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INTRODUCTION: Di(2-ethylhexyl) phthalate (DEHP) is a common plasticizer. Studies have revealed that DEHP exposure can cause kidney damage. Green tea is among the most popular beverages in China. Green tea polyphenols (GTPs) have been proven to have therapeutic effects on organ damage induced by heavy metal exposure. However, few studies have reported on GTP-relieving DEHP-induced kidney damage. METHODS: C57BL/6J male mice aged 6-8 weeks were treated with distilled water (control group), 1,500 mg/kg/d DEHP + corn oil (model group), 1,500 mg/kg/d DEHP + corn oil + 70 mg/kg GTP (treatment group), corn oil (oil group), and 70 mg/kg GTP (GTP group) by gavage for 8 weeks, respectively. The renal function of mice and renal tissue histopathology of each group were evaluated. The renal tissues of mice in the model, treatment, and control groups were analyzed using high-throughput sequencing. We calculated the differentially expressed microRNAs (miRNAs) and messenger RNAs (mRNAs) using the limma R package, the CIBERSORT algorithm was used to predict immune infiltration, the starBase database was used to screen the miRNA-mRNA regulatory axis, and immunohistochemical analyses were performed to verify protein expression. RESULTS: GTP alleviated the deterioration of renal function, renal inflammation and fibrosis, and mitochondrial and endoplasmic reticulum lesions induced by DEHP in mice. Differential immune infiltrations of plasma, dendritic, T, and B cells were noted between the model and treatment groups. We found that three differentially expressed miRNAs (mmu-miR-383-5p, mmu-miR-152-3p, and mmu-miR-144-3p), three differentially expressed mRNAs (Ddit4, Dusp1, and Snx18), and three differentially expressed proteins (Ddit4, Dusp1, and Snx18) played crucial roles in the miRNA-mRNA-protein regulatory axes when GTPs mitigate DEHP-induced kidney damage in mice. CONCLUSION: GTP can alleviate DEHP-induced kidney damage and regulate immune cell infiltration. We screened four important miRNA-mRNA-protein regulatory axes of GTP, mitigating DEHP-induced kidney damage in mice.
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Dietilexilftalato , MicroRNAs , Ácidos Ftálicos , Animais , Camundongos , Masculino , Dietilexilftalato/toxicidade , Óleo de Milho/farmacologia , Camundongos Endogâmicos C57BL , Antioxidantes , Rim , MicroRNAs/genética , MicroRNAs/farmacologia , RNA Mensageiro , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Guanosina Trifosfato/farmacologiaRESUMO
BACKGROUND AND AIMS: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence. CONCLUSION: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one.
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Sistema Cardiovascular , Hepatopatia Gordurosa não Alcoólica , Adulto , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Prospectivos , Pressão Sanguínea , AlgoritmosRESUMO
BACKGROUND: Prediabetes is an important risk factor of cardiovascular disease (CVD) and is associated with subclinical atherosclerosis. However, the evidence of prediabetes as a cardiovascular risk factor is mainly derived from middle-aged adults. Recently, multiple studies supported that prediabetes in older adults would not lead to higher risk of CVD or mortality. We aimed to investigate the age-specific difference in the association between prediabetes and subclinical atherosclerosis in a Chinese prospective cohort study. METHODS: We included 4739 individuals aged ≥ 40 years and without diagnosed diabetes or CVD history, and divided them into middle-aged adults (age < 60) and older adults (age ≥ 60). Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2 h-PPG) and glycated hemoglobin (HbA1c) were measured at baseline to identify prediabetes status. At follow-up visits, subclinical atherosclerosis status was assessed by branchial-ankle pulse wave velocity (baPWV) and carotid intima-media thickness (CIMT). Logistic regression analysis, restricted cubic splines and cross-lagged path analysis were used in statistical analysis. RESULTS: 1634 participants aged over 60 years, and 64.3% of them had prediabetes. 3105 participants aged 40-59 years, and 49.3% of them had prediabetes. We found that prediabetes was associated with increased risk of subclinical atherosclerosis in middle-aged adults, but the association attenuated substantially in older adults. Impaired glucose tolerance (IGT), compared to normal glucose tolerance, was associated with 39% lower risk of increased baPWV only in older adults. In accordance, the association between 2 h-PPG and risk of increased baPWV was "U-shaped" in older adults, while risk of elevated baPWV increased linearly with 2 h-PPG in middle-aged adults. In the cross-lagged analysis, increase in FPG and 2 h-PPG tended not to precede increase in baPWV in older adults, but appeared to increase simultaneously with baPWV in middle-aged ones. CONCLUSION: Our results indicated that prediabetes might be less related to subclinical atherosclerosis in older adults than in middle-aged adults and suggested that age was important to consider in the care of adults with prediabetes.
