Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive oxygen species-dependent ferroptosis.

Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia-reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.

P38 MAPK activated ADAM17 mediates ACE2 shedding and promotes cardiac remodeling and heart failure after myocardial infarction.

BACKGROUND: Heart failure (HF) after myocardial infarction (MI) is a prevalent disease with a poor prognosis. Relieving pathological cardiac remodeling and preserving cardiac function is a critical link in the treatment of post-MI HF. Thus, more new therapeutic targets are urgently needed. The expression of ADAM17 is increased in patients with acute MI, but its functional role in post-MI HF remains unclear. METHODS: To address this question, we examined the effects of ADAM17 on the severity and prognosis of HF within 1 year of MI in 152 MI patients with or without HF. In mechanistic studies, the effects of ADAM17 on ventricular remodeling and systolic function were extensively assessed at the tissue and cellular levels by establishing animal model of post-MI HF and in vitro hypoxic cell model. RESULTS: High levels of ADAM17 predicted a higher incidence of post-MI HF, poorer cardiac function and higher mortality. Animal studies demonstrated that ADAM17 promoted the occurrence of post-MI HF, as indicated by increased infarct size, cardiomyocyte hypertrophy, myocardial interstitial collagen deposition and cardiac failure. ADAM17 knock down significantly improved pathological cardiac remodeling and cardiac function in mice with MI. Mechanistically, activated ADAM17 inhibited the cardioprotective effects of ACE2 by promoting hydrolytic shedding of the transmembrane protein ACE2 in cardiomyocytes, which subsequently mediated the occurrence of cardiac remodeling and the progression of heart failure. Moreover, the activation of ADAM17 in hypoxic cardiomyocytes was dependent on p38 MAPK phosphorylation at threonine 735. CONCLUSIONS: These data highlight a novel and important mechanism for ADAM17 to cause post-MI HF, which will hopefully be a new potential target for early prediction or intervention of post-MI HF. Video abstract.

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study.

BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Neutrophil extracellular traps contribute to tissue plasminogen activator resistance in acute ischemic stroke.

Circulating neutrophil extracellular traps (NETs) resistant to t-PA have not been studied completely although NETs in thrombi may contribute to tissue plasminogen activator (t-PA) resistance. This research intended to elucidate whether circulating NETs are associated with t-PA resistance and the underlying mechanism. The levels of NETs were detected in the circulating neutrophils, ischemic brain tissue of acute ischemic stroke (AIS) patients, and transient middle cerebral artery occlusion (tMCAO) models. NET formation in blood, thrombi, and ischemic brain tissue of mice were analyzed by immunofluorescence. Exposed phosphatidylserine (PS) was assessed using flow cytometry and confocal microscopy. Procoagulant activity (PCA) was evaluated using fibrin formation assays, thrombin, and purified coagulation complex. The plasma levels of NETs in AIS patients were significantly higher than those in healthy individuals. After thrombolysis, a significant increase was noted in NET markers in no-improvement patients, while the changes in improvement patients were not significant. Importantly, NETs were decorated with von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) in the blood and thrombi, which could reverse the fibrinolytic effects. In addition, NETs activated platelets (PLTs) and endothelial cells (ECs), stimulating a procoagulant phenotype and facilitating vWF and PAI-1 release. DNase I, activated protein C (APC), and sivelestat markedly inhibited these effects. Furthermore, targeting NETs protected mice from tMCAO-induced cerebral ischemia, possibly by regulating vWF and PAI-1. In summary, NETs may contribute to t-PA resistance in AIS through activation of PLTs and ECs. Strategies against NETs may present a promising therapeutic approach to improve the thrombolysis efficiency of t-PA in AIS patients.

Macrophage-Enriched lncRNA RAPIA: A Novel Therapeutic Target for Atherosclerosis.

