Scopolamine-Induced Memory Impairment in Mice: Effects of PEA-OXA on Memory Retrieval and Hippocampal LTP.

Transient global amnesia, both persistent and transient, is a very common neuropsychiatric syndrome. Among animal models for amnesia and testing new drugs, the scopolamine test is the most widely used for transient global amnesia (TGA). This study examined the scopolamine-induced deficits in working memory, discriminative memory, anxiety, and motor activity in the presence of intranasal PEA-OXA, a dual antagonist of presynaptic α2 and H3 receptors. Male C57BL/6 mice were treated with intraperitoneal scopolamine (1 mg/kg) with or without pre-treatment (15 min) or post-treatment (15 min) with intranasal PEA-OXA (10 mg/kg). It was seen that scopolamine induced deficits of discriminative and spatial memory and motor deficit. These changes were associated with a loss of synaptic plasticity in the hippocampal dentate gyrus: impaired LTP after lateral entorhinal cortex/perforant pathway tetanization. Furthermore, hippocampal Ach levels were increased while ChA-T expression was reduced following scopolamine administration. PEA-OXA either prevented or restored the scopolamine-induced cognitive deficits (discriminative and spatial memory). However, the same treatment did not affect the altered motor activity or anxiety-like behavior induced by scopolamine. Consistently, electrophysiological analysis showed LTP recovery in the DG of the hippocampus, while the Ach level and ChoA-T were normalized. This study confirms the neuroprotective and pro-cognitive activity of PEA-OXA (probably through an increase in the extracellular levels of biogenic amines) in improving transient memory disorders for which the available pharmacological tools are obsolete or inadequate and not directed on specific pathophysiological targets.

VISTA+/CD8+ status correlates with favorable prognosis in Epithelial ovarian cancer.

Immunotherapy by blocking immune checkpoint regulators has emerged as a new targeted therapy for some cancers. Among them V-domain Ig suppressor of Tcell activation (VISTA) which is identified as a novel checkpoint regulator in ovarian cancer. This study aimed to investigate the VISTA role in Epithelial ovarian cancer (EOC), and its relationship with tumor-infiltrating lymphocytes (TILs) markers and its prognostic value. The expression of VISTA, CD3, CD8, CD4, FOXP3, and CD56 was assessed in 168 EOC tissue microarrays (TMA) by immunohistochemistry (IHC). In addition, associations between VISTA, TILs, clinicopathological variables, and overall survival (OS) were analyzed. VISTA expression in IGRov1 cells, as well as in PBMC of EOC patient, was evaluated by western blot. VISTA expression was detected in 64,28% of tissues, among which 42.3% were positive for tumor cells (TCs), and 47,9% were positive for immune cells (ICs). In univariate analysis, VISTA expression was significantly associated with a high density of TILs:CD3+ (p = 0,001), CD4+ (p = 0,002) and CD8+ (p≤0,001), in ICs but not in TCs. In terms of OS, multivariate analysis showed a significant association between the high density of CD8+ TILs and VISTA positive staining in ICs (p = 0,044), but not in TCs (p = 0,108). Kaplan-Meier curves demonstrated no correlation between VISTA expression and prolonged OS in both ICs (p = 0,841) and TCs (p = 0,090). Classification of EOC tumor microenvironment based on VISTA and CD8+TILs expression, demonstrated four immune subtypes: VISTA+/CD8+, VISTA+/CD8-, VISTA-/CD8+ and VISTA-/CD8-. The dual positive VISTA+/CD8+ subtype was significantly associated with prolonged OS in both TCs and ICs (p = 0,012 and p≤0,01, respectively), whereas patients with VISTA+/CD8- had the worst OS. Our results showed that VISTA is highly expressed in the IGRov1 cell line and LT-CD8 from a patient with EOC. Our results highlighted the association of VISTA expression and CD8+ TILs in EOC, with prolonged OS in patients with VISTA+/CD8+ and proposed VISTA as a potential immunotherapeutic target in EOC.

