Targeting Cytokine Storm to Manage Patients with COVID-19: A Mini-Review

Corona Virus Disease 2019 (COVID-19) pandemic is rapidly spreading all over the world. Excessive immune responses trigger life-threatening cytokine release syndrome (CRS) which can result in overproduction of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β with different pro-inflammatory roles. Anecdotal evidence suggests that the modulation of systemic immune responses may have a potential role in the treatment of patients with COVID-19. Given the importance of the issue and the lack of therapeutic treatment or vaccine; anti-cytokine therapy such as IL-6, TNFα and IL-1 antagonists have been suggested for the alleviation of hyper-inflammation status in these patients. In this mini-review, we addressed the inflammatory pathways of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relationship with the host cytokine storm. Furthermore, the proposed therapeutic options to reverse hyper-inflammation in infected patients were mentioned. © 2020 IMS

The effectiveness of ω-3 polyunsaturated fatty acid interventions during pregnancy on obesity measures in the offspring: an up-to-date systematic review and meta-analysis.

BACKGROUND: The potential role of ω-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on subsequent risk of obesity outcomes in the offspring is not clear and there is a need to synthesise this evidence. OBJECTIVE: A systematic review and meta-analysis of randomised controlled trials (RCTs), including the most recent studies, was conducted to assess the effectiveness of ω-3 LCPUFA interventions during pregnancy on obesity measures, e.g. BMI, body weight, fat mass in offspring. METHODS: Included RCTs had a minimum of 1-month follow-up post-partum. The search included CENTRAL, MEDLINE, SCOPUS, WHO's International Clinical Trials Reg., E-theses and Web of Science databases. Study quality was evaluated using the Cochrane Collaboration's risk of bias tool. RESULTS: Eleven RCTs, from ten unique trials, (3644 children) examined the effectiveness of ω-3 LCPUFA maternal supplementation during pregnancy on the development of obesity outcomes in offspring. There were heterogeneities between the trials in terms of their sample, type and duration of intervention and follow-up. Pooled estimates did not show an association between prenatal intake of fatty acids and obesity measures in offspring. CONCLUSION: These results indicate that maternal supplementation with ω-3 LCPUFA during pregnancy does not have a beneficial effect on obesity risk. Due to the high heterogeneity between studies along with small sample sizes and high rates of attrition, the effects of ω-3 LCPUFA supplementation during pregnancy for prevention of childhood obesity in the long-term remains unclear. Large high-quality RCTs are needed that are designed specifically to examine the effect of prenatal intake of fatty acids for prevention of childhood obesity. There is also a need to determine specific sub-groups in the population that might get a greater benefit and whether different ω-3 LCPUFA, i.e. eicosapentaenoic (EPA) vs. docosahexanoic (DHA) acids might potentially have different effects

Risk of stroke in hospitalized SARS-CoV-2 infected patients: A multinational study

Background: There is an increased attention to stroke following SARS-CoV-2. The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. Methods: This multicentre, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). The outcome was the risk of subsequent stroke. Centres were included by non-probability sampling. The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined protocol. Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Bivariate logistic regression was used to determine the parameters with predictive outcome value. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. Findings: We received data from 26,175 hospitalized SARS-CoV-2 patients from 99 tertiary centres in 65 regions of 11 countries until May 1st, 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9) patients had a stroke�123(79) ischaemic stroke, 27(17) intracerebral/subarachnoid hemorrhage, and 6(4) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5 among all centres in all countries, and 0.7 among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95 CI:1.1�3.5, p = 0.03) and the presence of ischaemic heart disease (OR: 2.5, 95 CI:1.4�4.7, p = 0.006) were predictive of stroke. Interpretation: The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5(pooled risk: 0.9). The need for mechanical ventilation and the history of ischaemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients. Funding: None. © 2020 The Author

Effect of surgical experience and spine subspecialty on the reliability of the {AO} Spine Upper Cervical Injury Classification System

