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Aim: To identify the DNA methylation status of related genes in major depressive disorder following selective serotonin-reuptake inhibitor treatment. Materials & methods: 45 patients with major depressive disorder and 45 healthy volunteers were considered experimental and control groups, respectively. High-resolution melting real-time PCR was implemented to evaluate DNA methylation. Results: After 100 days of selective serotonin-reuptake inhibitor treatment, methylation of promoter CpG sites of BDNF, NR3C1, FKBP5 and SLC6A4 was significantly reduced. Compared with before treatment, patients' Hamilton Depression Rating Scale scores were significantly reduced after selective serotonin-reuptake inhibitor treatment (p ≤ 0.0001). Conclusion: Based on the proven effect of antidepressants on DNA methylation and gene expression, these medications can improve the treatment process and reduce depression scores after treatment.

Thermal stress has a direct effect on various types of DNA damage, which depends on the stage of the cell cycle when the cell is exposed to different climate conditions. A literature review was conducted to systematically investigate and assess the overall effect of heat stress and DNA damage following heat exposure. In this study, electronic databases including PubMed, Scopus, and Web of Science were searched to find relevant literature on DNA damage in different ambient temperatures. Outcomes included (1) measurement of DNA damage in heat exposure, (2) three different quantification methods (comet assay, 8-hydroxy-2-deoxyguanosine (8-OHdG), and γ-H2AX), and (3) protocols used for moderate (31) and high temperatures (42). The evidence shows that long exposure and very high temperature can induce an increase in DNA damage through aggregate in natural proteins, ROS generation, cell death, and reproductive damage in hot-humid and hot-dry climate conditions. A substantial increase in DNA damage occurs following acute heat stress exposure, especially in tropical and subtropical climate conditions. The results of this systematic literature review showed a positive association between thermal stress exposure and inhibition of repair of DNA damage.

Hydrogen sulfide (H2S) is a toxic compound known as a member of the gasotransmitter family. H2S has the ability to inhibit the cytochrome c oxidase enzyme in the mitochondrial respiratory chain. Mitochondria play an important role in energy production and the brain needs energy for normal function. Mitochondrial dysfunction is associated with neurodegenerative diseases. This study investigated the mechanisms of cytotoxicity induced by H2S in brain neurons. thioacetamide has been used to produce H2S in water solutions. The results of the study showed that thioacetamide at concentrations of 116, 232 and 464 µg/ml was able to increase the level of reactive oxygen species (ROS), collapse in mitochondrial membrane potential (MMP), damage to the lysosomal membrane, increase in the level of oxidized glutathione (GSSG) and decrease in the level of reduced glutathione (GSH) in brain neurons. The results of the study suggested that H2S causes damage to mitochondria and lysosomes in brain neurons that could be associated with neurodegenerative diseases.

Irritable bowel syndrome (IBS) is a functional gut disorder with multi-factorial pathophysiology that causes recurring pain or discomfort in the abdomen, as well as altered bowel habits. Montelukast, a well-known cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is widely used for the anti-inflammatory management of asthma. The present study aimed to evaluate the effects of pharmacological inhibition of CysLT1R on acetic acid-induced diarrhea-predominant IBS (D-IBS) in rats. Behavioral pain responses to noxious mechanical stimulation were decreased in the montelukast-treated rats as compared to the model animals following colorectal distension (CRD)-induced visceral hypersensitivity. Stool frequency decreased dose-dependently by montelukast in IBS rats exposed to restraint stress. A significantly shorter immobility time was also observed in IBS rats who received montelukast vs IBS group in the forced swimming test (depression-like behavior). Furthermore, there were significant decreases in the NF-κB protein expression, inflammatory cytokine (TNF-α, and IL-1ß) levels, and histopathological inflammatory injuries concomitant with increased anti-inflammatory cytokine, IL-10, in montelukast-treated rats compared with the IBS group. Cysteinyl leukotriene production and CysLT1R mRNA expression showed no remarkable differences among the experimental groups. The present results suggest the possible beneficial effects of montelukast in the management of D-IBS symptoms. The molecular mechanism underlying such effects, at least to some extent, might be through modulating CysLT1R-mediated NF-κB signaling. Yet, more studies are required to demonstrate the clinical potential of this drug for IBS therapy.

Noise and combination-induced hearing loss is a common work-related disease among workers. The present research aimed to investigate the impact of independent and combined acute exposure to white noise plus Al2O3-NPs on changes in hearing and structural functions of the cochlea in rats. A total of 36 rats were randomly classified into six groups: Control, acute exposure to white noise, exposure to Al2O3-NPs (γ), exposure to noise plus Al2O3-NPs (γ ), exposure to Al2O3-NPs (α), and exposure to the combination of noise plus Al2O3-NPs (α). TTS and PTS were examined using DPOAE. Oxidative index (MDA, GSH-Px), gene expression (NOX3, TGF-ß, CYP1A1), protein expression (ß-Tubulin, Myosin VII), and histopathological changes were examined in the cochlea. The morphology of AL2O3-NPs was examined by TEM. The results of the DPOAE test, TTS in all groups, and the PTS in the groups exposed to noise, Al2O3-NPs (γ), and a combination of noise plus Al2O3-NPs increased significantly (p 2O3-NPs, the MDA levels increased, the level of GSH-Px decreased, the expression percentage of ß-Tubulin and Myosin VII decreased, and the expression of NOX3, TGF-ß, and CYP1A1, (except for AL2O3-NPs (α) group) significantly increased (p 2O3-NPs damaged hair and ganglion cells for high-frequency perception, thereby affecting the function and structure of the cochlea and leading to TTS and PTS.

