Mohamed Tahar Yacoubi

Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice

The nephroprotective effect of coenzyme Q10 was investigated in mice with acute renal injury induced by a single i.p. injection of cisplatin (5 mg/kg). Coenzyme Q10 treatment (10 mg/kg/day, i.p.) was applied for 6 consecutive days, starting 1 day before cisplatin administration. Coenzyme Q10 significantly reduced blood urea nitrogen and serum creatinine levels which were increased by cisplatin. Coenzyme Q10 significantly compensated deficits in the antioxidant defense mechanisms (reduced glutathione level and superoxide dismutase activity), suppressed lipid peroxidation, decreased the elevations of tumor necrosis factor-alpha, nitric oxide and platinum ion concentration, and attenuated the reductions of selenium and zinc ions in renal tissue resulted from cisplatin administration. Also, histopathological renal tissue damage mediated by cisplatin was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the cisplatin-induced overexpression of inducible nitric oxide synthase, nuclear factor-kappaB, caspase-3 and p53 in renal tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect against acute cisplatin nephrotoxicity commonly encountered in clinical practice.

Protective effect of hemin against cadmium-induced testicular damage in rats

The protective effect of hemin, the heme oxygenase-1 inducer, was investigated in rats with cadmium induced-testicular injury, in which oxidative stress and inflammation play a major role. Testicular damage was induced by a single i.p. injection of cadmium chloride (2mg/kg). Hemin was given for three consecutive days (40 micromol/kg/day, s.c.), starting 1 day before cadmium administration. Hemin treatment significantly increased serum testosterone level that was reduced by cadmium. Hemin compensated deficits in the antioxidant defense mechanisms (reduced glutathione, and catalase and superoxide dismutase activities), and suppressed lipid peroxidation in testicular tissue resulted from cadmium administration. Also, hemin attenuated the cadmium-induced elevations in testicular tumor necrosis factor-alpha and nitric oxide levels, and caspase-3 activity. Additionally, hemin ameliorated cadmium-induced testicular tissue damage observed by light and electron microscopic examinations. The protective effect afforded by hemin was abolished by prior administration of zinc protoporphyrin-IX, the heme oxygenase-1 inhibitor. It was concluded that hemin, through its antioxidant, anti-inflammatory and antiapoptotic effects, represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of cadmium.

Protective role of carnosine in mice with cadmium-induced acute hepatotoxicity

The hepatoprotective effect of carnosine was investigated against cadmium-induced acute liver injury in mice. Hepatotoxicity was induced by a single i.p. injection of cadmium chloride (6.5mg/kg). Carnosine treatment (10mg/kg/day, i.p.) was applied for three consecutive days, starting one day before cadmium administration. Carnosine significantly decreased the cadmium-induced elevations in serum aminotransferases. Carnosine suppressed lipid peroxidation and restored the deficits in the antioxidant defense mechanisms (reduced glutathione level, and catalase and superoxide dismutase activities) in liver tissue resulted from cadmium administration. Also, the reductions in hepatic nitric oxide and zinc ion levels, and the increases in hepatic cadmium ion concentration, and myeloperoxidase and caspase-3 activities following cadmium exposure were significantly attenuated by carnosine treatment. In addition, carnosine markedly ameliorated cadmium-induced liver tissue damage as evidenced by light and electron microscopic examinations. It was concluded that carnosine can be considered a potential candidate to protect the liver against the deleterious effect of acute cadmium intoxication.

Nephroprotective Effect of Telmisartan in Rats with Ischemia/Reperfusion Renal Injury

We investigated the protective effect of telmisartan, an angiotensin II receptor antagonist, against ischemia/reperfusion renal injury in rats. Bilateral ischemia was induced by clamping both renal vascular pedicles for 45 min followed by reperfusion for 3 h. Untreated rats exposed to ischemia/reperfusion showed significant elevations in blood urea nitrogen and serum creatinine levels, renal tissue levels of malondialdehyde, tumor necrosis factor-α and nitric oxide, and caspase-3 activity. This was associated with significant decreases in renal reduced glutathione level, catalase and superoxide dismutase activities. Also, significant increases in serum and renal tissue levels of homocysteine were detected following ischemia/reperfusion. Pre-ischemic treatment with telmisartan (0.3 mg/kg/day, i.p.) for 7 consecutive days significantly attenuated the increases in blood urea nitrogen, serum creatinine, renal malondialdehyde, tumor necrosis factor-α, nitric oxide, caspase-3 activity, and serum and renal homocysteine levels, and significantly restored the renal antioxidant defenses. In addition, light and electron microscopic examinations revealed that telmisartan pre-treatment markedly ameliorated ischemia/reperfusion-induced renal tissue damage. It was concluded that telmisartan, through its antioxidant, anti-inflammatory and antiapoptotic effects, can be considered a potential candidate to protect against acute ischemia/reperfusion renal injury.

