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Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 µL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.
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Cardiomiopatias , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hiperglicemia , Animais , Camundongos , Fator Natriurético Atrial , Cardiomegalia/etiologia , Cardiomiopatias/metabolismo , Colágeno , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Fibrose , Hiperglicemia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Peptídeo Natriurético Encefálico , Receptores para Leptina/genética , RNA Mensageiro , Transdução de Sinais , Sirtuína 1/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/metabolismoRESUMO
Monocyte and adhesion infiltration into the arterial subendothelium are initial steps in hypertension development. The endothelial intercellular adhesion molecule-1 (ICAM-1) has been implicated in the recruitment and adhesion of leukocytes in several cardiac diseases. However, the role of ICAM-1 in angiotensin II (Ang II)-induced hypertension development remains unknown. Hypertension was induced by administering an infusion of Ang II (1000 ng/kg/min) to wild-type (WT) mice treated with an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse/day, respectively). Blood pressure was determined using the tail-cuff system. Vascular remodeling was assessed by performing a histological examination. Inflammation and reactive oxygen species (ROS) levels were determined by using immunostaining. Vascular dysfunction was assessed by aortic ring assay. The expression of fibrotic markers, cytokines and NOX was evaluated by quantitative real-time PCR analysis. Our results demonstrate that Ang II infusion markedly increased the ICAM-1 level in the aorta. Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II-induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production and improved vascular relaxation. In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II-induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease.
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Angiotensina II/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/prevenção & controle , Molécula 1 de Adesão Intercelular , Animais , Aorta/metabolismo , Adesão Celular/fisiologia , Células Cultivadas , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/metabolismo , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
In this work, well-defined two-dimensional metallacycles have been successfully employed for the well-controlled self-assembly of gold nanoparticles (AuNPs) into discrete clusters such as dimers, trimers, tetramers, pentamers and even hexamers at the water-oil interface for the first time. Furthermore, the modular construction of metallacycle molecules allows precise control of spacing between the gold nanoparticles. Interestingly, it was found that interparticle spacing below 5â nm created by molecular metallacycles in the resultant discrete gold nanoparticle clusters led to a strong plasmon coupling, thus inducing great field enhancement inside the gap between the NPs. More importantly, different discrete clusters with precise interparticle spacing provide a well-defined system for studying the hot-spot phenomenon in surface-enhanced Raman scattering (SERS); this revealed that the SERS effects were closely related to the interparticle spacing.
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Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg-1·min-1) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases.NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.
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Adesão Celular , Endotélio Vascular/metabolismo , Insuficiência Cardíaca/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/fisiologia , Angiotensina II/toxicidade , Animais , Anticorpos Neutralizantes/imunologia , Endotélio Vascular/patologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Antígeno-1 Associado à Função Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Contração MiocárdicaRESUMO
This prospective study included 68,759 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Subjects were divided into four categories based on the quartiles of TC, LDL-C and non-HDL-C. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53; HR 1.16; HR 1.55); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR0.84; HR 0.82; HR 0.80) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. In a word, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers.
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Aterosclerose/epidemiologia , Colesterol/sangue , Neoplasias/epidemiologia , Adulto , Idoso , Aterosclerose/sangue , China/epidemiologia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Estudos Prospectivos , Fatores de RiscoRESUMO
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome. However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41â¯at two doses of 5 and 10â¯mg and infused with Ang II (1000â¯ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41-treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3, TGF-ß/Smad2/3 and NF-kB(p65)). In conclusion, these results indicate that inhibition of UBA1 suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases.
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Benzoatos/farmacologia , Cardiomegalia/prevenção & controle , Furanos/farmacologia , Pirazóis/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Remodelação Ventricular/efeitos dos fármacos , Angiotensina II , Animais , Benzoatos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/fisiopatologia , Fibrose , Furanos/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Pirazóis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
AIM: To compare the dosimetric advantages and disadvantages between hybrid intensity-modulated radiation therapy (h-IMRT) and the volumetric modulated arc therapy (VMAT) technique in hypofractionated whole-breast irradiation (HF-WBI) for early-stage breast cancer (BC). METHODS: The dose distribution of h-IMRT and VMAT plans was compared in 20 breast cancer patients. This comparison included evaluation of dosimetric parameters using dose volume histograms (DVHs) for the planning target volume (PTV) and organs-at-risk (OARs). Additionally, the study examined the normal tissue complication probability (NTCP), the second cancer complication probability (SCCP) and the tumor control probability (TCP) based on different models. RESULTS: Significant differences were detected between the two plans, in terms of Machine units (MUs), the control points, 95 % volume (V95 %), dose homogeneity index (DHI) and conformity index (CI). The endpoint of grade II radiation pneumonitis and cardiac death due to ischemic heart disease were assessed. In h-IMRT plan, the NTCP values were marginally lower for radiation pneumonitis and slightly higher for cardiac death compared to VMAT plan, as determined by the Lyman-Kutcher-Burman model. The Schneider model was employed to predict the SCCP for both the bilateral lungs and contralateral breast, the results demonstrate that the h-IMRT plan outperforms the VMAT plan, with statistical significance. Additionally, the LQ-Poisson model was employed to forecast the TCP of the PTV, showing that the h-IMRT plan outperformed the VMAT plan (P > 0.05). CONCLUSION: The h-IMRT technique, offering superior dose coverage and better therapeutic efficacy with fewer side effects as calculated by models, is more suitable for HF-WBI compared to the VMAT technique.
