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The analysis of cardiac wall mechanics is of importance for understanding coronary heart diseases (CHD). The inhalation of ultrafine particles could deteriorate CHD. The aim of the study is to investigate the effects of cardiac wall mechanics on rats of myocardial infarction (MI) after long-term inhalation of ultrafine Zn particles. Cardiac wall stresses and strains were computed, based on echocardiographic and hemodynamic measurements. It was found that MI resulted in the significantly elevated stresses and the reduced strains. The short-term inhalation of ultrafine Zn particles decreased stresses and increased strains in MI rats, but the long-term inhalation had the opposite effects. Hence, the short-term inhalation of ultrafine Zn particles could alleviate the MI-induced LV dysfunction while the long-term inhalation impaired it.
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Infarto do Miocárdio , Estresse Mecânico , Zinco , Infarto do Miocárdio/fisiopatologia , Animais , Zinco/administração & dosagem , Zinco/farmacologia , Ratos , Masculino , Fatores de Tempo , Administração por Inalação , Tamanho da Partícula , Ratos Sprague-Dawley , Fenômenos Biomecânicos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacosRESUMO
Potentially toxic elements (PTEs) in seawater and sediments may be amplified along the aquatic food chain, posing a health threat to humans. This study comprehensively analyzed the concentrations, distribution, potential sources, and health risk of 7 PTEs in multimedia (seawater, sediment and organism) in typical subtropical bays in southern China. The results indicated that Zn was the most abundant element in seawater, and the average concentration of Cd in sediment was 3.93 times higher than the background value. Except for As, the seasonal differences in surface seawater were not significant. The content of Zn in fishes, crustacea, and shellfish was the highest, while the contents of Hg and Cd were relatively low. Bioaccumulation factor indicated that Zn was a strongly bioaccumulated element in seawater, while Cd was more highly enriched by aquatic organisms in sediment. According to principal component analysis (PCA), and positive matrix factorization (PMF), the main sources of PTEs in Quanzhou Bay were of natural derivation, industrial sewage discharge, and agricultural inputs, each contributing 40.4 %, 24.2 %, and 35.4 %, respectively. This study provides fundamental and significant information for the prevention of PTEs contamination in subtropical bays, the promotion of ecological safety, and the assessment of human health risk from PTEs in seafood.
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Baías , Monitoramento Ambiental , Peixes , Sedimentos Geológicos , Água do Mar , Poluentes Químicos da Água , China , Poluentes Químicos da Água/análise , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Animais , Água do Mar/química , Água do Mar/análise , Medição de Risco , Organismos Aquáticos , Crustáceos , Frutos do Mar/análise , BioacumulaçãoRESUMO
Objectives: To analyze the clinical significance of seven autoantibodies (P53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGE, and CAGE) in patients with non-small cell lung cancer (NSCLC) and the factors that influence false-negative results. Methods: Seven autoantibodies were measured in the serum of 502 patients with non-small cell lung cancer (NSCLC) using ELISA, and their correlations with age, sex, smoking history, pathological type, clinical stage, and PD-L1 gene expression were analyzed. The clinicopathological data of the false-negative and positive groups for the seven autoantibodies were compared to determine the influencing factors. Results: P53 antibody expression level was correlated with lobulation sign, PGP9.5 antibody expression level with sex and vascular convergence; SOX2 antibody expression level with pathological type, clinical stage, and enlarged lymph nodes; and MAGE antibody expression level with the pathological type (P<0.05). False-negative autoantibodies are prone to occur in lung cancer patients with ground-glass nodules, no enlarged lymph nodes, no vascular convergence, and PD-L1 gene expression <1% (P <0.05). Conclusion: Detection of seven autoantibodies was clinically significant in patients with NSCLC. However, poor sensitivity should be considered in clinical diagnoses to prevent missed diagnoses.
