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Cellular senescence, a state of persistent growth arrest, is closely associated with aging and age-related diseases. Deciphering the heterogeneity within senescent cell populations and identifying therapeutic targets are paramount for mitigating senescence-associated pathologies. In this study, proteins on the surface of cells rendered senescent by replicative exhaustion and by exposure to ionizing radiation (IR) were identified using mass spectrometry analysis, and a subset of them was further studied using single-cell CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) analysis. Based on the presence of proteins on the cell surface, we identified two distinct IR-induced senescent cell populations: one characterized by high levels of CD109 and CD112 (cluster 3), the other characterized by high levels of CD112, CD26, CD73, HLA-ABC, CD54, CD49A, and CD44 (cluster 0). We further found that cluster 0 represented proliferating and senescent cells in the G1 phase of the division cycle, and CITE-seq detection of cell surface proteins selectively discerned those in the senescence group. Our study highlights the heterogeneity of senescent cells and underscores the value of cell surface proteins as tools for distinguishing senescent cell programs and subclasses, paving the way for targeted therapeutic strategies in disorders exacerbated by senescence.
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A group of previously undescribed diarylheptanoids with mono/di-glucose substitution, diodiarylheptosides A-F (1-6), together with six known diarylheptanoids (7-12) were isolated from the rhizomes of Dioscorea nipponica. Their structures were established by comprehensive UV, IR, HR-ESI-MS and NMR analyses, and their absolute configurations were determined by a comparison of calculated and experimental ECD, some with optical rotations, after acid-hydrolysis. Moreover, bioassay results showed that compounds 3 and 11 exhibited stronger NO inhibitions on lipopolysaccharides-induced RAW 264.7 cells, with the IC50 values of 14.91 ± 0.62 and 12.78 ± 1.12 µM.
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Diarileptanoides , Dioscorea , Glicosídeos , Compostos Fitoquímicos , Rizoma , Dioscorea/química , Rizoma/química , Diarileptanoides/isolamento & purificação , Diarileptanoides/química , Diarileptanoides/farmacologia , Camundongos , Células RAW 264.7 , Estrutura Molecular , Animais , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Glicosídeos/isolamento & purificação , Glicosídeos/química , Glicosídeos/farmacologia , Óxido Nítrico/metabolismo , ChinaRESUMO
This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.
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Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Ciclo-Oxigenase 2 , Fígado , NF-kappa B , Panax , Saponinas , Transdução de Sinais , Animais , Acetaminofen/efeitos adversos , Acetaminofen/toxicidade , Camundongos , Panax/química , Masculino , Saponinas/farmacologia , Saponinas/administração & dosagem , NF-kappa B/genética , NF-kappa B/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Transdução de Sinais/efeitos dos fármacos , Humanos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
BACKGROUND: The health effects of particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) might differ depending on compositional variations. Little is known about the joint effect of PM2.5 constituents on metabolic syndrome and cardiovascular disease (CVD). This study aims to evaluate the combined associations of PM2.5 components with CVD, identify the most detrimental constituent, and further quantify the mediation effect of metabolic syndrome. METHODS AND RESULTS: A total of 14 427 adults were included in a cohort study in Sichuan, China, and were followed to obtain the diagnosis of CVD until 2021. Metabolic syndrome was defined by the simultaneous occurrence of multiple metabolic disorders measured at baseline. The concentrations of PM2.5 chemical constituents within a 1-km2 grid were derived based on satellite- and ground-based detection methods. Cox proportional hazard models showed that black carbon, organic matter (OM), nitrate, ammonium, chloride, and sulfate were positively associated with CVD risks, with hazard ratios (HRs) ranging from 1.24 to 2.11 (all P<0.05). Quantile g-computation showed positive associations with 4 types of CVD risks (HRs ranging from 1.48 to 2.25, all P<0.05). OM and chloride had maximum weights for CVD risks. Causal mediation analysis showed that the positive association of OM with total CVD was mediated by metabolic syndrome, with a mediation proportion of 1.3% (all P<0.05). CONCLUSIONS: Long-term exposure to PM2.5 chemical constituents is positively associated with CVD risks. OM and chloride appear to play the most responsible role in the positive associations between PM2.5 and CVD. OM is probably associated with CVD through metabolic-related pathways.
