Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation.

Known as a pivotal immunohemostatic response, immunothrombosis is activated to restrict the diffusion of pathogens. This beneficial intravascular defensive mechanism represents the close interaction between the immune and coagulation systems. However, its uncontrolled form can be life-threatening to patients with the critical coronavirus disease 2019 (COVID-19).

Cytokine storm in the pathophysiology of COVID-19: Possible functional disturbances of miRNAs.

SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis.

Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.

Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders.

A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases.

MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases.

The role of β-d-mannuronic acid, as a new non-steroidal anti-inflammatory drug on expression of miR-146a, IRAK1, TRAF6, NF-κB and pro-inflammatory cytokines following a clinical trial in rheumatoid arthritis patients.

miR-146a, its targets (IRAK1, TRAF6) and NF-κB transcription factor play a fundamental role in rheumatoid arthritis (RA). Positive effects of drug β-d-mannuronic acid (M2000) were proven on their expression in the HEK-Blue hTLR2 cell line, and results of its phase III clinical trial on RA patients were encouraging. This research aimed to investigate the effects of M2000 on expression of these genes and serum levels of IL-6 and TNF-α as pro-inflammatory cytokines in RA patients.

The Situation of Chemokine Ligands and Receptors Gene Expression, Following the Oral Administration of Drug Mannuronic Acid in Rheumatoid Arthritis Patients.

Background: Regarding the leukocytes infiltration into the synovium of Rheumatoid Arthritis (RA) patients is mostly mediated by chemokine ligands and receptors, and following the efficient and motivating results of international Phase III clinical trial of β-D-Mannuronic acid (M2000) patented EP067919 (2017), as a novel anti-inflammatory drug, in patients with RA, the present research was designed.

Objectives: This study aimed to assess the oral administration effects of this new drug on gene expression of some chemokine receptors and ligands, including CXCR4, CXCR3, CCR2, CCR5 and CCL2/MCP-1 in PBMCs of patients with active form of RA.

Methods: Twelve patients suffering from RA, with inadequate response to conventional drugs were selected (Clinical trial identifier IRCT2017100213739N10) and 1000mg/day of M2000 was orally administrated to them for 12 weeks.

Immunopharmacological effect of β-d-mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR-155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients.

The positive impacts of β-d-mannuronic acid (M2000) on the gene expression of miR-155, its target molecules (SOCS1 and SHIP1), and NF-κB transcription factor were demonstrated in a study using the HEK293-TLR2 cell line. This new drug has been approved as a safe and effective medication by a randomized, multinational, phase III clinical trial on RA patients. The present study aimed to evaluate the oral administration effect of M2000 on the expression levels of the mentioned genes in RA patients.

Anti-Diabetic and Angio-Protective Effect of Guluronic Acid (G2013) as a New Nonsteroidal Anti-Inflammatory Drug in the Experimental Model of Diabetes.

Background: This study aimed to investigate the effects of guluronic acid (G2013) on blood sugar, insulin, and gene expression profile of oxLDL receptors (SR-A, CD36, LOX-1, and CD68) in the experimental model of diabetes.

Methods: 18 Sprague Dawley rats were randomly assigned to three groups of healthy control, diabetic control, and G2013 group. Diabetes was induced through intraperitoneal (IP) injection of 60 mg/kg streptozotocin.

International multicenter randomized, placebo-controlled phase III clinical trial of β-D-mannuronic acid in rheumatoid arthritis patients.

Background: The oral administration of drug β-D-mannuronic acid (M2000) showed a potent therapeutic effect in phase I/II study in rheumatoid arthritis (RA) patients. Here, our aim is to assess the efficacy and safety of this new drug in RA patients under a multinational, randomized placebo-controlled phase III clinical trial.

Method: Patients (n = 288) with active disease at baseline and inadequate response to conventional drugs were randomly allocated to three groups; (1) receiving mannuronic acid at a dose of two capsules (500 mg) per day orally for 12 weeks, (2) placebo-controlled, and (3) conventional.

Assessment of immunological profile in ankylosing spondylitis patients following a clinical trial with guluronic acid (G2013), as a new NSAID with immunomodulatory properties.

The present research aims to study the effects of guluronic acid (G2013) on gene expression levels of the T-bet, GATA3, RORγt, AHR, and FOXP3 transcription factors and on gene expression of their related cytokines following oral administration of this drug in ankylosing spondylitis (AS) patients. In this trial (clinical trial identifier: IRCT2016091813739N4), 14 AS patients and 12 age- and sex-matched healthy individuals were enrolled. The level of transcription factors' gene expression and expression of their related cytokines were measured by quantitative real-time PCR, before and 3 months after G2013 therapy.

Anti-diabetic effect of -D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property on insulin production, blood glucose, and inflammatory markers in the experimental diabetes model.

This research aimed to evaluate the anti-diabetic effects of β-d-mannuronic acid (M2000) on blood glucose, insulin production, and inflammatory markers in streptozotocin-induced diabetic rats. Our data showed that the final fasting serum glucose level was significantly lower in the M2000-treated group compared to the diabetic control group ( < .05).

Evaluation of the Effect of α-L-Guluronic Acid (G2013) on COX-1, COX-2 Activity and Gene Expression for Introducing this Drug as a Novel NSAID with Immunomodulatory Property.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat the pathological pain and inflammation through inhibition of cyclooxygenase (COX) enzyme and disruption of the synthesis of prostaglandins (PGs). The α-L-guluronic acid (G2013) patented (PCT/EP2017/067920), as a novel NSAID with the immunomodulatory property, has been shown its positive effects in experimental models of multiple sclerosis and anti-aging.

