The Oral Administration Effect of Drug Mannuronic Acid (M2000) on Gene Expression of Matrix and Tissue Inhibitor of Metalloproteinases in Rheumatoid Arthritis Patients

2020 ◽  
Vol 17 (5) ◽  
pp. 704-710
Author(s):  
Nada A.G. Gaafar ◽  
Mona Aslani ◽  
Zahra Aghazadeh ◽  
Alireza Razavi ◽  
Abbas Mirshafiey
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Oral Administration ◽  
Therapeutic Efficacy ◽  
Gene Expression Level ◽  
Expression Level ◽  
Mannuronic Acid ◽  
Significant Difference ◽  
Before And After ◽  
Immunosuppressive Property

Background: Rheumatoid Arthritis (RA) is a complex disease involving an unknown number of genes, and affecting a large number of organs, tissues, and sites across the body. It is affecting approximately 1% of the population worldwide. The safety and therapeutic efficacy of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property has been demonstrated under in vitro, in vivo examinations and clinical trials phase 1/11 in Ankylosing Spondylitis (AS) patients in addition to phase I/11 and 111 in Rheumatoid Arthritis (RA) patients. Objective: In this study, our goal is to evaluate the therapeutic efficacy of oral administration of M2000 on gene expression of the matrix metalloproteinase (MMP2, MMP9) and tissue inhibitor of metalloproteinase (TIMP1, TIMP2) as inflammatory molecules in the progression of rheumatoid arthritis. Methods: The study has included 15 RA patients who had an insufficient response to the conventional drug. Therefore, mannuronic acid was used as an additive to the conventional regime. The research was a single-blinded study. The dose of M2000 was 500mg orally twice per day for 12 weeks. There were 15 healthy participants considered as control. Blood samples have been collected from both groups once from the healthy control and twice from RA patients before and after treatment with M2000. The Peripheral Blood Mononuclear Cells (PBMCs) were isolated for assessment of the gene expression level of MMP2, MMP9, TIMP1, and TIMP2 using the real-time PCR method. Results: The gene expression level of MMP2 and MMP9 reported a significant reduction in RA patients after treatment with M2000 compared to before treatment. On the other hand, the gene expression level of TIMP2 demonstrated a significant increase in RA patients after treatment with mannuronic acid compared to before treatment, but there was no significant difference between the group of RA patients before treatment and the control group. Vice versa to other molecules, there was no significant difference in the level of TIMP1 in compression with RA patients before and after treatment. Conclusion: our findings proved that the β -D- mannuronic acid) as a novel NSAID with immunosuppressive property has a significant effect on the gene expression level of MMP2, MMP9 and TIMP2 molecules in RA patients.

scholarly journals Effects of mannuronic acid (M2000) on gene expression profile of signal transducer and activator of transcription proteins (STATs) in rheumatoid arthritis patients

Reumatismo ◽  
2020 ◽  
Vol 72 (2) ◽  
pp. 93-102
Author(s):  
N.A.G. Gaafar ◽  
M. Aslani ◽  
Z. Aghazadeh ◽  
S.S. Mortazavi-Jahromi ◽  
A. Razavi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Conventional Therapy ◽  
Gene Expression Level ◽  
Expression Level ◽  
Control Group ◽  
Healthy Controls ◽  
Signal Transducer ◽  
Mannuronic Acid ◽  
Significant Difference

Rheumatoid arthritis (RA), a form of inflammatory arthritis, is a chronic joint disease characterized by pain and inflammation that affects 0.5% to 1% of the population worldwide. The safety, efficacy, tolerability, and potency of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property has been reported by several in vitro studies, experimental models and clinical trials phase I/II and III in ankylosing spondylitis and rheumatoid arthritis (RA) patients This research is designed to study the therapeutic efficacy of oral administration of mannuronic acid in RA patients who had inadequate response to conventional drugs and to assess the effect of this drug on gene expression of the signal transducer and activator of transcription (STATs) protein (STAT1, STAT3, STAT4, and STAT6). The study has included 15 RA patients who had an insufficient response to the conventional therapy. The oral dose of mannuronic acid was 1000mg divided into two 500 mg doses per day for 3 months as an addition to conventional therapy. There were 15 healthy volunteer in the control group. Blood samples were collected from both groups, once from healthy controls and twice from RA patients before and after treatment by M2000. The peripheral blood mononuclear cells (PBMCs) were isolated to assess the gene expression level of STAT1, STAT3, STAT4, and STAT6 using the real-time PCR method. Results obtained in this study demonstrated a significant difference in the gene expression level of STAT1 between healthy controls and patients before treatment as well as a significant reduction in RA patients after treatment compared with the level before treatment. In addition, the gene expression level of STAT3 and STAT4 showed a significant reduction in RA patients after treatment compared to patients before treatment, while there was no significant difference between RA patients before treatment and the healthy control group for both molecules. On the other hand, there was no change in the gene expression level of STAT6 among all groups. The outcomes of this study confirmed that β-D-mannuronic acid (M2000) has the ability to control the levels of STAT1, STAT3 and STAT4 in RA patients, and might be beneficial in the management and therapy of RA.

