Manar Hamed Arafa

Fenugreek seed powder mitigates cadmium-induced testicular damage and hepatotoxicity in male rats.

Cadmium is a potential environmental and industrial pollutant affecting human tissues and organs including liver and testes. The protective role of fenugreek seed powder (FSP) was investigated in male rats subjected to cadmium-induced testicular injury and hepatic dysfunction. Testicular damage and hepatotoxicity were induced by oral administration of cadmium chloride (5 mg/kg body weight, once a day) for 7 weeks. FSP was given at 5% w/w in chow diet for 8 weeks, starting 1 week before cadmium administration. FSP intake significantly increased serum testosterone level and testis weight that were reduced by cadmium. FSP also compensated deficits in hepatic and testicular antioxidant defense system, interleukin-4 and nitric oxide levels, reduced serum liver function enzyme activities and suppressed lipid peroxidation in hepatic and testicular tissues resulted from cadmium administration. Additionally, FSP attenuated the cadmium-induced elevations in hepatic and testicular tumor necrosis factor-α and transforming growth factor-beta1 levels as well as cadmium deposition and hydroxyproline content. The protective effect afforded by FSP was mainly due its antioxidant, antifibrotic and anti-inflammatory effects. In conclusion, the results of the present work indicated that FSP may represent a promising medicinal herb to protect hepatic and testicular tissues from the detrimental effects of cadmium.

Sildenafil citrate attenuates the deleterious effects of elevated ammonia

Abstract Ammonia is a bi-product of protein metabolism in the body. It is able to cross the blood-brain barrier and elevated ammonia levels are toxic to the brain. Rats with hyperammonemia showed impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanosine monophosphate (glutamate-NO-cGMP) pathway in the brain. Chronic treatment with sildenafil restored learning ability. We therefore tested the hypothesis that sildenafil has a protective effect on the brains of hyperammonemic rats. Hyperammonemia was induced in male rats by daily intraperitoneal (i.p.) injection of ammonium chloride (100 mg/kg body weight) for 8 weeks. Sildenafil citrate was administered intraperitoneally (10 mg/kg body weight/3 days) for 8 weeks. Treatment with sildenafil resulted in a significant reduction in plasma liver enzymes, lipid profile as well as brain lipid peroxidation and caspase-3 mRNA. Meanwhile, plasma NO as well as cGMP, antioxidants and endothelial nitric oxide synthase (eNOS) gene expression were significantly elevated in the brains of hyperammonemic rats. Our results showed that sildenafil exerts a protective effect on the brain by reversing oxidative stress during hyperammonemia and this could be due to (i) cytoprotective, antioxidant and anti-apoptotic effects (ii) increasing cGMP and enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus preventing oxidative damage in the brain. The exact protective mechanism of sildenafil has to be still investigated and further studies are warranted. Consequently, therapeutic modulation of the NO/cGMP pathway might have important clinical applications to improve brain functions in patients with hyperammonemia or clinical hepatic encephalopathy.

Ameliorative effect of N‐acetyl cysteine on alpha‐cypermethrin‐induced pulmonary toxicity in male rats

Alpha‐cypermethrin (α‐CYP) is one of the most widely used insecticides. It may become an air pollutant and adversely affect the health. The present study was designed to determine whether treatment with N‐acetyl cysteine (NAC), a well‐known antioxidant, can be useful for the management of the deleterious effects of α‐CYP on lung tissues. For this purpose, thirty two male rats were divided into four different groups (eight rats for each). Group (I) gavaged with corn oil (control group), group (II) gavaged daily with NAC (150 mg kg−1 body weight), group (III) gavaged with α‐CYP (14.5 mg kg−1 body weight/day, dissolved in corn oil), group (IV) gavaged with NAC then with α‐CYP 2 h later for 12 weeks. α‐CYP significantly increased serum lactate dehydrogenase (LDH) and pulmonary malondialdehyde (MDA) levels, while decreased the activities of catalase (CAT) and superoxide dismutase (SOD) as well as reduced glutathione (GSH) content in lung. It also provoked higher levels of serum nitric oxide (NO), lung interleukin‐1 beta (IL‐1β), tumor necrosis factor‐alpha (TNF‐α), hydroxyproline (Hyp) as well as heme oxygenase‐1 (HO‐1), inducible nitric oxide synthase (iNOS) and nuclear factor‐kappa B (NF‐КB) gene expression in lung tissues. Histopathological alterations in lung with congestion, cellular infiltration, necrotic changes and thickening of inter‐alveolar septa were observed following α‐CYP administration. NAC reduced the adverse effects of α‐CYP on lung tissues and improved the histological architecture of lung since it showed antioxidant, anti‐inflammatory and antifibrotic effects on lung tissues. Our results indicate that NAC exerts a potent protective effect against α‐CYP‐induced oxidative damage and inflammation in lung tissues.

