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Abbas Mirshafiey - One of the best experts on this subject based on the ideXlab platform.

  • anti tumor effect of m2000 β d Mannuronic Acid on the expression of inflammatory molecules in the prostate cancer cell
    Immunopharmacology and Immunotoxicology, 2021
    Co-Authors: Monireh Mohsenzadegan, Abbas Mirshafiey, Fatemeh Moghbeli, Mohammad Farajollahi
    Abstract:

    Aim: The importance of chronic inflammation during the progression of prostate cancer (PCa) is well-known. M2000 (β-d-Mannuronic Acid) is a novel anti-inflammatory drug. According to its potential ...

  • β d Mannuronic Acid m2000 as a landmark in pharmacology
    Current Drug Discovery Technologies, 2021
    Co-Authors: Nada A G Gaafar, Alireza Razavi, Abbas Mirshafiey
    Abstract:

    Objectives The goal of this article is to retrace the studies of β-D-Mannuronic Acid (M2000) as a new immunosuppressive drug with non-steroidal anti-inflammatory drugs (NSAIDs) property in miscellaneous aspects including in vitro, in vivo examinations, clinical trials and related to clinical trials studies. Our goal is to compare the effect of this drug with other similar drugs through varied researches and to follow tolerability, biocompatibility, potency, safety, and efficacy of this medication in different studies, as well as to evaluate its therapeutic effectiveness in various diseases. Materials and methods Different methods were applied in the studies of β-D-Mannuronic Acid under in vitro, in vivo examinations, and clinical trials phase I, II and III and related investigations to these clinical trials using different techniques showing the efficacy of this medication in the treatment of various diseases. Results The administration of β -D-Mannuronic Acid showed the greatest tolerability and biocompatibility compared to diclofenac, piroxicam, and dexamethasone without or very low side effects. The drug has shown a punchy effect on many molecules which participate either in physiologic or in pathogenic activities in animal models and human. This new drug not only revealed the anti-inflammatory and immunosuppressive properties but also based on the results of various investigations, β-D-Mannuronic Acid showed the antidiabetic, cardioprotective and anti-tumoral effects. Conclusion β-D-Mannuronic Acid (M2000) as a novel immunosuppressive drug with NSAID properties along with antidiabetic, cardioprotective and anti-tumoral efficacy showed great tolerability and safety profile. In addition, it has no or mild adverse events compared with many other medicines, therefore this medicament could be considered as a landmark in pharmacology and represent turn point in the treatment of different diseases based on the experimental and in vitro studies explained and clinical and related studies proved.

  • assessment of biochemical determinants in multiple sclerosis patients following the oral administration of β d Mannuronic Acid m2000
    Current Drug Discovery Technologies, 2020
    Co-Authors: Mohamad Reza Nikouei Moghaddam, Monireh Movahedi, Maryam Bananej, Soheil Najafi, Nahid Beladi Moghadam, Payam Saadat, Fariba Mokhtarian, Abbas Mirshafiey
    Abstract:

    Background Multiple sclerosis is an autoimmune chronic inflammatory disease of the central nervous system that can lead to some serious disabilities. Despite using various immunomodulatory and anti-inflammatory drugs that have therapeutic effects, they cannot reduce its progression completely, and have some unwanted side effects too. The immunomodulatory and anti-inflammatory effects of the β-D-Mannuronic Acid [M2000] have been proven in several surveys, and the present research was designed to determine its toxicity and therapeutic effects in MS patients. Methods This study was performed on 15 MS patients who took 25 mg/kg/day the oral form of the β-D-Mannuronic Acid for six months, and 15 healthy people as a control group. Serum levels of Urea, Creatinine, GGT, Vitamin D3, Uric Acid, and Anti-Phospholipids were compared to evaluate the therapeutic and possible toxic effects of this drug after this period. Results Non- toxic effects through the study of Urea, Creatinine, GGT, and non-significant changes in Uric Acid and AntiPhospholipids levels, besides a significant rise in Vitamin, D3 levels in the M2000 treated cases were found. Conclusions Our results suggested that β-D-Mannuronic Acid is a safe drug and has no toxicity when administered orally and also has some therapeutic effects in MS patients.

