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Nervous system diseases are a global health problem, and with the increase in the elderly population around the world, their incidence will also increase. Harmful substances in the environment are closely related to the occurrence of nervous system diseases. China is a large agricultural country, and thus the insecticide cyfluthrin has been widely used. Cyfluthrin is neurotoxic, but the mechanism of this injury is not clear. Inflammation is an important mechanism for the occurrence of nervous system diseases. Mitochondria are the main regulators of the inflammatory response, and various cellular responses, including autophagy, directly affect the regulation of inflammatory processes. Mitochondrial damage is related to mitochondrial quality control (MQC) and PTEN-induced kinase 1 (PINK1). As an anti-inflammatory factor, stimulator of interferon genes (STING) participates in the regulation of inflammation. However, the relationship between STING and mitochondria in the process of cyfluthrin-induced nerve injury is unclear. This study established in vivo and in vitro models of cyfluthrin exposure to explore the role of MQC and to clarify the mechanism of action of STING and PINK1. Our results showed that cyfluthrin can increase the reactive oxygen species (ROS) level, resulting in mitochondrial damage and inflammation. In this process, an imbalance in MQC leads to the aggravation of mitochondrial damage, and high STING expression drives the occurrence of inflammation. We established a differential expression model of STING and PINK1 to further determine the underlying mechanism and found that the interaction between STING and PINK1 regulates MQC to affect the levels of mitochondrial damage and inflammation. When STING and PINK1 expression are downregulated, mitochondrial damage and STING-induced inflammation are significantly alleviated. In summary, a synergistic effect between STING and PINK1 on cyfluthrin-induced neuroinflammation may exist, which leads to an imbalance in MQC by inhibiting mitochondrial biogenesis and division/fusion, and PINK1 can reduce STING-driven inflammation.
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Mitocôndrias , Nitrilas , Proteínas Quinases , Piretrinas , Piretrinas/toxicidade , Mitocôndrias/efeitos dos fármacos , Animais , Nitrilas/toxicidade , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Doenças Neuroinflamatórias/induzido quimicamente , Inseticidas/toxicidade , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Inflamação/induzido quimicamente , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genéticaRESUMO
The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.
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AIMS: The association of diabetes onset age and duration with incident arrhythmias remains unclear. This study evaluates the association of diabetes onset age and duration with incident arrhythmias and assesses modiï¬cations by the genetic predisposition to atrial fibrillation (AF). METHODS: We included 457,151 participants from the UK Biobank study. Multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) were used for the association between diabetes status, genetic predisposition, and risk of incident arrhythmias. The polygenic risk score (PRS) for AF comprised 142 single-nucleotide variants. RESULTS: Over 12 years of follow-up, we documented 23,518 AF, 9079 bradyarrhythmia, 9280 conduction system diseases, 3358 supraventricular arrhythmias, and 3095 ventricular arrhythmias. Compared with non-diabetes, the risks of AF increased by 19%, 25%, and 36% for those with diabetes durations <5, 5-9, and ≥10 years, respectively. After multivariate adjustment, with the increase in diabetes onset age, the HRs of outcomes were gradually attenuated. The multivariable-adjusted HRs (95% CI) of diabetes for AF were 1.46 (1.24-1.71) in early middle age (<55 years), 1.21 (1.12-1.30) in late middle age (55-64 years), and 1.15 (1.06-1.24) in the elderly population (≥65 years). A significant interaction between diabetes status and AF-PRS for incident AF was observed (P for interaction <0.001). The same trends were observed for the other arrhythmias. CONCLUSIONS: Diabetes was associated with higher risks of incident arrhythmias, and younger age at onset of diabetes was significantly associated with higher risk of subsequent arrhythmias.
