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Antimony (Sb) and its compounds can be harmful to people and are known to cause cancer, so they are a key pollutant to control. This study investigated the influence of antimony on non-enzymatic antioxidants and the blood-brain barrier (BBB) in zebrafish(Danio rerio), a model organism that shares a high degree of genetic similarity with humans. Zebrafish were exposed to different doses of antimony in water for 7, 18, and 30â¯days. The results indicated that antimony accumulated most in the liver, followed by the gills, flesh, and brain, with the accumulation increasing as the exposure duration extends. Additionally, under identical antimony concentrations, the buildup in the four tissues was positively correlated with the duration of exposure. After 18â¯days of exposure, the total antioxidant capacity (T-AOC) and endogenous non-enzymatic antioxidants vitamin C (VC) and vitamin E (VE) decreased as a result of antimony ingestion in zebrafish, although cysteine secretion was increased in the liver, gills, and brain. The structural integrity of the BBB was compromised by the elevation of ApoE4 and MMP-9 levels as a result of antimony exposure, which led to the breakdown of the basal lamina, tight junctions, and nerve fibers in the brain. At this injured region, 5-HT and MBP were also able to easily enter and leave the BBB, albeit at variable rates. Additionally, when the antimony exposure level reached 16.58â¯mg·L-1, antimony penetrated the BBB and bound to erythrocytes, causing their lysis.
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BACKGROUND: Thyroid dysfunction plays an important role in the pathology of diabetes-associated cognitive dysfunction (DACD). However, thyroid hormone (TH) signaling and action changes in DACD brains remain unknown. This study evaluated the alternations in TH signaling and action in the brains of DACD mice, and explored the beneficial effects of levothyroxine (L-T4) treatment. METHODS: KK-Ay mice, serving as a spontaneous type-2 diabetes mellitus model, underwent intragastric administration of 10 ng/g and 20 ng/g of L-T4 solution or normal saline for 8 weeks. Age-matched C57BL/6J mice were used as normal controls. Cognitive and memory functions were examined through the open field and Morris water maze tests. Hippocampal TH signaling and pathogenic status were evaluated. The potential signaling pathways involved in the neuroprotective action of L-T4 were investigated through RNA sequencing and further verified through quantitative real-time PCR (qPCR), Western blotting (WB), immunofluorescence (IF), and fluorescent multiplex immunohistochemistry (mIHC) in vivo and vitro. RESULTS: The expressions of hippocampal TH transporters (Mct8 and Oatp1c1), Dio2, and TH receptor were up-regulated, while Dio3 as well as the TH positive-regulated genes MBP, Enpp2 and Klf9 were down-regulated in DACD mice. Exogenous L-T4 partially alleviated cognitive and memory dysfunction and restored hippocampal neuronal activity by optimizing TH signaling. RNA sequencing provided insights into the role of type-I interferon (IFN-I) signaling and necroptosis on the amelioration of hippocampal damage following L-T4 treatment. WB and qPCR further confirmed that the levels of key proteins for IFN-I signaling and necroptosis (p-STAT1, p-STAT2, IRF9, ZBP1, p-RIP3, and p-MLKL) were increased, but largely returned following L-T4 administration in vivo and T3 treatment in vitro. IF and mIHC revealed that IRF9 and p-MLKL co-localized in neurons, but not in astrocytes or microglia, of the hippocampus in DACD mice. The diabetes mellitus group had an increased number of IRF9+p-MLKL+NeuN+ cells, which decreased after L-T4 treatment. The elevated IFN-I signaling-mediated necroptosis in HT22 cells was also decreased by T3. CONCLUSION: We demonstrated abnormal hippocampal TH signaling and action in DACD. Promoting TH action with exogenous L-T4 ameliorated hippocampal impairment through inhibiting IFN-I signaling-induced necroptosis.
