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1.
Rev. bras. med. esporte ; 28(6): 686-689, Nov.-Dec. 2022. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1376754

RESUMO

ABSTRACT Introduction The rapid development of competitive sports in the world requires volleyball players not just sufficient physical fitness but also the ability to understand and learn advanced techniques and tactics. In response to the increasing pace of competitive sports, research on fatigue injuries in volleyball players must be deepened and expanded, making coaches and players aware of sports injuries and their means of prevention. Objective Explore the fatigue injury characteristics in volleyball players under jump resistance training. Methods 157 volleyball players from eight sports colleges were selected as the research subject. Composed of 94 male volleyball players and 63 female volleyball players. Results In the investigation of the 157 volleyball players, 153 had some degree of injury, representing a total of 97.1% of the players, and only four non-injured, representing 1.80%; 95 people were injured in special technical training (61.20%); 43 were injured in advanced training (27.62%); 17 people were injured in preparatory activities (10.86%). No one was injured during relaxation activities. Conclusion Preventive measures for fatigue injuries in volleyball players include strengthening with medical supervision and balanced exercise load distribution. With attention to rational preparation of activities including strengthening and knee joint flexibility. Evidence level II; Therapeutic Studies - Investigating the results.


RESUMO Introdução O rápido desenvolvimento dos esportes competitivos no mundo exige que os jogadores de voleibol não tenham apenas aptidão física suficiente, mas também a capacidade de compreender e apreender técnicas e táticas avançadas. Para atender ao ritmo crescente da competição esportiva, deve-se aprofundar e ampliar as pesquisas sobre lesões por fadiga em jogadores de voleibol, fazendo com que treinadores e jogadores se atentem às lesões esportivas e seus meios de prevenção. Objetivo Explorar as características da lesão por fadiga em jogadores de voleibol sob treino de resistência com salto. Métodos 157 jogadores de voleibol de oito faculdades esportivas foram selecionados como objeto de pesquisa. Compostos por 94 jogadores de voleibol masculinos e 63 jogadoras de voleibol feminino. Resultados Na investigação dos 157 jogadores de voleibol, 153 apresentaram algum grau de lesão, representando um total de 97,1% dos jogadores, e apenas 4 não lesionados, representando 1,80%; 95 pessoas ficaram feridas em treinos técnicos especiais (61,20%); 43 feriram-se no treino avançado (27,62%); 17 pessoas feriram-se em atividades preparatórias (10,86%). Ninguém se feriu durante as atividades de relaxamento. Conclusão Medidas preventivas para lesões por fadiga em jogadores de voleibol incluem principalmente o fortalecimento com supervisão médica, a distribuição equilibrada da carga de exercício. Com atenção ao preparo racional das atividades incluindo o fortalecimento e a flexibilidade articular do joelho. Nível de evidência II; Estudos terapêuticos - Investigação de resultados.


RESUMEN Introducción El rápido desarrollo de los deportes de competición en el mundo exige a los jugadores de voleibol no sólo una buena forma física, sino también la capacidad de entender y comprender técnicas y tácticas avanzadas. Para hacer frente al creciente ritmo de la competición deportiva, se debe profundizar y ampliar la investigación sobre las lesiones por fatiga en los jugadores de voleibol, concienciando a entrenadores y jugadores sobre las lesiones deportivas y sus medios de prevención. Objetivo Explorar las características de las lesiones por fatiga en jugadores de voleibol sometidos a un entrenamiento de resistencia con saltos. Métodos Se seleccionaron como objeto de investigación 157 jugadoras de voleibol de ocho escuelas deportivas. Compuesto por 94 jugadores de voleibol masculinos y 63 jugadores de voleibol femeninos. Resultados En la investigación de los 157 jugadores de voleibol, 153 presentaron algún grado de lesión, lo que representa un total del 97,1% de los jugadores, y sólo 4 no lesionados, lo que representa el 1,80%; 95 personas se lesionaron en el entrenamiento técnico especial (61,20%); 43 se lesionaron en el entrenamiento avanzado (27,62%); 17 personas se lesionaron en las actividades preparatorias (10,86%). Nadie resultó herido durante las actividades de relajación. Conclusión Las medidas preventivas de las lesiones por fatiga en los jugadores de voleibol incluyen principalmente el fortalecimiento con supervisión médica, la distribución equilibrada de la carga de ejercicio. Con atención a la preparación racional de las actividades, incluyendo el fortalecimiento y la flexibilidad de la articulación de la rodilla. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35932369

