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BACKGROUND: Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. METHODS: Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. RESULTS: Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. CONCLUSIONS: PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.
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Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Inflamação/metabolismo , Microcirculação , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Neutrófilos/metabolismoRESUMO
Findings from observational studies have suggested a possible association between dietary inflammatory index (DII) and risk of gestational diabetes mellitus (GDM) and preeclampsia (PE). However, the results of these studies were inconclusive. A systematic review and meta-analysis was carried out to illuminate this association. Systematic literature search was conducted in PubMed, Web of Science, Cochrane Library, EMBASE, Scopus and other databases from inception until January 2023. The qualities of included studies were assessed using the Newcastle-Ottawa scale. Nine studies (seven cohort, two case-control) were included in the meta-analysis, including 11 423 participants from five different countries. The meta-analysis indicated that a 1-unit increase in the DII score, representing pro-inflammatory diet, was associated with 13 % higher risk of GDM (OR = 1·13; 95 % CI 1·02, 1·25, I2 = 68·4 %, P = 0·004) and 24 % higher risk of PE (OR = 1·24; 95 % CI 1·14, 1·35, I2 = 52·0 %, P = 0·125). Subgroup analysis found that this association was evident among studies with Chinese populations (OR = 1·16; 95 % CI 1·06, 1·28) and studies with mid pregnancy (OR = 1·20; 95 % CI 1·07, 1·34). The findings indicate that pro-inflammatory diet can increase the risk of GDM and PE. Considering some limitations in this study, more studies are needed to verify this association.
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Diabetes Gestacional , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Diabetes Gestacional/etiologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Dieta/efeitos adversosRESUMO
Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.
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BACKGROUND AND AIM: Evidence from prospective cohort studies has revealed an inverse association between cheese consumption and the development of atherosclerosis (AS), atherosclerotic cardiovascular diseases (ASCVD), and their complications. However, it remains unclear whether this observed association is influenced by potential confounding factors that may arise during the long-term development process of AS, ASCVD, and its complications. Therefore, to further clarify the causal relationship between cheese consumption and AS, ASCVD, and its complications, we conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between cheese intake and the aforementioned health outcomes. METHODS AND RESULTS: We employed a two-sample MR analysis based on publicly available genome-wide association studies (GWAS) to infer the causal relationship, with no overlap between their participating populations. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Sensitivity analyses were conducted using Cochran's Q statistic, funnel plot, leave-one-out analysis, and MR-Egger intercept tests. The genetically predicted cheese intake was found to be associated with lower risks of coronary AS (odds ratio [OR] = 0.72, 95 % confidence interval [CI] 0.59-0.88, P = 0.001), peripheral vascular AS (OR = 0.56, 95 % CI 0.37-0.84, P = 0.006), other vascular AS (OR = 0.66, 95 % CI 0.44-0.99, P = 0.043), coronary artery disease (OR = 0.64, 95 % CI 0.56-0.74, P = 1.57e-09), angina pectoris (OR = 0.70, 95 % CI 0.58-0.84, P = 4.92e-05), myocardial infarction (OR = 0.63, 95 % CI 0.52-0.77, P = 3.56e-06), heart failure (OR = 0.62, 0.49-0.79, P = 1.20e-04), total ischemic stroke (OR = 0.76, 95 % CI 0.63-0.91, P = 0.003), peripheral artery disease (OR = 0.64, 95 % CI 0.43-0.95, P = 0.028), and cognitive impairment (OR = 0.65, 95 % CI 0.56-0.74, P = 3.40e-10). However, no associations were observed for cerebrovascular AS, arrhythmia, cardiac death, ischemic stroke (large artery AS), ischemic stroke (small vessel), ischemic stroke (cardioembolic), and transient ischemic attack. CONCLUSION: This two-sample MR analysis reveals a causally inverse association between cheese intake and multi-vascular AS (including coronary AS, peripheral vascular AS, and other vascular AS), as well as multiple types of ASCVD and its complications (such as coronary artery disease, angina pectoris, myocardial infarction, heart failure, total ischemic stroke, and peripheral artery disease). The findings from this study may lay a stronger theoretical foundation and present new opportunities for the dietary management of future atherosclerotic cardiovascular diseases.
