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Doxorubicin has been used extensively as a potent anticancer agent, but its clinical use is limited by its cardiotoxicity. However, the underlying mechanisms remain to be fully elucidated. In this study, we tested whether NADPH oxidase 2 (Nox2) mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced heart failure. Nox2 knockout (KO) and wild-type (WT) mice were randomly assigned to receive a single injection of doxorubicin (15 mg/kg, i.p.) or saline. WT doxorubicin mice exhibited the decreases in survival rate, left ventricular (LV) wall thickness and LV fractional shortening and the increase in the lung wet-to-dry weight ratio 1 week after the injections. These alterations were attenuated in Nox2 KO doxorubicin mice. In WT doxorubicin mice, myocardial oxidative stress was increased, myocardial noradrenergic nerve fibers were reduced, myocardial expression of PGP9.5, GAP43, tyrosine hydroxylase and norepinephrine transporter was decreased, and these changes were prevented in Nox2 KO doxorubicin mice. Myocyte autophagy was increased and myocyte size was decreased in WT doxorubicin mice, but not in Nox2 KO doxorubicin mice. Nox2 mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy-both of which contribute to cardiac atrophy and failure after doxorubicin treatment.
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Cardiomiopatías , Miocitos Cardíacos , NADPH Oxidasa 2 , Animales , Ratones , Autofagia , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Doxorrubicina/farmacología , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/metabolismo , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/metabolismo , Estrés Oxidativo , SimpatectomíaRESUMEN
Doxorubicin is widely used for the treatment of human cancer, but its clinical use is limited by a cumulative dose-dependent cardiotoxicity. However, the mechanism of doxorubicin-induced cardiac atrophy and failure remains to be fully understood. In this study, we tested whether the specific NADPH oxidase 2 (Nox2) inhibitor GSK2795039 attenuates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, leading to the amelioration of cardiac atrophy and dysfunction in chronic doxorubicin-induced cardiomyopathy. Mice were randomized to receive saline, doxorubicin (2.5 mg/kg, every other day, 6 times) or doxorubicin plus GSK2795039 (2.5 mg/kg, twice a day, 9 weeks). Left ventricular (LV) total wall thickness and LV ejection fraction were decreased in doxorubicin-treated mice compared with saline-treated mice and the decreases were prevented by the treatment of the specific Nox2 inhibitor GSK2795039. The ratio of total heart weight to tibia length and myocyte cross-sectional area were decreased in doxorubicin-treated mice, and the decreases were attenuated by the GSK2795039 treatment. In doxorubicin-treated mice, myocardial Nox2 and 4-hydroxynonenal levels were increased, myocardial expression of GAP43, tyrosine hydroxylase and norepinephrine transporter, markers of sympathetic nerve terminals, was decreased, and these changes were prevented by the GSK2795039 treatment. The ratio of LC3 II/I, a marker of autophagy, and Atg5, Atg12 and Atg12-Atg5 conjugate proteins were increased in doxorubicin-treated mice, and the increases were attenuated by the GSK2795039 treatment. These findings suggest that inhibition of Nox2 by GSK2795039 attenuates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, thereby ameliorating cardiac atrophy and dysfunction after chronic doxorubicin treatment.
