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The incidence of Parkinson's disease (PD) rises rapidly with the increase of age. With the advent of global aging, the number of patients with PD is rising along with the elderly population, especially in China. Previously, we found that Yishen chuchan decoction (YCD), prescribed based on clinical experience, has the potential of alleviating symptoms, delaying the progression, and controlling the development of PD. Nonetheless, the underlying mechanistic role is yet to be explored. Aim: This research examined the possible therapeutic effects of YCD in alleviating PD via a systematic approach with network pharmacology and experimental validation, aiming at providing a new understanding of traditional Chinese medicine management regarding PD. Methods: The chemical structure and properties of YCD were adopted from Traditional Chinese Medicine System Pharmacology Database (TCMSP), SwissADME, PubChem, and PubMed. The potential targets for YCD and PD were identified using Swiss Target Prediction, GeneCard, PubChem, and UniProt. The herbal-component-target network was created via the Cytoscape software. Moreover, by using the STRING database, the protein-protein interaction (PPI) network was screened. Gene function GO and KEGG pathway enrichment analyses were performed via the Metascape database. YCD-medicated Rat Serum from Sprague-Dawley (SD) Rats was prepared, and SH-SY5Y cells were preconditioned with rotenone to develop the PD model. To examine the impact of YCD on these cells and explore the mechanistic role of the p38 mitogen-activated protein kinase (MAPK) pathway, the cells were pretreated with either serum or a p38 MAPK pathway inhibitor. This study employed the Cell Counting Kit (CCK)-8 assay and Hoechst 33,342 staining to evaluate the viability and morphological changes induced by the YCD-medicated rat serum on rotenone-treated SH-SY5Y cells. Apoptosis was assessed by Flow cytometry. Immunofluorescence staining assessed the microtubule-associated protein 2 (MAP2) level. Enzyme-linked immunosorbent assay (ELISA) was employed to quantify the concentrations of inflammatory mediators interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Also, reactive oxygen species (ROS) and superoxide dismutase (SOD) levels were determined. Western Blotting measured the expression of total and phospho-p38 MAPK (p-p38). Results: This study identified 65 active components in YCD, which were found to target 801 specific genes. By screening, 63 potential core targets were identified from a pool of 172 overlapping targets between PD and YCD. These targets were examined by GO and KEGG analyses revealing their substantial correlation to MAPK, PI3K-Akt signaling pathways, positively controlling protein phosphorylation, and pathways of neurodegenerative diseases. SH-SY5Y cells were treated with 2 µM rotenone for 48 h, which reduced cell viability to 50 %, and reduced MAP2 expression, increased the rate of apoptosis, oxidative stress, inflammation, and p-p38 expressions. YCD-medicated rat serum significantly improved the viability, reduced the apoptosis rate, and increased the MAP2 expression. YCD-medicated serum increased SOD, reduced ROS and suppressed IL-6, IL-1ß and TNF-α levels, thus inhibiting oxidative stress and inflammation in rotenone-treated SH-SY5Y cells. Moreover, YCD-medicated serum substantially lowered the p-p38 expression induced by rotenone. SB203580, a specific inhibitor of p38 MAPK, could also inhibit the p-p38 expression, apoptosis, and restore morphological damage of cells, also improve inflammation and oxidative stress. Conclusion: YCD enhanced cell viability and reduced apoptosis rate, inflammation, and oxidative stress in vitro. These beneficial effects could potentially involve the suppression of p38 pathway and suppressed the phosphorylation of p38 MAPK.
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The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.
