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The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 µM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.
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Antineoplásicos , Ototoxicidade , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Sistemas Microfisiológicos , Antineoplásicos/farmacologia , Piridinas/farmacologia , Apoptose , Cisplatino/farmacologiaRESUMO
The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (ß=3.871,P<0.001) and depression symptoms (ß=2.458, P<0.001), family residence (in towns or rural areas) (ß=0.947, P<0.001), lack of support for local epidemic control strategies (ß=1.253, P<0.001), worry about the pandemic (ß=1.191, P<0.001), and symptoms of weakness among family members (ß=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (ß=-0.883, P<0.001) and social networks (ß=-0.726, P<0.001) were negatively, but social participation (ß=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.
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COVID-19 , Pandemias , Ansiedade/epidemiologia , China/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Humanos , SARS-CoV-2 , Inquéritos e Questionários , IncertezaRESUMO
OBJECTIVE: To evaluation the dietary quality of Zhejiang population aged 40 years and older using the Dietary Balance Index(DBI) and to analyze the association between dietary quality and cognitive function. METHODS: The dietary information was collected with the help of questionnaire survey, a 3-day dietary recall and household condiment weighing method from Zhejiang participants of the 2018 wave of the China Health and Nutrition Survey aged 40 years and older, and the food and energy intakes were calculated. The cognitive function was assessed by the Mini Mental Status Examination. Dietary quality was evaluated using the DBI method. A multivariate Logistic regression model was used to examine the association between dietary quality and the risk of cognitive impairment. RESULTS: Among 640 participants aged 40 years and older, 14.2% had cognitive impairment. Univariate analysis showed that those with cognitive impairment had higher cereal(P=0.001), particularly, higher rice and products intake(P<0.001), as well as higher egg intake(P=0.008) than those with normal cognitive function; while the intake of soybean and its product(P=0.025) was lower. Those with cognitive impairment had higher DBI score of cereal(P=0.006) and high bound score(HBS)(P=0.028)than those with normal cognitive function. After adjustment for possible confounding factors, Logistic regression showed that moderated and severe over-consumption was positively associated with cognitive impairment(OR=2.486, 95% CI 1.130-5.470, P=0.024). CONCLUSION: Over-consumption may increase the risk of cognitive impairment among aged Zhejiang population, and should be used to prevent or reduce cognitive decline by improving the quality of the diet through a reasonable dietary mix.
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Disfunção Cognitiva , Dieta , Adulto , Idoso , Cognição , Disfunção Cognitiva/epidemiologia , Dieta/efeitos adversos , Grão Comestível , Ingestão de Energia , Humanos , Pessoa de Meia-Idade , Inquéritos NutricionaisRESUMO
In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.
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Índice de Massa Corporal , Causalidade , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Neoplasias/epidemiologia , Obesidade Infantil/fisiopatologia , Adolescente , Criança , Estudo de Associação Genômica Ampla , Humanos , Neoplasias/patologia , Prognóstico , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: To determine the risk factors of the occurrence of nonsyndromic cleft lip and/or cleft palate (NSCL/P) in Xinjiang Province, China. DESIGN: The study included 359 patients of NSCL/P and 310 controls. Information about sociodemographic characteristics, lifestyle behaviors, negative life events, possible environmental hazards exposures, and use of supplementations were collected from cases and controls. Both t test and χ2 tests were used for group comparisons. Multivariable logistic regression was used to estimate the independent associations between environmental risk factors and the presence of NSCL/P. The receiver operating characteristic curve was used to establish the predictive variables for the occurrence of NSCL/P. RESULTS: The results showed that maternal pesticide exposure (odds ratio [OR] = 11.40, 95%CI: 5.40-24.10), antibiotic drugs use (OR = 1.32, 95%CI: 1.14-1.53), paternal smoking (OR = 3.30, 95%CI: 1.87-5.83), threatened abortion (OR = 12.2, 95%CI: 3.29-45.25) were associated with increased risk of NSCL/P in offspring. In contrast, maternal moderate (OR = 0.43, 95%CI: 0.20-0.92) and middle physical workload (OR = 0.48, 95%CI: 0.0.23-0.97), vitamin-B complex supplementations (OR = 0.11, 95%CI: 0.03-0.41), calcium and iron (OR = 0.27, 95%CI: 0.08-0.90) supplementations were associated with reduced risk of NSCL/P in offspring. These variables together explain nearly 60% of the variation of occurrence of NSCL/P. CONCLUSION: These findings from our study may help to develop primary prevention strategies for NSCL/P in Xinjiang.