OBJECTIVE The objective of this paper was to determine the interobserver reliability and intraobserver reproducibility of the AO Spine Upper Cervical Injury Classification System based on surgeon experience (< 5 years, 5–10 years, 10–20 years, and > 20 years) and surgical subspecialty (orthopedic spine surgery, neurosurgery, and "other" surgery). METHODS A total of 11,601 assessments of upper cervical spine injuries were evaluated based on the AO Spine Upper Cervical Injury Classification System. Reliability and reproducibility scores were obtained twice, with a 3-week time interval. Descriptive statistics were utilized to examine the percentage of accurately classified injuries, and Pearson’s chi-square or Fisher’s exact test was used to screen for potentially relevant differences between study participants. Kappa coefficients (κ) determined the interobserver reliability and intraobserver reproducibility. RESULTS The intraobserver reproducibility was substantial for surgeon experience level (< 5 years: 0.74 vs 5–10 years: 0.69 vs 10–20 years: 0.69 vs > 20 years: 0.70) and surgical subspecialty (orthopedic spine: 0.71 vs neurosurgery: 0.69 vs other: 0.68). Furthermore, the interobserver reliability was substantial for all surgical experience groups on assessment 1 (< 5 years: 0.67 vs 5–10 years: 0.62 vs 10–20 years: 0.61 vs > 20 years: 0.62), and only surgeons with > 20 years of experience did not have substantial reliability on assessment 2 (< 5 years: 0.62 vs 5–10 years: 0.61 vs 10–20 years: 0.61 vs > 20 years: 0.59). Orthopedic spine surgeons and neurosurgeons had substantial intraobserver reproducibility on both assessment 1 (0.64 vs 0.63) and assessment 2 (0.62 vs 0.63), while other surgeons had moderate reliability on assessment 1 (0.43) and fair reliability on assessment 2 (0.36). CONCLUSIONS The international reliability and reproducibility scores for the AO Spine Upper Cervical Injury Classification System demonstrated substantial intraobserver reproducibility and interobserver reliability regardless of surgical experience and spine subspecialty. These results support the global application of this classification system

Apelin-13 serum levels in type 2 diabetic obese women: possible relations with microRNAs-107 and 375

Objective: Apelin, an adipocytokine, is up-regulated by insulin and suppresses pancreatic insulin secretion. One of the key microRNAs in insulin resistance caused by obesity, is microRNA-107. MicroRNA-375 is expressed in the pancreatic islet cells. We aimed to explore apelin-13 and microRNA-107 and 375 in obese women with type 2 diabetes (T2D). Materials and Methods: Fifty obese women with newly diagnosed T2D and 50 non-diabetic obese women, as controls, were selected. Quantitative PCR and ELISA were used to measure the expression of microRNA-107 and 375 and Apelin-13 concentration, respectively. The role of apelin-13 was investigated in an in vitro model. Apoptosis was evaluated by flow cytometry. Results: Apelin-13 levels in diabetics were significantly more than controls (p = 0.012). The expressions of microRNA-107 and 375 of diabetic group were increased, in comparison to the control group. There was no correlation between apelin-13 and microRNA-107 and 375 in diabetic and control groups. Significant correlations between apelin-13 and serotonin (p <0.001) and estimated average glucose (p <0.02) and insulin (p <0.03) were only observed in the diabetic group. Conclusion: Serum levels of apelin-13 and circulating microRNA-107 and 375 could be used as biomarkers for diabetes, particularly in obese subjects. However, more study is needed in this field

A comprehensive systematic review of the effectiveness of Akkermansia muciniphila, a member of the gut microbiome, for the management of obesity and associated metabolic disorders

Aims and background: Obesity is recognised as a significant public health burden worldwide. Recently the cross-talk between gut microbiota and obesity has attracted much attention. To that end, Akkermansia muciniphila has been proposed as a promising microbe to manage obesity. In the present systematic review, we evaluated evidence on the effectiveness and mechanisms of action of Akkermansia muciniphila supplementation in the management of obesity. Methods: Electronic databases of MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar were searched thought March 2020 to identify relevant published articles, and eligible articles were systematically reviewed. Results and conclusions: Fifteen studies were included in the present study. Findings from the present review, which included human and animal (rodent) models support the effectiveness of Akkermansia supplementation as a novel therapeutic approach for the management of obesity and metabolic complications associated with obesity. However, future clinical trials are warranted to verify these outcomes. © 2021 Informa UK Limited, trading as Taylor & Francis Group