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Arritmias Cardíacas , Diabetes Mellitus , Predisposição Genética para Doença , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/etiologia , Estudos Prospectivos , Seguimentos , Incidência , Idoso , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Fatores de Risco , Adulto , Prognóstico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) shares common pathophysiological mechanisms with type 2 diabetes, making them significant risk factors for type 2 diabetes. The present study aimed to assess the epidemiological feature of type 2 diabetes in patients with NAFLD or MAFLD at global levels. METHODS: Published studies were searched for terms that included type 2 diabetes, and NAFLD or MAFLD using PubMed, EMBASE, MEDLINE, and Web of Science databases from their inception to December 2022. The pooled global and regional prevalence and incidence density of type 2 diabetes in patients with NAFLD or MAFLD were evaluated using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. RESULTS: A total of 395 studies (6,878,568 participants with NAFLD; 1,172,637 participants with MAFLD) from 40 countries or areas were included in the meta-analysis. The pooled prevalence of type 2 diabetes among NAFLD or MAFLD patients was 28.3% (95% confidence interval 25.2-31.6%) and 26.2% (23.9-28.6%) globally. The incidence density of type 2 diabetes in NAFLD or MAFLD patients was 24.6 per 1000-person year (20.7 to 29.2) and 26.9 per 1000-person year (7.3 to 44.4), respectively. CONCLUSIONS: The present study describes the global prevalence and incidence of type 2 diabetes in patients with NAFLD or MAFLD. The study findings serve as a valuable resource to assess the global clinical and economic impact of type 2 diabetes in patients with NAFLD or MAFLD.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Fatores de Risco , Bases de Dados Factuais , PacientesRESUMO
Small extracellular vesicles (sEVs) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNAs (miRNAs) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cells-derived sEVs (AML-sEVs) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEVs. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEVs impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEVs-delivered miRNAs contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.
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Novel 2D material-based supercapacitors are promising candidates for energy applications due to their distinctive physical, chemical, and electrochemical properties. In this study, a dandelion-like structure material comprised of Sm2O3, Co3O4, and 2D reduced graphene oxide (rGO) on nickel foam (NF) was synthesised using a hydrothermal method followed by subsequent annealing treatment. This dandelion composite grows further through the tremella-like structure of Sm2O3 and Co3O4, which facilitates the diffusion of ions and prevents structural collapse during charging and discharging. A substantial number of active sites are generated during redox reactions by the unique surface morphology of the Sm2O3/Co3O4/rGO/NF composite (SCGN). The maximum specific capacity the SCGN material achieves is 3448 F g-1 for 1 A g-1 in a 6 mol L-1 KOH solution. Benefiting from its morphological structure, the prepared composite (SCGN) exhibits a high cyclability of 93.2% over 3000 charge-discharge cycles at 10 A g-1 and a coulombic efficiency of 97.4%. Additionally, the assembled SCGN//SCGN symmetric supercapacitors deliver a high energy density of 64 W h kg-1 with a power density of 300 W kg-1, which increases to an outstanding power density of 12 000 W kg-1 at 28.7 W h kg-1 and long cycle stability (80.9% capacitance retention after 30 000 cycles). These results suggest that the manufactured SCGN electrodes could be viable active electrode materials for electrochemical supercapacitors.
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AIMS: Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. MATERIALS AND METHODS: We conducted a hospital-based case-control study including 1072 pairs (53.9 ± 9.7 years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2 ± 5.1 years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. RESULTS: Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. CONCLUSIONS: Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.
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Diabetes Mellitus Tipo 2 , Adulto , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/epidemiologia , Receptor para Produtos Finais de Glicação Avançada , Produtos Finais de Glicação Avançada , Estudos de Casos e Controles , Estudos Prospectivos , Reação de Maillard , China/epidemiologia , BiomarcadoresRESUMO
OBJECTIVE: This study aimed to examine the interactions between ultraprocessed food (UPF) consumption and genetic predisposition with the risk of gout. METHODS: This prospective cohort study analysed 181 559 individuals from the UK Biobank study who were free of gout at baseline. UPF was defined according to the NOVA classification. Assessment of genetic predisposition for gout was developed from a genetic risk score of 33 single nucleotide polymorphisms. Cox proportional hazards were used to estimate the associations between UPF consumption, genetic predisposition and the risk of gout. RESULTS: Among the 181 559 individuals in the study, 1558 patients developed gout over 1â648â167 person-years of follow-up. In the multivariable adjustment model, compared with the lowest quartile of UPF consumption, the hazard ratio (HR) and 95% CI of the highest UPF consumption was 1.16 (1.01, 1.33) for gout risk, and there was a non-linear correlation between UPF consumption and the development of gout. In substitution analyses, replacing 20% of the weight of UPF in the daily intake with an equal amount of unprocessed or minimally processed food resulted in a 13% lower risk of gout (HR: 0.87; 95% CI: 0.79, 0.95). In the joint-effect analysis, the HR (95% CI) for gout was 1.90 (1.39, 2.60) in participants with high genetic predisposition and high UPF consumption, compared with those with low genetic predisposition and low UPF consumption. CONCLUSION: In summary, UPF consumption was found to be associated with a higher risk of gout, particularly in those participants with genetic predisposition to gout. Our study indicated that reducing UPF consumption is crucial for gout prevention.
