RESUMO
Receptor-like kinases (RLKs) constitute the largest receptor family involved in the regulation of plant immunity and growth, but small-molecule inhibitors that target RLKs to improve agronomic traits remain unexplored. The RLK member FERONIA (FER) negatively regulates plant resistance to certain soil-borne diseases that are difficult to control and cause huge losses in crop yields and economy. Here, we identified 33 highly effective FER kinase inhibitors from 1494 small molecules by monitoring FER autophosphorylation in vitro. Four representative inhibitors (reversine, cenisertib, staurosporine and lavendustin A) inhibited the kinase activity of FER and its homologues in several crops by targeting the conserved ATP pocket in the kinase structure. FER contributes to the physiological impact of representative inhibitors in plants. The treatment of roots with reversine, staurosporine and lavendustin A enhanced innate immunity in plant roots and thus alleviated soil-borne diseases in tobacco, tomato and rice without growth penalties. Consistently, RNA sequencing assays showed that lavendustin A and reversine exert profound impacts on immunity-related gene expression. Our results will set a new milestone in the development of the plant RLK kinase regulation theory and provide a novel strategy for the prevention and control of plant soil-borne diseases without growth penalties.
Assuntos
Proteínas de Arabidopsis , Fosfotransferases , Estaurosporina , Fosfotransferases/genética , Imunidade Vegetal/genética , Plantas/metabolismo , Raízes de Plantas , Proteínas de Arabidopsis/genéticaRESUMO
Mammalian oocyte maturation is driven by strictly regulated polyadenylation and translational activation of maternal mRNA stored in the cytoplasm. However, the poly(A) polymerase (PAP) that directly mediates cytoplasmic polyadenylation in mammalian oocytes has not been determined. In this study, we identified PAPα as the elusive enzyme that catalyzes cytoplasmic mRNA polyadenylation implicated in mouse oocyte maturation. PAPα was mainly localized in the germinal vesicle (GV) of fully grown oocytes but was distributed to the ooplasm after GV breakdown. Inhibition of PAPα activity impaired cytoplasmic polyadenylation and translation of maternal transcripts, thus blocking meiotic cell cycle progression. Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPα, 537, 545 and 558, thereby leading to increased activity. This mechanism is responsible for translational activation of transcripts lacking cytoplasmic polyadenylation elements in their 3'-untranslated region (3'-UTR). In turn, activated PAPα stimulated polyadenylation and translation of the mRNA encoding its own (Papola) through a positive feedback circuit. ERK1/2 promoted Papola mRNA translation in a 3'-UTR polyadenylation signal-dependent manner. Through these mechanisms, PAPα activity and levels were significantly amplified, improving the levels of global mRNA polyadenylation and translation, thus, benefiting meiotic cell cycle progression.
Assuntos
Meiose , Oócitos/metabolismo , Oogênese , Polinucleotídeo Adenililtransferase/metabolismo , RNA Mensageiro Estocado/metabolismo , Animais , Ciclo Celular , Citoplasma/metabolismo , Vesículas Citoplasmáticas/metabolismo , Células HeLa , Humanos , Meiose/genética , Camundongos , Camundongos Endogâmicos ICR , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oogênese/genética , Fosforilação , Poliadenilação , Polinucleotídeo Adenililtransferase/antagonistas & inibidores , Polinucleotídeo Adenililtransferase/genética , Biossíntese de Proteínas , RNA Mensageiro Estocado/genética , RNA Interferente Pequeno , Fuso Acromático/genética , Fuso Acromático/metabolismo , Regulação para CimaRESUMO
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
OBJECTIVES: The efficacy of infliximab in treatment-naïve patients with stricturing small bowel Crohn's disease (CD) has not been well studied. We aimed to evaluate the efficacy of infliximab in these patients. MATERIALS AND METHODS: This was a retrospective study of all consecutive treatment-naïve patients with newly diagnosed CD with small bowel stricture who started regular infliximab therapy in Nanfang Hospital between January 2015 and December 2019. An effective infliximab therapy was defined as infliximab continuation without the use of steroids, new biologics, endoscopic interventions or intestinal surgery. RESULTS: Seventy-nine patients were included. After a median 38 months follow-up, an effective infliximab therapy was achieved in 37 patients. Long diagnostic delay (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.78; p= .008), pre-stenotic dilatation (HR 0.17, 95%CI 0.09-0.35; p < .001), long segmental stricture (HR 0.20, 95%CI 0.10-0.41; p < .001), and penetrating disease (HR 0.22, 95%CI 0.10-0.49; p < .001) were negatively correlated with an effective infliximab therapy. CONCLUSIONS: Infliximab is effective in nearly 50% of treatment-naïve patients with CD with small bowel stricture, and an effective therapy is more likely to be achieved in patients without long diagnostic delay, pre-stenotic dilatation, long segmental stricture or penetrating disease.