Seizure occurs as a result of uncontrolled electrical disturbances within the brain. Various biomolecules such as N-methyl-D-aspartate (NMDA), nitric oxide (NO), and cAMP response element-binding protein (CREB) have been implicated in the pathophysiology of seizure. Sumatriptan is a specific 5-Hydroxytryptamine 1B/1D receptor agonist and has neuroprotective effects in various neuropsychiatric disorders. In the current study, we tried to investigate the possible interaction of sumatriptan with NMDA/NO and CREB signaling pathway in PTZ induced seizure. For this purpose, various agonist and antagonist of NMDA such as MK-801 and Ketamine, NO precursor L-ARG, and NOS inhibitors L-NAME and 7-NI were co-administered with sumatriptan in PTZ induced seizure model. The level of nitrite in mice hippocampus was determined by Griess reaction. The gene expression of NR1, NR2A, NR2B, and CREB were quantified by quantitative real time-polymerase chain reaction (qRT-PCR). Furthermore, the involved neuronal nitric oxide synthase (nNOS) protein expression was examined via western blot analysis. Effective dose of sumatriptan (1.2 mg/kg) alone and subeffective dose of sumatriptan (0.3 mg/kg) in combination with NMDA and/or NO antagonist showed significant (P

Melatonin (MT), a neurohormone with immunomodulatory properties, is one of the metabolites produced in the brain from tryptophan (TRP) that has already strong links with the neuropathogenesis of Multiple sclerosis (MS). However, the exact molecular mechanisms behind that are not fully understood. There is some evidence showing that MS and MT are interconnected via different pathways: Relapses of MS has a direct correlation with a low level of MT secretion and a growing body of evidence suggest that MT be therapeutic in Experimental Autoimmune Encephalomyelitis (EAE, a recognise animal model of MS) severity. Previous studies have demonstrated that the kynurenine pathway (KP), the main pathway of TRP catabolism, plays a key role in the pathogenesis of MS in humans and in EAE. The present study aimed to investigate whether MT can improve clinical signs in the EAE model by modulating the KP. C57BL/6 mice were induced with EAE and received different doses of MT. Then the onset and severity of EAE clinical symptoms were recorded. Two biological factors, aryl hydrocarbon receptor (AhR) and NAD+ which closely interact in the KP were also assessed. The results indicated that MT treatment at all tested doses significantly decrease the EAE clinical scores and the number of demyelinating plaques. Furthermore, MT treatment reduced the mRNA expression of the KP regulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1) and other KP enzymes. We also found that MT treatment reduces the mRNA expression of the AhR and inhibits the enzyme Nicotinamide N-Methyltransferase (Nnmt) overexpression leading to an increase in NAD+ levels. Collectively, this study suggests that MT treatment may significantly attenuates the severity of EAE by altering the KP, AhR and NAD+ metabolism.

Drug response variability due to interpersonal genetic differences is a new and vital research interest. Many single nucleotide polymorphisms (SNPs) have been characterized for CYP3A4 (alleles *1–*22). PCR-RFLP method performed to check CYP3A4*22 polymorphism as an important allele in drug metabolism. 45 Blood samples were collected from the Iranian population with the depressive disorder. Hamilton Depression Rating Scale (HAM-D) used for evaluate the severity of depression before and after 100 days of treatment. Among the individuals, 40 (91.2%) patients showed wild type (CC) and 5 (91.2%) patients were heterozygous (CT) for the CYP3A4*22 allele. Comparing the rate of decrease in HAM-D score between two genotypic groups in CYP3A4*22 showed a significant difference (p

In this study, a deep eutectic solvent as the acceptor phase was applied in three-phase hollow fiber liquid-phase microextraction for the microextraction of two pyrethroids (permethrin as well as deltamethrin) from environmental water samples prior to HPLC-UV. A deep eutectic solvent was synthesized of tetrabutylammonium bromide-decanoic acid (in a ratio of 1:2) as an acceptor phase and 1-decanol was applied as a supported liquid membrane. Some main variables affecting the extraction recoveries, comprising the types/contents of extraction solvent and acceptor phase, stirring speed, sample phase pH and extraction time, were checked and optimized. Under optimal conditions, the detection limits and limits of quantitation determined were 0.09-0.12 and 0.29-0.39 μgl

A growing body of evidence demonstrates that an imbalance in the intensive communication between gut microbiota and the host might be associated with immune-related disorders such as multiple sclerosis. This study set out to determine whether antibiotic treatment during pregnancy and lactation can affect the onset and severity of clinical symptoms and inflammatory responses in offspring with experimental autoimmune encephalomyelitis (EAE; a mouse model of multiples sclerosis). Female C57BL/6 mice received antibiotics or vehicles during pregnancy and lactation, then their offspring were induced with EAE in adulthood. We also measured interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon-gamma (IFN-γ), IL-17A, IL-10, and transforming growth factor (TGF)-β in the serum of offspring. The findings indicate that antibiotic treatment in dams significantly exacerbated the severity of EAE clinical symptoms in both male and female offspring. However, antibiotic treatment only accelerated the onset of EAE disease in male but not female offspring. We did not find any significant changes in cytokines in non-EAE male and female offspring treated with antibiotics. Antibiotic treatment significantly enhanced levels of IL-6, TNF-α, IFN-γ, IL-17A, and TGF-β in EAE-induced male offspring, and IFN-γ, IL-17A, and IL-10 levels in EAE-induced female offspring. There were also sex differences in the onset and severity of EAE disease, and inflammatory cytokines (IL-6, IFN-γ, and IL-17A) between EAE-induced male and female offspring treated with antibiotics. Taken together, this study suggests that antibiotic treatment during pregnancy and lactation in dams might affect the development of the immune system in male and female offspring in adulthood.