Synthesis, Photophysical Characterization and Evaluation of Biological Properties of C7, a Novel Symmetric Tetra-Imidazolium-Bis-Heterocycle.

A novel symmetric tetra-imidazolium-bis-heterocycle, called C7, was designed and synthesized in a quick two-step pathway, with the objective to synthesize biologically active supramolecular assembly. The synthesized compound was then analyzed for its photophysical properties, for a potential application in theragnostic (fluorescence) or phototherapy (photodynamic therapy, with the production of reactive oxygen species, such as singlet oxygen 1O2). C7 was thus screened for its biological activity, in particular against important human pathogens of viral origin (respiratory viruses such as adenovirus type 2 and human coronavirus 229E) and of fungal and bacterial origin. The compound showed limited antiviral activity, combined with very good antiproliferative activity against breast cancer, and head and neck squamous cell carcinoma models. Interestingly, the selected compound showed excellent antibacterial activity against a large array of Gram-positive and Gram-negative clinically isolated pathogenic bacteria, with a possible inhibitory mechanism on the bacterial cell wall synthesis studied with electron microscopy and molecular docking tools. Collectively, the newly synthesized compound C7 could be considered as a potential lead for the development of new antibacterial treatment, endowed with basic photophysical properties, opening the door towards the future development of phototherapy approaches.

New Specific α-Glucosidase Inhibitor Flavonoid from Thymelaea tartonraira Leaves: Structure Elucidation, Biological and Molecular Docking Studies.

The phytochemical investigation of Thymelaea tartonraira leaves led to the isolation and characterization of six compounds, including one new flavonoid glycoside identified as hypolaetin 8-O-ß-D-galactopyranoside (4) along with five known compounds, daphnoretin (1), triumbelletin (2), genkwanin (3), tiliroside (5) and yuankanin (6). Their structures were established based on spectroscopic methods, such as UV, IR, NMR, and HR-ESI-MS. Triumbelletin (2) and tiliroside (5) were isolated for the first time from T. tartonraira leaves. The antioxidant property of all isolated compounds was tested based on DPPH, FRAP and total antioxidant capacity assays. Compound 4 displayed an antioxidant potency more interesting than vitamin C with an IC50 =15.00±0.50 µg/ml, followed by compound 5. Furthermore, the both compounds 4 and 5 were tested for their α-amylase inhibitory activity in-vitro. Compound 4 displayed higher potency to inhibit α-amylase, with an IC50 =46.49±2.32 µg/ml, than compound 5, with an IC50 =184.2±9.2 µg/ml, while the reference compound acarbose presented the highest potency to inhibit α-amylase with an IC50 =0.44±0.022 µg/ml. Compound 4 displayed a strong inhibitory ability of α-glucosidase activity approximately twice more than the reference compound, acarbose, with IC50 values of 60.00±3.00 and 125.00±6.25 µg/ml, respectively. Thus, compound 4 exhibited a specific inhibitory activity for α-glucosidase. The molecular docking studies have supported our findings and suggested that compound 4 has been involved in various binding interactions within the active site of both enzymes α-amylase and α-glucosidase.

PpSP32, the Phlebotomus papatasi immunodominant salivary protein, exerts immunomodulatory effects on human monocytes, macrophages, and lymphocytes.