Effects of saffron supplementation on glycemia and inflammation in patients with type 2 diabetes mellitus: A randomized double-blind, placebo-controlled clinical trial study

Background: New evidence indicates that overproduction of pro-inflammatory cytokines is responsible for the development of diabetes difficulties. Some herbals such as saffron, may control inflammation and improve the hyperglycemic states in diabetic patients. Therefore, this investigation aimed to assess the effects of saffron supplementation on fasting glucose and inflammatory markers levels in patients with type2 diabetes mellitus (T2DM). Methods: In this randomized double-blind, placebo-controlled clinical trial, 60 T2DM patients were randomly assigned into two groups as saffron and placebo (n = 30) receiving 100 mg/day saffron powder or starch capsules (1 capsule) for a duration of 8 weeks. Fasting blood sample was collected at baseline and at the end of the intervention. Fasting blood glucose (FBG) was immediately analyzed by the auto-analyzer. The serum level of Interleukin �6 (IL-6), Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) were measured using ELISA assay by laboratory kits. Also, Real-time quantitative reverse transcription (RT-PCR) assay measured the expression level of TNF-α, IL-6, and IL-10 at the mRNA level. Results: Saffron supplementation significantly decreased the FBG levels within 8 weeks compared to placebo (130.93 ± 21.21 vs 135.13 ± 23.03 mg/dl, P = 0.012). Moreover, the serum level of TNF-α notably reduced in the saffron group compared to the placebo group (114.40 ± 24.28 vs 140.90 ± 25.49 pg/ml, P < 0.001). Also, saffron supplementation significantly down-regulated the expressions of TNF-α (P = 0.035) and IL-6 mRNA levels (P = 0.014). Conclusion: In our study, it was indicated that saffron modulates glucose levels as well as inflammation status in T2DM patients through decreasing the expressions levels of some inflammatory mediators. Also, further investigations are necessary to confirm the positive effects of saffron as a complementary therapy for T2DM patients. © 2020 Diabetes Indi

The suppression of TXNIP and miR-200c improve beta-cell function in patients with Type 2 diabetes: A randomized, double-blind, placebo-controlled trial

The past decade has witnessed for high prevalence of various metabolic, lifestyle, and diet-related maladies such as diabetes. Currently, one of the new treatment methods and approaches for controlling chronic degenerative diseases such as diabetes is dissecting the disease's molecular mechanisms. The aim of this study was to evaluate the beneficial effects of sodium butyrate and inulin supplementation on the beta-cell function and inflammatory responses through molecule-based mechanisms in patients with Type 2 diabetes. In this clinical trial, 60 patients with Type 2 diabetes were recruited from the north-western part of Iran. The participants were allocated to one of the four treatment orders. Group A took six capsules of 100 mg of NaBut daily, group B took 10 g of HP inulin supplement powder daily, group C consumed both the supplements, and group D took placebo. Before and after the intervention, we assessed the thioredoxin-interacting protein (TXNIP), interleukin-6, and interleukin-10 mRNA expression, as well as noting the plasmatic levels of the miR-204, miR-200c, and miR-21. A homeostasis model assessment of beta-cells (HOMA-β) was used to evaluate the function of the pancreatic beta-cells. The results showed that TXNIP expression was over three times higher in the placebo group as compared to the butyrate + inulin group (p = 0.045). Furthermore, the plasmatic levels of miR-200c expression decreased in the groups A (butyrate) and C (butyrate + inulin) (p < 0.001), as opposed to its constant level in the placebo. Interestingly, IL-6 mRNA expression decreased after butyrate (p < 0.001) and butyrate + inulin supplementation (p < 0.001). Our results revealed new insights into how TXNIP functions have a role in controlling diabetes. The newly identified TXNIP-miR-200c-IL-6-beta-cell function pathway may contribute to diabetes progression. Inhibiting TXNIP and miR-200c activity may be a potential pharmacological target to promote beta-cell function. © 2018 Elsevier Lt

