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BACKGROUND: Health lifestyles exert a substantial influence on the quality of everyday life, primarily affecting health maintenance and enhancement. While health-related practices during the COVID-19 pandemic may have positively altered the health lifestyles of Canadians to a certain degree, government reports indicate that issues related to health behaviors, such as cigarette smoking, physical inactivity, and alcohol consumption, continue to pose challenges to the health of Canadians. Social determinants of these health behaviors thus hold significant academic value in the formulation of policy guidelines. OBJECTIVE: The aim of this study is to scrutinize the social determinants of health with respect to social factors that have may have impacts on the health-related behaviors of Canadians. We tested health behaviors including cigarette use, alcohol consumption, and participation in physical exercise, which are integral to the promotion and improvement of individual health. METHODS: To examine the social determinants of Canadians' health lifestyles, we utilized nationally representative data from the 2017-2018 Canadian Community Health Survey annual component. Our data analysis involved the bootstrapping method with two-level mixed-effect logistic regressions, ordered logistic regressions, and negative binomial regressions. Additionally, we conducted several robustness checks to confirm the validity of our findings. RESULTS: The findings show that demographic background, socioeconomic status, social connections, and physical and mental health conditions all play a role in Canadians' smoking, physical activity, and drinking behaviors. Noticeably, the association patterns linking to these social determinants vary across specific health lifestyles, shedding light on the complex nature of the social determinants that may influence young and middle-aged Canadians' health lifestyles. Moreover, in the context of Canada, the health-region level demographic, socioeconomic, and working conditions are significantly linked to residents' health lifestyles. CONCLUSIONS: Investigating the social determinants of health lifestyles is pivotal for policymakers, providing them with the necessary insights to create effective interventions that promote healthy behaviors among specific demographic groups. It is recommended that health education and interventions at the community level targeting smoking, physical inactivity, and alcohol consumption be introduced. These interventions should be tailored to specific subgroups, considering their demographic and socioeconomic characteristics, social networks, and health status. For instance, it is imperative to focus our attention on individuals with lower educational attainment and socioeconomic status, particularly in relation to their smoking habits and physical inactivity. Conversely, interventions aimed at addressing alcohol consumption should be targeted towards individuals of a higher socioeconomic status. This nuanced approach allows for a more effective and tailored intervention strategy.
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Consumo de Bebidas Alcoólicas , Exercício Físico , Fumar , Determinantes Sociais da Saúde , Humanos , Canadá/epidemiologia , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/psicologia , Masculino , Feminino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Fumar/epidemiologia , Fumar/psicologia , Adulto Jovem , Idoso , Adolescente , Inquéritos Epidemiológicos , Comportamentos Relacionados com a Saúde , Estilo de Vida , COVID-19/epidemiologia , COVID-19/prevenção & controle , População Norte-AmericanaRESUMO
Myocardial infarction (MI) is the leading cause of death worldwide, and oxidative stress is part of the process that causes MI. Calycosin, a naturally occurring substance with cardioprotective properties, is one of the major active constituents in Radix Astragali. In this study, effect of Calycosin was investigated in vivo and in vitro to determine whether it could alleviate oxidative stress and oxidative stress-induced cardiac apoptosis in neonatal cardiomyocytes (NCMs) via activation of aldehyde dehydrogenase 2 (ALDH2). Calycosin protected against oxidative stress and oxidative stress-induced apoptosis in NCMs. Molecular docking revealed that the ALDH2-Calycosin complex had a binding energy of -9.885 kcal/mol. In addition, molecular docking simulations demonstrated that the ALDH2-Calycosin complex was stable. Using BLI assays, we confirmed that Calycosin could interact with ALDH2 (KD = 1.9 × 10-4 M). Furthermore, an ALDH2 kinase activity test revealed that Calycosin increased ALDH2 activity, exhibiting an EC50 of 91.79 µM. Pre-incubation with ALDH2 inhibitor (CVT-10216 or disulfiram) reduced the cardio-protective properties Calycosin. In mice with MI, Calycosin therapy substantially reduced myocardial apoptosis, oxidative stress, and activated ALDH2. Collectively, our findings clearly suggest that Calycosin reduces oxidative stress and oxidative stress-induced apoptosis via the regulation of ALDH2 signaling, which supports potential therapeutic use in MI.
