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CONTEXT: Although Tongguan capsule (TGC) is used in the treatment of coronary atherosclerotic disease, the exact mechanism remains unclear. OBJECTIVE: Network pharmacology and experimental validation were applied to examine the mechanism of TGC for treating myocardial ischemia-reperfusion injury (MIRI). MATERIALS AND METHODS: The components and candidate targets were searched based on various databases such as TCMSP, TCMID, BATMAN-TCM. The binding ability was determined by molecular docking. The ischemia-reperfusion (I/R) model was constructed by ligating the left anterior descending (LAD) coronary artery. APOE-/- mice were divided into three groups (n = 6): Sham group, I/R group, and TGC group (1 g/kg/d). To further verification, HCAEC cells were subjected to hypoxia-reoxygenation (H/R) to establish in vitro model. RESULTS: The compounds, such as quercetin, luteolin, tanshinone IIA, kaempferol and bifendate, were obtained after screening. The affinity values of the components with GSK-3ß, mTOR, Beclin-1, and LC3 were all <-5 kcal/mol. In vivo, TGC improved LVEF and FS, reducing infarct size. In vitro, Hoechst 33258 staining result showed TGC inhibited apoptosis. Compare with the H/R model, TGC treatment increased the levels of GSK-3ß, LC3, and Beclin1, while decreasing the expression of mTOR and p62 (p < 0.05). DISCUSSION AND CONCLUSION: The findings revealed that TGC exerted a cardioprotective effect by up regulating autophagy-related proteins through the mTOR pathway, which may be a therapeutic option for MIRI. However, there are still some limitations in this research. It is necessary to search more databases to obtain information and further demonstrated through randomized controlled trials for generalization.
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Traumatismo por Reperfusão Miocárdica , Ratos , Camundongos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos Sprague-Dawley , Glicogênio Sintase Quinase 3 beta , Farmacologia em Rede , Simulação de Acoplamento Molecular , Serina-Treonina Quinases TOR/metabolismo , Isquemia , Apoptose , AutofagiaRESUMO
BACKGROUND: According to the theory of fetal-derived adult diseases, abnormal fetal development might affect the occurrence of diseases in adulthood, and appropriate fetal growth status intrauterine might have a beneficial effect on it. To adapt properly for fetal development, there are numerous changes in the maternal physiology during pregnancy, including blood lipid metabolism. The aim of this study is to evaluate the association between lipid profiles in the second and third trimesters of normal pregnancy and fetal birth weight. MATERIALS AND METHODS: The study population was derived from 5695 pregnant women, who maintained routine prenatal care at the women's hospital of Zhejiang University, School of medicine January 1, 2014, and December 31, 2014. The pregnant women in this study all carried uncomplicated singleton pregnancies to at least 37 weeks. RESULTS: The mean (standard deviation) birth weight was 3361.00 (385.94) g; 413 (7.3%) of the infants were large for gestational age, and 330 (5.8%) were macrosomia. On multiple linear regression analysis, positive determinants of birth weight were gravidity, parity, gestational age at delivery, male infant, maternal height, and weight before pregnancy, weight gain during pregnancy, fasting blood glucose (FBG) level, second-trimester cholesterol (TC) and third-trimester triglyceride (TG), gestational albumin (ALB), and third-trimester high-density lipoprotein (HDL-C) levels were each negatively associated with birth weight. On logistic regression analysis, the significant metabolic lipid predictors of delivering a large-for-gestational-age infant were second- and third-trimester TG (aOR = 1.178, 95% CI 1.032-1.344, p = 0.015; aOR = 1.106, 95% CI 1.043-1.173, p = 0.001, respectively) and second- and third-trimester HDL-C level (aOR = 0.655, 95% CI 0.491-0.874, p = 0.004; aOR = 0.505, 95% CI 0.391-0.651, p < 0.001, respectively). Third-trimester TG and HDL-C were stable predictors of large-for-gestational-age infants in stratification analysis. High TG and low HDL-C level during third trimester could be considered as indicators of a high risk of large for gestational age (LGA) and macrosomia, regardless of infant gender. CONCLUSION: These results suggest that future lifestyle programs in women of reproductive age with a focus on lowering TG levels (i.e., diet, weight reduction, and physical activity) may help to reduce the incidence of LGA and macrosomia.