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Doenças Cardiovasculares , Síndrome Metabólica , Material Particulado , Humanos , Material Particulado/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Masculino , China/epidemiologia , Feminino , Pessoa de Meia-Idade , Síndrome Metabólica/epidemiologia , Estudos Prospectivos , Adulto , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Exposição Ambiental/efeitos adversos , Medição de Risco , Idoso , Fatores de Tempo , Tamanho da Partícula , Fatores de Risco , Poluição do Ar/efeitos adversosRESUMO
Missing outcome data in clinical trials may jeopardize the validity of the trial results and inferences for clinical practice. Although sick and preterm newborns are treated as a captive patient population during their stay in the NICUs, their long-term outcomes are often ascertained after discharge. This greatly increases the risk of attrition. We surveyed recently published perinatal and neonatal randomized trials in 7 high-impact general medical and pediatric journals to review the handling of missing primary outcome data and any choice of imputation methods. Of 87 eligible trials in this survey, 77 (89%) had incomplete primary outcome data. The missing outcome data were not discussed at all in 9 reports (12%). Most study teams restricted their main analysis to participants with complete information for the primary outcome (61 trials; 79%). Only 38 of the 77 teams (49%) performed sensitivity analyses using a variety of imputation methods. We conclude that the handling of missing primary outcome data was frequently inadequate in recent randomized perinatal and neonatal trials. To improve future approaches to missing outcome data, we discuss the strengths and limitations of different imputation methods, the appropriate estimation of sample size, and how to deal with data withdrawal. However, the best strategy to reduce bias from missing outcome data in perinatal and neonatal trials remains prevention. Investigators should anticipate and preempt missing data through careful study design, and closely monitor all incoming primary outcome data for completeness during the conduct of the trial.
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Transtorno da Personalidade Antissocial , Líquidos Corporais , Recém-Nascido , Feminino , Gravidez , Humanos , Criança , Unidades de Terapia Intensiva Neonatal , Alta do Paciente , Projetos de PesquisaRESUMO
BACKGROUND: There is currently a lack of convincing evidence for microwave ablation (MWA) and laparoscopic liver resection (LLR) for patients ≥60 years old with 3-5 cm hepatocellular carcinoma. MATERIALS AND METHODS: Patients were divided into three cohorts based on restricted cubic spline analysis: 60-64, 65-72, and ≥73 years. Propensity score matching (PSM) was performed to balance the baseline variables in a 1:1 ratio. Overall survival (OS) and disease-free survival (DFS) were assessed, followed by a comparison of complications, hospitalization, and cost. RESULTS: Among 672 patients, the median age was 66 (IQR 62-71) years. After PSM, two groups of 210 patients each were selected. During the 36.0 (20.4-52.4) month follow-up period, the 1-year, 3-year, and 5-year OS rates in the MWA group were 97.6, 80.9, and 65.3% and 95.5, 78.7, and 60.4% in the LLR group (HR 0.98, P =0.900). The corresponding DFS rates were 78.6, 49.6, and 37.5% and 82.8, 67.8, and 52.9% (HR 1.52, P =0.007). The 60-64 age cohort involved 176 patients, with no a significant difference in OS between the MWA and LLR groups (HR 1.25, P =0.370), MWA was associated with a higher recurrence rate (HR 1.94, P =0.004). A total of 146 patients were matched in the 65-72 age cohort, with no significant differences in OS and DFS between the two groups (OS (HR 1.04, P =0.900), DFS (HR 1.56, P =0.110)). In 76 patients aged ≥73 years after PSM, MWA provided better OS for patients (HR 0.27, P =0.015), and there were no significant differences in DFS between the two groups (HR 1.41, P =0.380). Taken together, for patients older than 65 years, the recurrence rate of MWA was comparable with LLR. Safety analysis indicated that LLR was associated with more postoperative bleeding ( P =0.032) and hypoproteinemia ( P =0.024). CONCLUSIONS: MWA was comparable to LLR in patients aged 65 years and older. MWA could be an alternative for the oldest old or the ill patients who cannot afford LLR, while LLR is still the first option of treatments for early-stage 3-5 cm hepatocellular carcinoma in capable elderly's.
