Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

BackgroundInterleukin-6 (IL-6) is an inflammatory cytokine. Whether systemic IL-6 affects atrogene expression and disuse-induced skeletal muscle atrophy is unclear.\nMethodsTail-suspended mice were used as a disuse-induced muscle atrophy model. We administered anti-mouse IL-6 receptor antibody, beta-hydroxy-beta-methylbutyrate (HMB) and vitamin D to the mice and examined the effects on atrogene expression and muscle atrophy.ResultsSerum IL-6 levels were elevated in the mice. Inhibition of IL-6 receptor suppressed muscle RING finger 1 (MuRF1) expression and prevented muscle atrophy. HMB and vitamin D inhibited the serum IL-6 surge, downregulated the expression of MuRF1 and atrogin-1 in the soleus muscle, and ameliorated atrophy in the mice.ConclusionSystemic IL-6 affects MuRF1 expression and disuse-induced muscle atrophy

Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1

成人T細胞白血病リンパ腫の多段階発がん分子メカニズムを解明 --難治性疾患の新規治療標的候補を複数同定--. 京都大学プレスリリース. 2021-09-07.Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)–infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1–infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell–restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis

Testosterone Deficiency Accelerates Neuronal and Vascular Aging of SAMP8 Mice: Protective Role of eNOS and SIRT1

Oxidative stress and atherosclerosis-related vascular disorders are risk factors for cognitive decline with aging. In a small clinical study in men, testosterone improved cognitive function; however, it is unknown how testosterone ameliorates the pathogenesis of cognitive decline with aging. Here, we investigated whether the cognitive decline in senescence-accelerated mouse prone 8 (SAMP8), which exhibits cognitive impairment and hypogonadism, could be reversed by testosterone, and the mechanism by which testosterone inhibits cognitive decline. We found that treatment with testosterone ameliorated cognitive function and inhibited senescence of hippocampal vascular endothelial cells of SAMP8. Notably, SAMP8 showed enhancement of oxidative stress in the hippocampus. We observed that an NAD+-dependent deacetylase, SIRT1, played an important role in the protective effect of testosterone against oxidative stress-induced endothelial senescence. Testosterone increased eNOS activity and subsequently induced SIRT1 expression. SIRT1 inhibited endothelial senescence via up-regulation of eNOS. Finally, we showed, using co-culture system, that senescent endothelial cells promoted neuronal senescence through humoral factors. Our results suggest a critical role of testosterone and SIRT1 in the prevention of vascular and neuronal aging

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

L'Écho : grand quotidien d'information du Centre Ouest

12 septembre 19141914/09/12 (A43).Appartient à l’ensemble documentaire : PoitouCh

The State of Health in Older Adults in Japan: Trends in Disability, Chronic Medical Conditions and Mortality

<div><p>Both life expectancy and healthy life expectancy in Japan have been increasing and are among the highest in the world, but the gap between them has also been widening. To examine the recent trends in old age disability, chronic medical conditions and mortality in Japan, we retrospectively analyzed three nationally representative datasets: Comprehensive Survey of Living Conditions (2001–2013), Patient Survey (1996–2011) and Vital Statistics (1995–2010). We obtained the sex- and age-stratified trends in disability rate, treatment rates of nine selected chronic medical conditions (cerebrovascular diseases, joint disorders, fractures, osteoporosis, ischemic heart disease, diabetes mellitus, hypertension, pneumonia and malignant neoplasms), total mortality rate and mortality rates from specific causes (cerebrovascular diseases, heart diseases, pneumonia and malignant neoplasms) in both sexes in four age strata (65–69, 70–74, 75–79, 80–84 years). Disability rates declined significantly in both sexes. Treatment rates of all selected medical conditions also decreased significantly, except for fractures in women and pneumonia. Both total mortality rate and cause-specific mortality rates decreased in both sexes. We concluded that the recent decline in disability rates, treatment rates of chronic medical conditions and mortality rates points toward overall improvement in health conditions in adults over the age of 65 years in Japan. Nonetheless, considering the increase in the number of older adults, the absolute number of older adults with disability or chronic medical conditions will continue to increase and challenge medical and long-term care systems.</p></div

Trends in treatment rates of nine selected medical conditions in men from 1996 to 2011.

<p>(a) cerebrovascular diseases (b) joint disorders (c) fractures (d) osteoporosis (e) ischemic heart disease (f) diabetes mellitus (g) hypertension (h) pneumonia (i) malignant neoplasms The treatment rate is calculated as the estimated number of patients divided by the estimated population x 100,000. The black line represents those aged 80–84 years, the blue line represents those aged 75–79 years, the green line represents those aged 70–74 years and the red line represents those aged 65–69 years. The p values signify statistical significance for the trends in each age stratum.</p

Rehabilitation strategy for hip fracture, focused on behavioral psychological symptoms of dementia for older people with cognitive impairment: A nationwide Japan rehabilitation database.

The aim is to investigate the relationship between a positive outcome on rehabilitation after hip fracture and behavioral psychological symptoms of dementia (BPSD) transition during rehabilitation. This study is a retrospective cohort study based on the Japan Rehabilitation Database. We recruited 756 subjects 65 years of age or older from 31 hospitals in the database. All subjects were in the hospital as patients undergoing rehabilitation for hip fracture. Functional independence measure (FIM), walking ability, Mini-Mental State Examination (MMSE), and BPSD were measured both at the beginning and at the end of rehabilitation. MMSE for 23 or under was defined as the cognitive-impaired group. MMSE for 24 or over was used as the cognitively intact group. Cognitive impaired participants were divided into four groups: participants presented no BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (-/-)), participants presented BPSD at the beginning of rehabilitation but resolved at the end of rehabilitation (Group (+/-)), participants had no BPSD at the beginning of rehabilitation but appeared at the end of rehabilitation (Group (-/+)) and participants had sign of BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (+/+)). The endpoints were waking ability, FIM gain. As results, one hundred thirty-seven cognitive-impaired older people patients out of 471 (29.1%) suffered from BPSD at the beginning of rehabilitation. FIM gains in cognitively intact group, Group (-/-), Group (+/-), Group (-/+) and Group (+/+) were 24.8 ± 18.7, 17.5 ± 16.9, 27.3 ± 19.7, 17.8 ± 12.2 and 12.2 ± 17.2, respectively. The Group (+/-) was significantly connected to a positive outcome for rehabilitation. The present study suggested that the management of BPSD can lead to better functional recovery during rehabilitation