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Early detection of left ventricular remodeling (LVR) is crucial. While cardiac magnetic resonance (CMR) provides valuable information, it has limitations. Coronary angiography-derived fractional flow reserve (caFFR) and index of microcirculatory resistance (caIMR) offer viable alternatives. 157 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively included. 23.6% of patients showed LVR. Machine learning algorithms constructed three LVR prediction models: Model 1 incorporated clinical and procedural parameters, Model 2 added CMR parameters, and Model 3 included echocardiographic and functional parameters (caFFR and caIMR) with Model 1. The random forest algorithm showed robust performance, achieving AUC of 0.77, 0.84, and 0.85 for Models 1, 2, and 3. SHAP analysis identified top features in Model 2 (infarct size, microvascular obstruction, admission hemoglobin) and Model 3 (current smoking, caFFR, admission hemoglobin). Findings indicate coronary physiology and echocardiographic parameters effectively predict LVR in patients with STEMI, suggesting their potential to replace CMR.
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This study investigated mogrol's impact on non-small cell lung cancer (NSCLC) radiosensitivity and underlying mechanisms, using various methods including assays, bioinformatics, and xenograft models. CCK-8, clonogenic, flow cytometry, TUNEL, and Western blot assays evaluated mogrol and radiation effects on NSCLC viability and apoptosis. Ubiquitin-specific protease 22 (USP22) expression in NSCLC patient tissues was determined by RT-qPCR and Western blot. A xenograft model validated mogrol's effects on tumor growth. Bioinformatics identified four ubiquitin-specific proteases, including USP22, in NSCLC. Kaplan-Meier analysis confirmed USP22's value in lung cancer survival. Human Protein Atlas (HPA) database analysis indicated higher USP22 expression in lung cancer tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis implicated ERK1/2 in NSCLC progression, and molecular docking showed stability between mogrol and ERK1/2. Further in vivo and in vitro experiments have demonstrated that mogrol enhances the inhibitory effect of radiation on NSCLC cell viability and clonogenic capacity. Cell viability and clonogenic capacity are reduced by >50%, and an increase in cellular apoptosis is observed, with apoptotic levels reaching 10%. USP22 expression was significantly elevated in NSCLC tissues, particularly in radiotherapy-resistant patients. Mogrol downregulated USP22 expression by inhibiting the ERK/CREB pathway, lowering COX2 expression. Mogrol also enhanced radiation's inhibition of tumor growth in mice. Mogrol enhances NSCLC radiosensitivity by downregulating USP22 via the ERK/CREB pathway, leading to reduced COX2 expression.NEW & NOTEWORTHY Mogrol enhances non-small cell lung cancer (NSCLC) cell sensitivity to radiotherapy by downregulating USP22 through the ERK/CREB pathway, reducing COX2 expression. These findings highlight mogrol's potential as an adjunct to improve NSCLC radiotherapy and open avenues for further research and clinical applications.
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Apoptose , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Tolerância a Radiação , Ubiquitina Tiolesterase , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Animais , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Tolerância a Radiação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células A549 , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Masculino , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Feminino , Radiossensibilizantes/farmacologiaRESUMO
Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes.
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Carcinoma Endometrioide , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/metabolismo , Proteômica , Carcinoma Endometrioide/metabolismo , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de MembranaRESUMO
Myocardial infarction (MI) impaired both cardiac functions and peripheral arteries. The changes in normal and shear stresses in the peripheral artery wall are of importance for understanding the progression of MI-induced heart failure (HF). The aim of the study is to investigate the corresponding changes of normal and shear stresses. The coronary artery ligation was used to induce the MI in Wistar rats. The analysis of wall mechanics and hemodynamics was performed based on in vivo and in vitro measurements. Myocardial infarction increased wall stiffness in elastic carotid and muscular femoral arteries significantly albeit different changes occurred between the two vessels from 3 to 6 weeks postoperatively. Moreover, the hemodynamic analysis showed the gradually deteriorated wall shear stress, oscillatory shear index and relative residence time in the two arteries. This study probably shed light on understanding the interaction between abnormal systemic circulation and peripheral mechanics and hemodynamics during the development of MI-induced HF.