Numerous people suffer from accidental or deliberate exposure to different pesticides when poisoning with aluminum phosphate (AlP) is increasing in the eastern countries. Aluminum phosphate is a conventional insecticide that quickly reacts with water or the moistures in the atmosphere and produces fatal phosphine gas, which absorbs quickly by the body. Oral consumption or inhalation of AlP leads to excessive reaction of the body such as fatigue, vomiting, fever, palpitation, vasodilatory shock, increasing blood pressure, cardiac dysfunction, pulmonary congestion, shortness of breath, and death. The garlic smell from the patient's mouth or exhale is one of the methods to recognize the positioning. Due to the lack of individual antidotes, several supportive treatments are required. The present study focused on the available and new therapies that help reduce the effect of AlP poisoning and the mortality rate. The therapies are divided into the antioxidant-related agent and the other agents. The impacts of each agent on the experimental cases are reported.

Titanium dioxide (nano-TiO

Liver cirrhosis defines by regenerative nodules and fibrotic septa, causing a complication called cirrhotic cardiomyopathy (CCM) with chronotropic hypo-responsiveness. In addition to lowering cholesterol levels, statins yield antioxidant and anti-inflammatory effects. In liver diseases animal models, statins have been shown to decrease hepatic inflammation, fibrogenesis, and portal pressure (PP). Therefore, we evaluated the atorvastatin effect on the heart in cirrhotic rats.Bile duct ligation (BDL) or sham operation performed on male Wistar rats and grouped as cirrhotic; BDL/Saline, BDL/Ator-7d(days) (Atorvastatin 15 mg/kg/day), and BDL/Ator-14d groups, or control; Sham/Saline, Sham/Ator-7d, and Sham/Ator-14d groups. Corrected QT interval (QTc interval), chronotropic responses, serum brain natriuretic peptides (BNP), heart tumor necrosis factor-α (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2), and malondialdehyde (MDA) levels were studied along with atrial Ras homolog family member A (RhoA) and endothelial nitric oxide synthase (eNOS) gene expression.The chronotropic responses decreased in BDL/Saline and increased in BDL/Ator-7d group. The QTc interval, BNP, TNF-α, and MDA levels increased in BDL/Saline and decreased in BDL/Ator-14d group. The Nrf2 level did not change in BDL/Saline and increased in BDL/Ator-14d group. The liver inflammation and fibrosis increased in BDL/Saline and did not affect BDL/Ator-7d and BDL/Ator-14d groups. The RhoA expression was down-regulated in BDL/Saline, BDL/Ator-7d, and BDL/Ator-14d groups. The eNOS expression did not change in BDL/Saline and down-regulated in BDL/Ator-14d group.Atorvastatin alleviates the chronotropic hypo-responsiveness and down-regulates the atrial RhoA and eNOS gene expression along with anti-inflammatory, antioxidant, and anti-stress effects in CCM.

The relationship between maternal lead level and risk of preterm birth (PTB) remained controversial. Therefore, herein we performed this meta-analysis to investigate the association of maternal blood, urine and cord blood lead level with the risk of PTB using observational studies.A systematic search was conducted in PubMed, EMBASE and Ovid Medline databases from inception to August 2019, and sixteen studies with 65600 participants investigating the association between maternal lead level and PTB were included in our meta-analysis. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the highest versus lowest lead level by random-effects model.Overall, the pooled OR of all included articles for the highest versus lowest PTB score was 1.29 (95% CI = 1.14-1.46; I2 = 80.4%,Results of this meta-analysis showed that maternal BLL is directly associated with the risk of PTB.

Background There is limited evidence regarding the efficacy of different treatment options in patients with carpal tunnel syndrome (CTS). This study aimed at assessing the effectiveness of nerve and tendon gliding exercises in the treatment of patients with mild CTS. Methods The current prospective, randomized trial with pretest-posttest design was conducted on 80 patients with mild CTS randomly assigned to 2 groups. The treatment group was instructed to perform gliding exercises in addition to the wrist splint use. The control group only used the wrist splint. All the patients were instructed to use the splint at night and during the day if required. Patients were evaluated in terms of clinical parameters (ie, grip and pinch strength). The severity of symptoms and functional status was also determined using the Boston Carpal Tunnel Syndrome Questionnaire. The subjects were followed up for 6 weeks. Results There were no significant differences in all parameters between groups. The pretest-posttest analysis showed a statistically significant improvement in subjective and objective parameters in the treatment group. However, in the control group, only a significant improvement was observed in grip strength. Wrist splint use led to a significant change in the severity of symptoms only over the second week. Conclusions Both gliding exercise and wrist splint groups showed some improvement in the severity of symptoms and functional status scores. However, the gliding exercises did not offer additional benefit compared with wrist splint alone.

