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Parkinson's disease (PD) is one of the most common and complex Neurodegeneration, with an inherited metabolic disorder. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in metabolic regulation. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here, we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vitro, proteasome impairment models of PD were utilized. Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 µmol/L) for 12 h, then with 50 ng/ml FGF-21 with or without 5 mmol/L of 3-methyladenine.The cells were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. Our data indicate that FGF21 prevents dopaminergic neuron loss and shows beneficial effects against proteasome impairment induced PD syndrome, indicating it might be a potent candidate for developing novel drugs to deal with PD.
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Neuroblastoma , Doença de Parkinson , Humanos , Autofagia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.
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Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at an earlier stage could improve long-term patient outcomes. However, there is no consensus on the early detection strategies for EC and the current diagnostic practices such as transvaginal ultrasound, hysteroscopy and endometrial biopsy are invasive, costly and low in specificity. Thus, accurate and less invasive screening tests that detect EC in women with early stages of the disease are needed. Current research has revolutionized novel EC early detection methodologies in many aspects. This review aims to comprehensively characterizes minimally invasive screening techniques that can be applied to EC in the future, and fully demonstrate their potential in the early detection of EC.
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Neoplasias do Endométrio , Gravidez , Feminino , Humanos , Neoplasias do Endométrio/diagnóstico , Endométrio/diagnóstico por imagem , Endométrio/patologia , Biópsia , Ultrassonografia/métodos , Histeroscopia , Detecção Precoce de Câncer/métodosRESUMO
BACKGROUND: QP001, a novel meloxicam formulation, has been developed to manage moderate to severe postoperative pain. This study aimed to evaluate the efficacy and safety of QP001 injections for moderate to severe pain following abdominal surgery. METHOD: This prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial enlisted patients experiencing moderate to severe pain following abdominal surgery. These patients were randomized to receive either QP001 injections (30 mg or 60 mg) or a placebo pre-surgery. The primary efficacy endpoint was the total morphine consumption within 24 h after the first administration. RESULTS: A total of 108 patients were enrolled, and 106 patients completed the study. The total morphine consumption in the QP001 30 mg group and 60 mg group, versus placebo group, were significantly lower over the following 24 h (5.11[5.46] vs 8.86[7.67], P = 0.011; 3.11[3.08] vs 8.86[7.67], P < 0.001), respectively. The total morphine consumption in the QP001 30 mg and 60 mg groups, versus placebo group, was also significantly decreased over the following 48 h, including the 24-48 h period (P ≤ 0.001). The QP001 30 mg and 60 mg groups, versus placebo, showed a significant decrease in the area under the curve for pain intensity-time as well as a significant decrease in the effective pressing times of the analgesic pump over the 24 h and 48 h periods (P < 0.05). The QP001 groups, versus placebo, show no significant different in Adverse Events or Adverse Drug Reactions (P > 0.05). CONCLUSION: Preoperative/preemptive QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain following abdominal surgery, while maintaining a favorable safety profile.
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Analgesia , Analgésicos Opioides , Humanos , Analgésicos Opioides/efeitos adversos , Meloxicam/uso terapêutico , Estudos Prospectivos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológicoRESUMO
We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.
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Barreira Hematoencefálica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , AVC Isquêmico/metabolismo , NADPH Oxidases/antagonistas & inibidores , Acetofenonas/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , AVC Isquêmico/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Ocludina/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: There are few studies on the relative factors related to postoperative recurrence. OBJECTIVES: To compare the outcomes of pelvic floor reconstruction involving Herniamesh mesh and biological grafts and to investigate the correlative factors of postoperative recurrence. METHOD: Two hundred and thirty-two patients were randomly divided into 2 groups: Herniamesh mesh group (117) and biological graft group (115). Follow-ups for 6 months and 1 year after the surgery. The primary outcomes were recurrence, perioperative complications. Secondary outcome was a questionnaire about the life habits associated with relapse. RESULTS: The recurrence rate at 6 months or 1 year did not differ substantially between the 2 groups (p = 0.787 and 0.968, respectively). Adverse events occurred with significantly different frequencies over 1 year (p = 0.005). Twelve factors were investigated and analyzed by logistic regression analysis. It showed that recurrence had a strong association with a long-term vegetarian diet (OR 0.283, 95% CI 0.117-0.683), long-term soybean product diet (OR 8.010, 95% CI 2.514-25.523), and vaginal intercourse (OR 5.154, 95% CI 1.461-18.184). CONCLUSIONS: The surgical recurrence rate for the mesh was similar to biological grafts at short-term follow-up. Eating soy products often and vaginal intercourse after surgery can reduce recurrence.