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Aterosclerose , Doenças Cardiovasculares , Queijo , Doença da Artéria Coronariana , Insuficiência Cardíaca , AVC Isquêmico , Infarto do Miocárdio , Doença Arterial Periférica , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Estudos Prospectivos , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/genética , Angina PectorisRESUMO
Abnormal plasma uric acid (UA) levels, the lipid profile, and plasma proteins in blood are associated with a range of adverse health outcomes. This multicenter, prospective cohort study aimed to determine the possible effects of multiple apheresis plasma donations on plasma UA levels, the lipid profile, and major proteins in plasma donors. Participants were enrolled from 1 April 2021 to 31 August 2022. When their plasma UA (men: >420 µmol/L, women: >360 µmol/L) and/or lipid levels (total cholesterol [TC]: ≥6.2 mmol/L, triglycerides [TGs]: ≥2.3 mmol/L, low-density lipoprotein cholesterol: ≥4.1 mmol/L, or high-density lipoprotein cholesterol [HDL-C]: <1.0 mmol/L) were abnormal at their first plasma donation, the enrolled participants were followed up until they had completed 10 plasma donations. A total of 11485 participants were enrolled, of whom 1861 met the inclusion criteria. During the study period, 320 donors completed 10 plasma donations. None of the participants took any corrective medicine for their abnormal index. The measured parameters were significantly different from the first to the tenth plasma donations (donors with asymptomatic hyperuricemia: UA, P < 0.001; donors with asymptomatic hyperlipidemia: HDL-C, P < 0.001; TC, P = 0.025; TGs, P < 0.001; apolipoprotein B, P = 0.025; all of the plasma donors, immunoglobulin G, P < 0.001). The levels of HDL-C, TC, and apolipoprotein B were increased, and the levels of UA, TGs, and immunoglobulin G were decreased over this time. However, immunoglobulin G levels were still in the normal range. Moreover, the changes in these parameters were closely associated with the frequency of plasma donation during the study period. Repeated apheresis plasma donations can reduce plasma UA and TG levels and increase HDL-C levels; and further evaluation of the clinical significance with a larger sample size is required.
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Remoção de Componentes Sanguíneos , Doadores de Sangue , Proteínas Sanguíneas , Lipídeos , Ácido Úrico , Humanos , Ácido Úrico/sangue , Feminino , Masculino , Estudos Prospectivos , Remoção de Componentes Sanguíneos/métodos , China , Adulto , Lipídeos/sangue , Pessoa de Meia-Idade , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Plasma/metabolismo , Doação de SangueRESUMO
BACKGROUND: Obesity and postprandial hypertriglyceridemia, characterized by an increase in triglyceride-rich lipoproteins (TRLs), cause chronic low-grade inflammation. It is unclear how postprandial TRLs affect inflammation in white adipocytes. OBJECTIVES: The objectives of the study were to explore the inflammatory response of postprandial TRLs in white adipocytes and investigate the possible mechanism. METHODS: We measured postprandial triglyceride (TG) and high-sensitivity C-reactive protein (hsCRP) concentrations in 204 recruited subjects and treated white adipocytes from mice with postprandial TRLs from above patients with hypertriglyceridemia. RESULTS: Serum hsCRP concentrations and BMI were positively related to TG concentrations in the postprandial state. Postprandial TRLs increased mRNA and protein expression of inflammatory factors, including interleukin-1ß, via the NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway, and impaired autophagy flux in white adipocytes of mice. TRLs also induced lysosomal damage as evidenced by the reduced protein expression of lysosome-associated membrane proteins-1 and Cathepsin L. Inhibition of Cathepsin B, NLRP3, and mTOR signaling improved autophagy/lysosome dysfunction and inhibited the activation of the NLRP3/Caspase-1 pathway and inflammatory factors induced by TRLs in white adipocytes. CONCLUSIONS: Our results suggest that postprandial hypertriglyceridemia causes chronic inflammation in adipocytes through TRL-induced lysosomal dysfunction and impaired autophagic flux in an mTOR-dependent manner.