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Aterosclerose , Doenças Cardiovasculares , Estado Pré-Diabético , Fatores Etários , Idoso , Aterosclerose/complicações , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Glicemia , Espessura Intima-Media Carotídea , China/epidemiologia , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/epidemiologia , Estudos Prospectivos , Análise de Onda de Pulso , Fatores de RiscoRESUMO
BACKGROUND: Age has substantial influence on metabolic diseases patterns. Ethnic disparities of metabolic characteristics between Chinese and other populations also exist. Large-scale investigations of age-specific prevalence, subtypes and modifiable risk factors of metabolic disorders are essential to promote individualized strategies for the control and prevention of metabolic diseases in multi-ethnic populations. The study aims to address the age-specific prevalence, subtype characteristics and risk factor profiles of metabolic diseases among different races/ethnicities. METHODS: We analyzed data from the China Noncommunicable Disease Surveillance 2010 and the National Health and Nutrition Evaluation Survey (NHANES). We examined the prevalence and subtypes of hypertension, diabetes and hyperlipidemia across age groups in four ethnic populations. We also investigated the odds ratios (ORs) of metabolic diseases associated with 11 classical risk factors in the young and the elder Mainland Chinese. RESULTS: The sex and BMI standardized prevalence of hypertension in Chinese aged 18-40 years was 18.5% and was the highest among the four populations. The main pathophysiologic subtype of diabetes was characterized by insulin resistance, instead of ß-cell dysfunction in Mainland Chinese, and this pattern was more evident in obese subjects. The major subtype of hyperlipidemia in Mainland Chinese was hypertriglyceridemia, while Non-Hispanic Whites and Blacks were more prone to high low-density lipoprotein cholesterol. For risk of hypertension, diabetes and hyperlipidemia, young Chinese adults were more prone to general and central obesity than older ones. The other factors showed similar effects on the young and the old. CONCLUSIONS: The age-specific prevalence, subtypes and risk factors of metabolic diseases were substantially different in Chinese and other ethnic/racial populations.
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Diabetes Mellitus , Hipertensão , Adulto , Humanos , Idoso , Prevalência , Inquéritos Nutricionais , Fatores de Risco , Obesidade/complicações , Diabetes Mellitus/epidemiologia , HDL-Colesterol , Hipertensão/epidemiologia , Hipertensão/complicações , Fatores EtáriosRESUMO
Sow fertility is an economically important quantitative trait. Hundreds of quantitative trait loci (QTLs) containing tens of thousands of potential candidate genes are excavated. However, among these genes, non-coding RNAs including long non-coding RNAs (lncRNAs) are often overlooked. Here, it is reported that NORSF is a novel causal lncRNA for sow fertility traits in QTLs. QTLs are characterized for sow fertility traits at the genome-wide level and identified 4,630 potential candidate lncRNAs, with 13 differentially expressed during sow follicular atresia. NORSF, a lncRNA that involved in sow granulosa cell (sGC) function, is identified as a candidate gene for sow fertility traits as a G to A transversion at 128 nt in its transcript is shown to be markedly associated with sow fertility traits. Mechanistically, after forming the RNA:dsDNA triplexes with the promoter of Caspase8, NORSF transcript with allele G binds to an RNA-binding protein (RBP) NR2C1 and recruits it to the promoter of Caspase8, to induce Caspase8 transcription in sGCs. Functionally, this leads to a loss of inducing effect of NORSF on sGC apoptosis by inactivating the death receptor-mediated apoptotic pathway. This study identified a novel causal lncRNA that can be used for the genetic improvement of sow fertility traits.
