Renal, cardiac, neurological, cutaneous and coagulopathic long-term manifestations of COVID-19 after recovery; A review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel global coronavirus disease 2019 (COVID-19) disease outbreak. Its pathogenesis is mostly located in the respiratory tract. However, other organs are also affected. Hence, realising how such a complex disturbance affects patients after recovery is crucial. Regarding the significance of control of COVID-19-related complications after recovery, the current study was designed to review the cellular and molecular mechanisms linking COVID-19 to significant long-term signs including renal and cardiac complications, cutaneous and neurological manifestations, as well as blood coagulation disorders. This virus can directly influence on the cells through Angiotensin converting enzyme 2 (ACE-2) to induce cytokine storm. Acute release of Interleukin-1 (IL1), IL6 and plasminogen activator inhibitor 1 (PAI-1) have been related to elevating risk of heart failure. Also, inflammatory cytokines like IL-8 and Tumour necrosis factor-α cause the secretion of von Willebrand factor (VWF) from human endothelial cells and then VWF binds to Neutrophil extracellular traps to induce thrombosis. On the other hand, the virus can damage the blood-brain barrier by increasing its permeability and subsequently enters into the central nervous system and the systemic circulation. Furthermore, SARS-induced ACE2-deficiency decreases [des-Arg9]-bradykinin (desArg9-BK) degradation in kidneys to induce inflammation, thrombotic problems, fibrosis and necrosis. Notably, the angiotensin II-angiotensin II type 1 receptor binding causes an increase in aldosterone and mineralocorticoid receptors on the surface of dendritic cells cells, leading to recalling macrophage and monocyte into inflammatory sites of skin. In conclusions, all the pathways play a key role in the pathogenesis of these disturbances. Nevertheless, more investigations are necessary to determine more pathogenetic mechanisms of the virus.

Positive Correlation between Circulating Fetuin-A and Severity of Coronary Artery Disease in Men.

OBJECTIVE: Fetuin-A serves a dual function; its high levels are associated with metabolic syndrome, type 2 diabetes, obesity, insulin resistance, and nonalcoholic fatty liver disease, and on the other hand, it serves as a potent inhibitor of ectopic vascular calcification. Due to the opposing findings, the aim of the current study was to investigate serum fetuin-A levels in men with coronary artery disease (CAD). METHODS: In the case-control study, anthropometric and biochemical parameters were determined in 83 men (43 CAD patients and 40 control subjects). At last, the serum fetuin-A levels were measured using the fetuin-A human enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: A significant difference was detected among the two groups for triglyceride and cholesterol levels (P=0.003 and P=0.002, respectively). The mean fetuin-A levels were determined 230.57 ± 63.76 and 286.35 ± 64.07 µg/ml for the control group and the CAD patients, respectively (P<0.001). Fetuin- A was significantly correlated to the severity of CAD (r 0.393, P<0.001) and associated with the risk of CAD in subjects (OR [CI] = 1. 144 [1.060-1. 235]; p = 0.001). A cut-off value of 237.4 µg/ml had good sensitivity (76.7%) and specificity (65.0%) for differentiating between two groups [area under curve (AUC) = 0.732 (CI=0.621-0.842); p < 0.001]. CONCLUSION: Our results indicated that fetuin-A levels were positively correlated to the severity of CAD. The findings suggest that there is a possible link between pathogenic mechanisms of atherosclerosis and fetuin-A; however, more investigations are needed in this regard.

Anti-Inflammatory Effects of Plasma Circulating Exosomes Obtained from Normal-Weight and Obese Subjects on Hepatocytes.