BACKGROUND: The saliva of sand flies, vectors of Leishmania parasites, contains several components that exert pharmacological activity facilitating the acquisition of blood by the insect and contributing to the establishment of infection. Previously, we demonstrated that PpSP32 is the immunodominant salivary antigen in humans exposed to Phlebotomus papatasi bites and validated its usefulness as a predictive biomarker of disease. PpSP32, whose functions are little known to date, is an intriguing protein due to its involvement in the etiopathogenesis of pemphigus, an auto-immune disease. Herein, we aimed to better decipher its role through the screening of several immunomodulatory activity either on lymphocytes or on monocytes/macrophages. METHODS: Peripheral mononuclear cells from healthy volunteers were stimulated with anti-CD3/anti-CD28 antibodies, phytohemagglutinin, phorbol 12-myristate 13-acetate/ionomycin, or lipopolysaccharide in the presence of increasing doses of PpSP32. Cell proliferation was measured after the addition of tritiated thymidine. Monocyte activation was tested by analyzing the expression of CD86 and HLA-DR molecules by flow cytometry. Cytokine production was analyzed in culture supernatants by ELISA. THP-1-derived macrophages were stimulated with LPS in the presence of increasing doses of PpSP32, and cytokine production was analyzed in culture supernatants by ELISA and multiplex technique. The effect of PpSP32 on NF-kB signaling was tested by Western blot. The anti-inflammatory activity of PpSP32 was assessed in vivo in an experimental inflammatory model of carrageenan-induced paw edema in rats. RESULTS: Our data showed that PpSP32 down-modulated the expression of activation markers in LPS-stimulated monocytes and THP1-derived macrophages. This protein negatively modulated the secretion of Th1 and Th2 cytokines by human lymphocytes as well as pro-inflammatory cytokines by monocytes, and THP1-derived macrophages. PpSP32 treatment led to a dose-dependent reduction of IκB phosphorylation. When PpSP32 was injected into the paw of carrageenan-injected rats, edema was significantly reduced. CONCLUSIONS: Our data indicates that PpSP32 induces a potent immunomodulatory effect on monocytes and THP-1-derived macrophages. This inhibition could be mediated, among others, by the modulation of the NF-kB signaling pathway. The anti-inflammatory activity of PpSP32 was confirmed in vivo in the carrageenan-induced paw edema model in rats.

MARCKS as a Potential Therapeutic Target in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer (BC). We previously demonstrated that protein overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein was associated with shorter survival in IBC patients. MARCKS has been associated with the PI3K/AKT pathway. MARCKS inhibitors are in development. Our objective was to investigate MARCKS, expressed preferentially in IBC that non-IBC (nIBC), as a novel potential therapeutic target for IBC. The biologic activity of MPS, a MARCKS peptide inhibitor, on cell proliferation, migration, invasion, and mammosphere formation was evaluated in IBC (SUM149 and SUM190) and nIBC (MDA-MB-231 and MCF7) cell lines, as well as its effects on protein expression in the PTEN/AKT and MAPK pathways. The prognostic relevance of MARCKS and phosphatase and tensin homolog (PTEN) protein expression as a surrogate marker of metastasis-free survival (MFS) was evaluated by immunohistochemistry (IHC) in a retrospective series of archival tumor samples derived from 180 IBC patients and 355 nIBC patients. In vitro MPS impaired cell proliferation, migration and invasion, and mammosphere formation in IBC cells. MARCKS inhibition upregulated PTEN and downregulated pAKT and pMAPK expression in IBC cells, but not in nIBC cells. By IHC, MARCKS expression and PTEN expression were negatively correlated in IBC samples and were associated with shorter MFS and longer MFS, respectively, in multivariate analysis. The combination of MARCKS-/PTEN+ protein status was associated with longer MFS in IBC patient only (p = 8.7 × 10-3), and mirrored the molecular profile (MARCKS-downregulated/PTEN-upregulated) of MPS-treated IBC cell lines. In conclusion, our results uncover a functional role of MARCKS implicated in IBC aggressiveness. Associated with the good-prognosis value of the MARCKS-/PTEN+ protein status that mirrors the molecular profile of MPS-treated IBC cell lines, our results suggest that MARCKS could be a potential therapeutic target in patients with MARCKS-positive IBC. Future preclinical studies using a larger panel of IBC cell lines, animal models and analysis of a larger series of clinical samples are warranted in order to validate our results.