RESUMO

Diabetic retinopathy (DR) is a diabetes mellitus (DM) complication that causes visual acuity impairment and loss of sight in the working population, mainly in developed countries. According to the WHO, DR accounts for 5% of the world's 37 million blind people. The prevalence of diabetic retinopathy was highest in Africa, followed by North America and the Caribbean and South and Central America. Hyperglycemia can generate excessive ROS that activates multiple pathways, which can damage the cells. Oxidative stress and inflammatory process are intricate in the DR pathological mechanism. Bilobalide is the main bioactive compound isolated from the Ginkgo biloba, a plant utilized in folklore medicine. Bilobalide, a sesquiterpene trilactone, exhibits excellent antioxidant activity. But the molecular mechanisms associated with such effects, especially the antioxidant-related mechanism, have not been documented. Hence, this investigation explored whether bilobalide may attenuate DR in streptozotocin (STZ)-prompted diabetic rats. The effects of bilobalide on parameters of antioxidant content, oxidative stress, and inflammatory factors in the retinal tissues were evaluated by ELISA, RT-PCR, and immunohistochemistry methods. Bilobalide improved caloric management by reducing food consumption and increasing body weight. Furthermore, the administration of bilobalide decreases the blood glucose level and glycosylated (HbA1c) hemoglobin. The anti-retinopathy activity of bilobalide was established by the increase in the total retina thickness (TRT), inner nuclear layer (INL), and outer nuclear layer (ONL) in diabetic rats. Additionally, the serum level of MDA was decreased. In contrast, the antioxidant enzyme (SOD and CAT) levels were increased with TAC plus lower Keap1 and higher Nrf2 expression in the retina when associated with the DM rats. Moreover, bilobalide increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1) expression level and inflammatory mediators (NF-κß p65, TNF-α, IL-1ß, and VEGF), thus inhibiting oxidative stress. Bilobalide can be effective against DR, and the possible mechanism may be relatively elucidated by decreasing oxidative stress and anti-inflammatory activities. But the further investigation should be directed to expose the precise mechanism.

3.
Int J Ophthalmol ; 15(7): 1053-1061, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35919326

RESUMO

AIM: To clarify the role of inducible nitric oxide synthase (iNOS) in blood-retinal barrier (BRB) injury after acute high intraocular pressure (IOP) in rats. METHODS: Forty-two Sprague-Dawley (SD) rats were randomized into 7 groups [control (Cont), 3, 6, 12, 24, 48, and 72h, n=6]. Except Cont group, other groups' retina tissue was obtained at corresponding time points after a model of acute high IOP have been established in rats. The expression of iNOS and tight junction protein zonula occludens (ZO)-1 was detected by Western blotting. Evans blue (EB; 3% ) was injected into the great saphenous vein to detect the leakage of EB by spectrophotometer. Nine rats were divided into Cont, 6h, 12h groups, the expression of iNOS was localized by immunofluorescence. In order to verify the role of iNOS in the damage to BRB, thirty-six rats were randomly divided into 4 groups [Cont, Cont+inhibitor (Inh), 6h and 6h+Inh, n=9]. After treatment with the iNOS-specific inhibitor 1400W, the expression of iNOS and ZO-1 and the leakage of BRB were detected again. RESULTS: The immunofluorescence results showed that the expression of iNOS was observed in the Cont group and 6h group, but not in the 12h group. iNOS was mainly expressed in the retinal nerve fiber layer, ganglion cell layer and inner nuclear layer and that it did not colocalize with the retinal ganglion cell marker NeuN but was co-expressed with the vascular endothelial cell marker CD31. Western blotting showed that in the early period (3h, 6h) after acute high IOP, the expression of iNOS was upregulated, then the down-regulation of iNOS were tested in the follow-up timing spots. ZO-1 expression showed a continuous down-regulation after 6h. The quantitative results for EB showed that the amount of EB leakage began to increase at 3h after acute high IOP. At 6h, the leakage of EB was lower, but at 12h, the leakage of EB was highest, after which it gradually recovered but remained higher than that in the Cont group. The expression of iNOS was down-regulated after 1400W treatment. ZO-1 expression was not significantly changed in the Cont+Inh group and the 6h group, and significantly down-regulated in the 6h+Inh group, and the leakage of EB was significantly increased after 1400W treatment. CONCLUSION: These results suggest that the upregulation of iNOS expression in the early stage after acute high IOP may have a protective effect on BRB injury.