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Infarto do Miocárdio , Miócitos Cardíacos , Camundongos , Animais , Aldeído-Desidrogenase Mitocondrial/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo , Apoptose , Aldeído Desidrogenase/metabolismoRESUMO
Dyslipidemia often accompanies type 2 diabetes mellitus (T2DM). Elevated blood glucose in patients commonly leads to high levels of lipids. Lipid molecules can play a crucial role in early detection, treatment, and prognosis of T2DM with dyslipidemia. Previous lipid studies on T2DM mainly focused on Western diabetic populations with elevated blood glucose. In this research, we investigate both high blood sugar and high lipid levels to better understand changes in plasma lipid metabolism in newly diagnosed Chinese T2DM patients with dyslipidemia (NDDD). We used a plasma lipid analysis method based on ultra-high performance liquid chromatography coupled with mass spectrometry technology (UHPLC-MS) and statistical analysis to characterize lipid profiles and identify potential biomarkers in NDDD patients compared to healthy control (HC) subjects. Additionally, we examined the differences in lipid profiles between hyperlipidemia (HL) patients and HC subjects. We found significant changes in 15 and 23 lipid molecules, including lysophosphatidylcholine (LysoPC), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), and ceramide (Cer), in the NDDD and HL groups compared to the HC group. These altered lipid molecules are associated with five metabolic pathways, with sphingolipid metabolism and glycerophospholipid metabolism being the most relevant to glucose and lipid metabolism changes. These lipid biomarkers are strongly correlated with traditional markers of glucose and lipid metabolism. Notably, Cer(d18:1/24:0), SM(d18:1/24:0), SM(d18:1/16:1), SM(d18:1/24:1), and SM(d18:2/24:1) were identified as essential potential biomarkers closely linked to clinical parameters through synthetic analysis of receiver operating characteristic curves, random forest analysis, and Pearson matrix correlation. These lipid biomarkers can enhance the risk prediction for the development of T2DM in individuals with dyslipidemia but no clinical signs of high blood sugar. Furthermore, they offer insights into the pathological mechanisms of T2DM with dyslipidemia.
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Myocardial fibrosis is a pathological, physiological change that results from alterations, such as inflammation and metabolic dysfunction, after myocardial infarction (MI). Excessive fibrosis can cause cardiac dysfunction, ventricular remodeling, and heart failure. Caffeic acid (CA), a natural polyphenolic acid in various foods, has cardioprotective effects. This study aimed to explore whether CA exerts a cardioprotective effect to inhibit myocardial fibrosis post-MI and elucidate the underlying mechanisms. Histological observations indicated that CA ameliorated ventricular remodeling induced by left anterior descending coronary artery ligation in MI mice and partially restored cardiac function. CA selectively targeted transforming growth factor-ß receptor 1 (TGFBR1) and inhibited TGFBR1-Smad2/3 signaling, reducing collagen deposition in the infarcted area of MI mice hearts. Furthermore, cell counting (CCK-8) assay, 5-ethynyl-2'-deoxyuridine assay, and western blotting revealed that CA dose-dependently decreased the proliferation, collagen synthesis, and activation of the TGFBR1-Smad2/3 pathway in primary cardiac fibroblasts (CFs) stimulated by TGF-ß1 in vitro. Notably, TGFBR1 overexpression in CFs partially counteracted the inhibitory effects of CA. These findings suggest that CA effectively mitigates myocardial fibrosis and enhances cardiac function following MI and that this effect may be associated with the direct targeting of TGFBR1 by CA.