  • a controlled randomized phase ii clinical trial for efficacy and safety evaluation of Mannuronic Acid in secondary progressive form of multiple sclerosis
    International Journal of Neuroscience, 2020
    Co-Authors: Soheil Najafi, Hidenori Matsuo, Nahid Beladi Moghadam, Payam Saadat, Seyyedeh Masoomeh Noorbakhsh, Anita Vali Mohammadi, Ali Manouchehrinia, Mostafa Hosseini, Abbas Mirshafiey
    Abstract:

    The β-D-Mannuronic Acid (M2000) as a novel immunosuppressive drug, patented (PCT/EP2017/067920), has shown positive effects in experimental model of multiple sclerosis (MS). In this study, our aim ...

  • effects of Mannuronic Acid m2000 on gene expression profile of signal transducer and activator of transcription proteins stats in rheumatoid arthritis patients
    Reumatismo, 2020
    Co-Authors: Nada A G Gaafar, Alireza Razavi, Mona Aslani, Zahra Aghazadeh, Seyed Shahabeddin Mortazavijahromi, Abbas Mirshafiey
    Abstract:

    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.

Mohammad Javad Fattahi - One of the best experts on this subject based on the ideXlab platform.

  • A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-d-Mannuronic Acid in rheumatoid arthritis patients
    Inflammopharmacology, 2018
    Co-Authors: Hossein Ahmadi, Salvatore Cuzzocrea, Mohammad Javad Fattahi, Noushin Rastkari, Ahmadreza Jamshidi, Mahdi Mahmoudi, Mahdi Vojdanian, Farhad Gharibdoost, Shayan Mostafaei, Bernd H A Rehm
    Abstract:

    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. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. Results There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P  = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient’s adverse events occurred during this study. Conclusion Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

  • oral administration effects of β d Mannuronic Acid m2000 on th17 and regulatory t cells in patients with ankylosing spondylitis
    Biomedicine & Pharmacotherapy, 2018
    Co-Authors: Mohammad Javad Fattahi, Bernd H A Rehm, Salvatore Cuzzocrea, Hidenori Matsuo, Hossein Ahmadi, Fahimeh Jafarnezhadansariha, Seyed Shahabeddin Mortazavijahromi, Abbas Mirshafiey
    Abstract:

    Abstract 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. Results Significantly higher baseline Th17 cells and serum IL-17, TNF-α and IL-6 were observed in AS patients than in normal controls, whereas baseline levels of Treg cells and serum IL-10 were not significantly different between AS patients and healthy controls. After M2000 therapy, frequencies of Th17 and serum levels of IL-17 and IL-6 significantly decreased in AS patients. The frequencies of Treg cells and serum level of IL-10 were not significantly changed, in comparison to before therapy. Moreover, the correlation analysis showed that frequencies of Th17 and levels of IL-17, TNF-α and IL-6 were positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, whereas Treg cells were revealed to be negatively correlated with BASDAI and BASFI scores. Conclusions It can be concluded that the oral administration of M2000 as a novel NSAID with the immunosuppressive property that down-regulates Th17 and Th17-related cytokines and facilitates the correction of the Th17/Treg imbalance can be effective in the process of AS treatment.