5.
Cancer Med ; 2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35933720

RESUMO

BACKGROUND: Several studies have explored the relationship between intratumoral microvessel density (MVD) and the risk of postoperative biochemical recurrence (BCR) in prostate cancer (PCa), although the results are contradictory. Therefore, we conducted a meta-analysis to investigate the effect of MVD on BCR in PCa. METHOD: We searched PubMed, MEDLINE, Science Direct/Elsevier, the Cochrane Library, CNKI, and EMBase databases from inception through January 2022, with no year or language restrictions, and used NOS guidelines to evaluate the quality of the 19 eligible studies. The derived hazard ratio (HR) and 95% confidence interval (95%CI) were used to assess each endpoint. Data synthesis was performed with RevMan to assess the prognostic value of MVD in PCa and its heterogeneity, while the publication bias was examined using STATA 16.0. RESULTS: Our meta-analysis included 19 articles (4 for T1-2, 6 for T1-3, and 9 for T1-4) on postoperative biochemical recurrence of PCa, among which, 3933 patients were pooled. The predictive ability of intratumoral MVD for different stages of PCa on BCR was T1-2 (HR, 2.46; 95% CI, 1.08-5.58; p = 0.03; I2  = 83%), T1-3 (HR, 2.38, 95% CI, 1.41-4.01; p = 0.001; I2  = 82%), T1-4 (HR, 1.61; 95% CI, 1.19-2.19; p = 0.002; I2  = 61%).The subgroup analyses based on European and immunohistochemical antibody none-factor VII were consistent with primary one. Sensitivity analysis excluding those studies judged to be at high risk of bias in T1-2 showed a HR of 2.99[1.70,5.27] (I2  = 38%, p = 0.0001), demonstrating the robustness of risk estimates of MVD for the assessment of biochemical recurrence. CONCLUSION: Microvessel density is a predictor of BCR among patients with PCa, and earlier T stage PCa with a stronger MVD is associated with BCR. Further studies are needed to investigate neoangiogenesis in different T stages of PCa and whether MVD will be of benefit to the EAU-recommended tool for biochemical recurrence risk assessment.

6.
Int J Public Health ; 67: 1604612, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936995

RESUMO

Objectives: The objective of this study is to explore factors affecting the HIV testing behaviors among men who have sex with men (MSM) in China. Methods: A cross-sectional study was conducted in Guilin, China from April to June of 2021. Questionnaire data of 300 MSM were analyzed, and binary logistic regression models were used to examine the socio-demographic and sexual behavior characteristics associated with three HIV testing behaviors (self-testing, institutional testing, and regular testing). Results: The results showed that half of the respondents had the habit of regular HIV testing. Only 30.0% of MSM chose to do HIV testing after high-risk sexual behavior, and self-perceived luck was the main reason for not having HIV testing. Moreover, the influencing factors of three HIV testing behaviors after high-risk sexual behavior differ. Interestingly, income was not related to any of the three HIV testing behaviors among those MSM who participated. Conclusion: This research indicates insufficient health education on HIV testing behaviors among MSM in China. Health promotion practices targeting the MSM population to improve HIV-related knowledge, thus contributing to the HIV epidemic, are required.