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Bancos de Espécimes Biológicos , Gota , Humanos , Estudos Prospectivos , Biobanco do Reino Unido , Predisposição Genética para Doença , Gota/epidemiologia , Gota/genética , DietaRESUMO
AIMS: Non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) are important risk factors of chronic kidney disease (CKD). Whether adherence to a healthy lifestyle can modify these effects remain unknown. This study aimed to evaluate the modification effects of healthy lifestyle on the associations among NAFLD, MAFLD, and the risk of CKD, with taking into the effect of genetic risk. METHODS: The Tianjin Chronic Low-grade Systemic Inflammation and Health Cohort Study (TCLSIH), the UK Biobank Study (UKB). The outcome was incident CKD. The exposures including NAFLD, MAFLD, healthy lifestyle, and a genetic risk score (GRS) for CKD. RESULTS: After 1,135,334 person-year follow-up, we documented 2975 incident CKD cases in the two cohorts. MAFLD and NAFLD were associated with a higher risk of CKD, particularly in patients with MAFLD. In the TCLSIH and UKB, the hazard ratios (95% confidence intervals) of incident CKD for MAFLD were 1.47 (1.30, 1.66) and 1.73 (1.57, 1.91), respectively. Adherence to a healthier lifestyle decreased the risk of CKD from MAFLD with significant interaction effects (TCLSIH: Pinteraction = 0.02; UKB: Pinteraction = 0.04). Participants with a lower CKD-GRS experienced a higher risk of CKD from MAFLD, but achieved two healthy lifestyles can significantly decreased the risk of CKD in patients with MAFLD. CONCLUSIONS: MAFLD and NAFLD are associated with a higher CKD risk, particularly MAFLD. Adherence to a healthier lifestyle was associated with a lower risk of CKD from MAFLD. These results highlight the important role of following a healthy lifestyle to prevent CKD.
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Hepatopatia Gordurosa não Alcoólica , Insuficiência Renal Crônica , Humanos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos de Coortes , Estudos Prospectivos , Estilo de Vida Saudável , Inflamação , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/prevenção & controleRESUMO
BACKGROUND: Plant-based dietary patterns may affect colorectal cancer (CRC) related outcomes, while risks differ in the quality of plant foods. We aimed to examine the association of plant-based diet quality with risks of CRC incidence and mortality and whether this association was modified by genetic risk. METHODS: This prospective cohort study included 186,675 participants free of cancer when the last dietary recall was completed. We calculated three plant-based diet indices (PDIs), i.e., the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI) representing adherence to plant-based diets with diverse quality. Genetic risk was characterized using a weighted polygenic risk score (PRS), capturing overall risk variants associated with CRC. Hazard ratios (HR) and 95% confidential intervals (CI) were estimated by the cause-specific Cox proportional hazards model. RESULTS: Over a follow-up of 9.5 years, 2163 cases and 466 deaths from CRC were documented. The HR of CRC incidence was 0.88 (95% CI, 0.81-0.96) and 0.91 (95% CI, 0.84-0.99) per 10-score increase in PDI and hPDI, respectively. Compared to the lowest quartile, PDI, hPDI, and uPDI in the highest quartile were associated with a 13% decrease, a 15% decrease, and a 14% increase in risk of incident CRC, respectively. We found a joint association of genetic risk and PDIs with incident CRC, with the highest hazard observed in those carrying higher PRS and adhering to lower-quality PDIs. The inverse association of PDI and hPDI with CRC mortality was pronounced in males. CONCLUSIONS: Our results suggested that better adherence to overall and healthful plant-based diets was associated with a lower risk of CRC, whereas an unhealthful plant-based diet was associated with a higher CRC risk. Consumption of a higher-quality plant-based diet combined with decreased genetic risk conferred less susceptibility to CRC. Our findings highlighted the importance of food quality when adhering to a plant-based dietary pattern for CRC prevention in the general population.