OBJECTIVE: Despite the current antiatherosclerotic and antithrombotic therapies, the incidence of advanced atherosclerosis-associated clinical events remains high. Whether long noncoding RNAs (lncRNAs) affect the progression of atherosclerosis and whether they are potential targets for the treatment of advanced atherosclerosis are poorly understood. Approach and Results: The progression of atherosclerotic lesions was accompanied by dynamic alterations in lncRNA expression, as revealed by RNA sequencing and quantitative polymerase chain reaction. Among the dynamically changing lncRNAs, we identified a novel lncRNA, lncRNA Associated with the Progression and Intervention of Atherosclerosis (RAPIA), that was highly expressed in advanced atherosclerotic lesions and in macrophages. Inhibition of RAPIA in vivo not only repressed the progression of atherosclerosis but also exerted atheroprotective effects similar to those of atorvastatin on advanced atherosclerotic plaques that had already formed. In vitro assays demonstrated that RAPIA promoted proliferation and reduced apoptosis of macrophages. A molecular sponge interaction between RAPIA and microRNA-183-5p was demonstrated by dual-luciferase reporter and RNA immunoprecipitation assays. Rescue assays indicated that RAPIA functioned at least in part by targeting the microRNA-183-5p/ITGB1 (integrin ß1) pathway in macrophages. In addition, the transcription factor FoxO1 (forkhead box O1) could bind to the RAPIA promoter region and facilitate the expression of RAPIA. CONCLUSIONS: The progression of atherosclerotic lesions was accompanied by dynamic changes in the expression of lncRNAs. Inhibition of the pivotal lncRNA RAPIA may be a novel preventive and therapeutic strategy for advanced atherosclerosis, especially in patients resistant or intolerant to statins.

Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis.

CD4+ T cells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple T cell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ T cell dysfunction remains elusive. Our objective was to elucidate the mechanism of action for circulating exosomes in EAM pathogenesis. We found that serum exosomes harvested from EAM mice induced CD4+ T cell immunometabolic dysfunction. Treatment with the exosome inhibitor GW4869 protected mice from developing EAM, underlying that exosomes are indispensable for the pathogenesis of EAM. Furthermore, by transfer of EAM exosomes, we confirmed that circulating exosomes initiate the T cell pathological immune response, driving the EAM pathological process. Mechanistically, EAM-circulating exosomes selectively loaded abundant microRNA (miR)-142. We confirmed methyl-CpG binding domain protein 2 (MBD2) and suppressor of cytokine signaling 1 (SOCS1) as functional target genes of miR-142. The miR-142/MBD2/MYC and miR-142/SOCS1 communication axes are critical to exosome-mediated immunometabolic turbulence. Moreover, the in vivo injection of the miR-142 inhibitor alleviated cardiac injury in EAM mice. This effect was abrogated by pretreatment with EAM exosomes. Collectively, our results indicate a newly endogenous mechanism whereby circulating exosomes regulate CD4+ T cell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.

MicroRNA 182 promotes T helper 1 cell by repressing hypoxia induced factor 1 alpha in experimental autoimmune encephalomyelitis.

MicroRNA 182 is important for the clonal expansion of CD4+ T cells (Th) following IL-2 stimulation and is a potential therapeutic target for autoimmune diseases. In the present study, we investigated the role of microRNA 182 in the differentiation of pro-inflammatory CD4+ T helper cell by overexpressing or silencing microRNA 182 expression both in in vivo and in vitro settings. We report that in the studied Chinese cohort, microRNA 182 is upregulated in patients with relapse and remitting multiple sclerosis (RRMS) and this upregulation is associated with increased IFN-γ producing CD4+ Th1 cells in the circulation. In the murine experimental autoimmune encephalomyelitis (EAE) model, global microRNA 182 overexpression exacerbates clinical symptoms and results in augmented CD4+ IFN-γ+ Th1 and CD4+ IL-17+ Th17 differentiation in vivo. Addition of microRNA 182 mimics in vitro represses both the protein expression and transcriptional activity of hypoxia induced factor 1α (HIF-1α) but increases the level of IFN-γ transcripts in sorted murine CD4+ T cells. Together, our results provide evidence that microRNA 182 may be one of the transitional hubs contribution to regulate Th cells expansion in response to self-antigens and differentiation of antigen specific Th cells during the progression of autoimmune inflammations.

The association between glucose-related variables and plaque morphology in patients with ST-segment elevated myocardial infarction.

