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Toluene is a solvent widely produced and used by the industrial sector. Noise is a nuisance present in many professional sectors. We aimed to investigate in the present study the impact of exposure to toluene (300 ppm) and/or noise 85 dB(A) on rat heart and to assess the preventive effect of olive leaf extract OLE (40 mg/Kg/day) administrated for six weeks (5 days/week). Forty-eight male Wistar rats were divided into 8 groups (n = 6/group): C: control group, C+OLE: control group received OLE, N: group exposed to noise, N+OLE: group exposed to noise and received OLE, T: group exposed to toluene, T+OLE: group exposed to toluene and received OLE, NT: group co-exposed to noise and toluene, NT+OLE: group co-exposed to noise and toluene received. At the end of the experimental period, heart and blood samples were collected. Plasma cholesterol (CHOL), triglycerides (TG), lactate dehydrogenase (LDH) and creatine kinase (CK) levels were determined. Histopathological investigation was determined by HE staining. Superoxide dismutase (SOD), catalase (CAT) activities and malondialdehyde (MDA) level in heart tissue were also measured. Our results showed that Simultaneous exposure to noise and toluene altered CHOL, TG, LDH and CK levels. In parallel, an increase in lipid peroxidation levels and Superoxide dismutase activity with a decrease in catalase activity in the heart were shown. A significant alteration in the myocardium was also recorded. OLE treatment modulated theses oxidative and histological changes. In conclusion, OLE was found to correct the deleterious effects induced by combined exposure to noise and toluene.

New mono-iminophosphoranes and new bis-iminophosphoranes 3 were prepared by reaction of triphenylphosphine or tri-alkyl phosphite and azides 1. In order to reduce the reaction time and detect the phosphazides intermediates 2, the reactions of synthesis of iminophosphoranes 3 were evaluated by 31P-NMR spectroscopy. Two phosphazides intermediates 2 in the Z/E form were detected. Density Functional Theory (DFT) calculations were performed at B3LYP/6-311++G** and M062X/def2TZVP to determine the relative stability of Z/E intermediates. Antioxidant activities of iminophosphoranes 3 were evaluated by a 1,1-diphenyl-2-picryl hydrazyl (DPPH) test. The compounds were characterized on the basis of IR, NMR spectroscopy (1H, 13C and 31P) and by HRMS.

Hypericum genus is traditionally known for its medicinal use and its therapeutic and antioxidant effects. However, the toxic effect of this plant has not been much explored. Our study aimed at investigating the effect of Hypericum humifusum (Hh) leaf extracts on oxidative stress parameters in male rats. For it, we first focused on the phytochemical analysis of the aqueous and methanolic extracts of Hh leaves. Hence, Wistar rats were treated per gavage for 30 days and divided into Control (1 mL/rat, distilled water), A200 group (200 mg/kg body weight (bw) aqueous extract), A400 group (400 mg/kg bw aqueous extract), M10 group (10 mg/kg bw methanolic extract), M20 group (20 mg/kg bw methanolic extract). The phytochemical analysis revealed the presence of tannins, flavonoids, steroids, carbohydrates, and phenolic compounds. Biochemical and histological investigations were performed in plasma and liver tissue. Liver tissue homogenates were used for the measurement of malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) levels. At the same time, alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) were assayed in plasma samples. Histological study was also conducted in liver. We showed that Hh extracts reduced relative liver weight and increased ALT, AST, LDH activities in treated groups compared to control group. These results were associated with an increase of MDA levels and a decrease of antioxidant enzyme activities (CAT and SOD) in liver tissues of treated rats. Histology of liver demonstrated several alterations showing necrosis, altered hepatocytes and lymphocyte migration mainly in A200 group and dilated sinusoids, foamy appearance of hepatocytes and lymphocyte accumulation in the other treated groups. This original work indicated that chronic consumption of Hh leaf extracts has no antioxidant effect but instead it induces oxidative stress and enhances markers of cell damage which was confirmed by histological study of liver rats.