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BACKGROUND: Little is known about the combined effect of bisphenol mixtures and metal mixtures on type 2 diabetes mellitus (T2DM) risk, and the mediating roles of metabolites. METHODS: The study included 606 pairs of T2DM cases and controls matched by age and sex, and information of participants was collected through questionnaires and laboratory tests. Serum bisphenol and plasma metal concentrations were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS), respectively. Widely targeted metabolomics was employed to obtain the serum metabolomic profiles. Conditional logistic regression models were used to assess the single associations of bisphenols and metals with T2DM risk after multivariable adjustment. Additionally, the joint effects of bisphenol mixtures and metal mixtures were examined using quantile-based g-computation (QG-C) models. Furthermore, differential metabolites associated with T2DM were identified, and mediation analyses were performed to explore the role of metabolites in the associations of bisphenols and metals with T2DM risk. RESULTS: The results showed bisphenol mixtures were associated with an increased T2DM risk, with bisphenol A (BPA) identified as the primary contributor. While the association between metal mixtures and T2DM remained inconclusive, cobalt (Co), iron (Fe), and zinc (Zn) showed the highest weight indices for T2DM risk. A total of 154 differential metabolites were screened between the T2DM cases and controls. Mediation analyses indicated that 9 metabolites mediated the association between BPA and T2DM, while L-valine mediated the association between Zn and T2DM risk. CONCLUSIONS: The study indicated that BPA, Co, Fe, and Zn were the primary contributors to increased T2DM risk, and metabolites played a mediating role in the associations of BPA and Zn with the risk of T2DM. Our findings contribute to a better understanding of the mechanisms underlying the associations of bisphenols and metals with T2DM.
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Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Metais , Fenóis , Diabetes Mellitus Tipo 2/induzido quimicamente , Humanos , Compostos Benzidrílicos/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Metais/sangue , Estudos de Casos e Controles , Metabolômica , Adulto , Exposição Ambiental , Poluentes Ambientais/sangue , IdosoRESUMO
BACKGROUND: Although studies have assessed the association of metals and bisphenols with lipid metabolism, the observed results have been controversial, and limited knowledge exists about the combined and interactive effects of metals and bisphenols exposure on lipid metabolism. METHODS: Plasma metals and serum bisphenols concentrations were evaluated in 888 participants. Multiple linear regression and logistic regression models were conducted to assess individual associations of 18 metals and 3 bisphenols with 5 lipid profiles and dyslipidemia risk, respectively. The dose-response relationships of targeted contaminants with lipid profiles and dyslipidemia risk were captured by applying a restriction cubic spline (RCS) function. The bayesian kernel machine regression (BKMR) model was used to assess the overall effects of metals and bisphenols mixture on lipid profiles and dyslipidemia risk. The interactive effects of targeted contaminants on interested outcomes were explored by constructing an interaction model. RESULTS: Single-contaminant analyses revealed that exposure to iron (Fe), nickel (Ni), copper (Cu), arsenic (As), selenium (Se), strontium (Sr), and tin (Sn) was associated with elevated lipid levels. Cobalt (Co) showed a negative association with high density lipoprotein cholesterol (HDL-C). Bisphenol A (BPA) and bisphenol AF (BPAF) were associated with decreased HDL-C levels, with nonlinear associations observed. Vanadium (V), lead (Pb), and silver (Ag) displayed U-shaped dose-response relationships with most lipid profiles. Multi-contaminant analyses indicated positive trends between contaminants mixture and total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C). The interaction analyses showed that Se-Fe exhibited synergistic effects on LDL-C and non-HDL-C, and Se-Sn showed a synergistic effect on HDL-C. CONCLUSIONS: Our study suggested that exposure to metals and bisphenols was associated with changes in lipid levels, and demonstrated their combined and interactive effects.
