A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Male ; Alzheimer Disease/metabolism* ; Computational Biology ; Mice, Inbred C57BL ; High-Throughput Nucleotide Sequencing ; Amyloid beta-Protein Precursor/metabolism* ; Hippocampus/metabolism* ; Mice, Transgenic ; Presenilin-1/metabolism* ; Humans ; Memory/drug effects* ; Maze Learning/drug effects* ; Amyloid beta-Peptides/genetics* ; Disease Models, Animal

ObjectiveHuman Ku70 protein mainly involves the non-homologous end joining (NHEJ) repair of double-stranded DNA breaks (DSB) through its DNA-binding properties, and it is recently reported having an RNA-binding ability. This paper is to explore whether Ku70 has RNA helicase activity and affects miRNA maturation. MethodsRNAs bound to Ku protein were analyzed by RNA immunoprecipitation sequencing (RIP-seq) and bioinfomatic anaylsis. The expression relationship between Ku protein and miRNAs was verified by Western blot (WB) and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assays. Binding ability of Ku protein to the RNAs was tested by biolayer interferometry (BLI) assay. RNA helicase activity of Ku protein was identified with EMSA assay. The effect of Ku70 regulated miR-124 on neuronal differentiation was performed by morphology analysis, WB and immunofluorescence assays with or without Zika virus (ZIKV) infection. ResultsWe revealed that the Ku70 protein had RNA helicase activity and affected miRNA maturation. Deficiency of Ku70 led to the up-regulation of a large number of mature miRNAs, especially neuronal specific miRNAs like miR-124. The knockdown of Ku70 promoted neuronal differentiation in human neural progenitor cells (hNPCs) and SH-SY5Y cells by boosting miR-124 maturation. Importantly, ZIKV infection reduced the expression of Ku70 whereas increased expression of miR-124 in hNPCs, and led to morphologically neuronal differentiation. ConclusionOur study revealed a novel function of Ku70 as an RNA helicase and regulating miRNA maturation. The reduced expression of Ku70 with ZIKV infection increased the expression of miR-124 and led to the premature differentiation of embryonic neural progenitor cells, which might be one of the causes of microcephaly.

Protein phosphorylation modification is one of the key regulatory mechanisms in cellular signaling transduction and metabolic processes. The phosphorylation state of target proteins is regulated by specific protein kinases and phosphatases, which add or remove phosphate groups. Histidine phosphorylation (pHis) plays a crucial role in both prokaryotes and eukaryotes life activities and is linked to various pathological processes. Unlike the stable phosphorylation of proteins via phosphate ester bonds, histidine phosphorylation is linked through phosphoramide bonds, making it highly sensitive to high temperatures and low pH. This sensitivity has historically impeded progress in identifying and studying histidine phosphorylation. In recent years, the development of new techniques in phosphoproteomics and the emergence of pHis-specific antibodies have promoted the identification and functional research of pHis-modified substrates. For the first time, more than 700 pHis-modified proteins have been identified in mammalian cells, and pHis-modified substrates such as focal adhesion kinase (FAK) and phosphoglycerate mutase 1 (PGAM1) have been found to promote tumor development. This article mainly reviewed the key mechanisms and functions of histidine kinases and histidine phosphatases in regulating the histidine phosphorylation of specific substrates, and highlights their significant roles in human physiological and pathological processes, aiming to provide guidance for further research into the biological functions of histidine phosphorylation.