Recently, there has been increasing interest in Hypericum ( Hypericaceae ) genus. The first part of the present study focused on the phytochemical analysis of the methanolic and aqueous extracts of Hypericum humifusum leaves. The second part of the study investigated the effect of Hypericum humifusum leaf extracts on male reproductive parameters. 30 male rats were grouped into control (1 mL/rat, distilled water), treated by 200 mg/kg body weight (bw) aqueous extract (A200), 400 mg/kg bw aqueous extract (A400), 10 mg/kg bw methanolic extract (M10) and 20 mg/kg bw methanolic extract (M20) groups. The phytochemical analysis revealed the presence of tannins, flavonoids, steroids, carbohydrates, and phenolic compounds. After thirty-day treatment, body and reproductive organs were weighed. Testes in all rat groups were processed for biochemical assays and histopathological examinations. Epididymis sperm analyses were also performed. Testicular tissue homogenate samples were used for Malondialdehyde (MDA), catalase and superoxide dismutase (SOD) measurements. We showed that Hh extracts induced a severe seminiferous tubular damage with an increase in the percentage of empty seminiferous tubules. Epididymis sperm analysis revealed a significant reduction in density and viability of sperm with alteration of spermatozoa morphology. Also, we found that Hh leaf extracts decreased plasma total cholesterol, HDL-cholesterol and triglycerides levels. These results were associated with an increase of MDA levels and a decrease of catalase and SOD activities in testis tissues. Our finding revealed that chronic consumption of Hh extracts induces disruption of normal spermatogenesis by alteration of sperm density, viability, and morphology. This action may be due to an inhibition of the antioxidant-defense system.

Despite its deleterious effect on healthy cells and highly regenerating cells such as spermatozoa, Doxorubicin (DOX) is still one of the most used anticancer drugs in the last decades. The present work aimed to investigate the ability of the selenium (Se) and the thiocyanoacetamide (T) to reduce DOX toxicity in gonad. Adult male rats were treated with DOX intravenously (i.v.) at 3.7mg/kg/week associated with Se intragastrically (i.g.) at 0.2mg/kg/day or with T at 10mg/kg/day i.g. After 47days of treatment, sperm quality, biochemical parameters, blood cell count and histological changes in liver, testis and epididymis were assessed. The results showed a poor sperm quality, a perturbation of ionic stability and a significant alteration of lipid metabolism and hematological parameters after the sub-chronic administration of DOX. In testis, DOX exerted serious epithelium damage and numerous seminiferous tubules did not present a normal spermatogenesis. In epididymis, epithelium was altered and mastocytes infiltrated the interstitium. DOX did not exert any significant change in liver except dilatations of sinusoid capillaries. DOX association with Se or T reduced its toxicity on some hematological and biochemical parameters. Both combined treatment improved sperm quality and partially restored spermatogenesis as well as testis and epididymis' normal aspect. These findings brought new sights regarding the effect of Se and a new derivative of T in a combined treatment with DOX on germ cells, gonad and liver. The support of these relevant outcomes with further in vitro studies is necessary to highlight the accurate process involved in Se or T protection against DOX induced damages.

This study aimed to explore the analgesic, antioxidant, behavioral and toxicological effects of 3,5-diaminopyrazole and thiocyanoacetamide. Caffeine was used as reference drug whose effects are known after oral treatment with an efficient dose (10mg/kg/day) for 30days. The preliminary bioassays indicated that both compounds at this dose have strong antioxidant capacities and present highly analgesic effects. The behavioral study showed an activation of the rat memory by thiocyanoacetamide. This molecule caused a phobia state to open areas in the elevated plus maze and specifically agoraphobia in the open field with a lack in the development of the exploratory capacity. 3,5-Diaminopyrazole caused memory troubles in rats that forgot the pathway to the exit from the maze, and induced an anxiety state revealed by immobility in closed arms of the elevated plus maze. All these observations were compared to the treatment by the known analgesic, caffeine, which increased the state of vigilance of the rats and developed their exploratory capacity. The chronic treatment with the investigated compounds showed no sign of toxicity with the absence of effect on the body and organ weights, blood count, kidney and liver function and histology. 3,5-Diaminopyrazole and thiocyanoacetamide have potent antioxidant and analgesic activities that are higher than caffeine with a safety profile. The chronic treatment by thiocyanoacetamide activated the memory and caused an emotional state of agoraphobia, but 3,5-diaminopyrazole caused a memory impairment and an emotional state of anxiety. Thus, the present study warrants further investigations involving these novel molecules for a possible development of new strong analgesic and antioxidant drugs which have an effect on the memory capacity.