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Aminopiridinas , Doxorrubicina , Células Musculares , Sulfonamidas , Animales , Ratones , Atrofia/inducido químicamente , Autofagia , Doxorrubicina/efectos adversos , NADPH Oxidasa 2RESUMEN
Cardiac remodeling (CR), characterized by cardiac hypertrophy and fibrosis, leads to the development and progression of heart failure (HF). Nowadays, emerging evidence implicated that inflammation plays a vital role in the pathogenesis of CR and HF. Astragaloside IV (AS-IV), an effective component of Astragalus membranaceus, exerts cardio-protective and anti-inflammatory effects, but the underlying mechanism remains not fully elucidated. This present study aimed to investigate the effects of AS-IV on cardiac hypertrophy and fibrosis in cultured H9C2 cells stimulated with LPS, as well as explore its underlying mechanisms. As a result, we found AS-IV could reduce the cell surface size, ameliorate cardiac hypertrophy and fibrosis in LPS-induced H9C2 cells. To specify which molecules or signaling pathways play key roles in the process, RNA-seq analysis was performed. After analyzing the transcriptome data, CCL2 has captured our attention, of which expression was sharply increased in model group and reversed by AS-IV treatment. The results also indicated that AS-IV could ameliorate the inflammatory response by down-regulating NF-κB signaling pathway. Additionally, a classical inhibitor of CCL2 (bindarit) were used to further explore whether the anti-inflammatory effect of AS-IV was dependent on this chemokine. Our results indicated that AS-IV could exert a potent inhibitory effect on CCL2 expression and down-regulated NF-κB signaling pathway in a CCL2-dependent manner. These findings provided a scientific basis for promoting the treatment of HF with AS-IV.
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Lipopolisacáridos , FN-kappa B , Humanos , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Miocitos Cardíacos/metabolismo , Transducción de Señal , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Antiinflamatorios/farmacología , Colágeno/metabolismo , Fibrosis , Quimiocina CCL2/metabolismoRESUMEN
Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm-/- mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.
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Aminoácidos de Cadena Ramificada , Linfocitos T CD8-positivos , Animales , Ratones , Aminoácidos de Cadena Ramificada/metabolismo , Linfocitos T CD8-positivos/metabolismo , GlucosaRESUMEN
Doxorubicin (DOX), which is widely used for the treatment of cancer, induces cardiomyopathy associated with NADPH oxidase-derived reactive oxygen species. GSK2795039 is a novel small molecular NADPH oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte necroptosis in DOX-induced heart failure through NADPH oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2'-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum lactate dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.
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Insuficiencia Cardíaca , Miocitos Cardíacos , Ratones , Animales , Miocitos Cardíacos/metabolismo , Necroptosis , Necrosis/metabolismo , Apoptosis/fisiología , Estrés Oxidativo , Doxorrubicina/metabolismo , NADPH Oxidasas/metabolismo , Proteínas Quinasas/metabolismoRESUMEN
The location of logistics distribution centers is a crucial issue in modern logistics distribution systems. In order to obtain a more reasonable solution, an effective optimization algorithm is essential. This paper proposes a new hybrid method, named the beetle antennae search-rain algorithm (BRA), for the problem of logistics distribution centers' location. The innovation of the BRA is embodied in three aspects. Firstly, the beetle antennae search (BAS) algorithm is embedded into the rain algorithm (RA); thus, the BAS is improved from an individual search to a swarm intelligent search and the global search ability is improved. Secondly, the search direction strategy of the BAS algorithm is incorporated into the RA, which can improve response speed while ensuring optimization performance. Finally, the search precision is improved by the mechanism of eliminating the inferior solution and generating a new solution. The BRA is tested on 10 benchmark functions and applied to solve the logistics distribution centers' location problem. The performance of the BRA is compared to that of several classical heuristics by using relevant evaluation indexes and dynamic optimization convergence graphs. Experimental results show that the BRA outperforms the BAS algorithm, the RA and some other classic heuristics. It is also revealed that the BRA is an effective and competitive algorithm for logistics distribution centers' location.
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BACKGROUND: Postoperative insulin resistance (PIR) represents an important characteristic of metabolic response following surgical injury. Clinical outcomes are negatively correlated to postoperative insulin resistance and hyperglycemia, indicating a novel treatment for reducing postoperative insulin resistance is urgently needed. The current work aimed to assess the protective effects of branched-chain amino acids (BCAA) on glucose metabolism disorders induced surgically in a rat model, and to explore the underpinning mechanism. METHODS AND RESULTS: Rats were randomly assigned to 2 groups, including the control and BCAA groups. Rats were given a compulsory oral 3 mL load by gavage two hours before surgery. The results showed that BCAA remarkably reduced glycemia by suppressing liver gluconeogenesis via reduction of cAMP-response element-binding protein-regulated transcription coactivator 2 (CRTC2) and glucose-6-phosphatase (G6PC) gene and protein expression levels (all Ps < 0.05). CONCLUSIONS: This study revealed that BCAA lower blood glucose levels by reducing liver gluconeogenesis without significant elevation of plasma insulin levels. We anticipate that preoperative BCAA supplementation may be a means for preventing postoperative insulin resistance.