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Fenda Labial , Fissura Palatina , Estudos de Casos e Controles , China/epidemiologia , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVES: ß-Carotene-15,15'-oxygenase (BCO1) is a key enzyme involved in carotenoid metabolism and has been linked with the development of coronary atherosclerosis. This study investigated the association between BCO1 polymorphisms and the risk of coronary atherosclerosis in dyslipidemia participants, and analyzed the influence of personal behaviors on coronary atherosclerosis. METHODS AND STUDY DESIGN: A nested case-control study was conducted from 2013 to 2016 in which 1359 dyslipidemia participants were recruited. Personal lifestyle parameters, mainly physical activities and diet, were obtained by questionnaires and the genotypes of rs11641677, rs11646692, rs12934922, rs6564851 and rs7501331 in BCO1 were analyzed by ligase detection reaction. In 2016, 166 participants were diagnosed with coronary atherosclerosis and 498 age-and gendermatched controls were recruited. The association between BCO1 polymorphisms and risk of coronary atherosclerosis were analyzed with logistic regression, and the effect of gene-behaviors interaction on the risk of coronary atherosclerosis were determined with crossover analysis. RESULTS: After adjustment for potential confounders, logistic regression analysis showed that fried food intake (OR=1.637, 95% CI: 1.127~2.378; p=0.010), dessert intake (OR=1.733, 95% CI: 1.158~2.595; p=0.008), and physical activity (OR=0.511, 95% CI: 0.309~0.846; p=0.009) were risk factors for coronary atherosclerosis. Rs12934922 and rs11646692 reflected high susceptibility to coronary atherosclerosis. Crossover analysis indicated that rs12934922 and rs11646692 interacted with physical activity (Inter-OR=8.82; Inter-OR=3.69), fried food intake (Inter-OR=2.95; Inter-OR=2.36) and dessert intake (Inter-OR=3.95; Inter-OR=2.39) to influence the risk of coronary atherosclerosis. CONCLUSIONS: In dyslipidemia patients, rs12934922 and rs11646692 may influence the development of coronary atherosclerosis. A combination of BCO1 polymorphisms and several behavioral factors may affect the development of coronary atherosclerosis.
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Povo Asiático , Dislipidemias/etiologia , Predisposição Genética para Doença , Comportamentos Relacionados com a Saúde , Polimorfismo de Nucleotídeo Único , beta-Caroteno 15,15'-Mono-Oxigenase/genética , Alimentação com Mamadeira , Estudos de Casos e Controles , Doença da Artéria Coronariana , Dislipidemias/genética , Exercício Físico , Feminino , Humanos , Modelos Logísticos , Masculino , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Both aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism and lifestyle behaviors are involved in coronary artery disease (CAD), while the interaction between them is currently unknown. METHODS: A nested case-control study was conducted in 161 patients with CAD and 495 controls in dyslipidemia population in Yinzhou District, Ningbo, Zhejiang Province, China, in August 2013. Anthropometric data and blood samples were collected, demographic characteristics and lifestyle behaviors information were obtained by a face-to-face interview, dietary intake was assessed by a food frequency questionnaire, and genomic DNA was genotyped. RESULTS: Carriers with increasing number of A alleles had an elevated CAD risk compared with G allele carriers (adjusted OR = 1.483, 95% CI = 1.114-1.974). Carriers of rs671 A/G and A/A genotypes had a higher CAD risk than carriers of G/G genotype (adjusted OR = 1.492, 95% CI = 1.036-2.148). Similarly, individuals with rs671 A/A genotype had a higher CAD risk than individuals with A/G and G/G genotypes (adjusted OR = 2.161, 95% CI = 1.139-4.101). We found a borderline additive interaction between regular fried food intake and A/A and A/G genotypes, and a significantly additive interaction between sedentary/light physical activity and A/A and A/G genotypes. CONCLUSIONS: Individuals with A/A or A/G genotypes of rs671 have a higher CAD risk, if they lack physical activity and take fried food regularly, than individuals with G/G genotypes. These findings can help to provide a guide to targeted heart health management.