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Carcinoma Hepatocelular , Ablação por Cateter , Laparoscopia , Neoplasias Hepáticas , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Hepatectomia , Laparoscopia/efeitos adversos , Micro-Ondas/efeitos adversos , Pontuação de Propensão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Objective: Life's Essential 8 (LE8) is a new comprehensive metric based on Life's Simple 7 (LS7). Few studies have investigated the association between LE8 and the odds of hyperuricaemia (HUA). This study examined the association between LE8, LS7 with odds of HUA. Methods: We cross-sectionally analysed data from the China Multi-Ethnic Cohort (CMEC) study. LE8 and LS7 were categorized as low, moderate and high. The CMEC provided an ideal and unique opportunity to characterize the association between LE8, LS7 and the odds of HUA. Results: Of the 89 823 participants, 14 562 (16.2%) had HUA. A high level of LE8 was associated with lower odds of HUA after full adjustment. The adjusted odds ratios (ORs) were 1 (reference), 0.70 (95% CI 0.67, 0.73) and 0.45 (0.42, 0.48) across low, moderate and high LE8 groups, respectively (Ptrend < 0.001). Similar results were observed in LS7 and HUA. The adjusted ORs were 1 (reference), 0.68 (95% CI 0.65, 0.71) and 0.46 (95% CI 0.43, 0.49) across low, moderate and high LS7 groups, respectively (Ptrend < 0.001). There were significant interactions between LE8 and age, gender, ethnicity and drinking habits on HUA. Receiver operating characteristics analysis showed that the area under the curve for LE8 and LS7 were similar (0.638 and 0.635, respectively). Conclusion: This study indicated a clearly inverse gradient association between the cardiovascular health metrics LE8 and LS7 and the odds of HUA.
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This randomized controlled trial aimed to determine whether lung ultrasound-guided fluid resuscitation improves the clinical outcomes of neonates with septic shock. Seventy-two patients were randomly assigned to undergo treatment with lung ultrasound-guided fluid resuscitation (LUGFR), or with usual fluid resuscitation (Control) in the first 6 h since the start of the sepsis treatment. The primary study outcome was 14-day mortality after randomization. Fourteen-day mortalities in the two groups were not significantly different (LUGFR group, 13.89%; control group, 16.67%; p = 0.76; hazard ratio 0.81 [95% CI 0.27-2.50]). The LUGFR group experienced shorter length of neonatal intensive care unit (NICU) stays (21 vs. 26 days, p = 0.04) and hospital stays (32 vs. 39 days, p = 0.01), and less fluid was used in the first 6 h (77 vs. 106 mL/kg, p = 0.02). Further, our study found that ultrasound-guided fluid resuscitation can significantly reduce the incidence of acute kidney injury (25% vs. 47.2%, p = 0.05) and intracranial hemorrhage (grades I-II) within 72 h (13.9% vs. 36.1%, p = 0.03). However, no significant difference was found in the resolution of shock within 1 h or 6 h, use of mechanical ventilation or vasopressor support, time to achieve lactate level < 2 mmol/L, and the number of participants developing hepatomegaly in the first 6 h. CONCLUSION: Lung ultrasound is a noninvasive and convenient tool for predicting fluid overload in neonatal septic shock. Fluid resuscitation guided by lung ultrasound can shorten the length of hospital and NICU stays, reduce the amount of fluid used in the first 6 h, and reduce the risk of acute kidney injury and intracranial hemorrhage. TRIAL REGISTRATION: Registered in Guangdong Second Provincial General Hospital: 2021-IIT-156-EK, date of registration: November 13, 2021. And ClinicalTrials.gov: NCT06144463 (retrospectively registered). WHAT IS KNOWN: ⢠Excessive fluid resuscitation in neonates with septic shock had worse outcomes. WHAT IS NEW: ⢠Lung ultrasound should be routinely used to guide fluid resuscitation in neonatal septic shock.