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Ácidos Cafeicos , Fibrose , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Miocárdio , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Miocárdio/patologia , Miocárdio/metabolismo , Camundongos , Remodelação Ventricular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Colágeno/metabolismo , Proteína Smad2/metabolismo , Células CultivadasRESUMO
BACKGROUND: Sepsis-induced cardiac dysfunction (SICD) is a serious complication of sepsis that is associated with increased mortality. Ferroptosis has been reported in the SICD. TaoHe ChengQi decoction (THCQD), a classical traditional Chinese medicinal formula, has multiple beneficial pharmacological effects. The potential effects of THCQD on the SICD remain unknown. PURPOSE: To investigate the effect of THCQD on SICD and explore whether this effect is related to the regulation of myocardial ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. METHODS: We induced sepsis in a mouse model using cecal ligation and puncture (CLP) and administered THCQD (2 and 4 g/kg) and dexamethasone (40 mg/kg). Mice mortality was recorded and survival curves were plotted. Echocardiography, hematoxylin and eosin staining, and analysis of serum myocardial injury markers and inflammatory factors were used to evaluate cardiac pathology. Myocardial ferroptosis was detected by quantifying specific biomarker content and protein levels. Through HPLC-Q-Exactive-MS analysis, we identified the components of the THCQD. Network pharmacology analysis and Cellular Thermal Shift Assay (CETSA) were utilized to predict the targets of THCQD for treating SICD. We detected the expression of Nrf2 using Western blotting or immunofluorescence. An RSL3-induced ferroptosis model was established using neonatal rat cardiomyocytes (NRCMs) to further explore the pharmacological mechanism of THCQD. In addition to measuring cell viability, we observed changes in NRCM mitochondria using electron microscopy and JC-1 staining. NRF2 inhibitor ML385 and Nrf2 knockout mice were used to validate whether THCQD exerted protective effects against SICD through Nrf2-mediated ferroptosis signaling. RESULTS: THCQD reduced mortality in septic mice, protected against CLP-induced myocardial injury, decreased systemic inflammatory response, and prevented myocardial ferroptosis. Network pharmacology analysis and CETSA experiments predicted that THCQD may protect against SICD by activating the Nrf2 signaling pathway. Western blotting and immunofluorescence showed that THCQD activated Nrf2 in cardiac tissue. THCQDs consistently mitigated RSL3-induced ferroptosis in NRCM, which is related to Nrf2. Furthermore, the pharmacological inhibition of Nrf2 and genetic Nrf2 knockout partially reversed the protective effects of THCQD on SICD and ferroptosis. CONCLUSION: The effect of THCQD on SICD was achieved by activating Nrf2 and its downstream pathways.
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Medicamentos de Ervas Chinesas , Ferroptose , Fator 2 Relacionado a NF-E2 , Sepse , Animais , Masculino , Camundongos , Ratos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Ferroptose/efeitos dos fármacos , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Farmacologia em Rede , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Sepse/complicações , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.
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Objectives: About four percent of Canadians used illegal drugs in 2019, but it remains unknown whether their living arrangements are a relevant factor. Methods: We use the public version of the 2015-2016 Canadian Community Health Survey Annual Component. The binary logit model and complementary log-log model are applied to investigate to what extent living arrangements predict Canadians' recent illicit drug use. Results: Living alone is significantly associated with Canadians' illicit drug use. For young and older Canadians, those living with spouses/partners, children, or both are less likely to use illicit drugs than their solo-living counterparts. Middle-aged Canadians who lived with spouses/partners only or with children have significantly lower likelihoods of using illicit drugs compared to those living alone. Additionally, differences between men and women have been found. Spouses/partners and children play more positive roles for young and middle-aged women than for men. Conclusion: Our findings suggest that living with core families is a type of collectivity that may have positive effects on Canadians' health behaviours compared to those living alone, who, therefore, need more attention from health officials.
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Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canadá/epidemiologia , Saúde Pública , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Inquéritos e QuestionáriosRESUMO
Local anesthetics are frequently used by dentists to relieve localized discomfort of the patient and improve treatment conditions. The risk of paresthesia after local anesthesia is frequently encountered in dental clinics. The neurotoxicity of local anesthetics is a disregarded factor in paresthesia. The review summarizes the types of common local anesthetics, incidence and influencing factors of paresthesia after local anesthesia, and systematically describes the neurotoxicity mechanisms of dental local anesthetic. Innovative strategies may be developed to lessen the neurotoxicity and prevent paresthesia following local anesthesia with the support of a substantial understanding of paresthesia and neurotoxicity.