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OBJECTIVE: The objective of this study was to identify the risk factors that influence metastasis and prognosis in patients with nodular melanoma (NM), as well as to develop and validate a prognostic model using artificial intelligence (AI) algorithms. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for 4,727 patients with NM based on the inclusion/exclusion criteria. Their clinicopathological characteristics were retrospectively reviewed, and logistic regression analysis was utilized to identify risk factors for metastasis. This was followed by employing Multilayer Perceptron (MLP), Adaptive Boosting (AB), Bagging (BAG), logistic regression (LR), Gradient Boosting Machine (GBM), and eXtreme Gradient Boosting (XGB) algorithms to develop metastasis models. The performance of the six models was evaluated and compared, leading to the selection and visualization of the optimal model. Through integrating the prognostic factors of Cox regression analysis with the optimal models, the prognostic prediction model was constructed, validated, and assessed. RESULTS: Logistic regression analyses identified that marital status, gender, primary site, surgery, radiation, chemotherapy, system management, and N stage were all independent risk factors for NM metastasis. MLP emerged as the optimal model among the six models (AUC = 0.932, F1 = 0.855, Accuracy = 0.856, Sensitivity = 0.878), and the corresponding network calculator (https://shimunana-nm-distant-m-nm-m-distant-8z8k54.streamlit.app/) was developed. The following were examined as independent prognostic factors: MLP, age, marital status, sequence number, laterality, surgery, radiation, chemotherapy, system management, T stage, and N stage. System management and surgery emerged as protective factors (HR < 1). To predict 1-, 3-, and 5-year overall survival (OS), a nomogram was created. The validation results demonstrated that the model exhibited good discrimination and consistency, as well as high clinical usefulness. CONCLUSION: The developed prediction model more effectively reflects the prognosis of patients with NM and differentiates between the risk level of patients, serving as a useful supplement to the classical American Joint Committee on Cancer (AJCC) staging system and offering a reference for clinically stratified individualized treatment and prognosis prediction. Furthermore, the model enables clinicians to quantify the risk of metastasis in NM patients, assess patient survival, and administer precise treatments.
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Inteligência Artificial , Melanoma , Humanos , Melanoma/patologia , Melanoma/mortalidade , Feminino , Masculino , Prognóstico , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Estudos Retrospectivos , Metástase Neoplásica , Programa de SEER , Adulto , Algoritmos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Modelos LogísticosRESUMO
Circular RNAs (circRNAs) have emerged as key regulators of cancer occurrence and progression, as well as promising biomarkers for cancer diagnosis and prognosis. However, the potential mechanisms of circRNAs implicated in lymph node (LN) metastasis of gastric cancer remain unclear. Herein, we identify a novel N6-methyladenosine (m6A) modified circRNA, circPAK2, which is significantly upregulated in gastric cancer tissues and metastatic LN tissues. Functionally, circPAK2 enhances the migration, invasion, lymphangiogenesis, angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis of gastric cancer in vitro and in vivo. Mechanistically, circPAK2 is exported by YTH domain-containing protein 1 (YTHDC1) from the nucleus to the cytoplasm in an m6A methylation-dependent manner. Moreover, increased cytoplasmic circPAK2 interacts with Insulin-Like Growth Factor 2 mRNA-Binding Proteins (IGF2BPs) and forms a circPAK2/IGF2BPs/VEGFA complex to stabilize VEGFA mRNA, which contributes to gastric cancer vasculature formation and aggressiveness. Clinically, high circPAK2 expression is positively associated with LN metastasis and poor prognosis in gastric cancer. This study highlights m6A-modified circPAK2 as a key regulator of LN metastasis of gastric cancer, thus supporting circPAK2 as a promising therapeutic target and prognostic biomarker for gastric cancer.