  • targeting of circulating th17 cells by β d Mannuronic Acid m2000 as a novel medication in patients with rheumatoid arthritis
    Inflammopharmacology, 2018
    Co-Authors: Hossein Ahmadi, Zahra Aghazadeh, Mohammad Javad Fattahi, Ahmadreza Jamshidi, Mahdi Mahmoudi, Mahdi Vojdanian, Anis Barati, Farhad Gharibdoost, Abbas Mirshafiey
    Abstract:

    This study aimed at investigating the inhibitory effect of β-D-Mannuronic Acid (M2000) on the Th17 circulating levels and IL-17 a related cytokine in rheumatoid arthritis (RA) patients. The study included 27 patients with RA who had failed response to treatment. All patients were treated orally by M2000 at a dose of 500 mg twice daily for 12 weeks (Clinical trial identifier: IRCT2014011213739N2). The patients based on anti-tumor necrosis factor alpha (TNFα) blocker treatment were classified into two groups (conventional group and etanercept group). They were then allowed to continue their treatment excluding non-steroidal anti-inflammatory drugs (NSAIDs). The frequency of circulating Th17 cells and IL-17 serum level were determined before and 12 weeks after M2000 therapy and were compared to the healthy controls by using flow cytometry analysis and ELISA method, respectively. At baseline, higher circulating Th17 and IL-17 serum levels were significantly observed in both groups of RA patients than in the healthy controls (all P < 0.001). The frequency of Th17 cells significantly decreased in the conventional group as well as in the etanercept group after M2000 therapy but the level of reduction was higher in the conventional group compared to the etanercept group (P < 0.03 and P < 0.04, respectively). The IL-17 serum level significantly decreased in both groups after M2000 therapy (P < 0.01 and P < 0.02, respectively). Furthermore, the frequency of Th17 cells was positively correlated with Disease Activity Score (DAS28) (r = 0.34, P = 0.02). M2000 shows the inhibitory effect on the frequency of circulating Th17 cells as well as in the production of IL-17 in RA patients.

  • evaluation of the efficacy and safety of β d Mannuronic Acid in patients with ankylosing spondylitis a 12 week randomized placebo controlled phase i ii clinical trial
    International Immunopharmacology, 2018
    Co-Authors: Mohammad Javad Fattahi, Hossein Ahmadi, Ahmadreza Jamshidi, Mahdi Mahmoudi, Mahdi Vojdanian, Mir Saeed Yekaninejad, Fahimeh Jafarnezhadansariha, Bernd H A Rehm
    Abstract:

    Abstract Objective To evaluate the efficacy, safety and tolerability of β- d -Mannuronic Acid (M2000) in the treatment of ankylosing spondylitis (AS). Methods The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, β- d -Mannuronic Acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. Results Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 β- d -Mannuronic Acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving β- d -Mannuronic Acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P > 0.05) and 19% of the patients in the placebo group (P = 0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving β- d -Mannuronic Acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, β- d -Mannuronic Acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on β- d -Mannuronic Acid and placebo. Conclusion The present study demonstrated similar efficacy, but with a more favorable safety profile for β- d -Mannuronic Acid than naproxen and, therefore, suggest that β- d -Mannuronic Acid is suitable for the management of AS. Trial registration Iranian registry of clinical trials; www.irct.ir ; IRCT2013062213739N1.

  • the potent suppressive effect of β d Mannuronic Acid m2000 on molecular expression of the tlr nf kb signaling pathway in ankylosing spondylitis patients
    International Immunopharmacology, 2017
    Co-Authors: Maryam Roozbehkia, Mohammad Javad Fattahi, Mahdi Mahmoudi, Fahimeh Jafarnezhadansariha, Anis Barati, Somaye Aletaha, Nima Rezaei, Abbas Mirshafiey
    Abstract:

    Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease characterized by the inflammation of sacroiliac joints and axial skeleton. A combination of genetic, environmental and immunological factors are involved in AS's pathogenesis. TLRs are type I transmembrane glycoproteins that play a crucial role in the innate immune responses against invading pathogens. Observational studies have demonstrated a possible association between TLR dysregulation and AS. The β-d-Mannuronic Acid (M2000), as a novel NSAID with immunosuppressive property, has shown an inhibitory effect on Toll-like receptor (TLR) 2, 4 signaling in HEK293 cells. In the present study, we investigated the gene expression of Myd88, IKB-alpha, NF-kB and MAPK14 (genes of the TLR/NF-kB Signaling Pathway) in AS patients in comparison to healthy subjects and also the effect of β-d-Mannuronic Acid on disease activity and mRNA expression of these molecules in affected patients. We showed for the first time that the gene expression level of Myd88, IKB-alpha, NF-kB and MAPK14 was higher in AS patients in comparison to healthy subjects. Moreover we confirmed that the β-d-Mannuronic Acid not just reduced significantly the disease activity of AS individuals compared to placebo, but also it could significantly decrease the expression level of genes associated with TLR/NF-kB Signaling Pathway in treated patients with M2000. These results may provide a new therapeutic approach to attenuate inflammatory responses in AS patients, (Identified; IRCT 2013062213739N1).