Coenzyme Q10 and fish oil synergistically alleviate aluminum chloride-induced suppression of testicular steroidogenesis and antioxidant defense.

Abstract Aluminum (Al) is an environmental xenobiotic that stimulates free radical generation and hence reproductive toxicity. Coenzyme Q10 (CoQ10) effectively counteracts free radical-induced tissue damage. Omega-3 polyunsaturated fatty acids present in fish oil (FO) exert beneficial effects on reproduction in male animals. This study therefore investigated the effects of both agents on testicular dysfunction induced by aluminum chloride (AlCl3). Fifty male rats were gavaged with either 1% gum acacia (control group) or AlCl3 (34 mg/kg/day) for ten weeks. Concurrently, AlCl3-treated rats received no treatment, CoQ10 (10 mg/kg/day, p.o.), and/or FO (400 mg/kg/day, p.o.) for ten weeks. AlCl3 caused a significant decrease in serum testosterone, luteinizing hormone (LH), and follicular stimulating hormone (FSH), as well as testicular weight, antioxidant enzyme gene expression and activities, reduced glutathione, zinc, adenosine 3′,5′-cyclic monophosphate (cAMP) contents, and number of Leydig cells, along with down-regulation of 3beta-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, steroidogenic acute regulatory protein (STAR), and cholesterol side-chain cleavage enzyme (P450scc) gene expression. However, testicular Al, malondialdehyde (MDA), and nitric oxide (NO) levels were markedly increased. Treatment with CoQ10 and FO, alone or in combined form led to an improvement in the aforementioned biomarkers. Overall, individual or combined treatment with CoQ10 and FO could ameliorate the toxic effects of AlCl3 on testicular tissues by mechanisms related to their potent antioxidant potential and stimulatory effects on steroidogenic enzymes transcription. CoQ10 seems to be better than FO regarding oxidative and nitrosative stress, Zn deficiency, and Al overload. However, FO showed more pronounced effect than CoQ10 on hormones, steroidogenic markers, and cAMP. A cocktail of both demonstrated greater protective effects on testicular tissues than monotherapy.

The Effects of Monosodium Glutamate on Thymic and Splenic Immune Functions and Role of Recovery (Biochemical and Histological study)

Monosodium glutamate (MSG), a flavor enhancer, is used in modern nutrition to improve food palatability. The objectives of the current study were to investigate the effect of MSG on thymus as well as spleen structures and functions. Also, to evaluate the possibility of recovery after cessation of administration. Adult male rats were divided into three groups: control, MSG (3 g MSG/kg body weight daily for 8 weeks by oral gavages), and Recovery (MSG for same period and then left untreated for additional 4 weeks). The results showed that MSG treatments significantly increased serum interleukin (IL)-1β as well as thymic and splenic malondialdehyde and decreased serum levels of IL-10 and also reduced glutathione (GSH) levels and both catalase and superoxide dismutase activities in the thymus and spleen. Histological examination showed that MSG induced a remarkable disruption in the lobular architecture of the thymus with marked decrease of the T lymphocytes with darkly stained nuclei and dilated blood sinusoid in the cortical region. Medullary region were enlarged and repopulated with small lymphocytes and dilated blood sinusoids. The cortical-medullary differentiation was difficult to be determined. Small sized splenic lymphatic follicles with absence of germinal centers and large congested blood vessels were also noticed. The differentiation between the red and the white pulps was indistinct. Recovery groups showed preserved thymic lobular architecture with repopulation of the cortical thymocytes enclosing the paler staining medulla .Splenic lymphatic follicles of different sizes with absence of germinal centers were noticed. Marginal zone is differentiated from the red pulp. Immunohistochemical staining of MSG group demonstrated a marked decrease in CD3-positive T-lymphocytes in both thymus and spleen that significantly increased in recovery group. Taken together, the data showed that MSG consumption may have immunotoxic effects on the thymus and spleen of adult rats which is reversible but the normal structure of the spleen would need time to be regained. It is recommended that further studies aimed at corroborating these findings be carried out.

Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity

ABSTRACT Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol‐induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol‐treated and control groups. In tramadol‐treated patients, CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite, O‐desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10), suggesting oxidative stress. There were also significant increases in serum hepatic damage markers including alpha‐glutathione transferase (&agr;‐GST) levels and liver function enzyme activities in *DUP and *1 carriers compared to carriers of other alleles. Moreover, we reported that in 42 patients with allele *1, tramadol caused mild to moderate hepatotoxicity (grades: 1–2) within 13–16months while in 7 patients with duplicated allele (*DUP), tramadol caused moderate to severe hepatotoxicity (grades: 2–3) within 10–11months (moderately longer period but shorter than that observed in allele *1), implying that exposure to tramadol for longer time in extensive and ultra‐rapid metabolizers may contribute to hepatotoxicity development. Overall, our results suggest that CYP2D6 gene polymorphisms, particularly enhanced or normal function of CYP2D6, may increase the vulnerability to long term tramadol‐induced hepatotoxicity through the enhancement of accumulation of tramadol bioactive metabolite (M1) and hence oxidative stress. Therefore, tramadol doses should be adjusted according to patients CYP2D6 genotyping analysis to avoid hepatotoxicity. HIGHLIGHTSCYP2D6 polymorphisms increase vulnerability to tramadol‐induced hepatotoxicity.Accumulation of tramadol metabolite and oxidative stress mediate hepatotoxicity.CYP2D6 genotyping is necessary to adjust tramadol doses to avoid hepatotoxicity.

Asymmetric dimethylarginine and heart-type fatty acid-binding protein 3 are risk markers of cardiotoxicity in carbon monoxide poisoning cases in Zagazig university hospitals

Carbon monoxide (CO) poisoning is a leading cause of toxicity-related mortality and morbidity worldwide. Recent studies focused on CO-induced cardiovascular toxicity. Oxidative stress plays an important role in the pathophysiology of CO toxicity. The aim of this study was to elucidate the relationship between cardiac damage biomarkers and oxidative stress biomarkers in patients with CO-induced cardiotoxicity. This study was carried out on 36 CO-poisoned patients admitted to Zagazig University Hospitals. Forty healthy individuals (age- and sex-matched) were selected as a control group. Clinical examination and electrocardiography (ECG) were performed for CO-poisoned patients. These patients have been investigated for carboxyhaemoglobin percent (COHB%) and cardiac damage biomarkers; cardiac troponin I (cTn-I), heart-type fatty acid-binding protein 3 (H-FABP3). Oxidative stress biomarkers comprising malondialdehyde (MDA), asymmetric dimethylarginine (ADMA), and total antioxidant capacity (TAC) have been also assessed. All biomarkers have been assessed on admission (0 h) and 6 h after treatment of CO-poisoned patients with high-flow oxygen and compared with those of the control groups. ECG findings were abnormal in 31 patients (86.11%), where sinus tachycardia was the commonest finding (58.33%). There was a statistically significant increase of COHB%, MDA, ADMA, and H-FABP3 levels, and a significant decrease of TAC level in CO-poisoned patients compared to controls with no significant changes in cTn-I. Six hours following treatment, all measured parameters were significantly improved except for cTn-I, which was significantly increased when compared with admission status (0 h). Furthermore, H-FABP3 showed a significant positive correlation with COHB%, MDA, ADMA, and a negative correlation with TAC, while cTn-I was significantly correlated with COHB% only. ADMA and MDA seem to be the strongest determinants for the prediction of H-FABP3 changes and hence cardiovascular toxicity. Thus, cardiac damage in patients with CO poisoning could be partially mediated by CO-induced oxidative stress, where H-FABP3 level was directly and strongly associated with MDA and ADMA levels.