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Injúria Renal Aguda , Choque Séptico , Recém-Nascido , Humanos , Choque Séptico/terapia , Hidratação , Ressuscitação , Pulmão/diagnóstico por imagem , Hemorragias Intracranianas , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been rising rapidly in western China. Diet acts as an effective therapy for MAFLD. However, there has been scarce research on the association between a posteriori diet patterns (DPs) and MAFLD in this region. METHOD: We identified three a posteriori DPs which were "Sichuan Basin pattern" characterized by a high intake of fish/seafood, poultry, fresh fruit and vegetables, indicating a balanced and modern DP; the "Yunnan-Guizhou Plateau dietary pattern" characterized mainly by a high intake of animal oil and salt, indicating an agricultural and poor DP; and the "Qinghai-Tibet Plateau dietary pattern" characterized by a high intake of coarse grains, wheat products, tubers and tea, respectively, indicating a high-altitude DP. Then, we performed marginal structural models that combined logistic regression and inverse probability exposure weighting (IPEW) to examine the associations between MAFLD and these a posteriori DPs. RESULT: We found the "Yunnan-Guizhou Plateau dietary pattern" revealed stronger positive association (OR = 1.50, 95% CI 1.40-1.60) with MAFLD than that of the "Qinghai-Tibet Plateau dietary pattern" (OR = 1.21, 95% CI 1.14-1.30). In contrast, the "Sichuan Basin dietary pattern" showed no significant association with MAFLD. In the further stratified analysis, we found those above associations were stronger in ethnic minorities and rural residents than their counterparts. CONCLUSION: Our study implied the unfavourable effects of "Yunnan-Guizhou Plateau dietary pattern" on MAFLD and provided evidence that reducing the intake of oil and sodium may be optimal for MAFLD control in the multi-ethnic region in western China.
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Hepatopatias , Humanos , China/epidemiologia , Dieta/efeitos adversos , VerdurasRESUMO
Purpose: Depression and anxiety are two highly prevalent mental disorders that commonly coexist. However, little is known about the association between sleep and comorbid depressive and anxiety symptoms (CDAS). Therefore, this study aims to explore the relationship between sleep duration, insomnia and CDAS. Methods: This is a cross-sectional study of 22,004 community adults who participated in the China Multi-Ethnic Cohort (CMEC) study. Chinese version of Patient Health Questionnaire-2 and Generalized Anxiety Disorder-2 were used to screen CDAS in community adults. A positive score on each scale was considered indicative of CDAS. All participants received face-to-face interviews, medical examinations, and biochemical examinations to assess sleep duration and insomnia and collect covariates. The self-reported sleep duration was divided into three groups: <7 hr, 7-9 hr and >9 hr groups. Logistic regression was used to analyze the association between sleep duration, insomnia and CDAS. A restricted cubic spline (RCS) was used to explore the dose-response relationship between sleep duration and CDAS. Stratified analysis based on gender and age was conducted. Results: Overall, 2.8% (95% CI 2.6%~3.0%) of participants reported having CDAS. After adjusting the potential covariates, sleep duration <7 hr (OR=1.635, 95% CI=1.335~2.004) was significantly associated with CDAS, compared with sleep 7-9 hr. After RCS analysis, there was a nonlinear relationship between sleep duration and CDAS. The increase in the number of types of insomnia, the greater the likelihood of CDAS (p for trend<0.05). In sensitivity analysis, it was found that the results were consistent with those of the main analysis. After stratification by gender and age, the association between sleep duration and CDAS was only observed in female and young and middle-aged adults, not in men and older adults. Conclusion: Both insufficient sleep duration and insomnia are associated with a higher prevalence of CDAS in Chinese adults.