Bernd H A Rehm - One of the best experts on this subject based on the ideXlab platform.

  • Mannuronic Acid in low risk and intermediate 1 risk myelodysplastic syndromes
    The Journal of Clinical Pharmacology, 2020
    Co-Authors: Afshin Ghaderi, Bernd H A Rehm, Salvatore Cuzzocrea, Sayyed Reza Safaee Nodehi, Tahereh Bakhtiari, Mona Aslani, Zahra Aghazadeh, Hidenori Matsuo, Abbas Mirshafiey
    Abstract:

    The discovery of hematologic improvement and bone marrow modification by the drug β-D Mannuronic Acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open-label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low- and intermediate-1-risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β-D-Mannuronic Acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β-D-Mannuronic Acid, and the other half received only conventional drugs. In the conventional + β-D Mannuronic Acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β-D-Mannuronic Acid-treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β-D Mannuronic Acid to conventional treatment showed promising results in MDS patients with low and intermediate-1 risk with effects on hematologic improvements without significant adverse effect.

  • a randomized controlled phase ii clinical trial of β d Mannuronic Acid m2000 in pre surgical breast cancer patients at early stage t1 t2
    Clinical and Experimental Pharmacology and Physiology, 2019
    Co-Authors: Sarvenaz Kashefi, Bernd H A Rehm, Salvatore Cuzzocrea, Mostafa Hosseini, Ramesh Omranipour, Habibollah Mahmoodzadeh, Hamid Ahmadi, Afsaneh Alikhassi, Hidenori Matsuo
    Abstract:

    Following the potent efficacy of β-D-Mannuronic Acid in a breast cancer murine model, we evaluated the efficacy of this novel non-steroidal anti-inflammatory drug in breast cancer patients in the present clinical trial. The study was an 8-week randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre-surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting-list for surgery and were allocated to the study. β-D-Mannuronic was administrated at a dose of two capsules (1000 mg/d) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients' well-being status was followed up on for safety. There were no statistically significant differences between treatment and non-treatment groups at baseline. β-D-Mannuronic Acid therapy, from 20 patients, showed that in one patient (5%) tumour size was decreased; in five patients (25%) tumour growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non-treatment group. Evaluation of two tumour markers (carcinoembryonic antigen and cancer antigen 15-3) showed that there was no significant difference between before and after treatment. Although the use of some non-steroidal anti-inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β-D-Mannuronic Acid during 8 weeks could show 30% therapeutic effects in pre-surgical breast cancer patients.

  • A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-d-Mannuronic Acid in rheumatoid arthritis patients
    Inflammopharmacology, 2018
    Co-Authors: Hossein Ahmadi, Salvatore Cuzzocrea, Mohammad Javad Fattahi, Noushin Rastkari, Ahmadreza Jamshidi, Mahdi Mahmoudi, Mahdi Vojdanian, Farhad Gharibdoost, Shayan Mostafaei, Bernd H A Rehm
    Abstract:

    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. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. Results There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P  = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient’s adverse events occurred during this study. Conclusion Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.