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Dislipidemias , Metais , Fenóis , Humanos , Adulto , Dislipidemias/induzido quimicamente , Dislipidemias/epidemiologia , Metais/sangue , Masculino , Feminino , Pessoa de Meia-Idade , China , Lipídeos/sangue , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/sangue , Compostos Benzidrílicos , População do Leste AsiáticoRESUMO
Metal-halide perovskite nanocrystals (NCs) are one of the most promising emitters for the application of display and nanolight sources. The full width at half-maximum (FWHM) of photoluminescence (PL) emission is essential for color purity, which however remains a difficulty to further reduce the FWHM of the perovskite NCs at room temperature. Here, we show the quasi-sphere perovskite NCs with narrow PL emission at a deep-blue wavelength of â¼430 nm; its PL FWHM reaches â¼11 nm at room temperature, owing to the monodispersion in size distribution as well as the symmetric quasi-sphere morphology of NCs releasing the fine structure splitting-induced inhomogeneous broadening. Through regulating A cations with respect to the ratio of FA (or MA)-to-Cs and Cs-to-Pb, the PL emission of the NCs could be tuned from â¼505 to â¼430 nm combined with varied morphologies from large cube to small quasi-sphere. Such spectroscopic and morphological discrepancies are supposed to be attributed to the different crystalline kinetics that is strongly dependent on the synthetic condition. To be specific, in the case of increasing FA (or MA)-to-Cs, the growth rate of CsPbBr3 and FAPbBr3 (or MAPbBr3) perovskites is determined by the reactivity of transient species, while in the case of decreasing the Cs-to-Pb ratio, the growth rate of perovskites is slowed down by the serious reduction of Cs+ in the precursor. This study provides an effective strategy to adjust the emission across from green to deep-blue color and promotes the perovskite NCs with a narrow FWHM, and tunable PL emission facilitates in application of optoelectronic devices.
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AIMS: We aimed to prospectively evaluate the association of sarcopenic obesity (SO) with the incidence risk of heart failure (HF), and the mediating role of metabolomics and inflammation in people with type 2 diabetes (T2D). METHODS: 22,496 participants with T2D from the UK Biobank were included. SO was defined as the combination of obesity (body mass index ≥30 kg/m2) and sarcopenia (grip strength <27 kg in male or <16 kg in female). The incident HF was identified through linked hospital records. Cox proportional hazard regression models were used to estimate the associations. Mediation analysis was conducted to evaluate the mediating effect of the "metabolomic risk score" of HF, which was derived from 168 plasma metabolites through LASSO regression, and five inflammatory markers (e.g., C-reactive protein [CRP] level) on the aforementioned associations. RESULTS: 1946 (8.7 %) participants developed HF during a median follow-up of 12.0 years. Compared to participants with neither obesity nor sarcopenia, those with obesity & non-sarcopenia (hazard ratio [HR]: 1.80, 95 % confidence interval [CI]: 1.62, 2.00), sarcopenia & non-obesity (HR: 1.90, 95 % CI: 1.56, 2.31) and SO (HR: 2.29, 95 % CI: 1.92, 2.73) showed a higher risk of HF. The metabolomic risk score (20.0 %) and CRP (20.4 %) meditated this association. CONCLUSIONS: SO was associated with an increased risk of HF in people with T2D and metabolomics and inflammation partially mediated this association. Our findings suggest the importance of managing obesity and muscle strength simultaneously in preventing HF among people with T2D and shed light on the underlying mechanisms.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inflamação , Obesidade , Sarcopenia , Humanos , Sarcopenia/epidemiologia , Sarcopenia/sangue , Sarcopenia/etiologia , Sarcopenia/complicações , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Obesidade/complicações , Estudos Prospectivos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Pessoa de Meia-Idade , Inflamação/complicações , Seguimentos , Prognóstico , Idoso , Biomarcadores/sangue , Biomarcadores/análise , Fatores de Risco , IncidênciaRESUMO
Is childhood adversity associated with biological aging, and if so, does sex modify the association, and do lifestyle and mental health mediate the association? A lifespan analysis is conducted using data on 142 872 participants from the UK Biobank to address these questions. Childhood adversity is assessed through the online mental health questionnaire (2016), including physical neglect, physical abuse, emotional neglect, emotional abuse, sexual abuse, and a cumulative score. Biological aging is indicated by telomere length (TL) measured from leukocyte DNA using qPCR, and the shorter TL indicates accelerated biological aging; a lifestyle score is constructed using body mass index, physical activity, drinking, smoking, and diet; mental disorder is assessed using depression, anxiety, and insomnia at the baseline survey. The results reveal a sex-specific association such that childhood adversity is associated with shorter TL in women after adjusting for covariates including polygenic risk score for TL, but not in men. Unhealthy lifestyle and mental disorder partially mediate the association in women. The proportions of indirect effects are largest for sexual and physical abuse. These findings highlight the importance of behavioral and psychological interventions in promoting healthy aging among women who experienced childhood adversity, particularly sexual and physical abuse.