Assuntos
Doença de Crohn , Constrição Patológica , Doença de Crohn/tratamento farmacológico , Diagnóstico Tardio , Humanos , Infliximab/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: Deep remission should be induced early in the disease course of Crohn's disease (CD), because it significantly prevents disease progression. Identifying predictors of deep remission before treatment is important to guide therapeutic strategy. Little is known about the predictors of infliximab-induced deep remission in treatment-naïve patients with isolated small bowel CD. We aimed to investigate the predictors of infliximab-induced deep remission in these patients. MATERIALS AND METHODS: From January 2015 to December 2019, all consecutive treatment-naïve patients with isolated small bowel CD who started infliximab induction therapy (5 mg/kg at week 0, 2, and 6) and underwent capsule endoscopy (CE) at week 14 were retrospectively included. Deep remission was defined as clinical remission in combination with CE-identified mucosal healing. Logistic regression was used to investigate the predictors of 14-week deep remission. RESULTS: Ninety-one patients were included. At week 14 after infliximab induction therapy, deep remission was found in 42 patients. Multivariate logistic regression analysis showed that a moderate-to-severe endoscopic disease [odds ratio (OR), 0.28; p = .01] and the presence of fibrofatty proliferation (OR, 0.26; p = .04) at baseline were independently associated with a decreased possibility of deep remission. CONCLUSIONS: In treatment-naïve patients with isolated small bowel CD, a moderate-to-severe endoscopic disease and the presence of fibrofatty proliferation at baseline reduce the possibility of infliximab-induced deep remission. Patients with such risk factors may need more aggressive treatment at the beginning of induction therapy to promote deep remission at an early stage.
Assuntos
Endoscopia por Cápsula , Doença de Crohn , Doença de Crohn/tratamento farmacológico , Humanos , Infliximab/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.
Assuntos
Curcumina/farmacologia , Proteína Forkhead Box O3/metabolismo , Oócitos/efeitos dos fármacos , Reserva Ovariana , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/citologia , Oócitos/metabolismo , Oogênese , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Transdução de Sinais , Análise de Célula Única , TranscriptomaRESUMO
BACKGROUND: Growth differentiation factor-15 (GDF-15) is a marker of inflammation, oxidative stress and it is associated with adverse prognosis in cardiovascular disease. The aim of the present cohort study is to investigate the prognostic value of GDF-15 in patients with coronary artery disease (CAD) during long-term follow up. METHODS: A total of 3641 consecutive patients with CAD were prospectively enrolled into the study and followed up for major adverse cardiovascular events (MACEs) and all-cause death up to 5.3-7.6 years. Plasma GDF-15 was measured and clinical data and long-term events were registered. The patients were subsequently divided into three groups by the levels of GDF-15 and the prognostic value of GDF-15 level with MACEs and all-cause death was evaluated. RESULTS: After a median follow-up at 6.4 years later, 775 patients (event rate of 21%) had developed MACEs and 275 patients died (event rate of 7.55%). Kaplan-Meier analysis indicated that the patients with GDF-15 > 1800 ng/L were significantly associated with an increased risk of MACEs and all-cause death. Cox regression analysis indicated that GDF-15 > 1800 ng/L were independently associated with the composite of MACEs (HR 1.74; 95% CI 1.44-2.02; P < 0.001) and all-cause death (HR 2.04; 95% CI 1.57-2.61; P < 0.001). For MACEs, GDF-15 significantly improved the C-statistic (area under the curve, 0.583 [95% CI 0.559-0.606] to 0.628 [0.605-0.651]; P < 0.001), net reclassification index (0.578; P = 0.031), and integrated discrimination index (0.021; P = 0.027). For all-cause death, GDF-15 significantly improved the C-statistic (0.728 [95% CI 0.694-0.761] to 0.817 [0.781-0.846]; P < 0.001), net reclassification index (0.629; P = 0.001), and integrated discrimination index (0.035; P = 0.002). CONCLUSIONS: In the setting of CAD, GDF-15 is associated with long-term MACEs and all-cause death, and provides incremental prognostic value beyond traditional risks factors.