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BACKGROUND: Higher cardiovascular health (CVH) score is associated with lower risks of cardiovascular disease (CVD) and mortality in the general population. However, it is unclear whether cumulative CVH is associated with CVD, end-stage kidney disease (ESKD), and death in patients with chronic kidney disease. METHODS AND RESULTS: Among individuals from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we used the percentage of the maximum possible CVH score attained from baseline to the year 5 visit to calculate cumulative CVH score. Multivariable-adjusted Cox proportional hazards regression was used to investigate the associations of cumulative CVH with risks of adjudicated CVD (myocardial infarction, stroke, and heart failure), ESKD, and all-cause mortality. A total of 3939 participants (mean age, 57.7 years; 54.9% men) were included. The mean (SD) cumulative CVH score attained during 5 years was 55.5% (12.3%). Over a subsequent median 10.2-year follow-up, 597 participants developed CVD, 656 had ESKD, and 1324 died. A higher cumulative CVH score was significantly associated with lower risks of CVD, ESKD, and mortality, independent of the CVH score at year 5. Multivariable-adjusted hazard ratios and 95% CIs per 10% higher cumulative CVH score during 5 years were 0.81 (0.69-0.95) for CVD, 0.82 (0.70-0.97) for ESKD, and 0.80 (0.72-0.89) for mortality. CONCLUSIONS: Among patients with chronic kidney disease stages 2 to 4, a better CVH status maintained throughout 5 years is associated with lower risks of CVD, ESKD, and all-cause mortality. The findings support the need for interventions to maintain ideal CVH status for prevention of adverse outcomes in the population with chronic kidney disease.
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Doenças Cardiovasculares , Falência Renal Crônica , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/mortalidade , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Estudos Prospectivos , Idoso , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/mortalidade , Medição de Risco/métodos , Fatores de Tempo , Causas de Morte/tendências , Fatores de Risco , Nível de Saúde , PrognósticoRESUMO
Previous studies have found that the association between modifiable risk factors and arterial stiffness varied with age. We aimed to explore the age-specific difference in the relationship between new cardiovascular health (CVH) score and arterial stiffness and further detected the age-specific temporal relationships in a prospective cohort study. During a median 4.3 years follow-up, 3757 participants were recruited in this study. A modified AHA "Life's Essential 8" construct (mLE8 with lacking information on diet habits) was used to evaluate CVH. Branchial-ankle pulse wave velocity (baPWV) was measured to assess arterial stiffness. Data were analyzed with logistic regression models, restricted cubic splines (RCS), and cross-lagged path analysis (age < 60 vs. age ≥ 60). In age-stratified analysis, moderate (OR = 2.21, 95% CI 1.11-4.43) and low (OR = 3.37, 95% CI 1.63-7.00) CVH were related with a higher incidence of elevated baPWV compared to high CVH in middle-aged adults, while this association was not detected in older adults. RCS curve showed a steeper linear association between CVH score and elevated baPWV in middle-aged adults than older individuals. In the cross-lagged path analysis, the decline in CVH score preceded the increment in arterial stiffness in middle-aged adults, but they appeared to alter simultaneously in older adults. Our study detected an age-specific difference in the relationship between mLE8 CVH score and elevated baPWV and showed that low CVH preceded alterations of baPWV in middle-aged adults, suggesting the importance of improvement in CVH during the early stage of the lifespan.
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Rigidez Vascular , Humanos , Pessoa de Meia-Idade , Idoso , Análise de Onda de Pulso , Estudos Prospectivos , Fatores de Risco , Fatores EtáriosRESUMO
OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.