BACKGROUND: Plaque rupture (PR) and plaque erosion (PE) are main causes of acute myocardial infarction with different demographic and histology characteristics and need different treatment strategy. PR and PE can be identified with optical coherence tomography (OCT) accurately, but convenient and effective noninvasive markers for them are rarely found. History of diabetes mellitus (DM) was reported to be a potential predictor of PR in ST-segment elevated myocardial infarction (STEMI) patients, but the predictive value of other glucose-related variables for it is still uncertain. Present study aimed to clear the relationship between some glucose-related variables and plaque morphology in patients with STEMI. METHODS: We consecutively enrolled 872 STEMI patients and divided them into PR group (n = 616) and PE group (n = 256) based on OCT diagnostic criteria. The relationship of glucose-related variables, including random plasma glucose on admission (ARPG), glycosylated hemoglobin (HbA1c), post-PCI fasting plasma glucose (PFPG), DM history, glucose variable tendency (GVT) and the acute-to-chronic glycemic ratio (A/C), to the PR risk of STEMI patients was analyzed. The correlation between the glucose-related variables and plaque morphology was analyzed meanwhile. RESULTS: Among the glucose-related variables, ARPG and GVT were confirmed to be independent predictors for PR after adjusting for other traditional risk factors in nondiabetic patients. The higher the ARPG level, the more PR risk the STEMI patients had. And high HbA1c and APPG were demonstrated to have a weak and positive correlation with lipid constituents and stenosis degree of culprit vessel. CONCLUSIONS: Compared to HbA1c, DM history, and some other glucose-related variables, ARPG and GVT were risk factors for PR in STEMI patients, especially those without DM. And high HbA1c and ARPG were positively correlated with the development of vulnerable plaque in culprit vessels. Trial registration Present study is a retrospective one and the population came from the EROSION study of our center previously. It was approved by the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (Approval reference number, KY2017-249), and all patients provided written informed consent prior to the inclusion in the study and the investigation conformed to the principles outlined in the Declaration of Helsinki.

Proteomics Profiling Reveals Insulin-Like Growth Factor 1, Collagen Type VI α-2 Chain, and Fermitin Family Homolog 3 as Potential Biomarkers of Plaque Erosion in ST-Segment Elevated Myocardial Infarction.

BACKGROUND: Plaque erosion (PE) has been considered a secondary pathogenesis of ST-segment elevated myocardial infarction (STEMI) following plaque rupture (PR). Previous studies demonstrated that they had different demographic and histology characteristics and need different treatment strategy. But there are few non-invasive plasma biomarkers for distinguishing them. The present study aimed to identify non-invasive predictive biomarkers for PE and PR in patients with STEMI.Methods and Results:A total 108 patients were recruited and grouped into a PE group (n=36), a PR group (n=36), and an unstable angina pectoris (UAP) (n=36) group for analysis. A 9-plex tandem mass tag (TMT)-based proteomics was used to compare plasma protein profiles of PE, PR, and UAP. In total, 36 significant differential proteins (DPs) were identified among groups, 10 of which were screened out using bio-information analysis and validated with enzyme-linked immunosorbent assay (ELISA). The relationship of angiography and optical coherence tomography (OCT) imaging data and the 10 target DPs was analyzed statistically. Logistic regression showed elevated collagen type VI α-2 chain (COL6A2) and insulin-like growth factor 1 (IGF1), and decreased fermitin family homolog 3 (FERMT3), were positively associated with PE. Multivariate analysis indicated IGF1, FERMT3, and COL6A2 had independent predictive ability for PE. IGF1 was inversely correlated with lumen stenosis and the lipid arc of the plaque. CONCLUSIONS: IGF1, COL6A2, and FERMT3 are potential predictive biomarkers of PE in STEMI patients. And IGF1 was negatively correlated with the developing of culprit plaque.

Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice.

Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4+ T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4+ T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4+ T-cell immunological status. Adoptive transfer of CD4+ T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4+ T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.

Time Series Characteristics of Serum Branched-Chain Amino Acids for Early Diagnosis of Chronic Heart Failure.

Chronic heart failure (CHF) is an ongoing clinical syndrome with cardiac dysfunction that can be traced to alterations in cardiac metabolism. The identification of metabolic biomarkers in easily accessible fluids to improve the early diagnosis of CHF has been elusive to date. In this study, we took multidimensional analytical techniques to discover potentially new diagnostic biomarkers by focusing on the dynamic changes of metabolites in serum during the progression of CHF. Using mass-spectrometry-based untargeted metabolomics, we identified 23 cardiac metabolites that were altered in a rat model of myocardial infarction induced CHF. Among these differential metabolites, branched-chain amino acids (BCAAs) in serum, especially leucine and valine, showed a high capability to differentiate between CHF and sham-operated rats, of which area under the receiver operating characteristic curve was greater than 0.75. Combining with targeted analysis of the amino acids and related proteins and genes, we confirmed that BCAA metabolic pathway was significantly inhibited in rat failing hearts. On the basis of the time series data of serum samples, we characterized the fluctuation pattern of circulating BCAAs by the disease progression model. Finally, the time-resolved diagnostic potential of serum BCAAs was evaluated by the machine-learning-based classifier, and high diagnostic accuracy of 93.75% was achieved within 3 weeks after surgery. These findings provide a promising metabolic signature that can be further exploited for CHF early diagnostic development.