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Envelhecimento , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Envelhecimento/genética , Reino Unido/epidemiologia , Fatores Sexuais , Inquéritos e Questionários , Estilo de Vida , Experiências Adversas da Infância , Adulto , Idoso de 80 Anos ou maisRESUMO
Pharmacological studies have shown that Cedrol (CE) exhibits extensive biological activities, including anti-inflammatory and analgesic. Moreover, it can inhibit the NF-κB pathway and the expression of various associated proteins. This study aimed to investigate the role of CE in postmenopausal osteoporosis. The results showed that intragastric administration of CE (10 and 20 mg/kg) significantly improved the bone microstructure damage and increased bone mineral density, trabecular bone volume, and bone trabecular thickness in ovariectomized (OVX) rats (p < 0.05). CE treatment additionally made a well-organized arrangement of bone trabeculae and improved its thickness and density. Compared with the OVX group, the levels of tartrate-resistant acid phosphatase from 5b and C-terminal telopeptide of type I collagen were significantly reduced by 42.75% and 49.27% in the OVX + CE rats (p < 0.05). TRAP staining visually showed that the number of osteoclasts in the femur tissue of CE-treated rats was less than that of the OVX group. The expressions of nuclear factor of activated T-cells, cytoplasmic 1, acid phosphatase 5, and cathepsin K in OVX + CE rats were significantly decreased by 51.61%, 46.07%, and 50.34% compared to the OVX group (p < 0.01). In addition, CE intervention effectively reduced the phosphorylation levels of P65 and IκBα and inhibited the NF-κB signaling pathway. Meanwhile, CE diminished the number of multinucleated osteoclasts induced by receptor activator for nuclear factor-κB ligand and hindered cell fusion as well as nuclear translocation of osteoclast precursor cells P65. In conclusion, CE inhibits osteoclastogenesis by suppressing the activation of the NF-κB signaling pathway, thereby alleviating postmenopausal osteoporosis.
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Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Regulação para Cima , Animais , Humanos , Masculino , Camundongos , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/tratamento farmacológico , Chaperona BiP do Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
In our recent study, we explored the efficacy of three-dimensional (3D) measurement of tumor volume in predicting the improvement of quality of life (QoL) in patients suffering from renal cell cancer (RCC), who were treated with axitinib and anti-PD-L1 antibodies. This study encompassed 18 RCC patients, including 10 men and 8 women, with an average age of 56.83 ± 9.94 years. By utilizing 3D Slicer software, we analyzed pre- and post-treatment CT scans to assess changes in tumor volume. Patients' QoL was evaluated through the FKSI-DRS questionnaire. Our findings revealed that 3D models for all patients were successfully created, and there was a moderate agreement between treatment response classifications based on RECIST 1.1 criteria and volumetric analysis (kappa = 0.556, p = 0.001). Notably, nine patients reported a clinically meaningful improvement in QoL following the treatment. Interestingly, the change in tumor volume as indicated by the 3D model showed a higher area under the curve in predicting QoL improvement compared to the change in diameter measured by CT, although this difference was not statistically significant (z = 0.593, p = 0.553). Furthermore, a multivariable analysis identified the change in tumor volume based on the 3D model as an independent predictor of QoL improvement (odds ratio = 1.073, 95% CI 1.002-1.149, p = 0.045).In conclusion, our study suggests that the change in tumor volume measured by a 3D model may be a more effective predictor of symptom improvement in RCC patients than traditional CT-based diameter measurements. This offers a novel approach for assessing treatment response and patient well-being, presenting a significant advancement in the field of RCC treatment.