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OBJECTIVE: Previous studies proved the effect of long-term exposure to air pollution or physical activity (PA) on the risk of systemic inflammation-induced multimorbidity (SIIM), while the evidence regarding their joint effects was rare, especially in low- and middle-income countries. Therefore, we aimed to examine the extent of interaction or joint relations of PA and air pollution with SIIM. METHODS: This study included 72,172 participants from China Multi-Ethnic Cohort.The average concentrations of ambient particulate matter pollutants (PM1, PM2.5, and PM10) were estimated using satellite-based random forest models. Self-reported information on a range of physical activities related to occupation, housework, commuting, and leisure activities was collected by an interviewer-administered questionnaire. A total of 11 chronic inflammatory systemic diseases were assessed based on self-reported lifetime diagnosis or medical examinations. SIIM was defined as having ≥ 2 chronic diseases related to systemic inflammation. Logistic regression models were used to assess the complex associations of air pollution particulate matter and PA with SIIM. RESULTS: We found positive associations between long-term air pollution particulates exposure and SIIM, with odds ratios (95%CI) of 1.07 (1.03 to 1.11), 1.18 (1.13 to 1.24), and 1.08 (1.05 to 1.12) per 10 µg/m3 increase in PM1, PM2.5, and PM10. No significant multiplicative interaction was found between ambient air pollutant exposure and PA on SIIM, whereas negative additive interaction was observed between long-term exposure to PM2.5 and PA on SIIM. The positive associations between low volume PA and SIIM were stronger among those exposed to high-level air pollution particulates. Compared with individuals engaged in high volume PA and exposed to low-level ambient air pollutants, those engaged in low volume PA and exposed to high-level ambient air pollutants had a higher risk of SIIM (OR = 1.49 in PM1 exposure, OR = 1.84 in PM2.5 exposure, OR = 1.19 in PM10 exposure). CONCLUSIONS: Long-term (3 years average) exposure to PM1, PM2.5, and PM10 was associated with an increased risk of SIIM. The associations were modified by PA, highlighting PA's importance in reducing SIIM for all people, especially those living in high-level air pollution regions.
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Poluentes Atmosféricos , Poluição do Ar , Adulto , Humanos , Estudos de Coortes , Multimorbidade , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Poluição do Ar/análise , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Inflamação/epidemiologia , Poeira , China/epidemiologia , Exercício Físico , Dióxido de Nitrogênio/análiseRESUMO
OBJECTIVE: Sedentary behaviour is associated with a variety of adverse health outcomes, including obesity, oestrogen metabolism and chronic inflammation, all of which are related to the pathogenesis of uterine fibroids (UFs). This study aimed to explore the relationship between leisure sedentary time (LST) and UFs. DESIGN: Cross-sectional. SETTING: We conducted a cross-sectional analysis of data from patients from the Yunnan region in the China Multi-Ethnic Cohort Study. PARTICIPANTS: A total of 6623 non-menopausal women aged 30-55 years old were recruited. Menstrual status was self-reported. Participants who lacked a unique national identity card, suffered from serious mental illness, did not have a clear diagnosis of UFs, or provided incomplete information were excluded. PRIMARY AND SECONDARY OUTCOME: UFs were diagnosed by abdominal B-ultrasound. Leisure sedentary behaviour was assessed by using a face-to-face questionnaire interview. Logistic regression and restricted cubic spline were employed to explore the relationship between LST and UFs. RESULTS: A total of 562 participants had UFs, with a prevalence rate of 8.5% (7.8%, 9.2%). Multivariate adjusted logistic regression analysis showed that the risk of UFs in women with LST≥6 hour/day was 2.008 times that in women with LST<2 hour/day (95% CI 1.230 to 3.279). The restricted cubic spline results showed that there was a linear doseâresponse relationship between LST and UFs (p for non-linearity>0.05). According to the results of the stratified analysis for menstrual status and body mass index (BMI), there was a correlation between LST and the prevalence of UFs only in women with a BMI<24 kg/m2 or perimenopause. CONCLUSION: LST was independently associated with the prevalence of UFs, and a linear doseâresponse relationship was observed. Our study provides evidence on the factors influencing UFs, and further research is needed to propose feasible measures for UFs prevention.