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Neoplasias Colorretais , Predisposição Genética para Doença , Masculino , Humanos , Estudos Prospectivos , Bancos de Espécimes Biológicos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Diets rich in plant-based foods are associated with lower risks of non-alcoholic fatty liver disease (NAFLD), while the prospective evidence is limited. We aimed to examine longitudinal associations of plant-based diets and genetic susceptibility with NAFLD risk. METHODS: This longitudinal cohort study included 159,222 participants (58.0 ± 8.0 years old, 55.7% female) free of NAFLD in the UK Biobank. We calculated the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI). New-onset NAFLD was the primary outcome. The weighted polygenic risk score was calculated based on risk variants associated with NAFLD. Hazard ratios (HR) and 95% confidential intervals (CI) were estimated by Cox proportional hazards model. Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) measured liver fat content in a subsample of 20,692 participants (57.5 ± 7.4 years old, 52.6% female) was the secondary outcome. The associations between plant-based diet indices and MRI-PDFF were evaluated using generalized linear models. RESULTS: During a median follow-up of 9.5 years, 1541 new-onset NAFLD cases were documented. Compared to the lowest quintile, multivariable-adjusted hazard ratios (HRs) of NAFLD in the highest quintile were 0.78 (95% confidential intervals [CI], 0.66-0.93, p-trend =0.02), 0.74 (95% CI, 0.62-0.87, p-trend <0.0001), and 1.24 (95% CI, 1.05-1.46, p-trend = 0.02) for overall PDI, hPDI, and uPDI, respectively. For liver fat content, higher overall PDI and hPDI were associated with lower MRI-PDFF, while higher uPDI was associated with higher liver fat content. We observed a significant interaction between hPDI and PRS (p-interaction =0.03), and the NAFLD risk was lowest among participants with the highest hPDI and low genetic risk. CONCLUSIONS: Higher intake of plant-based diets especially healthful plant-based diets was associated with lower NAFLD risk and liver fat content regardless of genetic susceptibility, whereas an unhealthful plant-based diet was associated with higher NAFLD risk and intrahepatic steatosis. These results suggest that the quality of plant-based foods should be highlighted when adopting a plant-based diet.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Pessoa de Meia-Idade , Idoso , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Predisposição Genética para Doença , Estudos Longitudinais , Estudos Prospectivos , Dieta , Dieta VegetarianaRESUMO
Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Humanos , Animais , Camundongos , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/metabolismo , Células-Tronco Mesenquimais/metabolismo , Doença AgudaRESUMO
Importance: Cross-sectional evidence implicates high prevalent frailty in patients with Parkinson disease (PD), whereas the longitudinal association remains unknown. Objectives: To examine the longitudinal association of the frailty phenotype with the development of PD and to explore the modification role of genetic risk of PD in such an association. Design, Setting, and Participants: This prospective cohort study launched in 2006 to 2010 with a follow-up of 12 years. Data were analyzed from March 2022 to December 2022. The UK Biobank recruited over 500â¯000 middle-aged and older adults from 22 assessment centers across the United Kingdom. Participants who were younger than 40 years (n = 101), diagnosed with dementia or PD at baseline, and developed dementia, PD, or died within 2 years from baseline were excluded (n = 4050). Participants who had no genetic data or mismatch between genetic sex and reported gender (n = 15â¯350), were not of self-reported British White descent (n = 27â¯850), and had no data for frailty assessment (n = 100â¯450) or any covariates were also excluded (n = 39â¯706). The final analysis included 314â¯998 participants. Exposures: The physical frailty was assessed by the Fried criteria's frailty phenotype through 5 domains, ie, weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. The polygenic risk score (PRS) for PD comprised 44 single-nucleotide variants. Main Outcomes and Measures: New-onset PD was identified through the hospital admission electronic health records and death register. Results: Among 314â¯998 participants (mean age, 56.1 years; 49.1% male), 1916 new-onset PD cases were documented. Compared with nonfrailty, the hazard ratio (HR) of incident PD in prefrailty and frailty was 1.26 (95% CI, 1.15-1.39) and 1.87 (95% CI, 1.53-2.28), respectively, and the absolute rate difference per 100â¯000 person-years was 1.6 (95% CI, 1.0-2.3) for prefrailty and 5.1 (95% CI, 2.9-7.3) for frailty. Exhaustion (HR, 1.41; 95% CI, 1.22-1.62), slow gait speed (HR, 1.32; 95% CI, 1.13-1.54), low grip strength (HR, 1.27; 95% CI, 1.13-1.43), and low physical activity (HR, 1.12; 95% CI, 1.00-1.25) were associated with incident PD. A significant interaction between frailty and PRS on PD was found and the highest hazard was observed in participants with frailty and high genetic risk. Conclusions and Relevance: Physical prefrailty and frailty were associated with incident PD independent of sociodemographic factors, lifestyles, multiple morbidities, and genetic background. These findings may have implications for the assessment and management of frailty for PD prevention.