Promyelocytic extracellular chromatin exacerbates coagulation and fibrinolysis in acute promyelocytic leukemia.

Despite routine treatment of unselected acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA), early death because of hemorrhage remains unacceptably common, and the mechanism underlying this complication remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, which involves release of extracellular chromatin. However, the role of promyelocytic extracellular chromatin in APL-associated coagulation remains unclear. Our objectives were to identify the novel role of ATRA-promoted extracellular chromatin in inducing a hypercoagulable and hyperfibrinolytic state in APL and to evaluate its interaction with fibrin and endothelial cells (ECs). Results from a series of coagulation assays have shown that promyelocytic extracellular chromatin increases thrombin and plasmin generation, causes a shortening of plasma clotting time of APL cells, and increases fibrin formation. DNase I but not anti-tissue factor antibody could inhibit these effects. Immunofluorescence staining showed that promyelocytic extracellular chromatin and phosphatidylserine on APL cells provide platforms for fibrin deposition and render clots more resistant to fibrinolysis. Additionally, coincubation assays revealed that promyelocytic extracellular chromatin is cytotoxic to ECs, converting them to a procoagulant phenotype. This cytotoxity was blocked by DNase I by 20% or activated protein C by 31%. Our current results thus delineate the pathogenic role of promyelocytic extracellular chromatin in APL coagulopathy. Furthermore, the remaining coagulation disturbance in high-risk APL patients after ATRA administration may be treatable by intrinsic pathway inhibition via accelerating extracellular chromatin degradation.

Interleukin-35 promotes early endothelialization after stent implantation by regulating macrophage activation.

Background: Early strut coverage after sirolimus-eluting stent (SES) implantation is associated with the activation of inflammation, but the underlying mechanisms are not completely understood. The present study aimed to identify the relationship between the anti-inflammatory cytokine interleukin (IL) 35 (IL-35) and early strut coverage in vivo and in vitroMethods: We utilized a retrospective study design to measure IL-35 levels in 68 stents from 68 patients with coronary artery disease and recorded serial optical coherence tomography (OCT) images (0 and 3 months) to assess stent endothelialization. The mechanism underlying the regulatory effects of IL-35 on macrophages and human umbilical vein endothelial cells (HUVECs) was also investigated. SESs were surgically implanted into the right common carotid arteries of 200 male New Zealand White rabbits receiving intravenous injections of IL-35 or a placebo.Results: At the 3-month OCT evaluation, complete endothelium coverage was correlated with IL-35 levels. IL-35 induced the activation of an anti-inflammatory M2-like macrophage phenotype by targeting the signal transducer and activators of transcription (STAT)1/4 signalling pathway, and IL-35-treated macrophages induced endothelial proliferation and alleviated endothelial dysfunction. IL-35-treated New Zealand White rabbits with implanted SESs showed lower percentages of cross-sections with an uncovered strut, elevated mean neointimal hyperplasia (NIH) thickness, and inhibited inflammatory responses.Conclusions: We investigated the effect of IL-35 expression on early stent endothelialization in vivo and in vitro and identified a crucial role for IL-35 in inducing the activation of an anti-inflammatory M2-like macrophage phenotype. The present study highlights a new therapeutic strategy for early stent endothelialization.

Functional network analysis reveals biological roles of lncRNAs and mRNAs in MOG35-55 specific CD4+T helper cells.

Long non-coding RNAs have the potential to regulate immune responses. Their impact on multiple sclerosis has remained elusive. For illustrating their roles in experimental autoimmune encephalomyelitis (EAE) pathogenesis, we investigated the differential expression of lncRNAs and mRNAs in CD4+Th cells obtained from myelin oligodendrocytic glycoprotein35-55(MOG35-55)-induced EAE and complete Freund's adjuvant (CFA) controls. We observed differential expression of 1112 lncRNAs and 519 mRNAs in CD4+Th cells. The functional network showed lncRNAs had the capacity to modulate EAE pathogenesis via regulating many known EAE regulators such as Ptpn6. Predicting the function of lncRNAs demonstrated that dysregulated lncRNAs were closely associated with the development of EAE. These dysregulated lncRNAs may have function in EAE and they could be novel biomarkers and therapeutic targets of EAE. However, the precise mechanisms and biological functions of these specific lncRNAs in EAE pathogenesis require further study.

