Jaouida Abdelmoula

Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion-induced liver damages and immunotoxicity in rats

AIMS Occupational exposure to organophosphate pesticides is becoming a common and increasingly alarming world-wide phenomenon. The present study is designed to investigate the preventive effect of N-acetylcysteine on malathion-induced hepatic injury and inflammation in rats. MAIN METHODS Adult male Wistar rats of body weight 200-230 g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation and N-acetylcysteine (2g/l) in drinking water for 28 days. Rats were sacrificed on the 28th day, 2h after the last administration. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate desyhdogenase), inflammation (leukocyte counts, myeloperoxidase, immunophenotyping of CD4(+) and CD8(+), interleukin-1β, interleukin-6 and interferon-γ expression) and oxidative stress (lipid peroxidation, reduced glutathione and antioxidant status) were assessed. KEY FINDINGS Malathion induced an increase in activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) percent and pro-inflammatory cytokines, when decreased antioxidant status in liver was noted. When malathion-treated rats were compared to NAC supplemented rats, leukocytosis, T cell count and IL-1β, IL-6, INF-γ expression were reduced. Furthermore, NAC restored liver enzyme activities and oxidative stress markers. SIGNIFICANCE Malathion induces hepatotoxicity, oxidative stress and liver inflammation. N-acetylcysteine showed therapeutic effects against malathion toxicity.

Association of inflammatory response and oxidative injury in the pathogenesis of liver steatosis and insulin resistance following subchronic exposure to malathion in rats.

Insulin resistance and risk of type 2 diabetes are the most important complications following exposure to organophosphorous (OPs) pesticides. Regarding the importance of liver on metabolic pathways regulation, in particular blood glucose homeostasis, we focused on liver inflammation and oxidative damages in a subchronic model of toxicity by malathion. Adult male Wistar rats of body weight 200-250g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation for 28 days. Glycemic and insulin resistance indices, markers of liver injury, markers of inflammation and oxidative stress were assessed. Malathion-treated rats showed increased glycemia, insulinemia and glycated hemoglobin level, HOMA-IR and HOMA-β indices, plasma activities of hepatocellular enzymes, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) and pro-inflammatory cytokines when decreased antioxidant status in liver was noted. Most of our study indicates that malathion promotes insulin resistance, inflammation and Hepatosteatosis in subchronic model of exposure. On the basis of biochemical and molecular findings, it is concluded that insulin resistance induced by malathion occurs through oxidative stress and related pro-inflammatory markers in a way to result in a reduced function of insulin in liver cells.

Changes in glucose metabolism and reversion of genes expression in the liver of insulin-resistant rats exposed to malathion. The protective effects of N-acetylcysteine.

Organophosphorus pesticides are known to disturb glucose homeostasis and increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on insulin signaling pathways and the protective effects of N-acetylcysteine (NAC). Malathion (200 mg/kg) and NAC (2 g/l) were administered orally to rats, during 28 consecutive days. Malathion increases plasma glucose, plasma insulin and glycated hemoglobin levels. Further, we observed an increase of insulin resistance biomarkers and a decrease of insulin sensitivity indices. The GP, GSK3β and PEPCK mRNA expressions were amplified by malathion while, the expression of glucokinase gene is down-regulated. On the basis of biochemical and molecular findings, it is concluded that malathion impairs glucose homeostasis through insulin resistance and insulin signaling pathways disruptions in a way to result in a reduced function of insulin into hepatocytes. Otherwise, when malathion-treated rats were compared to NAC supplemented rats, fasting glucose and insulin levels, as well as insulin resistance indices were reduced. Furthermore, NAC restored liver GP and PEPCK expression. N-acetylcysteine showed therapeutic effects against malathion-induced insulin signaling pathways disruption in liver. These data support the concept that antioxidant therapies attenuate insulin resistance and ameliorate insulin sensitivity.

