobarbituric acid-reactive substances (TBARS), and decreased glutathione (GSH) and the activities of the antioxidant enzymes. Brain injury was confirmed by histopathological changes and DNA damage. Also, the reduction in the activities of acetylcholinesterase and monoamine oxidase (AChE & MAO), total protein, albumin and body weight, and the induction in triacylglycerol and cholesterol have been observed due to cypermethrin toxicity. Animals treated with sesame oil and cypermethrin together showed that brain TBARS and plasma triacylglycerol and cholesterol returned to the control level which indicating a protective effect of sesame oil. Also, sesame oil was able to attenuate the decrease in total protein, albumin, triacylglycerol and cholesterol, GSH, AChE and antioxidant enzymes induced by cypermethrin. In addition, sesame oil protected the brain histological changes and fragmentation of genomic DNA in animals treated with cypermethrin. The present results showed a protective effect of sesame oil against the cypermethrin induced brain toxicity and this could be associated mainly with the attenuation of the oxidative stress and the preservation in antioxidant enzymes.

Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil.

The involvement of reactive oxygen species (ROS) has been implicated in the toxicity of various pesticides. Our study was designed to investigate the induction of oxidative stress by cypermethrin; a Type II pyrethroid in rat liver and kidney. In addition, the protective role of sesame oil against the toxicity of cypermethrin was investigated. Animals were divided into four equal groups; the first group used as control while groups 2, 3 and 4 were treated with sesame oil (5 mL/kg b.w), cypermethrin (12 mg/kg b.w) and the combination of both sesame oil (5 mL/kg b.w) plus cypermethrin (12 mg/kg b.w), respectively. Rats were daily administered with their respective doses for 30 days by gavage. Repeated oral administration of cypermethrin was found to reduce the level of glutathione (GSH) and the activities of the antioxidant enzymes. While, the level of TBARS was elevated indicating the presence of oxidative stress. The activities of LDH, AST and ALT were decreased in the liver extract while increased in the plasma of the cypermethrin-treated group. Also, the levels of urea and creatinine were significantly increased after treatment with cypermethrin. Liver and kidney injury was confirmed by the histological changes. In conclusion, the administration of sesame oil provided significant protection against cypermethrin-induced oxidative stress, biochemical changes, histopathological damage and genomic DNA fragmentation.

Potential protective effects of quercetin and curcumin on paracetamol-induced histological changes, oxidative stress, impaired liver and kidney functions and haematotoxicity in rat.

The present study was carried out to evaluate the potential protective role of quercetin and curcumin against paracetamol-induced oxidative injury, liver damage and impairment of kidney function, as well as haematotoxicity in rats. Also, N-acetylcysteine was used to evaluate the potency of quercetin and curcumin. Paracetamol caused an elevation in thiobarbituric acid-reactive substances (TBARS) paralleled with significant decline in glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase activities (in plasma, brain, lung, heart, liver, kidney and testes) and glutathione content (in lung, liver and kidney). The apparent oxidative injury was associated with evident hepatic necrosis confirmed in histological examination, elevated plasma transmainases, alkaline phosphatase and lactate dehydrogenase. Paracetamol reduced plasma total protein, albumin and globulin, while increased bilirubin, urea and creatinine, and induced haematotoxicity. The presence of quercetin or curcumin with paracetamol successfully mitigated the rise in TBARS and restored the activities of antioxidant enzymes compared to the group treated with both paracetamol and N-acetylcysteine. They also protected liver histology, normalized liver and kidney functions, which was more pronounced with curcumin. Therefore, it can be concluded that concomitant administration of quercetin or curcumin with paracetamol may be useful in reversing the toxicity of the drug compared to N-acetylcysteine.

Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats.

Fluorosis is a serious public health problem in many parts of the world. As in the case of many chronic degenerative diseases, increased production of reactive oxygen species has been considered to play an important role, even in the pathogenesis of chronic fluoride toxicity. Black berry is closely linked to its protective properties against free radical attack. Therefore, the aim of this study was to demonstrate the role of black berry juice (BBJ) in decreasing the hepatotoxicity and oxidative stress of sodium fluoride (NaF). Results showed that NaF caused elevation in liver TBARS and nitric oxide (NO), and reduction in superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and glutathione (GSH). Plasma transaminases (AST and ALT), creatine kinase (CK), lactate dehydrogenase (LDH), total lipids (TL), cholesterol, triglycerides (TG), and low density lipoprotein-cholesterol (LDL-c) were increased, while high density lipoprotein-cholesterol (HDL-c) was decreased. On the other hand, BBJ reduced NaF-induced TBARS, NO, TL, cholesterol, TG, LDL-c, AST, ALT, CK and LD. Moreover, it ameliorated NaF-induced decrease in SOD, CAT, GSH, TAC and HDL-c. Therefore, the present results revealed that BBJ has a protective effect against NaF-induced hepatotoxicity by antagonizing the free radicals generation and enhancement of the antioxidant defence mechanisms.

