An in vitro assessment for evaluating the efficiency of β‐d‐mannuronic acid (M2000) in myelodysplastic syndrome

Abstract

β‐d‐Mannuronic acid (M2000), a novel non‐steroidal anti‐inflammatory drug (NSAID) with immunosuppressive properties, has been previously shown to exhibit potential therapeutic effects on autoimmune diseases. Immunosuppression therapy has been a standard approach for myelodysplastic syndrome (MDS) for many years. We evaluated the effect of M2000 on isolated peripheral blood mononuclear cells (PBMCs) from patients with MDS. The PBMCs were isolated from 13 patients with MDS and 13 normal donors. The cells were then treated with low, moderate, and high doses of M2000 and diclofenac as a control group. The level of interleukin (IL)‐6, tumor necrosis factor alpha (TNF‐α), IL‐3, granulocyte colony‐stimulating factor (G‐CSF) gene expression and the serum level of IL‐6 and TNF‐α production were evaluated by real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay methods, respectively. Our findings indicated a significant reduction in the production of IL‐6 and TNF‐α as inflammatory cytokines. Furthermore, the level of G‐CSF gene expression was significantly increased. In conclusion, M2000, a newly designed NSAID, has a remarkable effect on isolated PBMC in patients with MDS, which might bring a potential hope for its oral administrations in these patients.

Relationship of HIF‑1α expression with apoptosis and cell cycle in bone marrow mesenchymal stem cells from patients with myelodysplastic syndrome

“…As a consequence of these defective pathways, cytopenia and ineffective hemopoiesis takes place. However, prolonged late-stage MDS may lead to AML, with a decrease in apoptosis, and an increased degree of neoplastic cell survival may be observed ( 49 , 50 ). The mechanisms promoting the conversion of excessive apoptosis in the early stage to reduced apoptosis and accelerated progression in the late stage remain elusive and the effects of the bone marrow microenvironment during progression cannot be ignored.…”

Mannuronic Acid in Low‐Risk and Intermediate‐1‐Risk Myelodysplastic Syndromes

“…This finding by Bakhtiari and coworkers came from the reduction of IL-6 and TNF-α levels as pleiotropic cytokines, which promote inflammation and immune responses following the β-D-mannuronic acid treatment. 18 Parallel with the reduction of these inflammatory cytokines, the granulocyte colony-stimulating factor (G-CSF) as a hematopoietic cytokine was significantly increased in the MDS cell line derived from patients treated with β-D-mannuronic acid. 18 This could be a key point in MDS therapy because the ectopic injection of G-CSF could increase the risk of AML development.…”

“…18 Parallel with the reduction of these inflammatory cytokines, the granulocyte colony-stimulating factor (G-CSF) as a hematopoietic cytokine was significantly increased in the MDS cell line derived from patients treated with β-D-mannuronic acid. 18 This could be a key point in MDS therapy because the ectopic injection of G-CSF could increase the risk of AML development. This report showed that β-Dmannuronic acid has the potential efficacy to act as an immunomodulatory agent that could beneficially help the MDS patents.…”

“…17 Following this finding, Bakhtiari et al (2018) evaluated the in vitro efficacy of β-D-mannuronic acid using the peripheral blood mononuclear cells of MDS patients. 18 The results of this investigation showed a significant induction of G-CSF gene expression and reduction of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as inflammatory cytokines, in the mononuclear cells of patients with MDS. In accordance with these significant results, the current trial was designed to assess the efficacy and safety of the oral administration of β-D-mannuronic acid along with conventional therapy versus conventional therapy alone in low-and intermediate-risk MDS patients.…”

“…Previously, in a phase 1/2 clinical study by Ahmadi and coworkers (2017) notable hematologic improvement in patients with active rheumatoid arthritis by β‐D‐mannuronic acid therapy was reported 17 . Following this finding, Bakhtiari et al (2018) evaluated the in vitro efficacy of β‐D‐mannuronic acid using the peripheral blood mononuclear cells of MDS patients 18 . The results of this investigation showed a significant induction of G‐CSF gene expression and reduction of interleukin 6 (IL‐6) and tumor necrosis factor α (TNF‐α), as inflammatory cytokines, in the mononuclear cells of patients with MDS.…”