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Aldeído-Desidrogenase Mitocondrial/genética , Doença da Artéria Coronariana/genética , Dislipidemias/genética , Estilo de Vida , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , China , Doença da Artéria Coronariana/sangue , Dislipidemias/sangue , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVES: The magnitude of the influence that obesity contributes to the early stage of chronic kidney disease, especially among Asian population with higher obesity-related health risk, is unclear. The aim of this study was to investigate the association between body mass index (BMI) and mildly decreased estimated glomerular filtration rate (eGFR) among Chinese population. DESIGN AND METHODS: A cross-sectional study was conducted among 1,100 subjects under health screenings. BMI was used to classify overweight and obesity as a BMI greater than or equal to 23.0 kg/m2 and 25.0 kg/m2, respectively. Mildly decreased eGFR was defined as 60.0 to ≤89.0 mL/min/1.73 m2 based on modification of diet in renal disease Chinese equation. RESULTS: The prevalence of mildly decreased eGFR was increased significantly with increasing BMI categories. According to modification of diet in renal disease Chinese equation, obesity (odds ratio, 1.83; 95% confidence interval: 1.15-2.90) was positively associated with the odds of mildly decreased eGFR in the multivariate logistic regression model. BMI was significantly and negatively related to eGFR, and each increase in BMI (1.0 kg/m2) was associated with a decline in eGFR of 0.5 mL/min/1.73 m2. In subgroup analyses, BMI remained associated with an increased likelihood of mildly decreased eGFR independent of hypertension and diabetes. CONCLUSIONS: There was a positive relationship between BMI and mildly decreased eGFR among Chinese adults. Higher BMI may play a role in the onset and progression of renal damage, and maintaining a BMI in the healthy range may be contributed to the prevention of chronic kidney disease.
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Índice de Massa Corporal , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Adulto , Estudos Transversais , Humanos , SobrepesoRESUMO
Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target. Here, we demonstrated that ß-caryophyllene (BCP; 150 µM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways. Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice. In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.
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Ferroptose , Camundongos Endogâmicos C57BL , Sesquiterpenos Policíclicos , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Sesquiterpenos Policíclicos/farmacologia , Sesquiterpenos Policíclicos/química , Humanos , Masculino , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Sesquiterpenos/farmacologia , Sesquiterpenos/metabolismo , Ratos , Sequestradores de Radicais Livres/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacosRESUMO
SCOPE: Liver injury is a major complication associated with sepsis. Together with others, the study has shown that gallic acid (GA) exerts anti-inflammatory and antioxidant effects in vivo. However, the role of GA in sepsis-mediated hepatic impairment and the underlying mechanisms remains to be elucidated. METHODS AND RESULTS: C57BL/6J mice are pretreated with saline or GA and subjected to sham or cecal ligation and puncture (CLP). The pathological alterations are assessed by hematoxylin and eosin staining as well as immunohistochemical staining. RNA sequencing is employed to analyze hepatic transcriptome modifications. The study finds that GA supplementation significantly ameliorates CLP-induced mortality, liver dysfunction, and inflammation. RNA sequencing reveals that 1324 genes are markedly differentially regulated in livers of saline- or GA-treated sham or CLP mice. Gene ontology analysis demonstrates that the differentially expressed genes regulated by GA are predominantly correlated with the immune system process, oxidation-reduction process, and inflammatory response. Furthermore, mitogen-activated protein kinase (MAPK) signaling is localized in the center of the GA-mediated pathway network. Notably, activation of MAPK by C16-PAF significantly blocks GA-mediated protective effects on hepatic injury, inflammation, as well as CCAAT/enhancer-binding protein-ß (C/EBPß) dependent extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) signaling. CONCLUSION: Therefore, this study indicates that GA may offer a promising therapeutic opportunity for sepsis-associated liver injury.
