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The Juglans regia root aqueous extract (JRRAE) phytochemical variability and the investigation of their antimicrobial, antibiofilm, insecticidal, and anti-leishmanial properties were studied. As a result, the JRRAE chemical profile revealed the presence of biomolecules using UV, HPLC, and FT-IR analysis. The investigations showed marked antibacterial activities, highlighted inhibited biofilm formation, induced lethality Leishmania amazonensis promastigotes (50%), and possess an insecticidal activity at 100 µg/ml. A molecular docking study was performed against S. aureus gyrase, S. aureus tyrosyl-tRNA synthetase, human peroxiredoxin 5, cyclooxygenase-2, and trypanothione reductase and confirmed that the activities are mainly due to coumarin, epicatechin, juglone, epicatechin, and epicatechin presence, respectively. The stability of these complexes is essentially related to the strong hydrogen bonds formed between the most active compounds and the binding site amino acids. The identified compounds were found to pass the absorption, distribution, metabolism, and excretion property as well as five Lipinski’s rules with good drug-likeness and pharmacokinetic behavior. © 2023, Published with license by Taylor & Francis Group, LLC. © 2023 Ali Ellafi, Racha Farhat, Mejdi Snoussi, Emira Noumi, El Hassane Anouar, Ridha Ben Ali, Michèle Véronique El May, Sami Sayadi, Kaïss Aouadi, Adel Kadri and Sonia Ben Younes. Open Access funding provided by the Qatar National Library. Scopus

The use of doxorubicin (DOX) in clinical practice continues to be challenged by its severe toxicity. DOX cytotoxic activity is not only directed against malignant tumours, given that the treatment will damage healthy tissues as well leading to irreversible injuries. This study aimed to address the in vivo effects of DOX and its co-administration with a new analog of thioamide; thiocyanoacetamide (TA) on the germinal epithelium. Thus, male rats received either intravenous injection (iv) of 0.03 mg/kg of body weight/week, 0.9% NaCl and were regarded as the control group (CTR), treated with DOX (3.7 mg/kg/week iv), TA [10 mg/kg/day intragastrically (ig)] or a co-supplementation of DOX and TA. After 50 days, the left testes were dissected and used for toluidine blue, periodic acid-Schiff (PAS) staining (to evaluate the change in polysaccharides/glycoproteins content), and transmission electron microscopy (TEM) (to assess the morphological damages). To estimate the impact of the test compounds on mitochondrial biogenesis, the expression of NAD-dependent deacetylase sirtuin-3 (SIRT-3) and proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were evaluated by immunofluorescence. Apoptotic cells were observed using Hoechst 33324 fluorescent staining. Data showed testicular injuries in the DOX-treated group, manifested by a significant decrease in total germ cell (GC) number, alteration of Sertoli cell (SC) nucleolus, anchoring junction, along with modifications of the basement membrane (BM) regularity and increase in apoptotic cell count. Mitochondrial aspect and SIRT-3 and PGC-1α expression in the testis were unaffected by the DOX. Co-therapy increased GC number, decreased apoptotic cell count, and restored the BM and anchoring junction regular aspects. This study provides novel insights into understanding DOX-mediated impairment in rats' testis and might offer some basis for the emerging new alternative therapeutic schemes in male patients undergoing chemotherapy.

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.

The aim of this work was to synthesize a diethyl phenylcarbamothioyl phosphonate (EThmP) and evaluate its biological activities. ThmP has been prepared with high yields and its conformation was determined. This phosphonothioamidate derivative was characterized by IR, and NMR Spectroscopy (1H, 13C, and 31P). On the component of EThmP, the Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H···H (53.3%), H···O (12.9%) H···S (14.5%), and C···H (17.6%) interactions. An anti-nociceptive test (the formaline test) showed that the EThmP modulates the pain during the early and late phases proved by rat behavior characterized by absence of licking, biting and shaking of the affected paw. The modulation of pain by the EThmP may be due to its anti-inflammatory effect. The Hot Plate test showed that the pretreatment with the EThmP did not modulate the pain nociception induced by maintaining the rat at a fixed temperature of 48°C. The treated rats’ behavior was characterized by elevating, licking the paw, jumping and fleeing. EThmP did not affect the memory capacity and acetylcholinesterase activity. The morbidity of rats was normal with no mortality or sign of toxicity. The in vitro study showed that the EThmP has no antibacterial, antifungal and antioxidant activities. The EThmP has an important dose dependent anti-inflammatory activity.

The current study was aimed to evaluate the protective and curative effect of aqueous extract of edible desert truffle specie (Terfezia boudieri) against rat’s liver and kidney injuries induced by ...