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Diabetes Mellitus Tipo 2 , Controle Glicêmico , Treinamento Intervalado de Alta Intensidade , Obesidade , Sobrepeso , Treinamento Resistido , Humanos , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Controle Glicêmico/métodos , Treinamento Resistido/métodos , Sobrepeso/terapia , Sobrepeso/dietoterapia , Treinamento Intervalado de Alta Intensidade/métodos , Obesidade/terapia , Obesidade/dietoterapia , Adulto , Hemoglobinas Glicadas/metabolismo , Restrição Calórica/métodos , Glicemia/metabolismoRESUMO
Importance: With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective: To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants: This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions: Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures: The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results: The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance: In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.
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Adenosina , COVID-19 , Recidiva , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Tratamento Farmacológico da COVID-19 , China , Ritonavir , SARS-CoV-2 , Adenosina/análogos & derivadosRESUMO
Nationwide estimates of the impact of common modifiable risk factors on mortality remain crucial. We aim to assess the influence of social determinants, lifestyle, and metabolic factors on mortality in 174,004 adults aged ≥40 years from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We reveal that 17 modifiable factors are independently associated with mortality, accounting for 64.8% of all-cause mortality, 77.4% of cardiovascular mortality, and 44.8% of cancer mortality. Low education emerges as the leading factor for both all-cause and cancer mortality, while hypertension is predominant for cardiovascular mortality. Moreover, low gross domestic product per capita and high ambient particulate matter with a diameter of <2.5 µm (PM2.5) air pollution account for 7.8% and 4.3% for all-cause mortality, respectively, using a different method. Gender-specific analyses reveal distinct patterns, with women's mortality primarily associated with social determinants and men exhibiting stronger associations with lifestyle factors. Targeted health interventions are essential to mitigate mortality risks effectively in China.
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Background: Current guidelines for obesity prevention and control focus on body mass index (BMI) and rarely address central obesity. Few studies have been conducted on the association between normal-weight central obesity and the risk of diabetes mellitus (DM). Methods: 26,825 participants from the National Health and Nutrition Examination Survey (NHANES) were included in our study. A weighted multivariate logistic regression model was used to analyze the relationship between different obesity patterns and the risk of DM. Results: Our results suggest that normal-weight central obesity is associated with an increased risk of DM (OR: 2.37, 95% CI: 1.75-3.23) compared with normal-weight participants without central obesity. When stratified by sex, men with normal-weight central obesity, obesity and central obesity were found to have a similar risk of DM (OR: 3.83, 95% CI: 2.10-5.97; OR: 4.20, 95% CI: 3.48-5.08, respectively) and a higher risk than all other types of obesity, including men who were overweight with no central obesity (OR: 1.21, 95% CI: 0.96-1.51) and obese with no central obesity (OR: 0.53, 95% CI: 0.30-0.91). Conclusion: Our results highlight the need for more attention in people with central obesity, even if they have a normal BMI.
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The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral infection. So far, a few small-molecule antiviral drugs, including nirmatrelvir-ritonavir (Paxlovid), remdesivir, and molnupiravir have been marketed for the treatment of COVID-19. Nirmatrelvir-ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate COVID-19. However, the existing treatment options have limitations, and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still needed. To date, four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in China. These drugs include azvudine, simnotrelvir-ritonavir (Xiannuoxin), leritrelvir, and mindeudesivir (VV116). Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for progression. In this review, we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for COVID-19. These findings will expand our understanding and highlight the potential widespread application of China's homegrown anti-COVID-19 drugs.