  • oral administration effects of β d Mannuronic Acid m2000 on th17 and regulatory t cells in patients with ankylosing spondylitis
    Biomedicine & Pharmacotherapy, 2018
    Co-Authors: Mohammad Javad Fattahi, Bernd H A Rehm, Salvatore Cuzzocrea, Hidenori Matsuo, Hossein Ahmadi, Fahimeh Jafarnezhadansariha, Seyed Shahabeddin Mortazavijahromi, Abbas Mirshafiey
    Abstract:

    Abstract 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. Results Significantly higher baseline Th17 cells and serum IL-17, TNF-α and IL-6 were observed in AS patients than in normal controls, whereas baseline levels of Treg cells and serum IL-10 were not significantly different between AS patients and healthy controls. After M2000 therapy, frequencies of Th17 and serum levels of IL-17 and IL-6 significantly decreased in AS patients. The frequencies of Treg cells and serum level of IL-10 were not significantly changed, in comparison to before therapy. Moreover, the correlation analysis showed that frequencies of Th17 and levels of IL-17, TNF-α and IL-6 were positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores, whereas Treg cells were revealed to be negatively correlated with BASDAI and BASFI scores. Conclusions It can be concluded that the oral administration of M2000 as a novel NSAID with the immunosuppressive property that down-regulates Th17 and Th17-related cytokines and facilitates the correction of the Th17/Treg imbalance can be effective in the process of AS treatment.

  • evaluation of the efficacy and safety of β d Mannuronic Acid in patients with ankylosing spondylitis a 12 week randomized placebo controlled phase i ii clinical trial
    International Immunopharmacology, 2018
    Co-Authors: Mohammad Javad Fattahi, Hossein Ahmadi, Ahmadreza Jamshidi, Mahdi Mahmoudi, Mahdi Vojdanian, Mir Saeed Yekaninejad, Fahimeh Jafarnezhadansariha, Bernd H A Rehm
    Abstract:

    Abstract Objective To evaluate the efficacy, safety and tolerability of β- d -Mannuronic Acid (M2000) in the treatment of ankylosing spondylitis (AS). Methods The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, β- d -Mannuronic Acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. Results Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 β- d -Mannuronic Acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving β- d -Mannuronic Acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P > 0.05) and 19% of the patients in the placebo group (P = 0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving β- d -Mannuronic Acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, β- d -Mannuronic Acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on β- d -Mannuronic Acid and placebo. Conclusion The present study demonstrated similar efficacy, but with a more favorable safety profile for β- d -Mannuronic Acid than naproxen and, therefore, suggest that β- d -Mannuronic Acid is suitable for the management of AS. Trial registration Iranian registry of clinical trials; www.irct.ir ; IRCT2013062213739N1.

Gudmund Skjakbraek - One of the best experts on this subject based on the ideXlab platform.

  • the pseudomonas fluorescens algg protein but not its mannuronan c 5 epimerase activity is needed for alginate polymer formation
    Journal of Bacteriology, 2003
    Co-Authors: Martin Gimmestad, Gudmund Skjakbraek, Helga Ertesvag, Trond E Ellingsen, Havard Sletta, Karianne Bakkevig, Sumita Jain, Sangjin Suh, Dennis E Ohman, Svein Valla
    Abstract:

    Bacterial alginates are produced as 1-4-linked beta-D-mannuronan, followed by epimerization of some of the Mannuronic Acid residues to alpha-L-guluronic Acid. Here we report the isolation of four different epimerization-defective point mutants of the periplasmic Pseudomonas fluorescens mannuronan C-5-epimerase AlgG. All mutations affected amino Acids conserved among AlgG-epimerases and were clustered in a part of the enzyme also sharing some sequence similarity to a group of secreted epimerases previously reported in Azotobacter vinelandii. An algG-deletion mutant was constructed and found to produce predominantly a dimer containing a 4-deoxy-L-erythro-hex-4-enepyranosyluronate residue at the nonreducing end and a Mannuronic Acid residue at the reducing end. The production of this dimer is the result of the activity of an alginate lyase, AlgL, whose in vivo activity is much more limited in the presence of AlgG. A strain expressing both an epimerase-defective (point mutation) and a wild-type epimerase was constructed and shown to produce two types of alginate molecules: one class being pure mannuronan and the other having the wild-type content of guluronic Acid residues. This formation of two distinct classes of polymers in a genetically pure cell line can be explained by assuming that AlgG is part of a periplasmic protein complex.