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Neuronal apoptosis is an important factor in the etiology of Alzheimer's disease (AD). Aerobic exercise (AE) enhances learning and memory, improves cognitive impairment, increases telomere binding protein expression, and decreases apoptosis regulators, but it remains unclear whether it can improve cognitive impairment caused by neuronal apoptosis in AD. Therefore, this study investigated whether an 8-week running table exercise intervention could reduce apoptosis and improve cognitive function in the hippocampal neurons of AD model mice. After the exercise intervention, we evaluated the learning memory ability (positioning, navigation, and spatial search) of mice using a Morris water labyrinth, Nissl staining, immunohistochemistry, and protein application to detect hippocampal PI3K/Akt/GSK-3ß signaling pathway protein and hippocampal neuronal cell apoptosis protein B cell lymphoma 2 (Bcl-2) and apoptosis-promoting protein bcl-2-related X (Bax) protein expression. The results showed that aerobic exercise improved the location and spatial exploration ability of mice, increased the number of PI3K- and p-Akt-positive cells, increased the expression of PI3K, p-Akt, and bcl-2 proteins, decreased the expression of GSK-3ß and Bax proteins, and increased the bcl-2/Bax ratio of mice. The results suggest that aerobic exercise can reduce apoptosis and improve cognitive function in AD mice. The molecular mechanism may involve activation of the PI3K/Akt/GSK-3ß signaling pathway.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/metabolismo , Animales , Apoptosis/fisiología , Disfunción Cognitiva/terapia , Ejercicio Físico , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Proteínas de Unión a Telómeros/metabolismo , Agua , Proteína X Asociada a bcl-2RESUMEN
BACKGROUND: High-quality mental health services can improve outcomes for people with mental health problems and abate the burden of mental disorders. We sought to identify the challenges the country's mental health system currently faces and the human resource situation related to psychological services and to provide recommendations on how the mental health workforce situation could be addressed in China. METHODS: This study used a cross-sectional survey design. A web-based questionnaire approach and a convenience sampling method were adopted. It was carried out from September 2020 to January 2021 in China, and we finally included 3824 participants in the analysis. Descriptive statistical analysis of the characteristics of the study sample was performed. The risk factors for competence in psychological counseling/psychotherapy were assessed using multiple linear regression analysis. RESULTS: Workforce related to psychotherapy is scarce in China, especially in Western China and community mental health sectors. Psychiatrists (39.1%) and nurses (38.9%) were the main service providers of psychotherapy in psychiatric hospitals, and clinical psychologists (6.9%) and counsellors (5.0%) were seriously scarce in mental health care sectors. A total of 74.2% of respondents had no systematic psychological training, and 68.4 and 69.2% of them had no self-experience and professional supervision, respectively. Compared with clinical psychologists and counselors, psychiatrists and nurses had less training. Systematic psychological training (ß = - 0.88), self-experience (ß = - 0.59) and professional supervision (ß = - 1.26) significantly influenced psychotherapy capacity (P<0.001). CONCLUSIONS: Sustained effort will be required to provide a high-quality, equitably distributed psychotherapy workforce in China, despite challenges for community mental health sectors and western China being likely to continue for some time. Because mental illness is implicated in so many burgeoning social ills, addressing this shortfall could have wide-ranging benefits.