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Adenosina , COVID-19 , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir , Humanos , Ritonavir/uso terapêutico , Antivirais/uso terapêutico , China , Adenosina/análogos & derivadosRESUMO
BACKGROUND: Metabolic dysfunction is a major determinant in the progression of fatty liver disease. It is pivotal to evaluate the metabolic status and subsequent transition in fatty liver population and to identify the risk of subclinical atherosclerosis. METHODS: The prospective cohort study included 6260 Chinese community residents during 2010-2015. Fatty liver was determined as hepatic steatosis (HS) by ultrasonography. Metabolic unhealthy (MU) status was defined as having diabetes and/or ≥ 2 metabolic risk factors. Participants were categorized into 4 groups according to the combination of metabolic healthy (MH)/MU and fatty liver status (MHNHS, MUNHS, MHHS and MUHS). Subclinical atherosclerosis was assessed by elevated brachial-ankle pulse wave velocity, pulse pressure and/or albuminuria. RESULTS: 31.3% of the participants had fatty liver disease and 76.9% were in MU status. During a 4.3-year follow-up, 24.2% of participants developed composite subclinical atherosclerosis. Multivariable adjusted odds ratios for composite subclinical atherosclerosis risk were (1.66 [1.30-2.13]) in MUNHS group and (2.57 [1.90-3.48]) in MUHS group. It seemed that participants with fatty liver disease were more prone to be remained in MU status (90.7% vs.50.8%) and less likely to regress to MH status (4.0% vs. 8.9%). Fatty liver participants progressed to (3.11 [1.23-7.92]) or maintained MU status (4.87 [3.25-7.31]) significantly impelled the development of the composite risk, while regressing to MH status (0.15 [0.04-0.64]) were more intended to mitigate the risk. CONCLUSIONS: The current study emphasized the importance of assessing metabolic status and its dynamic changes, especially in the fatty liver population. Regressing from MU to MH status not only benefited the systematic metabolic profile but also ameliorated future cardiometabolic complications.
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BACKGROUND: Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM: To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS: C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS: GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION: This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.
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Importance: Spouses share common socioeconomic, environmental, and lifestyle factors, and multiple studies have found that spousal diabetes status was associated with diabetes prevalence. But the association of spousal diabetes status and ideal cardiovascular health metrics (ICVHMs) assessed by the American Heart Association's Life's Essential 8 measures with incident diabetes has not been comprehensively characterized, especially in large-scale cohort studies. Objective: To explore the association of spousal diabetes status and cardiovascular health metrics with risk of incident diabetes in Chinese adults. Design, Setting, and Participants: This cohort study included individuals in the China Cardiovascular Disease and Cancer Cohort without diabetes who underwent baseline and follow-up glucose measurements and had spouses with baseline glucose measurements. The data were collected in January 2011 to December 2012 and March 2014 to December 2016. The spousal study had a mean (SD) follow-up of 3.6 (0.9) years (median [IQR], 3.2 [2.9-4.5] years). Statistical analysis was performed from July to November 2022. Exposure: Spousal diabetes status was diagnosed according to the 2010 American Diabetes Association (ADA) criteria. All participants provided detailed clinical, sociodemographic, and lifestyle information included in cardiovascular health metrics. Main Outcomes and Measures: Incident diabetes, diagnosed according to 2010 ADA criteria. Results: Overall, 34â¯821 individuals were included, with a mean (SD) age of 56.4 (8.3) years and 16â¯699 (48.0%) male participants. Spousal diabetes diagnosis was associated with an increased risk of incident diabetes (hazard ratio [HR], 1.15; 95% CI, 1.03-1.30). Furthermore, participants whose spouses had uncontrolled glycated hemoglobin (HbA1c) had a higher risk of diabetes (HR, 1.20; 95% CI, 1.04-1.39) but the risk of diabetes in participants whose spouses had controlled HbA1c did not increase significantly (HR, 1.10; 95% CI, 0.92-1.30). Moreover, this association varied with composite cardiovascular health status. Diabetes risk in individuals who had poor cardiovascular health status (<4 ICVHMs) was associated with spousal diabetes status (3 ICVHMs: HR, 1.50; 95% CI, 1.15-1.97), while diabetes risk in individuals who had intermediate to ideal cardiovascular health status (≥4 ICVHMs) was not associated with it (4 ICVHMs: HR, 1.01; 95% CI, 0.69-1.50). Conclusions and Relevance: In this study, spousal diabetes diagnosis with uncontrolled HbA1c level was associated with increased risk of incident diabetes, but strict management of spousal HbA1c level and improving ICVHM profiles may attenuate the association of spousal diabetes status with diabetes risk. These findings suggest the potential benefit of couple-based lifestyle or pharmaceutical interventions for diabetes.