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Mangiferin, a natural C-glucoside xanthone, is one of the major bioactive ingredients derived from the dry rhizome of Anemarrhenae rhizome, which has been reported to exhibit various pharmacological effects, including anti-oxidant, anti-inflammatory, anti-fatty liver, anti-metabolic syndrome, and anti-diabetic. However, the precise molecular mechanisms underlying its impact on phospholipid metabolism in the erythrocyte membrane of type 2 diabetes mellitus (T2DM) remain unclear. The present research aimed to evaluate the effects of mangiferin on glucose and lipid metabolism in T2DM model rats and discuss the relationship between lipid metabolites and potential targets involved in the hypoglycemic effects by integrating lipidomics and network pharmacology method. After 8 consecutive weeks of treatment with mangiferin, the T2DM model rats exhibited significant improvements in several biochemical indices and cytokines, including fasting blood glucose (FBG) levels after 12 h of fasting, fasting insulin level (FINS), total cholesterol (T-CHO), triacylglycerols (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HMOA-IR), TNF-α and IL-6. A total of 22 differential lipid metabolites were selected from erythrocyte membrane phospholipids, which were closely associated with the processes of T2DM. These metabolites mainly belonged to glycerophospholipid metabolism and sphingolipid metabolism. Based on network pharmacology analysis, 22 genes were recognized as the potential targets of mangiferin against diabetes. Moreover, molecular docking analysis revealed that the targets of TNF, CASP3, PTGS2, MMP9, RELA, PLA2G2A, PPARA, and NOS3 could be involved in the modulation of inflammatory signaling pathways and arachidonic acid (AA) metabolism to improve IR and hyperglycemia. The combination of immunohistochemical staining and PCR showed that mangiferin could treat T2DM by regulating the expression of PPARγ protein and NF-κB mRNA expression to impact glycerophospholipids (GPs) and AA metabolism. The present study showed that mangiferin might alleviate IR and hyperglycemia of T2DM model rats via multiple targets and multiple pathways to adjust their phospholipid metabolism, which may be the underlying mechanism for mangiferin in the treatment of T2DM.
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Anemarrhena , Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas , Hiperglicemia , Xantonas , Ratos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/química , Lipidômica , Rizoma/química , Membrana Eritrocítica/metabolismo , Simulação de Acoplamento Molecular , Farmacologia em Rede , Xantonas/farmacologia , Xantonas/uso terapêutico , Hiperglicemia/tratamento farmacológico , Fosfolipídeos , ColesterolRESUMO
BACKGROUND: With an increasing number of myocardial infarction (MI) patients, myocardial fibrosis is becoming a widespread health concern. It's becoming more and more urgent to conduct additional research and investigations into efficient treatments. Ethyl ferulate (EF) is a naturally occurring substance with cardioprotective properties. However, the extent of its impact and the underlying mechanism of its treatment for myocardial fibrosis after MI remain unknown. PURPOSE: The goal of this study was to look into how EF affected the signaling of the TGF-receptor 1 (TGFBR1) in myocardial fibrosis after MI. METHODS: Echocardiography, hematoxylin-eosin (HE) and Masson trichrome staining were employed to assess the impact of EF on heart structure and function in MI-affected mice in vivo. Cell proliferation assay (MTS), 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques were employed to examine the influence of EF on native cardiac fibroblast (CFs) proliferation and collagen deposition. Molecular simulation and surface plasmon resonance imaging (SPRi) were utilized to explore TGFBR1 and EF interaction. Cardiac-specific Tgfbr1 knockout mice (Tgfbr1ΔMCK) were utilized to testify to the impact of EF. RESULTS: In vivo experiments revealed that EF alleviated myocardial fibrosis, improved cardiac dysfunction after MI and downregulated the TGFBR1 signaling in a dose-dependent manner. Moreover, in vitro experiments revealed that EF significantly inhibited CFs proliferation, collagen deposition and TGFBR1 signaling followed by TGF-ß1 stimulation. More specifically, molecular simulation, molecular dynamics, and SPRi collectively showed that EF directly targeted TGFBR1. Lastly, knocking down of Tgfbr1 partially reversed the inhibitory activity of EF on myocardial fibrosis in MI mice. CONCLUSION: EF attenuated myocardial fibrosis post-MI by directly suppressing TGFBR1 and its downstream signaling pathway.