A salting-out-assisted switchable hydrophilicity solvent-based liquid phase microextraction (SA-SHS-LPME) was developed for the separation and determination of trace amounts of imatinib and N-desmethyl imatinib in biological and environmental samples by HPLC-UV. Triethylamine as a hydrophobic compound and protonated triethylamine carbonate as a hydrophilic one were switched by the addition or elimination of CO2 . The use of NaOH resulted in the elimination of CO2 from the sample solution, which led to the conversion of P-TEA-C into triethylamine (TEA) and as a result, the analytes was extracted and entered the TEA phase. The salting out was performed to speed up the formation of the TEA in the shape of fine droplets in the specimen solution. Furthermore, the impact of several momentous factors that influence the recovery of the extraction was investigated. Under the optimum conditions, the limit of detection and limit of quantification were obtained in ranges of 0.03-0.05 and 0.1-0.15 μg L-1 for imatinib and 0.04-0.06 and 0.13-0.20 μg L-1 for N-desmethyl imatinib, respectively. The preconcentration factor was 250. Inter- and intraday precision (RSD, n = 5) was

In this study, we designed and synthesized some new tetrahydropyrimidinone(thione)-triazole hybrid derivatives by click and one-pot Biginelli reactions. FT IR, 1H NMR, and 13C NMR spectra and mass spectrometry, and elemental analysis were used to determine the structures of the derivatives. The cytotoxic and antimicrobial activities of these derivatives were evaluated against three cancer cell lines and two bacterial strains. Among all, benzyl 4-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine (THPM)-5-carboxylate (9f) revealed the highest cytotoxic activity against MCF7 and Hep-G2 cell lines. However, none of the derivatives display cytotoxic activity against A549 cell line. In addition, compounds methyl 4-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-thioxo-1,2,3,4- THPM-5-carboxylate (9d) and ethyl 4-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-6-methyl-2-thioxo-1,2,3,4- THPM-5-carboxylate (9e) were found to exhibit potent activity compared to other compounds and the standard drugs against two bacterial strains.

Major depressive disorder (MDD) is a debilitating disorder with adverse effects on mood, memory, and quality of life. In this study, the antidepressant potential of glatiramer acetate (GA), a drug used in the management of multiple sclerosis, was investigated in acute and chronic models of depression in male mice. The acute antidepressant screening was performed with the forced swim (FST) and tail suspension (TST) tests. In the chronic phase, post-weaning social isolation (SI) was used to induce depressive-/anxiety-like behaviors. Mice were reared in two different groups of social (SG) and isolated (IG) for 4 weeks. IG mice were treated with 0.5, 1.0, and 2.0 mg/kg of GA for the last 2 weeks of the SI period. Animals were assessed by the behavioral tests of depression, anxiety, learning, and memory, and hippocampal brain-derived neurotrophic factor (BDNF) level was measured. The acute tests confirmed the antidepressant potential of GA. In the chronic phase, GA could reduce immobility time in FST (P < 0.05), increase exploration activity in open field test (P < 0.05), increase open arms duration (P < 0.05) and entries in elevated plus maze (P

ObjectivesThe effects of Crocin as a cardioprotective material against Aluminum phosphide poisoning by reducing the oxidative stress is investigated.MethodsThe level of biomarkers of oxidative stress (Catalase, Superoxide dismutase, Malondialdehyde and Protein carbonyl) were measured in the cell culture model on Human Cardiac Myocyte cells to detect the protective effect of crocin. Initially, to define the pure impact of aluminum phosphide poison and crocin on the heart cells, their effects on the biomarkers quantity in cell line were measured, separately, using the standard related kits. Later the effect of crocin with different concentration as a treatment on the oxidative stress biomarkers of the poisoned heart cells were monitored. Note that in pre-treatment case, the crocin was initially added to the cells before poisoning them. Data were analyzed using the analysis of variance method.Key findingsResults showed that crocin treatment reduced the aluminum phosphide (AlP) poisoning effect significantly. The treatment resulted in substantial deviation in the biomarkers of oxidative stress at the pre- and post-treatment phases for all groups. The oxidative markers values of the poisoned cells were recovered by crocin treatment.ConclusionsCrocin is proposed as a potentially powerful antioxidant to treat the cardiotoxicity caused by aluminum phosphide poisoning.

Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. The c-MET receptor tyrosine kinase (RTK) which is frequently deregulated in GBM is considered as a promising target for GBM treatment. The c-MET plays a key role in cell proliferation, cell cycle progression, invasion, angiogenesis, and metastasis. Here, we investigated the anti-tumour activity of foretinib, a c-MET inhibitor, on three human GBM cells (T98G, U87MG and U251). Anti-proliferative effect of foretinib was determined using MTT, crystal violet staining, and clonogenic assays. PI and Annexin V/PI staining flow cytometry were used to evaluate the effects of foretinib on cell cycle and apoptosis, respectively. Scratch assay, qRT-PCR, western blot, and zymography analyses were applied to elucidate the molecular mechanisms underlying the anti-tumour activity of foretinib. Foretinib treatment reduced phosphorylation of c-MET on T98G and U251 cells, but not in U87MG cells. The highest inhibitory effect was observed in T98G cells (IC50 = 4.66 ± 0.29 µM) and the lowest one in U87MG cells (IC50 = 29.99 ± 1.31 µM). The results showed that foretinib inhibited the proliferation of GBM cells through a G2/M cell cycle arrest and mitochondrial-mediated apoptosis in association with alternation in expression of the related genes and protein-regulated G2/M phase and apoptosis. Foretinib diminished GBM cell invasion through downregulation of the proteolytic cascade of MMP2, uPA and uPAR and epithelial–mesenchymal transition (EMT)-related genes. A different GBM cell sensitivity pattern was noticeable in all experiments which demonstrated T98G as a sensitive and U87MG as a resistant phenotype to foretinib treatment. The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.