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Doenças Cardiovasculares , Diabetes Mellitus , População do Leste Asiático , Nível de Saúde , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Coortes , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etnologia , População do Leste Asiático/estatística & dados numéricos , Glucose , Hemoglobinas Glicadas , Fatores de Risco , Estados Unidos/epidemiologia , Cônjuges/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etnologia , IncidênciaRESUMO
BACKGROUND: The association between weight change during early adulthood and cardiometabolic diseases remains uncertain in Chinese population. Whether the association varies with comprehensive cardiovascular health (CVH) in midlife assessed by "Life's Essential 8" has not been characterized. We aim to examine the associations of early adulthood weight change and midlife "Life's Essential 8" CVH status with cardiometabolic outcomes in a Chinese cohort. METHODS: The study participants were from the China Cardiometabolic Disease and Cancer Cohort (4 C) Study. This analysis included 72,610 middle-aged and older participants followed for a median of 3.6 years. At baseline, the participants recalled body weight at age 20 and 40 years, and we calculated change in weight and BMI between 20 and 40 years of age. Health behaviors information in "Life's Essential 8" was collected by questionnaire, and health factors were measured in the study center. During follow-up, we ascertained incident cardiovascular events based on medical records, and diagnosed incident diabetes according to the American Diabetes Association 2010 criteria. RESULTS: 72,610 study participants were included with a mean age of 56.0 ± 8.8 years and 29% of them were males. Weight gain of more than 10 kg between 20 and 40 years of age was associated with 22% increased risk of incident cardiovascular events (HR: 1.22; 95%CI: 1.04-1.43) and 38% increased risk of diabetes (HR: 1.38; 95%CI: 1.25-1.53) compared to stable weight. Besides, the association of weight gain more than 10 kg in early adulthood with cardiometabolic risk was even stronger in those with low CVH score in midlife (HR: 2.44; 95%CI: 2.01-2.97 for incident cardiovascular events; HR: 2.20; 95%CI: 1.90-2.55 for incident diabetes) or with few ideal cardiovascular health metrics in midlife. CONCLUSIONS: Our study indicated that weight gain in early adulthood was associated with significantly increased risk of cardiometabolic diseases. And the association could be stronger in those with poor CVH profiles in midlife. These findings confirmed the significance of weight management during early adulthood and suggested that individuals who experienced substantial weight gain in early life should be encouraged to maintain good CVH status in Chinese population.
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Studies have found a U-shaped relationship between sleep duration and chronic kidney disease (CKD) risk, but limited research evaluated the association of reallocating excessive sleep to other behavior with CKD. We included 104 538 participants from the nationwide cohort of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study, with self-reported time of daily-life behavior. Using isotemporal substitution models, we found that substituting 1 h of sleeping with sitting, walking, or moderate-to-vigorous physical activity was associated with a lower CKD prevalence. Leisure-time physical activity displacement was associated with a greater prevalence reduction than occupational physical activity in working population. In stratified analysis, a lower CKD prevalence related to substitution toward physical activity was found in long sleepers. More pronounced correlations were observed in long sleepers with diabetes than in those with prediabetes, and they benefited from other behavior substitutions toward a more active way. The U-shaped association between sleep duration and CKD prevalence implied the potential effects of insufficient and excessive sleep on the kidneys, in which the pernicious link with oversleep could be reversed by time reallocation to physical activity. The divergence in the predicted effect on CKD following time reallocation to behavior of different domains and intensities and in subpopulations with diverse metabolic statuses underlined the importance of optimizing sleeping patterns and adjusting integral behavioral composition.