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Prolapso de Órgão Pélvico/cirurgia , Pelve/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Telas Cirúrgicas , Transplantes , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Método Simples-Cego , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Upper-excited state emission is not usually observed from molecules owing to competition with much faster nonradiative relaxation pathways; however, it can be made more efficient by modifying the photonic density of states to enhance the radiative decay rate. Here, we show that embedding the small molecule zinc tetraphenylporphyrin (ZnTPP) in a hyperbolic metamaterial enables an â¼18-fold increase in fluorescence intensity from the second singlet excited state ( S2) relative to that from the lowest singlet excited state ( S1). By varying the number of periods in the HMM stack, we are able to systematically tune the ZnTPP fluorescence spectrum from red (dominated by emission from S1) to blue (dominated by emission from S2) with an instrument-limited decay lifetime <10 ps. Our results are consistent with a broadband Purcell enhancement in the radiative rate of both transitions predicted via transfer matrix modeling and point to a general opportunity to harness upper-excited states for spectrally tunable, ultrafast fluorescence via radiative decay engineering.
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BACKGROUND: Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy. RESULTS: We demonstrated that the histone acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells. CONCLUSIONS: The effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição de p300-CBP/genética , Acetilação , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Ligação ProteicaRESUMO
Mammalian Sirtuin proteins (SIRTs) are homologs of yeast Sir2, and characterized as class III histone deacetylases of NAD(+) dependence. Unlike their lower counterparts that are directly involved in the extending of lifespan, mammalian SIRTs mainly function in metabolism and cellular homeostasis, among them, SIRT7 is the least understood. SIRT7 is localized in the nucleus and rich in nucleoli associated with RNA polymerase I, and correlated with cell proliferation. In contrast, SIRT7 has recently been demonstrated to specifically deacetylate H3K18ac in the chromatin, and in most cases represses proliferation. Although MicroRNA as miR-125b has been reported to down-regulate SIRT7 by binding to its 3'UTR, however, how SIRT7 gene is regulated remains unclear. Here, we identified the transcription initiation site of human SIRT7 gene at the upstream 23rd A nucleotide respective to the translational codon, and the SIRT7 is a TATA-less and initiator-less gene. The sequences in the upstream region between -256 and -129 bp are identical with important functions in the three species detected. A C/EBPα responding element is found that binds both C/EBPα and C/EBPß in vitro. We showed TSA induced SIRT7 gene transcription and only the HDAC3, but not its catalytic domain depleted mutant, interacted with C/EBPα to occupy the C/EBPα element and repressed SIRT7 gene in the hepatocellular carcinoma cells. To our knowledge, this is the first report on the regulation mechanism of SIRT7 gene, in which, HDAC3 collaborated with C/EBPα to occupy its responding element in the upstream region of SIRT7 gene and repressed its expression in human cells.
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Proteínas Estimuladoras de Ligação a CCAAT/genética , Carcinoma Hepatocelular/genética , Histona Desacetilases/genética , Neoplasias Hepáticas/genética , Sirtuínas/genética , Regiões 3' não Traduzidas , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/biossíntese , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cromatina/genética , Histona Desacetilases/biossíntese , Humanos , Neoplasias Hepáticas/patologia , Regiões Promotoras Genéticas , Sirtuínas/biossínteseRESUMO
Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, and cell differentiation. However, the mechanism by which the activity of KDM3A is regulated is largely unknown. Here, we demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (p-KDM3A), which is enriched in the regulatory regions of gene loci in the human genome. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p-KDM3A target genes under heat shock conditions. The demethylation of H3K9me2 at the Stat1 binding site specifically depends on the co-expression of p-KDM3A in the heat-shocked cells. In contrast to heat shock, IFN-γ treatment does not phosphorylate KDM3A via MSK1, thereby abrogating its downstream effects. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress.
