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ABSTRACT:
PROVIDER: PRJNA198764 | ENA |
REPOSITORIES: ENA
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Project description:compare of microRNA expression between IA and MMA
| PRJNA198766 | ENA
Project description:To exploring the difference of microRNA expression between IA and MMA, we have employed microRNA array expression profiling as a discovery platform to identify genes between the IA and MMA. Futher functional analyses were performed based on the data.
2013-04-25 | GSE46336 | GEO
Project description:To exploring the difference of microRNA expression between IA and MMA, we have employed microRNA array expression profiling as a discovery platform to identify genes between the IA and MMA. Futher functional analyses were performed based on the data. 3 IA and 3 MMA were used for the microarray.
2013-04-25 | E-GEOD-46336 | biostudies-arrayexpress
Project description:To exploring the difference of mRNA expression between IA and MMA, we have employed mRNA array expression profiling as a discovery platform to identify genes between the IA and MMA. It's a compensate experiment after microRNA array, we paired the mRNA data with miRNA targets, finally, these data were used for the functional analysis. 2 IA and 2 MMA tissue were used for the microarray
2013-04-25 | E-GEOD-46337 | biostudies-arrayexpress
Project description:To exploring the difference of mRNA expression between IA and MMA, we have employed mRNA array expression profiling as a discovery platform to identify genes between the IA and MMA. It's a compensate experiment after microRNA array, we paired the mRNA data with miRNA targets, finally, these data were used for the functional analysis.
2013-04-25 | GSE46337 | GEO
Project description:Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
2024-10-17 | GSE256487 | GEO
Project description:Objective: To investigate the independent and interactive effects of circulating folate and methylmalonic acid (MMA) status on cardiovascular disease (CVD) mortality. Methods: This study included 22,487 individuals from the U.S. National Health and Nutrition Examination Survey (NHANES) between 1999 and 2014. Kaplan-Meier and weighted Cox proportional hazards models were used to assess the associations of folate and MMA with CVD mortality. Restricted cubic splines (RCS) evaluated nonlinear relationships. Additive interaction method explored interactive effects. Sensitivity analysis tested the robustness of the findings. In vitro, CCK-8 assays were performed to assess the combined effects of folate and MMA on H9c2 cardiomyocyte viability. Transcriptomic analysis identified differentially expressed genes (DEGs) and their enriched pathways. Results: During 12.1 years of median follow-up, 1,510 cardiovascular deaths (4.4%) were recorded. RCS analysis demonstrated a U-shaped association between folate levels and CVD mortality, and a linear association for MMA. When MMA ≤ 182 nmol/L, folate levels were not associated with CVD mortality. However, among individuals with MMA > 182 nmol/L, both low and high folate levels were significantly associated with higher CVD mortality, with adjusted hazard ratios (aHRs) of 1.43 (95% CI: 1.19-1.71) and 2.36 (95% CI: 1.85-3.00), respectively (both P < 0.001). An additive interaction between folate and MMA on CVD mortality (RERI: 0.82 [95% CI: 0.06-1.58], API: 0.35 [95% CI: 0.03-0.67]; SI: 1.57 [95% CI: 1.27-2.00]). Sensitivity analyses confirmed these findings. In vitro, MMA (8 mM) significantly enhanced folate-induced (1.6 mM) cytotoxicity, reducing cell viability to 49.26% (P < 0.001). Transcriptomic analysis revealed 53 DEGs under combined treatment, enriched in inflammation-related pathways. Conclusions: Both population-based and experimental evidence suggest that elevated folate and MMA levels independently increase CVD mortality risk, with their interaction synergistically exacerbating cardiovascular outcomes.
2025-11-02 | GSE307146 | GEO
Project description:Background Heart failure burden is still considerable in diabetes patients despite optimal glycemic control. Metabolic remodeling is involved in this process, but current understanding is still in its infancy. Methylmalonic acid (MMA) is a diagnostic marker of cobalamin (Cbl) deficiency in clinical practice. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with higher Cbl levels. We investigated the mechanisms underlying these contradictory features in diabetic heart and translational relevance. Methods We assessed serum Cbl, MMA, and cardiac biomarkers in 12,751 participants, and the Mmut protein (allosteric enzyme of MMA catabolism) in failing human hearts with diabetes and healthy donors. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing (delivered by AAV-Mmut with cTnT promoter) mice were subjected to high-fat diet/streptozotocin-induced diabetes. High glucose and/or palmitate stimulation of primary neonatal mouse ventricular cardiomyocytes (NMVMs) imitates diabetic conditions in vitro. Molecular mechanism was explored through RNA sequencing, immunoprecipitation, isotope tracing mass spectrometry and biolayer interferometry assays. Results Higher serum MMA was significantly associated with subclinical heart damage and poor outcomes among adults with diabetes in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism in diabetic mice occurred before detectable cardiac damage and persisted even after glycemic control. Mechanistically, hyperglycemic memory-related molecule miR-499 binds to the mRNA of Mmut and inhibits its expression, leading to MMA overload under diabetes. Mmut knockout amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control in diabetic hearts. Conversely, AAV-Mmut injection significantly reduces MMA load and alleviates the progression of cardiac remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the main sources of cardiac MMA under diabetes. A restricted-branched chain amino acid diet alleviated diabetes-induced MMA accumulation and heart damage. However, Cbl supplementation did not correct MMA overload in diabetic mice, even at high doses or in activated forms. Strikingly, both clinical and preclinical data showed metformin, a risk factor for Cbl deficiency, may mitigate MMA overload and related heart damage via dual mechanisms—activating AMPK-dependent mitochondrial quality control, enhancing tolerance to MMA insults; and direct Mmut-cobalamin cooperation, promoting MMA clearance independent of AMPK. Conclusions: This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation.
2026-04-08 | GSE327065 | GEO