Effects of oral butyrate and inulin supplementation on inflammation-induced pyroptosis pathway in type 2 diabetes: A randomized, double-blind, placebo-controlled trial

Purpose: Pyroptosis, a form of inflammatory programmed cell death, is activated in diabetic patients. This study was conducted to investigate the effects of daily consumption of sodium butyrate (NaBut) and high-performance (HP) inulin supplementation, individually or in combination, on the expression of pyroptosis-related genes, microRNA (miR) 146a-5p, miR-9-5p and biomarkers of oxidative stress in patients with type 2 diabetes (T2DM). Methods: In this study, we conducted a randomized, double-blinded, placebo-controlled clinical involving sixty patients with type 2 diabetes. Participants received 600 mg/d of NaBut (group A), 10 g/d of HP inulin (group B), 600 mg/d of NaBut + 10 g/d of HP inulin (group C) or placebo (group D) for 45 consecutive days. We assessed the pyroptosis-related genes mRNA expression in peripheral blood mononuclear cells (PBMCs), as well as the plasmatic levels of miR-146a and miR-9 before and after the intervention. Moreover, blood samples of the patients at baseline and following the intervention were tested for total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase levels using enzyme-linked immunosorbent assay (ELISA). This study was registered on the Iranian Registry of Clinical Trials website (identifier: IRCT201605262017N29; https://www.irct.ir/). Results: Following butyrate supplementation, the relative expression levels of TLR2/4, NF-κB1, Caspase-1, NLRP3, IL-1β & IL-18 were significantly downregulated (p < 0.05). Furthermore, butyrate and concomitant use of butyrate and inulin caused a significant increase in the fold change of miR-146a and miR-9 compared with the placebo group (p < 0.05). Interestingly, the changes in total antioxidant capacity (p = 0.047) and superoxide dismutase (p = 0.006) were significantly increased after butyrate and concomitant use of butyrate and inulin supplement, respectively. Conclusion: In summary, the change in expression level of miR-146a-5p and miR-9-5p due to butyrate supplementation may have a pivotal role in alleviating of diabetes via inhibiting pyroptosis by targeting TLR2 and NF-κB1. These microRNAs might be considered as potential therapeutic targets in the treatment of type 2 diabetes but further researches is required to prove the link. © 202

The effects of sodium butyrate and high-performance inulin supplementation on the promotion of gut bacterium Akkermansia muciniphila growth and alterations in miR-375 and KLF5 expression in type 2 diabetic patients: A randomized, double-blind, placebo-controlled trial

Introduction: The aim of this study is to evaluate the effect of sodium butyrate and High-Performance (HP) inulin supplementation on the promotion of gut bacterium Akkermansia muciniphila growth and alterations in microRNA-375 and Krüppel-like factor 5 (KLF5) expression in patients with T2D. Methods: In this clinical trial, 60 patients with T2D were recruited and randomly allocated into four groups of equal size to receive 600 mg/day sodium butyrate (Group A), 10 g/day inulin powder (Group B), concomitant use of inulin and sodium butyrate (Group C), or placebo (Group D). Blood and stool samples were collected pre- and post-intervention. Quantitative real-time PCR analysis targeting the 16S rRNA gene of A.muciniphila was performed to determine its presence in the patient's stool. In addition, we assessed the KLF5 mRNA expression and the plasmatic level of the microRNA-375 before and after the intervention. Results: The results showed that A. muciniphila percent change increased significantly after supplementation with HP inulin (p = 0.017) and butyrate (p = 0.036). Also, supplementation with HP inulin significantly decreased the KLF5 fold change after intervention (fold change 0.42 ± 0.15, p = 0.037). In particular, in comparison to the placebo group, an increased expression of miR-375 was seen after butyrate and butyrate+ inulin supplementation (P = 0.003 and P = 0.007 respectively). Conclusions: We concluded that inulin and butyrate may potentially promote gut health and can be considered as novel therapeutic approache for the prevention and control of diabetes. © 2018 Elsevier Gmb