Objective:To establish a mesenchymal stem cell(MSC)-based in vitro cell model for the evaluation of mouse bone marrow acute graft-versus-host disease(aGVHD).Methods:Female C57BL/6N mice aged 6-8 weeks were used as bone marrow and lymphocyte donors,and female BALB/c mice aged 6-8 weeks were used as aGVHD recipients.The recipient mouse received a lethal dose(8.0 Gy,72.76 cGy/min)of total body γ irradiation,and injected with donor mouse derived bone marrow cells(1× 107/mouse)in 6-8 hours post irradiation to establish a bone marrow transplantation(BMT)mouse model(n=20).In addition,the recipient mice received a lethal dose(8.0 Gy,72.76 cGy/min)of total body γ irradiation,and injected with donor mouse derived bone marrow cells(1 × 107/mouse)and spleen lymphocytes(2 × 106/mouse)in 6-8 hours post irradiation to establish a mouse aGVHD model(n=20).On the day 7 after modeling,the recipient mice were anesthetized and the blood was harvested post eyeball enucleation.The serum was collected by centrifugation.Mouse MSCs were isolated and cultured with the addition of 2％,5％,and 10％recipient serum from BMT group or aGVHD group respectively.The colony-forming unit-fibroblast(CFU-F)experiment was performed to evaluate the potential effects of serums on the self-renewal ability of MSC.The expression of CD29 and CD105 of MSC was evaluated by immunofluorescence staining.In addition,the expression of self-renewal-related genes including Oct-4,Sox-2,and Nanog in MSC was detected by real-time fluorescence quantitative PCR(RT-qPCR).Results:We successfully established an in vitro cell model that could mimic the bone marrow microenvironment damage of the mouse with aGVHD.CFU-F assay showed that,on day 7 after the culture,compared with the BMT group,MSC colony formation ability of aGVHD serum concentrations groups of 2％and 5％was significantly reduced(P＜0.05);after the culture,at day 14,compared with the BMT group,MSC colony formation ability in different aGVHD serum concentration was significantly reduced(P＜0.05).The immunofluorescence staining showed that,compared with the BMT group,the proportion of MSC surface molecules CD29+and CD 105+cells was significantly dereased in the aGVHD serum concentration group(P＜0.05),the most significant difference was at a serum concentration of 10％(P＜0.001,P＜0.01).The results of RT-qPCR detection showed that the expression of the MSC self-renewal-related genes Oct-4,Sox-2,and Nanog was decreased,the most significant difference was observed at an aGVHD serum concentration of 10％(P＜0.01,P＜0.001,P＜0.001).Conclusion:By co-culturing different concentrations of mouse aGVHD serum and mouse MSC,we found that the addition of mouse aGVHD serum at different concentrations impaired the MSC self-renewal ability,which providing a new tool for the field of aGVHD bone marrow microenvironment damage.

Objective To observe the clinical effect of Dongjing Tiaoshen Comprehensive Therapy combined with computerized cognitive behavioral therapy for insomnia(CCBT-I)in the treatment of chronic insomnia patients with liver depression and spleen deficiency syndrome.Methods A total of 60 patients with chronic insomnia of liver depression and spleen deficiency type were randomly divided into observation group and control group,30 cases in each group.Both groups of patients were treated with CCBT-I as the basic treatment,the observation group was additionally treated with Dongjing Tiaoshen Comprehensive Therapy,i.e.,mind-regulating acupuncture therapy combined with regular aerobic exercises and Dantian Qigong exercises,and the control group was additionally treated with cranial electrotherapy stimulation.The course of treatment for the two groups covered 4 weeks.The changes of Pittsburgh Sleep Quality Index(PSQI)score,Self-rating Anxiety Scale(SAS)score and Self-rating Depression Scale(SDS)score in the two groups were observed before and after treatment,and the clinical efficacy of the two groups was evaluated after treatment.Results(1)After 4 weeks of treatment,the total effective rate of the observation group was 86.67%(26/30),and that of the control group was 70.00%(21/30).The intergroup comparison(tested by rank sum test)showed that the curative effect of the observation group was significantly superior to that of the control group,and the difference was statistically significant(P＜0.05).(2)After treatment,the PSQI scores of the two groups were significantly lower than those before treatment(P＜0.05),and the decrease of PSQI scores in the observation group was significantly superior to that in the control group,the difference being statistically significant(P＜0.05).(3)After treatment,the SAS and SDS scores of the two groups were significantly lower than those before treatment(P＜0.05),and the decrease of SAS and SDS scores in the observation group tended to be superior to that in the control group,but there was no significant difference between the two groups(P＞0.05).Conclusion For the treatment of chronic insomnia of liver depression and spleen deficiency type,the combination of Dongjing Tiaoshen Comprehensive Therapy with CCBT-I can significantly improve the sleep quality,relieve anxiety and depression,and improve the quality of life of the patients,which exerts significant efficacy.