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AIMS: This study sought to evaluate the association of coronary angiography-derived index of microcirculatory resistance (angio-IMR) measured after primary percutaneous coronary intervention (PPCI) with the evolution of infarct pathology during 3-month follow-up after ST-segment-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Patients with STEMI undergoing PPCI were prospectively enrolled between October 2019 and August 2021. Angio-IMR was calculated using computational flow and pressure simulation immediately after PPCI. Cardiac magnetic resonance (CMR) imaging was performed at a median of 3.6 days and 3 months. A total of 286 STEMI patients (mean age 57.8 years, 84.3% men) with both angio-IMR and CMR at baseline were included. High angio-IMR (>40 U) occurred in 84 patients (29.4%) patients. Patients with angio-IMR >40 U had a higher prevalence and extent of MVO. An angio-IMR >40 U was a multivariable predictor of infarct size with a three-fold higher risk of final infarct size >25% (adjusted OR 3.00, 95% CI 1.23-7.32, P = 0.016). Post-procedure angio-IMR >40 U significantly predicted presence (adjusted OR 5.52, 95% CI 1.65-18.51, P = 0.006) and extent (beta coefficient 0.27, 95% CI 0.01-0.53, P = 0.041) of myocardial iron at follow-up. Compared with patients with angio-IMR ≤40 U, those with angio-IMR >40 U had less regression of infarct size and less resolution of myocardial iron at follow-up. CONCLUSIONS: Angio-IMR immediately post-PPCI showed a significant association with the extent and evolution of infarct pathology. An angio-IMR >40 U indicated extensive microvascular damage with less regression of infarct size and more persistent iron at follow-up.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Circulação Coronária , Angiografia Coronária , Microcirculação , Resultado do Tratamento , FerroRESUMO
BACKGROUND: Assessing index of microcirculatory resistance (IMR) is customarily performed using intracoronary wires fitted with sensors by at least 3 intracoronary injections of 3 to 4 mL of room-temperature saline during sustained hyperemia, which is time- and cost-consuming. METHODS: The FLASH IMR study is a prospective, multicenter, randomized study to assess the diagnostic performance of coronary angiography-derived IMR (caIMR) in patients with suspected myocardial ischemia with nonobstructive coronary arteries using wire-based IMR as a reference. The caIMR was calculated by an optimized computational fluid dynamics model simulating hemodynamics during diastole based on coronary angiograms. TIMI frame count and aortic pressure were included in computation. caIMR was determined onsite in real time and compared blind to wire-based IMR by an independent core laboratory, using wire-based IMR ≥25 units as indicative of abnormal coronary microcirculatory resistance. The primary endpoint was the diagnostic accuracy of caIMR, using wire-based IMR as a reference, with a pre-specified performance goal of 82%. RESULTS: A total of 113 patients underwent paired caIMR and wire-based IMR measurements. Order of performance of tests was based on randomization. Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values of caIMR were 93.8% (95% CI: 87.7%-97.5%), 95.1% (95% CI: 83.5%- 99.4%), 93.1% (95% CI: 84.5%-97.7%), 88.6% (95% CI: 75.4%-96.2%) and 97.1% (95% CI: 89.9%-99.7%). The receiver-operating curve for caIMR to diagnose abnormal coronary microcirculatory resistance had area under the curve of 0.963 (95% CI: 0.928-0.999). CONCLUSIONS: Angiography-based caIMR has a good diagnostic yield with wire-based IMR. GOV IDENTIFIER: NCT05009667.