Over the past decades, an increase of male infertility through the decrease of sperm count has been noted. It has been suggested that environmental factors and lifestyle could a negative impact over sperm quality. Among these factors, the consumption of foods high in fat, which leads to overweight and obesity, can negatively influence fertility. The present study was designed to highlight the protective effect of Kefir, natural probiotic, against the decline in sperm quality related to fat high diet. Thirty adult rats were divided into four groups: Control (1 ml/100 g of body weight (bw) of semi-shimmed cow milk), KM (1 ml/100 g bw of Kefir milk), HFD (1 ml/100 g bw of semi-shimmed cow milk + high-fat diet) and KM/HFD (1 ml/100 g bw Kefir milk + high-fat diet). After 60 days of treatment, sperm quality, biochemical assays of lipids profil, blood cell count and histological examination in testis were assessed. The results described an improved of sperm density (64.28 10

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.

Natural green clay is mostly used in pharmaceutical and cosmetic products. The effect of this raw material from different outcrops around the world demonstrates its beneficial role on human health. The green clay from southern Tunisia is widely used in local traditional medicine and cosmetic preparations but its biological activity in vivo has not been studied yet. For this reason, this work was interested in deciphering the properties of the Tunisian green clay such as mineralogy composition and biological effect. In fact, the mineralogical study of this green clay shows two types of clay minerals such as illite and kaolinite with proportion of 75% and 25%, respectively. In order to study the biological effect, green clay was administered orally to rats for 1 h at 50, 75, 100 and 125 mg/kg doses. After that, ethanol 95% was given to these rats to induce a gastric ulcer. Then, several parameters (e.g. Ulcer index, protective rate, mucus production gastric and mucosa histology) were measured to evaluate the gastroprotective activity. The histology study shows normal gastric mucosa in rats pretreated at 75, 100 and 125 mg/kg doses and the decrease of Ulcer Index (%I = 97%) and lesions areas. The oral administing mixture of Tunisian green clay with ethanol in rats induces severe mucosal lesion and hemorrhagic bands. This clay colored by methylene blue shows that clay was linked to the mucus excreted by the stomach surface. The green clay didn't neutralize ethanol gastro toxicity and formed a layer on the gastric mucosa to protect it by a mechanical action. When investigated on rats at an effective dose treatment (75 mg/kg) for 30 days, the subchronic toxicity test of green clay did not reveal any signs of mortality and toxicity, and it demonstrated the normal hematological and biochemical parameters of rats. Thus, the Tunisian green clay can be considered as a safe natural product since it has a potential gastroprotective activity on ethanol induced gastric mucosal lesions in rats.

A series of phosphonoamidates and phosphonoamidines derivatives have been prepared with high yields and their conformations were determined. All compounds were characterized by IR, NMR Spectroscopy (1H, 13C, and 31P) and in some cases by elemental analysis and evolution study by 31P-NMR in an external lock with D2O. A DFT calculations studies was performed to identify the stability of all forms (Cis and Trans) (Syn and Anti) at the B3LYP/6-311G** level. The most stable geometry with an Anti-conformation. A comparison with the experimental results validates the level of theory. The biological activity of dimethyl cyclohexyl carbamoylphosphonate (MAmP) and diethyl cyclohexyl carbamoylphosphonate (EAmP) was evaluated. Only the association of ethyl group with phosphorus in amide gives antimicrobial capacity against S. aureus. The evaluation of the analgesic activity following a thermal stimulus showed that the rats treated with the MAmP do not present any sensation of pain. The MAmP molecule had a dose-dependent significant analgesic activity comparable to morphine effect. The hot plate test showed that the EAmP had a significant analgesic effect less than morphine and MAmP. The new compounds at low dose treatment cause an increase in the sensation of pain following a chemical stimulation that induces inflammation. So the EAmP and the MAmP can be morphemic molecules. The morphine mediates a proinflammatory phenotype and induces hyperalgesia. The MAmP was characterized by analgesic activity comparable to morphine and the EAmP was characterized by specific antimicrobial activity against S. aureus.

The crystal structure of dimethylphenylcarbamothioylphosphonate (MThmP) was obtained by reacting via one-pot synthesis without solvent at room temperature. The crystal structure of MThmP was determined by X-ray analysis (XRD). Two forms (a & b) were showed on the component MThmP which was crystallized in the monoclinic system with P21/c space group. In the first molecule (Form a), the Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H⋯H (40.6%), H⋯O (24.6%)and C⋯H (18.4%) interactions. In the second crystal (Form b), the Hirshfeld surface analysis indicates the different percentage interactions: H⋯H (43.1%), H⋯O (23.3%) and C⋯H (17.8%) interactions. A DFT calculation study was performed to identify the stability of the two structures. A Fukui functions, electrostatic potential surfaces and LUMO-HOMO energy were computed in this work. Geometries of reactants, transition states and products were optimized at the B3LYP/6-311+G(d,p) level. The nucleophilic and electrophilic binding site regions were elucidated using the molecular electrostatic potential (MEP). The pharmacological studies showed that MThmP gives a significant analgesic effect less than morphine with aggravation of inflammatory state. In addition, MThmP had a potential antioxidant activity.