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

2020 ◽  
Vol 14 (1) ◽  
pp. 69-77
Author(s):  
Mona Aslani ◽  
Arman Ahmadzadeh ◽  
Zahra Rezaieyazdi ◽  
Seyed S. Mortazavi-Jahromi ◽  
Anis Barati ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Clinical Trial ◽  
Oral Administration ◽  
Mrna Expression ◽  
Phase Iii ◽  
Inadequate Response ◽  
Mannuronic Acid ◽  
Target Molecules ◽  
Chemokine Ligands

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. The mRNA expression of target molecules was then evaluated in PBMCs of the patients before and after treatment with M2000 using real-time PCR and was compared to healthy controls. Patents related to this study were also reviewed. Results: The results showed that M2000 was able to significantly down-regulate the mRNA expression of CXCR4, CCR2 and CCL2/MCP-1 in the PBMCs of the RA patients. It should be noted that the gene expression situation of the target molecules was in coordinate with the clinical and paraclinical assessments in the patients. Conclusion: Taken together, the results of this investigation revealed the part of molecular and immunological mechanisms of drug Mannuronic acid (M2000) in the treatment of RA, based on chemokine ligands and receptors mediated processes.

scholarly journals Good response to methotrexate is associated with a decrease in the gene expression of the drug transporter ABCG2 in patients with rheumatoid arthritis

2020 ◽  
Author(s):  
Satoshi Muto ◽  
Nana Minamitani ◽  
Takehisa Ogura ◽  
Arata Nakajima ◽  
Koichi Nakagawa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Clinical Response ◽  
Characteristic Curve ◽  
Rate Of Change ◽  
Gene Expression Level ◽  
Expression Level ◽  
Drug Transporter ◽  
Cancer Resistance ◽  
Abcg2 Gene

Abstract Background Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). We previously performed a cross-sectional, observational study and reported an association between the gene expression level of the drug transporter ABCG2/BCRP (breast cancer resistance protein) and RA disease control in patients receiving MTX. Methods We designed a prospective study in two medical centers in Japan to confirm the association of ABCG2 gene expression level with the clinical response to MTX in MTX-naive patients with RA. The primary endpoint of this study was good response based on the European League Against Rheumatism (EULAR) response criteria by Disease Activity Score using 28-joint count (DAS28). We evaluated the association between the baseline expression of six genes involved in the intracellular pharmacokinetics of MTX, including ABCG2, as well as their temporal changes, and the clinical response at week 12 from the initiation of MTX. Results Based on the clinical response at 12 weeks after the initiation of MTX, a total of 24 patients were classified into the good responders (n = 9) and non-good responders (n = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of baseline gene expression levels for the prediction of the EULAR good response at week 12 showed a significant association with ABCG2 alone, and the rate of baseline expression of ABCG2 mRNA above the cut-off value determined by a receiver operating characteristic curve was higher in good responders than in non-good responders (p = 0.012). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median -76% versus +41% from baseline, respectively; p = 0.011). The ABCG2 gene expression level did not correlate with DAS28 at baseline or at week 12, and neither did the rate of change in ABCG2 gene expression level. Conclusions We have confirmed the association between the gene expression level of the drug transporter ABCG2 and the clinical response to MTX in patients with RA.

scholarly journals Gene Expression of GSK3 in Type II Diabetics Compared to Non-Diabetics (ex vivo)

2020 ◽  
Vol 10 (1) ◽  
pp. 30-37
Author(s):  
Somayeh A.H. Khorami ◽  
Mohd S. Abd Mutalib ◽  
Mohammad F. Shiraz ◽  
Joseph A. Abdullah ◽  
Zulida Rejali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Glycogen Synthase ◽  
Ex Vivo ◽  
Glycogen Synthesis ◽  
Gene Expression Level ◽  
Expression Level ◽  
Type Ii ◽  
Cross Sectional ◽  
Significant Difference