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Servicios de Salud Mental , China , Estudios Transversales , Atención a la Salud , Humanos , Recursos HumanosRESUMEN
Branched-chain amino acids (BCAAs) are the three essential amino acids including leucine, isoleucine, and valine. BCAA metabolism has been linked with the development of a variety of tumors. However, the impact of dietary BCAA intake on breast tumor progression and metastasis remains to be fully explored. Here, we unexpectedly find that the elevated BCAA, either in the genetic model or via increasing dietary intake in mice, suppresses the tumor growth and lung metastasis of breast cancer. The survival analysis shows that BCAA catabolic gene expression is strongly associated with long-term oncological outcomes in patients with breast cancer. In Pp2cm knockout mice in which BCAAs accumulate due to the genetic defect of BCAA catabolism, the breast tumor growth is suppressed. Interestingly, while the cell proliferation and tumor vasculature remain unaffected, more cell death occurs in the tumor in Pp2cm knockout mice, accompanied with increased natural killer (NK) cells. Importantly, increasing BCAA dietary intake suppresses breast tumor growth in mice. On the other hand, there are fewer lung metastases from primary breast tumor in Pp2cm knockout mice and the high BCAA diet-fed mice, suggesting high BCAA also suppresses the lung metastasis of breast cancer. Furthermore, low BCAA diet promotes lung colonization of breast cancer cells in tail vein model. The migration and invasion abilities of breast cancer cells are impaired by high concentration of BCAA in culture medium. The suppressed tumor metastasis and cell migration/invasion abilities by elevated BCAA are accompanied with reduced N-cadherin expression. Together, these data show high BCAA suppresses both tumor growth and metastasis of breast cancer, demonstrating the potential benefits of increasing BCAA dietary intake in the treatment of breast cancer.
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BACKGROUND: Little is known about the characteristics of Treatment-Resistant Depression (TRD) in China. In previous studies various identification approaches have led to a wide range of results, and it is unclear how Chinese patients compare to those in other studies. METHODS: This is a retrospective cohort study using electronic health records (EHR) from two major psychiatric hospitals in China. Adult major depressive disorder (MDD) patients who initiated pharmaceutical treatment during 2010-2018 were enrolled and follow-up was 1 year. TRD was primarily identified by consensus definition of two failures of adequate (≥4 weeks) regimens. Alternative regimens of 2-weeks and 6-weeks duration, and a data-driven definition were also applied. RESULTS: In the two hospitals, 12,257 (mean age: 40.8y, 63.6% female) and 8314 (mean age: 42.4y, 68.4% female) eligible patients were included. The 1-year incidence rate of TRD was estimated to be 5.2%-7.7% using the primary definition. TRD patients had mean treatment duration of 302.5 days and 285.7 days; had 3.6 and 3.7 treatment steps on average; 94.0% and 72.6% were prescribed polypharmacy regimens, which were all marginally greater than that of non-TRD patients. Alternative definitions resulted in a wide range of incidence estimates (0.5%-20.0%). LIMITATIONS: Medications were assumed to be consumed as prescribed and lack of rating scales from EHRs may limit our TRD identification. CONCLUSIONS: The incidence of TRD among Chinese MDD patients was comparable to other countries under similar settings and more complex treatment characteristics were observed among TRD patients. Alternative TRD definitions revealed the need for better treatment management in practices.
