The epigenetic landscape of exercise in cardiac health and disease

With the rising incidence of cardiovascular diseases,the concomitant mortality and morbidity impose huge burdens on quality of life and societal costs.It is generally accepted that physical inactivity is one of the major risk factors for cardiac disease and that exercise benefits the heart in both physiological and pathologic conditions.However,the molecular mechanisms governing the cardioprotective effects exerted by exercise remain incompletely understood.Most recently,an increasing number of studies indicate the involvement of epigenetic modifications in the promotion of cardiac health and prevention of cardiac disease.Exercise and other lifestyle factors extensively induce epigenetic modifications,including DNA/RNA methylation,histone post-translational modifications,and non-coding RNAs in multiple tissues,which may contribute to their positive effects in human health and diseases.In addition,several studies have shown that maternal or paternal exercise prevents age-associated or high-fat dietinduced metabolic dysfunction in the offspring,reinforcing the importance of epigenetics in mediating the beneficial effects of exercise.It has been shown that exercise can directly modify cardiac epigenetics to promote cardiac health and protect the heart against various pathological processes,or it can modify epigenetics in other tissues,which reduces the risk of cardiac disease and affords cardioprotection through exerkines.An in-depth understanding of the epigenetic landscape of cardioprotective response to exercise will provide new therapeutic targets for cardiac diseases.This review,therefore,aimed to acquaint the cardiac community with the rapidly advancing and evolving field of exercise and epigenetics.

Comparison of Antioxidant Status between Pilots and Non-flight Staff of the Army Force: Pilots May Need More Vitamin C

Objective To compare the blood antioxidant levels and dietary antioxidant intakes between pilots and non-flight staff of the Army Force in The Islamic Republic of Iran. Methods Thirty-seven helicopter pilots and 40 non-flight staff were included in this study. Their general characteristics were recorded and their weight, height, and waist circumference were measured. Their daily intake of energy and nutrients including antioxidants was assessed using a semi-quantitative food frequency questionnaire. Serum levels of total antioxidant capacity （TAC）, malondialdehyde （MDA）, and glutathione reductase （GR）, glutathione peroxidase （GPx）, superoxide dismutase （SOD）, and catalase （CAT） in red blood cells were also measured. Results The median erythrocytes SOD, serum MDA level and the mean serum level of TAC and erythrocytes GPx were significantly higher in pilots than in non-flight staff. The median vitamin C intake was significantly lower in pilots than in non-flight staff. The serum MDA levels were similar in non-flight staff and pilots when their vitamin C intake was 〈168 mg and significantly lower in non-flight staff than in pilots when their vitamin C intake was 〉168 mg. Conclusion The serum MDA level is lower in non-flight staff than in pilots when their vitamin C intake level is high, indicating that pilots need more vitamin C than non-flight staff.

Effect of rotary motion on Fos protein expression in the vestibular-related nucleus population in a mouse model of rapid retinal degeneration

BACKGROUND： Previous studies on integration mechanisms of visual and vestibular information in the central nervous system have focused on the vestibular system. Due to the lack of an appropriate animal model, few studies have addressed the visual system with regard to visual and vestibular information. OBJECTIVE： To investigate Fos protein expression differences of vestibular-related nucleus populations in a mouse model of rapid retinal degeneration and normal wild-type Kunming mice following rotary motion, and to verify integration regions of visual and vestibular information in the central nervous system. DESIGN, TIME AND SETTING： A randomized, controlled in vitro study was performed at the Key Laboratory of Aerospace Medicine of Ministry of Education, China from March 2008 to February 2009. MATERIALS： A rotary stimulation device was re-fit to an electric, rotating chair produced by the School of Aerospace Medicine, the Fourth Military Medical University. METHODS： A total of 12 rapid retinal degeneration mice and 12 normal wild-type male Kunming mice were randomly assigned to experimental and control subgroups, respectively （n = 6）. Mice in the experimental group were exposed to rotary motion at a speed of 180°/s, 3 minutes per cycle, in an alternating clockwise/counterclockwise movement. Mice in the control group were not exposed to rotary motion. MAIN OUTCOME MEASURES： Differences in the number of Fos-positive neurons were determined in the vestibular nucleus, prepositus hypoglossal nucleus, inferior olive subnucleus beta, Kooy cap of the inferior olive medial nucleus, and the flocculus and paraflocculus of the cerebellum in rapid retinal degeneration mice and normal wild-type Kunming mice. RESULTS： The number of Fos-positive neurons was reduced in the prepositus hypoglossal nucleus and the Kooy cap of the inferior olive medial nucleus in the rapid retinal degeneration mice following 30 minutes of rotary motion in the experimental group, compared with the normal wild-type Kunming mice （P 〈 0.01）. There was no significant difference in Fos protein expression in the vestibular nucleus, inferior olive subnucleus beta, and the flocculus and paraflocculus of the cerebellum between the rapid retinal degeneration mice and normal wild-type Kunming mice. CONCLUSION： Visual information affected neuronal activation in the prepositus hypoglossal nucleus and the Kooy cap of the inferior olive medial nucleus in mice following rotary motion. The prepositus hypoglossal nucleus and the dorsal cap of Kooy of inferior olive medial nucleus were shown to be key integration regions of visual information and vestibular information in the central nervous system.

