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 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 Dopamine adjusts the circadian gene expression of Per2 and Per3 in human dermal fibroblasts from ADHD patients

2021 ◽  
Author(s):  
Frank Faltraco ◽  
Denise Palm ◽  
Adriana Uzoni ◽  
Lena Borchert ◽  
Frederick Simon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dermal Fibroblast ◽  
Sleep Onset ◽  
Dermal Fibroblasts ◽  
Control Group ◽  
Adhd Group ◽  
Healthy Controls ◽  
Circadian Gene ◽  
Significant Difference ◽  
Circadian Preference

AbstractA link between dopamine levels, circadian gene expression, and attention deficit hyperactivity disorder (ADHD) has already been demonstrated. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after dopamine exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different dopamine concentrations in human dermal fibroblast (HDF) cultures, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analyzed via qRT-PCR. We found no statistical significant effect in the actigraphy of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, wake after sleep onset, and total number of wake bouts. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. Dopamine has no effect on Per3 expression in healthy controls, but produces a significant difference in the ADHD group at ZT24 and ZT28. In the ADHD group, incubation with dopamine, either 1 µM or 10 µM, resulted in an adjustment of Per3 expression to control levels. A similar effect also was found in the expression of Per2. Statistical significant differences in the expression of Per2 (ZT4) in the control group compared to the ADHD group were found, following incubation with dopamine. The present study illustrates that dopamine impacts on circadian function. The results lead to the suggestion that dopamine may improve the sleep quality as well as ADHD symptoms by adjustment of the circadian gene expression, especially for Per2 and Per3.

scholarly journals The role of albumin-to-globulin ratio in undifferentiated arthritis: Rheumatoid arthritis versus primary Sjögren syndrome

2021 ◽  
Author(s):  
Reyhan Köse Çobanoglu ◽  
Taşkın Şentürk
Keyword(s):  
Rheumatoid Arthritis ◽  
Sjögren Syndrome ◽  
Control Group ◽  
Sjogren Syndrome ◽  
Healthy Controls ◽  
Undifferentiated Arthritis ◽  
Characteristic Analysis ◽  
Primary Sjögren Syndrome ◽  
Significant Difference ◽  
Albumin To Globulin Ratio

Objectives: This study aims to compare initial albumin-to-globulin ratio (AGR) in patients with rheumatoid arthritis (RA) and primary Sjögren syndrome (pSS) presenting with undifferentiated arthritis (UA) and to investigate whether there was a difference in terms of AGR between the two patient groups and healthy controls. Patients and methods: Between January 2019 and December 2019, a total of 177 patients including 96 RA (10 males, 86 females; mean age: 53.6±10.8 years; range, 21 to 74 years) and 81 pSS (5 males, 76 females; mean age: 53.2±14.1 years; range, 23 to 79 years) and 82 healthy controls (20 males, 62 females; mean age: 50.5±13.6 years; range, 20 to 79 years) were included in this case-control study. Demographic characteristics, albumin, and globulin levels of all participants were recorded. The AGR, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-nuclear antibody (ANA), and anti-citrullinated protein antibodies (ACPA) were assessed. Results: The mean AGR was 1.50±0.16 in the control group, 1.48±0.24 in the RA group, and 1.30±0.23 in the pSS group, indicating a significant difference between the pSS and the other two groups (p<0.001). The receiver operating characteristic analysis revealed that the cut-off value for AGR was 1.39 (area under the curve=0.736) with a sensitivity of 0.642 and a specificity of 0.646 (p<0.001). The ESR and CRP values were higher (p<0.001), and ANA (p<0.001) and RF (p=0.003) positivity were lower in the RA group, compared to the pSS group. Conclusion: This study findings indicate that AGR is a helpful tool in the differential diagnosis of RA and pSS presenting with UA at the time of admission, and Sjögren syndrome should be considered in case of AGR ≤1.39.

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.

Expression of Interleukin 1, Interleukin 27 and TNF α Genes in Patients with Ischemic Cardiomyopathy Versus Idiopathic Dilated Cardiomyopathy

2021 ◽  
Author(s):  
Mahdiyar Iravani Saadi ◽  
Javad Salami ◽  
Hanieh Abdi ◽  
Ehsan Nabi Abdolyousefi ◽  
Ahmad Niknam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dilated Cardiomyopathy ◽  
Inflammatory Cytokines ◽  
Interleukin 1 ◽  
Expression Level ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Healthy Controls ◽  
Idiopathic Cardiomyopathy ◽  
Tnf Α ◽  
Significant Difference