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Demência , Fragilidade , Doença de Parkinson , Masculino , Humanos , Idoso , Feminino , Fragilidade/epidemiologia , Fragilidade/genética , Idoso Fragilizado , Predisposição Genética para Doença/genética , Estudos Prospectivos , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Estudos TransversaisRESUMO
Melon is an important horticultural crop with a pleasant aromatic flavor and abundance of health-promoting substances. Numerous melon varieties have been cultivated worldwide in recent years, but the high number of varieties and the high similarity between them poses a major challenge for variety evaluation, discrimination, as well as innovation in breeding. Recently, simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs), two robust molecular markers, have been utilized as a rapid and reliable method for variety identification. To elucidate the genetic structure and diversity of melon varieties, we screened out 136 perfect SSRs and 164 perfect SNPs from the resequencing data of 149 accessions, including the most representative lines worldwide. This study established the DNA fingerprint of 259 widely-cultivated melon varieties in China using Target-seq technology. All melon varieties were classified into five subgruops, including ssp. agrestis, ssp. melo, muskmelon and two subgroups of foreign individuals. Compared with ssp. melo, the ssp. agrestis varieties might be exposed to a high risk of genetic erosion due to their extremely narrow genetic background. Increasing the gene exchange between ssp. melo and ssp. agrestis is therefore necessary in the breeding procedure. In addition, analysis of the DNA fingerprints of the 259 melon varieties showed a good linear correlation (R2 = 0.9722) between the SSR genotyping and SNP genotyping methods in variety identification. The pedigree analysis based on the DNA fingerprint of 'Jingyu' and 'Jingmi' series melon varieties was consistent with their breeding history. Based on the SNP index analysis, ssp. agrestis had low gene exchange with ssp. melo in chromosome 4, 7, 10, 11and 12, two specific SNP loci were verified to distinguish ssp. agrestis and ssp. melon varieties. Finally, 23 SSRs and 40 SNPs were selected as the core sets of markers for application in variety identification, which could be efficiently applied to variety authentication, variety monitoring, as well as the protection of intellectual property rights in melon.