  • involvement of toll like receptor tlr 2 and tlr4 in cell activation by Mannuronic Acid polymers
    Journal of Biological Chemistry, 2002
    Co-Authors: Liv Ryan, Brian G Monks, Oyvind Halaas, Eicke Latz, Egil Lien, Gudmund Skjakbraek, Osamu Takeuchi, Douglas T Golenbock, Terje Espevik
    Abstract:

    nvolvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by Mannuronic Acid polymers

  • involvement of toll like receptor tlr 2 and tlr4 in cell activation by Mannuronic Acid polymers
    Journal of Biological Chemistry, 2002
    Co-Authors: Trude H Flo, Brian G Monks, Oyvind Halaas, Eicke Latz, Egil Lien, Gudmund Skjakbraek, Liv Ryan, Osamu Takeuchi, Shizuo Akira, Douglas T Golenbock
    Abstract:

    The alginate capsule produced by the human pathogen Pseudomonas aeruginosa is composed mainly of Mannuronic Acid polymers (poly-M) that have immunostimulating properties. Poly-M shares with lipopolysaccharide the ability to stimulate cytokine production from human monocytes in a CD14-dependent manner. In the present study we examined the role of Toll-like receptor (TLR) 2 and TLR4 in responses to poly-M. Blocking antibodies to TLR2 and TLR4 partly inhibited tumor necrosis factor production induced by poly-M in human monocytes, and further inhibition was obtained by combining the antibodies. By transiently transfecting HEK293 cells, we found that membrane CD14 together with either TLR2 or TLR4/MD-2 could mediate activation by poly-M. Transfection of HEK293 cells with TLR2 and fluorescently labeled TLR4 followed by co-patching of TLR2 with an antibody revealed no association of these molecules on the plasma membrane. However, macrophages from the Tlr4 mutant C3H/HeJ mice and TLR4 knockout mice were completely non-responsive to poly-M, whereas the tumor necrosis factor release from TLR2 knockout macrophages was half of that seen with wild type cells. Taken together the results suggest that both TLR2 and TLR4 are involved in cell activation by poly-M and that TLR4 may be required in primary murine macrophages.

  • involvement of cd14 and beta2 integrins in activating cells with soluble and particulate lipopolysaccharides and Mannuronic Acid polymers
    Infection and Immunity, 2000
    Co-Authors: Trude H Flo, Gudmund Skjakbraek, Liv Ryan, Douglas T Golenbock, Lars Kilaas, Robin R Ingalls, Anders Sundan, Terje Espevik
    Abstract:

    Lipopolysaccharide (LPS) and related bacterial products can be recognized by host inflammatory cells in a particulate, bacterium-bound form, as well as in various soluble, released forms. In the present study we have compared the mechanisms used by LPS, detoxified LPS (DLPS), and Mannuronic Acid polymers (M-polymers), in solution or covalently linked to particles, in stimulating monocytes to tumor necrosis factor (TNF) production. The addition of recombinant LPS binding protein (LBP) and/or soluble CD14 (sCD14) enhanced the production of TNF from monocytes stimulated with soluble LPS, DLPS, or M-polymer, but did not affect the response to M-polymer or DLPS attached to particles. Treatment of monocytes with antibody to CD14, CD18, or CD11b showed that CD14, but not CR3 (CD11b/CD18), mediated monocyte TNF production in response to the soluble antigens. In contrast, anti-CD14, anti-CD11b and anti-CD18 monoclonal antibodies all inhibited the response to the particulate stimuli. On the other hand, B975, a synthetic analog of Rhodobacter capsulatus lipid A, completely abrogated the monocyte TNF response induced by LPS but did not affect the TNF induction by DLPS or M-polymer, either in soluble or particulate forms. These data demonstrate that the engagement of immune receptors by bacterial products such as LPS, DLPS, and M-polymer is dependent upon the presentation form of their constituent carbohydrates, and that factors such as aggregation state, acylation, carbohydrate chain length, and solid versus liquid phase of bacterial ligands influence the mechanisms used by cells in mediating proinflammatory responses.

