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1.
Pain ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38787639

RESUMO

ABSTRACT: The profiles of muscle and joint pain throughout the menopausal transition and the factors associated with these symptoms have not been determined. A total of 609 participants from a longitudinal cohort study conducted in an urban Chinese community were enrolled in this study. We assessed the prevalence of musculoskeletal symptoms at different menopausal stages and explored the factors associated with these symptoms. The prevalence and severity of muscle and joint pain increase as menopausal stages progress, and late menopausal transition may be a crucial timepoint that triggers the onset of musculoskeletal pain. The results of the multivariate analysis revealed that poor health status (OR = 2.245, 95% CI = 1.714-2.94, P < 0.001), body mass index (BMI) (OR = 1.046, 95% CI = 1.01-1.084, P = 0.011), the presence of anxiety (OR = 1.601, 95% CI = 1.211-2.117, P < 0.001), and depression (OR = 1.368, 95% CI = 1.143-1.639, P < 0.001) were independently associated with muscle and joint pain. In addition, the severity of musculoskeletal pain was related to poor health status (OR = 2.738, 95% CI = 1.91-3.924, P < 0.001) and depression (OR = 1.371, 95% CI = 1.095-1.718, P = 0.006). Musculoskeletal symptoms are frequent somatic symptoms experienced by Chinese middle-aged women. Women with poor health status, high BMI, anxiety, and depression were at heightened risk of experiencing musculoskeletal pain. The severity of pain increased over time.

2.
Gut Microbes ; 16(1): 2295394, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38170622

RESUMO

Ovarian aging occurs prior to the aging of other organ systems and acts as the pacemaker of the aging process of multiple organs. As life expectancy has increased, preventing ovarian aging has become an essential goal for promoting extended reproductive function and improving bone and genitourinary conditions related to ovarian aging in women. An improved understanding of ovarian aging may ultimately provide tools for the prediction and mitigation of this process. Recent studies have suggested a connection between ovarian aging and the gut microbiota, and alterations in the composition and functional profile of the gut microbiota have profound consequences on ovarian function. The interaction between the gut microbiota and the ovaries is bidirectional. In this review, we examine current knowledge on ovary-gut microbiota crosstalk and further discuss the potential role of gut microbiota in anti-aging interventions. Microbiota-based manipulation is an appealing approach that may offer new therapeutic strategies to delay or reverse ovarian aging.


Assuntos
Microbioma Gastrointestinal , Microbiota , Feminino , Humanos , Ovário , Envelhecimento
3.
Immun Ageing ; 20(1): 70, 2023 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-38041117

RESUMO

Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.

4.
Int J Mol Sci ; 24(17)2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37686248

RESUMO

Cell division plays an indispensable role in leaf morphogenesis, which is regulated via the complexes formed by cyclin and cyclin-dependent kinase (CDK). In this study, gene family analysis, exogenous auxin stimulation, RNA-seq and WGCNA analysis were all used to investigate the molecular mechanisms by which cell-cycle-related factors participated in the auxin signaling pathway on leaf morphogenesis. Sixty-three cyclin members and seventeen CDK members in Populus alba were identified and systematically analyzed. During the evolution, WGD was the main reason that resulted in the expansion of cyclin and CDK genes. Firstly, after a short time treating with auxin to matured leaves of seedlings, genes related to cell division including GRF and ARGOS were both upregulated to restart the transition of cells from G1-to-S phase. Secondly, with three days of continuous auxin stimulation to leaves at different developmental stages, leaves area variation, transcriptomes and hormones were analyzed. By PCA, PCoA and WGCNA analyses, the turquoise module was both positively related to leaf development and auxin. Based on the co-expression analysis and Y2H experiment, PoalbCYCD1;4, PoalbCYCD3;3 and PoalbCYCD3;5 were supposed to interact with PoalbCDKA;1, which could be the trigger to promote the G1-to-S phase transition. The ARF transcription factor might play the key role of connecting the auxin signaling pathway and cell division in leaf morphogenesis by affecting CYC-CDK complexes.