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Cucurbitaceae , Cucurbitaceae/genética , Polimorfismo de Nucleotídeo Único/genética , Melhoramento Vegetal , Técnicas de Genotipagem/métodos , Impressões Digitais de DNA , Repetições de Microssatélites/genética , Variação GenéticaRESUMO
BACKGROUND: longitudinal evidence concerning frailty phenotype and the risk of cardiovascular disease (CVD) remained insufficient, and whether CVD preventive strategies exert low CVD risk on frail adults is unclear. OBJECTIVES: we aimed to prospectively evaluate the association of frailty phenotype, adherence to ideal cardiovascular health (CVH) and their joint associations with the risk of CVD. METHODS: a total of 314,093 participants from the UK Biobank were included. Frailty phenotype was assessed according to the five criteria of Fried et al.: weight loss, exhaustion, low physical activity, slow gait speed and low grip strength. CVH included four core health behaviours (smoking, physical activity and diet) and three health factors (weight, cholesterol, blood pressure and glycaemic control). The outcome of interest was incident CVD, including coronary heart disease, heart failure and stroke. RESULTS: compared with the non-frail people whose incident rate of overall CVD was 6.54 per 1,000 person-years, the absolute rate difference per 1,000 person-years was 1.67 (95% confidence interval, CI: 1.33, 2.02) for pre-frail and 5.00 (95% CI: 4.03, 5.97) for frail. The ideal CVH was significantly associated with a lower risk of all CVD outcomes. For the joint association of frailty and CVH level with incident CVD, the highest risk was observed among frailty accompanied by poor CVH with an HR of 2.92 (95% CI: 2.68, 3.18). CONCLUSIONS: our findings indicate that physical frailty is associated with CVD incidence. Improving CVH was significantly associated with a considerable decrease in CVD risk, and such cardiovascular benefits remain for the frailty population.
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Doenças Cardiovasculares , Fragilidade , Insuficiência Cardíaca , Humanos , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Fragilidade/prevenção & controle , Estudos Prospectivos , Idoso Fragilizado , Fatores de RiscoRESUMO
Actin cytoskeleton is essential for root hair formation. However, the underlying molecular mechanisms of actin dynamics in root hair formation in response to abiotic stress are largely undiscovered. Here, genetic analysis showed that actin-depolymerizing protein ADF7 and actin-bundling protein VILLIN1 (VLN1) were positively and negatively involved in root hair formation of Arabidopsis respectively. Moreover, RT-qPCR, GUS staining, western blotting, and genetic analysis revealed that ADF7 played an important role in inhibiting the expression and function of VLN1 during root hair formation. Filament actin (F-actin) dynamics observation and actin pharmacological experiments indicated that ADF7-inhibited-VLN1 pathway led to the decline of F-actin bundling and thick bundle formation, as well as the increase of F-actin depolymerization and turnover to promote root hair formation. Furthermore, the F-actin dynamics mediated by ADF7-inhibited-VLN1 pathway was associated with the reactive oxygen species (ROS) accumulation in root hair formation. Finally, ADF7-inhibited-VLN1 pathway was critical for osmotic stress-induced root hair formation. Our work demonstrates that ADF7 inhibits VLN1 to regulate F-actin dynamics in root hair formation in response to osmotic stress, providing the novel evidence on the F-actin dynamics and their molecular mechanisms in root hair formation and in abiotic stress.
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Proteínas de Arabidopsis , Arabidopsis , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Destrina/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Pressão Osmótica , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
tRNA-derived small RNAs (also known as tsRNAs) are novel kinds of non-coding RNAs. Although tsRNAs are aberrantly expressed in different tumor types, there is scanty of research investigating their expression profiling and functions in pulmonary adenocarcinoma (PADC). We identified the expression of AS-tDR-007872 in 30 non-small-cell lung carcinoma (NSCLC) patients' carcinoma tissues and conducted biological function evaluation. We also test the expression levels of AS-tDR-007872 in plasma samples obtained from 35 healthy people and 79 NSCLC cases. The results identified downregulated AS-tDR-007872 in both cancer tissues and plasma samples versus adjacent normal counterparts (p < 0.05) and healthy controls (p < 0.001). The area under the curve of AS-tDR-007872 was identified by receiver operating characteristic curve analysis to be 0.756 (95% CI, 0.663-0.849; p < 0.001). Furthermore, overexpression of AS-tDR-007872 in vitro inhibited tumor cell proliferation, invasion, and migration and promoted apoptosis. The knockdown of AS-tDR-007872 showed the opposite results. Meanwhile, we found significantly downregulated BCL2L11 after overexpressing AS-tDR-007872. From the above, our research suggests that AS-tDR-007872 can be a tumor suppressor and a promising biomarker for diagnosing lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , RNA Longo não Codificante , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/genética , RNA de Transferência/genéticaRESUMO