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Diabetes Gestacional , Macrossomia Fetal , Lipídeos/análise , Adulto , Peso ao Nascer , Feminino , Idade Gestacional , Humanos , Lipídeos/sangue , Masculino , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Aumento de PesoRESUMO
CONTEXT: Berberine (Ber) can increase the survival rate of septic mice and inhibit inflammation, but whether it has a protective effect on septic cardiomyopathy (SCM) is unclear. OBJECTIVE: To investigate whether Ber ameliorates SCM in a rat model and its potential mechanism. MATERIALS AND METHODS: Male SD rats were randomly divided into three groups: control (Con, n = 6) (DD H2O, 2 mL/100 g, ig, qd × 3 d, then saline, 10 mg/kg, ip); sepsis [LPS (lipopolysaccharide), n = 18] (LPS 10 mg/kg instead of saline, ip); and berberine intervention (Ber, n = 18) (Ber, 50 mg/kg instead of DD H2O, ig, qd × 3 d, LPS instead of saline, ip). Hemodynamics, HE staining, ELISA and western blot were performed at 6, 24, and 48 h after intraperitoneal injection of LPS to evaluate the effect of berberine in septic rats. RESULT: Berberine could recover myocardial injury by partially increased ± dp/dt max (1151, 445 mmHg/s) and LVEDP levels (1.49 mmHg) with LPS-induced rats, as well as an ameliorated increase of cTnT (217.53 pg/mL) in the Ber group compared with that in the LPS group (at 24 h). In addition, HE staining results showed that berberine attenuated the myocardial cell swelling induced by LPS. In contrast to the LPS group, the up-regulation of TLR4, p65 TNF-α, and IL-1ß were attenuated in the Ber group. DISCUSSION AND CONCLUSIONS: Berberine showed a protective effect on septic cardiomyopathy rats possibly through inhibiting the activation of TLR4/NF-κB signalling pathway. Whether it improves SCM through other mechanisms is our ongoing research.
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Berberina/farmacologia , Cardiomiopatias/prevenção & controle , Sepse/tratamento farmacológico , Animais , Cardiomiopatias/etiologia , Modelos Animais de Doenças , Lipopolissacarídeos , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Receptor 4 Toll-Like/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
CNKI, PubMed and other databases were retrieved to extract eligible randomized controlled trial(RCT) about modified Xuefu Zhuyu Decoction(MXZD) combined with Western medicine(trial group) versus Western medicine alone(control group) in the treatment of leiomyoma. Therefore, a total of 25 RCTs were included, involving 2 328 patients. Bias risk evaluation tool in Cochrane Handbook 5.1.0 was used for evaluating the quality of these RCTs. Meta-analysis was performed for the reported indicators, including total efficiency, serum hormone level [progesterone(P), luteinizing hormone(LH), estradiol(E_2), follicle stimulating hormone(FSH)], uterine size, fibroids size and adverse reactions by using Stata 14.0 software. Meta-analysis showed that the total efficiency(RR=1.21,95%CI[1.17,1.25],P<0.05) of trial group was better than that of control group. Serum hormone level(WMD_P=-3.86,95%CI[-4.31,-3.41],P<0.05; WMD_(LH)=-3.64,95%CI[-4.47,-2.82],P<0.05; WMD_(E_2)=-39.99,95%CI[-53.45,-26.52],P<0.05; WMD_(FSH)=-3.79,95%CI[-4.86,-2.72],P<0.05), uterine size(WMD=-50.02,95%CI[-55.98,-44.06],P<0.05), fibroids size(WMD=-15.79,95%CI[-18.11,-13.46],P<0.05) and adverse reactions(RR=0.65,95%CI[0.48,0.88],P<0.05) of trial group were all lower than those of control group, with statistical significances. Trial sequential analysis(TSA) was performed by using TSA 0.9 software, and showed a reliable therapeutic effect of the experimental group. In short, our study indicated that modified Xuefu Zhuyu Decoction combined with Western medicine had a better therapeutic effect on leiomyoma than Western medicine alone, but more high-quality studies are needed to verify this conclusion in the future.