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Regulação da Expressão Gênica , Resposta ao Choque Térmico/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Proteínas de Choque Térmico HSP90/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Interferon gama/farmacologia , Histona Desmetilases com o Domínio Jumonji/química , Células Jurkat , Modelos Biológicos , Dados de Sequência Molecular , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genéticaRESUMO
Lin28 is a small RNA-binding protein that plays an important role in regulating developmental timing, stem cell reprogramming, and oncogenesis. However, the significance of the effect of post-translational modifications on Lin28 activity is not fully understood. In this study, we demonstrated that PCAF directly interacted with and acetylated Lin28. We also showed that the acetylation of Lin28 can be specifically reversed by the deacetylase SIRT1. These findings suggest that the PCAF/SIRT1 balance plays an important role in regulating Lin28 activity. Furthermore, we found that the cold shock domain of Lin28 is the major target of PCAF-mediated acetylation, which leads to a severe reduction in the Lin28 protein levels and an increase in the level of mature let-7a. This study provides the first demonstration that post-translational modification regulates Lin28 activity during let-7a biogenesis and sheds light on the regulation of Lin28 in ES cells and carcinogenesis.
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Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Western Blotting , Imunofluorescência , Células HEK293 , Humanos , Imunoprecipitação , Luciferases/metabolismo , Mutagênese Sítio-Dirigida , Mutação/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirtuína 1/genética , Fatores de Transcrição de p300-CBP/genéticaRESUMO
OBJECTIVE: Aplasia Ras homolog member I (ARHI) is associated with human ovarian cancer (HOC) growth and proliferation; however, the mechanisms are unclear. The purpose of this study was to investigate ARHI effects in HOC SKOV3 cells. METHODS: We transfected SKOV3 cells with PIRES2-EGFP-ARHI and measured growth inhibition rates, cell cycle distribution, apoptosis rates, and expression of P-STAT3 (phosphorylated signal transduction and activators of transcription 3) and P-ERK (phosphorylated extracellular signal regulated protein kinase). RESULTS: Our data showed significant inhibition of growth, significantly increased S-phase arrest and apoptosis rates, and reduction of P-STAT3 and P-ERK1/2 expression levels. CONCLUSIONS: We propose the mechanism may involve ARHI-induced phosphorylation of ERK1/2 and STAT3 protein kinases, thereby blocking proliferation signaling pathways, to induce HOC SKOV3 apoptosis.
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Apoptose , Pontos de Checagem do Ciclo Celular , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fase S , Proteínas rho de Ligação ao GTP/metabolismo , Western Blotting , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Neoplasias Ovarianas/genética , Fosforilação , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas , Proteínas rho de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Endometrial cancer (EC) is one of the gynecologic malignancy cancer with increasing incidence and mortality rates, partly due to aging populations and genetic risks. This study explores the associations between biological age accelerations (BAA) and risk of incident EC and assesses the joint effect of genetic factor and BAA. MATERIALS AND METHODS: Based on the UK Biobank cohort, 132,315 women participants were included for primary analysis and 124,119 white participants for genetic risk analysis. Biological age(BA) was calculated using the Klemera-Doubal (KDM) and PhenoAge method based on clinical biomarkers. We calculated two metrics for BAA (including KDM residual and PhenoAge residual) using residual analysis, comparing them against chronological age. The risk of incident EC was evaluated using multivariable Cox proportional-hazards models, adjusting for relevant covariates. Polygenic risk scores (PRS) were computed from known EC-associated SNPs. RESULTS: Both KDM and PhenoAge residual, were significantly associated with increased EC risk. In fully adjusted models, the highest tertile of KDM and PhenoAge residual was significantly associated with incident EC compared with the lowest group, with HRs of 1.278 (P=0.0044) and 1.424 (P<0.0001), repectively. The population-attributable fractions were 7.84% for KDM residual (P=0.0044), 9.78% for PhenoAge residual (P=0.0005), and 8.47% for genetic risk (P=0.0005). Additionally, joint associations of BAA and genetic risk with incident EC was evaluated. Compared with low genetic risk and low BAA, high genetic risk and high BAA was significantly associated with the incidence of EC with HRs of up to 2.172 (95% CI 1.592-2.963) for KDM and 2.226 (95% CI 1.640-3.022) for PhenoAge. Overall, higher levels of PhenoAge residual were consistently associated with an increased risk of incident EC, regardless of genetic risk. CONCLUSION: BAA and genetics both enhance the risk of incident EC. The effect of the PhenoAge residual is greater than that of the investigated genes, which in turn is greater than that of the KDM residual. These findings highlight the importance of considering both BAA and genetic factors in EC prevention.