Assuntos
Doença da Artéria Coronariana/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Causas de Morte , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Accumulating evidence indicated that long noncoding RNAs (lncRNAs) have a wide range of biological functions and may play significant roles in tumorigenesis and progression. However, the understanding of its functions and related competitive endogenous RNAs (ceRNAs) networks is much less than that of protein-coding genes, particularly in colon adenocarcinoma. METHODS: We comprehensively analyzed the sequencing data of protein-coding and noncoding RNAs in colon adenocarcinoma patients from The Cancer Genome Atlas (TCGA) database. Next, we constructed colon adenocarcinoma-specific ceRNA network and evaluated the effect of these RNAs on overall survival (OS) for colon adenocarcinoma patients. RESULTS: Totally, 1138 differentially expressed lncRNAs (DElncRNAs), 245 microRNAs (DEmiRNAs), and 2081 mRNAs (DEmRNAs) were identified using a threshold of |log2FoldChange| >2.0 and adjusted P-value < 0.01. Subsequently, a colon adenocarcinoma-specific ceRNA network was successfully established with133 DElncRNAs, 29 DEmiRNAs, and 55 DEmRNAs. Among ceRNA network, seven DElncRNAs (AL590483.1, AP004609.1, ARHGEF26-AS1, HOX transcript antisense RNA (HOTAIR), ITCH-IT1, KCNQ1OT1, and LINC00491), four DEmiRNAs (hsa-mir-143, hsa-mir-183, hsa-mir-216a, and hsa-mir-424), and six DEmRNAs (FJX1, TPM2, ULBP2, PDCD4, PLAU, and SERPINE1) significantly correlated with OS (all P-value < 0.05). Notably, several interactions were highlighted in the ceRNA network, such as "KCNQ1OT1-hsa-mir-183-PDCD4", "KCNQ1OT1-hsa-mir-424-TPM2", "HOTAIR-hsa-mir-143-SERPINE1", and "ARHGEF26-AS1-hsa-mir-143-SERPINE1". CONCLUSIONS: These findings reveal several molecules might be novel important prognostic factors and potential treatment targets for colon adenocarcinoma. In addition, these observations contribute to a more comprehensive understanding of lncRNA-related ceRNA network and provide novel strategies for subsequent functional studies of lncRNAs in colon adenocarcinoma.
Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais , Neoplasias do Colo/mortalidade , Redes Reguladoras de Genes , Humanos , Canal de Potássio KCNQ1/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Prognóstico , RNA Mensageiro/genética , Tropomiosina/genéticaRESUMO
BACKGROUND: Robot-assisted gastrectomy (RAG) has been increasingly used for the treatment of advanced gastric cancer (AGC), and many advantages over laparoscopy-assisted gastrectomy (LAG) have been reported. However, its postgastrectomy complications still under investigation and the results remain controversial. This study aimed to objectively assess the incidence and severity of complications following RAG vs. LAG using Clavien-Dindo (C-D) classification and to identify risk factors related to complications. METHODS: Five hundred and twenty-seven patients with AGC who underwent RAG or LAG between January 2016 and May 2018 were enrolled in this study. Complications were categorized according to the C-D classification. The complications following RAG and LAG were compared using one-to-one propensity score matching (PSM) analysis and subgroup analyses. Logistic regression analyses were performed to identify risk factors related to complications. RESULTS: RAG was performed in 251 patients (47.6%) and LAG in 276 patients (52.4%). Before PSM, the RAG group had a smaller tumour size (P = 0.004) and less patients with previous abdominal operation (P = 0.013). After PSM, a well-balanced cohort of 446 patients (223 in each group) was further analyzed. Of interest, the incidence of overall and severe complications (C-D grade ≥ IIIa) following the RAG group were significantly fewer than the LAG group (overall, 24.5% vs. 18.8%, P < 0.001; severe, 8.9% vs. 17.5%, P = 0.002). Subgroup analyses showed statistically significant difference were also observed in most stratified parameters. Multivariable analysis identified age ≥ 65 years, total gastrectomy, stage T3-T4a, stage II-III, and operation time ≥ 250 min as independent predictors of overall complications. Additionally, age ≥ 65 years, stage II-III, and operation time ≥ 250 min were confirmed as independent risk factors for severe complications. CONCLUSIONS: RAG with D2 lymphadenectomy is feasible and safe for the treatment of AGC in terms of the lower incidence and severity of complications.
Assuntos
Gastrectomia/efeitos adversos , Laparoscopia/efeitos adversos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Neoplasias Gástricas/cirurgia , Fatores Etários , Idoso , Feminino , Gastrectomia/métodos , Humanos , Incidência , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/patologiaRESUMO
The pine wood nematode (PWN), Bursaphelenchus xylophilus, is the pathogen responsible for pine wilt disease (PWD), a devastating forest disease with a pathogenic mechanism that remains unclear. Autophagy plays a crucial role in physiological and pathological processes in eukaryotes, but its regulatory mechanism and significance in PWN are unknown. Therefore, we cloned and characterized three autophagy genes, BxATG5, BxATG9, and BxATG16, in PWN. BxATG9 and BxATG16 were efficiently silenced through RNA interference, and we found that BxATG16 positively regulated the expression of BxATG5. Silencing BxATG9 and BxATG16 severely inhibited feeding and reproduction in PWN, indicating that autophagy is essential for these processes. We then examined the expression patterns of these three autophagy genes in PWN under the stresses of α-pinene and H2O2, the main defense substances of pine trees, and during the development of PWD using quantitative reverse transcription polymerase chain reaction. The expression levels of BxATG5, BxATG9, and BxATG16 all significantly increased after nematodes were stressed with α-pinene and H2O2 and inoculated into pine trees, suggesting that autophagy plays an important role in the defense and pathogenesis of PWN. In this study, the molecular characteristics and functions of the autophagy genes BxATG5, BxATG9, and BxATG16 in PWN were elucidated.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Proteínas de Helminto/genética , Pinus/parasitologia , Doenças das Plantas/parasitologia , Tylenchida/genética , Animais , Autofagia , Proteína 5 Relacionada à Autofagia/genética , Regulação da Expressão Gênica , Tylenchida/fisiologiaRESUMO