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Medicamentos de Ervas Chinesas , Leiomioma , Medicina , Humanos , Leiomioma/tratamento farmacológicoRESUMO
What is already known about this topic?: Climate change has had a detrimental impact on global health, particularly through the rise of extreme heatwaves. Presently, the early warning system for heatwave-related health risks can forecast potential dangers several days in advance; however, long-term warnings fall short. What is added by this report?: This report introduces a novel early warning system aimed at predicting heatwave-induced health risks in China at sub-seasonal to seasonal timescales. The outcomes of the assessment suggest this system holds significant potential. What are the implications for public health practices?: The system facilitates advanced assessment of both the scale and dispersal of risk among various demographic groups. This allows for the proactive management of potential risks with extended lead times.
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Introduction: Non-small cell lung cancer (NSCLC) patients are particularly vulnerable to the Coronavirus Disease-2019 (COVID-19). Currently, no anti-NSCLC/COVID-19 treatment options are available. As ginsenoside Rg3 is beneficial to NSCLC patients and has been identified as an entry inhibitor of the virus, this study aims to explore underlying pharmacological mechanisms of ginsenoside Rg3 for the treatment of NSCLC patients with COVID-19. Methods: Based on a large-scale data mining and systemic biological analysis, this study investigated target genes, biological processes, pharmacological mechanisms, and underlying immune implications of ginsenoside Rg3 for NSCLC patients with COVID-19. Results: An important gene set containing 26 target genes was built. Target genes with significant prognostic value were identified, including baculoviral IAP repeat containing 5 (BIRC5), carbonic anhydrase 9 (CA9), endothelin receptor type B (EDNRB), glucagon receptor (GCGR), interleukin 2 (IL2), peptidyl arginine deiminase 4 (PADI4), and solute carrier organic anion transporter family member 1B1 (SLCO1B1). The expression of target genes was significantly correlated with the infiltration level of macrophages, eosinophils, natural killer cells, and T lymphocytes. Ginsenoside Rg3 may benefit NSCLC patients with COVID-19 by regulating signaling pathways primarily involved in anti-inflammation, immunomodulation, cell cycle, cell fate, carcinogenesis, and hemodynamics. Conclusions: This study provided a comprehensive strategy for drug discovery in NSCLC and COVID-19 based on systemic biology approaches. Ginsenoside Rg3 may be a prospective drug for NSCLC patients with COVID-19. Future studies are needed to determine the value of ginsenoside Rg3 for NSCLC patients with COVID-19.
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Autophagy is a highly conserved bulk degradation mechanism that degrades damaged organelles, aged proteins and intracellular contents to maintain the homeostasis of the intracellular microenvironment. Activation of autophagy can be observed during myocardial injury, during which inflammatory responses are strongly triggered. Autophagy can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged mitochondria. In addition, autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged tissue. In this paper, we briefly review the role of autophagy in different cell types in the inflammatory microenvironment of myocardial injury and discuss the molecular mechanism of autophagy in regulating the inflammatory response in a series of myocardial injury conditions, including myocardial ischemia, ischemia/reperfusion injury and sepsis cardiomyopathy.
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Background: Heat events increase the risk of preterm birth (PTB), and identifying the risk-related event thresholds contributes to developing early warning system for pregnant women and guiding their public health response. However, the event thresholds that cause the risk remain unclear. We aimed to investigate the effects of heat events defined with different intensities and durations on PTB throughout pregnancy, and to determine thresholds for the high-risk heat events. Methods: Using a population-based birth cohort data, we included 210,798 singleton live births in eight provinces in China during 2014-2018. Daily meteorological variables and inverse distance weighted methods were used to estimate exposures at a resolution of 1 km × 1 km. A series of cut off temperature intensities (50th-97.5th percentiles, or 18 °C-35 °C) and durations (at least 1, 2, 3, 4 or 5 consecutive days) were used to define the heat events. Cox regression models were used to estimate the effects of heat events on PTB in various gestational weeks during the entire pregnancy, and event thresholds were determined by calculating population attributable fractions. Findings: The hazard ratios of heat event exposure on PTB ranged from 1.07 (95% CI: 1.00, 1.13) to 1.43 (1.15, 1.77). Adverse effects of heat event exposure were prominently detected in gestational week 1-4, week 21-32 and the four weeks before delivery. The heat event thresholds were determined to be daily maximum temperature at the 90th percentile of the distribution or 30 °C lasting for at least one day. If pregnant women were able to avoid the heat exposures from the early warning systems triggered by these thresholds, approximately 15% or 17% of the number of total PTB cases could have been avoided. Interpretation: Exposure to heat event can increase the risk of PTB when thermal event exceeds a specific intensity and duration threshold, particularly in the first four gestational weeks, and between week 21 and the last four weeks. This study provides compelling evidence for the development of heat-health early warning systems for pregnant women that could substantially mitigate the risk of PTB. Funding: National Key R&D Program of China (No. 2018YFA0606200), National Natural Science Foundation of China (No. 42175183), Sanming Project of Medicine in Shenzhen (No. SZSM202111001).