Objectives Due to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured. Methods A pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated. Results Female cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms. Conclusions According to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Adipose derived mesenchymal stem cells (ASCs) transplantation is a novel immunomodulatory therapeutic tool to ameliorate the symptom of inflammatory bowel disease (IBD). The objective of this study was to investigate the therapeutic effects of combined sufasalazine and ASCs therapy in a rat model of IBD. After induction of colitis in rats, ASCs were cultured and intraperitoneally injected (3 x 10(6) cells/kg) into the rats on Days 1 and 5 after inducing colitis, in conjunction with daily oral administration of low dose of sulfasalazine (30 mg/kg). The regenerative effects of combination of ASCs and sulfasalazine on ulcerative colitis were assessed by measuring body weight, colonic weight/length ratio, disease activity index, macroscopic scores, histopathological examinations, cytokine, and inflammation markers profiles. In addition, western blot analysis was used to assess the levels of nuclear factor-kappa B (NF-kappaB) and apoptosis related proteins in colitis tissues. Simultaneous treatment with ASCs and sulfasalazine was associated with significant amelioration of disease activity index, macroscopic and microscopic colitis scores, as well as inhibition of the proinflammatory cytokines in trinitrobenzene sulfonic acid (TNBS)-induced colitis. Moreover, combined ASCs and sulfasalazine therapy effectively inhibited the NF-kappaB signaling pathway, reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of the rats with TNBS-induced colitis. Furthermore, combined treatment with ASCs and sulfasalazine shifted inflammatory M1 to anti-inflammatory M2 macrophages by decreasing the levels of MCP1, CXCL9 and increasing IL-10, Arg-1 levels. In conclusion, combination of ASCs with conventional IBD therapy is potentially a much more powerful strategy to slow the progression of colitis via reducing inflammatory and apoptotic markers than either therapy alone.

This paper introduces a new standardized testing procedure for nanomaterial environmental toxicity (International Organization for Standardization/Technical Specification (ISO/TS) 20787): 'aquatic toxicity assessment of manufactured nanomaterials in saltwater lakes using Artemia sp. Nauplii' intended to generate more reliable and repeatable aquatic toxicity data testing manufactured nanomaterials, using Artemia sp., to evaluate their possible ecotoxicity in saltwater lake ecosystems. The principles behind testing with Artemia sp. are reviewed and the paper gives an overview of research published between 2009 and 2018 in which manufactured nanomaterials were tested using Artemia sp.

An ultrasound-assisted switchable-hydrophilicity solvent (SHS)-based homogeneous liquid–liquid microextraction (UA-SHS-HLLME) coupled to gas chromatography–mass spectrometry (GC–MS) detection was applied to determine paraquat (PQ) in biological and environmental samples. A chemical reduction of the analyte was performed to produce a volatile derivative of PQ by adding sodium borohydride (NaBH4) to the sample solution. The reduced PQ derivative was extracted into triethylamine (TEA). Two ionic and non-ionic forms (TEA and protonated triethylamine carbonate, P-TEA-C) were reversed by adding or removing CO2. The two phases were separated by addition of sodium hydroxide. Ultrasound was used to form fine droplets of the extractant in the sample solution. The effects of some important parameters on the extraction recovery of the reduced PQ derivative were assessed. Under optimum conditions, the limits of detection and the limits of quantification were found in the range of 0.06–0.13 and 0.20–0.30 µg L−1 with preconcentration factors between 150 and 230 in biological and environmental samples, respectively. The intraday precision was less than 8% (n = 5) and the interday precision was less than 9% (n = 5). The applicability and accuracy of the method were tested by the analysis of spiked real samples. The obtained results indicated that the developed method could be an efficient analytical method for analysis of biological and environmental samples.

Objectives Diabetic neuropathy (DN) induces lifetime disability and there is currently no effective therapy to treat or to minimize patients suffering, so it is thereby imperative to develop therapeutic strategies for this disease. Since oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial mechanisms in development and progression of DN, it is important to explore tools by which one can reduce factors related to these pathways. Herein, the understandings of the sildenafil neuroprotective effect through increase of cGMP level and the mediation of oxidative stress, apoptosis, and inflammation pathways on neurotoxicity induced by high glucose (HG) in PC12 cells as an in vitro cellular model for DN were investigated. Methods We reported that the PC12 cells pre-treatment with sildenafil (0.008 μM) for 60 min and then exposing the cells to HG (25 mM for 72 h) or normal glucose (NG) (5 mM for 72 h) condition, show: Results (1) significant attenuation in reactive oxygen species, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, mitochondrial membrane potential, and ATP levels. Conclusion All these data together led us to propose neuroprotective effect of sildenafil is probably through its antioxidant, antiapoptotic, and anti-inflammatory activities. Of course, further studies are required to explain the underlying mechanism of the sildenafil effects.