BACKGROUND/AIMS: Melatonin has been demonstrated to protect cardiac microvascular endothelial cells (CMECs) against ischemia/reperfusion injury (IRI). Autophagy plays different roles in the heart during ischemia and reperfusion. The AMP activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway is associated with autophagy. This study sought to explore whether melatonin regulates CMEC autophagy through the AMPK/mTOR signaling pathway. METHODS: The effects of melatonin in IRI were investigated in vivo rat models and in vitro neonatal CMECs. Myocardial infarct size was achieved by Evans blue and triphenyltetrazolium chloride staining. The severity of cell injury was evaluated by cell vitality and lactate dehydrogenase (LDH) release assays, and autophagy was evaluated by transmission electron microscopy and the assessment of autophagy-related gene expression, such as that of Beclin 1 and light chain 3-II. RESULTS: In vivo, melatonin markedly reduced infarcted area, improved cardiac function and decreased LDH release. However, the AMPK activator AICAR and the mTOR inhibitor rapamycin reduced the protective effects of melatonin on IRI. In vitro, Beclin1 and light chain 3-II protein were found to be down-regulated and autophagosomes were found to be reduced in response to melatonin, together with an increase in cell vitality and a decrease in LDH. Treatment with AICAR or rapamycin ablated the benefit observed with melatonin treatment. CONCLUSIONS: Melatonin played an important and protective role in CMECs by inhibiting autophagy against IRI via the AMPK/mTOR system.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Melatonina/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Characterization of the genetic landscapes of familial ovarian cancer through integrated analysis of microRNA and mRNA by partial least squares (PLS) and Monte Carlo technique based on genome-wide association studies (GWAS). METHODS: The miRNA and mRNA transcriptional data in familial ovarian cancer were characterized from the Gene Expression Omnibus (GEO) database. The miRNA and mRNA expression profiles in peripheral blood lymphocytes (PBLs) of 74 familial ovarian cancer patients and 47 control subjects were analyzed with the integration of partial least squares (PLS) and Monte Carlo techniques. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also performed. RESULTS: Total of 16 miRNA-mRNA pairs were identified with the target gene prediction results of miRNAs and mRNAs. An innovated miRNA-mRNA integrated network was constructed in which 6 downregulated miRNAs and 1 upregulated miRNAs were included. KEGG and GO pathway enrichment analysis revealed over-representation of dysregulated miRNAs in various biological processes especially in cancer pathology. Hsa-miR-34b played a pivotal role in this network and interacted with other miRNAs. Hsa-miR-136 and hsa-miR-335 were associated with p53 and Erk1/2 pathways and tumor suppressors, such as PTEN. CONCLUSIONS: The results from this research provide insights on miRNA-mRNA networks and offer new tools for studying transcriptional variants in familial ovarian cancer.
Assuntos
Biomarcadores Tumorais/genética , Linfócitos/metabolismo , MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Epitelial do Ovário , China/epidemiologia , Feminino , Estudos de Associação Genética , Marcadores Genéticos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/diagnóstico , Prevalência , RNA Mensageiro/sangue , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Wilms' tumor 1 (WT1) encoding a transcription factor involved in the differentiation of granulosa cells (GCs) regulates androgen receptor in the development of male genitalia. However, the expression pattern and possible role of WT1 in ovaries of PCOS patients are still unknown. METHODS: GCs from 95 PCOS patients (PCOS group) and 62 healthy controls (control group) were isolated. The expression of WT1 in GCs was quantified using the reverse transcription-polymerase chain reaction. The correlation between WT1 expression and clinical characteristics was evaluated in PCOS patients. RESULTS: WT1 expression was increased in PCOS patients compared with the normal controls. The expression of WT1 was moderately correlated with testosterone (r = 0.334, p = 0.001) and luteinizing hormone (r = 0.357, p = 0.001) levels and the antral follicle counts (r = 0.337, p = 0.001). CONCLUSIONS: Our study provided novel insights into the relationship between hyperandrogenism and polycystic ovaries of PCOS and WT1.