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With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital factor affecting the survival of patients with breast cancer. Anthracyclines, such as doxorubicin, are still some of the most effective chemotherapeutic agents, but their resulting cardiotoxicity is generally considered to be progressive and irreversible. In addition to anthracyclines, platinum- and alkyl-based antitumor drugs also demonstrate certain cardiotoxic effects. Targeted drugs have always been considered a relatively safe option. However, in recent years, some random clinical trials have observed the occurrence of subclinical cardiotoxicity in targeted antitumor drug users, which may be related to the effects of targeted drugs on the angiotensin converting enzyme, angiotensin receptor and ß receptor. The use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers may prevent clinical cardiotoxicity. This article reviews the toxicity and mechanisms of current clinical anti-breast cancer drugs and proposes strategies for preventing cardiovascular toxicity to provide recommendations for the clinical prevention and treatment of chemotherapy-related cardiomyopathy.
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Neoplasias da Mama , Cardiomiopatias , Humanos , Feminino , Cardiotoxicidade , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Doxorrubicina/efeitos adversos , AntraciclinasRESUMO
Psoriasis (PSO) is a common skin disease affecting approximately 1%-3% of the population, and the incidence rate is increasing yearly. PSO is associated with a dramatically increased risk of cardiovascular disease, the most common of which is atherosclerosis (AS). In the past, inflammation was considered to be the triggering factor of the two comorbidities, but in recent years, studies have found that lipid metabolism disorders increase the probability of atherosclerosis in patients with psoriasis. In this review, we discuss epidemiological studies, clinical treatment methods, risk factors, and lipid metabolism of psoriasis and atherosclerosis comorbidities.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the leading cause of coronavirus disease-2019 (COVID-19), is an emerging global health crisis. Lung cancer patients are at a higher risk of COVID-19 infection. With the increasing number of non-small-cell lung cancer (NSCLC) patients with COVID-19, there is an urgent need of efficacious drugs for the treatment of COVID-19/NSCLC. Methods: Based on a comprehensive bioinformatic and systemic biological analysis, this study investigated COVID-19/NSCLC interactional hub genes, detected common pathways and molecular biomarkers, and predicted potential agents for COVID-19 and NSCLC. Results: A total of 122 COVID-19/NSCLC interactional genes and 21 interactional hub genes were identified. The enrichment analysis indicated that COVID-19 and NSCLC shared common signaling pathways, including cell cycle, viral carcinogenesis, and p53 signaling pathway. In total, 10 important transcription factors (TFs) and 44 microRNAs (miRNAs) participated in regulations of 21 interactional hub genes. In addition, 23 potential candidates were predicted for the treatment of COVID-19 and NSCLC. Conclusion: This study increased our understanding of pathophysiology and screened potential drugs for COVID-19 and NSCLC.