Inhibition of MicroRNA-96 Ameliorates Cognitive Impairment and Inactivation Autophagy Following Chronic Cerebral Hypoperfusion in the Rat.

BACKGROUND/AIMS: Chronic cerebral hypoperfusion (CCH) is a high-risk factor for vascular dementia and Alzheimer's disease. Autophagy plays a critical role in the initiation and progression of CCH. However, the underlying mechanisms remain unclear. In this study, we identified the effect of a microRNA (miR) on autophagy under CCH. METHODS: A CCH rat model was established by two-vessel occlusion (2VO). Learning and memory abilities were assessed by the Morris water maze. The protein levels of LC3, beclin-1, and mTOR were detected by western blotting and immunofluorescence assays, miR-96 expression was assessed by real-time PCR, luciferase assays were used to determine the effect of miR-96 on the 3' untranslated region (UTR) of mTOR, and the number of autophagosomes was examined by electron microscopy. RESULTS: The level of miR-96 was significantly increased in 2VO rats, and inhibition of miR-96 ameliorated the cognitive impairment induced by 2VO. Furthermore, the number of LC3- and beclin-1-positive autophagosomes was increased in 2VO rats, and was decreased after miR-96 antagomir injection. However, the protein level of mTOR was reduced in 2VO rats, and it was down-regulated by miR-96 overexpression and up-regulated by miR-96 inhibition in 2VO rats and primary culture cells. Moreover, the luciferase activity of the 3'-UTR of mTOR was suppressed by miR-96, which was relieved by mutation of the miR-96 binding sites. CONCLUSION: Our study demonstrated that miR-96 may play a key role in autophagy under CCH by regulating mTOR; therefore, miR-96 may represent a potential therapeutic target for CCH.

MicroRNA 182 inhibits CD4+CD25+Foxp3+ Treg differentiation in experimental autoimmune encephalomyelitis.

MicroRNA 182 has been found to have a distinct contribution in the clonal expansion of activated- and functioning of specialized-helper T cells. In this study we knocked down microRNA 182 in vivo and induced experimental autoimmune encephalomyelitis (EAE) to determine the influences of microRNA 182 in the Treg cells functional specialization through Foxo1 dependent pathway in the peripheral lymphoid organs. Down-regulation of microRNA 182 significantly increased the proportions of Foxp3+ T cells in the peripheral lymph nodes and spleen. In vivo study verified a positive correlation between microRNA 182 levels and symptom severity of EAE, and a negative correlation between microRNA 182 and the transcriptional factor Foxp3. In vitro polarization study also confirmed the contribution of Foxo1 in microRNA 182 mediated down-regulation of Foxp3+ T cells. Together, our results provide evidence that during the development of EAE, microRNA 182 repressed Treg cells differentiation through the Foxo1 dependent pathway.

Joint association of diabetes mellitus and inflammation status with biological ageing acceleration and premature mortality.

BACKGROUND: We aimed to investigate the associations of diabetes mellitus (DM) and C-reactive protein (CRP) with biological ageing acceleration and mortality risk. METHODS: We analyzed data from 41,634 adults with CRP and DM at baseline. Subjects were categorized into high CRP (>3 mg/L) and low CRP (≤3 mg/L) groups. The cross-sectional endpoints of the study were biological ageing indicators Klemera-Doubal method BioAge acceleration (KDMAccel) and Phenotypic age acceleration (PhenoAgeAccel), and the follow-up endpoints were all-cause mortality and cardiovascular mortality. RESULTS: In adults with high CRP, compared with those without DM, PhenoAgeAccel increased by 1.66 years (95 % CI: 1.38-1.93), and 8.74 years (95 % CI: 8.25-9.22) in adults with prediabetes and DM, respectively (p for interaction <0.001). Using the CRPlow/non-DM group as a reference, adults in the CRPhigh/non-DM, CRPlow/DM, and CRPhigh/DM groups had significantly advanced biological ageing. Compared to adults without DM, low CRP, and no ageing acceleration, the multivariable-adjusted HRs (95%CIs) of all-cause and cardiovascular mortality in those with DM, CRP, and ageing acceleration were 3.22 (2.79-3.72), and 3.57 (2.81-4.54), respectively. CONCLUSIONS: These findings suggest that the joint presence of low-grade inflammation and DM might be associated with higher odds of biological ageing acceleration and premature mortality.

