Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy.

BACKGROUND: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. OBJECTIVES: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. METHODS: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. RESULTS: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: -6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. CONCLUSIONS: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786).

Mini-review highlighting toxic effects of triflumuron in insects and mammalian systems.

Pesticides have been used to kill pests such as insects, fungi, rodents, and unwanted plants. As these compounds are potentially toxic to the target organisms, they could also be harmful to human health and the environment. Several chronic adverse effects have been identified even after months or years of exposure. The adverse effects of pesticides on the agricultural ecosystem have been a matter of concern in recent decades. In this review, we present an overview of the studies, including our previous studies, monitoring currently used pesticides in the Tunisian agricultural soils that belong to the class of insect growth regulators (IGRs). Triflumuron (TFM) is a benzoyl phenyl urea insecticide belonging to the class of IGRs. TFM is widely used around the world to increase crop yield by protecting them from damage caused by insects. TFM works by inhibiting the synthesis of chitin, an essential part of the insect cuticle, making it susceptible to pathogens and deformities. Consequently, insects become more susceptible to pathogens and malformations. However, studies revealing its toxicity and its mode of action in mammalian systems remain very limited. The aim of this review is to better inform the community about the impact of TFM on crops, the environment, and human beings by summarizing its toxic effects.

The protective effects of thymol and carvacrol against di (2-ethylhexyl) phthalate-induced cytotoxicity in HEK-293 cells.

The protective effects of thymol and carvacrol, two phenolic monoterpenes with a wide spectrum of pharmacological effects, against the oxidative stress produced by the di (2-ethylhexyl) phthalate (DEHP) in human embryonic kidney cells 293 cells (HEK-293 cells) were investigated in this study. The cytotoxicity was monitored by cell viability, while oxidative stress generation was assessed by reactive oxygen species (ROS) quantification, antioxidant enzyme activities measurement, glutathione concentration, and malondialdehyde (MDA) quantification. The genotoxicity was evaluated by the measurement of DNA fragmentation through the Comet assay. Our results demonstrated that the pretreatment of HEK-293 cells with thymol or carvacrol, 2 h before DEHP exposure, significantly increased the cell viability, decreased the ROS overproduction, modulated catalase (CAT), and superoxide dismutase (SOD) activities, restored the reduced glutathione content, and reduced the MDA level. The DNA fragmentation was also decreased by thymol and carvacrol pretreatment. These findings suggest that thymol and carvacrol could protect HEK-293 cells from DEHP-induced oxidative stress.

Moringa oleifera Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis.

Moringa oleifera (MO) is a medicinal plant that has been shown to possess antioxidant, anticarcinogenic and antibiotic activities. In a rat model, MO extract (MOe) has been shown to have a protective effect against brain damage and memory decline. As an extending study, here, we have examined the protective effect of MOe against oxidative stress and apoptosis caused in human neuroblastome (SH-SY5Y) cells by di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to induce neurotoxicity. Our data show that MOe prevents oxidative damage by lowering reactive oxygen species (ROS) formation, restoring mitochondrial respiratory chain complex activities, and, in addition, by modulating the expression of vitagenes, i.e., antioxidant proteins Nrf2 and HO-1. Moreover, MOe prevented neuronal damage by partly inhibiting endoplasmic reticulum (ER) stress response, as indicated by decreased expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and Glucose-regulated protein 78 (GRP78) proteins. MOe also protected SH-SY5Y cells from DEHP-induced apoptosis, preserving mitochondrial membrane permeability and caspase-3 activation. Our findings provide insight into understanding of molecular mechanisms involved in neuroprotective effects by MOe against DEHP damage.

Tebuconazole induced oxidative stress and histopathological alterations in adult rat heart.