Dual Mechanism of Action of Curcumin in Experimental Models of Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is characterized by a combination of inflammatory and demyelination processes in the spinal cord and brain. Conventional drugs generally target the autoimmune response, without any curative effect. For that reason, there is a great interest in identifying novel agents with anti-inflammatory and myelinating effects, to counter the inflammation and cell death distinctive of the disease. METHODS AND RESULTS: An in vitro assay showed that curcumin (Cur) at 10 µM enhanced the proliferation of C8-D1A cells and modulated the production of Th1/Th2/Th17 cytokines in the cells stimulated by LPS. Furthermore, two in vivo pathophysiological experimental models were used to assess the effect of curcumin (100 mg/kg). The cuprizone model mimics the de/re-myelination aspect in MS, and the experimental autoimmune encephalomyelitis model (EAE) reflects immune-mediated events. We found that Cur alleviated the neurological symptomatology in EAE and modulated the expression of lymphocytes CD3 and CD4 in the spinal cord. Interestingly, Cur restored motor and behavioral deficiencies, as well as myelination, in demyelinated mice, as indicated by the higher index of luxol fast blue (LFB) and the myelin basic protein (MBP) intensity in the corpus callosum. CONCLUSIONS: Curcumin is a potential therapeutic agent that can diminish the MS neuroimmune imbalance and demyelination through its anti-inflammatory and antioxidant effects.

Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats.

Natural polyphenols are widely reported to have a large range of pharmacological properties, especially antioxidant activities and free radical scavenging capacities. In this study, we investigate the effects of naringin, chlorogenic acid, and quercetin mixtures (NCQ) on renal fibrosis in streptozotocin (STZ)-induced diabetic aged rats and its underlying mechanisms for ten consecutive weeks. The oxidative defense system in the kidneys of treated rats was found to be improved. Several biomarkers were investigated including the blood urea nitrogen, creatinine, and uric acid. Moreover, antioxidant parameters were evaluated and we found that superoxide dismutase, catalase, glutathione peroxidase, Na+-K+-ATPase activities, the nitric oxide production, the protein carbonyl, the advanced oxidation protein products, lipid peroxidation, and reduced glutathione levels were all significantly balanced and close to control values. In addition, NCQ restored renal injuries and fibrosis as assessed by histological method and molecular biology investigation of the matrix metalloproteinase, the transforming growth factor-beta TGF-ß, the tumor necrosis factor TNFα, and p53 expression. Our study proposes the NCQ combination as potential plant-derived bioactive compounds to prevent diabetic nephropathy.

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide.

Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC50 value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.

Tunisian Native Mentha pulegium L. Extracts: Phytochemical Composition and Biological Activities.

Mint species (Lamiaceae family) have been used as traditional remedies for the treatment of several diseases. In this work, we aimed to characterize the biological activities of the total phenolic and flavonoid contents of Mentha pulegium L. extracts collected from two different regions of Tunisia. The highest amounts of total phenols (74.45 ± 0.01 mg GAE/g DW), flavonoids (28.87 ± 0.02 mg RE/g DW), and condensed tannins (4.35 ± 0.02 mg CE/g DW) were found in the Bizerte locality. Methanolic leaf extracts were subjected to HPLC-UV analysis in order to identify and quantify the phenolic composition. This technique allowed us to identify seven phenolic compounds: two phenolic acids and five flavonoid compounds, such as eriocitrin, hesperidin, narirutin, luteolin, and isorhoifolin, which were found in both extracts with significant differences between samples collected from the different regions (p < 0.05). Furthermore, our results showed that the methanolic extract from leaves collected from Bizerte had the highest antioxidant activities (DPPH IC50 value of 16.31 µg/mL and 570.08 µmol Fe2+/g, respectively). Both extracts showed high radical-scavenging activity as well as significant antimicrobial activity against eight tested bacteria. The highest antimicrobial activities were observed against Gram-positive bacteria with inhibition zone diameters and MIC values ranging between 19 and 32 mm and 40 and 160 µg/mL, respectively. Interestingly, at 10 µg/mL, the extract had a significant effect on cell proliferation of U87 human glioblastoma cells. These findings open perspectives for the use of Mentha pulegium L. extract in green pharmacy, alternative/complementary medicine, and natural preventive therapies for the development of effective antioxidant, antibacterial, and/or antitumoral drugs.