INTRODUCTION: Obesity is a disorder with low-grade chronic inflammation that plays a key role in hepatic inflammation and steatosis. Moreover, there are studies to support the role of exosomes in cellular communications, the regulation of metabolic homeostasis and immunomodulatory activity. Accordingly, we aimed to evaluate the influence of plasma circulating exosomes derived from females with normal-weight and obesity on the secretion of inflammatory cytokines in human liver cells. METHODS: Plasma circulating exosomes were isolated from four normal (N-Exo) and four obese (OExo) women. The exosomes were characterized and approved for CD63 expression (common exosomal protein marker) and morphology/size using the western blot and TEM methods, respectively. The exosomes were used for the stimulation of HepG2 cells in vitro. After 24 h of incubation, the protein levels of TNF-α, IL-6, and IL-1ß were measured in the culture supernatant of HepG2 cells using the ELISA kit. RESULTS: The protein levels of IL-6 and TNF-α in the cells treated with O-Exo and N-Exo reduced significantly in comparison with the control group (P=0.039 and P<0.001 respectively), while significant differences were not found between normal and obese groups (P=0.808, and P=0.978 respectively). However, no significant differences were found among the three groups in terms of IL-1ß levels (P=0.069). Based on the correlation analysis, the protein levels of IL-6 were positively correlated with TNF-α (r 0.978, P<0.001). CONCLUSION: These findings suggest that plasma circulating exosomes have probably antiinflammatory properties independent of body mass index and may decrease the secretion of inflammatory cytokines in the liver. However, further in vitro and in vivo investigations are needed to address the anti-inflammatory function of N-Exo and O-Exo in human liver cells and/or other cells.

Vitamin D Represses the Aggressive Potential of Osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the basic bone neoplasm with lower survival and poor prognosis. It is distinguished by its offensive nature and metastatic potential. The fundamental death source in OS patients is lung metastasis. In addition, the proliferation and cell migration are thus essential for cancer progression, especially for intrusion and transformation. Several studies have illustrated that 1,25-Dihydroxyvitamin D (1,25(OH)2D) has a critical role in the growth and differentiation of bone. However, knowledge of the outcome of 1,25(OH)2D on the progression and incursion of osteosarcoma cells is minimal. OBJECTIVE: The present study aimed to analyze the effect of different concentrations of 1,25(OH)2D on the multiplication, progression, and intrusion of OS cells and verify the effective doses of 1,25(OH)2D that can decrease the intensity of the disease and improving the prognosis in OS patients. METHODS: Saos-2 cells were treated with 1,25(OH)2D (0, 50, 100, and 200 nM) for 48, 72, and 96 hours. Proliferation, invasion, and migration were determined by MTT assay, Transwell assay, and Scratch test, respectively. The levels of c-Myc and FOXO1 proteins were determined by Western blotting. RESULTS: The proliferation, invasiveness, and migration of Saos-2 cells that were treated with 1,25(OH)2D were significantly decreased compared with untreated cells. Although 1,25(OH)2D notably decreased c-Myc protein levels (after 48 and 72 hours), FOXO1 protein levels have been significantly increased after 48 and 72 hours. 1,25(OH)2D and the vitamin D receptor (VDR) suppress c-Myc function through regulating the c-Myc/MXD1 network and thus, providing a molecular basis of 1,25(OH)2D related to the cancer-preventive actions. CONCLUSION: Based on the present results, 1,25(OH)2D by targeting c-Myc and FOXO1 expression displays anti-invasive, anti-migration and anti-proliferative effects on OS cells in vitro. Our findings suggest that effective doses of the 1,25(OH)2D may reduce the aggressive potential of the OS cell line. However, further investigation and clinical trials are needed.

Influence of plasma circulating exosomes obtained from obese women on tumorigenesis and tamoxifen resistance in MCF-7 cells.

Obesity is associated with breast cancer aggressiveness and drug resistance. Although the underlying mechanisms are unknown, recent studies indicated that exosomes have a principal contributory role in obesity-associated metabolic complications. Hence, we investigated whether obesity can mediate breast cancer progression and resistance to tamoxifen by plasma-derived-exosomes from obese women or not. Plasma exosomes isolated from five normal-weight (N-Exo) and five obese women (O-Exo) were characterized for size, zeta potential, and CD63 expression. After the treatment of MCF-7 cells with N-Exo and O-Exo, cell proliferation, migration, invasion as well as levels of MMP-9 and MMP-2 were evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing, transwell, and zymography methods, respectively. For evaluating resistance to tamoxifen, the cell viability, apoptosis, and the p53 protein were evaluated using the MTT assay, flow cytometry, and western blot methods, respectively. Cell proliferation, migration, and invasion were significantly increased in the cells treated with O-Exo than untreated cells (p = .001, p = .018, p = .034, respectively). Levels of MMP-2 and MMP-9 were remarkably increased in the cells treated with O-Exo in comparison with ones treated with N-Exo (p = .040, p = .043, respectively). As for resistance to tamoxifen, O-Exo had significantly the greater anti-apoptotic effects in comparison with the N-Exo group (p = .013). Besides, p53 levels were significantly decreased in the cells treated with O-Exo than ones treated with N-Exo (p = .045). The cell viability was significantly more in cells treated with O-Exo in comparison with the cells only treated with tamoxifen (p = .040). Our findings demonstrated that circulating exosomes derived from obese women could lead to tumorigenesis and tamoxifen resistance in breast cancer cells. However, more studies are needed to establish this notion.