Autophagy dysregulation mediates the damage of high glucose to retinal pigment epithelium cells

AIM:To observe the role and mechanism of autophagy in retinal pigment epithelial cell(RPE)damaged by high glucose,so as to offer a new idea for the treatment of diabetic retinopathy(DR).METHODS:ARPE-19,a human RPE cell line cultured in vitro was divided into the normal control(NC),autophagy inhibitor 3-methyladenine(3-MA),high-glucose(HG),and HG+3-MA groups.Cell viability was detected by CCK-8 assay and the apoptosis rate was measured by flow cytometry.The protein expressions of apoptosis markers,including Bax,Bcl-2,and Caspase-3,as well as autophagy marker including microtubule-related protein 1 light chain 3(LC3),p62,and mechanistic target of rapamycin(m TOR)were detected by Western blotting.Autophagic flux was detected by transfection with Ad-m Cherry-GFP-LC3 B.RESULTS:Under high glucose conditions,the viability of ARPE-19 was decreased,and the apoptosis rate increased,the protein expressions of Bax,Caspase-3,and LC3-II/LC3-I were all increased and the expressions of Bcl-2,p62 and p-m TOR decreased,and autophagic flux was increased compared with that of the controls.Treatment with 3-MA reversed all these changes caused by high glucose.CONCLUSION:The current study demonstrates the mechanisms of cell damage of ARPE-19 through high glucose/m TOR/autophagy/apoptosis pathway,and new strategies for DR may be developed based on autophagy regulation to manage cell death of RPE cells.

Visual electrophysiological examination in diagnosis of hepatic encephalopathy

Clinical observation of the neuropsychiatric condition, psychometric tests, and EEG recordings has been used to diagnose hepatic encephalopathy. However, no standardization for the diagnosis of minimal hepatic encephalopathy (MHE) has been achieved. According to the study in normal subjects, visual electrophysiology testing is a method of simple, objective record for the medical examination, which includes visual evoked potentials (VEP), electroretinograms (ERG), etc. 23 hepatic encephalopathy patients prospectively underwent visual electrophysiology testing and laboratory serum analysis, and it was found that 22 visual electrophysiology abnormalities which showed that the amplitudes were decreased and the implicit times were prolonged compared with the normal. The relationship between biochemical parameters and visual electrophysiology parameters showed that visual recording was related to the damage of the liver. On the basis of this preliminary study, we could conclude that this method can be as a way to predict for hepatic encephalopathy and it appears to be a method in the recognition of the MHE.