Pharmacological Investigation of CC-LAAO, an L-Amino Acid Oxidase from Cerastes cerastes Snake Venom.

Snake venom proteins, which are responsible for deadly snakebite envenomation, induce severe injuries including neurotoxicity, myotoxicity, cardiotoxicity, hemorrhage, and the disruption of blood homeostasis. Yet, many snake-venom proteins have been developed as potential drugs for treating human diseases due to their pharmacological effects. In this study, we evaluated the use of, an L-amino acid oxidase isolated from Cerastes cerastes snake venom CC-LAAO, as a potential anti-glioblastoma drug, by investigating its in vivo and in vitro pharmacological effects. Our results showed that acute exposure to CC-LAAO at 1 and 2.5 µg/mL does not induce significant toxicity on vital organs, as indicated by the murine blood parameters including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) activities, and creatinine levels. The histopathological examination demonstrated that only at high concentrations did CC-LAAO induce inflammation and necrosis in several organs of the test subjects. Interestingly, when tested on human glioblastoma U87 cells, CC-LAAO induced a dose-dependent apoptotic effect through the H2O2 generated during the enzymatic reaction. Taken altogether, our data indicated that low concentration of CC-LAAO may be safe and may have potential in the development of anti-glioblastoma agents.

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl3), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.

Does coronaviruses induce neurodegenerative diseases? A systematic review on the neurotropism and neuroinvasion of SARS-CoV-2.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 in Wuhan, China. Clinically, respiratory tract symptoms as well as other organs disorders are observed in patients positively diagnosed coronavirus disease 2019 (COVID-19). In addition, neurological symptoms, mainly anosmia, ageusia and headache were observed in many patients. Once in the central nervous system (CNS), the SARS-CoV-2 can reside either in a quiescent latent state, or eventually in actively state leading to severe acute encephalitis, characterized by neuroinflammation and prolonged neuroimmune activation. SRAS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2) as a cell entry receptor. The expression of this receptor in endothelial cells of blood-brain barrier (BBB) shows that SRAS-CoV-2 may have higher neuroinvasive potential compared to known coronaviruses. This review summarizes available information regarding the impact of SRAS-CoV-2 in the brain and tended to identify its potential pathways of neuroinvasion. We offer also an understanding of the long-term impact of latently form of SARS-CoV-2 on the development of neurodegenerative disorders. As a conclusion, the persistent infection of SRAS-CoV-2 in the brain could be involved on human neurodegenerative diseases that evolve a gradual process, perhapes, over several decades.

Neuroprotective effects of curcumin against acetamiprid-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: biochemical, histological, and behavioral changes.

Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. This study aimed to investigate the effect of curcumin on neurobehavioral and neuropathological alterations induced by acetamiprid on male rats. Three groups of ten male Wistar rats each were used for the study: the first was a control group (CTR) that did not consume acetamiprid (ACE); the second was an experimental group (ACE) that consumed 40 mg/kg body weight/day of acetamiprid; and the third group (CUR) received curcumin (100 mg/kg) and acetamiprid (40 mg/kg) in combination. Neurobehavioral evaluations including inclined plane performance and forepaw grip time were studied. Treatment with CUR significantly prevented ACE-treated rats from impairments in the performance of neurobehavioral tests, indicating the presence of deficits on sensorimotor and neuromuscular responses. In addition, Curcumin administration protects rats against acetamiprid-induced cerebellum toxicity such as increase in AChE and BChE activities, decrease on cells viability, oxidative stress, and an increase of intracellular calcium. Taken together, these results demonstrate for the first time that ACE treatment substantially impairs the survival of primary neuronal cells through the induction of necrosis concomitantly with the generation of an oxidative stress. Additionally, curcumin reduced histopathological changes caused by ACE.