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The increasing concentration of Antimony (Sb) in ecological environments has raised serious concerns about its potential biotoxicological impact. This study investigated the toxicokinetics, Global DNA Methylation (GDM), biomarker expression, and Integrated Biological Response (IBR) of Sb at different concentrations in zebrafish. The toxic mechanism of Sb exposure was simulated using molecular dynamics (MD). The results showed that significant differences effect existed (BCFk: liver > ovary > gut > brain) and uptake saturation phenomenon of Sb among zebrafish tissues. Over a 54-day exposure period, the liver emerged as the main target site for Sb-induced GDM, and the restoration was slower than in other tissues during the 54-day recovery period. Moreover, the concentration of Sb had a significant impact on the normally expression of biomarkers, with GSTM1 inhibited and MTF2, MT1, TET3, and p53 showing varying degrees of activation at different Sb concentrations. This could be attributed to Sb3+ potentially occupying the active site or tightly binding to the deep cavity of these genes. The IBR and MD results highlighted DNMT1 as the most sensitive biomarker among those assessed. This heightened sensitivity can be attributed to the stable binding of Sb3+ to DNMT1, resulting in alterations in the conformation of DNMT1's catalytic domain and inhibition of its activity. Consequently, this disruption leads to damage to the integrity of GDM. The study suggests that DNA methylation could serve as a valuable biomarker for assessing the ecotoxicological impact of Sb exposure. It contributes to a better understanding of the toxicity mechanisms in aquatic environments caused potential pollutants.
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Antimônio , Bioacumulação , Metilação de DNA , Poluentes Químicos da Água , Peixe-Zebra , Animais , Antimônio/toxicidade , Metilação de DNA/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Biomarcadores/metabolismo , Feminino , Toxicocinética , Simulação de Dinâmica Molecular , Fígado/efeitos dos fármacos , Fígado/metabolismoRESUMO
Objective: To examine the associations of dietary patterns with frailty and whether metabolic signatures (MSs) mediate these associations. Methods: We used UK Biobank data to examine (1) the associations of four dietary patterns (i.e., alternate Mediterranean diet [aMED], Recommended Food Score [RFS], Dietary Approaches to Stop Hypertension [DASH] and Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet) with frailty (measured by the frailty phenotype and the frailty index) using multivariable logistic regression (analytic sample 1: N = 124 261; mean age = 57.7 years), and (2) the mediating role of MSs (weighted sums of the metabolites selected from 168 plasma metabolites using the LASSO algorithm) in the above associations via mediation analysis (analytic sample 2: N = 26 270; mean age = 57.7 years). Results: Four dietary patterns were independently associated with frailty (all P < 0.001). For instance, compared to participants in the lowest tertile for RFS, those in the intermediate (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.74, 0.89) and highest (OR: 0.62; 95% CI: 0.56, 0.68) tertiles had a lower risk of frailty. We found that 98, 68, 123 and 75 metabolites were associated with aMED, RFS, DASH and MIND, respectively, including 16 common metabolites (e.g., fatty acids, lipoproteins, acetate and glycoprotein acetyls). The MSs based on these metabolites partially mediated the association of the four dietary patterns with frailty, with the mediation proportion ranging from 26.52% to 45.83%. The results were robust when using another frailty measure, the frailty index. Conclusions: The four dietary patterns were associated with frailty, and these associations were partially mediated by MSs. Adherence to healthy dietary patterns may potentially reduce frailty development by modulating metabolites.
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Dieta Mediterrânea , Fragilidade , Humanos , Pessoa de Meia-Idade , Padrões Dietéticos , Metabolômica , AlgoritmosRESUMO
Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.