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BACKGROUND: Inflammatory indices derived from complete blood tests have been reported to be associated with poor outcomes in patients with atrial fibrillation (AF). The data about the relationship between inflammatory indices and left atrial appendage thrombus (LAAT) or dense spontaneous echo contrast (SEC) are limited. AIM: To explore the value of inflammatory indices for predicting the presence of LAAT or dense SEC in nonvalvular AF patients. METHODS: A total of 406 patients with nonvalvular AF who underwent transesophageal echocardiography were included and divided into two groups based on the presence (study group) or absence (control group) of LAAT or dense SEC. Inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), were calculated from complete blood analysis. The associations of inflammatory indices with LAAT/dense SEC were analyzed using logistic regression. RESULTS: LAAT and dense SEC were detected in 11 (2.7%) and 42 (10.3%) patients, respectively. The PLR only showed an association with LAAT/dense SEC in the univariate model. Elevated NLR (odds ratio [OR] = 1.48, 95% confidence interval [CI]: 1.11-1.98, P = 0.007) and reduced LMR (OR = 0.59, 95%CI: 0.41-0.83, P = 0.003) were found to be independent risk factors for the presence of LAAT/dense SEC. The areas under the NLR and LMR curves for predicting LAAT/dense SEC were 0.73 (95%CI: 0.66-0.80, P < 0.001) and 0.73 (95%CI: 0.65-0.81, P < 0.001), respectively, while the cutoff values were 2.8 (sensitivity: 69.8%; specificity: 64.0%) and 2.4 (sensitivity: 71.7%; specificity: 60.6%), respectively. CONCLUSION: Increased NLR and decreased LMR may predict LAAT/dense SEC in patients with nonvalvular AF.
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Kaempferol (KPR), a flavonoid compound found in various plants and foods, has garnered attention for its anti-inflammatory, antioxidant, and anticancer properties. In preliminary studies, KPR can modulate several signaling pathways involved in inflammation, making it a candidate for treating cholecystitis. This study aimed to explore the effects and mechanisms of KPR on lipopolysaccharide (LPS)-induced human gallbladder epithelial cells (HGBECs). To assess the impact of KPR on HGBECs, the HGBECs were divided into control, KPR, LPS, LPS + KPR, and LPS + UDCA groups. Cell viability and cytotoxicity were evaluated by MTT assay and lactate dehydrogenase (LDH) assay, respectively, and concentrations of KPR (10-200 µM) were tested. LPS-induced inflammatory responses in HGBECs were to create an in vitro model of cholecystitis. The key inflammatory markers (IL-1ß, IL-6, and TNF-α) levels were quantified using ELISA, The modulation of the MAPK/NF-κB signaling pathway was measured by western blot using specific antibodies against pathway components (p-IκBα, IκBα, p-p65, p65, p-JNK, JNK, p-ERK, ERK, p-p38, and p38). The cell viability and LDH levels in HGBECs were not significantly affected by 50 µM KPR, thus it was selected as the optimal KPR intervention concentration. KPR increased the viability of LPS-induced HGBECs. Additionally, KPR inhibited the inflammatory factors level (IL-1ß, IL-6, and TNF-α) and protein expression (iNOS and COX-2) in LPS-induced HGBECs. Furthermore, KPR reversed LPS-induced elevation of p-IκBα/IκBα, p-p65/p65, p-JNK/JNK, p-ERK/ERK, and p-p38/p38 ratios. KPR attenuates the LPS-induced inflammatory response in HGBECs, possibly by inhibiting MAPK/NF-κB signaling.
Assuntos
Colecistite , NF-kappa B , Humanos , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Inibidor de NF-kappaB alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Quempferóis/farmacologia , Transdução de Sinais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Células Epiteliais/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-ß/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.