Background: GSK3 is a serine/threonine kinase that is involved in the storage of glucose into glycogen through the negative regulation of glycogen synthase. Defects in GSK3 and glycogen synthase function are early stages of the development of insulin resistance, which may cause impaired glycogen synthesis in Type II diabetes. Methods: In this cross-sectional study, the gene expression level of GSK3 from Type II diabetic and non-diabetic participants was compared via real-time RT-PCR. To investigate the relationships between GSK3 expression and indicators of insulin resistance, Pearson's correlation analysis was performed. To compare the differences between GSK3 expression levels based on BMI categories, one-way ANOVA was used. Results: Gene expression of GSK3 was slightly higher in diabetic participants compared to non-diabetics, but it was statistically insignificant. Also, no significant difference was found based on BMI categories in the two groups. No significant association between GSK3 expression and indicators of insulin resistance was observed in non-diabetic participants. There was only a positive significant correlation between GSK3 expression and FBS in diabetic participants. Conclusion: These results indicate that the regulation of GSK3 may occur at the translation level, as gene expression level was unaltered between diabetic and non-diabetic participants. Also, since circulating levels of both glucose and insulin regulate GSK3 activity, tissue specificity for the expression and post-translation regulations of GSK3 may exist, which cause hyperactivation or overexpression in some target tissues in diabetes. Furthermore, it is probable that glycogen synthase activity is also regulated by non-insulin mediated mechanisms like exercise or allosteric changes, independent of GSK3 expression.

scholarly journals Relationships Between the Expression of the ACTN3 Gene and Explosive Power of Soccer Players

2019 ◽  
Vol 69 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Daria Domańska-Senderowska ◽  
Paulina Szmigielska ◽  
Aleksandra Snochowska ◽  
Zbigniew Jastrzębski ◽  
Anna Jegier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood Lymphocytes ◽  
Gene Expression Level ◽  
Expression Level ◽  
Soccer Players ◽  
Simultaneous Increase ◽  
Explosive Power ◽  
Training Cycle ◽  
Before And After ◽  
Maximal Speed

Abstract Muscle strength and maximal speed are factors determining athlete’s results during competition. Their association with ACTN3 gene activity has been documented. The purpose of this study was the analysis of ACTN3 gene expression during a 2 month training cycle of soccer players and its correlation with the countermovement jump (CMJ) and squat jump (SJ). The study group consisted of 22 soccer players (aged 17‐18). The study material included peripheral blood lymphocytes. The relative expression (RQ) of the ACTN3 gene was analyzed by qPCR and performed before and after the two‐month training cycle. Before the training cycle low expression levels of ACTN3 (median RQ = 0.95) were observed, yet after the training cycle they were elevated (median RQ = 1.98) ( p = 0.003). There was an increase in performance of both jumps: SJ (p = 0.020) and CMJ (p = 0.012) at the end of the training cycle. A simultaneous increase in the ACTN3 gene expression level and height in both jump tests was observed in 73% of athletes (p > 0.05). There were no significant relationships between the ACTN3 gene expression level and the results of the CMJ and SJ. However, explosive strength is a complex feature shaped by many different factors and it could be the reason why we did not observe correlations between these variables.

scholarly journals AB0655 RHEUMATOID ARTHRITIS ACTIVITY BEFORE AND AFTER COVID-19 LOCKDOWN PERIOD

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1360.1-1360
Author(s):  
M. Jordhani ◽  
D. Ruci ◽  
F. Skana ◽  
E. Memlika
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Musculoskeletal Diseases ◽  
Statistical Tests ◽  
Laboratory Data ◽  
World Population ◽  
Chronic Patients ◽  
Das 28 ◽  
Significant Difference ◽  
Before And After

Background:The COVID-19 global pandemic has had a great impact on world population due to morbidity, mortality and restriction measures in order to stop the progression of COVID-19.Patients with rheumatic and musculoskeletic diseases, and especially rheumatoid arthritis (RA) patients, being one of the vulnerable classes of chronic patients, were recommended to follow the government’s rules1.Objectives:The aim of this study was to evaluate DAS-28-ESR in patients with rheumatoid arthritis before and after lockdown period.Methods:This is a multi-center observational study including 85 patients which were evaluated before and after lockdown for their disease activity score according to DAS-28-ESR score. They had been diagnosed with rheumatoid arthritis more than 5 years ago. A thorough physical examination was performed before and after the lockdown period. It included examination of tender and swollen joints and patient’s global health. They were completed with all required laboratory data, including erythrosedimentation rate. For a more accurate calculation, DAS-28-ESR was used in an electronic version. Patients with other inflammatory or infective diseases were excluded from the study. All data were statistically evaluated using statistical tests such as t-student test.Results:The first group (the one before lockdown) had an average DAS-28-ESR of 4.7 while after the lockdown period, the average DAS-28-ESR was 5.16.After statistically evaluating all data, it was found that there exists a significant difference between DAS-28-ESR score before and after COVID-19 lockdown (p=0.0011).Conclusion:Our study showed that lockdown period due to COVID-19 pandemic, has aggravated disease activity in patients with Rheumatoid Arthritis. This may be consequence of various causes such as physical inactivity and difficulty to follow-up or to take the medication properly.References:[1]Landewé RB, Machado PM, Kroon F, et al, EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2, Annals of the Rheumatic Diseases 2020;79:851-858.Disclosure of Interests:None declared.

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