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Infarto do Miocárdio , Miocárdio , Humanos , Camundongos , Animais , Miocárdio/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/uso terapêutico , Fibroblastos/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Colágeno/metabolismo , Fibrose , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disease that greatly affect patients' quality of life. Galangin extract is renowned for its anti-proliferative and anti-oxidative characteristics. However, galangin cytotoxicity studies are presently inadequate. We aimed to investigate the therapeutic potential of galangin on RA by investigating the PI3K/AKT signaling pathway.Fibroblast-like synovial cells (FLSs) were exposed to lipopolysaccharide (LPS) to establish an RA model in vitro. An ELISA assay was used to detect the levels of IL-1ß, TNF-α, and IL-6. Cell viability and apoptosis were determined by CCK8/EdU and flow cytometry assays. A western blot assay was used to analyze the protein expression levels. An RA rat model was established to evaluate the function of galangin through histopathological examination. Our results found that galangin induced apoptosis, inhibited cell proliferation, and increased cell invasion of rheumatoid arthritis fibroblast-like synovial cells (RAFLSs). Galangin inactivated the PI3K/AKT signaling pathway and the inflammatory response. An agonist of PI3K signaling, 740Y-P, restored the cellular functions of RAFLSs. Moreover, galangin suppressed the development of RA in vivo. Galangin effected its anti-arthritic influence through the PI3K/AKT signaling pathway. Galangin has potential as an alternative treatment for RA.
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Artrite Reumatoide , Fosfatidilinositol 3-Quinase , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Flavonoides , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Qualidade de Vida , Ratos , Transdução de SinaisRESUMO
As a commonly used anti-diabetic drug, metformin (MEF) is frequently detected in different water bodies which pose a potential threat to human health and the ecological environment. In this study, oxidative degradation of MEF under ultraviolet (UV) light was studied, and its influencing factors, photolysis mechanism, and intermediates identification carried out as well. The results showed that the hydroxyl radical contributed 73% during the 6 h MEF photolysis process among the reactive oxygen species (ROS). In addition, triplet excited-state organic matter and singlet oxygen also played a role in the photolysis process. The reaction rates of hydroxyl radical and singlet oxygen with MEF are (6.45 ± 0.4) × 109 and (5.4 ± 0.7) × 106 L·(mol s)-1, respectively. By calculating the light screening effect of environmental factors, it is found that the presence of NO3- and Cl- had a greater excitation effect on ROS than the screening effect, and generally promoted the photolysis rates of MEF from 90.3 to 193.5% and from 16.1 to 80.6% during the 6-h reaction process, respectively. For bicarbonate and fulvic acid, the light screening effects were dominant and inhibited photolysis rates by 10-52% and 13-71%, respectively. The results demonstrated that the photoreactivity of environmental factors in water is the cause of the different photodegradation rates of MEF. The oxidative degradation product of MEF under UV light was detected by UPLC/Q-TOF as methylbiguanide (MBG), 2,4-diamino-1,3,5-triazine (2,4-DAT), biguanide (BGN), 1,1-dimethylguanidine (1,1-DiMBG), 4-amino-2-imino-1-methyl-1,2-dihydro-1, 3,5-triazine (4,2,1-AIMT), and 2-amino-4-methylamino-1,3,5-triazine (2,4-AMT). The result which showed that the primary sites of âOH attacked is consistent with that of density functional theory calculation. Graphical abstract.