TEB belongs to the family of triazole fungicides and it is used to protect agricultural crop plants from fungal pathogens. The information regarding its cardiotoxic effects through different pathways particularly by perturbing the oxidative balance and causing damage to the myocardium is still limited. In the present study, oxidative and histopathologic damages caused by TEB in the cardiac tissue of male adult rats, were evaluated. Rats were exposed orally to TEB at 0.9, 9, 27 and 45 mg/kg b.w. for 28 days. Results showed that following TEB treatment malondialdehyde (MDA), protein carbonyl (PC), advanced oxidation protein product (AOPP), antioxidant enzyme activities (GPx and GR) and GSSG levels increased, while GSH levels and thus the GSH/GSSG ratio decreased. Superoxide dismutase (SOD) and catalase (CAT) initially increased at the doses of 0.9, 9 and 27 mg/kg b.w. and then decreased at the dose of 45 mg/kg b.w. Moreover, western blot analysis showed that TEB increased SOD1, CAT and HSP70 protein levels after 24 h. Furthermore, TEB induced various histological changes in the myocardium, including leucocytic infiltration, hemorrhage congestion of cardiac blood vessels and cytoplasmic vacuolization. Therefore, our investigation revealed, that TEB exhibits cardiotoxic effects by changing oxidative balance and damaging the cardiac tissue.

Oxidative stress, DNA damage and apoptosis induced by tebuconazole in the kidney of male Wistar rat.

Tebuconazole (TEB) is a broad-spectrum conazole fungicide that has been used in agriculture in the control of foliar and soil-borne diseases of many crops. The present study has investigated the adverse effects of subchronic exposure to TEB on the kidney of male rats. Animals were divided into four equal groups and treated with TEB at increasing doses 0.9, 9 and 27 mg/kg body weight for 28 consecutive days. The results showed that TEB induced oxidative stress in the kidney demonstrated by an increase in malondialdehyde (MDA), protein carbonyl (PC), advanced oxidation protein product (AOPP) levels and DNA damage, as compared to the controls. Furthermore, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities were increased in the renal tissue of treated rats. Moreover, significant decrease in reduced glutathione (GSH) content in TEB-treated rats was observed, while oxidized glutathione (GSSG) levels were increased, thus a marked fall in GSH/GSSG ratio was registered in the kidney. Glutathione reductase (GR) activity showed a significant increase after TEB exposure. Moreover, TEB down-regulated the expression of Bcl2 and up-regulated the expression of Bax and caspase 3, which triggered apoptosis via the Bax/Bcl2 and caspase pathway. Also, TEB administration resulted in altered biochemical indicators of renal function and varying lesions in the overall histo-architecture of renal tissues. Taken together, our findings brought into light the renal toxicity induced by TEB, which was found to be significant at low doses.

Effect of di(2-ethylhexyl) phthalate on Nrf2-regulated glutathione homeostasis in mouse kidney.

Environmental toxicants such as phthalate have been involved in multiple health disorders including renal diseases. Oxidative damage is implicated in many alterations caused by phthalate especially the di(2-ethylhexyl) phthalate (DEHP), which is the most useful phthalate. However, information regarding its mechanism of renal damage is lacking. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates gene expression implicated in free radical scavenging and cytoprotection including the antioxidant glutathione (GSH) pathway. The aim of this study was to assess whether DEHP affects the Nrf2 pathway and the GSH concentration. Mice were divided into four groups: a control group and three groups treated with DEHP at different concentrations (5, 50, and 200 mg/kg body weight) for 30 days. Our results showed that DEHP altered the normal levels of serum biochemical parameters creatinine (CREA), urea, and lactate dehydrogenase (LDH). This phthalate caused oxidative damage through the induction of lipid peroxidation and protein oxidation as marked by increase of protein carbonyl (PC) and loss of protein-bound sulfhydryls (PSH). Simultaneously, DEHP treatment decreased the protein level of Nrf-2, HO-1, and GCLC (responsible of GSH synthesis) and decreased the GSH level. Inhibition of the Nrf2 pathway is related to the activation of the mitochondrial pathway of apoptosis. This apoptotic process is evidenced by an upregulation of p53 and Bax protein levels in addition to a downregulation of Bcl-2. Collectively, our data demonstrated that depletion of Nrf2 and GSH was associated with the elevation of oxidative stress and the activation of intrinsic apoptosis in mouse kidney treated with DEHP.

Triflumuron induces genotoxicity in both mice bone marrow cells and human Colon cancer cell line.