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Angiotensina II , Fibrilação Atrial , Peptidase 7 Específica de Ubiquitina , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/prevenção & controle , Peptidase 7 Específica de Ubiquitina/metabolismo , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Humanos , Remodelamento Atrial/efeitos dos fármacosRESUMO
To ensure safety and prevent failure of engineering equipment throughout its lifespan, the concept of 'Safety Design' is proposed, which covers all the cradle-to-grave phases of engineering equipment, considers at least ten essential factors of failure causes, and conducts root cause analysis at three different scales, in order to proactively control the safety risks before the occurrence of failure rather than passively conduct the remedial measures after failure. Herein, in order to demonstrate how to implement this effective and efficient concept in engineering practice, a case study of failure analysis and prevention is addressed on the extraction column in the production line for methyl methacrylate. Based on the analysis results, the causes were finally determined to be all derived from the stages before operation, including inappropriate design, limited quality inspection of fabrication and installation. Pertinent countermeasures were then proposed from the 'Safety Design' point of view, which would not only solve the failure problem for this sole equipment but also contribute to safety risk control of other engineering equipment before operation.
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Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.
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AIMS/INTRODUCTION: To investigate the association between serum 25-hydroxyvitamin D (25-[OH]D) concentrations and metabolic syndrome (MetS) in the middle-aged and elderly Chinese population. METHODS: The present study included 2,764 participants (aged >50 years). The joint interim statement was used for the standard definition of MetS. Serum 25-(OH)D concentrations were measured by electrochemiluminescence immunoassay. The study participants were categorized into quartiles based on serum 25-(OH)D concentrations, and the quartiles were calculated for the differences using anova and the χ2 -test for continuous and categorical data, respectively. A logistic regression analysis model was applied to estimate the odds ratios and 95% confidence intervals (95% CI) for each quartile of serum 25-(OH)D concentrations compared with the highest quartile. RESULTS: Serum 25-(OH)D levels were markedly lower in men in the MetS group than in those without MetS. We observed a negative correlation between the higher quartiles of serum 25-(OH)D levels and the presence of MetS among men. The correlation between serum 25-(OH)D levels and the prevalence of MetS persisted even after adjusting for potential confounders, including age, cigarette smoking status, alcohol consumption, physical activity, low-density lipoprotein, creatinine and total serum cholesterol. Adjusted odds ratios of MetS in the second through fourth compared with the lowest quartile for serum 25-(OH)D levels were 0.93 (95% CI 0.54-1.59), 0.89 (95% CI 0.50-1.56) and 0.48 (95% CI 0.28-0.84), respectively. CONCLUSIONS: Decreased serum 25-(OH)D level is significantly correlated with MetS in middle-aged men.
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Povo Asiático/estatística & dados numéricos , Biomarcadores/sangue , Lipídeos/sangue , Síndrome Metabólica/diagnóstico , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , China/epidemiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Prospectivos , Vitamina D/sangueRESUMO
Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 µg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-ß/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.
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Fibrilação Atrial/tratamento farmacológico , Pressão Sanguínea/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Indóis/uso terapêutico , Oximas/uso terapêutico , Ubiquitina Tiolesterase/antagonistas & inibidores , Angiotensina II , Animais , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/fisiopatologia , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Indóis/farmacologia , Masculino , Camundongos , Oximas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismoRESUMO
The aim of our study was to investigate the effect of Patrinia scabra Bunge polysaccharide (PSB-P2) on cervical cancer cell (U14)-bearing mice. The tumor weight of mice treated with PSB-P2 (40, 80 mg/kg b.w.) was significantly lower than that of the control group and serum lactate dehydrogenase (LDH) activity was decreased, while serum alkaline phosphatase (AKP) level was only changed slightly. Meanwhile, the number of apoptotic tumor cells was significantly increased in the mice by the treatment of PSB-P2 (40, 80 mg/kg b.w.). At the same time, cell cycle analysis showed the accumulation of tumor cells in the G0/G1 phase and a relative decrease in the S phase. On the other hand, using the reverse transcription-polymerase chain reaction (RT-PCR) assay, PSB-P2 (40, 80 mg/kg b.w.) showed the up-regulation of p53 and Bax, and significant inhibition of Bcl-2 in tumor tissues. It suggests a possible mechanism of the inhibitory effect of PSB-P2 on tumor growth.