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Next-generation sequencing (NGS) technologies have changed the landscape of genetic testing in rare diseases. However, the rapid evolution of NGS technologies has outpaced its clinical adoption. Here, we re-evaluate the critical steps in the clinical application of NGS-based genetic testing from an informatics perspective. We suggest a 'fit-for-purpose' triage of current NGS technologies. We also point out potential shortcomings in the clinical management of genetic variants and offer ideas for potential improvement. We specifically emphasize the importance of ensuring the accuracy and reproducibility of NGS-based genetic testing in the context of rare disease diagnosis. We highlight the role of artificial intelligence (AI) in enhancing understanding and prioritization of variance in the clinical setting and propose deep learning frameworks for further investigation.
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Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Raras/diagnóstico , Doenças Raras/genética , Inteligência Artificial , Testes Genéticos/métodos , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
Highly selective and sensitive H2 S sensors are in high demand in various fields closely related to human life. However, metal oxide semiconductors (MOSs) suffer from poor selectivity and single MOS@metal organic framework (MOF) core-shell nanocomposites are greatly limited due to the intrinsic low sensitivity of MOF shells. To simultaneously improve both selectivity and sensitivity, heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell nanowires (NWs) are meticulously synthesized with the assistance of atomic layer deposition. The ZIF-8 shell with regular pores and special surface functional groups is attractive for excellent selectivity and the heterostructured α-Fe2 O3 @ZnO core with an additional electron depletion layer is promising with enhanced sensitivity compared to a single MOS core. As a result, the heterostructured α-Fe2 O3 @ZnO@ZIF-8 core-shell NWs achieve remarkable H2 S sensing performance with a high response (Rair /Rgas = 32.2 to 10 ppm H2 S), superior selectivity, fast response/recovery speed (18.0/31.8 s), excellent long-term stability (at least over 3 months), and relatively low limit of detection (down to 200 ppb) at low operating temperature of 200 °C, far beyond α-Fe2 O3 @ZIF-8 or α-Fe2 O3 @ZnO core-shell NWs. Furthermore, a micro-electromechanical system-based H2 S gas sensor system with low power consumption is developed, holding great application potential in smart cities.
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BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. METHODS: The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. RESULTS: High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. CONCLUSION: WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Camundongos , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases , Proteína Fosfatase 2C/genética , Proteína Fosfatase 2C/metabolismo , Mutações Sintéticas LetaisRESUMO
Stretchable strain sensor, an important paradigm of wearable sensor which can be attached onto clothing or even human skin, is widely used in healthcare, human motion monitoring and human-machine interaction. Pattern-available and facile manufacturing process for strain sensor is pursued all the time. A carbon nanotube (CNT)/silver nanowire (AgNW)-based stretchable strain sensor fabricated by a facile process is reported here. The strain sensor exhibits a considerable Gauge factor of 6.7, long-term durability (>1000 stretching cycles), fast response and recovery (420 ms and 600 ms, respectively), hence the sensor can fulfill the measurement of finger movement. Accordingly, a smart glove comprising a sensor array and a flexible printed circuit board is assembled to detect the bending movement of five fingers simultaneously. Moreover, the glove is wireless and basically fully flexible, it can detect the finger bending of wearer and display the responses distinctly on an APP of a smart phone or a host computer. Our strain senor and smart glove will broaden the materials and applications of wearable sensors.