Effect of circulating exosomes derived from normal-weight and obese women on gluconeogenesis, glycogenesis, lipogenesis and secretion of FGF21 and fetuin A in HepG2 cells.

BACKGROUND: It is generally accepted that obesity can lead to metabolic disorders such as NAFLD and insulin resistance. However, the underlying mechanism has been poorly understood. Moreover, there is evidence to support the possible role of exosomes in the metabolic homeostasis regulation. Accordingly, we aimed to determine the effect of plasma circulating exosomes derived from obese and normal-weight women on insulin signaling and the secretion of hepatokines in human liver cells. METHODS: Plasma exosomes isolated from four obese (O-Exo) women and four normal-weight (N-Exo) female candidates were characterized for size, zeta potential, and CD63 protein expression and were used for stimulation of HepG2 cells. Then, cell viability, as well as levels of glycogen and triglyceride (TG), were evaluated. Levels of fetuin-A and FGF21 were measured using the ELISA kit. Expression of glucose 6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) genes were determined using qRT-PCR. Western blot analysis was carried out to evaluating the phosphorylation of GSK3ß. RESULTS: The TG levels increased significantly in the cells treated with O-Exo than the control (vehicle) group (P = 0.005) and normal-weight group (P = 0.018). Levels of p-GSK3ß and glycogen were significantly reduced by O-Exo in comparison with control (P = 0.002, P = 0.018, respectively). The mRNA expression of G6pase and PEPCK enzymes increased in the cells treated with O-Exo in comparison with the vehicle group (P = 0.017, P = 0.010, respectively). The levels of FGF21 in the supernatant of cells treated with O-Exo and N-Exo were significantly lower than the control group (P = 0.007). CONCLUSION: It appears that obesity-related circulating exosomes can impair insulin signaling pathways and associated components, increase intracellular TG content, and decrease FGF21 secretion in the hepatocytes.

The Influence of Psychological Stress on the Initiation and Progression of Diabetes and Cancer.

CONTEXT: Psychological stress can be considered a risk factor for the initiation and progression of many pathological conditions, including type 1 and 2 diabetes mellitus and cancer. OBJECTIVES: The aim of this review article was to evaluate the molecular and cellular mechanisms linking psychological stress to the onset and progression of diabetes and cancer. EVIDENCE ACQUISITION: The current review was conducted to survey and analyze studies related to the effects of psychological stress on diabetes and cancer. RESULTS: Psychological stress may make individuals prone to the development of diabetes through the impairment of the hypothalamic-pituitary-adrenal (HPA) axis function, sympathetic nerves system (SNS), lipid profile, cytokines balance, renin-angiotensin system (RAS), and insulin signaling pathway. Additionally, psychological stress can contribute to the development of cancer through the perturbation in the HPA axis, SNS function, and cytokines balance. Psychological stress is also capable of decreasing the levels of oxytocin and dopamine, leading to an increased risk of cancer in susceptible individuals. CONCLUSIONS: It seems that psychological stress plays a significant role in the onset and progression of diabetes and cancer. The identification of the pathways triggered by psychological stress would open up a new avenue for the understanding of molecular mechanisms by which diabetes and cancer could be managed or even prevented.

Prevalence of Metabolic Syndrome among Iranian Population: A Systematic Review and Meta-analysis.

