Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
FASEB J ; 38(14): e23839, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39037418

RESUMO

During early pregnancy in mice, the establishment of uterine receptivity and endometrial decidualization require the extensive proliferation and differentiation of endometrial epithelial cells or stromal cells. Pin1 has been suggested to act as a molecular 'timer' of the cell cycle and is involved in the regulation of cellular proliferation and differentiation by binding many cell-cycle regulatory proteins. However, its physiological role during early pregnancy is still not fully understood. Here, we employed immunohistochemistry to determine the spatiotemporal pattern of Pin1 expression during early pregnancy. We found that Pin1 was mainly localized in subluminal stromal cells on day 4, in the decidual zone on days 5 to 8 of pregnancy and in artificial decidualization. Using a uterine stromal cell culture system, we found that progesterone, but not estrogen, induced the expression of Pin1 in a progesterone receptor-dependent manner. Inhibition of Pin1 in the uterus leads to impaired embryo implantation and decidualization in mice. Notably, a decrease in Pin1 activation affected the functional execution of several implantation- or decidualization-related factors. These findings provide new evidence for a previously unknown function of Pin1 in mediating embryo implantation and decidualization during successful pregnancy establishment and maintenance.


Assuntos
Decídua , Implantação do Embrião , Peptidilprolil Isomerase de Interação com NIMA , Útero , Animais , Feminino , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Implantação do Embrião/fisiologia , Camundongos , Gravidez , Decídua/metabolismo , Decídua/citologia , Útero/metabolismo , Útero/citologia , Progesterona/metabolismo , Células Estromais/metabolismo , Receptores de Progesterona/metabolismo , Células Cultivadas , Endométrio/metabolismo , Endométrio/citologia
2.
Cell Biol Int ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886911

RESUMO

Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.

3.
Free Radic Biol Med ; 222: 275-287, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38925315

RESUMO

As a prevalent neurodegenerative disorder, Parkinson's disease is associated with oxidative stress. Our recent investigations revealed that reactive oxygen species (ROS) and PD-toxins like 6-hydroxydopamine (6-OHDA) can induce neuronal apoptosis through over-activation of Akt signaling. Chlorogenic acid (CGA), a natural acid phenol abundant in the human diet, is well-documented for its ability to mitigate intracellular ROS. In this study, we utilized CGA to treat experimental models of PD both in vitro and in vivo. Our study results demonstrated that SH-SY5Y and primary neurons exhibited cell apoptosis in response to 6-OHDA. Pretreatment with CGA significantly attenuated PD toxins-induced large amount of ROS, inhibiting Erk1/2 activation, preventing Akt inhibition, and hindering neuronal cell death. Combining the Erk1/2 inhibitor U0126 with CGA could reverse 6-OHDA-induced Akt inhibition, ROS, and apoptosis in the cells. Crucially, the Akt activator SC79 and ROS scavenger NAC both could eliminate excessive ROS via Akt and Erk1/2 signaling pathways, and CGA further potentiated these effects in PD models. Behavioral experiments revealed that CGA could alleviate gait abnormalities in PD model mice. The neuroprotective effects have been demonstrated in several endocrine regions and in the substantia nigra tissue, which shows the positive tyrosine hydroxylase (TH). Overall, our results suggest that CGA prevents the activation of Erk1/2 and inactivation of Akt by removing excess ROS in PD models. These findings propose a potential strategy for mitigating neuronal degeneration in Parkinson's disease by modulating the Akt/Erk1/2 signaling pathway through the administration of CGA and/or the use of antioxidants to alleviate oxidative stress.

4.
Heliyon ; 10(7): e28497, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38689980

RESUMO

Background: While hepatocellular carcinoma (HCC) represents a highly heterogeneous disease with variable oncogenesis mechanisms and biological features, little is understood about differences in distant metastasis (DM) and prognosis between early-onset and late-onset HCC. This study defined early-onset disease as cancer diagnosed at age younger than 50 years and aimed to present a comprehensive analysis to characterize these disparities based on age. Methods: Information of HCC patients was retrospectively collected from the SEER database and our hospital. Patient demographics, tumor characteristics, and survival were compared between the two groups. A 1:1 propensity score matching (PSM) was adopted to adjust confounding factors. Logistic and cox analysis were utilized to explore risk factors of DM and prognosis, respectively. Besides, the survival differences were assessed by the Kaplan-Meier curve and log-rank test. Results: In total, 19187 HCC patients obtained from the SEER database and 129 HCC patients obtained from our own center were enrolled. Among 19187 patients with HCC, 3376 were identified in the matched cohort, including 1688 early-onset patients and 1688 late-onset patients. Compared with late-onset HCC, early-onset HCC was more likely to occur in female (25.2% vs. 22.9%, P = 0.030), have large tumors (>10.0 cm, 24.1% vs. 14.6%, P = 0.000), harbor poorly differentiated/undifferentiated cancers (17.0% vs. 14.0%, P = 0.003), present advanced clinical stage (T3+T4, 33.7% vs. 28.5%; N1, 9.2% vs. 6.7%; P = 0.000), and develop DM (13.0% vs. 9.5%, P = 0.000). After adjustment for confounders by PSM, we discovered that early-onset HCC remained an independent risk factor for DM. However, combined with Kaplan-Meier curve and cox analysis, early-onset HCC was an independent favorable predictor of survival. We validated these data on an independent cohort from our hospital. Conclusion: In this population-based study, despite developing DM more frequently, early-onset HCC exhibited a superior prognosis than late-onset HCC. Nevertheless, further research is warranted to understand the underlying aetiologic basis for the disparities.