Abstract Objective: Congestive Heart failure (CHF) is a complex multifactorial syndrome due to tissue hypo perfusion that is affected by some factors like inflammatory cytokines. In our study we investigated the exact gene expression of three inflammatory cytokines in ischemic and idiopathic cardiomyopathy patients.Materials and Methods: From 49 studied recipients in ischemic group, 23 (46.9%) were male and from 40 studied recipients in idiopathic dilated cardiomyopathy group, 19 (47.5%) were male. For the quantitative analysis of Interleukin (IL)1, IL-27 and TNF-α mRNAs expression level, the SYBR Green Real-Time PCR method was performed using SYBRPremix Ex TaqTM II (Tli RNaseH Plus) (Takara, Japan) and designed primers specific for each genes in an iQ5 thermocycler (BioRad Laboratories, USA) according to the manufacturer’s instructions.Results: Our results showed that the expression level of IL-1 and TNF-α were significantly higher in the ischemic patients compared to healthy controls (P<0.001, P<0.01, respectively); also we found higher levels of IL-1 and IL-27 gene expressions in idiopathic patients compared to healthy controls (P<0.001, P<0.001, respectively). There were not any significant difference of IL-1, IL-27 and TNF-α expression levels between ischemic patients and idiopathic ones.Conclusion: Although we would introduce IL1, IL-27 and TNF α as effective inflammatory cytokines on myocardial functions in ischemic and idiopathic cardiomyopathy patients; there is not any difference between these two groups in gene expression of three main inflammatory cytokines.

scholarly journals Salivary citrullinated proteins in rheumatoid arthritis and associated periodontal disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ildikó Tar ◽  
Éva Csősz ◽  
Edit Végh ◽  
Karin Lundberg ◽  
Nastya Kharlamova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Periodontal Disease ◽  
Control Group ◽  
Healthy Controls ◽  
Periodontal Status ◽  
Protein Levels ◽  
Reduced Height ◽  
Significant Difference ◽  
Citrullinated Proteins ◽  
Citrullinated Protein

AbstractPeriodontal disease (PD) can be an important precipitating factor in the production of citrullinated proteins. Its importance is emphasized, but it is not the only way to produce citrullinated proteins. The aim of the current study was to determine the periodontal conditions and the salivary citrullinated protein content in patients with rheumatoid arthritis (RA) compared to healthy controls. We also wished to correlate citrullinated protein levels in the saliva and serum biomarkers with the periodontal status and temporomandibular joint (TMJ) involvement of patients with RA. Twenty-three patients with RA and 17 healthy controls participated the study. Saliva samples were taken: citrulline content of saliva was measured. Blood test results for patients with RA were collected. TMJ disorders were described. Cariological and periodontal indices were registered. Periodontal conditions and periodontal staging were also registered. Comparison of measured values between groups was performed. Intragroup correlation of patients’ values was counted. The prevalence of TMJ complaints was significantly higher in the RA group (8/23) versus controls (1/17). The patients with RA had worse periodontal condition because more patients with RA had gingivitis with a significantly higher bleeding on probing (BOP) (RA: 22.4 ± 25.0%; controls: 6.36 ± 11.6%; p = 0.018). Gingival index (GI) was also significantly higher in the patients than in controls (RA: 0.68 ± 0.58; controls: 0.19 ± 0.38; p = 0.010). The citrullinated protein (relative) content of saliva did not differ significantly (p = 0.147) between patients with RA (1102.2 ± 530.8) and healthy controls (1873.1 ± 1594.9). In RA, the salivary anti-CCP levels positively correlated with PD staging (R = 0.464, p = 0.039) . Control subjects more commonly had healthy gingiva than RA patients. Moreover, in the control group more individuals had intact and reduced height periodontium than periodontitis compared to the RA group. There was no significant difference in the levels of salivary citrulline between patients with RA and controls, despite the significant differences in their periodontal status. Thus, salivary citrulline levels are not associated with RA disease severity.

scholarly journals RUNX1 gene expression in Egyptian acute myeloid leukemia patients: may it have therapeutic implications?

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Fadwa Said ◽  
Roxan E. Shafik ◽  
Naglaa M. Hassan
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Gene Expression Level ◽  
Expression Level ◽  
Control Group ◽  
Therapeutic Implications ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia represents the highest percentage of all adult acute leukemia variants. Runt-related transcription factor1 (RUNX1), a transcription factor with a known tumor suppressor function, was recently reported as a tumor promoter in acute myeloid leukemia (AML). We investigated the role of RUNX1 gene expression level in Egyptian AML patients and delineated its clinical significance. Results We measured RUNX1 gene expression level using reverse transcription-quantitative polymerase chain reaction and found that the RUNX1 gene expression level was significantly higher than the control group (p < 0.001). Patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations had a higher expression level of RUNX1 (p = 0.023). The male patients expressed a significantly higher level of RUNX1 (p = 0.046). Conclusions The RUNX1 gene is highly expressed in Egyptian AML patients. It has a relation to FLT3-ITD, which may give a clue that patients carrying this mutation may benefit from new treatments that target RUNX1 in the future. Further studies on a larger number of patients with different ethnic groups may give a clearer vision of the therapeutic implications of a new molecular target.