Triflumuron (TFM) is an insect growth regulator (IGR), an insecticide commonly used over the world. It is known for its several toxic manifestations, such as reprotoxicity, immunotoxicity and hematotoxicity, which could affect public health. However, studies that reveal its toxic effects on mammalians are limited. To reach this purpose, our study aimed to elucidate the eventual genotoxic effects of TFM in mice bone marrow cells and in HCT 116 cells after a short term exposition. TFM was administered intraperitoneally to Balb/C male mice at doses of 250, 350 and 500 mg/kg bw for 24 h. Genotoxicity was monitored in bone marrow cells using the comet test, the micronucleus test and the chromosome aberration assay. Our results showed that TFM induced DNA damages in a dose-dependent manner. This genotoxicity was confirmed also in vitro on human intestinal cells HCT 116 using the comet test. It was then asked whether this genotoxicity induced by TFM could be due to an oxidative stress. Thus, we found that TFM significantly decreased HCT 116 cell viability. In addition, it induced the generation of reactive oxygen species (ROS) followed by lipid peroxidation as revealed by the increase in the malondialdehyde (MDA) levels. Similarly, the activation of the antioxidant enzymes (catalase and superoxide dismutase) was also observed. Our results indicated that, in our experimental conditions, TFM had a genotoxic effect on bone morrow cells and in HCT 116 cells. Moreover, we demonstrated that this genotoxicity passes through an oxidative stress.

Hericium Erinaceus Prevents DEHP-Induced Mitochondrial Dysfunction and Apoptosis in PC12 Cells.

Hericium Erinaceus (HE) is a medicinal plant known to possess anticarcinogenic, antibiotic, and antioxidant activities. It has been shown to have a protective effect against ischemia-injury-induced neuronal cell death in rats. As an extending study, here we examined in pheochromocytoma 12 (PC12) cells, whether HE could exert a protective effect against oxidative stress and apoptosis induced by di(2-ethylhexyl)phthalate (DEHP), a plasticizer known to cause neurotoxicity. We demonstrated that pretreatment with HE significantly attenuated DEHP induced cell death. This protective effect may be attributed to its ability to reduce intracellular reactive oxygen species levels, preserving the activity of respiratory complexes and stabilizing the mitochondrial membrane potential. Additionally, HE pretreatment significantly modulated Nrf2 and Nrf2-dependent vitagenes expression, preventing the increase of pro-apoptotic and the decrease of anti-apoptotic markers. Collectively, our data provide evidence of new preventive nutritional strategy using HE against DEHP-induced apoptosis in PC12 cells.

Triflumuron induces cytotoxic effects on hepatic and renal human cell lines.

Insect growth regulator insecticides are a new class of pesticides, commonly used around the world to control insect damages. Among those compounds, we focused our interest on triflumuron (TFM), which is less toxic than other conventional insecticides. However, not much is known about its toxic effects on mammalian systems. Therefore, our study aimed toward evaluating the cytotoxic and genotoxic effects of TFM using two different cell lines, the human renal embryonic cells (HEK 293) and hepatocytes (Hep G2). We showed, according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, that TFM reduced significantly the cell viability and increased the reactive oxygen species generation, malondialdehyde levels, and mitochondrial membrane potential in both cell lines. The antioxidant system was disturbed as assessed by the increased activities in both catalase and superoxide dismutase. We demonstrated also, that TFM is an inductor of DNA damages quantified by the comet assay. Moreover, we showed an overexpression of proapoptotic Bax and a decrease in antiapoptotic Bcl-2 expression. As a conclusion, we demonstrate that the liver presents the major target organ to TFM, in which the cytotoxicity and the genotoxic effects were significantly higher in hepatic cells than in renal cells and by consequence its uses must be controlled.

Tebuconazole induced cardiotoxicity in male adult rat.