Assuntos
Infecções por HIV , Minorias Sexuais e de Gênero , China/epidemiologia , Estudos Transversais , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Teste de HIV , Homossexualidade Masculina , Humanos , Masculino , Comportamento Sexual , Inquéritos e Questionários
7.
Biomaterials ; 287: 121686, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35926357

RESUMO

Renal ischemia-reperfusion (IR) injury (RIRI) is the leading cause of acute kidney injury (AKI), a common disease with high morbidity and mortality. However, due to the lack of effective diagnostic and therapeutic tools, patients have to resort to conservative treatment. To address this issue, we have developed a novel prophylactic strategy that involves the pre-treatment use of ceria nanoparticles (CNPs) before surgery. Based on our careful study of the three different sizes of CNPs that we synthesized, 46 nm (NP46), 81 nm (NP81), and 118 nm (NP118), we have found that NP118 can be used as effective prophylactic agents against RIRI and subsequent renal fibrosis. In our experiments, the CNPs exhibited excellent antioxidant and anti-inflammatory activities in vitro and effectively protected the kidney against RIRI and renal fibrosis in vivo, as proved by the decreases in renal lesions, serum creatinine, blood urea nitrogen, apoptotic cell, KIM-1 expression, and fibrotic area in CNPs treated samples relative to RIRI group. Mechanistically, not only did the CNPs reduce oxidative stress by regulating the Nrf2 pathway, but they also attenuated RIRI induced inflammatory response by decreasing macrophage infiltration and polarization to M1 phenotype, and reducing pro-inflammatory cytokine and chemokine production. In vitro results further confirmed that CNPs pre-treatment not only dramatically decreased intracellular ROS production in renal tubular epithelial cells and vascular endothelial cells, but also effectively attenuated lipopolysaccharide-induced inflammation in RAW264.7 cells. In addition, we found that one fourth of the NP118 persisted for more than 21 days in IR kidneys, and that out of the three sizes of CNPs, NP118 achieved the best results in all our experiments. Our study provides new insights into the usage and majorization of CNPs as a potential therapy to treat or prevent RIRI and renal fibrosis.

8.
Front Immunol ; 13: 896958, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35928814

RESUMO

Vaccines can prevent many millions of illnesses against infectious diseases and save numerous lives every year. However, traditional vaccines such as inactivated viral and live attenuated vaccines cannot adapt to emerging pandemics due to their time-consuming development. With the global outbreak of the COVID-19 epidemic, the virus continues to evolve and mutate, producing mutants with enhanced transmissibility and virulence; the rapid development of vaccines against such emerging global pandemics becomes more and more critical. In recent years, mRNA vaccines have been of significant interest in combating emerging infectious diseases due to their rapid development and large-scale production advantages. However, their development still suffers from many hurdles such as their safety, cellular delivery, uptake, and response to their manufacturing, logistics, and storage. More efforts are still required to optimize the molecular designs of mRNA molecules with increased protein expression and enhanced structural stability. In addition, a variety of delivery systems are also needed to achieve effective delivery of vaccines. In this review, we highlight the advances in mRNA vaccines against various infectious diseases and discuss the molecular design principles and delivery systems of associated mRNA vaccines. The current state of the clinical application of mRNA vaccine pipelines against various infectious diseases and the challenge, safety, and protective effect of associated vaccines are also discussed.


Assuntos
COVID-19 , Doenças Transmissíveis Emergentes , COVID-19/prevenção & controle , Doenças Transmissíveis Emergentes/prevenção & controle , Humanos , RNA Mensageiro/genética , Tecnologia , Vacinação , Vacinas Atenuadas , Vacinas Sintéticas , Vacinas de mRNA
9.
Transl Androl Urol ; 11(7): 943-958, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35958899