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Adenosina , Metástase Linfática , RNA Circular , Proteínas de Ligação a RNA , Transdução de Sinais , Neoplasias Gástricas , Fator A de Crescimento do Endotélio Vascular , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Metástase Linfática/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Transdução de Sinais/genética , Camundongos , Masculino , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Prognóstico , Feminino , Camundongos NusRESUMO
BACKGROUND: This study aimed to develop a novel six-gene expression biomarker panel to enhance the early detection and risk stratification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer (LAGC). METHODS: We used genome-wide transcriptome profiling and rigorous bioinformatics to identify a six-gene expression biomarker panel. This panel was validated across multiple clinical cohorts using both tissue and liquid biopsy samples to predict peritoneal recurrence and micrometastasis in patients with LAGC. RESULTS: Through genome-wide expression profiling, we identified six mRNAs and developed a risk prediction model using 196 samples from a surgical specimen training cohort. This model, incorporating a 6-mRNA panel with clinical features, demonstrated high predictive accuracy for peritoneal recurrence in gastric cancer patients, with an AUC of 0.966 (95% CI: 0.944-0.988). Transitioning from invasive surgical or endoscopic biopsy to noninvasive liquid biopsy, the model retained its predictive efficacy (AUC = 0.963; 95% CI: 0.926-1.000). Additionally, the 6-mRNA panel effectively differentiated patients with or without peritoneal metastasis in 95 peripheral blood specimens (AUC = 0.970; 95% CI: 0.936-1.000) and identified peritoneal micrometastases with a high efficiency (AUC = 0.941; 95% CI: 0.874-1.000). CONCLUSIONS: Our study provides a novel gene expression biomarker panel that significantly enhances early detection of peritoneal recurrence and micrometastasis in patients with LAGC. The RSA model's predictive capability offers a promising tool for tailored treatment strategies, underscoring the importance of integrating molecular biomarkers with clinical parameters in precision oncology.
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Biomarcadores Tumorais , Perfilação da Expressão Gênica , Micrometástase de Neoplasia , Recidiva Local de Neoplasia , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Biópsia Líquida/métodos , Feminino , Micrometástase de Neoplasia/genética , Masculino , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Pessoa de Meia-Idade , Transcriptoma , IdosoRESUMO
BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal (GI) system. However, the lack of reliable biomarkers has made its diagnosis, prognosis, and treatment challenging. Immunogenic cell death (ICD) is a type of programmed cell death that is strongly related to the immune system. However, its function in GC requires further investigation. METHOD: We used multi-omics and multi-angle approaches to comprehensively explore the prognostic features of ICD in patients with stomach adenocarcinoma (STAD). At the single-cell level, we screened genes associated with ICD at the transcriptome level, selected prognostic genes related to ICD using weighted gene co-expression network analysis (WGCNA) and machine learning, and constructed a prognostic model. In addition, we constructed nomograms that incorporated pertinent clinical features and provided effective tools for prognostic prediction in clinical settings. We also investigated the sensitivity of the risk subgroups to both immunotherapy and drugs. Finally, in addition to quantitative real-time polymerase chain reaction, immunofluorescence was used to validate the expression of ICD-linked genes. RESULTS: Based on single-cell and transcriptome WGCNA analyses, we identified 34 ICD-related genes, of which 11 were related to prognosis. We established a prognostic model using the least absolute shrinkage and selection operator (LASSO) algorithm and identified dissimilarities in overall survival (OS) and progression-free survival (PFS) in risk subgroups. The nomograms associated with the ICD-related signature (ICDRS) demonstrated a good predictive value for clinical applications. Moreover, we detected changes in the tumor microenvironment (TME), including biological functions, mutation landscapes, and immune cell infiltration, between the high- and low-risk groups. CONCLUSION: We constructed an ICD-related prognostic model that incorporated features related to cell death. This model can serve as a useful tool for predicting the prognosis of GC, targeted prevention, and personalized medicine.
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Objective: Magnoflorine (Mag) has been reported to have anxiolytics, anti-cancer, and anti-inflammatory properties. In this study, we aim to investigate the effects of Mag on the rheumatoid arthritis (RA) and explore the underlying mechanism using a collagen-induced arthritis (CIA) mouse model and a lipopolysaccharide (LPS)-stimulated macrophage inflammation model. Methods: The in vivo effects of Mag on CIA were studied by inducing CIA in a mouse model using DBA/1J mice followed by treatment with vehicle, methotrexate (MTX, 1 mg/kg/d), and Mag (5 mg/kg/d, 10 mg/kg/d, and 20 mg/kg/d), and the in vitro effects of Mag on macrophages were examined by stimulation of RAW264.7 cells line and peritoneal macrophages (PMs) by LPS in the presence of different concentrations of Mag. Network pharmacology and molecular docking was then performed to predict the the binding ability between Mag and its targets. Inflammatory mediators were assayed by quantitative real-time PCR and enzyme linked immunosorbent assay (ELISA). Signaling pathway changes were subsequently determined by Western blotting and immunohistochemistry (IHC). Results: In vivo experiments demonstrated that Mag decreased arthritis severity scores, joints destruction, and macrophages infiltration into the synovial tissues of the CIA mice. Network pharmacology analysis revealed that Mag interacted with TNF-α, IL-6, IL-1ß, and MCP-1. Consistent with this, analysis of the serum, synovial tissue of the CIA mice, and the supernatant of the cultured RAW264.7 cells and PMs showed that Mag suppressed the expression of TNF-α, IL-6, IL-1ß, MCP-1, iNOS, and IFN-ß. Furthermore, Mag attenuated the phosphorylation of p65, IκBα, ERK, JNK, and p38 MAPKs in the synovial tissues of the CIA mice and LPS-stimulated RAW 264.7 cells. Conclusion: Mag may exert anti-arthritic and anti-inflammatory effects by inhibiting the activation of NF-κB and MAPK signaling pathways.