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This work aimed to reflect the advancements in water-related science, technology, and policy and shed light on future research opportunities related to water through a systematic overview of Water Research articles published in the first 21.5 years of the 21st century. Specific bibliometric analyses were performed to i) reveal the temporal and spatial trends of water-related research themes and ii) identify the underlying connections between research topics. The results showed that while top topics including wastewater (treatment), drinking water, adsorption, model, biofilm, and bioremediation remained constantly researched, there were clear shifts in topics over the years, leading to the identification of trending-up and emerging research topics. Compared to the first decade of the 21st century, the second decade not only experienced significant uptrends of disinfection by-products, anaerobic digestion, membrane bioreactor, advanced oxidation processes, and pharmaceuticals but also witnessed the emerging popularity of PFAS, anammox, micropollutants, emerging contaminants, desalination, waste activated sludge, microbial community, forward osmosis, antibiotic resistance genes, resource recovery, and transformation products. On top of the temporal evolution, distinct spatial evolution existed in water-related research topics. Microplastics and Covid-19 causing global concerns were hot topics detected, while metagenomics and machine learning were two technical approaches emerging in recent years. These consistently popular, trending-up and emerging research topics would most likely attract continuous/increasing research input and therefore constitute a major part of the prospective water-related research publications.
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Bibliometria , COVID-19 , Água Potável , Humanos , Plásticos , Estudos Prospectivos , Águas ResiduáriasRESUMO
Bladder cancer(BC)is one of the most common urinary system tumors, which characterized by a high incidence. Polyporus polysaccharide is the main active component of polyporus, which is clinically used in the treatment of bladder cancer, but the mechanism is not clear. In previous study, we isolated homogeneous polyporus polysaccharide(HPP) with high purity from polyporus. The goal of this study was to assess the polarization of macrophages induced by HPP in the bladder tumor microenvironment and explored its anti-bladder cancer mechanism through BBN bladder cancer rat model and Tumor associated macrophages(TAM). The results suggested that HPP regulates TAM polarization to improve the tumor inflammatory microenvironment, possibly through the NF-κB/NLRP3 signaling pathway. Our results suggested that HPP may be a potential therapeutic agent for bladder tumors.
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Polyporus , Neoplasias da Bexiga Urinária , Animais , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Polyporus/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Ratos , Transdução de Sinais , Microambiente Tumoral , Macrófagos Associados a Tumor , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismoRESUMO
Context: Maternal lipid levels affect birthweight and the long-term health of the offsprings. However, this association could be influenced by genetic and other common factors. Objective: This work aimed to explore the relationship between maternal lipid levels and birthweight of two pregnancies in the same mother. Methods: In this population-based cohort study, 705 women and their 1 410 offsprings were included. From an initial sample of women with more than one singleton birth in the database, we made the following exclusions: missing data for pre-pregnancy BMI, pregnancy weight gain, birthweight and lipid values; maternal age less than 19 or older than 44 years old; gestational age < 37 weeks or > 41weeks, gestational diabetes mellitus/diabetic. In the second and third trimesters, serum samples were collected for the determination of fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels. Then we assessed the association between maternal lipids and birthweight. Results: Infants of women whose 2nd-trimester TC increased by 10th-20th percentile (-0.92~-0.56 mmol/L) from 1st to 2nd pregnancy were 239.69 (62.32~417.06) g lighter at birth than were infants of women those of 40th-50th percentile (-0.20~-0.03 mmol/L). Parity, gestational age, neonatal gender, maternal pre-pregnancy body mass index, maternal weight gain, and 3rd-trimester TC and HDL-C were all associated with higher birth weight. Every unit increase in TC in the third trimester increases birthweight by 53.13 (14.32 ~91.94) g. Conclusion: Maternal TC level is associated with birthweight independent of shared genes. TC may be used to guide diet and predict birthweight combined with ultrasound and other indicators.
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Ganho de Peso na Gestação , Adulto , Peso ao Nascer , HDL-Colesterol , LDL-Colesterol , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , TriglicerídeosRESUMO
Frequent heatwaves under global warming can increase the risk of preterm birth (PTB), which in turn will affect physical health and human potential over the life course. However, what remains unknown is the extent to which anthropogenic climate change has contributed to such burdens. We combine health impact and economic assessment methods to comprehensively evaluate the entire heatwave-related PTB burden in dimensions of health, human capital and economic costs. Here, we show that during 2010-2020, an average of 13,262 (95%CI 6,962-18,802) PTBs occurred annually due to heatwave exposure in China. In simulated scenarios, 25.8% (95%CI 17.1%-34.5%) of heatwave-related PTBs per year on average can be attributed to anthropogenic climate change, which further result in substantial human capital losses, estimated at over $1 billion costs. Our findings will provide additional impetus for introducing more stringent climate mitigation policies and also call for more sufficient adaptations to reduce heatwave detriments to newborn.