RESUMO

Background: As an immunogenic cancer, crosstalk between cancer cells and immune cells has been gradually recognized in bladder cancer (BC). Several studies have emphasized the clinical significance of the molecular stratification of BC without highlighting the role of the immune microenvironment. Although immunotherapy acted as a prospective treatment, more precise molecular stratification should be established to select those sensitive to immunotherapy. Methods: To select specific immune genes forming subtypes indicating disparate prognoses, we performed bioinformatic analysis using BC transcriptomic profiles from six published datasets, with 408 BC samples in The Cancer Genome Atlas (TCGA) database and 295 individuals in International Cancer Genome Consortium (ICGC) database. Survival analyses were conducted using Kaplan-Meier curves, while Kruskal-Wallis tests were applied to test the differences among groups. Except for unsupervised clustering based on the differential expression of genes, we additionally performed binomial logistic regression, focusing on the mRNA level of a single sample. Results: Unsupervised clustering showed that 4 clusters captured the best segmentation. After validation with survival data and simplification using binomial logistic regression, we found that cluster B and cluster D showed worse survival outcomes (P=0.012). Considering the similar survival outcomes of these two clusters, we recombined and performed another survival analysis, which also showed significant survival differences (P=0.0041). Bonding with clinical data, a greater proportion of risk factors were assigned to the worse prognosis subtype, especially showing higher grades in the subtype (P<0.001). In addition, immune cell infiltration, single nucleotide polymorphism (SNP) and copy number variation (CNV) all showed differences between clusters, indicating changes in the immune microenvironment and mutation burden. Through phenotypical analysis, we found metabolism and proliferation phenotypes associated with the immune clusters and mutually exclusive in BC, of which proliferation contributed to worse outcomes. Using the tumor immune dysfunction and exclusion (TIDE) score, a worse immunotherapy benefit was predicted in clusters B&D, defined as the worse prognosis subtype. Conclusions: With this novel clustering criterion based on immune-related genes, we provide a better understanding of the immune microenvironment, further guiding the use of immunotherapy.

11.
Front Cell Dev Biol ; 10: 923371, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912097

RESUMO

Background: Metastases are the main cause of breast cancer-related deaths. Breast cancer has a more aggressive phenotype and less favorable prognosis in young females than in older females. In this study, we aimed to compare the metastatic patterns, survival outcomes and tumor immune microenvironment of young and non-young breast cancer patients. Methods: Patients with a diagnosis of breast cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The significance of young age (≤40 years) in the metastatic profile and prognosis of breast cancer was investigated. The transciptome expression data were acquired from The Cancer Genome Atlas (TCGA) database. And the differentially expressed genes (DEGs) and primarily enriched function pathways were identified by comparing between young and non-young breast cancer samples, and tumor immune infiltrating cell types in the tumor microenvironment were compared. Results: A total of 281,829 female breast cancer patients were included in SEER: 18,331 young (6.5%) and 263,498 non-young (93.5%) women. The metastatic rates of bone, liver and distant lymph nodes (DLNs) in the young cohort were significantly higher than those in the non-young cohort. The most frequent two-site metastatic combination was bone and liver (0.61%) in the young cohort, whereas it was bone and lung (0.32%) in the non-young cohort. Breast cancer-specific survival (BCSS) was significantly shortened among those in the young cohort compared with those in the non-young cohort (p < 0.001). Young age was associated with significantly shorter BCSS only among patients with HR+/HER2- tumors (p < 0.001). The enriched biological pathways based on DEGs between two cohorts were related to the regulation of immune response and several metabolic processes. M2 macrophages were significantly abundant in non-young breast cancer than young breast cancer. Conclusion: Young and non-young breast cancer patients present with different metastatic patterns. Young age is a negative prognostic factor, particularly for HR+/HER2- breast cancer. The differences in metastatic patterns between young and non-young cohorts should be taken into account in the clinical management of metastatic breast cancer. The young breast cancer patients may gain better response to immunotherapy due to immune activated TME than non-young breast cancer.