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Nanotubos de Carbono , Nanofios , Dispositivos Eletrônicos Vestíveis , Humanos , Movimento , PrataRESUMO
Sinoacutine is a natural isoquinoline alkaloid isolated from traditional Chinese medicine Stephanina yunnanensis H. S. Lo. Our aim was to study the pharmacokinetic characteristics of sinoacutine, which is essential during the development of new drugs.In this study, an accurate, sensitive, and efficient liquid chromatography (HPLC) method was developed and applied to evaluate the pharmacokinetics, tissue distribution, plasma protein binding rate, and excretion after intravenous injection of sinoacutine in rats.The pharmacokinetic parameters of sinoacutine were accorded with a two-compartment model in rats, and the AUC0-t in female was greater than that in male. Sinoacutine could be detected in heart, liver, spleen, lung, kidney, and brain, and the content in liver and kidney was relatively high. Meanwhile, it had a high plasma protein binding rate of 79.16%. Excretion of sinoacutine through faeces and urine was low, and the average excretion rate was 9.96%. There were gender differences in blood drug concentration, tissue distribution, and excretion significantly (p < 0.05).In summary, this study lays a foundation for elucidating the pharmacokinetic rule of sinoacutine and the data can provide a reliable scientific resource for further research.
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Distribuição Tecidual , Administração Intravenosa , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Injeções Intravenosas , Masculino , Morfinanos , Ligação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The aim of this study was to investigate the relationship between dietary n-6: n-3 poly-unsaturated fatty acids (PUFA) ratio and the risk of developing gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A total of 100 pregnant women were prospectively included for detailed information on dietary intake at 16-18 weeks evaluated using a three-day food record, and subsequent GDM diagnosis at 24-28 weeks. Participants were divided into two groups for analysis: GDM group (n = 22) and control group (n = 78) based on oral glucose tolerance test results performed between 24 and 28 weeks. RESULTS: The average dietary n-6: n-3 PUFA ratio in the control group was 5.63 ± 2.12 and that in the GDM group was 8.35 ± 3.45, within a significant difference (p < .05). A significant difference was associated with a higher dietary n-6: n-3 PUFA ratio and GDM (adjusted odds ratio = 4.29, 95%confidence interval:1.303, 14.124). CONCLUSIONS: Higher dietary n-6: n-3 PUFA ratio was associated with higher odds of GDM. Given the small sample, further studies are required to confirm this hypothesis.
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Diabetes Gestacional , Ácidos Graxos Ômega-3 , Dieta , Feminino , Teste de Tolerância a Glucose , Humanos , Gravidez , Estudos ProspectivosRESUMO
Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.
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Anti-Inflamatórios , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Descoberta de Drogas , Prostaglandinas/fisiologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Infarto do Miocárdio/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Prostaglandina-E Sintases/efeitos dos fármacos , Prostaglandinas/biossíntese , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Remodelação VascularRESUMO
BACKGROUND The demand for plasma and plasma products has increased in China, which has a short supply. Compared with whole blood donors, plasma donors and their donation behavior have received less attention. This study aimed to investigate the demographic characteristics and lifestyle habits of Chinese plasma donors. MATERIAL AND METHODS During 2018-2019, information on plasma donors was collected from blood product companies using a 25-item questionnaire, including sex, age, height, weight, blood group, donation frequency, occupation, smoking and drinking, and sleeping and dietary habits. RESULTS Among 15 497 plasma donors, 70.5% were women and 78.5% were aged 46-55 years. Among 4847 plasma donors, the average height of men was 169.5±6.2 cm and the average height of women was 157.0±4.6 cm. In addition, the average weight of men was 67.0±10.4 kg and the average weight of women was 60.0±8.3 kg. The prevalence of obesity (body mass index ≥30.0 kg/m²) of all donors was 14.8%; 14.7% of men were obese, and 15% of women were obese. Among all plasma donors, 88.8% were farmers and 60% were frequent donors with a donation history of at least 5 years. Among all donors, 84.0% did not smoke, 67.3% did not drink, and 95.1% reported good sleep quality. All respondents reported healthy dietary habits. CONCLUSIONS Healthy lifestyle habits considerably affect the health of plasma donors and the quality of source plasma. Chinese plasma donors in this study demonstrated imbalances in terms of characteristics, which became more marked with age.