Effect of processing on folic acid fortified Baladi bread and its possible effect on the prevention of colon cancer.

This paper studied the possible effect of folic acid in fortified Baladi bread on the prevention of colon cancer development in rats. Wheat flour samples (82% extraction rate) and soy bean flour were analyzed to determine their folic acid contents using the High Performance Liquid Chromatography (HPLC). Unfortified and folic acid fortified Baladi breads were prepared. Samples from each step of bread preparation were analyzed for folic acid concentration. Protein, fat, ash, fibers and carbohydrates percentages were also determined. Rats were divided into five groups, four of them were injected subcutaneously with dimethylhydrazine (DMH). After 15 weeks, the rats were sacrificed for pathological examination. Results showed that the folic acid content in wheat flour (82% extraction rate) was found to be highly significantly lower than that in soybean flour. After baking, folic acid content in all breads was found to decrease significantly. The highest protein and fat contents were found in soybean flour fortified Baladi bread. The colons of rats of groups 3 (fed 5% soy flour fortified Baladi bread) and 5 (fed Baladi bread fortified with 5% soy flour+8 mg folic acid/kg wheat flour) were the mostly affected by DMH injection as premalignant changes were observed.

Cadmium-induced changes in lipid peroxidation, blood hematology, biochemical parameters and semen quality of male rats: protective role of vitamin E and beta-carotene.

Cadmium is a well-known human carcinogen and a potent nephrotoxin. Lipid peroxidation is involved in cadmium-related toxicity. Vitamin E and beta-carotene are effective antioxidants and free radical scavengers. Therefore, the present study was carried out to investigate the potential protective effects of vitamin E and beta-carotene alone or in combination against cadmium (Cd) toxicity. Cadmium chloride (CdCl2, 5 mg/kg BW, 1/15 LD50), vitamin E (100 mg/kg BW), beta-carotene (10 mg/kg BW), and vitamin E with beta-carotene (100 + 10 mg/kg BW, respectively) were orally administered by gavage alone or in combination. The tested doses were given to rats every other day (15 times). Results obtained showed that CdCl2 significantly (P < 0.05) induced free radicals in plasma, liver and brain. The activities of glutathione S-transferase (GST) (plasma and liver), alkaline phosphatase (AlP) (plasma and liver), aspartate aminotransferase (AST), alanine aminotransferase (ALT) (liver) and acetylcholinesterase (AChE) (plasma and brain) were significantly (P < 0.05) decreased due to CdCl2 administration, whereas, the activities of AST and ALT were increased in plasma. Treatment with CdCl2 caused a significant (P < 0.05) increase in glucose, urea, creatinine and bilirubin in plasma. On the other hand, results showed that CdCl2 significantly (P < 0.05) decreased plasma total protein (TP), albumin (A), blood hemoglobin (Hb), total erythrocytic count (TEC) and packed cell volume (PCV), while total leukocyte count (TLC) increased. Treatment with CdCl2 caused a significant (P < 0.05) decrease in sperm concentration, motility (%), weight of testes and epididymis, and increase in dead and abnormal sperm. Results demonstrated the beneficial influences of vitamin E, -carotene alone and/or in combination in reducing the harmful effects of CdCl2.

Antioxidant activities and lipid lowering effects of isoflavone in male rabbits.

Dietary flavonoids appear to play a role in the prevention of a number of chronic diseases such as cancer and cardiovascular disease and the soy isoflavones have been the focus of particular. Consumption of soy isoflavones may reduce the risk of cardiovascular disease both through reduction in serum lipids and by the antioxidant properties. We have therefore investigate the effects of either 2.5 or 5 mg/kg B.W. doses of isoflavones on the levels of free radicals, lipids and lipoproteins in male New Zealand White rabbits. Animals were orally given 2.5 or 5 mg/kg B.W. doses of isoflavones. The tested doses were given to rabbits every other day for 13 weeks. Treatment with isoflavones caused significant (P<0.05) decrease in the concentrations of free radicals in plasma by 33% and 35%, liver by 18% and 27%, brain by 12% and 33%, testes by 40% and 21%, and kidney by 38% and 20% for 2.5 or 5 mg/kg B.W. doses, respectively, as compared to the control. On the other hand, the activity of glutathione S-transferase (GST) did not change in treated animals as compared to control. Also, results showed that isoflavones caused a significant decrease (P<0.05) in the levels of plasma total lipids (TL) by 16% and 19%, total cholesterol by 20% and 20%, triglyceride (TG) by 18% and 23%, low density lipoprotein (LDL) by 19%, 22%, very low density lipoprotein (VLDL) by 18% and 23%, and LDL:HDL ratio by 36% and 39% for 2.5 or 5 mg/kg B.W. doses, respectively, as compared to the control. While the level of high density lipoprotein (HDL) increased by 29% and 32%. The present results showed that the 5 mg/kg dose of isoflavone seemed to be related to a better plasma lipid and lipoprotein profiles and antioxidant activity.