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OBJECTIVE: The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1m) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB). METHODS: Data from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1m, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot. RESULTS: Age (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131-37.700), cytology (OR, 24.978; 95% CI, 3.085-540.236), and PAX1 methylation levels by grade (PAX1m grade) (OR, 7.801; 95% CI, 1.548-44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901-0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model's strong agreement between predicted and observed probabilities. CONCLUSION: The clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.
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Colposcopia , Metilação de DNA , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Nomogramas , Fatores de Transcrição Box Pareados , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Fatores de Transcrição Box Pareados/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Adulto , Metilação de DNA/genética , Pessoa de Meia-Idade , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologia , Curetagem/métodos , Curva ROC , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/patologia , Colo do Útero/patologia , Colo do Útero/virologiaRESUMO
BACKGROUND: Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multi-omics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. METHODS: Two-sample Mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and non-endometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. RESULTS: We identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and non-endometrioid EC, and 125 causal relationships between plasma proteins and non-endometrioid EC were observed. Substantial differences were observed between endometrioid and non-endometrioid histological types of EC at both the metabolite and protein levels. We identified 7 overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and 6 overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in non-endometrioid subtype and network analysis of above proteins and metabolites to identify coregulated nodes. CONCLUSIONS: Our findings observed substantial differences between endometrioid and non-endometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.
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AIM: Ubiquitin-proteasome system (UPS) and autophagosome-lysosome pathway (ALP) are the most important machineries responsible for protein degradation in Parkinson's disease (PD). The aim of this study is to investigate the adaptive alterations in autophagy upon proteasome inhibition in dopaminergic neurons in vitro and in vivo. METHODS: Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 µmol/L) for 5, 12, or 24 h. The expression of autophagy-related proteins in the cells was detected with immunoblotting. UPS-impaired mouse model of PD was established by microinjection of lactacystin (2 µg) into the left hemisphere of C57BL/6 mice that were sacrificed 2 or 4 weeks later. The midbrain tissues were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. RESULTS: Both in SH-SY5Y cells and in the midbrain of UPS-impaired mouse model of PD, treatment with lactacystin significantly increased the expression levels of LC3-I/II and Beclin 1, and reduced the levels of p-mTOR, mTOR and p62/SQSTM1. Furthermore, lactacystin treatment in UPS-impaired mouse model of PD caused significant loss of TH-positive neurons in the substantia nigra, and dramatically increased the number of autophagosomes in the left TH-positive neurons. CONCLUSION: Inhibition of UPS by lactacystin in dopaminergic neurons activates another protein degradation system, the ALP, which includes both the mTOR signaling pathway and Beclin 1-associated pathway.