Endoplasmic reticulum is an important organelle in eukaryotic cells,which is responsible for the folding,processing and transportation of secretory proteins.A variety of stimuli inside and outside cells can lead to the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum,resulting in abnormal structure and function of the endoplasmic reticulum,which is called endoplasmic reticulum stress(ERS).Endoplasmic reticulum autophagy is an important endogenous mechanism to alleviate ERS.It is often considered as a cell protective procedure,which participates in many important physiological processes,such as metabolism,immune response,inflammatory response and cell proliferation.Endoplasmic reticulum autophagy is an important endogenous protective mechanism to alleviate endoplasmic reticulum stress and restore the endoplasmic reticulum homeostasis,through eliminating redundant and disabled endoplasmic reticulum membrane and macromolecular protein complexes,which is critical to cell function and fate.This paper reviews the types of endoplasmic reticulum autophagy,related specific receptors,main regulatory mechanisms,and its role and significance in the related diseases.

Objective:To analyze the comorbidity status and influencing factors of hypertension, diabetes, and dyslipidemia among middle-aged and elderly Chinese adults and to provide support for the "co-management of three diseases".Methods:Using the relevant information collected from the National Chronic Disease and Risk Factor Surveillance in China in 2018, 134 950 permanent residents aged ≥45 years were selected as the research objects. After being weighed, the prevalence and comorbidity of hypertension, diabetes, and dyslipidemia in residents with different groups were compared; a multivariate logistic regression model was used to explore the influencing factors of comorbidity of the "three diseases".Results:The prevalence of hypertension, diabetes, and dyslipidemia among middle-aged and elderly Chinese adults were 46.0% (95% CI:45.1%-47.0%), 19.5% (95% CI:18.7%-20.2%), 43.3% (95% CI:42.3%-44.4%), respectively. The comorbidity rates of hypertension and diabetes, hypertension and dyslipidemia, and diabetes and dyslipidemia were 12.3% (95% CI:11.7%-12.8%), 22.8% (95% CI:22.1%-23.4%),11.6% (95% CI:11.1%-12.0%), respectively; the comorbidity rate of hypertension, diabetes, and dyslipidemia was 7.6% (95% CI: 7.2%-8.0%). These comorbidity rates increased with age and BMI, which was more significant in the urban areas than rural areas and more outstanding in North and Northeast China ( P<0.05). The comorbidity rate of hypertension, diabetes, and higher cholesterol was 1.9% (95% CI:1.7%-2.1%). The comorbidity rate of hypertension, diabetes, and higher low-density lipoprotein was 1.6% (95% CI:1.4%-1.7%), which was higher in women than in men ( P<0.05). Multivariate logistic regression results showed that male, age, city, overweight/obesity, excessive drinking, physical inactivity, daily sedentary behavior time ≥5 hours, and sleep duration <7 hours were risk factors for the comorbidity of the "three diseases". Conclusions:The comorbidity of hypertension, diabetes, and dyslipidemia, is common among middle-aged and elderly adults in China; comprehensive prevention and control of risk factors and "co-management of three diseases" are critical measures for health promotion in middle-aged and elderly populations.