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Proteína beta Intensificadora de Ligação a CCAAT , Ácido Gálico , Fígado , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Sepse , Animais , Ácido Gálico/farmacologia , Sepse/complicações , Sepse/tratamento farmacológico , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Masculino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Hepatopatias/etiologia , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismoRESUMO
AIM: To investigate the role of Cytochrome P4502E1 in sensitizing Kupffer cells to lipopolysaccharide (LPS)-mediated inflammation after ethanol induction. METHODS: Sprague-Dawley rats were fed a liquid ethanol diet, control diet or ethanol diet supplemented with CYP2E1 inhibitor, chlormethiazole (CMZ), for 4 weeks. Hepatic CYP2E1 protein, nuclear factor-kappa B (NF-κB) p65 protein and tumor necrosis factor (TNF)-α mRNA were measured. In vitro, isolated Kupffer cells from control rats were exposed to ethanol with different CMZ concentration; CYP2E1 expression and reactive oxygen species (ROS) generation were compared. The identified CMZ concentration was further utilized to evaluate the role of CYP2E1 on the sensitization of ethanol-induced Kupffer cell to LPS. The effect of LPS alone was tested in controlled Kupffer cells without ethanol. TNF-α, nuclear NF-κB p65 and cytoplasm IκB-α were monitored for all groups. RESULTS: Ethanol feeding increased hepatic CYP2E1 level, nuclear accumulation of NF-κB p65 and TNF-α expression in rats. These changes were inhibited by CMZ supplementation. In cultured Kupffer cells, increased CYP2E1 content and ROS production by in vitro ethanol induction were dose-dependently inhibited by CMZ. Compared with LPS alone, the ethanol induction group produced significantly more TNF-α, nuclear NF-κB p65 and less cytoplasm IκB-α under LPS stimuli. CMZ abolished the effects of ethanol on LPS-stimulated NF-κB translocation and TNF-α generation in Kupffer cells. CONCLUSION: In cultured Kupffer cell, using CMZ as inhibitor, ethanol-induced CYP2E1 overexpression was proved to contribute to the sensitization of Kupffer cells to LPS stimuli, with amplification of ROS production and activation of NF-κB, resulting in increased TNF-α production.
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CONTEXT: Resting heart rate (HR) is increasingly recognized as an indicator of disease and overall morbidity and mortality. Whether chronic coffee consumption affects resting HR is an important consideration for individual consumers as well as from a public health perspective. OBJECTIVE: A meta-analysis of randomized controlled trials (RCTs) was conducted to examine the effectiveness of coffee consumption on resting HR. DATA SOURCES: Original RCTs assessing the effect of coffee consumption on resting HR and published prior to March 2023 were identified by searching online databases, including PubMed, Web of Science, and Cochrane Library databases. DATA EXTRACTION AND ANALYSIS: Data searches and extraction and risk-of-bias assessments were performed according to the Cochrane guidelines, and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews were followed. Data on study characteristics, type, and amount of coffee and net change and measurement resting HR were extracted. A random-effects or a fixed-effects model was used to estimate the pooled effect sizes. Homogeneity was determined with the Cochran Q test, and publication bias was assessed through Begg's test, Egger's test, and funnel plots. RESULTS: A total of 6 RCTs with 11 intervention trials or arms involving 485 individuals were included. The participants were generally healthy, although some had hypertension, hypercholesterolemia, or were overweight. The trial duration ranged from 2 weeks to 24 weeks. The overall pooled analysis showed that coffee consumption resulted in a negligible increase in resting HR of 0.40 beats per minute (95% CI: -0.78 to 1.57; P = 0.506), which was statistically insignificant. Subgroup analysis of all specified categories was consistent with the overall analysis. No heterogeneity was observed among included trials (I2 = 0.0%, P = 0.756). CONCLUSION: The results of the present meta-analysis study demonstrate that daily coffee consumption of 3 to 6 cups for a period of 2 to 24 weeks has no statistically significant effect on resting HR.
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OBJECTIVE: To evaluate the associations between serum uric acid (SUA) levels and cardiovascular disease (CVD) risk factors, focusing on potential sex-specific differences. DESIGN: A retrospective cohort study. SETTING: A large community-based survey was conducted every two years from 2010 to 2018 in Hangzhou, Zhejiang Province, outheastern China. PARTICIPANTS: 6119 participants aged 40 years and above who underwent at least three times of physical examinations were enrolled. METHODS: Participants were categorised into four groups (Q1-Q4) based on baseline SUA quartiles within the normal range, with hyperuricaemia (HUA) as the fifth group. The Q1 was the reference. By stratifying participants by gender, the relationships between SUA levels and systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG) and total cholesterol (TC) were investigated using linear regression models in the generalised estimating equation. Additionally, the associations of elevated SUA levels and HUA with hypertension, hyperglycaemia and dyslipidaemia were correspondingly examined using multivariate logistic regression models. RESULTS: After adjusting for confounding variables, we found positive associations between SUA levels and SBP, DBP, FBG and TC in women, and with TC in men (p<0.01). Likewise, elevated SUA quartiles and HUA were linked to increased dyslipidaemia risk in both sexes, and increased hyperglycaemia risk only in women, with HRs (95% CI) of 1.64 (1.05 to 2.55) and 2.37 (1.47 to 3.81) in the Q4 and HUA group, respectively. Women with HUA had higher hypertension risk (HR=1.45, 95% CI 1.21 to 1.73), while no such association was observed in men. Stratified analyses revealed significant associations between elevated SUA levels and CVD risk factors in postmenopausal and non-obese women. CONCLUSIONS: Elevated SUA levels increase the risk of dyslipidaemia in both sexes. SUA levels within normal range and HUA are positively associated with hyperglycaemia and hypertension in postmenopausal women, but not in men.