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Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Nascimento Prematuro/epidemiologia , Mudança Climática , Aquecimento Global , China/epidemiologiaRESUMO
Acute myocardial infarction is a major global health problem, and the repair of damaged myocardium is still a major challenge. Myocardial injury triggers an inflammatory response: immune cells infiltrate into the myocardium while activating myofibroblasts and vascular endothelial cells, promoting tissue repair and scar formation. Fragments released by cardiomyocytes become endogenous "danger signals", which are recognized by cardiac pattern recognition receptors, activate resident cardiac immune cells, release thrombin factors and inflammatory mediators, and trigger severe inflammatory responses. Inflammatory signaling plays an important role in the dilation and fibrosis remodeling of the infarcted heart, and is a key event driving the pathogenesis of post-infarct heart failure. At present, there is no effective way to reverse the inflammatory microenvironment in injured myocardium, so it is urgent to find new therapeutic and diagnostic strategies. Nanomedicine, the application of nanoparticles for the prevention, treatment, and imaging of disease, has produced a number of promising applications. This review discusses the treatment and challenges of myocardial injury and describes the advantages of functional nanoparticles in regulating the myocardial inflammatory microenvironment and overcoming side effects. In addition, the role of inflammatory signals in regulating the repair and remodeling of infarcted hearts is discussed, and specific therapeutic targets are identified to provide new therapeutic ideas for the treatment of myocardial injury.
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Psoriasis is an immune-mediated, persistent inflammatory disease with a genetic predisposition, and the involvement of multiple organs in psoriasis remains indicative of systemic disease. Atherosclerosis (AS) is a common complication of patients with severe or prolonged psoriasis. The specific pathogenesis of psoriasis is still unclear. Current studies suggest that psoriasis is a polygenic genetic disease with the interaction of multiple factors such as heredity and environment. Keratinocytes are proliferated through immune-mediated inflammatory pathway, which leads to cell activation, infiltration of dermis cells and release of inflammatory factors. Activation of inflammatory cells and pro-inflammatory factors play an important role in the progression of psoriasis and atherosclerosis. Studies have found that there is a close relationship between psoriasis and atherosclerosis, and systemic inflammation may be the common feature of psoriasis and AS. This paper attempts to explore the possibility of the relationship between psoriasis and atherosclerotic comorbidities from the aspects of potential epidemiology and immune mechanism, in order to provide some reference for the subsequent scientific research.
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Aterosclerose , Psoríase , Humanos , Comorbidade , Queratinócitos , InflamaçãoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease synthesized primarily by the liver. It mainly promotes the degradation of low-density lipoprotein receptor (LDL-R) by binding LDL-R, reducing low-density lipoprotein cholesterol (LDL-C) clearance. In addition to regulating LDL-R, PCSK9 inhibitors can also bind Toll-like receptors (TLRs), scavenger receptor B (SR-B/CD36), low-density lipoprotein receptor-related protein 1 (LRP1), apolipoprotein E receptor-2 (ApoER2) and very-low-density lipoprotein receptor (VLDL-R) reducing the lipoprotein concentration and slowing thrombosis. In addition to cardiovascular diseases, PCSK9 is also used in pancreatic cancer, sepsis, and Parkinson's disease. Currently marketed PCSK9 inhibitors include alirocumab, evolocumab, and inclisiran, as well as small molecules, nucleic acid drugs, and vaccines under development. This review systematically summarized the application, preclinical studies, safety, mechanism of action, and latest research progress of PCSK9 inhibitors, aiming to provide ideas for the drug research and development and the clinical application of PCSK9 in cardiovascular diseases and expand its application in other diseases.