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Gastric cancer is one of the top causes of cancer-related death globally. Although novel treatment strategies have been developed, attempts to eradicate gastric cancer have been proven insufficient. Oxidative stress is continually produced and continually present in the human body. Increasing evidences show that oxidative stress contributes significantly to the development of gastric cancer, either through initiation, promotion, and progression of cancer cells or causing cell death. As a result, the purpose of this article is to review the role of oxidative stress response and the subsequent signaling pathways as well as potential oxidative stress-related therapeutic targets in gastric cancer. Understanding the pathophysiology of gastric cancer and developing new therapies for gastric cancer depends on more researches focusing on the potential contributors to oxidative stress and gastric carcinogenesis.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Estresse Oxidativo , Carcinogênese , Transdução de Sinais , Morte CelularRESUMO
Cancer is the second most common cause of mortality in the world. One of the unresolved difficult pathological mechanism issues in malignant tumors is the imbalance of substance and energy metabolism of tumor cells. Cells maintain life through energy metabolism, and normal cells provide energy through mitochondrial oxidative phosphorylation to generate ATP, while tumor cells demonstrate different energy metabolism. Neuroendocrine control is crucial for tumor cells' consumption of nutrients and energy. As a result, better combinatorial therapeutic approaches will be made possible by knowing the neuroendocrine regulating mechanism of how the neuroendocrine system can fuel cellular metabolism. Here, the basics of metabolic remodeling in tumor cells for nutrients and metabolites are presented, showing how the neuroendocrine system regulates substance and energy metabolic pathways to satisfy tumor cell proliferation and survival requirements. In this context, targeting neuroendocrine regulatory pathways in tumor cell metabolism can beneficially enhance or temper tumor cell metabolism and serve as promising alternatives to available treatments.
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Metabolismo Energético , Neoplasias , Humanos , Neoplasias/metabolismo , Fosforilação Oxidativa , Mitocôndrias/metabolismo , Redes e Vias MetabólicasRESUMO
Background: Non-small cell lung cancer (NSCLC) is still a slightly less orphan disease after immunotherapy, and routine treatment has low efficiency and adverse events. Ginseng is commonly used in the treatment of NSCLC. The purpose of this study is to assess the efficacy and hemorheological indexes of ginseng and its active components in patients with non-small cell lung cancer. Methods: A comprehensive literature search was performed in PubMed, the Cochrane Library, Medline (Ovid), the Web of Science, Embase, CKNI, Wan Fang, VIP, and SinoMed up to July 2021. Only randomized controlled trials evaluating ginseng in combination with chemotherapy versus chemotherapy alone in NSCLC patients were included. Primary outcomes included patients' condition after using ginseng or its active components. Secondary outcomes included changes in immune cells, cytokines, and secretions in serum. Data were extracted by two independent individuals, and the Cochrane Risk of Bias tool version 2.0 was applied for the included studies. Systematic review and meta-analysis were performed by RevMan 5.3 software. Results: The results included 1480 cases in 17 studies. The results of the integration of clinical outcomes showed that the treatment of ginseng (or combination of ginseng with chemotherapy) can improve the