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Doenças Cardiovasculares , Hiperglicemia , Hipertensão , Hiperuricemia , Masculino , Feminino , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Ácido Úrico , Estudos Retrospectivos , Hipertensão/epidemiologia , China/epidemiologia , Hiperglicemia/epidemiologia , Hiperuricemia/complicações , Hiperuricemia/epidemiologiaRESUMO
Objective: To evaluate the associations between serum uric acid (SUA) levels and estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), with a focus on gender differences, and variations among women pre-and post-menopausal stages. Design: A retrospective cohort study. Setting: A large community-based survey was conducted every two years from 2010 to 2018 in Hangzhou, Zhejiang Province, Southeastern China. Participants: 10,218 participants (40 years or above) without CKD at baseline who underwent three physical examinations were enrolled. CKD was defined as an eGFR of less than 60 mL/min/1.73m2. Methods: Participants with SUA levels were divided into four groups (Q1-Q4) based on baseline SUA quartiles. The Q1 was the reference. By stratifying participants by gender, the relationships between SUA levels and eGFR were investigated using the generalized additive mixture model. The associations of SUA and the risk of incident CKD were examined using multivariate logistic regression models in the generalized estimating equation. Results: After adjusting for confounding variables, a nonlinear association between SUA and eGFR was observed in females, while an approximately linear relationship was observed in males, suggesting that elevated SUA levels are associated with renal function decline. Furthermore, the highest quartile of SUA was associated with a 2.16-fold (95% CI: 1.31-3.58) increased risk of CKD in males and a 2.76-fold (95% CI: 1.59-4.78) increased risk in females, compared with the lowest quartile. And the spline curves demonstrated a U-shaped pattern, suggesting a potential threshold effect of SUA on the risk of CKD. Additionally, Subgroup analyses revealed significant associations between elevated SUA levels with CKD in postmenopausal women, but not in premenopausal women. Conclusion: Elevated SUA levels are associated with an increased risk of CKD development and renal function decline in middle-aged and elderly individuals, particularly in postmenopausal women.
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Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R-induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+ -dependent malic enzyme 1 (Me1). Mice with hepatocyte-specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L-malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R-induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)-dependent suppression of the mechanistic target of rapamycin/sterol regulatory element-binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over-expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis-related hepatic conditions.
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Fígado , Traumatismo por Reperfusão , Humanos , NADP/metabolismo , Fígado/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Traumatismo por Reperfusão/patologia , Glutationa/metabolismoRESUMO
BACKGROUND AND AIMS: The beneficial effect of low-glycemic index (GI) diet on gestational diabetes mellitus (GDM) has been suggested in many observational studies; however, results from intervention trials remain inconsistent. This study aims to estimate the effect of interventions with low-GI dietary advice on pregnant outcomes in women with elevated risk of GDM. DESIGN: PubMed, Web of Science, Embase, and Cochrane Library databases were searched for randomized clinical trials (RCTs) through March 2022. Studies reporting the effect of low-GI diet advice intervention on maternal and fetal outcomes in pregnant women with increased risks of GDM were included. Random or fixed effects model was used to calculate combined treatment effects. Publication bias was assessed via Begg's and Egger's tests and funnel plot inspection. RESULTS: Nine RCTs recruiting 3416 participants were included. Low-GI diet advice did not modulate the risk of GDM. Compared with control diets, low-GI diet advice significantly reduced gestational weight gain (GWG) (weighted mean differences, WMD = -0.93 kg, 95% CI: -1.31, -0.55; p < 0.001; n = 7) and the risk of premature birth (RR = 0.55, 95% CI: 0.35, 0.88; p = 0.012; n = 5). In subgroup analyses, the effect of low-GI diet interventions on premature birth was significant only in women with BMI higher than 30 kg/m2 (RR = 0.28, 95% CI: 0.10, 0.77, p = 0.014; n = 3); the significant effect on GWG was not altered by stratification of BMI and the type of GDM risk factors. No significant changes in other maternal and newborn outcomes were found. CONCLUSIONS: Low-GI diet advice interventions during pregnancy decreased GWG and the risk of premature birth in women with elevated GDM risk; however, the interventions did not significantly prevent GDM development in these women.