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This paper proposes two optimal design schemes for improving the kinematic and dynamic performance of the 3-PSS flexible parallel micromanipulator according to different application requirements and conditions. Firstly, the workspace, dexterity, frequencies, and driving forces of the mechanism are successively analyzed. Then, a progressive optimization design is carried out, in which the scale parameters of this mechanism are firstly optimized to maximize the workspace, combining the constraints of the minimum global dexterity of the mechanism. Based on the optimized scale parameters, the minimum thickness and the cutting radius of the flexure spherical hinge are further optimized for minimizing the required driving forces, combined with constraints of the minimum first-order natural frequency of the mechanism and the maximum stress of the flexure spherical hinge during the movement of the mechanism. Afterward, a synchronous optimization design is proposed, in which the scale parameters are optimized to maximize the first-order natural frequency of the mechanism, combined with the constraints of a certain inscribed circle of the maximum cross-section of the workspace, the maximum stroke of the selected piezoelectric stages, and the maximum ultimate angular displacement of the flexure spherical hinge. The effectiveness of both optimization methods is verified by the comparison of the kinematic and dynamic characteristics of the original and optimized mechanism. The advantage of the progressive optimization method is that both the workspace and the driving forces are optimized and the minimum requirements for global dexterity and first-order natural frequency are ensured. The merit of the synchronous optimization method is that only the scale parameters of the mechanism need to be optimized without changing the structural parameters of the flexible spherical hinge.
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Myocardial fibrosis refers to the pathological changes of heart structure and morphology caused by various reasons of myocardial damage. It has become an important challenge in the later clinical treatment of acute myocardial infarction/ischemic cardiomyopathy or diabetes complicated with heart failure. Ginseng Dingzhi Decoction (GN), a Chinese herbal medicine, can reduce heart failure and protect cardiomyocytes. We infer that this may be related to the interaction with intestinal microbiota and mitochondrial homeostasis. The regulatory mechanism of GN on gut microbiota and mitochondria has not yet been elucidated. The intestinal microbiota was analyzed by the 16S rRNA gene; the fecal samples were sequenced and statistically analyzed to determine the changes of microbiota in the phenotype of heart failure rats. In addition, GN can regulate the microbial population that increases the proportion of short-chain fatty acids and anti-inflammatory bacteria and reduces the proportion of conditional pathogens to diabetic phenotype. The results suggest that GN may improve myocardial injury by regulating intestinal flora. Our data also show that stress-type heart failure caused by TAC (transverse aortic constriction) is accompanied by severe cardiac hypertrophy, reduced cardiac function, redox imbalance, and mitochondrial dysfunction. However, the use of GN intervention can significantly reduce heart failure and myocardial hypertrophy, improve heart function and improve myocardial damage, and maintain the mitochondrial homeostasis and redox of myocardial cells under high glucose stimulation. Interestingly, through in vitro experiments after TMBIM6 siRNA treatment, the improvement effect of GN on cell damage and the regulation of mitochondrial homeostasis were eliminated. TMBIM6 can indirectly regulate mitophagy and mitochondrial homeostasis to attenuate myocardial damage and confirms the regulatory effect of GN on mitophagy and mitochondrial homeostasis. We further intervened cardiomyocytes in high glucose through metformin (MET) and GN combination therapy. Research data show that MET and GN combination therapy can improve the level of mitophagy and protect cardiomyocytes. Our findings provide novel mechanistic insights for the treatment of diabetes combined with myocardial injury (myocardial fibrosis) and provide a pharmacological basis for the study of the combination of Chinese medicine and conventional diabetes treatment drugs.
Assuntos
Cardiomiopatias , Microbioma Gastrointestinal , Insuficiência Cardíaca , Panax , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomegalia/patologia , Cardiomiopatias/metabolismo , Fibrose , Glucose/metabolismo , Insuficiência Cardíaca/patologia , Medicina Tradicional Chinesa , Proteínas de Membrana/metabolismo , Mitocôndrias , Miócitos Cardíacos/metabolismo , RNA Ribossômico 16S/genética , RatosRESUMO
Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.