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Doença da Artéria Coronariana , Humanos , Angiografia Coronária , Microcirculação , Estudos Prospectivos , Resistência Vascular , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Valor Preditivo dos Testes , Circulação CoronáriaRESUMO
Hepatocellular carcinoma (HCC) is a common solid tumor with high rate of recurrence and mortality. Anti-angiogenesis drugs have been used for the therapy of HCC. However, anti-angiogenic drug resistance commonly occurs during HCC treatment. Thus, identification of a novel VEGFA regulator would be better understanding for HCC progression and anti-angiogenic therapy resistance. Ubiquitin specific protease 22 (USP22) as a deubiquitinating enzyme, participates in a variety of biological processes in numerous tumors. While the molecular mechanism underlying the effects of USP22 on angiogenesis is still needed to be clarified. Here, our results demonstrated that USP22 acts as a co-activator of VEGFA transcription. Importantly, USP22 is involved in maintenance of ZEB1 stability via its deubiquitinase activity. USP22 was recruited to ZEB1-binding elements on the promoter of VEGFA, thereby altering histone H2Bub levels, to enhance ZEB1-mediated VEGFA transcription. USP22 depletion decreased cell proliferation, migration, Vascular Mimicry (VM) formation, and angiogenesis. Furthermore, we provided the evidence to show that knockdown of USP22 inhibited HCC growth in tumor-bearing nude mice. In addition, the expression of USP22 is positively correlated with that of ZEB1 in clinical HCC samples. Our findings suggest that USP22 participates in the promotion of HCC progression, if not all, at least partially via up-regulation of VEGFA transcription, providing a novel therapeutic target for anti-angiogenic drug resistance in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ubiquitina Tiolesterase , Homeobox 1 de Ligação a E-box em Dedo de Zinco , Animais , Camundongos , Inibidores da Angiogênese/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Hepáticas/patologia , Camundongos Nus , Ubiquitina Tiolesterase/genética , Humanos , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Background: Choline has important and diverse functions in both cellular maintenance and growth. However, the relationships between the prediagnosis of the different forms of dietary choline intake and ovarian cancer (OC) survival are relatively unknown. This study is the first to investigate this topic based on the Ovarian Cancer Follow-Up Study, a prospective cohort study conducted in China. Methods: In the present study, 635 new cases of ovarian cancer between the ages of 18 and 79 were enrolled. A valid and reliable 111-item food frequency questionnaire was used to assess dietary choline intake. Deaths were ascertained until March 31, 2021, via medical records and active follow-up. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 37.2 months (interquartile: 24.7-50.2 months), 114 deaths were identified. Higher lipid-soluble choline intake was significantly associated with better overall survival for patients with OC (Tertile 3 vs. Tertile 1: HR = 0.56; 95% CI: 0.34, 0.92; P trend = 0.02) in the fully adjusted model. Similar associations were observed for phosphatidylcholine intake (Tertile 3 vs. Tertile 1: HR = 0.55; 95% CI: 0.33, 0.91; P trend = 0.02). However, no associations were found between total water-soluble choline (free choline, phosphocholine, and glycerophosphocholine), sphingomyelin, and betaine intake and OC survival. Significant additive interactions between higher fat-soluble choline intake and positive expression of estrogen receptor and Wilms tumor-1 as well as higher phosphatidylcholine intake and positive expression of estrogen receptor and Wilms tumor-1 on OC survival were detected. Conclusions: Our findings indicate that prediagnosis, total lipid-soluble choline and phosphatidylcholine intake were associated with improved overall survival among OC patients.
