RESUMO
Mild cognitive impairment poses an increasing challenge to middle-aged and elderly populations. Traditional Chinese medicinal herbs like Cistanche tubulosa and Ginkgo biloba (CG) have been proposed as potential agents to improve cognitive and memory functions. A randomized controlled trial involving 100 Chinese middle-aged and elderly participants was conducted to investigate the potential synergistic effects of CG on cognitive function in individuals at risk of neurodegenerative diseases. Over 90 days, both CG group and placebo group received two tablets daily, with each pair of CG tablets containing 72 mg echinacoside and 27 mg flavonol glycosides. Cognitive functions were assessed using multiple scales and blood biomarkers were determined at baseline, Day 45, and Day 90. The CG group exhibited significant improvements in the scores of Mini-Mental State Examination (26.5 at baseline vs. 27.1 at Day 90, p < 0.001), Montreal Cognitive Assessment (23.4 at baseline vs. 25.3 at Day 90, p < 0.001), and World Health Organization Quality of Life (81.6 at baseline vs. 84.2 at Day 90, p < 0.001), all surpassing scores in placebo group. Notably, both the Cognitrax matrix test and the Wechsler Memory Scale-Revised demonstrated enhanced memory functions, including long-term and delayed memory, after CG intervention. Moreover, cognitive-related blood biomarkers, including total tau, pT181, pS199, pT231, pS396, and thyroid-stimulating hormone, significantly decreased, whereas triiodothyronine and free triiodothyronine significantly increased. No treatment-related adverse events were reported, and routine blood and urine tests remained stable. These findings indicated that CG supplementation could potentially serve as an effective supplementary solution for enhancing cognitive and memory functions.
Assuntos
Cistanche , Cognição , Disfunção Cognitiva , Ginkgo biloba , Extratos Vegetais , Humanos , Ginkgo biloba/química , Cistanche/química , Método Duplo-Cego , Masculino , Pessoa de Meia-Idade , Feminino , Extratos Vegetais/farmacologia , Idoso , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Qualidade de Vida , Glicosídeos/farmacologia , Biomarcadores/sangue , Extrato de GinkgoRESUMO
Objective: Study the relationship between ß2 microglobulin, small density, low-density lipoprotein and carotid plaque instability after acute thrombolysis in ischemic stroke patients (IS). Methods: 319 patients with acute cerebral infarction who were treated by thrombolysis in the Department of Neurology, Chongming Branch of Shanghai Xinhua Hospital from January 2017 to May 2022 were included retrospectively. All subjects have undergone a carotid artery ultrasound examination for plaque. According to the ultrasound results, the subjects were divided into plaque-free group (94 cases), a stable plaque group (38 cases) and an unstable plaque group (187 cases). Use an automatic blood biochemical analyzer to detect routine indicators. At the same time, compare the differences of risk factors and biochemical indicators among the groups according to the demographic data of the patient's previous hospitalization. To further evaluate the related risk factors of the instability of carotid plaque in patients through the multivariate logistic regression analysis, the odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Analysis the predictive value of ß2 microglobulin and small density low density lipoprotein on the instability of carotid plaque in I.S. patients after acute thrombolysis through subject work characteristic curve (ROC). Results: Among 319 patients, 187 had unstable plaque accounting for 58.6% and 38 had stable plaque accounting for 11.9%, according to the comparison of general clinical data. Lymphocyte, neutrophil ratio, triglyceride, T3, Hcy, ß2 microglobulin has statistical significance in the presence or absence of plaque. Lymphocytes, small dense low-density lipoprotein, ß2 microglobulin have statistical significance in the stability of plaque (P < .05). Total cholesterol, hypertension, ß2 microglobulin and small density low-density lipoprotein may be independent risk factors of carotid plaque instability through multivariate logistic regression analysis (P < .05). The area under ROC curve showed that ß2 microglobulin AUC: 0.6388, P < .05, small density low-density lipoprotein AUC: 0.6086, P < .05, combined diagnosis AUC: 0.6924, P < .05. Conclusion: ß2 microglobulin and density low-density lipoprotein are independent risk factors of carotid artery plaque instability in I.S. patients after acute thrombolysis. Moreover, the sensibility and differential of combined diagnosis are higher, which has certain predictive value for the instability of carotid plaque in such patients.
