A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control

Appropriate control of hepatic gluconeogenesis is essential for the organismal survival upon prolonged fasting and maintaining systemic homeostasis under metabolic stress. Here, we show protein arginine methyltransferase 1 (PRMT1), a key enzyme that catalyzes the protein arginine methylation process, particularly the isoform encoded by Prmt1 variant 2 (PRMT1V2), is critical in regulating gluconeogenesis in the liver. Liver‐specific deletion of Prmt1 reduced gluconeogenic capacity in cultured hepatocytes and in the liver. Prmt1v2 was expressed at a higher level compared to Prmt1v1 in hepatic tissue and cells. Gain‐of‐function of PRMT1V2 clearly activated the gluconeogenic program in hepatocytes via interactions with PGC1α, a key transcriptional coactivator regulating gluconeogenesis, enhancing its activity via arginine methylation, while no effects of PRMT1V1 were observed. Similar stimulatory effects of PRMT1V2 in controlling gluconeogenesis were observed in human HepG2 cells. PRMT1, specifically PRMT1V2, was stabilized in fasted liver and hepatocytes treated with glucagon, in a PGC1α‐dependent manner. PRMT1, particularly Prmt1v2, was significantly induced in the liver of streptozocin‐induced type 1 diabetes and high fat diet‐induced type 2 diabetes mouse models and liver‐specific Prmt1 deficiency drastically ameliorated diabetic hyperglycemia. These findings reveal that PRMT1 modulates gluconeogenesis and mediates glucose homeostasis under physiological and pathological conditions, suggesting that deeper understanding how PRMT1 contributes to the coordinated efforts in glycemic control may ultimately present novel therapeutic strategies that counteracts hyperglycemia in disease settings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/10/fsb221018-sup-0005-FigS5.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/9/fsb221018-sup-0001-FigS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/8/fsb221018-sup-0003-FigS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/7/fsb221018-sup-0008-FigS8.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/6/fsb221018-sup-0002-FigS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/5/fsb221018_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/4/fsb221018.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/3/fsb221018-sup-0007-FigS7.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/2/fsb221018-sup-0006-FigS6.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163465/1/fsb221018-sup-0004-FigS4.pd

Proteomic and Transcriptomic Responses of the Desiccation-Tolerant Moss <i>Racomitrium canescens</i> in the Rapid Rehydration Processes

The moss Racomitrium canescens (R. canescens) has strong desiccation tolerance. It can remain desiccated for years and yet recover within minutes of rehydration. Understanding the responses and mechanisms underlying this rapid rehydration capacity in bryophytes could identify candidate genes that improve crop drought tolerance. We explored these responses using physiology, proteomics, and transcriptomics. Label-free quantitative proteomics comparing desiccated plants and samples rehydrated for 1 min or 6 h suggesting that damage to chromatin and the cytoskeleton had occurred during desiccation, and pointing to the large-scale degradation of proteins, the production of mannose and xylose, and the degradation of trehalose immediately after rehydration. The assembly and quantification of transcriptomes from R. canescens across different stages of rehydration established that desiccation was physiologically stressful for the plants; however, the plants recovered rapidly once rehydrated. According to the transcriptomics data, vacuoles appear to play a crucial role in the early stages of R. canescens recovery. Mitochondria and cell reproduction might recover before photosynthesis; most biological functions potentially restarted after ~6 h. Furthermore, we identified novel genes and proteins related to desiccation tolerance in bryophytes. Overall, this study provides new strategies for analyzing desiccation-tolerant bryophytes and identifying candidate genes for improving plant drought tolerance

Proteomic and Transcriptomic Responses of the Desiccation-Tolerant Moss Racomitrium canescens in the Rapid Rehydration Processes