  • biochemical properties and substrate specificities of a recombinantly produced azotobacter vinelandii alginate lyase
    Journal of Bacteriology, 1998
    Co-Authors: Helga Ertesvag, Bernd H A Rehm, Gudmund Skjakbraek, Frode Erlien, Svein Valla
    Abstract:

    Alginate is a polysaccharide composed of beta-D-Mannuronic Acid (M) and alpha-L-guluronic Acid (G). An Azotobacter vinelandii alginate lyase gene, algL, was cloned, sequenced, and expressed in Escherichia coli. The deduced molecular mass of the corresponding protein is 41.4 kDa, but a signal peptide is cleaved off, leaving a mature protein of 39 kDa. Sixty-three percent of the amino Acids in this mature protein are identical to those in AlgL from Pseudomonas aeruginosa. AlgL was partially purified, and the activity was found to be optimal at a pH of 8.1 to 8.4 and at 0.35 M NaCl. Divalent cations are not necessary for activity. The pI of the enzyme is 5.1. When an alginate rich in Mannuronic Acid was used as the substrate, the Km was found to be 4.6 x 10(-4) M (sugar residues). AlgL was found to cleave M-M and M-G bonds but not G-M or G-G bonds. Bonds involving acetylated residues were also cleaved, but this activity may be sensitive to the extent of acetylation.

Jeroen D. C. Codée - One of the best experts on this subject based on the ideXlab platform.

  • Chemical synthesis of guanosine diphosphate Mannuronic Acid (GDP-ManA) and its C-4-O-methyl and C-4-deoxy congeners.
    Carbohydrate research, 2017
    Co-Authors: Qingju Zhang, P. Lynne Howell, Herman S. Overkleeft, Dmitri V. Filippov, Gijsbert A. Van Der Marel, Jeroen D. C. Codée
    Abstract:

    Described is the first synthesis of guanosine diphosphate Mannuronic Acid (GDP-ManA), the sugar donor used by algae and bacteria for the production of alginate, an anionic polysaccharide composed of β-d-Mannuronic Acid (ManA) and α-l-guluronic Acid (GulA). Understanding the biosynthesis of these polyanionic polysaccharides on the molecular level, opens up avenues to use and modulate the biosynthesis machinery for biotechnological and therapeutic applications. The synthesis reported here delivers multi-milligram amounts of the GDP-ManA donor that can be used to study the polymerase (Alg8 in Pseudomonas aeruginosa) that generates the poly-ManA chain. Also reported is the assembly of two close analogues of GDP-ManA: the first bears a C-4-O-methyl group, while the second has been deoxygenated at this position. Both molecules may be used as "chain stoppers" in future enzymatic ManA polymerisation reactions. The crucial pyrophosphate linkage of the GDP-Mannuronic Acids has been constructed by the phosphorylation of the appropriate ManA-1-phosphates with a guanosine phosphoramidite.

  • conformational behaviour of azasugars based on Mannuronic Acid
    ChemBioChem, 2017
    Co-Authors: Erwin R. Van Rijssel, Herman S. Overkleeft, Gijsbert A. Van Der Marel, Antonius P A Janssen, Alexandra Males, Gideon J Davies, Jeroen D. C. Codée
    Abstract:

    A set of Mannuronic-Acid-based iminosugars, consisting of the C-5-carboxylic Acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under Acidic conditions the methyl ester and the carboxylic Acid adopted an "inverted" 1 C4 chair conformation as opposed to the "normal" 4 C1 chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the Mannuronic Acid ester oxocarbenium ion. Because of this solution-phase behaviour, the Mannuronic Acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a 3 H4 transition state. No binding was observed for the Mannuronic Acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ⋅CkGH47 complex, showing two conformations-3 S1 and 1 C4 -for the DMJ inhibitor.