In this study we investigated the protective effects and possible mechanisms of pirfenidone (PF) in paraquat (PQ)-induced lung injury and fibrosis in mice. Lung injury was induced by injection of PQ (20 mg/kg). Thereafter, mice orally received water and PF (100 and 200 mg/kg) for four weeks. After 28 days, the inflammation and fibrosis were determined in the lungs by analysis of histopathology, bronchoalveolar lavage fluid (BALF) cell count, lung wet/dry weight ratio, hydroxyproline content, and oxidative stress biomarkers. Expression of several genes involved in fibrogenesis and modulation of reactive oxygen species (ROS) production, such as TGF-β1, α-SMA, collagen Iα and IV, NOX1, NOX4, iNOS, and GPX1 were determined using RT-qPCR. PF significantly decreased the lung fibrosis and edema, inflammatory cells infiltration, TGF-β1 concentration, and amount of hydroxyproline in the lung tissue. PF dose-dependently improved the expression level of the studied genes to the near normal. Decreasing of lung lipid peroxidation and catalase activity, and increasing of SOD activity in the treated mice were significant compared to the control group. Pirfenidone ameliorate paraquat induced lung injury and fibrosis partly through inhibition of inflammation and oxidative stress, and downregulation of genes encoding for profibrotic cytokines and enzymatic systems for ROS production.

Aluminum phosphide is a well-known hazardous agent used as an agricultural pesticide to protect stored grains from insect damage. However, accidental consumption of a trivial amount of it caused irreversible damage to the human body or even death in acute cases. The present study used taurine and grape seed extract as a natural cardioprotective medicine against aluminum phosphide poisoning by decreasing oxidative stress. The activity of oxidative stress biomarkers (Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase) were evaluated in the cell line model on Human Cardiac Myocyte cells. In the beginning, to clarify the pure impact of aluminum phosphide poison, taurine, and grape seed extract on the human heart cells, their effects on the biomarkers quantity in cell line were measured. Subsequently, the effect of taurine and grape seed extract with various concentrations as a treatment on the oxidative stress biomarkers of the poisoned heart cells were studied. Data analysis reveals that taurine and grape seed extract treatment can successfully diminish the poisoning effect by their antioxidant properties. The oxidative markers values of the poisoned cells were recovered by taurine and grape seed extracts treatment. Taurine (2 g/l) can recover Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase by 56%, 78%, 88%, 78%, when the recovering power of grape seed extract (100 g/l) for the aforementioned enzymes are 56%, 0.71%,74%, 51%, respectively. Therefore, it is clear that the performance of taurine in the recovery of the biomarkers’ value is better than grape seed extract.

Objective: Ionizing radiation is a critical threat to biomolecules, especially DNA. Various combinatorial compounds have been studied to protect this biomolecule. Melatonin has been reported as a direct and indirect free radical scavenger, but in this study, we explored the effect of melatonin on assisting in DNA repair by expression of Cdkn1a and Rad50; both of these genes are involved in DNA repair signaling, induced by radiation in rat peripheral blood. Materials and Methods: Rats were irradiated with single whole-body linear accelerator X-ray radiation doses of 2 and 8 Gy with or without melatonin (100 mg/kg body weight) pretreatments. The rats were randomly divided into nine groups and given an intraperitoneal injection of melatonin or the same volume of vehicle alone 1 h before radiation. Blood samples were taken 8, 24, and 48 h postradiation to measure gene expression of Cdkn1a and Rad50 using quantitative reverse transcription polymerase chain reaction technique. Results: Melatonin pretreatment increased the expression of Cdkn1a and Rad50 in 8 and 24 h postradiations (2 and 8 Gy) (P < 0.05), and there was no significant difference in 48 h postradiation compared to the radiation-only and vehicle plus radiation (2 and 8 Gy) groups. Conclusions: Based on our results, pretreatment with melatonin (100 mg/kg) may ameliorates injurious effects of 2 and 8 Gy ionization radiation by increasing the expression level of Cdkn1a and Rad50 in rat peripheral blood and assist in DNA double-strand breaks repair, especially during the early postradiation.

A green switchable solvent based on liquid phase microextraction (SS-LPME), has proposed to extract some heavy metal ions (Cd, Ni, Pb and Co) from various samples by micro sampling flame atomic absorption spectrometry (FAAS). Triethylamine (TEA) and protonated triethylamine carbonate (P-TEA-C) as green switchable solvents were used in two forms in the presence of CO2. Sodium hydroxide (NaOH) was performed to convert protonated triethylamine carbonate to triethylamine and as a result, the complexes of metal ions were extracted into TEA phase. Ultrasonic energy was introduced to accelerate formation of fine droplets of the extractant into the aqueous solution, and enlarge contact surface between both immiscible liquids. Several factors influencing the recovery and determination of analytes were studied. According to the results, the limits of detection were in the range of 0.24 and 0.76 μg L− 1 and the relative standard deviations (RSDs, n = 10) in the range of 1.3 to 3.8% at 50 μg L− 1 for all analytes were found. Also, preconcentration factors (PFs) > 100 were obtained for all analytes. The accuracy of the proposed method was verified using a certified reference material (CRM). Finally, the method was effectively utilized to the analysis of Cd, Ni, Pb and Co in water, urine and tea infusion samples.

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic drug and is used to treat chronic pain. In this study, the effects of Bile Duct Ligation (BDL) on the pharmacokinetics of tramadol in a liver recirculating perfusion system of male rats were used. Twenty-four Wistar male rats were randomly divided into four groups: control, sham and two weeks BDL and four weeks BDL. Serum levels of liver enzymes were measured before perfusion and the pharmacokinetics of tramadol was evaluated by using liver recirculating perfusion system. Tramadol and metabolites concentrations were determined by HPLC-FL. The sharp increase in liver enzymes level in both BDL groups was observed and significant changes were also observed in liver weight and volume. Tramadol metabolites concentration significantly decreased compared with the control and sham group (P