BACKGROUND: Metabolic syndrome (MetS) is the major risk factor for development of type 2 diabetes and cardiovascular diseases in different populations. The aim of this study was to evaluate the prevalence of MetS among Iranian population. METHODS: Thirty-four cross-sectional studies were analyzed with a sample of 83227 people. National and international English electronic databases (PubMed, Google scholar, Web of Science, Science Direct, and Scopus) and Persian language databases (SID, Medlib, Iran medex, Magiran, Medlib, and IranDoc) were used to search the articles published on MetS in Iranian population from Jan 2005 to May 2016. The MetS diagnosis was performed according to the ATP-III, NCEP/ATP-III, IDF and WHO criteria. RESULTS: The overall weighted prevalence of MetS was 31% (95% CI: 28-35). According to ATP III criteria, total and gender-stratified prevalence of MetS in women and men were 29% (95% CI: 22-36), 37% (95% CI: 26-48) and 29% (95% CI: 23-36), respectively. Total prevalence of MetS based on NCEP/ATP III criteria was 29% (95% CI: 24-35) that the prevalence was 24% (95% CI: 18-30) and 35% (95% CI: 25-44) in men and women, respectively. According to the IDF and WHO criteria, total prevalence of MetS were 38% (95% CI: 32-43) and 30% (95% CI: 7-53), respectively. CONCLUSION: The findings demonstrate an emerging high prevalence of MetS in total and in particular among Iranian women population. Therefore, to minimize the risk of cardiovascular events in Iranian population, screening and early detection of risk factors for MetS are required.

Salivary Testosterone Levels Under Psychological Stress and Its Relationship with Rumination and Five Personality Traits in Medical Students.

OBJECTIVE: The purpose of this study was to evaluate the salivary testosterone levels under psychological stress and its relationship with rumination and five personality traits in medical students. METHODS: A total of 58 medical students, who wanted to participate in the final exam, were selected by simple random sampling. Two months before the exam, in the basal conditions, the NEO Inventory short form, and the Emotional Control Questionnaire (ECQ) were completed. Saliva samples were taken from students in both the basal conditions and under exam stress. Salivary testosterone was measured by ELISA. Data was analyzed using multivariate analysis of variance with repeated measures, paired samples t-test, Pearson correlation and stepwise regression analysis. RESULTS: Salivary testosterone level of men showed a significant increase under exam stress (p<0.05). However, a non-significant although substantial reduction observed in women. A significant correlation was found between extroversion (r=-0.33) and openness to experience (r=0.30) with salivary testosterone (p<0.05). Extraversion, aggression control and emotional inhibition predicted 28% of variance of salivary testosterone under stress. CONCLUSION: Salivary testosterone reactivity to stress can be determined by sexual differences, personality traits, and emotional control variables which may decrease or increase stress effects on biological responses, especially the salivary testosterone.

Levels of salivary immunoglobulin A under psychological stress and its relationship with rumination and five personality traits in medical students

Background and Objectives: The measurement of salivary immunoglobulin A is a useful and non-invasive method for measuring stress. Personality traits and rumination act as possible mediators in the relationship between psychological stressors and the immune system. This study was aimed to evaluate the levels of salivary IgA under psychological stress and its relationship with rumination and five personality traits in medical students. Methods: In this cross- sectional study, 45 medical students who intended to participate in the final exam were selected by simple random sampling. Two months before the exam, in the peribasal conditions, the NEO Personality Inventory-Short Form and Emotional Control Questionnaire(ECQ) were completed. Saliva samples were taken from students in both the basal conditions and exam stress conditions. Salivary IgA was measured by an ELISA test. Data was analyzed using paired samples T-test, Pearson correlation analysis, and stepwise regression. Results: A significant reduction of salivary IgA levels was found in exam stress conditions. Also, a significant negative correlation was found between traits of neuroticism and rumination with salivary IgA, as well as a significant positive correlation between of openness to experience and emotional inhibition with salivary IgA. Openness to experience and emotional inhibition may predict a substantial variance (34%) of salivary IgA under exam stress. Conclusions: Salivary IgA is reduced in response to exam stress. In addition, the rumination and personality traits may reduce or increase stress effects on the immune system, particularly the salivary IgA (AU)

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