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Doenças Cardiovasculares , Ácidos Nucleicos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/metabolismo , Humanos , Lipoproteínas VLDL , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Pró-Proteína Convertase 9/metabolismo , SubtilisinasRESUMO
BACKGROUND: Although 5-aminolevulinic acid photodynamic therapy (ALA-PDT) has been extensively used to treat various skin diseases, application for the treatment of cutaneous infection caused by Mycobacterium marinum (M. marinum), especially drug-resistant M. marinum, is unclear. OBJECTIVES: We evaluated the efficacy of ALA-PDT on M. marinum in a mouse infection model and tested its killing effect on M. marinum in vitro. We also investigated the clinical effect of ALA-PDT on cutaneous granuloma caused by drug-resistant M. marinum. MATERIALS AND METHODS: A total of 9 M. marinum strains isolated from patients were tested for anti-mycobacterial susceptibility. The effects of ALA-PDT on M. marinum in vitro and in mice model were investigated. Therapeutic efficacy was further assessed in two patients with cutaneous granuloma caused by drug- resistant M. marinum. RESULTS: We demonstrated that ALA-PDT directly killed M. marinum in vitro. The cutaneous lesions on mouse paws caused by M. marinum were fully recovered 4 weeks after the ALA-PDT treatment. ALA-PDT was also effective in two patients with cutaneous infection caused by drug-resistant M. marinum. The level of intracellular ROS in M. marinum treated with ALA-PDT was significantly higher than that of M. marinum alone. CONCLUSIONS: The results suggest that ALA-PDT is effective in treating M. marinum cutaneous infections by releasing more reactive oxygen species to kill M. marinum directly, and these effects are independent of systemic immune responses. The data highlights that ALA-PDT is a promising therapeutic choice for treatment of M. marinum cutaneous infections, especially drug-resistant M. marinum infections.
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Mycobacterium marinum , Fotoquimioterapia , Neoplasias Cutâneas , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Animais , Granuloma/tratamento farmacológico , Humanos , Camundongos , Infecções por Mycobacterium não Tuberculosas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Background: In China, most previous projections of heat-related mortality have been based on modeling studies using global climate models (GCMs), which can help to elucidate the risks of extreme heat events in a changing climate. However, spatiotemporal changes in the health effects of climate change considering specific regional characteristics remain poorly understood. We aimed to use credible climate and population projections to estimate future heatwave-attributable deaths under different emission scenarios and to explore the drivers underlying these patterns of changes. Methods: We derived climate data from a regional climate model driven by three CMIP5 GCM models and calculated future heatwaves in China under Representative Concentration Pathway (RCP) 2.6, RCP4.5, and RCP8.5. The future gridded population data were based on Shared Socioeconomic Pathway 2 assumption with different fertility rates. By applying climate zone-specific exposure-response functions to mortality during heatwave events, we projected the scale of heatwave-attributable deaths under each RCP scenario. We further analyzed the factors driving changes in heatwave-related deaths and main sources of uncertainty using a decomposition method. We compared differences in death burden under the 1.5°C target, which is closely related to achieving carbon neutrality by mid-century. Findings: The number of heatwave-related deaths will increase continuously to the mid-century even under RCP2.6 and RCP4.5 scenarios, and will continue increasing throughout the century under RCP8.5. There will be 20,303 deaths caused by heatwaves in 2090 under RCP2.6, 35,025 under RCP4.5, and 72,260 under RCP8.5, with half of all heatwave-related deaths in any scenario concentrated in east and central China. Climate effects are the main driver for the increase in attributable deaths in the near future till 2060, explaining 78% of the total change. Subsequent population decline cannot offset the losses caused by higher incidence of heatwaves and an aging population under RCP8.5. Although health loss under the 1.5°C warming scenario is 1.6-fold higher than the baseline period 1986-2005, limiting the temperature rise to 1.5°C can reduce the annual mortality burden in China by 3,534 deaths in 2090 compared with RCP2.6 scenarios. Interpretation: With accelerating climate change and population aging, the effects of future heatwaves on human health in China are likely to increase continuously even under a low emission scenario. Significant health benefits are expected if the optimistic 1.5°C goal is achieved, suggesting that carbon neutrality by mid-century is a critical target for China's sustainable development. Policymakers need to tighten climate mitigation policies tailored to local conditions while enhancing climate resilience technically and infrastructurally, especially for vulnerable elderly people. Funding: National Key R&D Program of China (2018YFA0606200), Wellcome Trust (209734/Z/17/Z), Natural Science Foundation of China (41790471), and Guangdong Major Project of Basic and Applied Basic Research (2020B0301030004).