Mechanisms underlying the protective effect of eugenol in rats with acute doxorubicin cardiotoxicity.

The protective effect of eugenol and its possible mechanisms were investigated in rats with acute doxorubicin cardiotoxicity. Cardiac toxicity was induced by a single intraperitoneal injection of doxorubicin (20 mg/kg). Eugenol treatment (5 mg/kg/day, orally) was started 2 days before doxorubicin administration and continued for five consecutive days. Eugenol significantly reduced the elevated serum creatine kinase and lactate dehydrogenase levels, and restored the electrocardiographic disturbances resulted from doxorubicin administration. Also, eugenol reversed doxorubicin-induced deficits in the antioxidant defense mechanisms, decreased lipid peroxidation and attenuated the elevations in cytosolic Ca2+ and nitric oxide levels in cardiac tissue. In addition, doxorubicin-induced cardiac tissue damage observed by histopathological examination was markedly ameliorated with eugenol. Immunohistochemical analysis revealed that eugenol prevented the doxorubicin-induced activation of caspase-3 in cardiomyocytes. The cardioprotective effect afforded by eugenol was not significantly inhibited by prior administration of capsazepine, the transient potential vanilloid receptor-1 antagonist. It was concluded that eugenol, through its antioxidant activity and its ability to reduce cardiac Ca2+ accumulation and nitric oxide levels, is a potential candidate to protect against acute doxorubicin cardiotoxicity, a major and dose-limiting clinical problem.

Effects of hexavalent chromium on reproductive functions of male adult rats

Hexavalent chromium is an environmental contaminant which may be associated with reproductive abnormalities in male rats. In the present study, we examined the effect of hexavalent chromium on male reproductive function of rats. Male Wistar rats received a daily intraperitoneal injection of potassium dichromate (1 or 2 mg/kg body weight) for fifteen consecutive days. A decrease in testis weight and an increase in seminal vesicles and prostate weights were demonstrated after chromium treatment. Moreover, a dose-dependent increase in blood and testis chromium levels as well as an increase in FSH and a decrease in LH and testosterone serum levels were detected in treated rats. Histological analysis revealed pronounced morphological alterations with enlarged intracellular spaces, tissue loosening and dramatic loss of gametes in the lumen of the seminiferous tubules of treated rats. In addition, a decreased sperm motility and number of epididymal spermatozoa together with an increased sperm abnormality rate was found in chromium-treated rats in comparison to controls. In rats receiving the higher chromium dose, histological images presented considerably increased areas filled with seminal vesicle and prostate secretions. The mucosal crypts of seminal vesicles and the typical invaginations of prostate were altered. The results suggest that subacute treatment of potassium dichromate promotes reproductive system toxicity and affects testicular function of adult male rats.

Coenzyme Q10 counteracts testicular injury induced by sodium arsenite in rats

The protective effect of coenzyme Q10 against testicular toxicity induced by sodium arsenite (10mg/kg/day, orally for two consecutive days) was investigated in rats. Coenzyme Q10 treatment (10mg/kg/day, i.p.) was applied for five consecutive days, starting three days before arsenite administration. Coenzyme Q10 significantly increased serum testosterone level which was reduced by sodium arsenite. Coenzyme Q10 significantly suppressed lipid peroxidation, restored the depleted antioxidant defenses, and attenuated the increases of tumor necrosis factor-α and nitric oxide resulted from arsenic administration. Also, the elevation of arsenic ion, and the reductions of selenium and zinc ions in testicular tissue were mitigated by coenzyme Q10. Histopathological examination showed that testicular injury mediated by arsenic was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the arsenic-induced expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand and caspase-3 in testicular tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of arsenic intoxication.

