Understanding the pathophysiology of Covid-19 : a review of emerging concepts

Coronavirus disease 2019 (COVID-19) was first described in the Chinese city of Wuhan in December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the causative agent. It was quickly established that SARS-CoV-2 is transmitted through respiratory droplets when individuals are in close contact with asymptomatic or symptomatic carriers. The incubation period is around 5 days, and it is estimated in up to 97% of infected individuals symptoms will present within 14 days. To date, new presentations are being described. COVID-19 presentation spans from asymptomatic, mild disease to sever systemic disease. The most commonly described symptoms include pneumonia, dyspnea, dry cough, headache and fever. Various companies have developed quantitative polymerase chain reaction (qPCR) assays for the detection of SARS-CoV-2 from mainly nasopharyngeal or throat swab. Several serological tests have also now been approved for use. A lot has been learnt of the laboratory and clinical characteristics of this disease, questions still remain as to the actual pathophysiology leading to either asymptomatic, mild or sever disease. However, despite this, the disease carries the risk of sepsis and acute respiratory failure with increased number of death tolls, forced social distance and lockdowns in many countries. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death. With the exception of when there is a pre-existing co-morbidity, most reports indicate sever disease occurring in the older population and mild disease or asymptomatic infection in children. Over 120 SARS-CoV-2 vaccines are at various stages of development. As the roll-out of approved vaccines is happens at different rates globally, the prescribed methods to reduce transmission remain facemasks, social distancing, and contact tracing

Modulation of miRNAs by natural agents: Nature’s way of dealing with cancer: DOI: 10.14800/rd.861

Accumulating lines of evidence have revealed that microRNAs (miRNAs) play critical roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation. They act either as tumour suppressors or oncogenes, and alteration in their expression patterns has been linked to onset, progression and chemoresistance of various cancers. Moreover, miRNAs are also crucial for the regulation of cancer stem cells (CSCs) self-renewal and proliferation as well as control of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Several experimental and epidemiologic studies have shown that dietary intake of natural agents such as baicalin, ginsenoside, curcumin, resveratrol, genistein, epigallocatechin-3-gallate (EGCG), indole-3-carbinol, 3,3?-diindolylmethane (DIM) including antioxidants among others is inversely associated with the risk for cancer, demonstrating the inhibitory effects of natural agents on carcinogenesis. Moreover, the anticancer agents from natural plants have been found to inhibit the development and progression of cancer through the regulation of cellular signaling pathways. Importantly, natural agents also up-regulate the expression of tumor-suppressive miRNAs and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of cancer cell growth and cancer stem cell self-renewal through modulation of cellular signaling network. Furthermore, natural agents also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in cancer cells. Therefore, natural agents could have much broader use in the prevention and/or treatment of various types of cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of natural agents in the prevention and/or treatment of cancer. Herein, we provide an overview of natural agents’ modulation of miRNA expression as well as highlight the significance of these observations as potential new strategies in cancer therapies. This review will help us to know in detail how miRNAs are regulated by natural agents and also help to develop more effective and secure natural agents for clinical therapies

Long Term Perinatal Deltamethrin Exposure Alters Electrophysiological Properties of Embryonic Ventricular Cardiomyocyte

Increased use of pyrethroids and the exposure to pyrethroids for pregnant women and children have raised the concerns over the potential effect of pyrethroids on developmental cardiotoxicity and other abnormalities. The purpose of this study was to investigate whether long term perinatal deltamethrin exposure altered embryonic cardiac electrophysiology in mice. Pregnant mice were administered with 0 or 3 mg/kg of deltamethrin by gavage daily from gestational day (gd) 10.5 to gd 17. 5. Whole cell patch-clamp technique was used in electrophysiological study, and real time RT-PCR was applied to analyze the molecular changes for the electrophysiological properties. Deltamethrin exposure resulted in increased mortality of pregnant mice and decreased viability of embryos. Moreover, deltamethrin slowed the maximum depolarization velocity (Vmax), prolonged the action potential duration (APD) and depolarized the maximum diastolic potential (MDP) of embryonic cardiomyocytes. Additionally, perinatal deltamethrin exposure decreased the mRNA expression of Na+ channel regulatory subunit Nav1, inward rectifier K+ channel subunit Kir2.1, and delayed rectifier K+ channel subunit MERG while the L-type Ca2+ channel subunit, Cav1.2 expression was increased. On the contrary, deltamethrin administration did not significantly alter the regulation of -adrenergic or muscarinic receptor on embryonic cardiomyocytes. In conclusion, deltamethrin exposure at perinatal stage significantly alters mRNA expression of embryonic cardiac ion channels and therefore influences embryonic cardiac electrophysiological properties. This highlights the need to understand the persistent effects of pyrethroid exposure on cardiac function during embryonic development due to potential for cardiac arrhythmogenicity