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Leiomioma , Comportamento Sedentário , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Estudos de Coortes , Estudos Transversais , China/epidemiologia , Leiomioma/complicaçõesRESUMO
High dose intravenous vitamin C (IVC) has been proposed as a pro-oxidant anticancer agent. However, there is a lack of biomarkers that are specific for this treatment. Here, we explored profiles of gene expression responding to IVC treatment in non-small cell lung cancer (NSCLC) cells as an effort for potential biomarker discovery. Genome-wide RNA-seq was performed in human NSCLC cell lines treated with pharmacological concentrations of vitamin C(VitC) for differential expression of genes. The identified genes were analyzed for correlations with patient prognosis using data from the Kaplan-Meier Plotter and the Human Protein Atlas databases. Further, tumor samples from a retrospective study of 153 NSCLC patients were analyzed with immunohistochemistry for expression of targeted genes, and patient prognosis was correlated to these genes. Two genes, namely SERPINE1 and SERPINB7 were found to be downregulated in NSCLC cells following VitC treatment. Combined patient data from the cohort analysis and online databases revealed that these 2 genes presented an unfavorable prognostic prediction of overall survival (OS) in NSCLC patients receiving standard of care. However, high expression level of these 2 genes were associated with prolonged OS in NSCLC patients receiving IVC in addition to standard of care. These data revealed that SERPINE1 and SERPINB7 have the potential to serve as predictive factors indicating favorable responses to IVC treatment in patients with NSCLC. Further validations are warranted.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Serpinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Ácido Ascórbico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antineoplásicos/uso terapêutico , Serpinas/genética , Inibidor 1 de Ativador de Plasminogênio/genéticaRESUMO
Senescent cells are beneficial for repairing acute tissue damage, but they are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) and proliferating cells (P-EVs) and found that P-EVs were readily taken up by proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not. We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We found that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to selectively prevent uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP4-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes.
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Senescência Celular , Vesículas Extracelulares , Humanos , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Células HeLa , Vesículas Extracelulares/metabolismo , EnvelhecimentoRESUMO
Extracellular vesicles and particles (EVPs) are secreted by organs across the body into different circulatory systems, including the bloodstream, and reflect pathophysiologic conditions of the organ. However, the heterogeneity of EVPs in the blood makes it challenging to determine their organ of origin. We hypothesized that small (s)EVPs (<100 nm in diameter) in the bloodstream carry distinctive protein signatures associated with each originating organ, and we investigated this possibility by studying the proteomes of sEVPs produced by six major organs (brain, liver, lung, heart, kidney, fat). We found that each organ contained distinctive sEVP proteins: 68 proteins were preferentially found in brain sEVPs, 194 in liver, 39 in lung, 15 in heart, 29 in kidney, and 33 in fat. Furthermore, we isolated sEVPs from blood and validated the presence of sEVP proteins associated with the brain (DPP6, SYT1, DNM1L), liver (FABPL, ARG1, ASGR1/2), lung (SFPTA1), heart (CPT1B), kidney (SLC31), and fat (GDN). We further discovered altered levels of these proteins in serum sEVPs prepared from old mice compared to young mice. In sum, we have cataloged sEVP proteins that can serve as potential biomarkers for organ identification in serum and show differential expression with age.