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Trastorno Depresivo Mayor , Trastorno Depresivo Resistente al Tratamiento , Adulto , China/epidemiología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/epidemiología , Femenino , Humanos , Incidencia , Masculino , Estudios RetrospectivosRESUMEN
In cardiac myocytes in vitro, hydrogen peroxide induces autophagic cell death and necroptosis. Oxidative stress, myocyte autophagy and necroptosis coexist in heart failure (HF). In this study, we tested the hypothesis that excessive oxidative stress mediates pathological autophagy and necroptosis in myocytes in pressure overload-induced HF. HF was produced by chronic pressure overload induced by abdominal aortic constriction (AAC) in rats. Rats with AAC or sham operation were randomised to orally receive an antioxidant N-acetylcysteine (NAC) or placebo for 4 weeks. Echocardiography was performed for the assessments of left ventricular (LV) structure and function. AAC rats exhibited decreased LV fractional shortening (FS) at 4 weeks after surgery. NAC treatment attenuated decreased LV FS in AAC rats. In AAC rats, myocardial level of 8-hydroxydeoxyguanosine assessed by immunohistochemical staining, indicative of oxidative stress, was increased, LC3 II protein, a marker of autophagy, Beclin1 protein and Atg4b, Atg5, Atg7 and Atg12 mRNA expression were markedly increased, RIP1, RIP3 and MLKL expression, indicative of necroptosis, was increased, and all of the alterations in AAC rats were prevented by the NAC treatment. NAC treatment also attenuated myocyte cross-sectional area and myocardial fibrosis in AAC rats. In conclusion, NAC treatment prevented the increases in oxidative stress, myocyte autophagy and necroptosis and the decrease in LV systolic function in pressure overload-induced HF. These findings suggest that enhanced oxidative stress mediates pathological autophagy and necroptosis in myocytes, leading to LV systolic dysfunction, and antioxidants may be of value to prevent HF through the inhibition of excessive autophagy and necroptosis.
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Autofagia , Insuficiencia Cardíaca/patología , Miocitos Cardíacos/patología , Necroptosis , Estrés Oxidativo , Acetilcisteína/farmacología , Animales , Autofagia/efectos de los fármacos , Presión Sanguínea , Ecocardiografía , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/fisiología , Necroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Disfunción Ventricular IzquierdaRESUMEN
Objective: To describe persistence with and adherence to paliperidone palmitate once-monthly injection (PP1M) compared to oral second-generation antipsychotics (SGAs) in patients with schizophrenia in real-world settings in China and Japan.Methods: Patients with a schizophrenia diagnosis (ICD-10: F20.x) who received oral or injectable antipsychotics from study start (China: January 1, 2012; Japan: January 1, 2014) until December 31, 2017, were enrolled in this retrospective cohort study. The first PP1M or oral SGA prescription date during the study period was defined as the index date. Eligible patients were followed up for up to 1 year after the index date. Persistence was measured from the index date until discontinuation or reaching 1 year. Adherence was assessed by calculating the proportion of days covered (PDC). Multivariable regression models were used to adjust for potential confounders.Results: The study cohorts comprised 44,266 patients from Japan and 7,564 and 5,189 patients, respectively, from 2 hospitals in China. The PP1M group showed consistently lower risk of discontinuation; adjusted hazard ratios and 95% CIs were 0.75 (0.72-0.90) (Japan), and 0.76 (0.68-0.84) and 0.65 (0.56-0.76) (China) compared to oral SGAs. The PP1M group also showed better adherence; adjusted odds ratios and 95% CIs were 1.61 (1.22-2.11) (Japan), and 1.92 (1.53-2.41) and 2.25 (1.58-3.23) (China).Conclusions: Persistence and adherence were significantly higher in PP1M users than in oral SGAs users across 3 databases comprising patients in 2 countries in Asia.