Traditional Chinese Medicine Baicalin Suppresses mESCs Proliferation through Inhibition of miR-294 Expression

Background: Traditional Chinese herbal medicines (TCMs) have been widely used against a broad spectrum of biological activities, including influencing the cardiac differentiation from mouse embryonic stem cells (mESCs). However, their effects and mechanisms of action on ESCs proliferation remain to be determined. The present study aimed to determine the effect of three TCMs, baicalin, ginsenoside Rg1, and puerarin, on mESCs proliferation and to elucidate the possible mechanism of their action. Methods: Cell proliferation was examined with a cell proliferation assay Cell Counting Kit-8 (CCK-8), propidium iodide (PI) staining was used to visualize cell cycle. The mRNA expression level of c-myc, c-fos, c-jun, GAPDH and microRNAs were measured by quantitative real time RT-PCR. Results: We found that baicalin 50 mu M suppressed the proliferation of mESCs as observations in more cells in G1 phase and less cells in either S phase or G2/M phase. Moreover, baicalin suppressed the expressions of c-jun and c-fos in mESCs and down-regulated the expression of miR-294. Overexpression of miR-294 in mESCs significantly reversed the effects of baicalin both on mESC proliferation and c-fos/c-jun expression. Conclusions: Baicalin down-regulation of miR-294 may be its key mechanism of action in decreasing mESCs proliferation. Copyright (C) 2015 S. Karger AG, Base

Thymosin beta 4 impeded murine stem cell proliferation with an intact cardiovascular differentiation

Thymosin beta 4 (T beta 4) is a key factor in cardiac development, growth, disease, epicardial integrity, blood vessel formation and has cardio-protective properties. However, its role in murine embryonic stem cells (mESCs) proliferation and cardiovascular differentiation remains unclear. Thus we aimed to elucidate the influence of T beta 4 on mESCs. Target genes during mESCs proliferation and differentiation were detected by real-time PCR or Western blotting, and patch clamp was applied to characterize the mESCs-derived cardiomyocytes. It was found that T beta 4 decreased mESCs proliferation in a partial dose-dependent manner and the expression of cell cycle regulatory genes c-myc, c-fos and c-jun. However, mESCs self-renewal markers Oct4 and Nanog were elevated, indicating the maintenance of self-renewal ability in these mESCs. Phosphorylation of STAT3 and Akt was inhibited by T beta 4 while the expression of RAS and phosphorylation of ERK were enhanced. No significant difference was found in BMP2/BMP4 or their downstream protein smad. Wnt3 and Wnt11 were remarkably decreased by T beta 4 with upregulation of Tcf3 and constant beta-catenin. Under mESCs differentiation, T beta 4 treatment did not change the expression of cardiovascular cell markers alpha-MHC, PECAM, and alpha-SMA. Neither the electrophysiological properties of mESCs-derived cardiomyocytes nor the hormonal regulation by Iso/Cch was affected by T beta 4. In conclusion, T beta 4 suppressed mESCs proliferation by affecting the activity of STAT3, Akt, ERK and Wnt pathways. However, T beta 4 did not influence the in vitro cardiovascular differentiation

Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency

Mbd3, a member of nucleosome remodeling and deacetylase (NuRD) co-repressor complex, was previously identified as an inhibitor for deterministic induced pluripotent stem cell (iPSC) reprogramming, where up to 100% of donor cells successfully complete the process. NuRD can assume multiple mutually exclusive conformations, and it remains unclear whether this deterministic phenotype can be attributed to a specific Mbd3/NuRD subcomplex. More-over, since complete ablation of Mbd3 blocks somatic cell proliferation, we aimed to explore functionally relevant alternative ways to neutralize Mbd3-dependent NuRD activity. We identify Gatad2a, a NuRD-specific subunit, whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC differentiation and reprogramming without ablating somatic cell proliferation. Inhibition of Gatad2a facilitates deterministic murine iPSC reprogramming within 8 days. We validate a distinct molecular axis, Gatad2a-Chd4-Mbd3, within Mbd3/NuRD as being critical for blocking reestablishment of naive pluripotency and further highlight signaling-dependent and post-translational modifications of Mbd3/NuRD that influence its interactions and assembly