Doxorubicin (DOX) exhibits a wide-ranging spectrum of antitumor activities which maintain its clinical use despite its devastating impact on highly proliferating cells. The present work was designed to develop a new approach which aims to protect male germ cells from DOX cytotoxicity. Thus, an assessment of the protective potential of a new thioamide analog (thiocyanoacetamide; TA) compared to selenium (Se) was performed in rat sperms exposed to DOX in vitro. Oxygen consumption rate (OCR) was measured after exposure to three different doses (0.5, 1, 1.5 and 2 μM) of DOX, Se or TA, and the suitable concentrations were selected for further studies afterwards. Motility, OCR in a time-dependent manner, glucose extracellular concentration and lipid peroxidation (LPO) were measured. Fatty acid (FA) content was assessed by gas chromatography (GC-FID). Cell death, superoxide anion (O2 −), mitochondrial membrane potential (MMP), and DNA damage were evaluated by flow cytometry. TA association with DOX increased OCR and glucose uptake, improved cell survival and decreased DNA damage. The co-administration of DOX with Se increased OCR, significantly prevented O2 − overproduction, and decreased LPO. Collected data brought new insights regarding this transformed TA, which showed better efficiency than Se in reducing DOX cytotoxic stress in sperms.

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.

Thioamides (Thm) have diverse biological activities. This work presents the development and validation of simple, rapid and accurate spectrophotometric method for the analysis of Thm derivatives in pure form and in plasma. This spectrophotometric method has not been used before for determination of Thm. A review of the literature revealed that the monitoring of S− group assay is based on the reaction with DTNB according to the Ellman method to form a yellow complex which absorbs at 412 nm. To assay the thioamides according to this method it is necessary to make the basic medium have S− to react with the DTNB. Experimental conditions affecting the color development were studied and optimized. The proposed spectrophotometric procedures were effectively validated with respect to linearity, ranges, precision, accuracy, specificity, robustness, detection and quantification limits. Calibration curves of the formed colored product with DTNB showed good linear relationships over the concentration ranges (0, 50, 100, 500, 1000, 1500 mg/L). The proposed method was successfully applied to the assay of Thm monitoring with good accuracy. The principal advantages of the proposed method were rapidity and suitability for the routine quality control assay of the drug alone and in monitoring form without interference.

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.

Summary Aims The objective of this study was to compare the protein expression profile between well-differentiated (papillary) and undifferentiated (anaplastic) thyroid carcinoma in Tunisian patients. Methods This first Tunisian retrospective study concerned data of 38 thyroid cancer cases (19 papillary carcinoma PTC and 19 anaplastic carcinoma ATC) collected at Salah Azaiez Institute of Tunisia. Immunohistochemistry was used to evaluate tumor expression of different molecular markers (p53, Ki67, E-cadherin, cyclin D1, bcl2, S100 and Her-2). The molecular expression was correlated with the clinicopathological characteristics of the tumors. Results There were 6 differentially expressed markers when comparing anaplastic thyroid carcinoma ATC with papillary thyroid carcinoma PTC. Expression of p53 and Ki67 were significantly increased in 16 and 18 ATC cases respectively, the Ki67 expression was lost in PTC. Cyclin D1, E-cadherin, bcl2 and S100 were overexpressed in PTC tumors; however, they were significantly decreased in ATC. The last marker, Her-2 was expressed in one case of PTC only. Conclusion Our results, similar with findings of other ethnic groups, showed alteration in expression of molecular markers associated with tumor dedifferentiation, indicating loss of cell cycle control with increased proliferative activity in ATC carcinoma. These data support the hypothesis that ATC may derive from dedifferentiation of preexisting PTC tumor.

Neutrophils constitute the first line of cellular defense against pathogens and autophagy is a fundamental cellular homeostasis pathway that operates with the intracellular degradation/recycling system. Induction of the autophagic process in neutrophils, in response to invading pathogens, constitutes a crucial mechanism in innate immunity. Exploration of autophagy has greatly progressed and diverse strategies have been reported for studying this molecular process in different biological systems; especially in infectious and inflammatory diseases. Furthermore, the role of autophagy in neutrophils, during pathogenic infection, continues to be of interest, due to the role of the cell in immunity function, its recruitment to the site of infection and its implication in inflammatory diseases. This review focuses on the known role of autophagy in neutrophils defence against pathogenic infections. A more detailed discussion will concern the recent findings highlighting the role of autophagy in inflammation and cell death in infected neutrophils.

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.