Objective: This study was aimed to investigate the effects of G2013 on the gene expression and activity of COX-1/COX-2 enzymes in order to introduce a novel NSAID for the treatment of inflammatory diseases.

Effect of β-D-Mannuronic Acid (M2000) on Oxidative Stress Enzymes' Gene Using Healthy Donor Peripheral Blood Mononuclear Cells for Evaluating the Anti-Aging Property.

Objective: This research aimed to study the anti-aging and anti-inflammatory effects of low and high doses of the β-D-mannuronic (M2000) on gene expression of enzymes involved in oxidative stress (including SOD2, GST, GPX1, CAT, iNOS, and MPO) in peripheral blood mononuclear cells (PBMCs) of healthy donors under in vitro conditions.

Methods: The PBMCs were separated and the RNAs were then extracted and the cDNAs synthesized, and expression levels of the mentioned genes were detected by qRT-PCR.

Results: Our results indicated that the high dose of this drug could significantly reduce the expression level of the SOD2 gene compared to the lipopolysaccharide (LPS) group (p < 0.

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients.

Background: Following the potent efficacy of β-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy.

Method: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study.

Modification of Sexual Hormones in Rheumatoid Arthritis Patients by M2000 (β-D-mannuronic Acid) as a Novel NSAID with Immunosuppressive Property.

Background: Based on in-vitro, in-vivo and human studies, the β-D-mannuronic acid (M2000) has been introduced as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive properties.

Objective: This study aimed to evaluate the efficacy of this drug on serum level of sex hormones (Estradiol, Progesterone, and DHEAS) in rheumatoid arthritis (RA) patients.

Methods: The present research was performed on 10 RA patients who had an inadequate response to conventional treatments (clinical trial identifier: IRCT2014011213739N2).

Cardioprotective effect of β-d-mannuronic acid (M2000) as a novel NSAID on gene expression of oxLDL scavenger receptors in the experimental diabetic model.

Context: The investigations have shown that patients with diabetes have the elevated levels of glucose and oxLDL. These two play an important role in increased expression levels of oxLDL scavenger receptors on the surface of macrophages and endothelial cells that leads to deposition of oxLDL and macrophages in vascular walls.

Objective: The present study intends to show the effects of β-d-mannuronic acid (M2000) on the expression profile of ox-LDL scavenger receptors (including SR-A, LOX-1, CD36, and CD68) in an experimental model of diabetes.

Oral administration effects of β-d-mannuronic acid (M2000) on Th17 and regulatory T cells in patients with ankylosing spondylitis.

Background: To explore the effects of β-d-mannuronic acid (M2000) on levels of Th17, regulatory T (Treg) cells and their related cytokines in patients with ankylosing spondylitis (AS).

Methods: 30 AS patients and 15 age and sex-matched healthy individuals were enrolled in this study. The frequencies of Th17 and Treg cells and serum levels of related cytokines were measured by flow cytometry analysis and ELISA respectively, before (baseline) and 3 months after M2000 therapy.

Effects of guluronic acid (G2013) on SHIP1, SOCS1 induction and related molecules in TLR4 signaling pathway.

Objective: This research aimed to study the anti-inflammatory and immunomodulatory effects of guluronic acid (G2013) on gene expression of TLR4, MyD88, SHIP1, SOCS1, NF-κB, and assessment of the level of IL-1β as a pro-inflammatory cytokine in HEK-Blue hTLR4 cell line.

Methods: The cytotoxicity of G2013 was assessed by the MTT assay. The mRNA expression levels of the mentioned genes were measured by qRT-PCR.

Anti-angiogenesis effect of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model.

Angiogenesis is a process through which new capillaries are formed from pre-existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The β-D-mannuronic acid (M2000) is a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive effects and is a matrix metalloproteinase (MMP) inhibitor. This research aimed to study the anti-angiogenesis effects of M2000 under in vitro and in vivo models.

Introduction of β-d-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property based on COX-1/COX-2 activity and gene expression.

Background: The NSAIDs which inhibit the cyclooxygenase (COX) enzymes are among medications widely used to treat pain and inflammation. These drugs cause digestive complications resulting in inhibition of the COX-1 enzyme, while the inhibition of the COX-2 enzyme has therapeutic effects. Therefore research focuses on the production of medications that specifically inhibit the COX-2 enzyme.

An in vitro evaluation of anti-aging effect of guluronic acid (G2013) based on enzymatic oxidative stress gene expression using healthy individuals PBMCs.

Background: Aging is usually associated with increased levels of oxidants, and may result in damages caused by oxidative stress. There is a direct relationship between aging and increased incidence of inflammatory diseases. The present research intended to study the anti-aging and anti-inflammatory effects of the drug G2013 (guluronic acid) at low and high doses on the genes expression of a number of enzymes involved in oxidative stress (including SOD2, GPX1, CAT, GST, iNOS, and MPO) in peripheral blood mononuclear cells (PBMCs) of healthy individuals under in vitro conditions.

Pharmacological effects of β-d-mannuronic acid (M2000) on miR-146a, IRAK1, TRAF6 and NF-κB gene expression, as target molecules in inflammatory reactions.

Background: Impaired expression and function of microRNAs (miRNAs) are involved in the pathogenesis of many autoimmune and inflammatory diseases. Moreover, there is a close relationship between TLRs and miRNAs and impairment in regulating their expression which can play a vital role in the immunopathogenesis of many inflammatory reactions. This research aimed to study the pharmaceutical effects of M2000 (β-d-mannuronic acid) on the expression of miR-146a and its two target molecules (IRAK1 and TRAF6), and the transcription factor NF-κB in the HEK-Blue hTLR2 cell line.