Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)—short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain—a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).

Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences from in vitro and in vivo disease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.

(1) Background: Cannabis and tramadol are featuring prominently in Egypt; however, their prevalence in first episode psychosis is still uncertain. We aimed at determining the prevalence of cannabis and tramadol among the first-psychotic episode in Egyptian inpatients and to compare the demographic and psychopathological profiles of substance abusers versus patients with the comorbid diagnosis. (2) Methods: Patients presented with psychotic episode and admitted to Mansoura Psychiatric Department were recruited. Diagnosis of psychiatric illness and drug/substance use was carried out using the Diagnostic and Statistical Manual- Fourth Edition (DSM-IV) criteria. Standard urine tests and thin layer chromatography were performed to detect cannabis and tramadol. (3) Results: Of the 100 subjects in the study, the majority (55.6%) of patients were cannabis-only positive. Overall, cannabis-alone showed the highest frequency of substance used among the currently diagnosed psychotic disorders. According to urine tests, cannabis demonstrates the higher frequency of intake in both studied groups. 66.7% of the studied population had 1–5 years self-reported histories of substance abuse predating the first psychotic episode. (4) Conclusions: The percentage of cannabis and tramadol among the first episode psychotic patients has been unexpectedly high and the standard urine testing should be considered in emergency and mental health facilities.

The study aims to investigate: (1) the prevalence of cannabis among epileptic patients seen at Mansoura University Hospital, (2) serum levels and gene expression of cytokines in epilepsy patients and the controls. and (3) the possibility that cannabis use affects the cytokine levels in epilepsy patients, triggering its future use in treatment. We recruited 440 epilepsy patients and 200 controls matched for age, gender, and ethnicity. Of the epileptic patients, 37.5% demonstrated lifetime cannabis use with a mean duration of 15 ± 73 years. Serum levels of interleukin IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α), were analyzed and gene expression analysis was conducted only for those cytokines that were different between groups in the serum analysis. The “Epilepsy-only” patients had significantly higher serum and mRNA levels of IL-1α, β, IL-2,6,8, and TNF-α compared to the controls and the “Cannabis+Epilepsy” group (p = 0.0001). IL-10 showed significantly lower levels in the “Epilepsy-only” patients compared to the controls and “Cannabis+Epilepsy” (p = 0.0001). Cannabis use is prevalent among epilepsy patients. Epilepsy is characterized by a pro-inflammatory state supported by high serum and gene expression levels. Cannabis users demonstrated significantly lower levels of inflammatory cytokines compared to epilepsy non-cannabis users which might contribute to its use in the treatment of resistant epilepsy.

Background: Tramadol is an opioid analgesic with several adverse reactions. Oxidative and endoplasmic reticulum (ER) stresses have been involved in the molecular mechanisms underlying tramadol neurotoxicity. Importantly, protein kinase RNA-like ER kinase (PERK) is a key ER-downstream pathway that mediates apoptosis. We aimed to determine the cellular stresses interaction that mediates PERK-induced apoptosis in tramadol-treated rats and to assess the effect of thyme in enhancing the antioxidant defense system in the face of such stresses.Methods: Forty male Sprague Dawley rats were randomized into 4 groups. Control group, thyme group received thyme extract (500 mg/kg/day) orally. Tramadol group received tramadol HCL (40 mg/Kg/day) dissolved in saline orally. Tramadol + Thyme group received tramadol and thyme extract. After 30 days, frontal motor and cerebellar cortex specimens were biochemically assessed for oxidative stress biomarkers and evaluated for histological, ultrastructural and immunohistochemical changes. Results: Tramadol group showed a significant elevation in malondialdehyde level with a reduction in superoxide dismutase and catalase enzyme activities. Histologically and ultrastructurally, there were remarkable degenerative and apoptotic changes in the neurons and glial cells. In parallel, we detected a significant increase in integrated density for PERK immunostaining and number of caspase-3 positive cells/HPF compared to control. Tramadol + Thyme group showed improvement in oxidative stress parameters, histological and ultrastructural changes. Moreover, integrated density for PERK immunostaining and number of caspase-3 positive cells/HPF were significantly lower than Tramadol group.Conclusions: Oxidative and ER stress-mediated PERK/apoptosis axis corroborates to the tramadol-induced neurotoxicity. Therapeutic strategies enhancing antioxidant activity and/or blocking ROS-mediated ER stress pathway may resolve tramadol neurotoxicity.

Introduction:Crises, wars, and disasters are remarkably increasing across the world. Responders are frequently tackled with an ever-greater number of challenges, and undoubtedly, they are physically and mentally affected during and after their missions, during which posttraumatic stress disorder (PTSD) is considered high-risk. To the authors’ knowledge, no studies have addressed which type of incident has the greatest influence to trigger stress, and consequently, to cause PTSD for the responders after their missions.Methods:A prospective longitudinal study was conducted with 69 participants of the “Safety and Security” course at the Federal Office for Civil Protection and Disaster Aid of the Federal Ministry of Interior Affairs (Berlin, Germany). The course is certified by the Hostile Environment Awareness Training (HEAT) guidelines of Europe’s New Training Initiative for Civilian Crisis Management (ENTRi; Center for International Peace Operations; Berlin, Germany). Four incidents were evaluated: hostage-taking, carjacking, evacuation, and border-crossing. The participants completed the Positive and Negative Affect Schedule (PANAS) before and after each incident. For each incident, the delta of the PANAS scores was calculated. The differences between the described incidents, as well as the differences between novice and experienced responders, were evaluated.Results:The hostage-taking incident had the greatest influence on the participants’ temper, followed by carjacking and evacuation. Ultimately, the border-crossing event had the least effect on the responders. Novices were more affected by hostage-taking than experienced responders; however, no significant difference had been demonstrated between novices and experienced responders for the other evaluated incidents.Conclusion:Different incidents have big psychological impacts on humanitarian responders, in which consequences vary from short-term effects to PTSD. Therefore, humanitarian responders should be selected very carefully. They should also have more specific preparation for their missions. Mental after-care should be obligatory. Further studies are needed to understand and avoid reasons for the development of PTSD or other potential problems of responders.