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BACKGROUND & AIMS: Recent cross-sectional studies found that exposure to ambient air pollution (AP) was associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). The alternation of blood lipids may explain the association, but epidemiological evidence is lacking. We aimed to examine whether and to what extent the association between long-term exposure to AP and incident MAFLD is mediated by blood lipids and dyslipidemia in a prospective cohort. METHODS: We included 6350 participants from the China Multi-Ethnic Cohort (CMEC, baseline 2018-2019, follow-up 2020-2021). Three-year average (2016-2018) of AP (PM1, PM2.5, PM10, NO2), blood lipids (TC, LDL-C, HDL-C, TG with their combinations) and incident MAFLD for each individual were assessed chronologically. Linear and logistic regression was used to assess the associations among AP, blood lipids, and MAFLD, and the potential mediation effects of blood lipids were evaluated using causal mediation analysis. RESULTS: A total of 744 participants were newly diagnosed with MAFLD at follow-up. The odds ratios of MAFLD associated with a 10 µm increase in PM1, PM2.5, and NO2 were 1.35 (95 % CI: 1.14, 1.58), 1.34 (1.10, 1.65) and 1.28 (1.14, 1.44), respectively. Blood lipids are important mediators between AP and incident MAFLD. LDL-C (Proportion Mediated: 6.9 %), non-HDL (13.4 %), HDL-C (20.7 %), LDL/HDL (30.1 %), and dyslipidemia (6.5 %) significantly mediated the association between PM2.5 and MAFLD. For PM1, the indirect effects were similar to those for PM2.5, with a larger value for the direct effect, and the mediation proportion by blood lipids was less for NO2. CONCLUSION: Blood lipids are important mediators between AP and MAFLD, and can explain 5 %-30 % of the association between AP and incident MAFLD, particularly cholesterol-related variables, indicating that AP could lead to MAFLD through the alternation of blood lipids. These findings provided mechanical evidence of AP leading to MAFLD in epidemiological studies.
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Poluentes Atmosféricos , Poluição do Ar , Dislipidemias , Humanos , Poluentes Atmosféricos/análise , Estudos Longitudinais , Dióxido de Nitrogênio/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Estudos Prospectivos , LDL-Colesterol , Poluição do Ar/análise , Estudos de Coortes , Lipídeos , China/epidemiologia , Dislipidemias/epidemiologia , Dislipidemias/induzido quimicamente , Exposição Ambiental/análiseRESUMO
BACKGROUND: Existing evidence shows that there is an independent correlation between nephrolithiasis and gout, and hyperuricemia is the most important risk factor for gout. However, hyperuricemia was often used as an accompanying symptom of gout to explore its association with nephrolithiasis, there were few studies to explore whether hyperuricemia itself or serum uric acid (SUA) is related to the risk of nephrolithiasis. Evidence on the relationship between hyperuricemia and nephrolithiasis is still insufficient. METHODS: A total of 22,303 participants aged 30 to 79 years who participated in the China Multi-Ethnic Cohort (CMEC) study in Yunnan Province from May 2018 to September 2019 were included in the study. All participants received standardized face-to-face interviews, medical examinations, and biochemical examinations. Logistic regression was used to estimate the association between hyperuricemia and nephrolithiasis, and a restricted cubic spline (RCS) model was used to explore the dose-response relationship between SUA and the risk of nephrolithiasis. RESULTS: 14.5% of all participants were diagnosed with hyperuricemia, and 12.1% were diagnosed with nephrolithiasis. After adjusting for all potential confounders, the OR (95%CI) for nephrolithiasis in participants with hyperuricemia compared with participants without hyperuricemia was 1.464 (1.312,1.633), p < 0.001. Restricted cubic spline regression analysis showed that the risk of nephrolithiasis increased with the increase of SUA, and when the level of SUA is higher than 356 µmol/L in males and higher than 265 µmol/L in females, there is a dose-response relationship between the increase of SUA and the risk of nephrolithiasis in both males and females (p for nonlinearity = 0.1668, p for nonlinearity = 0.0667). CONCLUSION: Asymptomatic hyperuricemia is associated with an increased risk of developing nephrolithiasis. Before reaching the diagnostic criteria for hyperuricemia, the risk of nephrolithiasis rises with the increase in SUA. This suggests that controlling SUA levels may be significant for the prevention of nephrolithiasis.
