Effect of citalopram and sertraline on the expression of miRNA- 124, 132, and 16 and their protein targets in patients with depression.

Objectives: This study aimed to evaluate the effect of SSRIs on the expression of miRNAs and their protein targets. Materials and Methods: In a 100 day open-label study of citalopram (n=25) and sertraline (n=25), levels of miRNA 16, 132, and 124 and glucocorticoid receptor (GR), Brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) protein expression were measured by QRT-PCR and western blot in healthy control (n=20), patients with depression at the baseline, and same patients after 100 days of treatment. Results: Expression levels of GR and BDNF proteins were lower in the depressed group before treatment as compared with the healthy group (P<0.0001). The SERT level was higher among the depressed group before treatment in comparison with the healthy group (P<0.0001). The level of GR and BDNF significantly increased, and SERT expression decreased after receiving sertraline (P<0.05). When the depressed group received citalopram, only SERT and GR were altered (P<0.05). Among the microRNAs' expression investigated, mir-124 and mir-132 were higher, and mir-16 was lower among the depressed compared with the healthy group (P<0.0001). Individuals receiving citalopram only showed an increase in the expression of mir-16 while administration of sertraline led to a significant increase in the expression of mir-16 and a decrease in mir-124 and mir-132 (P<0.05). Conclusion: This elucidated the relationship between antidepressant treatment and the expression of different microRNA that control gene expression in various pathways involved in depressed patients. Receiving SSRI can affect the level of these proteins and their relevant microRNAs.

Evaluation of DNA methylation in BDNF, SLC6A4, NR3C1 and FKBP5 before and after treatment with selective serotonin-reuptake inhibitor in major depressive disorder.

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.

A comprehensive review on human health effects of chromium: insights on induced toxicity.

The growing use of heavy metals in most industrial activities has led to it being considered as the most important environmental pollutant that may cause harm and toxicity to animals and humans. Chromium has been found in the environment in different oxidation states such as Cr0, Cr(III), and Cr(VI) and is released from a variety of anthropogenic and natural activities. At among, trivalent and hexavalent chromium are the most stable forms. Considerably, Cr(VI) is frequently more toxic than Cr(III) because of its particular solubility and high mobility. Chronic exposure and bioaccumulation of chromium, as a heavy metal, can cause toxicity and numerous pathophysiological defects, including allergic reactions, anemia, burns, and sores especially in the stomach and small intestine, damage to sperm along with the male reproductive system, and affect various biological systems. Chromium pollution can have severe consequences for water and the soil environment. This article reviews the toxicological effects of Cr(VI) and Cr(III) and their mechanisms of toxicity and carcinogenicity.

Glatiramer acetate attenuates depressive/anxiety-like behaviors and cognitive deficits induced by post-weaning social isolation in male mice.

RATIONALE: Major depressive disorder (MDD) is a debilitating disorder with adverse effects on mood, memory, and quality of life. OBJECTIVES: 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. METHODS: 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. RESULTS: 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<0.001), and improve memory and learning in passive avoidance test (P < 0.05). The BDNF level was increased in IG mice and decreased in IG mice treated with GA. CONCLUSIONS: Our results showed that GA improved depressive-/anxiety-like behaviors and cognitive dysfunction of SI reared mice without increasing the BDNF level which may be associated with other mechanisms of actions of GA.

A Systematic Review on the Genotoxic Effects of Selective Serotonin Reuptake Inhibitors.

Depression is a mental disorder and a major public health concern affecting millions of people worldwide. It is a common disorder that has been associated with several medical comorbidities often linked with aging, such as dementia, type II diabetes, cardiovascular and cerebrovascular diseases, as well as metabolic syndrome. There are a variety of medications available for depression treatment. Selective serotonin reuptake inhibitors (SSRIs) are one of the antidepressant drug classes that are most widely used to treat depressive disorders and depressive symptoms in other diseases. Due to many contradictory findings on the adverse effects and toxicities of SSRIs (especially genotoxicities), we reviewed the genotoxic effects of these drugs. Based on the guidelines proposed in the PRISMA statement, we performed a systematic review by searching international electronic databases including PubMed, Scopus, Embase, and Web of Science to find the published documents on SSRIs and their genotoxic effects from January 1990 to November 2019. After the removal of 203 duplicate articles, 385 articles were screened and 167 articles met the inclusion criteria and qualified for evaluation of their full texts. After this, 26 articles were appropriate for final review. This revealed that the proportion of genotoxicities was highest for citalopram and fluoxetine, with a smaller proportion for sertraline. Limited documentations showed genotoxic and partial genotoxic effects for paroxetine and escitalopram, respectively. Although a number of studies have found genotoxic effects of SSRIs, there are also some factors including doses, duration of exposure, model of experiments, and the type of technique assay that may affect the results.