Tebuconazole is an effective systemic fungicide that belongs to the triazoles family. It has been widely used in both agricultural and medical sectors for the control of fungal diseases. Although TEB poses serious threats to mammals health, studies regarding its cardiotoxicity are very limited. Thus, we aimed to evaluate the effects of TEB on some biochemical parameters, the induction of apoptosis and DNA damage in the heart tissue. Male Wistar rats were treated with TEB at varied oral doses for 28 consecutive days. This study demonstrates that TEB decreased cardiac acetylcholinesterase, increased serum marker enzymes such as creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH), and altered the lipid profile by increasing serum levels of total cholesterol (T-CHOL), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, TEB increased levels of p53 and Bax/Bcl2 ratio, released the cytochrome c into the cytosol and activated caspase-9 and caspase-3. Besides, our results showed that TEB induced genotoxic effects. TEB induced DNA fragmentation and increased the frequency of micronucleated bone marrow cells. Moreover, TEB treatment developed fibrosis in the myocardium. Our results suggest that TEB exposure may affect myocardial cells normal functioning and triggers apoptosis.

Protective effects of fennel essential oil against oxidative stress and genotoxicity induced by the insecticide triflumuron in human colon carcinoma cells.

The increased use of pesticides is the origin of multiple damages to the environment and to humans; thus, the search for new strategies to reduce or even protect the toxic effects caused by these synthetic products became a necessity. In this context, our study attempted to evaluate the protective effects of fennel essential oil (FEO), the main essential oil extracted from Faeniculum vulgare Mill., a plant with aromatic, flavorful, and medicinal uses, against toxicity induced by an insecticide-triflumuron (TFM)-in human carcinoma cells (HCT116). Our methodological approach consists of the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase (CAT) and superoxide dismutase (SOD). Also, we measured the mitochondrial transmembrane potential. The outcome of the current study showed clearly that after 2 h of HCT 116 cell pretreatment with FEO, there were increase in cell viability, reduction in ROS generation, and modulation in CAT and SOD activities induced by TFM. In the same manner, significant decreases in MDA levels were found. Mainly, the results indicated a perceptible decrease in DNA damages and a significant reduction in the mitochondrial membrane potential loss. Our work demonstrates that FEO can be an important protector against toxic effects induced by TFM in HCT 116 cells.

Di (2-ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice.

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that gives flexibility to various polyvinyl chloride products. It is a pollutant easily released into the environment and can cause many adverse effects to living organisms including hepatotoxicity. The thioredoxin system is a determining factor in the redox balance maintaining in the liver, which is a vulnerable tissue of reactive oxygen species overproduction because of its high energy needs. In order to determine if the thioredoxin system is a target in the development of DEHP hepatotoxicity, Balb/c mice were administered with DEHP intraperitoneally daily for 30 days. Results demonstrated that after DEHP exposure, biochemical profile changes were observed. This phthalate causes oxidative damage through the induction of lipid peroxydation as well as the increase of superoxide dismutase and catalase activities. As new evidence provided in this study, we demonstrated that the DEHP affected the thioredoxin system by altering the expression and the activity of thioredoxin (Trx) and thioredoxin Reductase (TrxR1). The two enzyme activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase were also affected by this phthalate. This leads to a decrease in the level of nicotinamide adenine dinucleotide phosphate used by the TrxR1 to maintain the regeneration of the reduced Trx. We also demonstrated that such effects can be responsible of DEHP-induced DNA damage.

Di(2-ethylhexyl) phthalate inhibits glutathione regeneration and dehydrogenases of the pentose phosphate pathway on human colon carcinoma cells.

Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are compounds widely used as plasticizers and have become serious global contaminants. Because of the bioaccumulation of such substances, the food chain is at risk. The food contamination by some phthalates has been linked to different side effects in experimental animals. That is why we have chosen the intestinal system's cells which represent the primary targets of these compounds to test their toxic effects. Human colon carcinoma cells (HCT 116) were chosen to elucidate whether DEHP triggers oxidative stress and apoptosis. Our results indicated that DEHP is cytotoxic; it induces the overexpression of Hsp70 protein and causes oxidative damage through the generation of free radicals leading to lipid peroxidation induction and the increase of superoxide dismutase (SOD) and catalase (CAT) activities. In addition, cell treatment with DEHP resulted in a glutathione (GSH) content decrease and a decrease in the glutathione reductase (GR) activity. As new evidence provided in this study, we demonstrated that the DEHP affected the two enzymes' activities of the oxidative phase of the pentose phosphate pathway: Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). This leads to a decrease in the level of NADPH used by the GR to maintain the regeneration of the reduced GSH. We also demonstrated that such effects can be responsible for DEHP-induced apoptosis.