Specific immune responses in mice following subchronic exposure to acetamiprid.

AIMS: Acetamiprid (ACE) is an insecticide of the neonicotinoid family, the most widely used in the world. Herein, we assessed the effect of ACE on either the humoral or cellular immune responses of rodents. We also evaluated the role of curcumin in the restoration of altered immune responses after ACE treatment. METHODS: Five groups of five Swiss Albino mice were immunized intraperitoneally with the recombinant form of CFP32, a virulence factor of Mycobacterium tuberculosis. One group received ACE (5mg/kg) during 61days, a second one received ACE associated with curcumin (100mg/kg). Three control groups were included; one untreated, the second received corn oil and the third received curcumin alone. The humoral immune response was assessed by ELISA testing the anti-rCFP32 antibody concentrations in the serum. The cellular immune response was assessed by analyzing the cellular proliferation of the splenocytes stimulated in vitro by a mitogen or rCFP32. RESULTS: The ACE-treated mice showed a significant immunosuppression of the specific humoral response with a restorative effect of curcumin when administered with ACE. Similarly, ACE significantly decreased the level of splenocyte proliferation after either a non specific or a specific activation. Curcumin partially restores the antigen specific cellular immune response. Moreover, when administered alone, curcumin significantly inhibits the proliferative responses to the mitogen confirming its anti-mitogenic effect. Histological analysis showed alteration of spleens of mice exposed to ACE. SIGNIFICANCE: Altogether, our data indicated that ACE could potentially be harmful to the immune system.

From immunotoxicity to carcinogenicity: the effects of carbamate pesticides on the immune system.

The immune system can be the target of many chemicals, with potentially severe adverse effects on the host's health. In the literature, carbamate (CM) pesticides have been implicated in the increasing prevalence of diseases associated with alterations of the immune response, such as hypersensitivity reactions, some autoimmune diseases and cancers. CMs may initiate, facilitate, or exacerbate pathological immune processes, resulting in immunotoxicity by induction of mutations in genes coding for immunoregulatory factors and modifying immune tolerance. In the present study, direct immunotoxicity, endocrine disruption and inhibition of esterases activities have been introduced as the main mechanisms of CMs-induced immune dysregulation. Moreover, the evidence on the relationship between CM pesticide exposure, dysregulation of the immune system and predisposition to different types of cancers, allergies, autoimmune and infectious diseases is criticized. In addition, in this review, we will discuss the relationship between immunotoxicity and cancer, and the advances made toward understanding the basis of cancer immune evasion.

A minireview on N-acetylcysteine: An old drug with new approaches.

N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of toxicity-induced by pesticides. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against oxidative stress caused by pesticide in many organs. The possible mechanisms of action may be associated to its antioxidant properties. The anti-oxidative activity of NAC has been attributed to the fast reaction with free radicals as well as the restitution of reduced glutathione (GSH).

Comparison between electronic cigarette refill liquid and nicotine on metabolic parameters in rats.