MSCs-derived apoptotic extracellular vesicles promote muscle regeneration by inducing Pannexin 1 channel-dependent creatine release by myoblasts

Severe muscle injury is hard to heal and always results in a poor prognosis.Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine,however,whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown.Herein,we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells(MSCs-Apo EVs)to treat cardiotoxin induced tibialis anterior(TA)injury and found that MSCs-Apo EVs promoted muscles regeneration and increased the proportion of multinucleated cells.Besides that,we also found that apoptosis was synchronized during myoblasts fusion and MSCs-Apo EVs promoted the apoptosis ratio as well as the fusion index of myoblasts.Furthermore,we revealed that MSCs-Apo EVs increased the relative level of creatine during myoblasts fusion,which was released via activated Pannexin 1 channel.Moreover,we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived Apo EVs(Myo-Apo EVs)instead of apoptotic myoblasts,and creatine was the pivotal metabolite involved in myoblasts fusion.Collectively,our findings firstly revealed that MSCs-Apo EVs can promote muscle regeneration and elucidated that the new function of Apo EVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel,which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.

Microgravity-induced cardiovascular deconditioning:mechanisms and countermeasures

It has been demonstrated that individuals exposed to actual or simulated microgravity often experience cardiovascular dysfunctions when returning to Earth.The underlying mechanisms of orthostatic intolerance and countermeasure treatment are still poorly understood.In this paper,the progress in the mechanism of cardiovascular deconditioning from the view of vascular remodeling,increased venous compliance in the lower limbs,cellular proliferation and differentiation,and cell signaling pathway was reviewed.Meanwhile,an overview of the countermeasures including exercise,lower body negative pressure,thigh cuffs,traditional Chinese herb medicine and artificial gravity was presented.

Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p

Background:Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects.Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs(miRNAs)after exercise and found that some of them act as exerkines.However,whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown.Methods:A 9-day treadmill training was used as an exercise model in C57BL/6 mice.Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p(miR-122-5p).Human umbilical vein endothelial cells were used in vitro.Results:Among these differentially expressed extracellular vesicle miRNAs,miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro.Exercise increased circulating levels of miR-122-5p,which was produced mainly by the liver and shuttled by extracellular vesicles in mice.Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles,and exerciseimproved muscle performance in mice.Mechanistically,miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells,and miR-122-5p upregulated endothelial cell fatty-acid utilization by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase(AGPAT1).In addition,miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice.Conclusion:These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p,which enhances fatty acid utilization by targeting AGPAT1 in endothelial cells,highlighting the therapeutic potential of miR-122-5p in tissue repair.

Thermal comfort and thermoregulation in manned space flight

Exposure to thermal environment is one of the main concerns for manned space exploration. By focusing on the works performed on thermoregulation at microgravity or simulated microgravity, we endeavored to review the investigation on space thermal environmental physiology. First of all, the application of medical requirements for the crew module design from normal thermal comfort to accidental thermal emergencies in a space craft will be addressed. Then, alterations in the autonomic and behavioral temperature regulation caused by the effect of weightlessness both in space flight and its simulation on the ground are also discussed. Furthermore, countermeasures like exercise training, simulated natural ventilation, encouraged drink, etc., in the protection of thermoregulation during space flight is presented. Finally, the challenge of space thermal environment physiology faced in the future is figured out.

Mental health service to military retired cadres

Military retired cadres were commonly in aged period with high-incidence of diseases. They were troubled with senility, illness, empty-nest syndrome and spouse-bereft, so they were more vulnerable to some psychological problems. Therefore, promoting the mental health service for retired cadres should be highly concerned and more professional service work should be provided to them.

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

The role of the Notch signaling pathway in liver injury and repair

This review aims to compile recent advances regarding the significance of Notch signaling in different types of intrahepatic cells during liver injury and repair.The functions of Notch signaling in regulating cell development,fate decisions,and organ homeostasis have been widely acknowledged.Notch is also expressed and activated in hepatocytes,macrophages,liver sinusoidal endothelial cells,endothelial progenitor cells,and hepatic progenitor cells during the process of development,injury,inflammation,fibrosis,and carcinoma.During acute/chronic liver injury,Notch interacts with many signaling pathways that are involved in liver repair.Recent research,including ours,has confirmed the crucial role of Notch signaling in modulating the function of diverse intrahepatic cells during liver injury and reconstruction.Thus,Notch signaling may serve as a potential therapeutic target for liver diseases.

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15%.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFNstimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral replication.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type I IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3^(-/-)mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.