Eugenol protects against citrinin-induced cytotoxicity and oxidative damages in cultured human colorectal HCT116 cells.

This study aimed to investigate the protective effects of Eugenol (EUG), an effective antioxidant phenolic compound with a radical scavenging activity against citrinin (CTN)-induced toxicity in vitro using HCT116 cells. CTN is a well-known mycotoxin found in different constituents of the food chain. This environmental contaminant produces free radicals which interacts with cellular macromolecules and produces oxidation of protein, lipid, and DNA. The cytotoxic effects were monitored by measuring cell viability, reactive oxygen species (ROS) generation, antioxidant enzyme activities, malondialdehyde (MDA) production, protein oxidation, and DNA fragmentation. Our results have shown that the pretreatment of HCT116 cells with EUG, 2 h prior to citrinin (CTN) exposure, significantly decreased CTN-induced cell death, inhibited ROS generation, modulated activities of both catalase (CAT) and superoxide dismutase (SOD), and reduced MDA production. Level of protein-bound sulfhydryls and DNA fragmentation were also declined as compared with CTN-treated cells. These findings suggest that EUG would be an effective protective agent against CTN-induced oxidative stress, and thereby, it may complement and add to the functions of antioxidant vitamins and enzymes as a protection against the cytotoxicity of this mycotoxin.

Di (2-ethylhexyl) phthalate induces cytotoxicity in HEK-293 cell line, implication of the Nrf-2/HO-1 antioxidant pathway.

The di (2-ethylhexyl) phthalate (DEHP) is a plasticizer used in the polyvinyl chloride industry. Human exposure to this plasticizer is inevitable and contributes to several side effects. In this study, we examined whether DEHP induces apoptosis and oxidative stress in embryonic kidney cells (HEK-293) and whether the nuclear factor E2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) antioxidant pathway is involved in the pathogenesis of this process. We demonstrated that DEHP is cytotoxic to HEK-293 cells. It causes oxidative damage through the generation of free radicals, induces lipid peroxidation, and alters superoxide dismutase and catalase activities. Simultaneously, DEHP treatment decreases the expression and the protein level of Nrf-2 and HO-1. Inhibition of the Nrf-2/HO-1 pathway is related to the mitochondrial pathway of apoptosis. This apoptotic process is characterized by a loss of mitochondrial transmembrane potential (ΔΨm) and upregulation of the expression of caspase-3 mRNA as well as its protein level.

GABA-containing compound gammapyrone protects against brain impairments in Alzheimer's disease model male rats and prevents mitochondrial dysfunction in cell culture.

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer's disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma-aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: "free" moiety attached to the position 4 of the 1,4-dihydropyridine (DHP) ring, and two "crypto" moieties as part of the DHP scaffold. The "free" and "crypto" GABA moieties are linked by a peptide bond (-CONH-), resulting in a peptide-mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di-2-ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA-A and GABA-B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide-like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti-dementia drugs.

Di (2-ethylhexyl) phthalate induces cardiac disorders in BALB/c mice.