RESUMO
Ionizing radiation, a standard therapeutic approach for lung cancer, often leads to cellular senescence and the induction of epithelial-mesenchymal transition (EMT), posing significant challenges in treatment efficacy and cancer progression. Overcoming these obstacles is crucial for enhancing therapeutic outcomes in lung cancer management. This study investigates the effects of ionizing radiation and gemcitabine on lung cancer cells, with a focus on induced senescence, EMT, and apoptosis. Human-derived A549, PC-9, and mouse-derived Lewis lung carcinoma cells exposed to 10 Gy X-ray irradiation exhibited senescence, as indicated by morphological changes, ß-galactosidase staining, and cell cycle arrest through the p53-p21 pathway. Ionizing radiation also promoted EMT via TGFß/SMAD signaling, evidenced by increased TGFß1 levels, altered EMT marker expressions, and enhanced cell migration. Gemcitabine, a first-line lung cancer treatment, was shown to enhance apoptosis in senescent cells caused by radiation. It inhibited cell proliferation, induced mitochondrial damage, and triggered caspase-mediated apoptosis, thus mitigating EMT in vitro. Furthermore, in vivo studies using a lung cancer mouse model revealed that gemcitabine, combined with radiation, significantly reduced tumor volume and weight, extended survival, and suppressed malignancy indices in irradiated tumors. Collectively, these findings demonstrate that gemcitabine enhances the therapeutic efficacy against radiation-resistant lung cancer cells, both by inducing apoptosis in senescent cells and inhibiting EMT, offering potential improvements in lung cancer treatment strategies.
Assuntos
Antimetabólitos Antineoplásicos , Senescência Celular , Desoxicitidina , Transição Epitelial-Mesenquimal , Gencitabina , Neoplasias Pulmonares , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Animais , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Camundongos , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Células A549 , Radiação Ionizante , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiaçãoRESUMO
PURPOSE: This study aims to appraise the therapeutic effectiveness of intravitreal injections anti-vascular endothelial growth factor (anti-VEGF) vs alternative therapies in managing radiation retinopathy (RR). DESIGN: Systematic review and meta-analysis. METHODS: We obtained comprehensive data retrieval using PubMed, Embase, Web of Science, Scopus, and the Cochrane Library from their inception until December 15, 2023. This review included randomized controlled trials (RCTs) and nonrandomized studies (NRSs) reporting on best-corrected visual acuity (BCVA) among RR patients treated with intravitreal anti-VEGF. Study selection and data extraction were meticulously performed by 2 independent reviewers. The Cochrane Risk of Bias Tool 2.0 (RoB 2.0) and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) scales were utilized for bias risk assessment. Quantification of heterogeneity was executed using Q, H, and I2 statistics. The primary endpoint was the BCVA at the final observation point of each study. Secondary endpoints included central retinal thickness (CRT), foveal avascular zone (FAZ) area, and capillary density (CD) at the level of superficial capillary plexus. Subgroup analyses were undertaken to explore potential heterogeneity sources possibly due to treatment duration and study design. Sensitivity analyses were conducted to ascertain result stability. RESULTS: This analysis incorporated 7 studies (including 3 RCTs) encompassing 922 patients afflicted with RR. Relative to other treatment modalities, intravitreal anti-VEGF therapy was associated with a statistically significant mean decrease in BCVA of -0.34 logMAR (95% CI, -0.39 to -0.30 logMAR; I2 = 87.70%; P < .001), and a substantial reduction in CRT of -34.65 µm (95% CI, -50.70 to -18.60 µm; I2 = 30.40%; P < .001). Additionally, a reduction in the FAZ area by -0.69 mm² (95% CI, -0.91 to -0.46 mm², I2 = 0%; P < .001) was observed. A positive tendency was noted in CD at the superficial capillary plexus between anti-VEGF and other therapeutic interventions. CONCLUSIONS: Intravitreal anti-VEGF injections, in comparison to other treatments, demonstrate superior efficacy in enhancing BCVA and reducing CRT, thereby underscoring the potential of anti-VEGF in ameliorating radiation retinopathy outcomes. However, the conclusions are constrained by the incorporation of data from some NRSs and the small sample sizes.