Background: Adherence to a healthy lifestyle (no smoking, consuming a healthy diet, engaging in physical activity, and maintaining a healthy weight) is recommended in current guidelines for hypertension prevention. However, evidence regarding the association between sleep behaviors, independently and jointly with traditional lifestyle factors, and the risk of hypertension is limited. Methods: This prospective study included 165,493 participants who are free of hypertension at baseline from the UK Biobank. Sleep behaviors, including chronotype, sleep duration, insomnia, snoring, and daytime sleepiness were used to construct a healthy sleep score. We also derived a healthy lifestyle score based on smoking status, diet quality, physical activity, and body mass index (BMI). Cox proportional hazards regression models and competing risk analyses were used to estimate the associations of the healthy sleep score and healthy lifestyle score with the risk of hypertension. The population attributable risk percent (PAR%) was estimated for increased cases of hypertension due to poor adherence to a healthy sleep pattern or a healthy lifestyle. Results: A total of 10,941 incident hypertension cases were documented during a median of 11.8 years of follow-up. The multivariable-adjusted hazard ratio (HR) for hypertension was 0.58 [95% confidence interval (CI): 0.52, 0.65] for participants with a sleep score of 5 compared with 0-1, and 0.48 (95% CI: 0.43, 0.54) for participants with a lifestyle score of 4 compared with those who scored 0. For joint association, those with a poor sleep pattern and a poor lifestyle had the highest risk of hypertension [HR: 2.41 (95% CI: 2.12, 2.74)]. PAR% was 14.7% (95% CI: 12.3%, 17.1%), 20.1% (95% CI: 17.6%, 22.6%), and 31.7% (95% CI: 27.6%, 35.6%) for poor adherence to a healthy sleep pattern, a healthy lifestyle, and the combination of a healthy sleep pattern and a healthy lifestyle. Conclusion: Both a healthy sleep pattern and a healthy lifestyle were associated with a lower risk of hypertension, and the benefits of adhering to a healthy sleep pattern complement the well-established lifestyle for the optimal primary prevention of hypertension. These findings support the current perspective that a healthy sleep pattern is an important part of a healthful and productive lifestyle for hypertension prevention.
RESUMO
BACKGROUND: Several cardioprotective mechanisms attributed to n-3 polyunsaturated fatty acids (PUFAs) have been widely documented. Significant interest has recently focused on the role of human gut microbiota in metabolic disorders. However, the role of plant-derived n-3 PUFAs on blood lipid profiles is controversial and the effect on gut microbiota is still unclear. OBJECTIVES: We aimed to perform a double-blind randomized controlled trial to test the effect of plant-derived n-3 PUFAs on the blood lipids and gut microbiota of patients with marginal hyperlipidemia. METHODS: According to the inclusion and exclusion criteria, 75 participants with marginal hyperlipidemia were randomly assigned to the intervention group (supplied with n-3 PUFA-enriched plant oil) or control group (supplied with corn oil), respectively, for a 3-month treatment. Participants and assessors were blinded to the allocation. The primary outcomes of the trial were the changes in serum lipid levels. Secondary outcomes were changes in gut microbiota and metabolites. For the primary outcomes, we conducted both an intent-to-treat (ITT) analysis and a per protocol (PP) analysis. For the secondary outcomes, we only conducted the PP analysis among the participants who provided fecal sample. RESULTS: Fifty-one participants completed the trial. Relative to the control group, the n-3 PUFA supplementation resulted in significant reduction in total cholesterol (TC) levels (-0.43 mmol/L, 95% CI-0.84 to-0.01 mmol/L, P < 0.05). The n-3 PUFA supplementation was also associated with significantly increased relative abundance of Bacteroidetes in phylum level (P < 0.01; false discovery rate (FDR) corrected p = 0.11), and decreased the ratio between Firmicutes and Bacteroidetes (P < 0.05; FDR corrected p = 0.16). At genus level, the intervention of plant derived n-3 PUFAs resulted in a significant decrease in relative abundance of Phascolarctobacterium (P < 0.01; FDR corrected p = 0.18) and Veillonella (P < 0.01; FDR corrected p = 0.18) after the intervention. CONCLUSIONS: Our results demonstrated that plant-derived n-3 PUFAs beneficially affected the serum levels of TC and decreased the ratio between Firmicutes and Bacteroidetes during the 12-week intervention period, which might confer advantageous consequences for lipid metabolism and intestinal health.