A meta-meta-analysis: Evaluation of meta-analyses published in the effectiveness of cardiovascular comorbidities on the severity of COVID-19.

On January 2020, WHO confirmed the epidemic outbreak of SARS-CoV-2 as a Health Emergency of International Concern. The aim of this meta-meta-analysis is quantifying meta-analytic findings on the association of cardiovascular disease (CVD) comorbidities and COVID-19 severity. Findings suggest that chances of getting severe COVID-19 disease in patients with CVD is greater than those without CVD. Also, prevalence of CVD in patents with COVID-19 is 0.08 (95% CI = 0.07-0.08). The OR as 3.44 indicates that the odds of getting severe COVID-19 is more than 3 times higher in those with CVD. Also, prevalence of hypertension in patient with COVID-19 is 0.27 (95%CI = 0.27-0.28) and the OR as 2.68 indicates that the odds of getting severe COVID-19 in cases with high blood pressure is more than 2.5 times higher than those without hypertension. It is rational to suppose that persons with coronary artery disease are prone to severe viral infection thereby, guideline-directed diagnosis and medical therapy is vital in CVD patients.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

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.

A systematic review on the genotoxic effect of serotonin and norepinephrine reuptake inhibitors (SNRIs) antidepressants.

RATIONALE: Depression is a major mental disorder affecting millions of people worldwide. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are one of the antidepressant drugs prescribed for depression treatment. OBJECTIVE AND METHOD: There are many contradiction studies about the adverse effect and genotoxicity of SNRIs. So here, based on the guidelines proposed at the PRISMA statement, we performed a quantitative systematic review by searching international electronic databases (PubMed, Scopus, Embase, and Web of Science) for published documents on SSNRIs and their genotoxicity effects. RESULTS: The database searches retrieved 336 records, 18 of which met the inclusion criteria. Evaluation of the selected articles showed that a total of 9 articles were appropriate for final review. Most of these studies (78%) reported positive results for the genotoxicity of SNRIs CONCLUSION: Finally, we can conclude that these drugs have the potential to damage DNA.

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms.

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.

Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression.

BACKGROUND: The relationship between depression and increased oxidative stress is well known. DNA damage by oxidation factors is an important cause of the aging process in psychiatric disorders. AIMS: Owing to the scarcity of human studies and high inconsistencies in studies of the effects of antidepressants on DNA damage, the current study was undertaken to investigate the effects of depression and its treatment on DNA damage. METHODS: In a 15-week open-label study of citalopram (n = 25) and sertraline (n = 20), levels of DNA damage were measured by comet assay, proinflammatory (Interlukin-6 (IL-6)) and oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)) markers by ELISA, and gene expression of base excision repair enzymes (8-oxoguanine glycosylase (OGG1) and poly (ADP)-ribose polymerase-1 (PARP1)) by quantitative real-time polymerase chain reaction in healthy control patients (n = 14), with depression at the baseline and the same patients after week 15. RESULTS: DNA damage, 8-OHdG, IL-6 and expression of PARP1 were elevated in patients with depression compared with the healthy controls (p < 0.001). Selective serotonin reuptake inhibitor (SSRI) therapy could significantly reduce the depression score (p < 0.01), DNA damage (p < 0.001), as well as 8-OHdG and IL-6 (p < 0.0001). Nevertheless, the expression of PARP1 and OGG1 showed no significant changes after treatment. CONCLUSIONS: This is the first study on the effect of SSRIs on the DNA damage and some of the repair enzymes in depression. Based on the results, depression can cause increased DNA damage. This damage is followed by activation of compensatory mechanisms whereby the expression of DNA damage repair enzymes is elevated. Finally, the treatment of psychiatric disorder by antidepressants can lower the level of oxidative DNA damage.

Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans.

Sulfur Mustard (SM) is the most widely used chemical weapon. It was used in World War 1 and in the more recent Iran-Iraq conflict. Genetic toxicity and DNA alkylation effects of SM in molecular and animal experiments are well documented. In this study, lymphocytic telomere lengths and serum levels of isoprostane F2α were measured using q-PCR and enzyme immunoassay-based methods in 40 Iranian veterans who had been exposed to SM between 1983-88 and 40 non-exposed healthy volunteers. The relative telomere length in SM-exposed individuals was found to be significantly shorter than the non-exposed individuals. In addition, the level of 8-isoprostane F2α was significantly higher in the SM-exposed group compared to controls. Oxidative stress can be caused by defective antioxidant responses following gene mutations or altered activities of antioxidant enzymes. Chronic respiratory diseases and infections may also increaseoxidative stress. The novel finding of this study was a the identification of 'premature ageing phenotype'. More specifically, telomere shortening which occurs naturally with aging is accelerated in SM-exposed individuals. Oxidative stress, mutations in DNA repair genes and epimutaions may be among the major mechanisms of telomere attrition. These findings may help for a novel therapeutic strategy by telomere elongation or for validation of an exposure biomarker for SM toxicity.

Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients.

BACKGROUND: Seizure is one of the important symptoms of tramadol poisoning, but its causes are still unknown. The aim of this study is to find a relationship between tramadol and the concentrations of its metabolites versus the incidence of seizures following the consumption of high doses of tramadol. METHODS: For this purpose, the blood samples of 120 tramadol-intoxicated patients were collected. The patients were divided in two groups (seizure and non-seizure). The concentrations of tramadol and its metabolites (M1, M2 and M5) were measured by using a high-performance liquid chromatography method. The relationship between tramadol and the levels of its metabolites and seizure incidences was also investigated. RESULTS: In 72% of the patients, seizures occurred in the first 3 h after the ingestion of tramadol. The seizure incidences were significantly correlated with the patients' gender, concentrations of tramadol, M1 and M2 and the history of previous seizures (p<0.001). The average concentration of M2 was significantly higher in males (p=0.003). A previous history of the use of sedative-hypnotics and the co-ingestion of benzodiazepines and other opioids were shown to significantly decrease the rate of seizure. The rate of seizure was directly related to the concentrations of tramadol and its metabolites. Higher M2 concentration in males can be considered a reason for increased incidences of seizures in males. The plasma concentration of M1 affected the onset of seizure. CONCLUSIONS: Therefore, it can be concluded that differences in the levels of the metabolites can affect the threshold of seizure in tramadol-intoxicated patients.

Simultaneous measurement of formic acid, methanol and ethanol in vitreous and blood samples of postmortem by headspace GC-FID.

BACKGROUND: Formic acid (formate) is the main reason for toxicity and death through methanol poisoning. The simultaneous determination of methanol, ethanol, and formate in the body can help to discover the cause of death and is useful in the diagnosis of acute methanol poisoning. The measurement of formate is not yet available in Iran. With regard to the increasing rate of methanol poisoning and its related mortality in Iran, as well as the main role of formate in methanol poisoning, this study was designed to set up an analytical method for the concurrent determination of ethanol, methanol, and formate. METHODS: Following the modification of a previously developed gas chromatography method, vitreous and blood samples of 43 postmortem cases with a history of methanol intoxication were collected over a period of 2 years at the Legal Medicine Organization of Mashhad. Thereafter, ethanol, methanol, and formate concentrations were measured by headspace GC/FID. Formate esterification was performed by the methylation of formate with sulfuric acid and methanol. In order to confirm the esterification method for the production of methyl formate, we used gas chromatography with a mass detector (GC/MS) because of its higher sensitivity and accuracy. Furthermore, the correlations between formate and methanol concentrations in blood and vitreous samples, and between formate and methanol were investigated. RESULTS: A significant relationship was found only between methanol concentrations in blood and vitreous samples (P < 0.03). CONCLUSIONS: In postmortems, with the passage of time since alcohol ingestion, the measurement of only methanol concentration cannot determine the degree of toxicity or the cause of death. Therefore, using the present analytical method and measurement of formic acid, we can estimate the degree of toxicity and cause of death.