quality of life for patients with NSCLC. Analysis of immune cell subtypes revealed that ginseng and its active ingredients can upregulate the percentages of antitumor immunocyte subtypes and downregulate the accounts of immunosuppressive cells. In addition, a reduction of the inflammatory level and an increase of antitumor indicators in serum were reported. Meta-analysis showed that Karnofsky score: WMD = 16, 95% CI (9.52, 22.47); quality-of-life score: WMD = 8.55, 95%CI (6.08, 11.03); lesion diameter: WMD = -0.45, 95% CI (-0.75, -0.15); weight: WMD = 4.49, 95% CI (1.18, 7.80); CD3+: WMD = 8.46, 95% CI (5.71, 11.20); CD4+: WMD = 8.45, 95% CI (6.32, 10.57)+; CD8+: WMD = -3.76, 95% CI (-6.34, -1.18); CD4+/CD8+: WMD = 0.32, 95% CI (0.10, 0.53); MDSC: WMD = -2.88, 95% CI (-4.59, -1.17); NK: WMD = 3.67, 95% CI (2.63, 4.71); Treg: WMD = -1.42, 95% CI (-2.33, -0.51); CEA: WMD = -4.01, 95% CI (-4.12, -3.90); NSE: WMD = -4.00, 95% CI (-4.14, -3.86); IL-2: WMD = 9.45, 95% CI (8.08, 10.82); IL-4: WMD = -9.61, 95% CI (-11.16, -8.06); IL-5: WMD = -11.95, 95% CI (-13.51, -10.39); IL-6: WMD = -7.65, 95% CI (-8.70, -6.60); IL-2/IL-5: WMD = 0.51, 95% CI (0.47, 0.55); IFN-γ: WMD = 15.19, 95% CI (3.16, 27.23); IFN-γ/IL-4: WMD = 0.91, 95% CI (0.85, 0.97); VEGF: WMD = -59.29, 95% CI (-72.99, -45.58); TGF-α: WMD = -10.09, 95% CI (-12.24, -7.94); TGF-ß: WMD = -135.62, 95% CI (-147.00, -124.24); TGF-ß1: WMD = -4.22, 95% CI (-5.04, -3.41); arginase: WMD = -1.81, 95% CI (-3.57, -0.05); IgG: WMD = 1.62, 95% CI (0.18, 3.06); IgM: WMD = -0.45, 95% CI (-0.59, -0.31). All results are statistically significant. No adverse events were reported in the included articles. Conclusion: It is a reasonable choice to use ginseng and its active components as adjuvant therapy for NSCLC. Ginseng is helpful for NSCLC patients' conditions, immune cells, cytokines, and secretions in the serum.
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BACKGROUND: Adolescent and young adult (AYA) cancer survivors (first diagnosed with cancer at age 15-39) are distinct within the cancer community due to their unique challenges and diverse psycho-behavioral characteristics. This study aimed to analyze psycho-behavioral pathways and further explore the mediating role of cognitive appraisals on AYA cancer survivors' quality of life (QoL). METHODS: Three hundred and eighty-nine AYA cancer survivors were eligible for analyses and recruited to self-administer questionnaires on QoL (the Chinese version of EORTC Quality of Life Questionnaire-C30 v3.0), resilience, coping, and appraisal on site. This study performed structural equation modeling (SEM) to examine pathways on QoL based on the Rapkin & Schwartz QoL Appraisal Model. RESULTS: The average age of participants (47.6% female) was 32.7 ± 4.1 years. The SEM results closely fit the measured data (RMSEA = 0.053, GFI = 0.955, CFI = 0.964, SRMR = 0.052). The final model showed direct negative effects of later clinical-stage, more comorbidities, and more Acceptance-Resignation coping on QoL; indirect positive effects of better resilience on QoL through less Acceptance-Resignation coping (ß = 0.286, P = 0.002). Appraisal mediated the effects of treatment and resilience on QoL (ß = -0.024, P = 0.038). Further, Calm, Peaceful, and Active appraisal patterns were associated with improved Cognitive Functioning (ß = 0.119, P = 0.009). CONCLUSION: Appraisal, coping, and resilience could significantly mediate the effects of cancer and its treatment on the QoL of AYA cancer survivors. Future interventions targeting cognitive appraisals and psycho-behaviors will be helpful. Figuring out what matters to such a unique population and how they appraise a cancer diagnosis through treatment trajectories could help nurses adjust support.