Oral tongue cancer remains an aggressive tumour in Tunisia, and patients often present with locally advanced disease, leading to high mortality. The molecular pathway of its tumorigenesis is not yet understood. This study aimed to assess the biologic significance of p53, heat shock protein 70 (Hsp70), Ki67, and CD34 and their influence on survival in patients with tongue cancer.Archival tissues from 68 patients with squamous cell carcinoma of the tongue were examined for p53, Hsp70, Ki67, and CD34 by immunohistochemistry and correlated with 5-year survival.p53 and Ki-67 were detected in 55% and 77% of tumours, respectively; a significant association between p53 and Ki67 expression was found (p = .038). Forty-seven percent of cases of tongue cancer expressed Hsp70, and only 9% of tumours expressed CD34 angiogenic factor. No significant correlation was noted between survival and expression of p53, Hsp70, Ki67, and CD34 in patients.None of the markers p53, Hsp70, Ki67, and CD34 demonstrated prognostic significance for 5-year survival in patients with squamous cell carcinoma of the tongue.

Aim: To investigate the effects of crude garlic on adult male rat reproductive functions. Methods: Thirty male rats were divided into five groups: group 1 (untreated) and groups 2, 3, 4 and 5 were fed for 30 days with 5%, 10%, 15% and 30% crude garlic, respectively. Testes and accessory organs were weighed and some markers were assessed. Light and electron microscopy observations were also performed. Results: A significant decrease was observed in the body weight of groups 4 (14%; P < 0.01) and 5 (20%; P < 0.01); of the prostate weight in group 5 (29.1%; P < 0.05) and of seminal vesicle weight in groups 3 (14.4%; P < 0.01), 4 (18.3%; P < 0.01) and 5 (27.3%; P < 0.01). In contrast, testis and epididymis weights were unchanged. In epididymis tissue, the alpha glucosidase activity and the spermatozoa density were unchanged. The treatment resulted in a significant decrease in testosterone serum levels in groups 3 (77.3%; P < 0.01), 4 (77.3%; P < 0.01) and 5 (90.9%; P < 0.01), associated with a significant increase in LH serum levels (P < 0.01). Testicular histology showed a dose-dependent increase in the percentage of empty seminiferous tubules. Moreover, testicular function was affected; a significant decrease in phosphatase acid activity (P < 0.01) and testosterone (P < 0.05) contents were observed. Conclusion: Crude garlic consumption during 1 month reduced testosterone secretion and altered spermatogenesis at 10%, 15% and 30% doses.

Hypoxia-inducible factor-1 (HIF1) is a master transcription factor that orchestrates the adaptation of tumor cells to hypoxia by activating the expression of a broad range of genes promoting neoangiogenesis, tumor growth, glycolysis, metastasis, and resistance to treatments. Accumulating evidence now suggests that this adaptation depends on the stabilization or the increased synthesis of the HIF1A subunit. To have a better understanding of HIF1A regulation, we focused our attention on the environmental carcinogen cadmium (Cd). Our data now challenge these hypotheses and reveal unique and opposing activities of Cd on HIF1A expression and activity. Instead of a mere action on synthesis, Cd increases by itself the stability of HIF1A protein under normoxia; independently of proteasome impairment, oxidative damage or endoplasmic reticulum stress. However, little if any HIF1A is able to translocate to the nucleus of Cd-treated cells where it activates barely HIF1 transcriptional function. Consistently, Cd dominantly inhibited hypoxia-induced HIF1 activity. Interestingly, HIF1A stabilization and inhibition of activity coincided with its association with cytosolic K63-linked ubiquitinated aggregates. We therefore propose that Cd would stabilize HIF1A but the exaggerated K63 ubiquitination would foster aggregation of HIF1A with ubiquitinated proteins, thus precluding HIF1A from interacting with its downstream nuclear targets. The unique stabilization and sequestration of HIF1A we highlighted with cadmium unravels a novel regulatory mechanism of HIF1 activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C282. Citation Format: Abderrahman Chargui, Amine Belaid, Valérie Vouret, Michel Tauc, Jacques Pouysségur, Michèle Véronique El May, Paul Hofman, Philippe Poujeol, Baharia Mograbi. The carcinogen cadmium is a HIF1A stabilizer that reduces HIF1 activity through cytosolic sequestration of HIF1A within K63-linked ubiquitinated aggregates. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C282.