Assuntos
Gota , Hiperuricemia , Nefrolitíase , Masculino , Feminino , Humanos , Hiperuricemia/complicações , Hiperuricemia/epidemiologia , Ácido Úrico , Estudos Transversais , China/epidemiologia , Gota/complicações , Gota/epidemiologia , Fatores de Risco , Nefrolitíase/epidemiologia , Nefrolitíase/complicaçõesRESUMO
BACKGROUND: Ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) consists of various toxic constituents. However, the health effect of PM2.5 may differ depending on its constituents, but the joint effect of PM2.5 constituents remains incompletely understood. OBJECTIVE: Our goal was to evaluate the joint effect of long-term PM2.5 constituent exposures on dyslipidemia and identify the most hazardous chemical constituent. METHODS: This study included 67,015 participants from the China Multi-Ethnic Cohort study. The average yearly levels of PM2.5 constituents for all individuals at their residences were assessed through satellite remote sensing and chemical transport modeling. Dyslipidemia was defined as one or more following abnormal blood lipid concentrations: total cholesterol (TC) ≥ 6.22 mmol/L, triglycerides (TG) ≥ 2.26 mmol/L, high-density lipoprotein cholesterol (HDL-C) < 1.04 mmol/L, and low-density lipoprotein cholesterol (LDL-C) ≥ 4.14 mmol/L. The logistic regression model was utilized to examine the single effect of PM2.5 constituents on dyslipidemia, while the weighted quantile sum regression model for the joint effect. RESULTS: The odds ratio with a 95 % confidence interval for dyslipidemia positively related to per-SD increase in the three-year average was 1.29 (1.20-1.38) for PM2.5 mass, 1.25 (1.17-1.34) for black carbon, 1.24 (1.16-1.33) for ammonium, 1.33 (1.24-1.43) for nitrate, 1.34 (1.25-1.44) for organic matter, 1.15 (1.08-1.23) for sulfate, 1.30 (1.22-1.38) for soil particles, and 1.12 (1.05-1.92) for sea salt. Stronger associations were observed in individuals < 65 years of age, males, and those with low physical activity. Joint exposure to PM2.5 constituents was positively related to dyslipidemia (OR: 1.09, 95 %CI: 1.05-1.14). Nitrate was identified as the constituent with the largest weight (weighted at 0.387). CONCLUSIONS: Long-term exposure to PM2.5 constituents poses a significant risk to dyslipidemia and nitrate might be the most responsible for the risk. These findings indicate that reducing PM2.5 constituent exposures, especially nitrate, could be beneficial to alleviate the burden of disease attributed to PM2.5-related dyslipidemia.
Assuntos
Poluentes Atmosféricos , HDL-Colesterol , Dislipidemias , Nitratos , Material Particulado , Adulto , Humanos , Masculino , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , HDL-Colesterol/sangue , Estudos de Coortes , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/etiologia , População do Leste Asiático , Nitratos/análise , Material Particulado/efeitos adversos , Material Particulado/análise , Material Particulado/químicaRESUMO
BACKGROUND: Restricted ventilation is common after rhinoplasty with an endogenous extension stent. The authors proposed an exogenous extension stent concept for Asian rhinoplasty patients to avoid this problem. Herein, we introduce an innovative stent in rhinoplasty for Asians, which is an application of this concept. METHODS: An L-shaped expanded polytetrafluoroethylene is hand-carved, and the long arm is placed at the nose back to improve the flatness of the nose, while the short arm supports the nasal column to raise the nose tip. The prosthesis does not occupy nasal volume and therefore theoretically does not affect nasal ventilation. The fan-shaped ear cartilage was placed at the nasal tip to prevent visualization of the nasal tip. The safety and effectiveness of this method were verified through 20 years of clinical practice. The difficulty of learning and popularizing the method was tested through the course of rhinoplasty among 22 plastic surgeons. RESULTS: After 20 years of clinical practice, it was found that this stent could not only effectively improve the nasal dorsum and tip morphology, but also did not actually affect the nasal volume and thus did not affect the nasal ventilation of patients. Among the trainees in plastic surgery, we found that it was not difficult to learn this method of rhinoplasty and the trainees could complete the prosthesis carving well after standardized training. CONCLUSION: This stent consisting of expanded polytetrafluoroethylene and ear cartilage is suitable in rhinoplasty for Asians with significant advantages, one of which is that it has no risk of resulting in restricted nasal ventilation. LEVEL OF EVIDENCE: Level IV.