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Adenina , Antineoplásicos , Neuralgia , Humanos , Adenina/análogos & derivados , Metiltransferases/genética , Neuralgia/induzido quimicamente , Neuralgia/genética , Receptores de N-Metil-D-Aspartato/genética , Proteínas de Ligação a RNARESUMO
BACKGROUND: Research has estimated the associations of lifestyle at one-time point with the risk of dementia and hippocampal volume, but the impact of lifestyle transition on dementia and hippocampal volume remains unclear. This study aims to examine the associations of lifestyle transition with the risk of dementia and hippocampal volume. METHODS: Based on data from the UK Biobank, a weighted lifestyle score was constructed by incorporating six lifestyle factors. Within each baseline lifestyle group (i.e., healthy, intermediate, and unhealthy), lifestyle transition was classified into decline, maintenance, and improvement. Cox proportional hazard regression was used to estimate the association of lifestyle transition and incident dementia (N = 16,305). A multiple linear regression model was used to estimate the association between lifestyle transition and hippocampal volume (N = 5849). RESULTS: During a median follow-up period of 8.6 years, 120 (0.7 %) dementia events were documented. Among participants with healthy baseline lifestyles, the improvement group had a lower risk of incident dementia (HR: 0.18, 95 % CI: 0.04-0.81) and a larger hippocampal volume (ß = 111.69, P = 0.026) than the decline group. Similar results were observed among participants with intermediate baseline lifestyles regarding dementia risk but not hippocampal volume. No benefits were observed in the improvement group among those with unhealthy baseline lifestyles. LIMITATIONS: A lower incidence of dementia than other cohort study and this may have resulted in an underestimation of the risk of dementia. CONCLUSIONS: Earlier transitions to healthier lifestyle were associated with reduced risk of incident dementia and decreased hippocampal atrophy.
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Demência , Estilo de Vida , Humanos , Estudos de Coortes , Demência/epidemiologia , Demência/prevenção & controle , Demência/patologia , Atrofia/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Fatores de RiscoRESUMO
BACKGROUND: With two well-validated aging measures capturing mortality and morbidity risk, this study examined whether and to what extent aging mediates the associations of unhealthy lifestyles with adverse health outcomes. METHODS: Data were from 405,944 adults (40-69 years) from UK Biobank (UKB) and 9972 adults (20-84 years) from the US National Health and Nutrition Examination Survey (NHANES). An unhealthy lifestyles score (range: 0-5) was constructed based on five factors (smoking, drinking, physical inactivity, unhealthy body mass index, and unhealthy diet). Two aging measures, Phenotypic Age Acceleration (PhenoAgeAccel) and Biological Age Acceleration (BioAgeAccel) were calculated using nine and seven blood biomarkers, respectively, with a higher value indicating the acceleration of aging. The outcomes included incident cardiovascular disease (CVD), incident cancer, and all-cause mortality in UKB; CVD mortality, cancer mortality, and all-cause mortality in NHANES. A general linear regression model, Cox proportional hazards model, and formal mediation analysis were performed. RESULTS: The unhealthy lifestyles score was positively associated with PhenoAgeAccel (UKB: ß = 0.741; NHANES: ß = 0.874, all p < 0.001). We further confirmed the respective associations of PhenoAgeAccel and unhealthy lifestyles with the outcomes in UKB and NHANES. The mediation proportion of PhenoAgeAccel in associations of unhealthy lifestyles with incident CVD, incident cancer, and all-cause mortality were 20.0%, 17.8%, and 26.6% (all p < 0.001) in UKB, respectively. Similar results were found in NHANES. The findings were robust when using another aging measure-BioAgeAccel. CONCLUSIONS: Accelerated aging partially mediated the associations of lifestyles with CVD, cancer, and mortality in UK and US populations. The findings reveal a novel pathway and the potential of geroprotective programs in mitigating health inequality in late life beyond lifestyle interventions.