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Colina , Neoplasias Ovarianas , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Seguimentos , Estudos Prospectivos , Receptores de Estrogênio , Proteínas WT1 , Fatores de Risco , Dieta , FosfatidilcolinasRESUMO
(1) Background: Heart failure with preserved ejection fraction (HFpEF) is a major subtype of HF with no effective treatments. Mitochondrial dysfunctions relevant to the imbalance of fusion and fission occur in HFpEF. Drp1 is a key protein regulating mitochondrial fission, and PINK1 is the upstream activator of Drp1, but their relationship with HF has not been clarified. The aim of the study is to investigate molecular mechanisms of mitochondrial dysfunctions in animals with hypertension-induced HFpEF. (2) Methods and Results: The hypertension-induced HFpEF model was established by feeding Dahl/SS rats with high salt, showing risk factors such as hypertension, mitochondrial dysfunctions, and so on. Physiological and biological measurements showed a decrease in the expression of mitochondrial function-related genes, ATP production, and mitochondrial fission index. PINK1 knockout in H9C2 cardiomyocytes showed similar effects. Moreover, PINK1 myocardium-specific overexpression activated Drp1S616 phosphorylation and enhanced mitochondrial fission to slow the progression of hypertension-induced HFpEF. (3) Conclusions: PINK1 could phosphorylate Drp1S616 to improve mitochondrial fission and relieve mitochondrial dysfunctions, which highlights potential treatments of HFpEF.
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Dinaminas , Insuficiência Cardíaca , Hipertensão , Proteínas Quinases , Trifosfato de Adenosina/metabolismo , Animais , Dinaminas/genética , Dinaminas/metabolismo , Insuficiência Cardíaca/genética , Hipertensão/genética , Dinâmica Mitocondrial , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ratos , Ratos Endogâmicos Dahl , Volume SistólicoRESUMO
OBJECTIVE: To determine whether tumor shear stiffness, as measured by magnetic resonance elastography, corresponds with intratumoral consistency and histotype. MATERIALS AND METHODS: A total of 88 patients with 89 meningiomas (grade 1, 74 typical [13 fibroblastic, 61 non-fibroblastic]; grade 2, 12 atypical; grade 3, 3 anaplastic) were prospectively studied, each undergoing preoperative MRE in conjunction with T1-, T2- and diffusion-weighted imaging. Contrast-enhanced T1-weighted sequences were also obtained. Tumor consistency was evaluated as heterogeneous or homogenous, and graded on a 5-point scale intraoperatively. MRE-determined shear stiffness was associated with tumor consistency by surgeon's evaluation and whole-slide histologic analyses. RESULTS: Mean tumor stiffness overall was 3.81+/-1.74 kPa (range, 1.57-12.60 kPa), correlating well with intraoperative scoring (r = 0.748; p = 0.001). MRE performed well as a gauge of tumor consistency (AUC = 0.879, 95 % CI: 0.792-0.938) and heterogeneity (AUC = 0.773, 95 % CI: 0.618-0.813), significantly surpassing conventional MR techniques (DeLong test, all p < 0.001 after Bonferroni adjustment). Shear stiffness was independently correlated with both fibrous content (partial correlation coefficient = 0.752; p < 0.001) and tumor cellularity (partial correlation coefficient = 0.547; p < 0.001). MRE outperformed other imaging techniques in distinguishing fibroblastic meningiomas from other histotypes (AUC = 0.835 vs 0.513 â¼ 0.634; all p < 0.05), but showed limited ability to differentiate atypical or anaplastic meningiomas from typical meningiomas (AUC = 0.723 vs 0.616 â¼ 0.775; all p > 0.05). Small (<2.5 cm, n = 6) and intraventricular (n = 2) tumors displayed inconsistencies between MRE and surgeon's evaluation. CONCLUSIONS: The results of this prospective study provide substantial evidence that preoperative evaluation of meningiomas with MRE can reliably characterize tumor stiffness and spatial heterogeneity to aid neurosurgical planning.
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Técnicas de Imagem por Elasticidade , Neoplasias Meníngeas , Meningioma , Humanos , Técnicas de Imagem por Elasticidade/métodos , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Meningioma/patologia , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Neoplasias Meníngeas/patologiaRESUMO
Myocardial infarction (MI) can induce heart failure with reduced ejection fraction (HFrEF). Systemic circulation is of importance to interact with MI-induced HFrEF. Hence, we studied the changes of myofiber stresses and peripheral hemodynamics during the progression from MI to HFrEF. MI was induced in Wistar male rats by the coronary artery ligation surgery. Physiological and hemodynamic measurements were carried out in the LV and peripheral arteries at postoperative 3 and 6 weeks, based on which LV myofiber stresses were computed and peripheral hemodynamic analysis was demonstrated. This study showed that MI significantly impaired cardiac functions and peripheral hemodynamics and altered the corresponding histological properties of cardiac wall and peripheral arterial wall, which deteriorated with time after operation. In summary, the interplay of cardiac dysfunctions and hemodynamic impairments accelerates the progression of MI-induced HF.