Objective:To understand the regular leisure-time physical activity status of residents aged ≥60 years in China and to explore the potential influencing factors.Methods:National Chronic Disease and Risk Factor Surveillance were conducted in 298 counties (districts) in China in 2018, which covered 31 provinces (autonomous regions, municipalities), using a multi-stage stratified cluster random sampling method to select 194 779 permanent residents aged ≥18 years, using a questionnaire containing the Global Physical Activity Questionnaire. A face-to-face survey to obtain demographic information about the survey respondents, the frequency of moderate and vigorous-intensity leisure-time physical activity in their spare time and time, and other information related to chronic diseases and risk factors. Daily temperatures of 298 monitored counties (districts) in 2018 were obtained by inversion of satellite remote sensing data information such as MODIS, OMI, and AIRS, and the number of parks in 2017 was obtained by me. In this study, 68 379 residents aged ≥60 years who completed the survey and had complete information on leisure-time physical activity-related variables, temperature, and parks were used as survey respondents, and the prevalence of regular leisure-time physical activity and average weekly exercise time was calculated by gender in groups of age, urban and rural areas, education level, and geography. Multi-factor logistic regression models were used to analyze the individual and environmental influences on the regular exercise rate. All the results were weighted according to a complex sampling scheme.Results:The prevalence of regular leisure-time physical activity of residents aged ≥60 years in China in 2018 was 13.1% (95% CI: 12.1%-14.0%). The figures were slightly higher for men [13.6% (95% CI: 12.6%-14.7%)] than for women [12.5% (95% CI: 11.5%-13.5%)]; urban [17.5% (95% CI: 15.9%-19.1%)] were significantly higher than those in rural areas [9.6% (95% CI: 8.8%-10.4%)]; the prevalence of regular leisure-time physical activity in East China [15.1% (95% CI: 13.3%-16.9%)] was higher than those in other regions; older residents in counties (districts) with ≥28 parks [17.3% (95% CI: 15.3%-19.2%)] the highest. The average weekly exercise time of elderly residents in China was 68.3 (95% CI: 63.5-73.2) minutes; among them, men [74.3 (95% CI: 68.1-80.5) minutes] was higher than women [62.5 (95% CI: 57.8-67.2) minutes]; urban [89.8 (95% CI: 82.0-97.7) minutes] were higher than rural [51.4 (95% CI: 46.8-56.1) minutes]. The results of the multi-factorial logistic analysis showed that factors such as: living in rural areas, lower annual household income for literacy, poorer self-rated health status, and lack of parks in the area of residence were associated with a lower prevalence of regular leisure-time physical activity among elderly residents. Conclusions:The prevalence of regular leisure-time physical activity among elderly residents in China is still at a low level, and exercise time needs to be improved. We should increase the publicity of "national fitness", pay attention to the disadvantaged elderly groups and provide more suitable activity places to encourage more elderly residents to participate in leisure-time physical activity.

Objective: To explore the relationship between sleep/physical activity and metabolic syndrome (MS) in urban population of Xinjiang. Methods: This is a prospective, cross-sectional study. From July 2019 to September 2021, a two-stage random sampling method was used to randomly select residents aged 30-74 years from two communities in Urumqi of northern Xinjiang and Korla of southern Xinjiang. General situation questionnaire, Pittsburgh Sleep Quality Index Scale (PSQI) survey, International Physical Activity Questionnaire (IPAQ) survey, physical examination, physiological and biochemical indicators were obtained and analyzed. The dose-response curves of healthy sleep score and physical activity with metabolic syndrome were plotted using restricted cubic spline curves. Multivariate logistic regression model was used to analyze the independent and combined effects of sleep quality and physical activity on MS risk. Results: A total of 10 209 participants were included. The mean age of the subjects was (47.1±9.1) years, and males accounted for 51.3% (5 275/10 209). The prevalence of MS was significantly associated with the healthy sleep score and physical activity. Compared to the subjects with healthy sleep, OR (95%CI) of MS with intermediate, and poor sleep were 1.20(1.06-1.35), 1.23(1.04-1.45), respectively. Compared to the subjects with high physical activity, OR (95%CI) of MS with medium, low physical activity was 1.34(1.15-1.56), 1.42(1.19-1.70), respectively. There was a significant interaction between sleep and physical activity in MS (P for interaction=0.002). Compared to the subjects with high physical activity and healthy sleep, OR (95%CI) of MS with poor sleep and high physical activity was 2.03 (1.24-3.33, P for trend=0.016). Conclusion: Poor sleep quality and lack of physical activity are not only independent risk factors for an increased risk of MS but also have a combined effect with an increased risk of MS.
Male ; Humans ; Adult ; Middle Aged ; Sleep Quality ; Metabolic Syndrome/epidemiology* ; Urban Population ; Cross-Sectional Studies ; Prospective Studies ; Exercise