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Acetilcisteína/análogos & derivados , Autofagia/efeitos dos fármacos , Mesencéfalo/patologia , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ubiquitina/metabolismo , Acetilcisteína/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Linhagem Celular Tumoral , Humanos , Masculino , Proteínas de Membrana/metabolismo , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: To identify the optimal triage procedure for endometrial biopsies in postmenopausal women. METHODS: The clinical information of 470 postmenopausal women with endometrial biopsy results and postmenopausal bleeding (PMB) and/or transvaginal ultrasonography (TVU) abnormalities were collected at the gynecology departments of four general hospitals from March 2021 to March 2022. In the validation cohort, 112 women with TVU abnormalities who underwent endometrial biopsy at Xiangya hospital between May 2022 and May 2023 were enrolled. The endpoint was the final diagnosis based on hysteroscopy reports and biopsy pathology results. The sensitivity, specificity, positive predictive value, and negative predictive value were compared among the three triage methods. A nomogram prediction model was developed and validated. RESULTS: Referring women with TVU abnormalities for endometrial biopsy identified 100% malignant/premalignant lesions despite low specificity (19.7%). Among women with measurable endometrial thickness (ET), we suggest that the ET cutoff value for biopsy referral should be ≥4 mm. The PMB (odds ratio [OR], 3.241; 95% confidence interval [CI], 1.073-9.789), diabetes (OR, 10.915; 95% CI, 3.389-35.156), and endometrial thickness (OR, 1.277; 95% CI, 1.156-1.409) were independent predictive factors for endometrial (pre)malignancy. A nomogram prediction model was constructed (area under curve [AUC] = 0.802, 95% CI: 0.715 to 0.889). The ideal cutoff point was 22.5, with a sensitivity of 100.0% and a specificity of 15.7%. The external validation achieved an AUC of 0.798 (95% CI, 0.685-0.911). CONCLUSIONS: It was possible to refer all postmenopausal women with TVU abnormity (ET ≥ 4 mm or other abnormal findings) for endometrial biopsy. Among women with TVU abnormalities, a nomogram was constructed, and a score greater than 22.5 suggested the need for referral for endometrial biopsy, while a score less than 22.5 suggested that regular follow-up was required, further improving the triage procedure.
Assuntos
Neoplasias do Endométrio , Pós-Menopausa , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Triagem , Ultrassonografia , Endométrio/diagnóstico por imagem , Endométrio/patologia , Biópsia , Hemorragia Uterina/diagnóstico por imagem , Histeroscopia , Neoplasias do Endométrio/patologia , Sensibilidade e EspecificidadeRESUMO
The JmjC-domain-containing protein Hairless (HR) and the vitamin D receptor (VDR) play a critical role in the maintenance of hair growth. Mutations in HR or VDR cause alopecia in humans and mice. Here we show that HR interacts with VDR and induces VDR relocalization in the nuclei. HR associates and colocalizes with nuclear receptor co-repressor (N-CoR) which is localized to subnuclear structures termed matrix-associated deacetylase (MAD) bodies. It is found that the HR mutants (C622G, N970S, D1012N, V1136D), associated with alopecia universalis congenita (AUC) or atrichia with papular lesions (APL), exhibit an abnormal subcellular distribution in addition to the impaired co-repressor activity with VDR. Studies on deletion mutants of HR indicate that the JmjC domain contributes to the co-repressor activity of HR. Our work provides new clues and evidence for the understanding on the role of HR in hair growth.
Assuntos
Receptores de Calcitriol/metabolismo , Fatores de Transcrição/metabolismo , Substituição de Aminoácidos , Linhagem Celular , Núcleo Celular/metabolismo , Proteínas Correpressoras/química , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases de Renilla/biossíntese , Luciferases de Renilla/genética , Mutagênese Sítio-Dirigida , Correpressor 1 de Receptor Nuclear/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Transporte Proteico , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Deleção de Sequência , Fatores de Transcrição/química , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis. Here we identified two transcription start sites (TSSs) of the mouse Gap43 gene designated as a proximal site at +1, and a distal TSS at -414. RT-qPCR data reveal that the transcripts from +1 increase 10-fold on day-1 post-all-trans retinoic acid (RA) treatment, reached a peak value at day-4 and gradually reduced. By contrast, the distal TSS directs a late, remarkably sharp increase of the transcripts from the day-5 on. An intense signal of Gap43 at the neurites and neural network is determined by the efficient transcription of the distal promoter as shown in Northern blot and RT-qPCR assay. In addition, the targeting of p300 in combination with a differential enrichment of Brm to Brg1 change at the distal promoter region of the gene is induced under RA treatment. The over hundreds of GA rich stretches and the GAGAG elements located between the two TSSs may take parts in the differential transcription of the two TSSs of the Gap43. Our findings provide the first evidence on the identification and differential transcription of the two TSSs of the mouse Gap43 gene, and the preferential distribution of their protein products in the specific stages of RA induced P19 differentiation. These data suggest the efficient transcription of the distal promoter of Gap43 is an important mark for the transition of P19 cells from the progenitor stage into neuronal differentiation.