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Consumo de Bebidas Alcoólicas/epidemiologia , Doadores de Sangue/estatística & dados numéricos , Índice de Massa Corporal , Comportamento Alimentar , Estilo de Vida , Fumar/epidemiologia , Adolescente , Adulto , China/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
Coronary artery disease (CAD) is a high-incidence of heart disease. We aimed to identify potential biomarkers linked to the progression of CAD using multiple sets of data mining analysis methods. The long noncoding RNA (lncRNA) + messenger RNA (mRNA) data set GSE113079 and microRNA (miRNA) data set GSE28858 were downloaded from Gene Expression Omnibus. After data preprocessing, differentially expressed mRNA, lncRNA, and miRNA were identified using limma software. In addition, weighted gene co-expression network analysis (WGCNA) was used for the construction and screening of modules related to disease states. Besides, key mRNAs and lncRNAs were extracted for protein-protein interaction (PPI) network construction and lncRNA-mRNA co-expression analysis. Additionally, the final integration resulted in the lncRNA-miRNA-mRNA relationship pairs (competing endogenous RNA (ceRNA) network). Finally, CTD 2020 update database was used for the verification of the expression level of the candidate genes. A total of 1319 differentially expressed mRNAs and 1983 lncRNAs were screened. After WGCNA, a total of 234 mRNAs and 546 lncRNAs were identified. A PPI network including 127 mRNA corresponding proteins was constructed. The ceRNA network included 24 up-regulated lncRNAs, 16 down-regulated miRNAs, and 42 up-regulated mRNAs. Through the validation of CTD 2020 update database, 21 CAD related mRNAs, and four important ceRNAs those may be participated in the pathogenesis of CAD were obtained. In this study, through multiple sets of data mining methods, the regulatory relationship of lncRNA, miRNA, and mRNA was comprehensively analyzed, and the important role of lncRNA-miRNA-mRNA in the pathogenesis of CAD was emphasized.
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Doença da Artéria Coronariana/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Doença da Artéria Coronariana/genética , Mineração de Dados , Conjuntos de Dados como Assunto , Regulação para Baixo , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mapas de Interação de Proteínas , Regulação para CimaRESUMO
The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrateï¼fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstlyï¼the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondlyï¼tumor stromal cells including adipocyteï¼fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdlyï¼the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistanceï¼in terms of transportersï¼tumor microenvironment and metabolic enzymesï¼to provide insight for improving the therapeutic efficacy for drug-resistant tumors.
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Glutamina , Neoplasias , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Glutamina/metabolismo , Glicólise , Humanos , Neoplasias/tratamento farmacológico , Fosforilação Oxidativa , Microambiente TumoralRESUMO
Neointimal formation and atherogenesis are major vascular complications following percutaneous coronary intervention, and there is lack of pharmacological therapy. This study was aimed to examine the effect of forskolin (FSK), a cyclic adenosine monophosphate (cAMP)-elevating agent, on vascular response to angioplasty wire injury and on atherogenesis in mice. Forskolin treatment reduced neointima formation at 7 and 28 days after wire injury. Early morphometrics of the injured vessels revealed that FSK treatment enhanced endothelial repair and reduced inflammatory cell infiltration. In vitro treatment of primary aortic cells with FSK, at 3-100 µmol/L, increased endothelial cell proliferation, whereas FSK, at 30-100 µmol/L, inhibited smooth muscle cell proliferation. FSK inhibited lipopolysaccharide-induced leucocyte-endothelial interaction in vitro and in vivo. In a mouse model of atherosclerosis driven by dyslipidaemia and hypertension, FSK administration increased endothelial repair and reduced atherosclerotic plaque formation, without affecting blood pressure, plasma lipids or aortic aneurysms formation. In summary, FSK, at doses relevant to human therapeutic use, protects against neointimal hyperplasia and atherogenesis, and this is attributable to its activities on pro-endothelial repair and anti-inflammation. This study raises a potential of clinical use of FSK as an adjunct therapy to prevent restenosis and atherosclerosis after percutaneous coronary intervention.