Assuntos
Populus , Populus/genética , Ciclinas , Quinases Ciclina-Dependentes/genética , Ácidos Indolacéticos , Folhas de Planta/genética
5.
J Thorac Dis ; 15(4): 2167-2183, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37197505

RESUMO

Background: Cyclin O (CCNO) is a novel cyclin family protein containing a cyclin-like domain, which plays a role in cell cycle regulation. Recent research suggests that inhibition of CCNO leads to cell apoptosis in gastric cancer, cervical squamous cell carcinoma, and post-operative lung cancer. Methods: The protein expression and signal transduction were detected by Western blot (WB) and immunohistochemistry (IHC). Overexpression or lacking CCNO stable cell lines were transfected with lentiviruses and selected with puromycin. The tumor behaviors of lung adenocarcinoma (LUAD) cells were assessed: cell proliferation by 5-Ethynyl-2'-deoxyuridine (EdU) staining and Cell Counting Kit-8 (CCK8) assay, cell cycle and by flow cytometry analysis, and migration and invasion using wound healing and Transwell system. Co-immunoprecipitation was used to detect protein-protein interactions. Xenograft models for evaluating tumor growth and anti-tumor drug efficacy. Results: A higher expression of CCNO was observed in LUAD cancer tissues and predicted the overall survival of LUAD patients. Moreover, CCNO expression was negatively correlated with cancer cell proliferation, migration, and invasion. Co-immunoprecipitation and western blot indicated that CCNO interacted with CDK13 to promote cancer cell proliferation signaling activation. Furthermore, CCNO promoted tumor cell growth and cetuximab resistance in vivo, and a CDK13 inhibitor effectively inhibited the oncological effect of CCNO. Conclusions: The current study suggests that CCNO may be a driver in the development of LUAD and that its function is related to CDK13 interaction that promotes proliferation signaling activation.

6.
Mol Cancer Res ; 21(7): 713-725, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37011005

RESUMO

Lung adenocarcinoma (LUAD) is a major lung cancer subtype. In this study, we discovered that the eukaryotic translation initiation factor EIF4A3 expression was significantly higher in LUAD tissues and that this higher expression was closely linked to a poor prognosis for LUAD. In addition, we demonstrated that the knockdown of EIF4A3 significantly inhibited the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. The findings of mass spectrometry analysis revealed that EIF4A3 could interact with Flotillin-1 in LUAD cells and that EIF4A3 could positively regulate the expression of FLOT1 at the protein level. Meanwhile, transcriptome sequencing showed that EIF4A3 could influence the development of LUAD by affecting PI3K-AKT-ERK1/2-P70S6K and PI3K class III-mediated autophagy in the Apelin pathway. In addition, we confirmed that Flotillin-1 expression was upregulated in LUAD based on the existing literature, and knockdown of FLOT1 could inhibit the proliferation and migration of LUAD cells. In addition, the knockdown of Flotillin-1 reversed the increase of cell proliferation and migration caused by EIF4A3 overexpression. Furthermore, we found that the activation of PI3K-AKT-ERK1/2-P70S6K signaling pathway and PI3K class III-mediated autophagy caused by EIF4A3 overexpression was rescued by the knockdown of FLOT1. In a word, we proved that EIF4A3 positively regulates the expression of FLOT1 and plays a procancer role in LUAD. IMPLICATIONS: Our study revealed the role of EIF4A3 in prognosis and tumor progression in LUAD, indicating that EIF4A3 could be used as the molecular diagnostic and prognostic therapeutic target.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Fator de Iniciação 4A em Eucariotos/metabolismo , RNA Helicases DEAD-box/metabolismo
7.
Cell Death Discov ; 9(1): 5, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635258

RESUMO

Circular RNAs play important roles in many cancers, including esophageal squamous cell carcinoma (ESCC), but the precise functions of most circular RNAs are poorly understood. Here we detected significant downregulation of circTRPS1-2 in ESCC based on high-throughput sequencing of three pairs of ESCC tissue and adjacent normal tissue, followed by PCR validation with another 30 tissue pairs. Patients with ESCC whose circTRPS1-2 expression was below the median level for the sample showed significantly shorter median overall survival (13 months) than patients whose circTRPS1-2 expression was above the median (36 months). Overexpressing circTRPS1-2 in the human ESCC cell lines K150 and E109, which express low endogenous levels of circTRPS1-2, inhibited cell proliferation and migration. Conversely, knocking down circTRPS1-2 using short interfering RNA promoted cell proliferation and migration. Similar results were observed in mice bearing K150 xenografts in which circTRPS1-2 was overexpressed or knocked down. Several ribosomal proteins co-immunoprecipitated with circTRPS1-2 from K150 cells in culture, and K150 cells overexpressing circTRPS1-2 showed reduced numbers of ribosomes by A260 absorbance measure and electron microscopy. Our results suggest that circTRPS1-2 can inhibit ESCC proliferation and migration by reducing the production of ribosomes, establishing its potential usefulness in ESCC treatment and prediction of prognosis.