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Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Hemodinâmica/fisiologia , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Ratos , Ratos Wistar , Volume Sistólico , Remodelação Ventricular/fisiologiaRESUMO
Substantial ultrafine zinc particles exist in air pollutions. The level of Zn concentrations in serum and tissue could affect patients with myocardial infarction (MI). The aim of the study is to investigate the change of cardiac functions and peripheral hemodynamics in MI rats after long-term inhalation of ultrafine Zn particles. Coronary artery ligation surgery was performed to induce MI in Wistar rats. The inhalation of ultrafine Zn particles was carried out for 6 weeks after the operation. Physiological and hemodynamic measurements and computational biomechanics analysis were demonstrated in eight groups of rats at postoperative 4 and 6 weeks. There was no statistical significance between shams and shams with inhalation of ultrafine Zn particles. There were significant impairments of cardiac and hemodynamic functions in MI rats. In comparison with MI rats, the inhalation of ultrafine Zn particles for 4 weeks slowed down the progression from MI to heart failure, but the inhalation for 6 weeks accelerated the process. The long-term inhalation of ultrafine zinc particles induced excessive accumulation of zinc in serum and tissue, which deteriorated cardiac and hemodynamic dysfunctions in MI rats. The findings suggested the importance for regulating Zn intake of MI patients as well as looking at ways to lower zinc concentrations in air pollutions.
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INTRODUCTION: Non-obstructive coronary arteries (NOCA) are present in 39.7% to 62.4% of patients who undergo elective angiography. Coronary microcirculation (<400 µm) is not visible on angiography therefore functional assessment, invasive or noninvasive plays a prior role to help provide a more personalized diagnosis of angina. AREA COVERED: In this review, we revisit the pathophysiology, clinical importance, and invasive assessment of the coronary microcirculation, and discuss angiography-derived indices of microvascular resistance. A comprehensive literature review over four decades is also undertaken. EXPERT OPINION: The coronary microvasculature plays an important role in flow autoregulation and metabolic regulation. Invasive assessment of microvascular resistance is a validated modality with independent prognostic value, nevertheless, its routine application is hampered by the requirement of intravascular instrumentation and hyperemic agents. The angiography-derived index of microvascular resistance has emerged as a promising surrogate in pilot studies, however, more data are needed to validate and compare the diagnostic and prognostic accuracy of different equations as well as to illustrate the relationship between angiography-derived parameters for epicardial coronary arteries and those for the microvasculature.
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Doença da Artéria Coronariana , Vasos Coronários , Angina Pectoris , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Circulação Coronária/fisiologia , Vasos Coronários/diagnóstico por imagem , Coração , Humanos , Microcirculação/fisiologiaRESUMO
Androgen receptor (AR) signaling drives prostate cancer (PC) progression. Androgen deprivation therapy (ADT) is temporally effective, whereas drug resistance inevitably develops. Abnormal expression of AR/ARV7 (the most common AR splicing variant) is critical for endocrine resistance, while the detailed mechanism is still elusive. In this study, bioinformatics and immunohistochemical analyses demonstrate that RNF8 is high expressed in PC and castration-resistant PC (CRPC) samples and the expression of RNF8 is positively correlated with the Gleason score. The high expression of RNF8 in PCs predicts a poor prognosis. These results provide a potential function of RNF8 in PC progression. Furthermore, the mRNA expression of RNF8 is positively correlated with that of AR in PC. Mechanistically, we find that RNF8 upregulates c-Myc-induced AR transcription via altering histone modifications at the c-Myc binding site within the AR gene. RNF8 also acts as a co-activator of AR, promoting the recruitment of AR/ARV7 to the KLK3 (PSA) promoter, where RNF8 modulates histone modifications. These functions of RNF8 are dependent on its E3 ligase activity. RNF8 knockdown further reduces AR transactivation and PSA expression in CRPC cells with enzalutamide treatment. RNF8 depletion restrains cell proliferation and alleviates enzalutamide resistance in CRPC cells. Our findings indicate that RNF8 may be a potential therapeutic target for endocrine resistance in PC.