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Antipsicóticos/uso terapéutico , Cumplimiento de la Medicación/estadística & datos numéricos , Palmitato de Paliperidona/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Antipsicóticos/administración & dosificación , China , Preparaciones de Acción Retardada , Femenino , Humanos , Inyecciones , Japón , Masculino , Persona de Mediana Edad , Palmitato de Paliperidona/uso terapéutico , Estudios Retrospectivos , Adulto JovenRESUMEN
Sphingosine-1-phosphate (S1P)/S1P receptor 1 signaling exerts cardioprotective effects including inhibition of myocyte apoptosis. However, little is known about the effect of S1P treatment on myocyte autophagy after myocardial infarction (MI). In the present study, we tested the hypothesis that S1P induces myocyte autophagy through inhibition of the mammalian target of rapamycin (mTOR), leading to improvement of left ventricular (LV) function after MI. Sprague-Dawley rats underwent MI or sham operation. The animals were randomized to receive S1P (50 µg/kg/day, i.p.) or placebo for one week. H9C2 cardiomyocytes cultured in serum- and glucose-deficient medium were treated with or without S1P for 3 h. MI rats exhibited an increase in LV end-diastolic dimension (EDD) and decreases in LV fractional shortening (FS) and the maximal rate of LV pressure rise (+dP/dt). S1P treatment attenuated the increase in LV EDD and decreases in LV FS and +dP/dt. In the MI placebo group, the LC3 II/I ratio, a marker of autophagy, was increased, and increased further by S1P treatment. S1P also enhanced the autophagy-related proteins Atg4b and Atg5 after MI. Similarly, in cultured cardiomyocytes, autophagy was increased under glucose and serum deprivation, and increased further by S1P treatment. The effect of S1P on myocyte autophagy was associated with mTOR inhibition after MI or in cultured cardiomyocytes under glucose and serum deprivation. S1P treatment prevents LV remodeling, enhances myocyte autophagy and inhibits mTOR activity after MI. These findings suggest that S1P treatment induces myocyte autophagy through mTOR inhibition, leading to the attenuation of LV dysfunction after MI.
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Lisofosfolípidos , Esfingosina/análogos & derivados , Animales , Autofagia , Infarto del Miocardio , Miocitos Cardíacos , Ratas , Ratas Sprague-DawleyRESUMEN
Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced-to-oxidized glutathione ratio and an increased 4-hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non-infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia-induced reduction of NGF. Recombinant NGF attenuated hypoxia-induced apoptosis. Apocynin prevented hypoxia-induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF.
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Acetofenonas , Animales , Miocardio , Factor de Crecimiento Nervioso , ConejosRESUMEN
PURPOSE: Antepartum hemorrhage (APH) in women with placenta previa (PP) has been associated with increased perinatal complications. The present study aims to evaluate the maternal and neonatal outcomes, and risk factors related to this condition. METHODS: This retrospective study was conducted in the Obstetrics and Gynecology Department of the Second Affiliated Hospital of Army Military Medical University from January 2016 to September 2019, which included all women with PP. The clinical and ultrasound features in patients with or without APH were compared. RESULTS: There were 233 women with APH and 302 women without APH in the cohort. Most of the women with APH were prone to adverse maternal and neonatal outcomes. In the logistic regression analysis, cervical length was inversely correlated to APH (OR: 0.972, 95% CI: 0.952~0.993), while complete PP increased the risk for APH (OR: 2.121, 95% CI: 1.208~3.732). Furthermore, the anterior placenta increased the risk for APH (OR: 1.664, 95% CI: 1.139~2.430), the partial absence of the over lying myometrium increased the risk for APH (OR: 2.015, 95% CI: 1.293~3.141), and the previous history of uterine artery embolization (UAE) increased the highest risk for APH (OR: 11.706, 95% CI: 1.424~96.195). CONCLUSION: Obstetricians should be aware of the increased risk of adverse pregnancy outcomes related to APH in women with complete PP, short cervical length, anterior placenta, and partially absent over lying myometrium. Prior UAE is a novel risk factor associated with increased prevalence of APH.
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Sepsis-induced myocardial dysfunctions are associated with high morbidity and mortality. Selenium, an essential trace element, has been reported to exert anti-inflammation, anti-oxidative stress, and anti-apoptosis. However, the protective effects of selenium on LPS-induced heart injury are still poorly illustrated. Therefore, in the present study, we sought to explore the effects of selenium pretreatment on LPS-induced myocardial injury in mice. We firstly found that selenium pretreatment significantly improved markers of myocardial injury and alleviated LPS-induced myocardial dysfunctions. Moreover, selenium supplementation reduced pro-inflammatory cytokines expression, decreased oxidative stress, and inhibited myocardial apoptosis. In addition, selenium supplementation inactivated the Sting pathway. In conclusion, our study suggests that selenium exerts protective effects on LPS-induced myocardial injury, and the underlying molecular mechanism may be related to the inactivation of Sting pathway, implying a potential therapy for sepsis-induced myocardial dysfunctions.