The moss Racomitrium canescens (R. canescens) has strong desiccation tolerance. It can remain desiccated for years and yet recover within minutes of rehydration. Understanding the responses and mechanisms underlying this rapid rehydration capacity in bryophytes could identify candidate genes that improve crop drought tolerance. We explored these responses using physiology, proteomics, and transcriptomics. Label-free quantitative proteomics comparing desiccated plants and samples rehydrated for 1 min or 6 h suggesting that damage to chromatin and the cytoskeleton had occurred during desiccation, and pointing to the large-scale degradation of proteins, the production of mannose and xylose, and the degradation of trehalose immediately after rehydration. The assembly and quantification of transcriptomes from R. canescens across different stages of rehydration established that desiccation was physiologically stressful for the plants; however, the plants recovered rapidly once rehydrated. According to the transcriptomics data, vacuoles appear to play a crucial role in the early stages of R. canescens recovery. Mitochondria and cell reproduction might recover before photosynthesis; most biological functions potentially restarted after ~6 h. Furthermore, we identified novel genes and proteins related to desiccation tolerance in bryophytes. Overall, this study provides new strategies for analyzing desiccation-tolerant bryophytes and identifying candidate genes for improving plant drought tolerance

Catheter ablation for treatment of patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials

Abstract Background There is a little evidence for the effects of catheter ablation (CA) on hard endpoints in patients with atrial fibrillation (AF) and heart failure (HF). Methods PubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) enrolling patients with AF and HF who were assigned to CA, rate control or medical rhythm control groups. This meta-analysis was performed by using random-effect models. Results Seven RCTs enrolling 856 participants were included in this meta-analysis. CA reduced the risks of all-cause mortality (risk ratio [RR] 0.52, 95% CI 0.35 to 0.76), HF readmission (RR 0.58, 95% CI 0.46 to 0.66) and the composite of all-cause mortality and HF readmission (RR 0.55, 95% CI 0.47 to 0.66) when compared with control. But there was no significant difference in cerebrovascular accident (RR 0.56, 95% CI 0.23 to 1.36) between two groups. Compared with control, CA was associated with improvement in left ventricular ejection fraction (mean difference [MD] 7.57, 95% CI 3.72 to 11.41), left ventricular end systolic volume (MD -14.51, 95% CI -26.84 to − 2.07), and left ventricular end diastolic volume (MD -3.78, 95% CI -18.51 to 10.96). Patients undergoing CA exhibited increased peak oxygen consumption (MD 3.16, 95% CI 1.09 to 5.23), longer 6-min walk test distance (MD 26.67, 95% CI 12.07 to 41.27), and reduced Minnesota Living with Heart Failure Questionnaire scores (MD -9.49, 95% CI -14.64 to − 4.34) than those in control group. Compared with control, CA was associated with improved New York Heart Association class (MD -0.74, 95% CI -0.83 to − 0.64) and lower B-type natriuretic peptide levels (MD -105.96, 95% CI -230.56 to 19.64). Conclusions CA was associated with improved survival, morphologic changes, functional capacity and quality of life relative to control. CA should be considered in patients with AF and HF

Causal relationship between particulate matter and COVID-19 risk: A mendelian randomization study

Background: Observational studies have linked exposure to fine (PM2.5) and coarse (PM10) particulate matter air pollution with adverse COVID-19 outcomes, including higher incidence and mortality. However, some studies questioned the effect of air pollution on COVID-19 susceptibility, raising questions about the causal nature of these associations. To address this, a less biased method like Mendelian randomization (MR) is utilized, which employs genetic variants as instrumental variables to infer causal relationships in observational data. Method: We performed two-sample MR analysis using public genome-wide association studies data. Instrumental variables correlated with PM2.5 concentration, PM2.5 absorbance, PM2.5-10 concentration and PM10 concentration were identified. The inverse variance weighted (IVW), robust adjusted profile score (RAPS) and generalized summary data-based Mendelian randomization (GSMR) methods were used for analysis. Results: IVW MR analysis showed PM2.5 concentration [odd ratio (OR) = 3.29, 95% confidence interval (CI) 1.48–7.35, P-value = 0.0036], PM2.5 absorbance (OR = 5.62, 95%CI 1.98–15.94, P-value = 0.0012), and PM10 concentration (OR = 3.74, 95%CI 1.52–9.20, P-value = 0.0041) increased the risk of COVID-19 severity after Bonferroni correction. Further validation confirmed PM2.5 absorbance was associated with heightened COVID-19 severity (OR = 6.05, 95%CI 1.99–18.38, P-value = 0.0015 for RAPS method; OR = 4.91, 95%CI 1.65–14.59, P-value = 0.0042 for GSMR method) and hospitalization (OR = 3.15, 95%CI 1.54–6.47, P-value = 0.0018 for RAPS method). No causal links were observed between particulate matter exposure and COVID-19 susceptibility. Conclusions: Our study established a causal relationship between smaller particle pollution, specifically PM2.5, and increased risk of COVID-19 severity and hospitalization. These findings highlight the importance of improving air quality to mitigate respiratory disease progression