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Antineoplásicos/farmacologia , Patrinia/química , Polissacarídeos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Fosfatase Alcalina/sangue , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , L-Lactato Desidrogenase/sangue , Camundongos , Fitoterapia , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fase S/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Proteína X Associada a bcl-2/genéticaRESUMO
Many children with autism spectrum disorder (ASD) suffer from concurrent medical symptoms, including gastrointestinal (GI) and sleeping problems. However, there is limited information on the correlation between co-morbidities and autistic behavioral symptoms. In this study, we estimated the prevalence of GI and sleep problems in Chinese ASD children, examined the impacts of GI and sleep problems on autistic behavioral symptoms, and investigated the factors associated with GI and sleep problems. The survey included 169 ASD and 172 healthy children. Data regarding demographic characteristics, GI symptoms, sleep disturbances and behavioral symptoms were collected through questionnaires. GI and sleep problems were prevalent in Chinese ASD children. Moreover, ASD children with GI symptoms reported more severe ASD core symptoms than others. Autistic children's GI symptoms were associated with maternal sleep problems during pregnancy, child's 0-6 month food sources and picky eating. ASD children with sleep disturbances had lower performance in daily living skills, social cognition, social communication and intellectual development than ASD children without sleep disturbances. Sleep disturbances were associated with extra nutrient supply during lactation and feeding, and child's picky eating. Autistic children with GI or/and sleep problems may represent clinically relevant subtypes of ASD, for which targeted treatments may be needed.
Assuntos
Transtorno do Espectro Autista/psicologia , Sintomas Comportamentais/psicologia , Gastroenteropatias/psicologia , Transtornos do Sono-Vigília/psicologia , Povo Asiático/psicologia , Transtorno do Espectro Autista/complicações , Sintomas Comportamentais/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Comorbidade , Feminino , Gastroenteropatias/epidemiologia , Humanos , Masculino , Prevalência , Transtornos do Sono-Vigília/epidemiologia , Comportamento Social , Inquéritos e QuestionáriosRESUMO
To explore the distribution of bacterial community and its relationship with soil environmental factors in degraded alpine grasslands in the eastern Qilian Mountains, we analyzed the changes of bacterial community structure and diversity across lightly, moderately and severely degraded grasslands by using high-throughput sequencing technology. Redundancy analysis (RDA) was performed to analyze the relationship between soil bacterial communities and soil environmental factors by using CANOCO 4.5 software. The results showed that there were significant differences in soil physicochemical properties among different degraded alpine grasslands. There were 257125 effective sequences, 180826 high-quality sequences and 4790 OTUs. The Chao1 index was lightly degraded grassland > moderately degraded grassland > severely degraded grassland; Shannon index was lightly degraded grassland > severely degraded grassland > moderately degraded grassland. Phylogenetic analysis indicated that the soil bacterial groups of each plot belonged to 33 phyla, with Actinomycetes, Proteobacteria and Firmicutes being the dominant groups in the three grasslands. From analysis of the proportion of soil bacteria in different degraded grassland, we found that the Actinomycetes, Acidobacteria and Proteobacteria increased first and then decreased with the degree of degradation, and the Firmicutes showed an opposite trend. The results of RDA analysis showed that the dominant groups of bacteria were significantly correlated with invertase, cellulase, phosphatas, pH, electronic conductivity, available nitrogen and available potassium. It was concluded that there were significant differences in soil bacterial communities among different degraded alpine grasslands in the eastern Qilian Mountains, and the soil environmental factors were the important factors driving the distribution of soil bacterial communities.
Assuntos
Monitoramento Ambiental , Pradaria , Microbiologia do Solo , Bactérias , China , Filogenia , SoloRESUMO
Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II-induced AF in immunosubunit PSMB10 (also known as ß2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II-treated mice or serum from patients with AF. Moreover, Ang II-infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10-treated mice. Administration of IKKß-specific inhibitor IMD 0354 reduced Ang II-induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-ß-Smad2/3 signaling leading to cardiac fibrosis but also induced IKKß activation and ubiquitin-mediated degradation of IkBα ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1ß, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II-induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Cisteína Endopeptidases/genética , Quinase I-kappa B/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/diagnóstico por imagem , Cisteína Endopeptidases/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma , Distribuição Aleatória , Valores de Referência , Sensibilidade e Especificidade , Transdução de Sinais/efeitos dos fármacosRESUMO
Given the low substitution rate in plastomes, the polymorphic and codominant nature of chloroplast SSRs (cpSSRs) makes them ideal markers, complementing their nuclear counterpart. In Cupressaceae, cpSSRs are mostly paternally inherited, thus, they are useful in mating systems and pollen flow studies. Using e-PCR, 92 SSR loci were identified across six Cupressaceae plastomes, and primers were designed for 26 loci with potential interspecific transferability. The 26 developed cpSSRs were polymorphic in four genera, Platycladus, Sabina, Juniperus, and Cupressus and are suitable for Cupressaceae molecular genetic studies and utilization. We genotyped 192 Platycladus orientalis samples from a core breeding population using 10 of the developed cpSSRs and 10 nuclear SSRs, and these individuals were identified with high confidence. The developed cpSSRs can be used in (1) a marker-assisted breeding scheme, specifically when paternity identification is required, (2) population genetics investigations, and (3) biogeography of Cupressaceae and unraveling the genetic relationships between related species.