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Lesiones Cardíacas , Selenio , Animales , Apoptosis , Suplementos Dietéticos , Lipopolisacáridos/toxicidad , Ratones , Selenio/farmacologíaRESUMEN
The purpose of the study is to solve problems, i.e., increasingly significant processing delay of massive monitoring data and imbalanced tasks in the scheduling and monitoring center for a railway network. To tackle these problems, a method by using a smooth weighted round-robin scheduling based on backpressure flow control (BF-SWRR) is proposed. The method is developed based on a model for message queues and real-time streaming computing. By using telemetry data flow as input data sources, the fields of data sources are segmented into different sets by using a distributed model of stream computing parallel processing. Moreover, the round-robin (RR) scheduling method for the distributed server is improved. The parallelism, memory occupancy, and system delay are tested by taking a high-speed train section of a certain line as an example. The result showed that the BF-SWRR method for clusters can control the delay to within 1 s. When the parallelism of distributed clusters is set to 8, occupancy rates of the CPU and memory can be decreased by about 15%. In this way, the overall load of the cluster during stream computing is more balanced.
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Almacenamiento y Recuperación de la Información/métodos , Algoritmos , Análisis por Conglomerados , Computadores , Suministros de Energía Eléctrica/tendencias , Almacenamiento y Recuperación de la Información/tendencias , Modelos Teóricos , Programas InformáticosRESUMEN
OBJECTIVE: We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. METHODS: Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. RESULTS: In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. CONCLUSIONS: Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.
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Compuestos Alílicos/farmacología , Hipertensión/tratamiento farmacológico , Mitocondrias Musculares/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Sulfuros/farmacología , Remodelación Vascular/efectos de los fármacos , Angiotensina II , Animales , Movimiento Celular/efectos de los fármacos , Plasticidad de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Dinaminas/metabolismo , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Ratones Endogámicos C57BL , Mitocondrias Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/metabolismo , Fenotipo , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Quinasas Asociadas a rho/metabolismoRESUMEN
Previous studies have reported associations of short-term exposure to different sources of ambient fine particulate matter (PM2.5) and increased mortality or hospitalizations for respiratory diseases. Few studies, however, have focused on the short-term effects of source-specific PM2.5 on emergency room visits (ERVs) of respiratory diseases. Source apportionment for PM2.5 was performed with Positive Matrix Factorization (PMF) and generalized additive model was applied to estimate associations between source-specific PM2.5 and respiratory disease ERVs. The association of PM2.5 and total respiratory ERVs was found on lag4 (RRâ¯=â¯1.011, 95%CI: 1.002, 1.020) per interquartile range (76⯵g/m3) increase. We found PM2.5 to be significantly associated with asthma, bronchitis and chronic obstructive pulmonary disease (COPD) ERVs, with the strongest effects on lag5 (RRâ¯=â¯1.072, 95%CI: 1.024, 1.119), lag4 (RRâ¯=â¯1.104, 95%CI: 1.032, 1.176) and lag3 (RRâ¯=â¯1.091, 95%CI: 1.047, 1.135), respectively. The estimated effects of PM2.5 changed little after adjusting for different air pollutants. Six primary PM2.5 sources were identified using PMF analysis, including dust/soil (6.7%), industry emission (4.5%), secondary aerosols (30.3%), metal processing (3.2%), coal combustion (37.5%) and traffic-related source (17.8%). Some of the sources were identified to have effects on ERVs of total respiratory diseases (dust/soil, secondary aerosols, metal processing, coal combustion and traffic-related source), bronchitis ERVs (dust/soil) and COPD ERVs (traffic-related source, industry emission and secondary aerosols). Different sources of PM2.5 contribute to increased risk of respiratory ERVs to different extents, which may provide potential implications for the decision making of air quality related policies, rational emission control and public health welfare.