Beta-blockers for the primary prevention of anthracycline-induced cardiotoxicity: a meta-analysis of randomized controlled trials

Abstract Background The effects of β blockers on the primary prevention of anthracycline-induced cardiotoxicity were controversial. Methods We searched PubMed, Embase and Cochrane Library for randomized controlled trials of the comparison of β blockers versus placebo in patients undergoing anthracycline chemotherapy. This meta-analysis was performed by using random-effect models. Results Nine hundred forty participants from 11 trials were included in this meta-analysis. β blockers led to a significant reduction in symptomatic heart failure (risk ratio [RR] 0.29, 95% CI 0.10 to 0.85). Compared with placebo, β blockers were associated with improved left ventricular ejection fraction (mean difference [MD] 4.46, 95% CI 1.77 to 7.15) and s’ (MD 0.78, 95% CI 0.01 to 1.55) in parallel with reduced left ventricular diameter (left ventricular end systolic diameter, MD -3.19, 95% CI -6.17 to − 0.21; left ventricular end diastolic diameter, MD -2.28, 95% CI 4.50 to − 0.05). β blockers also improved strain and strain rate when compared with placebo. There were no significant differences in diastolic function variables between β blockers and placebo except e’ (MD 2.33, 95% CI 0.16 to 4.51). In addition, β blockers compared with placebo reduced the risk of cardiac troponin I elevation > 0.04 ng/ml (RR 0.60, 95% CI 0.42 to 0.85). There was no marked difference in adverse events (RR 0.94, 95% CI 0.56 to 1.59) between β blockers and placebo. Conclusions In cancer patients with anthracycline therapy, prophylactic β blockers were associated with reduced risk of heart failure, decreased left ventricular diameter, improved left ventricular systolic function, and alleviative cardiomyocyte injury

Acetylcholine‐synthesizing macrophages in subcutaneous fat are regulated by β2‐adrenergic signaling

Non‐neuronal cholinergic signaling, mediated by acetylcholine, plays important roles in physiological processes including inflammation and immunity. Our group first discovered evidence of non‐neuronal cholinergic circuitry in adipose tissue, whereby immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis. Here, we reveal that macrophages are the cellular protagonists responsible for secreting acetylcholine to regulate thermogenic activation in subcutaneous fat, and we term these cells cholinergic adipose macrophages (ChAMs). An adaptive increase in ChAM abundance is evident following acute cold exposure, and macrophage‐specific deletion of choline acetyltransferase (ChAT), the enzyme for acetylcholine biosynthesis, impairs the cold‐induced thermogenic capacity of mice. Further, using pharmacological and genetic approaches, we show that ChAMs are regulated via adrenergic signaling, specifically through the β2 adrenergic receptor. These findings demonstrate that macrophages are an essential adipose tissue source of acetylcholine for the regulation of adaptive thermogenesis, and may be useful for therapeutic targeting in metabolic diseases.SynopsisImmune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis, yet the identity of these acetylcholine‐secreting cells is unclear. This study shows that a subpopulation of adipose macrophages—named cholinergic adipose macrophages (ChAMs)—is responsible for β2 adrenergic receptor‐dependent secretion of acetylcholine upon acute cold to stimulate thermogenesis in neighboring beige adipocytes within murine subcutaneous fat.A non‐neuronal cholinergic circuitry consisting of ChAMs and beige adipocytes in subcutaneous adipose tissue influences both thermogenic response to cold and energy homeostasis in mice.Loss of acetylcholine production in macrophages compromises the adaptive thermogenic capacity of subcutaneous fat.The β2 adrenergic receptor mediates cholinergic macrophage activation in subcutaneous fat after cold exposure.Acute cold stimulates thermogenesis in murine beige adipocytes by triggering β2 adrenergic receptor‐dependent secretion of acetylcholine from a subpopulation of adipose macrophages.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171127/1/embj2020106061.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171127/2/embj2020106061.reviewer_comments.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171127/3/embj2020106061_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171127/4/embj2020106061-sup-0001-EVFigs.pd