Assuntos
Células da Granulosa/metabolismo , Ovário/citologia , Síndrome do Ovário Policístico/genética , Tumor de Wilms/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hormônio Luteinizante/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Testosterona/metabolismoRESUMO
STUDY QUESTION: What is the physiological function of Yes-associated protein-1 (Yap1), a susceptibility gene for polycystic ovary syndrome (PCOS), in ovarian granulosa cells (GCs)? SUMMARY ANSWER: Physiologically, steroid sex hormones stimulate follicle growth by activating YAP1; however, the preovulatory inhibition of YAP1 activity in GCs is a prerequisite of LH actions. WHAT IS KNOWN ALREADY: PCOS is a common gynecologic and endocrine disease with multiple short and long-term consequences. Many PCOS patients suffer anovulation caused by hyperandrogenism, but its etiology remains unclear. STUDY DESIGN, SIZE, DURATION: To study the effect of acute hyperandrogenism on ovulation, we injected pregnant mare serum gonadotrophin (PMSG)-primed (44 h) pubertal mice with dihydrotestosterone (DHT), the major biologically active form of androgen, in a superovulation assay. We investigated if YAP1 is regulated by testosterone and if it is potentially involved in follicle development and ovulation. Cultured primary GCs were subjected to Yap1 depletion by RNA interference and Yap1 overexpression by adenoviral infections. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female mice at postnatal day (PD)-21~23 were analyzed to avoid the complexity of ovarian functions associated with estrous cycles and endogenous surges of gonadotropins. Immature mice were injected intraperitoneally with five IU PMSG to stimulate preovulatory follicle development followed 44 h later with five IU hCG to stimulate ovulation. For DHT treatments, female mice at PD23 were injected intraperitoneally with five IU PMSG followed 44 h later with five IU hCG alone (as control) or five IU hCG plus 100 µg DHT, which was dissolved in 0.1 ml DMSO. Methods of gene expression detection used include immunohistochemistry, immunofluorescence, Western blotting and quantitative PCR. More than three biological and technical replicates were included in each experiments. MAIN RESULTS AND THE ROLE OF CHANCE: we provide novel evidence in a mouse model that YAP1 is required for proliferation of ovarian GCs, but is down-regulated by LH through the extracellular-regulated kinase-1/2 (ERK1/2) cascade. Acute hyperandrogenism blocks LH actions and causes oligo-ovulation by activating YAP1. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Results shown were obtained only in mouse, and need to be further confirmed in human samples. WIDER IMPLICATIONS OF THE FINDINGS: These findings not only elucidated the role of YAP1 in maintaining normal ovarian functions, but also link the YAP1 deregulation to the pathogenesis of PCOS. STUDY FUNDING AND COMPETING INTEREST(S): This study is funded by the National Key Research and Development Program of China (2016YFC1000600 and 2017YFSF1001500) and National Natural Science Foundation of China (31528016, 31371449 and 31671558). The authors have no competing interests.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Gonadotropina Coriônica/farmacologia , Di-Hidrotestosterona/farmacologia , Células da Granulosa/efeitos dos fármacos , Hiperandrogenismo/genética , Fosfoproteínas/genética , Síndrome do Ovário Policístico/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Gonadotropinas Equinas/farmacologia , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Cavalos , Humanos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/patologia , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ovário/citologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovulação/efeitos dos fármacos , Fosfoproteínas/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Cultura Primária de Células , Transdução de Sinais , Proteínas de Sinalização YAPRESUMO
PURPOSE: This study aims to ascertain whether an association exists between hepatocyte nuclear factor 1 alpha (HNF1A) and polycystic ovary syndrome (PCOS). METHODS: One thousand one hundred thirty-eight PCOS and 1125 healthy control Han Chinese women were recruited from Reproductive Hospital Affiliated to Shandong University. Serum hormone, blood lipid level, and genomic DNA were obtained from the peripheral blood for this research. Two single-nucleotide polymorphisms (SNPs)-rs2393791 and rs7305618-located in HNF1A were genotyped using the Sequenom MassARRAY system. RESULTS: The allele frequencies of SNP rs7305618 had significant differences between PCOS patients and controls after adjusting for age and BMI (p = 0.023). Besides, PCOS patients carrying the rs7305618 CC genotype shown a higher testosterone level than the patients with CT + TT genotypes after being adjusted by age and BMI (p = 0.019). CONCLUSIONS: A SNP located in the HNF1A gene is associated with PCOS among Han Chinese women. This suggested that variations in HNF1A might confer risk for PCOS.