Assuntos
Inibidores da Angiogênese , Injeções Intravítreas , Lesões por Radiação , Doenças Retinianas , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Humanos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Lesões por Radiação/tratamento farmacológico , Acuidade Visual/fisiologia , Doenças Retinianas/tratamento farmacológico , Resultado do Tratamento , Tomografia de Coerência ÓpticaRESUMO
Creatine is an essential metabolite for the storage and rapid supply of energy in muscle and nerve cells. In humans, impaired metabolism, transport, and distribution of creatine throughout tissues can cause varying forms of mental disability, also known as creatine deficiency syndrome (CDS). So far, 80 mutations in the creatine transporter (SLC6A8) have been associated to CDS. To better understand the effect of human genetic variants on the physiology of SLC6A8 and their possible impact on CDS, we studied 30 missense variants including 15 variants of unknown significance, two of which are reported here for the first time. We expressed these variants in HEK293 cells and explored their subcellular localization and transport activity. We also applied computational methods to predict variant effect and estimate site-specific changes in thermodynamic stability. To explore variants that might have a differential effect on the transporter's conformers along the transport cycle, we constructed homology models of the inward facing, and outward facing conformations. In addition, we used mass-spectrometry to study proteins that interact with wild type SLC6A8 and five selected variants in HEK293 cells. In silico models of the protein complexes revealed how two variants impact the interaction interface of SLC6A8 with other proteins and how pathogenic variants lead to an enrichment of ER protein partners. Overall, our integrated analysis disambiguates the pathogenicity of 15 variants of unknown significance revealing diverse mechanisms of pathogenicity, including two previously unreported variants obtained from patients suffering from the creatine deficiency syndrome.
Assuntos
Encefalopatias Metabólicas Congênitas , Creatina , Deficiência Intelectual Ligada ao Cromossomo X , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Humanos , Creatina/deficiência , Células HEK293 , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Encefalopatias Metabólicas Congênitas/genética , Análise Mutacional de DNA/métodos , Mutação de Sentido Incorreto , Biologia Computacional/métodosRESUMO
Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.
Assuntos
Ferroptose , Neoplasias , Humanos , Ácidos Graxos não Esterificados/farmacologia , Mitofagia , Ferro/metabolismo , Neoplasias/metabolismo , Peroxidação de Lipídeos , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismoRESUMO
Radiotherapy is an important cancer treatment strategy that causes DNA damage in tumor cells either directly or indirectly. Autophagy is a physiological process linked to DNA damage. Mitophagy is a form of autophagy, which specifically targets and eliminates impaired mitochondria, thereby upholding cellular homeostasis. However, the connection between DNA damage and mitophagy has yet to be fully elucidated. We found that mitophagy, as an upstream signal, increases ionizing radiation-induced DNA damage by downregulating or overexpressing key mitophagy proteins Parkin and BNIP3. Enhancing the basal level of mitophagy in conjunction with X-ray irradiation can potentially diminish cell cycle arrest at the G2/M phase, substantially elevate the accumulation of γ-H2AX, 53BP1, and PARP1 foci within the nucleus, augment DNA damage, and facilitate the demise of tumor cells. Consequently, this approach prolongs the survival of melanoma-bearing mice. The findings of this study are anticipated to offer a therapeutic approach for enhancing the therapeutic effectiveness of radiotherapy.
RESUMO
The coronavirus SARS-CoV-2, the agent of the deadly COVID-19 pandemic, is an enveloped virus propagating within the endocytic and secretory organelles of host mammalian cells. Enveloped viruses modify the ionic homeostasis of organelles to render their intra-luminal milieu permissive for viral entry, replication and egress. Here, we show that infection of Vero E6 cells with the delta variant of the SARS-CoV-2 alkalinizes the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) as well as lysosomes, mimicking the effect of inhibitors of vacuolar proton ATPases. We further show the envelope protein of SARS-CoV-2 accumulates in the ERGIC when expressed in mammalian cells and selectively dissipates the ERGIC pH. This viroporin action is prevented by mutations of Val25 but not Asn15 within the channel pore of the envelope (E) protein. We conclude that the envelope protein acts as a proton channel in the ERGIC to mitigate the acidity of this intermediate compartment. The altered pH homeostasis of the ERGIC likely contributes to the virus fitness and pathogenicity, making the E channel an attractive drug target for the treatment of COVID-19.