12.
Brain Connect ; 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35974665

RESUMO

OBJECTIVE: Vagal nerve stimulation (VNS) has emerged as an important modality in treating drug-resistant epilepsy (DRE), but its mechanism remains unclear. To obtain insight into the mechanism of VNS reducing epileptic seizures, the immediate effects of VNS in the brain networks of DRE patients were investigated when the patients' vagal nerve stimulators were running. METHODS: The brain-network characteristics of 14 DRE patients with a vagal nerve stimulator and 14 healthy controls were assessed with magnetoencephalography (MEG) in six commonly used frequency bands. RESULTS: The DRE patients exhibited significant increases in the theta, alpha, beta, and gamma bands in functional connectivity, and significant reductions in the theta and beta bands in the small-world measure in contrast to healthy controls. During the periods of the patients' vagal nerve stimulators running, the DRE patients showed significant reductions in the theta and alpha bands in functional connectivity and a significant increase in the theta band in the small-world measure in contrast to the periods of the patients' vagal nerve stimulators non-running. CONCLUSIONS: Our results indicate that the MEG-based brain functional networks of DRE patients were pathologically hypersynchronous, and the instantaneous VNS can decrease the synchronization of brain functional networks of epileptic patients, which might play an important part in the mechanism of VNS reducing epileptic seizures. In the theta band, the instantaneous VNS can increase the network efficiency of the DRE patients, and the increment in the network efficiency may be helpful for improving the brain cognitive function of epileptic patients.

13.
J Clin Immunol ; 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-35976469

RESUMO

PURPOSE: Mutations in signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) infection, which is attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency. METHODS: Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways. RESULTS: Four, heterozygous STAT1 deficiency mutations were identified, three of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1-deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also intracellular non-mycobacterial bacterial infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ-mediated STAT1 phosphorylation, gamma-activated sequence (GAS), and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients. CONCLUSION: The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host-pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity. Aberrant splice of STAT1 RNA could result in AD-LOF for STAT1 signaling which need more cases for confirmation.

14.
J Am Heart Assoc ; 11(16): e025058, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35929455

RESUMO

Background Insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS-1, CYP2C19*2 genotypes, platelet reactivity, and 1-year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. Methods and Results Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS-1 CG genotype had significantly lower levels of ADP-induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS-1 CG or GG genotype had a 2.09-fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04-4.19; P=0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP-induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19-fold higher risk than those with GG homozygotes (95% CI, 1.13-4.24; P=0.0200). No interaction between IRS-1 and CYP2C19*2 genotypes was observed. Conclusions In patients following percutaneous coronary intervention, IRS-1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09- and 2.19-fold increased cardiovascular risk, respectively, at 1-year follow-up. The association between IRS-1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01968499.

15.
Theranostics ; 12(13): 5727-5743, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35966596

RESUMO

RNA N6 -methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. This study aims to uncover the essential role and the underlying molecular mechanism(s) of the m6A reader YTHDC1 in promoting triple negative breast cancer (TNBC) metastasis. METHODS: In vitro and in vivo models were employed to determine the pathological function of YTHDC1 in TNBC metastasis. To identify bona fide YTHDC1 target RNAs, we conducted RNA-seq, m6A-seq, and RIP-seq, followed by integrative data analysis and validation assays. RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we found that elevated expression of YTHDC1 is positively correlated with poor prognosis in breast cancer patients. Using a mammary fat pad mouse model of TNBC, YTHDC1 significantly promoted lung metastasis of TNBC cells. Through multiple transcriptome-wide sequencing and integrative data analysis, we revealed dysregulation of metastasis-related pathways following YTHDC1 depletion and identified SMAD3 as a bona fide YTHDC1 target RNA. Depletion of YTHDC1 caused nuclear retention of SMAD3 mRNA, leading to lower SMAD3 protein levels. Loss of YTHDC1 led to impaired TGF-ß-induced gene expression, leading to inhibition of epithelial-mesenchymal transition (EMT) and suppressed TNBC cell migration and invasion. SMAD3 overexpression was able to restore the response to TGF-ß in YTHDC1 depleted TNBC cells. Furthermore, we demonstrated that the oncogenic role of YTHDC1 is mediated through its recognition of m6A as m6A-binding defective mutants of YTHDC1 were unable to rescue the impaired cell migration and invasion of YTHDC1 knockout TNBC cells. CONCLUSIONS: We show that YTHDC1 plays a critical oncogenic role in TNBC metastasis through promoting the nuclear export and expression of SMAD3 to augment the TGF-ß signaling cascade. Overall, our study demonstrates that YTHDC1 is vital for TNBC progression by enhancing TNBC cell survival and TGF-ß-mediated EMT via SMAD3 to enable the formation of distant metastasis and highlights the therapeutic potential of targeting the YTHDC1/m6A/SMAD3 axis for TNBC treatment.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Humanos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , RNA , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
16.
PLoS Genet ; 18(8): e1010323, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35972957

RESUMO

A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution's effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases.

17.
Free Radic Biol Med ; 189: 111-121, 2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-35918012

RESUMO

The S-nitrosoglutathione reductase (GSNOR) is a key denitrosating enzyme that regulates protein S-nitrosation, a process which has been found to be involved in the pathogenesis of Parkinson's disease (PD). However, the physiological function of GSNOR in PD remains unknown. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that GSNOR expression was significantly increased and accompanied by autophagy mediated by MPTP-induced cyclin dependent kinase 5 (CDK5), behavioral dyskinesias and dopaminergic neuron loss. Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP.


Assuntos
Intoxicação por MPTP , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Autofagia , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nitrosação , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo
18.
Front Psychiatry ; 13: 875141, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795028

RESUMO

Objectives: Conventional biochemical indexes may have predictive values in clinical identification between bipolar disorder (BD) and major depressive disorder (MDD). Methods: This study included 2,470 (BD/MDD = 1,333/1,137) hospitalized patients in Shanghai as training sets and 2,143 (BD/MDD = 955/1,188) in Hangzhou as test sets. A total of 35 clinical biochemical indexes were tested, including blood cells, immuno-inflammatory factors, liver enzymes, glycemic and lipid parameters, and thyroid and gonadal hormones. A stepwise analysis of a multivariable logistic regression was performed to build a predictive model to identify BD and MDD. Results: Most of these biochemical indexes showed significant differences between BD and MDD groups, such as white blood cell (WBC) in the hematopoietic system, uric acid (UA) in immuno-inflammatory factors, direct bilirubin (DBIL) in liver function, lactic dehydrogenase (LDH) in enzymes, and fasting blood glucose (FBG) and low-density lipoprotein (LDL) in glucolipid metabolism (p-values < 0.05). With these predictors for discrimination, we observed the area under the curve (AUC) of the predictive model to distinguish between BD and MDD to be 0.772 among men and 0.793 among women, with the largest AUC of 0.848 in the luteal phase of women. The χ2 values of internal and external validation for male and female datasets were 2.651/10.264 and 10.873/6.822 (p-values < 0.05), respectively. The AUCs of the test sets were 0.696 for males and 0.707 for females. Conclusion: Discrimination and calibration were satisfactory, with fair-to-good diagnostic accuracy and external calibration capability in the final prediction models. Female patients may have a higher differentiability with a conventional biochemical index than male patients. Trial Registration: ICTRP NCT03949218. Registered on 20 November 2018. Retrospectively registered. https://www.clinicaltrials.gov/ct2/show/NCT03949218?id=NCT03949218&rank=1.

19.
J Anal Methods Chem ; 2022: 7015311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800972

RESUMO

Nucleotide sugars, the activated forms of monosaccharides, are important intermediates of carbohydrate metabolism in all organisms. Here, we describe a method for the detection and quantification of UDP-glucose and UDP-galactose in maize in order to compare their metabolism in both wild-type and mutated plants. Triple quadrupole operating in a multiple reaction monitoring mode was used to quantify nucleotide sugars. The limits of detection for UDP-glucose and UDP-galactose were 0.50 and 0.70 ng·mL-1, respectively. The recoveries of the method ranged from 98.3% to 103.6% with the relative standard deviations less than 6.3%. To prove the applicability of this method, we analyzed several sets of maize extracts obtained from different cultivars grown under standardized greenhouse conditions. All the results demonstrated the suitability of the developed method to quantify UDP-glucose and UDP-galactose in maize extracts.

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