8.
Front Microbiol ; 13: 985465, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338101

RESUMO

Parageobacillus thermoglucosidasius is a thermophilic bacterium of interest for lignocellulosic biomass fermentation. However, carbon catabolite repression (CCR) hinders co-utilization of pentoses and hexoses in the biomass substrate. Hence, to optimize the fermentation process, it is critical to remove CCR in the fermentation strains with minimal fitness cost. In this study, we investigated whether CCR could be removed from P. thermoglucosidasius DSM 2542 by mutating the Ser46 regulatory sites on HPr and Crh to a non-reactive alanine residue. It was found that neither the ptsH1 (HPr-S46A) nor the crh1 (Crh-S46A) mutation individually eliminated CCR in P. thermoglucosidasius DSM 2542. However, it was not possible to generate a ptsH1 crh1 double mutant. While the Crh-S46A mutation had no obvious fitness effect in DSM 2542, the ptsH1 mutation had a negative impact on cell growth and sugar utilization under fermentative conditions. Under these conditions, the ptsH1 mutation was associated with the production of a brown pigment, believed to arise from methylglyoxal production, which is harmful to cells. Subsequently, a less directed adaptive evolution approach was employed, in which DSM 2542 was grown in a mixture of 2-deoxy-D-glucose(2-DG) and xylose. This successfully removed CCR from P. thermoglucosidasius DSM 2542. Two selection strategies were applied to optimize the phenotypes of evolved strains. Genome sequencing identified key mutations affecting the PTS components PtsI and PtsG, the ribose operon repressor RbsR and adenine phosphoribosyltransferase APRT. Genetic complementation and bioinformatics analysis revealed that the presence of wild type rbsR and apt inhibited xylose uptake or utilization, while ptsI and ptsG might play a role in the regulation of CCR in P. thermoglucosidasius DSM 2542.

9.
Sci Rep ; 12(1): 16805, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36207355

RESUMO

Cyclin-dependent kinases (CDKs) control the progression of the cell cycle. D-type cyclin (CYCD) is generally believed to form a complex with CDK and control the G1/S transition. In plants, CYCD and CDK gene families can be divided into 6 (D1-D7) and 7 (CDKA-CDKG) subclasses, respectively. Different subclasses in the CYCD and CDK families have different numbers, structures and functions. In some heterologous woody plants, the functions of these subclass family members remain unclear. In this study, 43 CYCD and 27 CDK gene family members were identified in the allodiploid Populus tomentosa Carr. Phylogenetic analysis suggested that these CYCDs and CDKs were divided into 6 and 7 subclasses, respectively, which were the same as other species. The analysis of protein properties, gene structure, motifs, domains, cis-acting elements and tissue-specific expression of all members of these CYCDs and CDKs showed that the differences between members of different subclasses varied widely, but members of the same subclass especially in the CDK gene family were very similar. These findings also demonstrated a strong correlation between CYCD and CDK gene family members in response to hormones and specific expression. The collinear analysis of P. tomentosa, Populus trichocarpa and Arabidopsis thaliana showed that the expansion patterns of CYCD and CDK gene families were predominantly whole genome duplications (WGD). The protein interaction prediction results of different subclasses of CYCD and CDKs showed that the interaction between different subclasses of CYCD and CDKs was significantly different. Our previous study found that transgenic PtoCYCD2;1 and PtoCYCD3;3 poplars exhibited opposite phenotypes. Y2H and BIFC results showed that the interaction between PtoCYCD2;1 and PtoCYCD3;3 was significantly different with CDKs. This finding might suggest that the functional differences of different CYCD subclasses in plant growth and development were closely related to the different interactions between CYCD and CDK. Our results provide a good idea and direction for the functional study of CYCD and CDK proteins in woody plants.


Assuntos
Arabidopsis , Populus , Arabidopsis/genética , Arabidopsis/metabolismo , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Hormônios/metabolismo , Filogenia , Plantas/metabolismo , Populus/genética , Populus/metabolismo
10.
Microbiol Res ; 256: 126957, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35032723

RESUMO

Though carbon catabolite repression (CCR) has been intensively studied in some more characterised organisms, there is a lack of information of CCR in thermophiles. In this work, CCR in the thermophile, Parageobacillus thermoglucosidasius DSM 2542 has been studied during growth on pentose sugars in the presence of glucose. Physiological studies under fermentative conditions revealed a loosely controlled CCR when DSM 2542 was grown in minimal medium supplemented with a mixture of glucose and xylose. This atypical CCR pattern was also confirmed by studying xylose isomerase expression level by qRT-PCR. Fortuitously, the pheB gene, which encodes catechol 2, 3-dioxygenase was found to have a cre site highly similar to the consensus catabolite-responsive element (cre) at its 3' end and was used to confirm that expression of pheB from a plasmid was under stringent CCR control. Bioinformatic analysis suggested that the CCR regulation of xylose metabolism in P. thermoglucosidasius DSM 2542 might occur primarily via control of expression of pentose transporter operons. Relaxed control of sugar utilization might reflect a lower affinity of the CcpA-HPr (Ser46-P) or CcpA-Crh (Ser46-P) complexes to the cre(s) in these operons.


Assuntos
Regulação Bacteriana da Expressão Gênica , Proteínas Repressoras , Bacillaceae , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Xilose
11.
Exp Biol Med (Maywood) ; 247(5): 426-432, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34787019

RESUMO

Mut L homolog-1 (MLH1) is a key DNA mismatch repair protein which participates in the sensitivity to DNA damaging agents. However, its role in the radiosensitivity of tumor cells is less well characterized. In this study, we investigated the role of MLH1 in cellular responses to ionizing radiation (IR) and explored the signaling molecules involved. The isogenic pair of MLH1 proficient (MLH1+) and deficient (MLH1-) human colorectal cancer HCT116 cells was exposed to IR for 24 h at the dose of 3 cGy. The clonogenic survival was examined by the colony formation assay. Cell cycle distribution was analyzed with flow cytometry. Changes in the protein level of MLH1, DNA damage marker γH2AX, and protein kinase A catalytic subunit (PRKAC), a common target for anti-tumor drugs, were examined with Western blotting. The results showed that the HCT116 (MLH1+) cells demonstrated increased radio-resistance with increased S population, decreased G2 population, a low level of γH2AX, a reduced ratio of phosphorylated PRKACαß to total PRKAC, and an elevated level of total PRKAC and phosphorylated PRKACßII following IR compared with the HCT116 (MLH1-) cells. Importantly, silencing PRKAC in HCT116 (MLH1+) cells increased the cellular radiosensitivity. In conclusion, MLH1 may increase cellular resistance to IR by activating PRKAC. Our finding is the first to demonstrate the important role of PRKAC in MLH1-mediated radiosensitivity, suggesting that PRKAC has potential as a biomarker and a therapeutic target for increasing radio-sensitization.


Assuntos
Antineoplásicos , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Proteína 1 Homóloga a MutL , Tolerância a Radiação , Antineoplásicos/farmacologia , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Células HCT116 , Histonas , Humanos , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo
12.
Cancer Med ; 11(4): 1037-1047, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34939343

RESUMO

BACKGROUND: We compared the dosimetry, application, and acute toxicity of a 3D-printed and a conventional bolus for postmastectomy radiotherapy (PMRT) with volumetric modulated arc therapy (VMAT). Materials and Methods Eligible patients (n = 75) with PMRT breast cancer were randomly selected to receive VMAT with a conventional bolus or a 3D-printed bolus. The primary endpoint was a 10% decrease in the mean heart dose to left-sided breast cancer patients. The secondary endpoint was a 5% decrease in the mean ipsilateral lung dose to all patients. A comparative analysis was carried out of the dosimetry, normal tissue complication probability (NTCP), acute skin toxicity, and radiation pneumonitis. RESULTS: Compared to a conventional bolus, the mean heart dose in left-sided breast cancer was reduced by an average of 0.8 Gy (5.5 ± 1.3 Gy vs. 4.7 ± 0.8 Gy, p = 0.035) and the mean dose to the ipsilateral lung was also reduced by an average of 0.8 Gy (12.4 ± 1.0 Gy vs. 11.6 ± 0.8 Gy, p < 0.001). The values for V50Gy of the PTV of the chest wall for the 3D-printed and conventional boluses were 95.4 ± 0.6% and 94.8 ± 0.8% (p = 0.026) and the values for the CI of the entire PTV were 0.83 ± 0.02 and 0.80 ± 0.03 (p < 0.001), respectively. The NTCP for the 3D-printed bolus was also reduced to an average of 0.14% (0.32 ± 0.19% vs. 0.18 ± 0.11%, p = 0.017) for the heart and 0.45% (3.70 ± 0.67% vs. 3.25 ± 0.18%, p < 0.001) for the ipsilateral lung. Grade 2 and Grade 1 radiation pneumonitis were 0.0% versus 7.5% and 14.3% versus 20.0%, respectively (p = 0.184). CONCLUSIONS: The 3D-printed bolus may reduce cardiopulmonary exposure in postmastectomy patients with volumetric modulated arc therapy.


Assuntos
Neoplasias da Mama , Radioterapia de Intensidade Modulada , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Órgãos em Risco , Impressão Tridimensional , Pneumonite por Radiação/etiologia , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Neoplasias Unilaterais da Mama/radioterapia , Neoplasias Unilaterais da Mama/cirurgia
13.
Ann Transl Med ; 9(18): 1464, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34734016

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer-related mortality. While recent studies have documented the presence of extrachromosomal circular DNAs (eccDNAs) in various tumors, to date, there have been no studies examining the distribution and function of eccDNAs in ESCC. METHODS: The eccDNAs from three surgically matched ESCC tissue samples were extracted and amplified by rolling circle amplification after removal of linear DNA and mitochondrial circular DNA. High-throughput eccDNA sequencing and bioinformatics analysis was performed to study the distribution pattern and the level of eccDNA expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the genes associated with the differentially expressed eccDNAs. Five up-regulated and five down-regulated candidate eccDNAs were validated by routine polymerase chain reaction (PCR), TOPO-TA cloning and Sanger sequencing. The nucleotides flanking the eccDNA junctions were analyzed to explore the mechanisms of eccDNA formation. RESULTS: A total of 184,557 eccDNAs was identified. The overall length distribution ranged from 33 to 968,842 base pairs (bp), with the peak at approximately 360 bp. These eccDNAs mainly originated from 5'- and 3'-untranslated regions (UTRs), and rarely from exons, introns, LINE, or Alu repeat regions. The chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between ESCC samples and matched normal epithelium. Nevertheless, 16,031 eccDNAs were found to be differentially expressed between ESCC and matched normal epithelium, including 10,126 up-regulated eccDNAs and 5,905 down-regulated eccDNAs. GO analysis and KEGG pathway analysis showed enriched in cancer pathways, mitogen-activated protein kinase (MAPK) pathway, GTPase-related activity, and cytoskeleton function. PCR, TOPO-TA cloning, and Sanger sequencing validated the junctional sites of five up-regulated candidate eccDNAs and four other unexpected eccDNAs. A repeat nucleotide pattern between the position flanking the start site and that flanking the end site was detected. CONCLUSIONS: This study demonstrated the genome-wide presence of eccDNAs, explored the differential expression of eccDNAs, and revealed the potential mechanisms of eccDNAs in ESCC. This work provides further insights into our understanding of genome plasticity, the role of eccDNAs in ESCC, and may contribute to the development of potential clinical therapies.

14.
Chem Biol Drug Des ; 98(6): 1065-1078, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34587363

RESUMO

This study was conducted to develop novel fasudil derivatives after incorporation of substituted thiazoles as potent anti-breast cancer (BC) agents. The compounds were developed using a facile synthetic route in excellent yields. The entire set of developed compounds was tested for inhibitory activity against rho-associated coiled-coil kinase (ROCK; ROCK1 and ROCK2) kinase, where they exhibit potent and selective inhibition of ROCK1 as compared to ROCK2. The most potent ROCK2 inhibitor, compound 6h significantly inhibited the viability of BC cells (MCF-7). It also causes inhibition of migration and invasion of MCF-7 cells. Moreover, the anti-BC activity of compound 6h was studied in 7,12 dimethyl Benz(a)anthracene (DMBA)-induced BC in female Sprague Dawley rats. Results suggest that it causes significant improvement in the bodyweight of the animals with a reduction in oxidative stress in the liver and mammary tissues of rats. It showed improvement in the intestinal barrier function of rats by restoring the level of Diamine oxidase, d-lactate, and endotoxin. In western blot analysis, it showed improvement in (ZO-1), occludin, and claudin-1 in the colon tissue of the rat as compared to the DMBA group. Our study demonstrated the development of the novel class of fasudil derivatives potent anti-BC agent that improves intestinal flora and intestinal barrier function in rats.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Animais , Antineoplásicos/síntese química , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Ratos Sprague-Dawley , Tiazóis/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/genética
15.
Sci Rep ; 11(1): 16696, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404882

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a life-threatening thoracic tumor with a poor prognosis. The role of molecular alterations and the immune microenvironment in ESCC development has not been fully elucidated. The present study aimed to elucidate key candidate genes and immune cell infiltration characteristics in ESCC by integrated bioinformatics analysis. Nine gene expression datasets from the Gene Expression Omnibus (GEO) database were analysed to identify robust differentially expressed genes (DEGs) using the robust rank aggregation (RRA) algorithm. Functional enrichment analyses showed that the 152 robust DEGs are involved in multiple processes in the tumor microenvironment (TME). Immune cell infiltration analysis based on the 9 normalized GEO microarray datasets was conducted with the CIBERSORT algorithm. The changes in macrophages between ESCC and normal tissues were particularly obvious. In ESCC tissues, M0 and M1 macrophages were increased dramatically, while M2 macrophages were decreased. A robust DEG-based protein-protein interaction (PPI) network was used for hub gene selection with the CytoHubba plugin in Cytoscape. Nine hub genes (CDA, CXCL1, IGFBP3, MMP3, MMP11, PLAU, SERPINE1, SPP1 and VCAN) had high diagnostic efficiency for ESCC according to receiver operating characteristic (ROC) curve analysis. The expression of all hub genes except MMP3 and PLAU was significantly related to macrophage infiltration. Univariate and multivariate regression analyses showed that a 7-gene signature constructed from the robust DEGs was useful for predicting ESCC prognosis. Our results might facilitate the exploration of potential targeted TME therapies and prognostic evaluation in ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/imunologia , Redes Reguladoras de Genes , Humanos , Imunidade Celular , Prognóstico , Microambiente Tumoral
16.
Oncol Lett ; 22(1): 531, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34079590

RESUMO

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer that results in the majority of cancer-associated mortality. Multiple copies in T-cell lymphoma-1 (MCTS1) is an oncogene that is expressed at high levels in several types of cancer tissues. However, its exact role and pathomechanism in the development of LUAD remains unknown. Reverse transcription-quantitative PCR analysis was performed to detect MCTS1 expression. Immunohistochemistry analysis was performed to detect MCTS1 expression in LUAD tissues and normal tissues. The MTT, colony formation, EdU, flow cytometry, wound healing and Transwell assays were performed to assess the proliferation, apoptosis, migration and invasion of LUAD cells. Western blot analysis was performed to detect protein expression levels. The present study aimed to investigate the effects of MCTS1 on the progression of LUAD and the potential mechanisms underlying its effects. The results demonstrated that MCTS1 expression was upregulated in LUAD tissues and cells, which was associated with an unfavorable outcome in patients with LUAD. MCTS1 knockdown inhibited LUAD progression by suppressing cell viability and motility, and promoting apoptosis. In addition, E2F1 protein expression was attenuated following MCTS1 knockdown. The silencing MCTS1-induced inhibitory effect on LUAD malignancy was reversed following overexpression of E2F1 by modulating the c-Myc signaling pathway. Taken together, the results of the present study suggest that MCTS1 facilitates cell proliferation and migration, and suppresses apoptosis of LUAD cells by regulating E2F1 expression and the c-Myc signaling pathway.

17.
Transl Lung Cancer Res ; 10(4): 1841-1856, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34012797

RESUMO

BACKGROUND: Lung cancer is a malignant tumor with the highest morbidity and mortality rates worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Overall, current treatments of LUAD are not satisfactory; therefore, novel targets need to be explored. Let-7b-3p is an important member of the let-7 family of microRNAs (miRNAs), and has not been studied separately in LUAD. This study aimed to investigate the role and molecular mechanism of let-7b-3p in LUAD. METHODS: Herein, let-7b-3p expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) assays. MTT, colony formation assay, flow cytometry analysis, wound-healing, Transwell and in vivo experiments were conducted to assess let-7b-3p's function in LUAD. The downstream target TFIIB-related factor 2 (BRF2) was predicted using bioinformatics analyses and confirmed by dual-luciferase reporter assay and rescue experiments. Additionally, BRF2 was found to affect the MAPK/ERK pathway through transcriptome sequencing analysis and western blot (WB) assay. RESULTS: Let-7b-3p is downregulated in LUAD cells and tissue samples and low let-7b-3p expression is correlated with a poor prognosis in LUAD patients. Let-7b-3p suppresses the proliferation and metastasis of LUAD cells both in vivo and in vitro by directly targeting the BRF2-mediated MAPK/ERK pathway. CONCLUSIONS: Let-7b-3p inhibits the development of LUAD and is an ideal novel therapeutic target for the treatment of LUAD.

18.
Psychol Assess ; 33(10): 940-951, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33939455

RESUMO

The Alabama Parenting Questionnaire-9 (APQ-9) is a widely used brief measure of parenting behaviors. However, the reliability coefficients of the three APQ-9 subscales vary substantially. A reliability generalization meta-analysis was conducted on the three APQ-9 subscales to (a) estimate mean internal consistency reliability values and (b) examine the sources of variance. A total of 113 coefficient alphas from 31,572 informants, across 32 studies were included in this meta-analysis. Results showed acceptable mean α values (.84 for positive parenting, .66 for inconsistent discipline, and .70 for poor supervision subscales). Moderator analyses results found that differences in coefficient αs of the three subscales were influenced by numerous variables including administration format, country, language version, population, the mean and standard deviation of scores, and sample size. Our findings support the utility of the parent-report APQ-9 as a useful measure of parenting behaviors. Future research direction is also discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Poder Familiar , Inquéritos e Questionários , Alabama , Humanos , Poder Familiar/psicologia , Reprodutibilidade dos Testes
19.
Proc Natl Acad Sci U S A ; 118(14)2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33785600

RESUMO

The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a "reverse model of heart failure" at the molecular level, suggesting a strategy for treating heart diseases.


Assuntos
Sinalização do Cálcio , Hibernação , Miócitos Cardíacos/metabolismo , Animais , Caveolinas/genética , Caveolinas/metabolismo , Células Cultivadas , Acoplamento Excitação-Contração , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Nucleares/sangue , Proteínas Nucleares/metabolismo , Sciuridae , Transativadores/sangue , Transativadores/metabolismo
20.
Int J Oncol ; 58(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33786609

RESUMO

Lung adenocarcinoma (LUAD) is a common malignant cancer worldwide. It is urgent to explore its underlying molecular mechanism and identify novel diagnostic biomarkers. Abnormal spindle­like microcephaly (ASPM) has recently received considerable attention due to its function in tumor progression. However, its role in LUAD is unclear. The present study aimed to explore the clinical role of ASPM in LUAD. Seven pairs of LUAD and adjacent normal tissues were collected to identify potential LUAD biomarkers using transcriptome sequencing. The association between ASPM expression and LUAD progression was evaluated using bioinformatics analysis and data obtained from clinical specimens. Using small interfering RNA technology, the function of ASPM was analyzed in the LUAD H1299 and A549 cell lines. Transcriptional profiling of ASPM­deficient H1299 cells was then performed to determine the downstream targets of ASPM. Using databases and clinical specimens, it was revealed that ASPM expression was frequently elevated in LUAD tissues, and this upregulation was highly associated with LUAD progression. ASPM served as an oncogenic regulator of LUAD cell proliferation and metastasis. Mechanistically, ASPM facilitated epithelial­mesenchymal transition (EMT) via the PI3K/AKT signaling pathway and 740 Y­P, an activator of this pathway, restored the migratory ability of ASPM­knockdown LUAD cells. The current study identified ASPM as an independent prognostic biomarker of LUAD that served an important oncogenic role in regulating LUAD cell metastasis by promoting EMT via the PI3K/AKT signaling pathway. Targeting ASPM may therefore be a therapeutic strategy for treating LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/patologia , Proteínas do Tecido Nervoso/genética , Regulação para Cima , Células A549 , Adenocarcinoma de Pulmão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Prognóstico , Transdução de Sinais
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