Assuntos
COVID-19 , Proteínas do Envelope Viral , Animais , Humanos , Proteínas do Envelope Viral/metabolismo , Proteínas Viroporinas/metabolismo , COVID-19/metabolismo , Prótons , Pandemias , SARS-CoV-2/metabolismo , Complexo de Golgi/metabolismo , Lisossomos/metabolismo , Mamíferos/metabolismoRESUMO
Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+ /H+ exchanger (CHE). Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell-based and cell-free biochemical assays demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout or pH-sensing site mutants, respectively, and pH-dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.
Assuntos
Antiporters , Prótons , Antiporters/genéticaRESUMO
Calreticulin is an endoplasmic Ca2+ binding protein and molecular chaperone. As a cardiac embryonic gene, calreticulin is essential for heart development. The protein supports Ca2+-dependent signaling events that are critical to cardiomyocyte differentiation and cardiogenesis. The increased expression of calreticulin and endoplasmic reticulum/sarcoplasmic reticulum Ca2+ capacity produces cardiomyocytes with enhanced efficiency, and detrimental mechanical stretching of cardiac fibroblasts, leading to cardiac pathology. Deletion of the calreticulin gene in adult cardiomyocytes results in left ventricle dilation, an impaired electrocardiogram, and heart failure. These observations indicate that a well-adjusted endoplasmic reticulum and calreticulin-dependent Ca2+ pool in cardiomyocytes are critical for the maintenance of proper cardiac function.
Assuntos
Cálcio , Calreticulina , Cálcio/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Retículo Endoplasmático/metabolismo , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMO
NPM1 plays an important role in the occurrence and development of leukemia and various solid tumors. This study aimed to investigate the expression of NPM1 in gastric cancer (GC) and adjacent normal tissues, study the relationship between NPM1 expression and clinicopathological characteristics in GC patients, and explore the impact of NPM1 expression on the diagnosis and prognosis of GC. We used tissue microarray immunohistochemical analysis to examine the expression level of NPM1 in GC and adjacent tissues and analyzed the relationship between NPM1 expression, clinicopathological factors, and GC prognosis. Prognostic values of NPM1 mRNA were also investigated using an online database. qRT-PCR was used to detect the expression of NPM1 mRNA in cancer and adjacent tissues. According to microarray immunohistochemical analysis and qRT-PCR results, NPM1 had a high expression in all adjacent normal tissues. Microarray immunohistochemical analyses demonstrated that the NPM1 was lowly expressed in 75.5% of GC tissues but highly expressed in 24.5% of GC tissues. qRT-PCR results showed NPM1 mRNA low expression in most GC tissues. NPM1 high expression group was associated with a better overall survival rate and disease-free survival rate than the NPM1 low expression group (p<0.01). This result is consistent with that of the online database. The receiver operating characteristics curve showed that NPM1 was valuable in the diagnosis of GC. The assessment of NPM1 expression in GC samples may represent a useful tool for GC diagnosis and prognosis assessment.
Assuntos
Neoplasias Gástricas , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
The stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum (ER) Ca2+ sensor that regulates the activity of Orai plasma membrane Ca2+ channels to mediate the store-operated Ca2+ entry pathway essential for immunity. Uncoordinated 93 homolog B1 (UNC93B1) is a multiple membrane-spanning ER protein that acts as a trafficking chaperone by guiding nucleic-acid sensing toll-like receptors to their respective endosomal signaling compartments. We previously showed that UNC93B1 interacts with STIM1 to promote antigen cross-presentation in dendritic cells, but the STIM1 binding site(s) and activation step(s) impacted by this interaction remained unknown. In this study, we show that UNC93B1 interacts with STIM1 in the ER lumen by binding to residues in close proximity to the transmembrane domain. Cysteine crosslinking in vivo showed that UNC93B1 binding promotes the zipping of transmembrane and proximal cytosolic helices within resting STIM1 dimers, priming STIM1 for translocation. In addition, we show that UNC93B1 deficiency reduces store-operated Ca2+ entry and STIM1-Orai1 interactions and targets STIM1 to lighter ER domains, whereas UNC93B1 expression accelerates the recruitment of STIM1 to cortical ER domains. We conclude that UNC93B1 therefore acts as a trafficking chaperone by maintaining the pool of resting STIM1 proteins in a state primed for activation, enabling their rapid translocation in an extended conformation to cortical ER signaling compartments.