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Doenças Cardiovasculares , Neoplasias , Humanos , Inquéritos Nutricionais , Disparidades nos Níveis de Saúde , Estilo de Vida , Envelhecimento , Neoplasias/complicações , Fatores de RiscoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder, and its strongest risk factor is aging. A few studies have explored the relationship between aging and AD, while the underlying mechanism remains unclear. We assembled data across multi-omics (i.e., epigenetics, transcriptomics, and proteomics, based on frozen tissues from the dorsolateral prefrontal cortex) and neuropathological and clinical traits from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Aging was assessed using six DNA methylation clocks (including the Horvath clock, Hannum clock, Levine clock, HorvathSkin clock, Lin clock, and Cortical clock) that capture mortality risk in literature. After accounting for age, we first identified a gene module (including 263 genes) that was related to the integrated aging measure of six clocks, as well as three neuropathological traits of AD (i.e., ß-amyloid, Tau tangles, and tangle density). Interestingly, among 20 key genes with top intramodular connectivity of the module, PBXIP1 was the only one that was significantly associated with all three neuropathological traits of AD at the protein level after Bonferroni correction. Furthermore, PBXIP1 was associated with the clinical diagnosis of AD in both ROSMAP and three independent datasets. Moreover, PBXIP1 may be related to AD through its role in astrocytes and hippocampal neurons, and the mTOR pathway. The results suggest the critical role of PBXIP1 in AD and support the potential and feasibility of using multi-omics data to investigate mechanisms of complex diseases. However, more validations in different populations and experiments in vitro and in vivo are required in the future.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Multiômica , Peptídeos beta-Amiloides/metabolismo , Envelhecimento/metabolismo , Epigênese Genética , Encéfalo/metabolismo , Proteínas Correpressoras/metabolismoRESUMO
Arctii Fructus is the dried ripe fruit of Arctium lappa L. (family Asteraceae) and is in the Chinese pharmacopoeia. Previous research showed that the total lignans from Arctii Fructus (TLAF) have pharmacological activities related to diabetes. This study evaluated the acute and chronic (26 weeks) toxicities associated with oral daily administration of TLAF in Sprague-Dawley (SD) rats. An acute-toxicity test showed that TLAF caused 10% mortality at 3,000 mg/kg × 2 (6-h interval), with toxic symptoms, such as dyspnea and tonic convulsions, indicating potential neurotoxicity. A chronic-toxicity study showed no mortality after administration. The no observed adverse-effect level was 1,800 mg/kg (approximately 54 times higher than the human clinical dose) for 26 weeks of TLAF oral administration in SD rats, with toxicity signs of excessive oral and nasal secretions and moist circumferential hair that recovered after TLAF discontinuation. In the toxicokinetic study, the two main components of TLAF, arctigenin plasma level was positively correlated with dose and tended to accumulate after multiple doses. At 1,800 mg/kg, arctiin plasma level increased and tended to accumulate after multiple doses. These results indicated that TLFA has relatively low toxicity and the potential for clinical treatment of diabetes.
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Diabetes Mellitus , Medicamentos de Ervas Chinesas , Lignanas , Ratos , Humanos , Animais , Ratos Sprague-Dawley , Preparações Farmacêuticas , Diabetes Mellitus/tratamento farmacológico , Lignanas/toxicidadeRESUMO
OBJECTIVES: Childhood adversity and lifestyle have been associated with frailty in later life, but not much is known about factors that may explain these associations. Therefore, this study aims to investigate the association of childhood adversity with frailty, and the mediating role of unhealthy lifestyle in the association. METHODS: This lifespan analysis included 152,914 adults aged 40-69 years old from the UK Biobank. We measured childhood adversity with five items: physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse through online mental health survey. Frailty was measured by the frailty index; an unhealthy lifestyle score (range: 0-5) was calculated based on unhealthy body mass index, smoking, alcohol consumption, physical inactivity, and unhealthy diet at the baseline survey. Multiple logistic regression and mediation analysis were performed. RESULTS: A total of 10,078 participants (6.6%) were defined as having frailty. Participants with any childhood adversity had higher odds of frailty. For example, in the fully adjusted model, with a one-point increase in cumulative score of childhood adversity, the odds of frailty increased by 38% (odds ratio: 1.38; 95% Confidence Interval: 1.36, 1.40). Unhealthy lifestyle partially mediated the associations of childhood adversity with frailty (mediation proportion: 4.4%-7.0%). The mediation proportions were largest for physical (8.2%) and sexual (8.1%) abuse. CONCLUSIONS: Childhood adversity was positively associated with frailty, and unhealthy lifestyle partially mediated the association. This newly identified pathway highlights the potential of lifestyle intervention strategies among those who experienced childhood adversity (in particular, physical, and sexual abuse) to promote healthy aging.