  • chemoselective cleavage of p methoxybenzyl and 2 naphthylmethyl ethers using a catalytic amount of hcl in hexafluoro 2 propanol
    Journal of Organic Chemistry, 2015
    Co-Authors: Anne Geert Volbeda, Herman S. Overkleeft, Dmitri V. Filippov, Gijsbert A. Van Der Marel, Hans A V Kistemaker, Jeroen D. C. Codée
    Abstract:

    A new, fast, mild and chemoselective deprotection method to cleave p-methoxybenzyl and 2-naphthylmethyl ethers using catalytic amounts of hydrochloric Acid in a 1:1 mixture of hexafluoro-2-propanol (HFIP) and methylene chloride (DCM) is described. The scope of the methodology becomes apparent from 14 examples of orthogonally protected monosaccharides that are subjected to HCl/HFIP treatment. The applicability of the HCl/HFIP method is illustrated by the synthesis of a sulfated β-Mannuronic Acid disaccharide.

  • acceptor reactivity in the total synthesis of alginate fragments containing α l guluronic Acid and β d Mannuronic Acid
    Angewandte Chemie, 2015
    Co-Authors: Qingju Zhang, Herman S. Overkleeft, Gijsbert A. Van Der Marel, Erwin R. Van Rijssel, Marthe T C Walvoort, Jeroen D. C. Codée
    Abstract:

    The total synthesis of mixed-sequence alginate oligosaccharides, featuring both β-D-Mannuronic Acid (M) and α-L-guluronic Acid (G), is reported for the first time. A set of GM, GMG, GMGM, GMGMG, GMGMGM, GMGMGMG, and GMGGMG alginates was assembled using GM building blocks, having a guluronic Acid acceptor part and a Mannuronic Acid donor side to allow the fully stereoselective construction of the cis-glycosidic linkages. It was found that the nature of the reducing-end anomeric center, which is ten atoms away from the reacting alcohol group in the key disaccharide acceptor, had a tremendous effect on the efficiency with which the building blocks were united. This chiral center determines the overall shape of the acceptor and it is revealed that the conformational flexibility of the acceptor is an all-important factor in determining the outcome of a glycosylation reaction.

  • chair interconversion and reactivity of Mannuronic Acid esters
    Organic and Biomolecular Chemistry, 2013
    Co-Authors: Jerk Ronnols, Gijsbert A. Van Der Marel, Jeroen D. C. Codée, Marthe T C Walvoort, Goran Widmalm
    Abstract:

    Mannopyranosyluronic Acids display a very unusual conformation behavior in that they often prefer to adopt a 1C4 chair conformation. They are endowed with a strikingly high reactivity when used in a glycosylation reaction as a glycosyl donor. To investigate the unusual conformational behavior a series of Mannuronic Acid ester derivatives, comprising anomeric triflate species and O-methyl glycosides, was examined by dynamic NMR experiments, through lineshape analysis of 1H and 19F NMR spectra at various temperatures from −80 °C to 0 °C. Exchange rates between 4C1 and 1C4 chair conformations were found to depend on the electronic properties and the size of the C2 substituent (F, N3 or OBn) and the aglycon, with higher exchange rates for the glycosyl triflates and smaller C2 substituents. Low temperature 19F exchange spectroscopy experiments showed that the covalently bound anomeric triflates did not exchange with free triflate species present in the reaction mixture. To relate the conformational behavior of the intermediate triflates to their reactivity in a glycosylation reaction, their relative reactivity was determined via competition reactions monitored by 1H NMR spectroscopy at low temperature. The 2-O-benzyl ether compound was found to be most reactive whereas the 2-fluoro compound – the most flexible of the studied compounds – was least reactive. Whereas the ring-flip of the Mannuronic Acids is important for the enhanced reactivity of the donors, the rate of the ring-flip has little influence on the relative reactivity.