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Proteínas de Ligação a DNA , Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Ubiquitina-Proteína Ligases , Antagonistas de Androgênios/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Humanos , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Regulação para CimaRESUMO
Vascular intimal injury initiates various cardiovascular disease processes. Exposure to subendothelial collagen can cause platelet activation, leading to collagen-activated platelet-derived microvesicles (aPMVs) secretion. In addition, vascular smooth muscle cells (VSMCs) exposed to large amounts of aPMVs undergo abnormal energy metabolism; they proliferate excessively and migrate after the loss of endothelium, eventually contributing to neointimal hyperplasia. However, the roles of aPMVs in VSMC energy metabolism are still unknown. Our carotid artery intimal injury model indicated that platelets adhered to injured blood vessels. In vitro, phosphorylated Pka (cAMP-dependent protein kinase) content was increased in aPMVs. We also found that aPMVs significantly reduced VSMC glycolysis and increased oxidative phosphorylation, and promoted VSMC migration and proliferation by upregulating phosphorylated PRKAA (α catalytic subunit of AMP-activated protein kinase) and phosphorylated FoxO1. Compound C, an inhibitor of PRKAA, effectively reversed the enhancement of cellular function and energy metabolism triggered by aPMVs in vitro and neointimal formation in vivo. We show that aPMVs can affect VSMC energy metabolism through the Pka-PRKAA-FoxO1 signaling pathway and this ultimately affects VSMC function, indicating that the shift in VSMC metabolic phenotype by aPMVs can be considered a potential target for the inhibition of hyperplasia. This provides a new perspective for regulating the abnormal activity of VSMCs after injury.
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Lesões das Artérias Carótidas , Músculo Liso Vascular , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Plaquetas/metabolismo , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Humanos , Hiperplasia/complicações , Hiperplasia/metabolismo , Hiperplasia/patologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/complicações , Neointima/metabolismo , Neointima/patologiaRESUMO
As one of the most productive marine ecosystems in the tropics and subtropics, mangroves are an important part of the global mercury (Hg) cycling. The environmental processes and effects of Hg in mangroves are complex and affect human Hg exposure, and it is crucial to understand Hg behaviors in the mangrove ecosystem. However, clarifying Hg behaviors in the mangrove ecosystem remains difficult because of an insufficient understanding of the dominant pathways. In this study, measurements of mercury (Hg) concentration and isotope ratios in sediment and plant tissues from a mangrove wetland were used to investigate Hg isotope fractionation in mangrove plants and sediments. Spatial patterns in Hg concentration and isotope signatures indicate that Hg re-emission in the sediment was suppressed by mangrove plants. The ratio of Δ199Hg/Δ201Hg was 0.93 for all sediments, indicating that Hg mass-independent fractionation in the mangrove ecosystem was primarily affected by photoreduction, while the ratios of Δ199Hg/Δ201Hg and Δ199Hg/δ202Hg for plant tissues suggested that natural organic matter reduction of Hg(II) was occurred in the plants. The distinct positive Δ199Hg values found in mangrove plants were supposed to be the results of the unique physiological characteristics of mangroves. The exterior Hg sources from atmosphere and seawater emphasize the role of mangrove ecosystems in the global Hg biogeochemistry. Our study highlights the distinct Hg isotope signatures in the mangrove from that in forests and indicates unique Hg behaviors in the mangrove ecosystem.