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Diabetes Gestacional , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Gravidez , Terapia Combinada , Bases de Dados Factuais , Índice Glicêmico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Lycopene has been shown to be beneficial in protecting against high-fat diet-induced fatty liver. The recent demonstration that lycopene can be converted by carotene 9',10'-oxygenase into a biologically active metabolite, ALA, led us to propose that the function of lycopene can be mediated by ALA. In the present study, male ob/ob mice were fed a liquid high-fat diet (60% energy from fat) with ALA supplementation (ALA group, 240 µg · kg body weight(-1) · d(-1)) or without ALA supplementation as the control (C group) for 16 wk. Steatosis, SIRT1 expression and activity, genes involved in lipid metabolism, and ALA concentrations in the livers of mice were examined. The results showed that ALA supplementation resulted in a significant accumulation of ALA in the liver and markedly decreased the steatosis in the ALA group without altering body and liver weights compared to the C group. The mRNA and protein levels of hepatic SIRT1 were higher in the ALA group compared to the C group. SIRT1 activity also was higher in the ALA group, as indicated by the lower levels of acetylated forkhead box class O1 protein levels. In addition, the mRNA level of acetyl CoA carboxylase 1 was significantly lower in the ALA group than in the C group. Because SIRT1 plays a key role in lipid homeostasis, the present study suggests that the lycopene metabolite, ALA, protects against the development of steatosis in ob/ob mice by upregulating SIRT1 gene expression and activity.
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Tecido Adiposo/efeitos dos fármacos , Carotenoides/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Fígado Gorduroso/prevenção & controle , Fígado/efeitos dos fármacos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Acetil-CoA Carboxilase/genética , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/metabolismo , Animais , Carotenoides/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Ácidos Graxos Insaturados/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/anatomia & histologia , Fígado/metabolismo , Licopeno , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Background: Mental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders. Methods: Genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses. Results: Genetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. Conclusion: Our findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.
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Arsenic-based therapeutic strategies, even though promising for acute promyelocytic leukemia (APL), are limited by arsenic-related toxic effect and resistance with unknown mechanisms. The purpose of this study is to better understand the different sensitivities of hepatocellular carcinoma cells to arsenic and its mechanism. Arsenic-sensitive liver cancer cell line (HepG2) and arsenic-resistant HepG2 (AsHepG2) cells are employed to study the role of aquaporin 9 (AQP9) in arsenic uptake and tolerance. The half-maximal inhibitory concentration (IC50) value of arsenic in AsHepG2 cells (15.59 ± 1.36 µM) is significantly higher than that in HepG2 cells (7.33 ± 0.93 µM; p= 0.0288). We demonstrated that, with the treatment of sodium arsenite (NaAsO2), arsenic was accumulated at a significantly lower level in AsHepG2 cells in comparison with HepG2 cells (p= 0.00549). Further, arsenic level in AsHepG2 cells reaches a plateau after six hours of treatment, whereas arsenic continues to increase in HepG2 cells during the entire experimental period. Mechanistic study showed that the expression of AQP9 is decreased in a dose-dependent manner in AsHepG2 cells, but no significant difference in HepG2 cells. Furthermore, NaAsO2 dramatically increases AQP9 and p38 phosphorylation, which may partially regulate arsenic sensitivity in both cell lines. In conclusion, the expression and phosphorylation of AQP9 regulated by p38 kinase are involved in the arsenic uptake, thus regulating cellular arsenic sensitivity.
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OBJECTIVES: As the global aging phenomenon intensifies, the incidence of Alzheimer's disease (AD) is gradually increasing. Diet appears to be an effective way to prevent and delay the progression of AD. Previous studies have found that cognitive impairment and neuronal damage were effectively alleviated by blueberry extract (BBE) in AD mice, but its mechanism is still unclear. The aims of this study were to detect the main anthocyanins of BBE; then to verify the protective effects of anthocyanin-rich BBE on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid (PCA), a major metabolite of BBE, for promoting autophagy and thus playing a neuroprotective role. METHODS: APP/PS1 mice were given 150 mg/kg BBE daily for 16 wk. Morphology of neurons was observed and autophagy-related proteins were detected. RESULTS: Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after BBE treatment. In vitro, Aß25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by PCA. Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by PCA. CONCLUSION: This study elucidated the mechanism of BBE for reducing neuronal damage by promoting neuronal autophagy and proved PCA may be the main bioactive metabolite of BBE for neuroprotective effects, providing a basis for dietary intervention in AD.