Assuntos
Predisposição Genética para Doença , Fator 1-alfa Nuclear de Hepatócito/genética , Síndrome do Ovário Policístico/genética , Adulto , Alelos , Povo Asiático , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
The pine wood nematode (PWN), Bursaphelenchusxylophilus, is the pathogen of pine wilt disease (PWD) and causes huge economic losses in pine forests and shows a remarkable ability to survive under unfavorable and changing environmental conditions. This ability may be related to autophagy, which is still poorly understood in B.xylophilus. Our previous studies showed that autophagy exists in PWN. Therefore, we tested the effects of autophagy inducer rapamycin on PWN and the results revealed that the feeding rate and reproduction were significantly promoted on fungal mats. The gene expression patterns of BxATG1 and BxATG8 under the different stress were determined by quantitative reverse transcription PCR (qRT-PCR). We tested the effects of RNA interference on BxATG1 and BxATG8 in PWN during different periods of infection in Pinus thunbergii. The results revealed that BxATG1 and BxATG8 may play roles in allowing PWN to adapt to changing environmental conditions and the virulence of PWN was influenced by the silence of autophagy-related genes BxATG1 and BxATG8. These results provided fundamental information on the relationship between autophagy and PWN, and on better understanding of gene function of BxATG1 and BxATG8 in PWN.
Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Helminto/metabolismo , Nematoides/metabolismo , Estresse Fisiológico , Adaptação Fisiológica , Animais , Autofagia , Proteínas Relacionadas à Autofagia/genética , Proteínas de Helminto/genética , Nematoides/genética , Nematoides/patogenicidade , Pinus/parasitologia , VirulênciaRESUMO
OBJECTIVE: The objectives of this retrospective study were to analyze the short-term and long-term effects and complications of stereotactic anterior capsulotomy for patients with refractory obsessive-compulsive disorder (OCD). The advantages and disadvantages of stereotactic anterior capsulotomy have been discussed. MATERIALS AND METHODS: Between October 2007 and June 2010, 37 patients with OCD underwent anterior capsulotomy in West China Hospital of Sichuan University or Mian Yang Central Hospital. The clinical effects were evaluated by an independent psychiatrist preoperatively and after 1 week, and after 1, 3, 6, 12, 36, and 60 months postoperatively. The main parameters were evaluated by scores on the Yale-Brown obsessive compulsive scale (Y-BOCS), Hamilton depression scale (HAMD), and Hamilton anxiety scale (HAMA). 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion tensor imaging (DTI) were performed preoperatively and at 3 and 6 months postoperatively. RESULTS: On comparing the scores obtained at various time points, the effects of anterior capsulotomy were as follows: The Y-BOCS score of the 37 patients decreased in the fifth year postoperatively (P < 0.05); 27 (73.0%) patients exhibited significant improvement (>50% decrease in the Y-BOCS score); 6 (16.2%) patients exhibited partial improvement (20-50% decrease in the Y-BOCS score); and, 4 (10.8%) patients exhibited no evident improvement (<20% decrease in the Y-BOCS score). Moreover, depression and anxiety improved among all the patients (P < 0.05). FDG-PET showed that the glucose metabolic rate had decreased in bilateral frontal cerebral lobe and basal ganglia. DTI showed that the transverse fibers in bilateral anterior limb of the internal capsule were disconnected. CONCLUSION: Using MRI guidance, stereotactic treatment of refractory OCD via bilateral anterior internal capsulotomy significantly improved several OCD symptoms such as compulsive behavior, depression, and anxiety. In addition, the assessment of the effects and complications of this treatment was most accurate at 6 months postoperatively.