5.
Eur J Pharmacol ; 975: 176646, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38762157

RESUMO

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death.


Assuntos
Melatonina , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Pancreatite , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Melatonina/farmacologia , Melatonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Pancreatite/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Camundongos Knockout , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Camundongos Endogâmicos C57BL , Doença Aguda
6.
Metabolism ; 156: 155914, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38642829

RESUMO

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood. METHODS: O-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT-qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function. RESULTS: O-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH. CONCLUSIONS: O-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.


Assuntos
Antígenos CD36 , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Masculino , Camundongos , Antígenos CD36/metabolismo , Antígenos CD36/genética , Progressão da Doença , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Processamento de Proteína Pós-Traducional , Regulação para Cima
7.
Genes Genomics ; 44(11): 1415-1424, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35305240

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors and the fourth leading cause of cancer death worldwide. Constitutive activation of the PI3K/AKT signaling pathway is a hallmark of colon tumor growth. CATSPER1 gene encodes a pore-forming and pH-sensing subunit of the CatSper Ca2+-permeable channel, a sperm-specific calcium channel essential for hyperactivated motility and male fertility. However, the function of CATSPER1 outside the male reproductive system is unclear. OBJECTIVE: This study was designed to explore whether CatSper exerted its functional role in the progress of CRC, and investigate the possible mechanisms. METHODS: Microarray data (GSE146587) from 6 patients diagnosed with stage III CRC post-surgery was analyzed by Limma R package. The Kaplan Meier plotter (KM plotter) database was used to assess the relevance of CATSPER1 mRNA expression to the overall survival (OS) rates in CRC. Western blot, real-time PCR and luciferase reporter assays were used to determine the SOX11-CATSPER1 axis in CRC cells. Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate CATSPER1 knockout (KO) CRC cells. The proliferation of CRC cells was determined by BrdU incorporation and colony formation assays. The effect of CATSPER1 on CRC tumor growth in vivo was investigated in a mice tumor xenograft model. RESULTS: Here, we show that CATSPER1 expression was significantly up-regulated in CRC and elevated CATSPER1 was associated with poor overall survival (OS). Moreover, the transcription factor SOX11 (SRY-related high-mobility-group (HMG) box 11) activated CATSPER1 transcription in CRC cells. Functionally, we showed that CATSPER1 promoted CRC cells proliferation both in vitro and in vivo. At the molecular level, we demonstrated that CATSPER1 might maintain CRC malignant process partly through the activation of the PI3K/AKT signaling pathway. CONCLUSION: Increased CATSPER1 expression facilitates CRC cells proliferation, suggesting that targeting CATSPER1 might represent a promising strategy for colon cancer treatment.


Assuntos
Neoplasias do Colo , Fosfatidilinositol 3-Quinases , Animais , Bromodesoxiuridina , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Neoplasias do Colo/genética , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro , Fatores de Transcrição SOXC/metabolismo , Sêmen/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo
8.
Nat Prod Res ; 35(12): 2044-2050, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31437007

RESUMO

A new monoterpene (1) along with eight known compounds were isolated from the roots of Astilbe grandis Stapf ex E.H. Wilson. Their structures were determined by extensive spectroscopic analysis and ECD experiments as (S)-3-(2-hydroxyethyl)-5-(2-methylprop-1-en-1-yl)furan-2(5H)-one (1), caffeic acid (2), mandelic acid (3), sonchifolinin B (4), α-viniferin (5), euscaphic acid (6), cianidanol (7), ß-sitosterol (8), and stigmasterol (9), respectively. Compounds 5 and 6 exhibited inhibitory effects against BRD4 protein with IC50 values of 13.20 and 17.39 µM, respectively. In vitro, compounds 5 and 6 showed moderate cytotoxicity to A549 cells, HCC827 cells and Hela cells with IC50 values ranging from 31.98 to 154.90 µM.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Saxifragaceae/química , Fatores de Transcrição/antagonistas & inibidores , Células A549 , Benzofuranos/química , Benzofuranos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Sitosteroides/química , Sitosteroides/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Estigmasterol/química , Estigmasterol/farmacologia , Triterpenos/química , Triterpenos/farmacologia
9.
Micromachines (Basel) ; 11(9)2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854190

RESUMO

To study the effect of material properties on the surface morphology of potassium dihydrogen phosphate (KDP) crystals, an ultra-precision fly cutting machine tool with a single-point diamond tool was used to perform a cutting experiment on (100) crystal plane of the KDP crystal. The elastic modulus, shear modulus, hardness, and dislocation of KDP crystals are taken into the cutting force model by introducing the strain gradient plasticity theory. Since the size effect and dynamic response will affect the surface roughness during ultra-precision machining, the surface roughness of workpieces in ultra-precision fly cutting is hard to predict. Based on the previously established strain gradient plasticity theoretical model, cutting force model, and the dynamic characteristics of the ultra-precision fly cutting system, a surface morphology prediction model under the influence of KDP crystal material properties was established. Finally, the accuracy of the surface morphology prediction model was verified by ultra-precision fly cutting experiments, and identified the frequency range of the characteristic signal caused by the anisotropy of the KDP crystal from the frequency, thereby verifying the KDP crystal material properties has a significant effect on the surface of the machined workpiece roughness.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA