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BACKGROUND: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. However, it is still not well understand about the relationship between PCDH15 variants and RP. METHODS: In this study, we enrolled a Chinese autosomal recessive retinitis pigmentosa (arRP) pedigree and identified the causative gene in the proband by targeted whole exome sequencing (WES). The variants were validated in the family members by Sanger sequencing and co-segregation analysis. RESULTS: Novel compound heterozygous, Frame shift variants of the PCDH15 gene, NM_001384140.1:c.4368 - 2147_4368-2131del and NM_001384140.1:c exon19:c.2505del: p. T836Lfs*6 were identified in the arRP pedigree, which co-segregated with the clinical RP phenotypes. The PCDH15 protein is highly conserved among species. CONCLUSION: This is the first study to identify novel compound heterozygous variants c.4368 - 2147_4368-2131del and c.2505del(p.T836Lfs*6) in the PCDH15 gene which might be disease-causing variants, and extending the variant spectra. All above findings may be contribute to genetic counseling, molecular diagnosis and clinical management of arRP disease.
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Proteínas Relacionadas con las Cadherinas , Cadherinas , Heterocigoto , Linaje , Retinitis Pigmentosa , Humanos , Masculino , Femenino , Cadherinas/genética , Retinitis Pigmentosa/genética , Adulto , China/epidemiología , Secuenciación del Exoma , Análisis Mutacional de ADN , Pueblo Asiatico/genética , Fenotipo , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
Retinal vascular leakage is a major event in several retinal diseases, including diabetic retinopathy (DR). In a previous study, we demonstrated that the aqueous humor concentration of Cystatin C (CST3), a physiological inhibitor of cysteine protease, is negatively correlated with the severity of diabetic macular edema. However, its function in the retina has not been clearly elucidated. In this study, we found a significant decrease in the aqueous humor concentration of CST3 with DR progression. Furthermore, we found that CST3 was expressed in retinal endothelial cells and that its expression was significantly downregulated in high glucose-treated human retinal microvascular endothelial cells (HRMECs) and the retinal vessels of oxygen-induced retinopathy (OIR) mice. Silencing CST3 expression resulted in decreased HRMEC migration and tubule formation ability. Exogenous addition of the CST3 protein significantly improved HRMEC migration and tubular formation. In-vivo experiments demonstrated that CST3 silencing induced retinal vascular leakage in WT mice, while its intravitreal injection significantly reduced retinal leakage in OIR mice. Mechanistically, CST3 promoted the expression of the downstream adhesion molecules, claudin5, VE-cadherin, and ZO-1, in retinal vascular cells by regulating the Rap1 signaling pathway. Therefore, this study revealed a novel mechanism by which CST3 improves retinal vascular function and provided evidence that it is a potential therapeutic target for retinal vascular leakage.
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Objectives: In this study, we compared the dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer. Furthermore, we investigated the potential impact of these changes on the occurrence of toxic side effects. Methods: Patients with gastric cancer who received adjuvant or first-line XELOX/SOX chemotherapy between January 2020 and June 2023 were enrolled. The Brief Conghua Scale was used to assess energy intake, and nutritional management was carried out with reference to the Chinese Guidelines for Nutritional Therapy of Cancer 2020. The NRS 2002 Nutritional Risk Screening Scale, PG-SGA scale, bioelectrical impedance analysis, and dynamic changes in lumbar 3 vertebral skeletal muscle index were compared between baseline and post-chemotherapy in the study. The neutropenia was evaluated using the Common Terminology Criteria for Adverse Events V.5.0, developed by the National Institutes of Health. Results: Dynamic follow-up was completed in 39 cases, with a mean follow-up time of 117.62 ± 43.38 days. The incidence of sarcopenia increased significantly after chemotherapy, escalating from 46.2% to 51.3%. After chemotherapy, the mean L3SMI decreased from 36.00 cm2/m2 to 34.99 cm2/m2. Furthermore, when compared to pre-chemotherapy values, the body composition indexes body mass index (BMI), SL3, fat mass free index (FFMI), lean body mass (LBM), and body surface area (BSA) were significantly reduced after chemotherapy. Regardless of baseline or post-chemotherapy status, the incidence of grade ≥ 3 neutropenia was significantly higher in the sarcopenia group than in the non-sarcopenia group. Furthermore, when the skeletal muscle index decreased during chemotherapy, the incidence of grade ≥ 3 neutropenia was significantly higher in both the sarcopenia and non-sarcopenia groups compared to baseline. When the incidence of grade ≥ 3 neutropenia in the post-chemotherapy sarcopenia group was compared to baseline status, the increase was significantly higher in the sarcopenia group than in the maintenance/increase group. Conclusions: Skeletal muscle mass decreased progressively during XELOX/SOX chemotherapy in gastric cancer patients, followed by a higher incidence of grade ≥ 3 neutropenia.
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Background: Despite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty. Methods: We conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis. Results: Univariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (ß = 0.059, 95% confidence interval [CI], 0.042-0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (ß = 0.063, 95% CI, 0.021-0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (ß= 0.019, 95% CI, 0.013-0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (ß= 0.004, 95% CI, 0.001-0.006, P=1.75E-03, mediated proportion, 6.411%). Conclusions: Within immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.
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Artritis Reumatoide , Asma , Fragilidad , Humanos , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Recuento de LeucocitosRESUMEN
Objective: To review the research progress of reltionship between antitumor drugs and the dynamic changes of the skeletal muscles during treatment phase. Background: Sarcopenia is a common disease in patients with tumors, and it has been agreed that patients with tumors and sarcopenia experience more serious adverse reactions and have a shorter long-term survival after antitumor therapy than patients without sarcopenia. Antitumor drugs whilst beneficial for tumor regression, interferes and synergizes with cancer-induced muscle wasting/sarcopenia, induced myodemia or intramuscular fat and the two conditions often overlap making it difficult to drive conclusions. In recent years, increasing attention has been paid to the dynamic changes in skeletal muscles during antitumor drug therapy. Dynamic changes refer not only measurement skeletal muscle quantity at baseline level, but give more emphasis on the increasing or decreasing level during or end of the whole treatment course. Methods: We retrievaled published English-language original research articles via pubmed, those studies mainly focused on repeated measurements of skeletal muscle index using computed tomography (CT) in cancer patients who received antitumor drug treatment but not received interventions that produced muscle mass change (such as exercise and nutritional interventions). Conclusion: This article will summarize the research progress to date. Most of antineoplastic drug cause skeletal muscle loss during the treatment course, loss of L3 skeletal muscle index is always associated with poor clinical outcomes.
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BACKGROUND: Computed tomography (CT) imaging can help to predict the pathological invasiveness of early-stage lung adenocarcinoma and guide surgical resection. This retrospective study investigated whether CT imaging could distinguish pre-invasive lung adenocarcinoma from IAC. It also compared final pathology prediction accuracy between CT imaging and intraoperative frozen section analysis. METHODS: This study included 2093 patients with early-stage peripheral lung adenocarcinoma who underwent CT imaging and intraoperative frozen section analysis between March 2013 and November 2014. Nodules were classified as ground-glass (GGNs), part-solid (PSNs), and solid nodules according to CT findings; they were classified as pre-IAC and IAC according to final pathology. Univariate, multivariate, and receiver operating characteristic (ROC) curve analyses were performed to evaluate whether CT imaging could distinguish pre-IAC from IAC. The concordance rates of CT imaging and intraoperative frozen section analyses with final pathology were also compared to determine their accuracies. RESULTS: Multivariate analysis identified tumor size as an independent distinguishing factor. ROC curve analyses showed that the optimal cut-off sizes for distinguishing pre-IAC from IAC for GGNs, PSNs, and solid nodules were 10.79, 11.48, and 11.45 mm, respectively. The concordance rate of CT imaging with final pathology was significantly greater than the concordance rate of intraoperative frozen section analysis with final pathology (P = 0.041). CONCLUSION: CT imaging could distinguish pre-IAC from IAC in patients with early-stage lung adenocarcinoma. Because of its accuracy in predicting final pathology, CT imaging could contribute to decisions associated with surgical extent. Multicenter standardized trials are needed to confirm the findings in this study.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón/diagnóstico por imagen , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/cirugía , Estudios de Cohortes , Secciones por Congelación , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Invasividad Neoplásica , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Baiyangdian Lake is the largest shallow lake in the North China Plain. Due to the increases in upstream water consumption in recent decades, the amount of natural water entering the lake has decreased, resulting in a significant drop in the water level of Baiyangdian Lake. Severe eutrophication has occurred in Baiyangdian Lake owing to the discharge of domestic sewage around the sub-lakes. With the establishment of the Xiong'an New Area in 2017, the importance of environmental governance and protection of Baiyangdian Lake has been unprecedentedly increased. The implementation of ecological water supplement from upstream reservoirs and other basins has significantly increased water level of Baiyangdian Lake. Moreover, domestic sewage from surrounding rural areas was collected. In order to understand the current state of water quality in Baiyangdian Lake, and to evaluate the effects of the previous water replenishment and pollution control projects, we investigated water physicochemical variables and aquatic organisms of Baiyangdian Lake in August 2019. We evaluated water quality status of Baiyangdian Lake based on water quality, phytoplankton, zooplankton and macrozoobenthos, by comparing with the evaluation based on the survey data in 2010. In addition, submerged macrophytes were used to evaluate the water ecological status. The results showed that the water quality state of Baiyangdian Lake in 2019 was greatly improved compared with 2010. Among them, total phosphorus concentration decreased by 88.6%, total nitrogen concentration decreased by 83.9%, chlorophyll a concentration decreased by 47.8%, and the Seechi depth increased by 43.4%. The diversity of zooplankton and macrozoobenthos were significantly increased, the density of phytoplankton was significantly reduced, the dominant species of phytoplankton changed from a general highly eutrophic type to a eutrophic type, and the distribution of the clean-type submerged macrophytes was narrowed. The evaluation methods based on submerged macrophytes species and based on zooplankton diversity were not suitable for water quality evaluation in Baiyangdian Lake. In the early stage, the pollution source of Baiyangdian Lake was concentrated in the west, which led to lower water quality. Nowadays, due to the water replenishment from the west, north and south, the hydrodynamic conditions changed significantly. In the west, pollution control projects were carried out, and the spatial distribution of water quality in Baiyangdian Lake are showing a characteristics of homogenization.
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Conservación de los Recursos Naturales , Lagos , China , Clorofila A , Monitoreo del Ambiente , Política Ambiental , Eutrofización , Fósforo/análisis , Fitoplancton , Calidad del AguaRESUMEN
Introduction: Cognitive decline is the core schizophrenia symptom, which is now well accepted. Holding a role in various aspects of cognition, lentiform nucleus (putamen and globus pallidus) dysfunction contributes to the psychopathology of this disease. However, the effects of lentiform nucleus function on cognitive impairments in schizophrenia are yet to be investigated. Objectives: We aim to detect the fractional amplitude of low-frequency fluctuation (fALFF) alterations in patients with schizophrenia, and examine how their behavior correlates in relation to the cognitive impairments of the patients. Methods: All participants underwent magnetic resonance imaging (MRI) and cognitive assessment (digit span and digit symbol coding tests). Screening of brain regions with significant changes in fALFF values was based on analysis of the whole brain. The data were analyzed between Jun 2020 and Mar 2021. There were no interventions beyond the routine therapy determined by their clinicians on the basis of standard clinical practice. Results: There were 136 patients (75 men and 61 women, 24.1 ± 7.4 years old) and 146 healthy controls (82 men and 64 women, 24.2 ± 5.2 years old) involved in the experiments seriatim. Patients with schizophrenia exhibited decreased raw scores in cognitive tests (p < 0.001) and increased fALFF in the bilateral lentiform nuclei (left: 67 voxels; x = -24, y = -6, z = 3; peak t-value = 6.90; right: 16 voxels; x = 18, y = 0, z = 3; peak t-value = 6.36). The fALFF values in the bilateral lentiform nuclei were positively correlated with digit span-backward test scores (left: r = 0.193, p = 0.027; right: r = 0.190, p = 0.030), and the right lentiform nucleus was positively correlated with digit symbol coding scores (r = 0.209, p = 0.016). Conclusion: This study demonstrates that cognitive impairments in schizophrenia are associated with lentiform nucleus function as revealed by MRI, involving working memory and processing speed.
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BACKGROUND: Emerging evidence suggests structural and functional disruptions of the thalamus in schizophrenia, but whether thalamus abnormalities are able to be used for disease identification and prediction of early treatment response in schizophrenia remains to be determined. This study aims at developing and validating a method of disease identification and prediction of treatment response by multi-dimensional thalamic features derived from magnetic resonance imaging in schizophrenia patients using radiomics approaches. METHODS: A total of 390 subjects, including patients with schizophrenia and healthy controls, participated in this study, among which 109 out of 191 patients had clinical characteristics of early outcome (61 responders and 48 non-responders). Thalamus-based radiomics features were extracted and selected. The diagnostic and predictive capacity of multi-dimensional thalamic features was evaluated using radiomics approach. RESULTS: Using radiomics features, the classifier accurately discriminated patients from healthy controls, with an accuracy of 68%. The features were further confirmed in prediction and random forest of treatment response, with an accuracy of 75%. CONCLUSION: Our study demonstrates a radiomics approach by multiple thalamic features to identify schizophrenia and predict early treatment response. Thalamus-based classification could be promising to apply in schizophrenia definition and treatment selection.
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OBJECTIVE: To investigate the expression of aquaporin-4 (AQP4) in thyroid carcinoma (TC) and explore its clinical significance. MATERIALS AND METHODS: The formalin-fixed paraffin-embedded specimens including 275 TC cancer tissues, 258 corresponding paracancerous thyroid tissues and their clinicopathologic data were retrospectively analyzed. Immunohistochemical EnVision two-step method was used to detect the expression of AQP4 in the cancer tissues and adjacent thyroid tissues, and its clinical significance was analyzed. RESULTS: AQP4 could be expressed in both TC cancer tissues and paracancerous thyroid tissues. In TC cancer tissues, the positive expression rate was 99.3% (273/275), and the positive expression rate was 86.4% (223/258) in paracancerous thyroid tissues. The expression level of AQP4 in cancer tissues was significantly higher than that in paracancerous thyroid tissues, and the difference was statistically significant (P < 0.05). The positive expression rates of AQP4 in papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC) and undifferentiated thyroid carcinoma (UTC) were 99.2% (258/260), 100.0% (6/6), 100.0% (6/6) and 100.0% (3/3), respectively and there was little difference in different types of TC. Analysis of relationship between expression level of AQP4 in 275 TC cancer tissues and 260 PTC cancer tissues and clinicopathologic characteristics of patients was not significant correlation (P > 0.05). Among the 275 patients, one (0.4%, 1/275) was diagnosed as neuromyelitis optica spectrum disorder (NMOSD) associated with TC. CONCLUSIONS: AQP4 is generally expressed in TC cancer tissues and paracancerous thyroid tissues. Expression level of AQP4 in cancer tissues was significantly higher than that in paracancerous thyroid tissue. Expression level of AQP4 in TC cancer tissues is not related to the clinicopathological characteristics of the patients. Paraneoplastic NMOSD caused by TC is rare, and whether its specific pathogenesis is related to the expression of AQP4 in TC still needs further study.
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Neuromielitis Óptica , Neoplasias de la Tiroides , Acuaporina 4 , Autoanticuerpos , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: This study will systematically synthesize the evidence on the potential association between non-alcoholic fatty liver (NAFL) and acute cerebral infarction (ACI). METHODS: We will propose literature search in electronic databases (MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science, WANGFANG, and China National Knowledge Infrastructure) from the source to March 1, 2020. There are no restrictions related to the language and publication status. Two review authors will separately carry out records selection, data extraction and study quality assessment. Any divisions will be solved by discussion with consulting a third review author. We will use RevMan 5.3 software to perform data analysis. RESULTS: The present study will afford additional insight into the investigation the association between NAFL and ACI. CONCLUSION: The results of this study will provide helpful evidence to explore the association between NAFL and ACI.Study registration number: INPLASY202040102.
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Isquemia Encefálica/patología , Infarto Cerebral/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad Aguda , Infarto Cerebral/epidemiología , China/epidemiología , Femenino , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Evaluación de Resultado en la Atención de Salud , Metaanálisis como AsuntoRESUMEN
BACKGROUND: This study aims to explore the impact of transcranial Doppler sonography (TDS) for detecting ischemic stroke (IS). METHODS: PUBMED, EMBASE, Cochrane Library, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge In-frastructure will be utilized to examine case-controlled studies that used TDS for detecting IS. All electronic databases will be searched from inception to March 20, 2020. All study selection, data extraction, and study quality assessment will be carried out by 2 independent reviewers. All study quality will be assessed by Quality Assessment of Diagnostic Accuracy Studies tool, and statistical analysis will be performed by RevMan V.5.3 software and Stata V.12.0 software. RESULTS: This study will explore the impact of TDS for detecting IS through sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. CONCLUSION: This study expects to find out whether TDS can be utilized for IS detection.Systematic review registration: INPLASY202040155.
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Isquemia Encefálica/diagnóstico por imagen , Metaanálisis como Asunto , Accidente Cerebrovascular/diagnóstico por imagen , Revisiones Sistemáticas como Asunto , Ultrasonografía Doppler Transcraneal , HumanosRESUMEN
BACKGROUND: This study will specifically investigate the effect of butylphthalide on hemodynamics in patients with watershed stroke (WS). METHODS: We will search the following databases from their inceptions to the March 1, 2020: Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All relevant randomized controlled trials on exploring the effect of butylphthalide on hemodynamics in patients with WS will be considered for inclusion. No language limitation will be imposed to this study. All study quality will be checked using Cochrane risk of bias tool. RevMan 5.3 software will be utilized for data analysis. RESULTS: This study will summarize the latest evidence to investigate the effect of butylphthalide on hemodynamics in patients with WS. CONCLUSION: Findings from this study will provide theoretical basis of butylphthalide on hemodynamics in patients with WS for clinician and future research. DISSEMINATION AND ETHICS: This study is carried out based on the published data, thus, no ethical approval is required. We will submit this study to a peer-reviewed journal for publication. SYSTEMATIC REVIEW REGISTRATION: INPLASY 202030006.
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Benzofuranos/farmacología , Hemodinámica/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , China/epidemiología , Humanos , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Resultado del Tratamiento , Metaanálisis como AsuntoRESUMEN
Rationale: Transmembrane member 16A (TMEM16A) is a component of calcium-activated chloride channels that regulate vascular smooth muscle cell (SMC) proliferation and remodeling. Autophagy, a highly conserved cellular catabolic process in eukaryotes, exerts important physiological functions in vascular SMCs. In the current study, we investigated the relationship between TMEM16A and autophagy during vascular remodeling. Methods: We generated a transgenic mouse that overexpresses TMEM16A specifically in vascular SMCs to verify the role of TMEM16A in vascular remodeling. Techniques employed included immunofluorescence, electron microscopy, co-immunoprecipitation, and Western blotting. Results: Autophagy was activated in aortas from angiotensin II (AngII)-induced hypertensive mice with decreased TMEM16A expression. The numbers of light chain 3B (LC3B)-positive puncta in aortas correlated with the medial cross-sectional aorta areas and TMEM16A expression during hypertension. SMC-specific TMEM16A overexpression markedly inhibited AngII-induced autophagy in mouse aortas. Moreover, in mouse aortic SMCs (MASMCs), AngII-induced autophagosome formation and autophagic flux were blocked by TMEM16A upregulation and were promoted by TMEM16A knockdown. The effect of TMEM16A on autophagy was independent of the mTOR pathway, but was associated with reduced kinase activity of the vacuolar protein sorting 34 (VPS34) enzyme. Overexpression of VPS34 attenuated the effect of TMEM16A overexpression on MASMC proliferation, while the effect of TMEM16A downregulation was abrogated by a VPS34 inhibitor. Further, co-immunoprecipitation assays revealed that TMEM16A interacts with p62. TMEM16A overexpression inhibited AngII-induced p62-Bcl-2 binding and enhanced Bcl-2-Beclin-1 interactions, leading to suppression of Beclin-1/VPS34 complex formation. However, TMEM16A downregulation showed the opposite effects. Conclusion: TMEM16A regulates the four-way interaction between p62, Bcl-2, Beclin-1, and VPS34, and coordinately prevents vascular autophagy and remodeling.
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Anoctamina-1/fisiología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Remodelación Vascular , Animales , Autofagia , Células Cultivadas , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/citología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Transcripción TFIIH/metabolismoRESUMEN
Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl- channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H2O2)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H2O2-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H2O2-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H2O2-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H2O2-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.
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Apoptosis/efectos de los fármacos , Canales de Cloruro/fisiología , Peróxido de Hidrógeno/farmacología , Proteínas Inmediatas-Precoces/fisiología , Presión Osmótica/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología , Animales , Arteria Basilar/citología , Proteína 11 Similar a Bcl2/metabolismo , Regulación hacia Abajo , Proteína Forkhead Box O3/metabolismo , Masculino , Miocitos del Músculo Liso , Ratas Sprague-DawleyRESUMEN
BACKGROUND: This study aims to assess the impact of contrast-enhanced transcranial Doppler ultrasound (cTCD) diagnosis for young adult with cryptogenic stroke (CS). METHODS: This study will analyze data from case-controlled studies investigating the impact of cTCD diagnosis for young adult with CS. A comprehensive literature search will be performed from PUBMED, EMBASE, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang Data from their inceptions up to the August 1, 2019. All databases will be searched with no language limitations. Two researchers will independently carry out study selection, data collection, and study quality assessment. Any discrepancies between two researchers will be solved by a third researcher. We will apply RevMan 5.3 software and Stata 12.0 software for statistical analysis. RESULTS: Outcomes consist of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio for determination of cTCD diagnosis for young adult with CS. CONCLUSION: The results of this study may summarize up-to-date evidence of cTCD diagnosis for young adult with CS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019145641.
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Medios de Contraste/farmacología , Accidente Cerebrovascular/diagnóstico , Ultrasonografía Doppler Transcraneal/métodos , Humanos , Curva ROC , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Hypotonic challenge evoked vascular cell proliferation through activation of volume-regulated Cl- channel (VRCC), leading to a decrease in the intracellular Cl- concentration ([Cl-]i). We hypothesize that the decrease in [Cl-]i may activate one or several Cl--sensitive kinases, resulting in a subsequent signaling cascade. In this study we demonstrated that WNK1, a Cl--sensitive kinase, was involved in VRCC-induced proliferative signaling pathway in A10 vascular smooth muscle cells in vitro. A10 cells were exposed to a hypotonic challenge (225 mosmol·kg-1·H20), which caused significantly increase in WNK1 phosphorylation without altering WNK1 protein expression. WNK1 overexpression significantly increased hypotonic-induced A10 cell proliferation, whereas silencing of WNK1 caused an opposite action. WNK1 mutation did not affect hypotonic-induced WNK1 phosphorylation and cell proliferation. Silencing of WNK1 caused cell cycle arrest at G0/G1 phase and prevented transition from G1 to S phase, whereas the WNK1 overexpression accelerated cell cycle transition from G1 to S phase. Silencing of WNK1 significantly inhibited cyclin D1/cyclin E1 expression and increased p27kip/p21cip expression. WNK1 overexpression significantly increased cyclin D1/cyclin E1 expression and reduced p27KIP/p21CIP expression. In addition, WNK1 knockdown or overexpression significantly attenuated or increased the hypotonic-induced phosphorylation of Akt and PI3K respectively.In conclusion, the reduction in [Cl-]i caused by hypotonic challenge-induced VRCC opening evokes WNK1 phosphorylation in A10 VSMCs, which mediates cell cycle transition from G0/G1 to S phase and proliferation through the PI3K-Akt signaling pathway.
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Proliferación Celular , Cloruros/metabolismo , Proteína Quinasa Deficiente en Lisina WNK 1/metabolismo , Animales , Línea Celular , Ciclina D1/metabolismo , Ciclinas/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Soluciones Hipotónicas , Músculo Liso Vascular , Mutación , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Proteína Quinasa Deficiente en Lisina WNK 1/química , Proteína Quinasa Deficiente en Lisina WNK 1/genéticaRESUMEN
Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.
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Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Inflamación/metabolismo , Inflamación/patología , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Biomarcadores/metabolismo , Línea Celular , Proliferación Celular/fisiología , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Fibrosis/metabolismo , Fibrosis/patología , Inflamasomas/metabolismo , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratones , Transducción de Señal/fisiologíaRESUMEN
Imperviousness in watershed is a key index to measure urbanization status which exerts an important impact on both eco-hydrological process and spatio-temporal pattern. Taking Yuqiao Reservoir Watershed as a case study area, based on the ENVI 5.1 software, the basic impervious surface information was extracted from remote sensing images taken in 1984, 1994, 2004 and 2013. The linear spectral mixture analysis (LSMA) model was applied to extract the impervious surface area (ISA) in nine coverage classes of watershed in order to analyze its spatio-temporal varying trend in terms of the landscape pattern metrics. Results showed that the RMSE and IS pixel accuracy of all samples were 0.005 and 85.4% respectively, which indicated that the method of extracting impervious surface on a basin scale was feasible. The average of ISA showed a linear growth, from 0.16 to 0.23, the impervious surface area increased by 4.9% in the whole watershed, and the total impervious surface area increased by 1 time. In the sub-basin road network, the impervious surface area increased gradually with the density of the road network, and its expansion pattern was of infilling growth. The patch shape of the middle coverage degree was irregular, and its fragmentation degree was the highest. The fragmentation degree and diversity of the landscape in the whole river basin increased year by year due to increasing human disturbance.
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Hidrología , Urbanización , Movimientos del Agua , China , Humanos , Modelos Teóricos , Ríos , Análisis Espacio-TemporalRESUMEN
Common variants of the transcription factor 7-like 2 (TCF7L2) gene were identified as one of the few genetic polymorphisms with powerful effects on the risk of type 2 diabetes (T2D). Given the genetic overlap between polycystic ovary syndrome (PCOS) and T2D, the present study was undertaken to investigate whether the TCF7L2 variants are also associated with PCOS. We analyzed single nucleotide polymorphisms (SNPs) rs11196218 and rs290487 of the TCF7L2 gene, which showed robust associations with T2D in Chinese population, in 430 PCOS patients and 360 control subjects by pyrosequencing, and also assessed the effect of genotype on clinical and biochemical traits in the PCOS group. We found no evidence for association between SNP rs11196218 and PCOS. The SNP rs290487 showed marginal differences in genotype frequencies between the PCOS and control group, with the minor C allele being the at-risk allele for PCOS. In PCOS women, the C allele carriers of rs290487 had higher levels of 2h blood glucose but lower insulinogenic index than noncarriers, suggesting impaired insulin secretion. Our data suggested that the TCF7L2 variants may confer an increased risk for early impairment of glucose homeostasis in PCOS.