AIMS: Nicotine is known to promote body weight loss and to disturb glucose homeostasis and lipoprotein metabolism. Electronic cigarettes, as a substitute to nicotine, are becoming increasingly popular, although there is no evidence regarding their safety. Considering the dearth of information about e-cigarette toxicity, the present study was designed to compare nicotine alone to e-liquid with or without nicotine on metabolic parameters in Wistar rats. MAIN METHODS: For this purpose, e-liquid with or without nicotine and nicotine alone (0.5mg/kg of body weight) were administered intra-peritoneally during 28 days. KEY FINDINGS: Our results show a significant decrease in food and energy intake after nicotine or e-liquid with nicotine exposure, when compared to control or e-liquid without nicotine. Analysis of lipid status identified a significant decrease in cholesterol and LDL levels in e-cigarette groups, suggesting an improvement in lipid profile. Interestingly, e-liquid without nicotine induced hyperglycemia which is negatively correlated to hepatic glycogen level, acting like nicotine alone. Furthermore, an increase in liver biomarkers was observed in all treated groups. qRT-PCR analysis showed GSK3ß up-regulation in e-liquid with nicotine as well as, surprisingly, in e-liquid without nicotine exposure. In contrast, PEPCK genes were only up-regulated in e-liquid with nicotine. SIGNIFICANCE: While some features observed in rats may not be observed in human smokers, most of our data are consistent with, e-liquid per se i.e. without nicotine, not being neutral from a metabolic stand point since disrupting glucose homeostasis in rats.

Disruption of steroidogenesis after dimethoate exposure and efficacy of N-acetylcysteine in rats: an old drug with new approaches.

Organophosphates (OPs) like dimethoate (DMT), are pesticides used worldwide, which can affect both animals and human. Whereas their toxicity is due to acetylcholinesterase inhibition, their secondary toxic effects have been related to free oxygen radical biosynthesis. The present study was designed to investigate the reprotoxic effects of DMT and the protective role of N-acetylcysteine (NAC) in male rat. DMT (20 mg/ kg/body weight) was administered daily to rats via gavage in corn oil and NAC (2 g/l) was added to drinking water for 30 days. Rats were sacrificed on the 30th day, 2 h after the last administration. Markers of testis injury (steroidogenesis impairment) and oxidative stress (lipid peroxidation, reduced glutathione, and antioxidant status) were assessed. In DMT-exposed rats, the serum level of testosterone was decreased. Further, a significant increase in lipid peroxidation level and a significant decrease in the activities of antioxidant enzymes were observed in the testis of rats during DMT intoxication. Real-time PCR (RT-PCR) analysis demonstrated a decrease in messenger RNA (mRNA) levels for testicular steroidogenic acute regulatory StAR protein, cytochrome P450scc, 3ß-hydroxysteroid dehydrogenase (3ß-HSD), and 17ß hydroxysteroid dehydrogenase (17ß-HSD) in the testis after DMT exposure. No significant changes in the oxidative stress status and selected reproductive variables were observed on CTN group, whereas NAC restored the oxidative stress and the steroidogenesis on NAC group. Dimethoate induces reprotoxicity and oxidative stress. N-acetylcysteine showed therapeutic recovery effects against dimethoate toxicity.

A comparative study on toxicity induced by carbosulfan and malathion in Wistar rat liver and spleen.

Organophosphorus (OP) and carbamate (CM) pesticides are widely used in agriculture. These pesticides are highly toxic to humans and their residues in food pose potential threat to human health. In this comparative study, we investigated the effect of subchronic exposure of OPs (malathion, MAL) and CM (Carbosulfan, CB) on rat liver and spleen. Biochemical analysis showed that levels of hepatic enzymes (ALT, ALP, LDH and PAL) changed after exposure to the pesticides. In the liver extracts, lipid peroxidation index increased after the treatment by pesticides. Our results indicated that exposure to MAL and CB leads to alteration of liver redox status. Both pesticides induced focal inflammation and fibrosis in the liver. After subchronic administration of MAL (200 mg/kg) and CB (25 mg/kg), systemic inflammation, as depicted by the increase in IFN-δ activity in liver, was observed in both malathion and carbosulfan treated animals. In addition, the results showed that MAL significantly increased TCD4+ and TCD8+ lymphocyte number. It also decreased INF-δ and IL-4 production. However, CB induced a reduction of TCD8+ number and cytokine production in spleen cells. In conclusion, malathion and carbosulfan had significant immunomodulatory properties in the spleen with inflammation and oxidative stress induction in the liver.