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Experiências Adversas da Infância , Maus-Tratos Infantis , Fragilidade , Humanos , Idoso , Criança , Longevidade , Fragilidade/epidemiologia , Estilo de Vida , Maus-Tratos Infantis/psicologiaRESUMO
Synthetic biology harnesses the power of natural microbes by re-engineering metabolic pathways to manufacture desired compounds. Droplet technology has emerged as a high-throughput tool to screen single cells for synthetic biology, while the challenges in sensitive flexible single-cell secretion assay for bioproduction of high-value chemicals remained. Here, a novel droplet modifiable graphene oxide (GO) aptasensor was developed, enabling sensitive flexible detection of different target compounds secreted from single cells. Fluorophore-labeled aptamers were stably anchored on GO through π-π stacking interactions to minimize the non-specific interactions for low-background detection of target compounds with high signal-to-noise ratios. The assay's versatility was exhibited by adapting aptamer sequences to measure metabolic secretions like ATP and naringenin. To show the case, engineered E. coli were constructed for the bioproduction of naringenin. The high signal-to-noise ratio assay (â¼2.72) was approached to precisely measure the naringenins secreted from single E. coli in the droplets. Consequently, secretory cells (Gib) were clearly distinguished from wild-type (WT) cells, with a low overlap in cell populations (â¼0%) for bioproduction.
Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Grafite , Óxidos/química , Biologia Sintética , Escherichia coli/metabolismo , Aptâmeros de Nucleotídeos/química , Grafite/química , Limite de DetecçãoRESUMO
OBJECTIVES: Adults without diabetes are not completely healthy; they are probably heterogeneous with several potential health problems. The management of hemoglobin A1c (HbA1c) is crucial among patients with diabetes; but whether similar management strategy is needed for adults without diabetes is unclear. Thus, this study aimed to investigate the associations of visit-to-visit HbA1c variability with incident dementia and hippocampal volume among middle-aged and older adults without diabetes, providing potential insights into this question. METHODS: We conducted a prospective analysis for incident dementia in 10,792 participants (mean age 58.9 years, 47.8 % men) from the UK Biobank. A subgroup of 3793 participants (mean age 57.8 years, 48.6 % men) was included in the analysis for hippocampal volume. We defined HbA1c variability as the difference in HbA1c divided by the mean HbA1c over the 2 sequential visits ([latter - former]/mean). Dementia was identified using hospital inpatient records with ICD-9 codes. T1-structural brain magnetic resonance imaging was conducted to derive hippocampal volume (normalized for head size). The nonlinear and linear associations were examined using restricted cubic spline (RCS) models, Cox regression models, and multiple linear regression models. RESULTS: During a mean follow-up (since the second round) of 8.4 years, 90 (0.8 %) participants developed dementia. The RCS models suggested no significant nonlinear associations of HbA1c variability with incident dementia and hippocampal volume, respectively (All P > 0.05). Above an optimal cutoff of HbA1c variability at 0.08, high HbA1c variability (increment in HbA1c) was associated with an increased risk of dementia (Hazard Ratio, 1.88; 95 % Confidence Interval, 1.13 to 3.14, P = 0.015), and lower hippocampal volume (coefficient, -96.84 mm3, P = 0.037), respectively, in models with adjustment of covariates including age, sex, etc. Similar results were found for a different cut-off of 0. A series of sensitivity analyses verified the robustness of the findings. CONCLUSIONS: Among middle-aged and older adults without diabetes, increasing visit-to-visit HbA1c variability was associated with an increased dementia risk and lower hippocampal volume. The findings highlight the importance of monitoring and controlling HbA1c fluctuation in apparently healthy adults without diabetes.