Embryotoxicity and fetotoxicity following intraperitoneal administrations of hexavalent chromium to pregnant rats

Heavy metals are omnipresent in the environment, and industrial use has greatly increased their presence in soil, water and air. Their inevitable transfer to the human food chain remains an important environmental issue as many heavy metals cause a range of toxic effects, including developmental toxicity. Administration of chromium VI (1 and 2 mg/kg as potassium dichromate) through intraperitoneal (i.p.) injection during organogenesis (days 6 to 15 of gestation) in rats revealed embryo- and fetotoxic effects. Reduced fetal weight, retarded fetal development, number of fetuses per mother and high incidences of dead fetuses and resorptions in treated mothers were also observed. Gross morphological abnormalities, such as displayed form of edema, facial defect, lack of tail, hypotrophy, severs subdermal haemorrhage patches and hypotrophy of placenta were observed in fetuses after chromium VI-treated mothers. A skeletal development of fetuses presented an incomplete ossification in nasal, cranium, abdominal or caudal bones in rats treated with 1 mg/kg of chromium, whereas rats treated with 2 mg/kg showed ossification and absence of the sacral vertebrae compared with the control. At a higher dose of chromium, histological changes were found in fetuses with atrophy of theirs vital organs. Placental histological observations revealed a pronounced morphological alteration, with atrophy of decidual cells, a degenerated of chorionic villi and hypertrophy of blood lacuna. The present study suggests a risk to the developing embryo when the mother is exposed to a high concentration of chromium VI during organogenesis.

p16INK4A overexpression in precancerous and cancerous lesions of the uterine cervix in Tunisian women

Uterine cervix cancer is an important public health problem in developing countries. However, there is a substantial lack of inter-observer diagnostic reproducibility for its precursor lesions (CIN1). The study was performed to evaluate the usefulness of p16(INK4A) overexpression as a surrogate marker for uterine cervix precancerous lesions and high-risk human papillomavirus (HPV) infection. We conducted a retrospective study of 87 uterine cervix specimens, including 7 normal tissue samples, 17 benign lesions, 34 precancerous lesions, 22 invasive squamous cell carcinomas (SCC), and 7 adenocarcinomas. Immunohistochemistry was used to find p16(INK4A) overexpression. HPV infection was detected by PCR. No immunoreactivity for p16(INK4A) was detected in normal tissue or benign lesions. p16(INK4A) immunoreactivity was focal in CIN1, whereas strong and diffuse immunoreactivity for p16(INK4A) was uniformly observed in both the nucleus and the cytoplasm of all CIN2 and 3, as well as in those of invasive SCC and adenocarcinomas. A statistically significant association was observed between p16(INK4A) overexpression, lesion grade, and high-risk HPV infection (p<0.0001). p16(INK4A) overexpression is a useful additional marker for the interpretation of problematic uterine cervical lesions and can help to reduce the variability during evaluation of suspicious biopsies of the uterine cervix.

Ameliorative effects of telmisartan in diabetic rats with indomethacin-induced gastric ulceration

The protective effects of telmisartan, the angiotensin II-receptor antagonist, were investigated in rats with type 2 diabetes mellitus exposed to acute gastric ulceration. Following successful induction of diabetes, telmisartan treatment (1 mg/kg/day, orally) was started and continued for 8 weeks, after which acute gastric ulceration was induced by indomethacin. Telmisartan significantly attenuated the hyperglycemia and hypoinsulinemia in diabetic rats. Also, telmisartan significantly reduced the elevations of total gastric acid output, pepsin activity, gastric ulcer index and gastric mucosal tumor necrosis factor-alpha, nitric oxide, malondialdehyde and caspase-3 activity, and restored the depleted antioxidant defenses (reduced glutathione level, and superoxide dismutase and catalase activities) caused by indomethacin administration in diabetic rats. Histopathological gastric tissue damage induced by indomethacin in diabetic rats was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan markedly attenuated the reduction in insulin content of pancreatic islet beta-cells, and prevented the indomethacin-induced overexpression of inducible nitric oxide synthase and nuclear factor-kappaB in gastric mucosa of diabetic rats. It was concluded that telmisartan represents a potential therapeutic option to reduce the risk of gastric ulceration induced by nonsteroidal anti-inflammatory drugs in type 2 diabetic patients.