Testicular toxic changes induced by bisphenol A in adult albino rats: a histological, biochemical, and immunohistochemical study

Introduction Bisphenol A (BPA) is an endocrine disruptor that is incorporated in many plastic industries worldwide. The exposure of humans to such substances starts from the fetal life to the postnatal life and extends throughout the life of the individual. Many agencies have raised warnings against the excessive use of such substances. Aim of work The present study was designed to evaluate the biochemical and histological changes induced by BPA in the testis of adult male albino rats and to detect the ability of self-regeneration after stoppage. Materials and methods Thirty-two adult male albino rats were used. The rats were divided equally into four groups (eight animals each). Groups I and II were used as negative and positive control groups, respectively. Rats of group III were given an oral dose of 50 mg/kg of BPA per day for 8 weeks. In group IV, the rats were treated in the same manner as in group III and then left without treatment for 4 weeks for recovery. At the time of sacrifice, all rats were anesthetized with ether, and blood samples were collected for estimation of testosterone. The testes were dissected out and processed for testicular malondialdehyde and glutathione measurement and light and electron microscopic examination. The diameter and epithelial height of the seminiferous tubules were estimated morphometrically and statistically analyzed. Results Biochemical results of the BPA-treated group (group III) revealed testicular affection with oxidative stress. Testes of this group showed many distorted seminiferous tubules lined by disorganized epithelium and separated with wide interstitium containing congested blood vessels. Apoptotic nuclei of some spermatids and intercellular spaces were also seen. There was a decrease in estrogen receptors. Statistical analysis of epithelial height and tubular diameter confirmed the results. However, in the recovery group (group IV), the histological and the biochemical changes were reduced but did not return to normal. Conclusion These results demonstrated that BPA had deleterious effects on the testis with some sort of self-recovery after stoppage.

Selenium nanoparticles prevents lead acetate-induced hypothyroidism and oxidative damage of thyroid tissues in male rats through modulation of selenoenzymes and suppression of miR-224

Selenium nanoparticles (Se-NPs) are customizable drug delivery vehicles that show good bioavailability, higher efficacy and lower toxicity than ordinary Se. Pre-treatment of male rats with these NPs has been recently shown to exert a protective effect against chromium-induced thyroid dysfunction. This study, therefore, aimed to investigate and characterize the potential protective mechanism of Se-NPs against lead (Pb) acetate-induced thyrotoxicity. We found that prophylactic and concurrent treatment of Pb acetate-exposed rats with Nano-Se (0.5 mg/kg, i.p) for 15 wk significantly alleviated the decrease in free triiodothyronine (fT3) and free thyroxine (fT4) levels as well as fT3/fT4 ratio% and the increase in thyroid stimulating hormone (TSH) levels to approach control values. This was accompanied by a reduction in the accumulation of Pb in serum and thyroid tissues as well as maintenance of thyroidal pro-oxidant/antioxidant balance and iodothyronine deiodinase type 1 (ID1), an essential enzyme for metabolizing of T4 into active T3, gene expression. Surprisingly, miR-224, a direct complementary target of ID1 mRNA, expression in the thyroid tissues was significantly down-regulated in Nano-Se-pre- and co-treated Pb acetate intoxicated animals. Such changes in miR-224 expression were negatively correlated with the changes in ID1 gene expression and serum fT3 level. These results suggest that Se-NPs can rescue from Pb-induced impairment of thyroid function through the maintenance of selenoproteins and down-regulation of miR-224.