Decreased cobalamin sensitivity and biological aging acceleration in the general population.

BACKGROUND: The evidence on the association between cobalamin (Cbl) and aging or relevant outcomes is limited and controversial. We aimed to investigate the relationships between cobalamin intake- and function-related biomarkers and biological aging. METHODS: The study encompassed 22,812 participants aged 20 years and older from the National Health and Nutrition Examination Survey. A panel of biomarkers or algorithms was used to assess biological aging, including Klemera-Doubal Age Acceleration (KDMAccel), Phenotypic age acceleration (PhenoAgeAccel), telomere length, α-Klotho, and PhenoAge advancement. Weighted generalized linear regression analysis was used to assess the associations between cobalamin-intake biomarkers (serum cobalamin, cobalamin intake from food, cobalamin supplement use, serum methylmalonic acid [MMA], and homocysteine [Hcy]) and function-related biomarkers (functional cobalamin deficiency and cobalamin insensitivity index). RESULTS: Among the 22,812 individuals, the weighted mean (SE) age was 48.3 (0.2) years and 48.0% were males. Unexpectedly, serum and dietary cobalamin as well as serum MMA and Hcy levels were positively associated with most indicators of biological aging. Cobalamin sensitivity was assessed by the combination of binary Cbllow/high and MMAlow/high or Hcylow/high (cutoff values: 400 pg/mL for cobalamin, 250 nmol/L for MMA, and 12.1 µmol/l for Hcy) and a newly constructed cobalamin insensitivity index (based on the multiplicative term of serum cobalamin and serum MMA or Hcy). The multivariable-adjusted ß (95%CIs) of KDMAccel in the MMAlowCbllow, MMAlowCblhigh, MMAhighCbllow, and MMAhighCblhigh groups were reference, 0.27 (0.03 to 0.51), 0.85 (0.41 to 1.29), and 7.97 years (5.77 to 10.17) respectively, which were consistent for the combination of serum Hcy and cobalamin. Both cobalamin insensitivity indices were robustly associated with biological aging acceleration in a dose-response pattern (each p < 0.001). CONCLUSIONS: Decreased cobalamin sensitivity but not cobalamin insufficiency might be associated with biological aging acceleration. Further studies would improve understanding of the underlying mechanisms between decreased cobalamin sensitivity and biological aging acceleration.

Pseudo-targeted metabolic profile differences between emergency patients with type 1 and type 2 myocardial infarction diagnosed by optical coherence tomography.

BACKGROUND: It is difficult to distinguish type 2 myocardial infarction (T2MI) from type 1 myocardial infarction (T1MI), although their management varies. OBJECTIVES: Using optical coherence tomography (OCT) and pseudo-targeted metabolomics to identify biomarkers, investigate metabolic differences, and establish a T2MI subclassification. METHODS: Among 1519 patients with MI, 97 T2MI patients are identified who are 1:1 matched with 97 T1MI patients after considering age, gender, ST-segment elevation, time from onset to coronary angiography, and hs-cTnI on admission by propensity score matching. Plasma pseudo-targeted metabolomics at baseline was determined. RESULTS: The clinical characteristics of the two groups were comparable, while the T1MI showed more severe coronary lesions than T2MI according to OCT imaging. 90 differential metabolites were identified between the two groups, among 1027 endogenous metabolites in 20 classes. N-Acetyl-L-Leucine, free fatty acid (15:1), Thymidine-5'-triphosphate, Mevalonic acid 5-pyrophosphate, and five oligopeptides were candidate biomarkers (AUC ≥ 0.85) distinguishing T2MI from T1MI. 12 KEGG pathways showed significant differences, mainly involving amino acid, nucleotide, and their derivatives metabolism, and signaling pathways such as mTOR, cGMP-PKG, and cAMP. Other differences were observed in TCA cycle (P = 0.08) and ROS (P = 0.05). Proteolysis and coronary heart disease risk lipid level were lower in T2MI. T2MI had a decrease of differential abundance score in almost all the KEGG enrichment pathways. Furthermore, T2MI can be subdivided into three subtypes by hierarchical cluster analysis of AUCs with causes/triggers of T2MI. CONCLUSIONS: There are significant metabolic profile differences between T1MI and T2MI. Several candidate metabolic biomarkers can effectively distinguish the two groups. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov NCT03297164.