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Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Colforsina/farmacologia , AMP Cíclico/metabolismo , Neointima/tratamento farmacológico , Neointima/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Medicina/métodos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. METHODS: HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APCmin/+ and APCmin/+ HSF1+/-mice. RESULTS: HSF1 expression and activity were reduced after the inhibition of WNT/ß-catenin signaling by pyrvinium or ß-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or ß-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with ß-catenin expression in cell lines and primary tissues. After ß-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3'-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued ß-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APCmin/+ mice when HSF1 was genetically knocked-out or chemically inhibited. CONCLUSIONS: ß-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for ß-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of ß-catenin-driven cancers.
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Adenosina/análogos & derivados , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição de Choque Térmico/genética , MicroRNAs/genética , RNA Mensageiro/genética , beta Catenina/metabolismo , Adenosina/metabolismo , Animais , Apoptose/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Humanos , Metilação , Camundongos , Modelos Biológicos , Biossíntese de Proteínas , Interferência de RNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In vitro toxicogenomics (TGx) has the potential to replace or supplement animal studies. However, TGx studies often suffer from a limited sample size and cell types. Meanwhile, transcriptomic data have been generated for tens of thousands of compounds using cancer cell lines mainly for drug efficacy screening. Here, we asked the question of whether these types of transcriptomic data can be used to support toxicity assessment. We compared transcriptomic profiles from three cancer lines (HL60, MCF7, and PC3) from the CMap data set with those using primary hepatocytes or in vivo repeated dose studies from the Open TG-GATEs database by using our previously reported pair ranking (PRank) method. We observed an encouraging similarity between HL60 and human primary hepatocytes (PRank score = 0.70), suggesting the two cellular assays could be potentially interchangeable. When the analysis was limited to drug-induced liver injury (DILI)-related compounds or genes, the cancer cell lines exhibited promise in DILI assessment in comparison with conventional TGx systems (i.e., human primary hepatocytes or rat in vivo repeated dose). Also, some toxicity-related pathways, such as PPAR signaling pathways and fatty acid-related pathways, were preserved across various assay systems, indicating the assay transferability is biological process-specific. Furthermore, we established a potential application of transcriptomic profiles of cancer cell lines for studying immune-related biological processes involving some specific cell types. Moreover, if PRank analysis was focused on only landmark genes from L1000 or S1500+, the advantage of cancer cell lines over the TGx studies was limited. In conclusion, repurposing of existing cancer-related transcript profiling data has great potential for toxicity assessment, particularly in predicting DILI.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Perfilação da Expressão Gênica , Avaliação Pré-Clínica de Medicamentos , Células HL-60 , Humanos , Células MCF-7 , Células PC-3 , Toxicogenética/métodos , TranscriptomaRESUMO
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is a lack of effective treatments. In this meta-analysis, we assessed the efficacy and safety of inorganic nitrate in patients with HFpEF. METHODS AND RESULTS: We systematically searched PubMed, Embase, and the Cochrane Library from the inception of the database through March 2020. We included randomized controlled trials that compared the efficacy and safety of inorganic nitrate with a placebo in the treatment of patients with HFpEF. The primary outcome of the meta-analysis was exercise capacity (measured as a change in peak oxygen uptake). We also assessed the effect of inorganic nitrate on diastolic function (measured as changes in E/A and E/e', assessed by echocardiography), quality of life (estimated using the Kansas City Cardiomyopathy Questionnaire), and rest and exercise hemodynamics (measured by invasive cardiac catheterization). In the pooled data analysis, there were no significant differences in peak oxygen uptake (mL/kg/min) [mean difference (MD), 0.25; 95% CI, - 0.07 to 0.57], diastolic function [E/A-standardized mean difference (SMD), 0.51; 95% CI, - 0.17 to 1.20; or E/e'-SMD, 0.02; 95% CI, - 0.23 to 0.27], or quality of life. However, a significant change was observed in the rest and exercise hemodynamics between the inorganic nitrate and placebo treatment in HFpEF patients. No study has reported the effect of inorganic nitrate on hospitalization and mortality of patients with HFpEF. CONCLUSIONS: In patients with HFpEF, the use of inorganic nitrate is not associated with improvements in exercise capacity, diastolic function, and quality of life but is associated with significant changes in rest and exercise hemodynamics.