Assuntos
Cálcio , Retículo Endoplasmático , Proteínas de Membrana Transportadoras , Molécula 1 de Interação Estromal , Animais , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Membrana Celular/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Mamíferos/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismoRESUMO
Hyccin/FAM126A mutations are linked to hypomyelination and congenital cataract disease (HCC), but whether and how Hyccin/FAM126A deficiency causes hypomyelination remains undetermined. This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila. Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα. Additionally, PI4KIIIα knockdown in glia phenocopied Hyccin/FAM126A knockdown, and this was partially rescued by overexpressing the recombinant PI4KIIIα, but not human FAM126A or FAM126B. This study establishes an animal model of HCC and indicates that Hyccin/FAM126A plays an essential role in glial enrichment and axonal sheath in a cell-autonomous manner in the visual system via controlling the expression and stabilization of the PI4KIIIα complex at the plasma membrane.
Assuntos
Axônios , Membrana Celular , Proteínas de Drosophila , Drosophila melanogaster , Antígenos de Histocompatibilidade Menor , Neuroglia , Fosfotransferases (Aceptor do Grupo Álcool) , Animais , Axônios/metabolismo , Membrana Celular/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Fluorescência Verde/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Complexos Multiproteicos/metabolismo , Neuroglia/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ligação Proteica , Vias Visuais/metabolismoRESUMO
Efficient immune responses require Ca2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 promotes TCR recruitment and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel remained in cholesterol-poor domains upon enforced ZDHHC20 expression and was recruited less efficiently to the IS along with actin and TCR. Our results establish S-acylation as a critical regulator of ORAI1 channel trafficking and function at the IS and reveal that ORAI1 S-acylation enhances TCR recruitment to the synapse.
Assuntos
Aciltransferases/genética , Cálcio/metabolismo , Proteína ORAI1/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Acilação , Aciltransferases/metabolismo , Células Apresentadoras de Antígenos/metabolismo , Células HEK293 , Humanos , Células Jurkat/metabolismo , Microdomínios da Membrana/metabolismo , Proteína ORAI1/metabolismo , Enxofre/metabolismo , Linfócitos T/metabolismoRESUMO
The endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) interacts with ORAI Ca2+ channels at the plasma membrane to regulate immune and muscle cell function. The conformational changes underlying STIM1 activation, translocation, and ORAI1 trapping and gating, are stringently regulated by post-translational modifications and accessory proteins. Here, we review the recent progress in the identification and characterization of ER and cytosolic proteins interacting with STIM1 to control its activation and deactivation during store-operated Ca2+ entry (SOCE).
Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio/genética , Proteínas de Membrana/genética , Proteína ORAI1/genética , Molécula 1 de Interação Estromal/genéticaRESUMO
Stroke is one of the diseases that seriously threaten the survival and health of human beings. In Europe and the United States, stroke is the second leading cause of death after heart disease and tumors. Stroke is also one of the fatal diseases in Asian countries. On average, about 1.5 million new stroke patients are added each year in China, and the incidence of stroke is increasing year by year. About 80% of all stroke patients are ischemic stroke, and symptomatic internal carotid atherosclerotic stenosis is another important cause of ischemic stroke. Ipsilateral carotid stenosis ≥50% increases the incidence of transient cerebral ischemia and stroke in the carotid artery region by 10% to 15%, and is also closely related to the recurrence of acute and long-term stroke in patients. Therefore, the clinical application and efficacy of carotid stenting in patients with symptomatic internal carotid artery stenosis are analyzed and evaluated to provide a basis for the selection of clinical treatment options.The clinical data of patients with symptomatic carotid stenosis who underwent carotid stenting and the clinical data of conservative treatment of patients with symptomatic carotid stenosis were retrospectively analyzed, and the carotid stenosis rate, symptoms, and National Institute of Health stroke scale where compared before and after surgery. And activities of daily living score. Because the control group treatment method in this article is completely free for patients to choose, and belongs to a retrospective analysis, the results suggest that it can provide a high-quality treatment approach for the treatment of patients with symptomatic carotid stenosis, without causing any harm to the patient, So no ethical approval is needed, and no patient informed consent is required.In recent years, with the continuous advancement of science and technology and new stent materials, intravascular interventional technology has developed rapidly. In continuous clinical practice and research, the safety and effectiveness of stent technology have also been gradually improved. Arterial stenting has gradually become an important method for the treatment of atherosclerotic carotid stenosis. This technique can not only improve the symptoms and prognosis of patients with symptomatic internal carotid stenosis, but also prevent the occurrence of ischemic events. The promotion of this technology has the effect of reducing disability and mortality.The alternative therapy of drug therapy, namely arterial stent implantation, has become a new way to treat atherosclerotic stroke. This treatment technology can quickly relieve the abnormal hemodynamics of distal blood vessels caused by arterial stenosis, which is ischemic. Cerebrovascular disease provides new ideas for treatment. Carotid angioplasty and stenting for symptomatic internal carotid stenosis under a distal cerebral protection device is a safe and effective treatment.
Assuntos
Estenose das Carótidas/cirurgia , Stents , Atividades Cotidianas , Idoso , Angiografia , Artéria Carótida Interna , Estenose das Carótidas/tratamento farmacológico , Procedimentos Endovasculares , Feminino , Humanos , Masculino , Estudos Retrospectivos , Acidente Vascular Cerebral/prevenção & controleRESUMO
Evidence indicates that aberrantly expressed long non-coding RNAs (lncRNAs) are involved in the development and progression of advanced gastric cancer (AGC). Using RNA sequencing data and clinical information obtained from The Cancer Gene Atlas, we combined differential lncRNA expression profiling and weighted gene co-expression network analysis to identify key lncRNAs associated with AGC progression and prognosis. Cancer susceptibility 19 (CASC19) was the top hub lncRNA among the lncRNAs included in the gene module most significantly correlated with AGC's pathological variables. CASC19 was upregulated in AGC clinical samples and was significantly associated with higher pathologic TNM stage, pathologic T stage, lymph node metastasis, and poor overall survival. Multivariable Cox analysis confirmed that CASC19 overexpression is an independent prognostic factor for overall survival. Furthermore, quantitative real-time PCR assay confirmed that CASC19 expression in four human gastric cancer cells (AGS, BGC-823, MGC-803, and HGC-27) was significantly upregulated compared with human normal gastric mucosal epithelial cell line (GES-1). Functionally, CASC19 knockdown inhibited GC cell proliferation and migration in vitro. These findings suggest that CASC19 may be a novel prognostic biomarker and a potential therapeutic target for AGC.
Assuntos
RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
Ca2+ is an important intracellular messenger affecting diverse cellular processes. In eukaryotic cells, Ca2+ is handled by a myriad of Ca2+-binding proteins found in organelles that are organized into the cellular reticular network (CRN). The network is comprised of the endoplasmic reticulum, Golgi apparatus, lysosomes, membranous components of the endocytic and exocytic pathways, peroxisomes, and the nuclear envelope. Membrane contact sites between the different components of the CRN enable the rapid movement of Ca2+, and communication of Ca2+ status, within the network. Ca2+-handling proteins that reside in the CRN facilitate Ca2+ sensing, buffering, and cellular signaling to coordinate the many processes that operate within the cell.
Assuntos
Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Organelas/metabolismo , Animais , Endocitose , Exocitose , HumanosRESUMO
Endoplasmic reticulum (ER) luminal Ca2+ influences many functions of this organelle, notably the synthesis and quality control of proteins and lipids. Cholesterol is an essential component of biological membranes and a precursor for many biologically important signaling molecules. The sterol regulatory element-binding proteins (SREBPs) are key regulators of lipid metabolism. These transcription factors are synthesized as ER membrane-bound precursor proteins that are proteolytically processed in response to cellular cholesterol status. Recently, ER Ca2+ status was shown to be an important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway. This article discusses the emerging relationship between cellular Ca2+ and cholesterol metabolism.