Catecholamine neurotransmitters, specifically, dopamine (DA), epinephrine (EP), and norepinephrine (NE), are known as substantial indicators of various neurological diseases. Developing rapid detection methods capable of simultaneously screening their concentrations is highly desired for early clinical diagnosis of such diseases. To this aim, we have designed an optical sensor array using three fluorescent dyes with distinct emission bands and have monitored variations in their emission profiles upon the addition of DA, EP, and NE in the presence of gold ions. Because of the different reducing power of catecholamines, differently sized gold nanoparticles (GNPs) with different levels of aggregation were generated, resulting in different amounts of spectral overlap between the absorption band of the in situ generated plasmonic GNPs and the emission bands of the fluorescent dyes. These energy-transfer-based fingerprint profiles were used to discriminate the neurotransmitters by applying pattern recognition methods including linear discriminant analysis (LDA) and artificial neural networks (ANN) and to determine their concentration using multiple linear regression (MLR). Our proposed array also showed a good performance in the discrimination of DA, EP, and NE in complex biological media such as human urine.

Objective(s): Rapamycin is an immunosuppressant compound with a broad spectrum of pharmaco-logical activities. In recent years, it has been used successfully to decrease ischemia-reperfusion injury in several organ systems. The purpose of the present study was to examine the effect of rapamycin on testicular ischemia-reperfusion injury. Materials and Methods: Seventy-two adult male Wistar rats were divided into six groups: control (group1), sham-operated (Group2), T/D + DMSO as vehicle group (group3), and groups 4–6; respectively received 0.5, 1, and 1.5 mgkg-1 of rapamycin, IP 30 min before detorsion. Ischemia was achieved by twisting the right testis 720° clockwise for 1 hr. The right testis of 6 animals from each group were excised 4 hr after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and TUNEL test in right testis of 6 animals per group, 24 hr after detorsion. Results: Testicular T/D caused increases in the apoptosis, malondialdehyde (MDA), and caspase-3 levels and decreases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in ipsilateral testis (P

Background: Activation of inflammatory cells can cause more chemicals induced-hepatotoxicity. Aflatoxin B1 (AFB1) is a fungal toxin that induces acute hepatotoxicity in humans and animals. This study was conducted to examine the effect of co-exposure LPS and various aflatoxin B1 doses on the damage hepatic parameters in isolated perfused rat liver. Methods: Thirty-two male wistar rats (250-300g) were divided to eight groups including Control and LPS; three groups with various doses of AFB1 (0.01, 0.1 and 1 ppm) and three groups with various doses of AFB1 and Lipopolysaccharide (LPS) (300 ppm). Activity of Aspartate transaminase (AST) and Alanine transaminase (ALT) were determined in perfusate. Thiobarbituric acid reactive substances (TBARS) and Glutathione (GSH) concentrations were measured in homogenate liver. Results: At two groups of AFB 1 (with LPS and without LPS) at AFB1 concentrations of 0.1 and 1 ppm, elevation of AST and ALT enzymes activity were indicated. Values of GSH in both of groups (AFB 1 with LPS and without LPS) had reduced at concentration of 1 ppm. TBARS concentrations were enhanced in AFB1 concentration of 1 ppm in both of groups (with LPS and without LPS), however in comparison between groups (with LPS and without LPS) in similar concentrations significant different did not observe (P

Ketoconazole is widely used in human and veterinary medicine; however, residual amounts of this antifungal agent have potential adverse effects on ecological health. The present study describes the use of laccase from Trametes versicolor for biotransformation and detoxification of ketoconazole. The substrate was removed at optimum conditions of 45 °C, pH 4.5, incubation time 6 h, ketoconazole concentration 0.3 mg ml−1, 1-hydroxybenzotriazole (HBT) concentration 1 mM, and laccase activity 1 U ml−1. The use of HBT (1 mM), a laccase mediator, enhanced the yield of elimination. A micro-toxicity study with Pseudokirchneriella subcapitata, Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae showed a decrease in the toxicity of laccase-treated ketoconazole and its isolated metabolites. The kinetic parameters Km and Vmax of laccase-catalyzed removal of the substrate were determined as 0.099 μM and 4.43 μmol h−1 mg−1, respectively. Two major bioconverted metabolites were also purified and identified.

Amphetamine withdrawal (AW) is accompanied by diminished pleasure and depression which plays a key role in drug relapse and addictive behaviors. There is no efficient treatment for AW-induced depression and underpinning mechanisms were not well determined. Considering both transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and N-Methyl-d-aspartate (NMDA) receptors contribute to pathophysiology of mood and addictive disorders, in this study, we investigated the role of TRPV1 and NMDA receptors in mediating depressive-like behaviors following AW in male mice. Results revealed that administration of capsaicin, TRPV1 agonist, (100μg/mouse, i.c.v.) and MK-801, NMDA receptor antagonist (0.005mg/kg, i.p.) reversed AW-induced depressive-like behaviors in forced swimming test (FST) and splash test with no effect on animals' locomotion. Co-administration of sub-effective doses of MK-801 (0.001mg/kg, i.p.) and capsaicin (10μg/mouse, i.c.v) exerted antidepressant-like effects in behavioral tests. Capsazepine, TRPV1 antagonist, (100μg/mouse, i.c.v) and NMDA, NMDA receptor agonist (7.5mg/kg, i.p.) abolished the effects of capsaicin and MK-801, respectively. None of aforementioned treatments had any effect on behavior of control animals. Collectively, our findings showed that activation of TRPV1 and blockade of NMDA receptors produced antidepressant-like effects in male mice following AW, and these receptors are involved in AW-induced depressive-like behaviors. Further, we found that rapid antidepressant-like effects of capsaicin in FST and splash test are partly mediated by NMDA receptors.