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Metformina , Poluentes Químicos da Água/análise , Teoria da Densidade Funcional , Cinética , Fotólise , Raios Ultravioleta , ÁguaRESUMO
The precise population estimation, short-term or real-time, is crucial to social and civil management, such as public resource distribution, education budgets, health care, and public safety. In this paper, we reviewed the methods for estimation of real-time population. For real-time population estimation, especially for a certain wastewater treatment plant catchment, many water quality indicators and biomarkers were selected as potential markers and their stability, consumption coefficient, and uncertainty were assessed. The conventional water quality indicators, such as wastewater discharge volume, chemical oxygen demand, biochemical oxygen demand, ammonia nitrogen, and total phosphorus, were used to calculate the serving population within a WWTP catchment. These parameters are all affected by the behavior, living habits and health conditions of people in different regions. Among them, wastewater discharge volume and ammonia might be more suitable for population estimation than the other parameters which may be influenced by additional industrial discharge. Moreover, acesulfame could be used to estimate the general population, while caffeine, tobacco, and carbamazepine could be applied as biomarkers for a specific population. Furthermore, the per capita loading differ should be considered and measured independently. To reduce the uncertainty of population, comprehensive model with multi-parameters should be developed and applicability should be checked.
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Demografia/métodos , Biomarcadores Ambientais , Densidade Demográfica , Qualidade da Água , Monitoramento Ambiental/métodos , Humanos , Fatores de Tempo , Águas Residuárias/análiseRESUMO
The proliferation and migration of vascular smooth muscle cells (VSMC) is extensively involved in pathogenesis of neointimal hyperplasia. All-trans-retinoic acid (ATRA) is a natural metabolite of vitamin A. Here, we investigated the involvement of AMP-activated protein kinase (AMPK) in the anti-neointimal hyperplasia effects of ATRA. We found that treatment with ATRA significantly reduced neointimal hyperplasia in the left common carotid artery ligation mouse model. ATRA reduced the proliferation and migration of VSMC, A7r5 and HASMC cell lines. Our results also demonstrated that ATRA altered the expression of proliferation-related proteins, including CyclinD1, CyclinD3, CyclinA2, CDK2, CDK4, and CDK6 in VSMC. ATRA dose-dependently enhanced the phosphorylation level of AMPKα (Thr172) in the left common carotid artery of experimental mice. Also, the phosphorylation level of AMPKα in A7r5 and HASMC was significantly increased. In addition, ATRA dose-dependently reduced the phosphorylation levels of mTOR and mTOR target proteins p70 S6 kinase (p70S6K) and 4E-binding protein 1 (4EBP1) in A7r5 and HASMC. Notably, the inhibition of AMPKα by AMPK inhibitor (compound C) negated the protective effect of ATRA on VSMC proliferation in A7r5. Also, knockdown of AMPKα by siRNA partly abolished the anti-proliferative and anti-migratory effects of ATRA in HASMC. Molecular docking analysis showed that ATRA could dock to the agonist binding site of AMPK, and the binding energy between AMPK and ATRA was -7.91 kcal/mol. Molecular dynamics simulations showed that the binding of AMPK-ATRA was stable. These data demonstrated that ATRA might inhibit neointimal hyperplasia and suppress VSMC proliferation and migration by direct activation of AMPK and inhibition of mTOR signaling.
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OBJECTIVE: To observe the influence of Qingxiang San (QS) on substance P (SP), somatostatin (SS) in rats model of spleen and stomach wet heat syndrome. METHODS: 24 rats were divided into 3 groups (each group 8 rats) randomly: the normal control group (NCG), wet heat group (WHG), QS group (QSG). We set up the spleen and stomach wet heat syndrome of rats model by the composite factors such as greasy and sweet food, wet and hot environment, pathogen and so on. Then the contents of SP, SS were detected by radioimmuno assay. RESULTS: The content of SP, SS in WHG were obviously lower than NCG (P<0.01); QSG compared with WHG, the content of SP, SS increased (P<0.01); The content of SP obviously increased when QSG compared with NCG (P<0.01); About the content of SS, there was no significant difference between QSG and NCG (P>0.05), illustrating that QS can increase the content of SP, SS which had decreased. CONCLUSION: QS can regulate the content of SP and SS and increase them which had decreased.