Because of the extensive use of phthalates for domestic, medical, and industrial applications, the evaluation of their toxic effects is of major concern to public health. The aim of the present study was to assess the propensity of di (2-ethylhexyl) phthalate (DEHP), one of the most used phthalates, to cause oxidative cardiac damage in mice. DEHP was administered intraperitoneally at doses of 5, 50, and 200 mg/kg body weight for 30 consecutive days in BALB/c mice. We assessed the effect of DEHP on cardiac injury using biochemical profile (such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), total cholesterol (T-CHOL), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)), parameters related to myocardiac oxidative stress, such as malondialdehyde (MDA) level, protein carbonyl (PC) concentration, and DNA fragmentation. In addition, we evaluated antioxidant status; enzymatic (catalase (CAT) and superoxide dismutase (SOD) activities) and non-enzymatic (protein-bound sulfhydryl concentration (PSH)) antioxidants. Acetylcholinesterase (AChE) activity and histopathological changes were also assessed in heart mice treated with DEHP. Our results showed that DEHP induced an elevation of serum marker enzymes and perturbated the lipid profile. In addition, this phthalate increased lipid peroxidation, protein carbonyl levels, and DNA fragmentation in the heart in a dose-dependent manner. Antioxidant status was also perturbated by the increase of the CAT and SOD activities and the decrease of the protein-bound sulfhydryl concentration. AChE activity was also inhibited in the heart following the treatment with DEHP. These biochemical alterations were also confirmed by histopathological changes. Increased free radical production at various doses of DEHP would result in impairment of the redox status leading to an enhanced dose-dependent cardiotoxicity.

Acute triflumuron exposure induces oxidative stress responses in liver and kidney of Balb/C mice.

Triflumuron (TFM) is one of the most widely used insecticides over the world. It is a benzoylphenyl urea that belongs to the class of insect growth regulators. This insecticide acts by inhibiting insect's chitin synthesis and by consequences, making insect more susceptible to pathogens and malformations. TFM effects have been reported in mammalians and crops. However, studies that reveal its toxicity mechanisms are limited. In this line, the current study aimed to determine the implication of oxidative stress in the toxicity induced by TFM and particularly in the perturbation of biochemical parameters in male Balb/C mice. Male Balb/C mice were divided into three groups receiving TFM at doses of 250, 350, and 500 mg/kg bw respectively. The occurrence of oxidative stress in both kidney and liver tissues was monitored by measuring of oxidative stress markers. TFM caused an increase as protein carbonyls generation, malondialdehyde induction (MDA) and catalase (CAT), superoxide dismutase (SOD), glutathion peroxidase (Gpx), as well as glutathion S transferase (GST) activities. In the same conditions, we have evaluated the effect of TFM treatment on biochemical parameters. In response to the three TFM doses, we showed significant dose dependent inductions in all tested oxidative stress markers. However, TFM caused an increase in the liver enzyme activities as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), g-glutamyltranspeptidase (GTT), and total bilirubin (BILT) in a dose-dependent manner. Equally, renal markers as urea, uric acid, albumin, and creatinine were increased in the same manner. We can conclude that oxidative damage seems to be a key determinant of TFM-induced toxicity in both liver and kidney of male Balb/C mice. Moreover, the oxidative stress is more pronounced in the liver than in the kidney. Thus, TFM may be considered as a hepatotoxic insecticide.

Beneficial effects of mycophenolate mofetil on cardiotoxicity induced by tacrolimus in wistar rats.

The immunosuppressive drug tacrolimus (TAC) is used clinically to reduce the rejection rate in transplant patients. TAC has contributed to an increased prevalence of cardiovascular disease in patients receiving solid organ transplantation. Mycophenolate mofetil (MMF), a potent inhibitor of de novo purine synthesis, is known to prevent ongoing rejection in combination with TAC. In the present study, we investigated the antioxidant and antigenotoxic effect of MMF on TAC-induced cardiotoxicity in rats. Oral administration of TAC at 2.4, 24, and 60 mg/kg b.w. corresponding, respectively, to 1, 10, and 25% of LD50 for 24 h caused cardiac toxicity in a dose-dependant manner. TAC increased significantly DNA damage level in hearts of treated rats. Furthermore, it increased malondialdehyde (MDA) and protein carbonyl (PC) levels and decreased catalase (CAT) and superoxide dismutase (SOD) activities. The oral administration of MMF at 50 mg/kg b.w. simultaneously with TAC at 60 mg/kg b.w. proved a significant cardiac protection by decreasing DNA damage, MDA, and PC levels, and by increasing the antioxidant activities of CAT and SOD. Thus, our study showed, for the first time, the protective effect of MMF against cardiac toxicity induced by TAC. This protective effect was mediated via an antioxidant process.