This study describes the enzymatic elimination of imipramine and four other tricyclic antidepressants (TCAs) by laccase-mediated catalysis in aqueous solution. The results showed that TCAs demonstrated dissimilar enzymatic elimination behavior: up to 67% of clomipramine and 82% of imipramine were significantly removed during the first 6 h. The elimination percentages of amitriptyline, doxepin, and nortriptyline were 11%, 6%, and 23%, respectively, after 72 h laccase-based treatment. Due to the rapid and high percentage of removal, imipramine was selected for detailed toxicity evaluation. Optimal levels for the main factors in the enzymatic removal process of imipramine were obtained as pH (4.9), incubation time (5.7 h), imipramine concentration (0.12 μg mL −1 ), and enzyme activity (1.63 U mL −1 ). Laccase-catalyzed transformation of imipramine led to the formation of an unknown metabolite which was subsequently purified and spectroscopically characterized as 3-(2,7-dihydroxy-10,11-dihydro-5 H -dibenzo[ b,f ]azepin-5-yl)-1-hydroxy- N , N -dimethyl-3-oxopropan-1-amine oxide. The toxicity reduction of the bio-product was assessed by MTT cell and Caco-2 cell line.

Tramadol is an opioid agonist with activation monoaminergic properties. It can be administered orally, rectally, intravenously, or intramuscularly as a centrally acting analgesic. Liver injury can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolism in rats with damaged liver induced by ethanol and acetaminophen was assessed in a recirculation perfusion system. Acetaminophen is a mild analgesic and antipyretic agent, which can cause centrilobular hepatic necrosis in toxic doses, whereas alcohol causes death due to liver diseases. Alcoholic liver disease (ALD), such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis, is the most common liver disease. The aim of this study was to investigate the alteration in tramadol metabolism in different hepatotoxicity conditions in animal models. Male rats were randomly assigned to three groups. The control group received normal saline, group 2 received acetaminophen at the dose of 250 mg/kg/day, and group 3 received ethanol at the beginning dose of 3 g/kg/day, which was slowly increased to 6 g/kg/day. Tramadol was added to the perfusion solution at the concentration of 500 ng/mL. Samples were collected during 180 min, and analyte concentrations were determined by the High-Performance Liquid Chromatography (HPLC) method. The concentration of tramadol and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2), and N,O-didesmethyltramadol (M5), were determined in perfusate samples. Ethanol and acetaminophen significantly affected the pattern of weight gain and liver weights before perfusion and caused a significant increase in enzyme activities. Moreover, histopathologic examination revealed that ethanol and acetaminophen caused liver damage. An increase in the elimination half-life and reduced clearance rate of tramadol were seen in the acetaminophen and ethanol groups, in comparison to the control group. Additionally, significant reductions in the Area Under the Curve (AUC) of metabolites of tramadol (M1, M2, and M5) were observed in the acetaminophen and ethanol groups in the perfused rat liver model. Liver damage caused by ethanol and acetaminophen during 45 days in animals leads to a significant reduction in the level of tramadol metabolites. Therefore, in patients with liver damage caused by ethanol and acetaminophen, caution needs to be considered when prescribing tramadol.

The aim of this study was to investigate the effects of rapamycin (rapa) and metformin (met), combined administration on testicular torsion-detorsion (T/D) injury. A total of 108 male rats were divided randomly into six groups (n = 18), control, sham-operated, T/D, T/D + met (100 mg/kg), T/D + rapa (0.25 mg/kg) and T/D + met (100 mg/kg)+rapa (0.25 mg/kg). Except for the control and sham groups, torsion was created by rotating the right testis 720° in a clockwise direction for 1 h. Treatment groups received drug intraperitoneally, 30 min before detorsion. The right testis of 6 animals from each group was excised 4 h after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate–biotin nick end labeling (TUNEL) test in rest of animals, 24 h after detorsion. In T/D group tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased in comparison with the control group after detorsion. Met and rapa separately pre-treatment reduced MDA and caspase-3 levels, normalized antioxidant enzyme activities, reduced germ cell apoptosis and improved the MSTD in comparison with T/D group. However combined administration of met and rapa indicated a significant augmented effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress, apoptosis, and histologic changes, suggesting a synergistic response. Thus, this study shows that rapa and met combination have significant synergistic effects against oxidative stress and apoptosis and opens up further possibilities for the design of new combinatorial therapies to prevent tissue damage after ischemia-reperfusion (I/R).

N-Acetylcysteine (NAC) loaded PLGA nanoparticles were prepared by electrospray method. The influence of independent parameters such as concentration, flow rate and nozzle to collector distance was studied on particle size and size distribution of generated nanoparticles using a Box–Behnken experimental design. Smallest size was found to be obtained at minimum value for both flow rate and concentration of polymer, regardless of collecting distance value in the ranges studied. Additionally, the minimum value of size distribution was observed at lowest values of both concentration of polymer and collecting distance, regardless of flow rate value. In total, a sample with minimum size and polydispersity was predicted to have flow rate, polymer concentration and collecting distance values of 0.06 (ml/h), 0.5 (%w/w) and 9.28 (cm), respectively. The experimentally prepared nanoparticles with lowest size and size distribution values, had a size of 122 (nm) and size distribution of 24. Zeta potential, drug loading and encapsulation efficiency of optimized nanoparticles were −6.58, 5% and 54.5%, respectively.