Association of serum levels of aggrecan ARGS, NITEGE fragments and radiologic knee osteoarthritis in Tunisian patients

OBJECTIVES Proteolytic degradation of aggrecan is a hallmark of the pathology of osteoarthritis. The aim of this study was to develop enzyme-linked immunosorbent assay (ELISA) to quantify the serum levels of specific aggrecan fragments generated by aggrecanases-mediated cleavage. We investigated the relationships between these two aggrecan degradations fragments and urinary CTX-II levels. METHODS The competitive ELISAs employ a polyclonal antibody raised against the aggrecan fragments containing two neoepitopes NITEGE(373)and (374)ARGSVI. We measured serum levels of ARGSV and NITEGE in 125 women with knee osteoarthritis (mean±SD age of 53.6±7.6 years, mean±SD disease duration of 3.6±3.8 years), and 57 women age-matched controls. RESULTS Aggrecan neoepitopes assays showed an intra- and inter-assay imprecision (CV) lower than 20% for both tests and good linearity. Median serum ARGSVI (by 18%; P=0.002), and NITEGE (36.4%; P<0.001) levels were significantly decreased in patients with knee osteoarthritis compared with controls. Minimal joint space width was negatively correlated with ARGSVI (r=-0.368, P=0.04) and NITEGE (r=-0.274, P=0.038) in knee osteoarthritis patients. Median urinary CTX-II levels were significantly increased by 39.5% (P=0.001) in knee OA patients compared with controls. CONCLUSION Markers of degradation aggrecan were analyzed for the first time in an African osteoarthritis population. These markers can be used to monitor aggrecanase activity in human joint disease. Their combination with CTX-II can improve clinical investigation of patients with osteoarthritis patients.

Effects of N-acetyl-l-cysteine, in vivo, against pathological changes induced by malathion

Abstract Malathion toxicity has been related to the inhibition of acetylcholinesterase, induction of oxidative stress, liver damage and impairment of kidney function as well as hematotoxicity. N-acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the protective effect of NAC against toxic consequences of malathion exposure in Wistar rats. Malathion was given daily to rats via oral gavage and NAC in drinking water during seven days. When malathion-treated rats were compared with control, a leukocytosis and reduced hemoglobin (HGB) content were detected. Furthermore, malathion produced a significant increase in liver enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and creatinine kinase. In addition, a decrease in acid phosphatase activity, protein and globulin levels were observed in malathion-treated rats compared with control. Moreover, analyses of the mineral status showed a disturbance in calcium, magnesium, phosphore and iron contents of the malathion-treated rats. Interestingly, NAC showed therapeutic effects against malathion toxicity. Indeed, HGB content and all liver enzymes were restored to normal values. Finally, the use of NAC as therapeutic agent for only seven days during malathion exposure showed interesting results on tissues damages.

Prevalence of hemoglobin variants in a diabetic population at high risk of hemoglobinopathies and optimization of HbA1c monitoring by incorporating HPLC in the laboratory workup

Background In Tunisia, diabetes mellitus and hemoglobinopathies are major public health problems. Glycated hemoglobin (HbA1c) is recommended for long-term monitoring of diabetes mellitus, but the presence of hemoglobin variants may interfere with HbA1c measurement. The aim was to determine the prevalence of hemoglobin variants in Tunisian diabetics and optimize the monitoring of diabetics using HbA1c. Methods The study enrolled 9,792 Tunisian diabetic patients. HbA1c was measured by cation-exchange high-pressure liquid chromatography (HPLC). All the chromatograms were analyzed for the presence of Hb variants. Results We identified 228 cases (2.33%) of Hb variants with D-10 HPLC (Bio-Rad): 191 with HbA/S trait, 27 with HbA/C trait, and 10 hemoglobin variants with the mention ‘Variant-Window’ on the chromatograms and subsequently identified as HbA/S on Variant I HPLC (Bio-Rad). Thus, the prevalence of HbS was 2.05%. We did not find any homozygous variant. All HbA1c results were reported to the treating physician. Conclusions To evaluate glycated hemoglobin in populations with a high prevalence of hemoglobinopathies, we should use the HPLC method, which is easy, economical, and reliable. Based on an algorithm, hemoglobin variants visualized on HPLC should be reported to the physician to improve the management of patients.

Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat

Abstract Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

Hereditary Xanthinuria with Recurrent Urolithiasis Occurring in Infancy

Introduction: Hereditary xanthinuria, due to a purine metabolism disorder, is a rare cause of urinary lithiasis in children. Case: We report the case of a three and half-year old child, who presented recurrent urinary lithiasis that, has led to the destruction of the right kidney. Infrared spectrophotometric analysis of the calculus showed that it was composed of 100% xanthine. Laboratory tests revealed hypouricemia and hypouricosuria with elevated urinary excretion of oxypurines. These findings led to a diagnosis of hereditary xanthinuria. Conclusions: Early diagnosis of this rare disease is essential to avoid its complications. Metabolic causes must be sought in children with lithiasis.

P226 Stéatose hépatique non alcoolique et insulinorésistance chez un groupe de diabétiques de type 2 tunisiens

Objectif L’objectif de notre etude est d’estimer la frequence de la steatose hepatique chez des patients diabetiques, determiner les facteurs de risque cliniques et biologiques de la steatose hepatique et analyser sa relation avec l’insulinoresistance. Materiels et Methodes Etude prospective portant sur 110 patients diabetiques de type 2 recrutes a l’Institut National de Nutrition de Tunis. Tous les patients ont beneficie d’un examen clinique (BMI, tour de taille, masse grasse par impedancemetrie) et d’un bilan biologique : glycemie, HbA1C, insulinemie, bilan lipidique, bilan hepatique, CRP ultrasensible. L’insulinoresistance a ete evaluee par le calcul de l’indice de HOMA. La steatose hepatique a ete recherchee par echographie abdominale. Resultats la steatose hepatique est trouvee chez 60 % de la population et elle est plus frequente chez les femmes (67 % vs 56 %). Les diabetiques atteints de steatose hepatique avaient un tour de taille, un indice de masse corporelle et une masse grasse significativement plus eleves que ceux indemnes de steatose avec respectivement (p = 0,0001 ; p = 0,0001 ; p = 0,01). Les taux des triglycerides, cholesterol, ASAT, ALAT et insulinemie etaient significativement plus eleves chez les patients avec steatose hepatique. Une correlation positive entre l’insulinoresistance et la presence de steatose hepatique a ete constatee (p = 0,005). Conclusion la steatose hepatique semble correlee a l’insulinoresistance et a ses differents composants clinico biologiques.

P123 Dépistage du diabète type 2 chez le personnel paramédical de l’hôpital Charles Nicolle de Tunis

Introduction Le diabete est un probleme de sante publique, representant un cout financier important en raison du taux eleve de complications degeneratives. De ce fait son depistage revet une importance primordiale d’autant plus que cette pathologie est caracterisee par une phase asymptomatique. Le but de notre travail est d’evaluer les differentes methodes de depistage du diabete de type 2 chez une population asymptomatique. Materiels et Methodes C’est une etude prospective interessant 460 patients appartenant au personnel paramedical de l’hopital Charles Nicolle de Tunis. on a pratique un examen clinique et une mesure la glycemie au doigt (GAD). Mais 213 personnes seulement ont beneficie d’un bilan biologique comprenant une HGPO (75 g), une HbA1C et un bilan lipidique. Resultats Dans notre serie, 266 sujets ont des antecedents familiaux de diabete (57,8 %) et 10 parmi les femmes ont des antecedents de diabete gestationnel (2,9 %). Une GAD = 2 g/l est retrouvee chez 6 personnes. Une GAD entre 1,4 g/l et 2 g/l est retrouvee chez 21 personnes. Chez les sujets ayant eu une HGPO (75 g), 9 ont un diabete (4,3 %), 20 ont une intolerance au glucose (9,66 %) et 3 ont une hyperglycemie moderee a jeun -HGMJ- (1,45 %). Pour les diabetiques, 3 ont une GAD = 2 g/l, 2 ont une GAD entre 1,4 et 2 g/l et 4 ont une GAD Dans le groupe des intolerants au glucose, 4 ont une GAD entre 1,4 et 2 g/l et 16 ont une GAD Dans le groupe ayant une HGMJ, 2 ont une GAD entre 1,4 et 2 g/l et un a une GAD Conclusion Plusieurs etudes ont montre l’interet du depistage du diabete de type 2. Cependant les modalites du programme de depistage n’ont pas ete definies avec precision.