Assuntos
Cápsula Interna/cirurgia , Procedimentos Neurocirúrgicos/métodos , Transtorno Obsessivo-Compulsivo/cirurgia , Adulto , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Técnicas EstereotáxicasRESUMO
Soil moisture data can reflect valuable information on soil properties, terrain features, and drought condition. The current study compared and assessed the performance of different interpolation methods for estimating soil moisture in an area with complex topography in southwest China. The approaches were inverse distance weighting, multifarious forms of kriging, regularized spline with tension, and thin plate spline. The 5-day soil moisture observed at 167 stations and daily temperature recorded at 33 stations during the period of 2010-2014 were used in the current work. Model performance was tested with accuracy indicators of determination coefficient (R 2), mean absolute percentage error (MAPE), root mean square error (RMSE), relative root mean square error (RRMSE), and modeling efficiency (ME). The results indicated that inverse distance weighting had the best performance with R 2, MAPE, RMSE, RRMSE, and ME of 0.32, 14.37, 13.02%, 0.16, and 0.30, respectively. Based on the best method, a spatial database of soil moisture was developed and used to investigate drought condition over the study area. The results showed that the distribution of drought was characterized by evidently regional difference. Besides, drought mainly occurred in August and September in the 5 years and was prone to happening in the western and central parts rather than in the northeastern and southeastern areas.
Assuntos
Secas , Monitoramento Ambiental/métodos , Solo/química , Análise Espacial , China , TemperaturaRESUMO
Knowledge of soil texture variations is critical for agricultural and engineering applications because texture influences many other soil properties. This study used random forest method to evaluate the effects of human activities and topographic parameters on the spatial variability of soil texture in hilly areas where soil parent material was uniform. The study site covers 252 km2 and is located in the Upper Yangtze River Basin of south-west China. A total of 3636 samples were collected from the cultivated soils at a depth of 20 cm of dryland (sloping field and terraced land) landscape. The soil texture class for each sample was estimated by experienced soil scientists in the field. Two soil texture classes (loam and clay) were observed in the watershed. Eleven terrain parameters were derived from a digital elevation model with a resolution of 30 m. Compared with loamy soils, clayey soils were mostly observed in the areas with lower elevation and gentle slopes. The outcome of random forest indicated that human activities and elevation had strong effects on soil texture class variations across the study site. Further results showed that the relative importance of terrain parameters to soil texture class variations varied with dryland landscape. Topographic wetness index and elevation were the most important variables for sloping field and terraced land landscapes, respectively.
Assuntos
Monitoramento Ambiental , Solo/química , Agricultura , Silicatos de Alumínio , China , Argila , Atividades Humanas , RiosRESUMO
This study demonstrated the potential effects of internal waves (IWs) on heterotrophic bacterial activities for the first time. Nine anchored studies were conducted from 2009-2012 in the South China Sea areas with different physical conditions, i.e. areas subjected to elevation IWs, to depression IWs, and to weak/no IWs. The latter two areas were treated as the Control sites. Field survey results indicated that within the euphotic zone, the minima of the depth-averaged bacterial production (IBP; â¼1.0 mgC m-3 d-1 ) and growth rate (IBµ; â¼0.1 d-1 ) at all sites were similar. Except for one case, the maxima of IBP (6-12 mgC m-3 d-1 ) and IBµ (0.55-1.13 d-1 ) of the elevation IWs areas were â¼fivefolds higher than those of the Control sites (IBP 1.7-2.1 mgC m-3 d-1 ; IBµ 0.13-0.24 d-1 ). Replicate surveys conducted at the north-western area of the Dongsha atoll during spring-to-neap (NW1 survey) and neap-to-spring (NW2 survey) tide periods showed a great contrast to each other. Low variation and averages of IBµ in NW1 survey were similar to those of the Control sites, while those in NW2 were similar to the other elevation IWs sites with larger variation and higher averages of IBµ. This finding suggests that bacterial activities may be a function of the lunar fortnightly (14-day) cycle. Enrichment experiments suggested more directly that the limiting inorganic nutrients introduced by the elevation waves (EIWs) may contribute a higher IBµ within the euphotic zone.