Development of a Multiplex Assay for Rapid Assessment of Gene Expression Profiling of Rho GTPases Family Genes In MDS Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2907-2907
Author(s):  
Xuejun Shao ◽  
Meihua Miao ◽  
Zi-Xing Chen
Keyword(s):  
Gene Expression ◽  
Expression Profiling ◽  
Rho Gtpase ◽  
Rapid Assessment ◽  
Multiplex Assay ◽  
Expression Level ◽  
Control Group ◽  
Qrt Pcr ◽  
Flow Cytometric ◽  
Significant Difference

Abstract Abstract 2907 We have previously identified a panel of genes by gene expression profiling which differentially expressed between primary bone marrow CD34+ cell of MDS patients and the normal control cells. The expression pattern of these genes were also confirmed individually by qRT-PCR in expanded cohort of MDS patients. To further explore the feasibility of using proper number of these genes as biomarkers and evaluate the clinical significance in the diagnosis and prognostic prediction of MDS patients, a convenient, robust, sensitive, specific and less expensive method need to be developed. Therefore, endeavors have been made to establish a bead-based flow-cytometric multiplex assay. To establish this method, a technique called Multiplex ligation-dependent probe amplification (MLPA) was employed to amplify several targeted cDNAs by using single pair of identical primers. Each MLPA probe consists of two short synthetic oligonucleotide, and the tag which was coupled chemically to the fluorescent beads was complementary to one probe. Just as a pilot study to simultaneously detect the expression of four genes of the Rho GTPase family, five beads with different fluorescence intensity coupled to RAC2, RhoBTB3, SPA-1, Rap1GAP and GAPDH were designed. Biotinylated PCR amplicons were then hybridized to the complementary tag on each bead set. Bound amplicons were then detected by flow cytometry using a streptavidin-linked reporter dye, PE. 111 BM specimens were analyzed in total, consisting of RA(22), RAEB(22), RAEBt(9), AML(33), and control group (22, including hyperplastic anemia, iron deficiency anemia, aplastic anemia etc). The difference in the transcriptional level of RAC2, RhoBTB3, SPA-1 and Rap1GAP relative to GAPDH were analyzed using wilcoxon non-parametric test and SNK method among different groups. The results were confirmed by qRT-PCR. The bead-based flow-cytometric array had a excellent sensitivity and a wide linear range, could get a positive signal for PCR product from 0.0025 to 0.1umol, the fine specificity was proved by no cross-hybridization signals presented among different bead set, and the reproducibility were also good enough(P<0.001). the expression profiling of RAC2, RhoBTB3, SPA-1,Rap1GAP and GAPDH detected by this liquid bead-based flow-cytometric array were thus obtained. A significant difference among five groups for the expression level of RAC2, RhoBTB3, SPA-1 and Rap1GAP relative to GAPDH was found (P<0.0001, P=0.0491, P=0.0206 and P=0.0046 respectively). For RAC2, no difference existed between AML and control groups, while both these two groups demonstrated significant difference compared with RA, RAEB and REABt groups. The RA group had the highest expression level, AML the lowest; and RAEB in between. For RhoBTB3, a significant difference could be seen between RAEBt and other groups, RAEBt had the highest level of RhoBTB3. There was no difference in SPA-1 expression level determined between each two groups. However, an increasing tendency from control group to RA, RAEB, and REABt could be observed, whereas the expression of SPA-1 dramatically dropped to the lowest level in AML. For Rap1GAP, differences were found between AML and other group; These results were validated by qRT-PCR, and the data obtained by each method had close linear correlation, the Pearson correlation coefficient was 0.930, 0.946, 0.945 and 0.921 for RAC2, RhoBTB3, SPA-1 and Rap1GAP respectively (P<0.001 for all four). Based on these preliminary results, A liquid bead-based flow-cytometric multiplex assay for a rapid assessment of gene expression profile had been successfully developed and validated by qRT-PCR. This method will facilitates the clinical usage of a certain group of Rho GTPase family genes as well as other appropriate genes as useful biomarkers in the diagnosis of MDS patients and provide interesting clues to further explore the pathogenesis of MDS. Disclosures: No relevant conflicts of interest to declare.

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.

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