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Sobreviventes de Câncer , Neoplasias , Humanos , Feminino , Adulto Jovem , Adolescente , Adulto , Masculino , Qualidade de Vida/psicologia , Sobreviventes de Câncer/psicologia , Neoplasias/psicologia , Emoções , Adaptação Psicológica , Inquéritos e QuestionáriosRESUMO
Oxidative stress is crucial to the biology of tumors. Oxidative stress' potential predictive significance in colorectal cancer (CRC) has not been studied; nevertheless here, we developed a forecasting model based on oxidative stress to forecast the result of CRC survival and enhance clinical judgment. The training set was chosen from the transcriptomes of 177 CRC patients in GSE17536. For validation, 65 samples of colon cancer from GSE29621 were utilized. For the purpose of choosing prognostic genes, the expression of oxidative stress-related genes (OXEGs) was found. Prognostic risk models were built using multivariate Cox regression analysis, univariate Cox regression analysis, and LASSO regression analysis. The outcomes of the western blot and transcriptome sequencing tests were finally confirmed. ATF4, CARS2, CRP, GPX1, IL1B, MAPK8, MRPL44, MTFMT, NOS1, OSGIN2, SOD2, AARS2, and FOXO3 were among the 14 OXEGs used to build prognostic characteristics. Patients with CRC were categorized into low-risk and high-risk groups according on their median risk scores. Cox regression analysis using single and multiple variables revealed that OXEG-related signals were independent risk factors for CRC. Additionally, the validation outcomes from western blotting and transcriptome sequencing demonstrated that OXEGs were differently expressed. Using 14 OXEGs, our work creates a predictive signature that may be applied to the creation of new prognostic models and the identification of possible medication candidates for the treatment of CRC.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Fatores de Risco , Estresse Oxidativo/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Background: Cuproptosis, a newly described method of regulatory cell death (RCD), may be a viable new therapy option for cancers. Long noncoding RNAs (lncRNAs) have been confirmed to be correlated with epigenetic controllers and regulate histone protein modification or DNA methylation during gene transcription. The roles of cuproptosis-related lncRNAs (CRLs) in Colon adenocarcinoma (COAD), however, remain unknown. Methods: COAD transcriptome data was obtained from the TCGA database. Thirteen genes associated to cuproptosis were identified in published papers. Following that, correlation analysis was used to identify CRLs. The cuproptosis associated prognostic signature was built and evaluated using Lasso regression and COX regression analysis. A prognostic signature comprising six CRLs was established and the expression patterns of these CRLs were analyzed by qRT-PCR. To assess the clinical utility of prognostic signature, we performed tumor microenvironment (TME) analysis, mutation analysis, nomogram generation, and medication sensitivity analysis. Results: We identified 49 prognosis-related CRLs in COAD and constructed a prognostic signature consisting of six CRLs. Each patient can be calculated for a risk score and the calculation formula is: Risk score =TNFRSF10A-AS1 * (-0.2449) + AC006449.3 * 1.407 + AC093382.1 *1.812 + AC099850.3 * (-0.0899) + ZEB1-AS1 * 0.4332 + NIFK-AS1 * 0.3956. Six CRLs expressions were investigated by qRT-PCR in three colorectal cancer cell lines. In three cohorts, COAD patients were identified with different risk groups, with the high-risk group having a worse prognosis than the low-risk group. Furthermore, there were differences in immune cell infiltration and tumor mutation burden (TMB) between the two risk groups. We also identified certain drugs that were more sensitive to the high-risk group: Paclitaxel, Vinblastine, Sunitinib and Elescloml. Conclusions: Our findings may be used to further investigate RCD, comprehension of the prognosis and tumor microenvironment infiltration characteristics in COAD.
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PURPOSE: Regular physical activity (PA) is essential for childhood cancer survivors (CCS), yet most CCS have difficulty participating in it. The level of PA participation among CCS in China is lower than those of western countries, leading to a worse long-term survival of CCS in China. Here, the study aims to explore the associated factors on the PA performance among CCS. METHODS: From September to December 2020, the study used purposive sampling to recruit 35 families (88.9%) as sampling units among two hospitals in Hangzhou City, China. The data collection conducted two designs on semi-structured interviews with different roles under family structure - children (n = 35) and parents (n = 35) - respectively. The design of predetermined questions relied on the health belief model (HBM) as a thematic framework. The qualitative analysis applied codebook thematic analysis and used the deductive approach to finalize the main findings. RESULTS: The study only presented preliminary conclusions from interviews with CCS, which resulted in four themes (changes in PA performance; perceptions on participating PA; cognitions of PA; impacts from others) with eight sub-themes. In particular, CCS replied diversity changes in PA, but most of them mentioned the inactive PA after diagnosis, especially the decline of moderate-to-vigorous PA (MVPA). As for the "perceptions of PA," almost all CCS had substantial perceived benefits about PA, specifically on their physical well-being. All children also expressed perceived barriers to PA, including the side effects of disease and treatment, fatigue, academic burden, changes in psychological status, and lack of companions. On the cognitions of PA, the CCS had limited realizations of regular PA and low self-efficacy on MVPA. Furthermore, CCS expressed their need for support from their parents, school teachers, and healthcare providers. But in reality, they recieved less support on PA from these important people. CONCLUSION: The changes in PA after illness among CCS are apparent and unavoidable because of the interaction impacts from internal factors (e.g., personal characters, cognization, perceptions of PA) and external factors (e.g., disease effects, interpersonal supports). The findings explained the main elements under HBM but also provided explored views as the evidence on developing theories and guiding motivations and practices on PA among CCS. IMPLICATIONS FOR CANCER SURVIVORS: In this exploratory study of 35 CCS, we identified the current situation of PA among CCS in China and explored the associated factors. As the first qualitative study on the CCS in mainland China, the study considered particular effects on social culture and living environment.
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Sobreviventes de Câncer , Neoplasias , Humanos , Criança , Neoplasias/psicologia , Exercício Físico/psicologia , Pesquisa Qualitativa , Modelo de Crenças de SaúdeRESUMO
Background: The correlation between exosomes and the tumor immune microenvironment has been proved to affect tumorigenesis and progression of colon adenocarcinoma (COAD). However, it remained unclear whether exosomes had an impact on the prognostic indications of COAD patients. Methods: Expression of exosome-related genes (ERGs) and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The ERGs associated with prognosis were identified and exosome-related prognostic signature was constructed. Patients in two risk groups were classified according to the risk score calculation formula: Risk score = 1.0132 * CCKBR + 0.2416 * HOXC6 + 0.7618 * POU4F1. The expression of three ERGs was investigated by qRT-PCR. After that, we developed a nomogram predicting the likelihood of survival and verified its predictive efficiency. The differences of tumor immune microenvironment, immune cell infiltration, immune checkpoint and sensitivity to drugs in two risk groups were analyzed. Results: A prognostic signature was established based on the three ERGs (CCKBR, HOXC6, and POU4F1) and patients with different risk group were distinguished. Survival analysis revealed the negative associated of risk score and prognosis, ROC curve analyses showed the accuracy of this signature. Three ERGs expression was investigated by qRT-PCR in three colorectal cancer cell lines. Moreover, risk score was positively correlated with tumor mutational burden (TMB), immune activities, microsatellite instability level, the expression of immune checkpoint genes. Meanwhile, the expression level of three ERGs and the risk score were markedly related with the sensitive response to chemotherapy. Conclusion: The novel signature composed of three ERGs with precise predictive capabilities can be used to predict prognosis and provide a promising therapeutic target for improving the efficacy of immunotherapy.
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Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Currently, surgery is the treatment of choice for GC. However, the associated expenses and post-surgical pain impose a huge burden on these patients. Furthermore, disease recurrence is also very common in GC patients, thus necessitating the discovery and development of other potential treatment options. A growing body of knowledge about ferroptosis in different cancer types provides a new perspective in cancer therapeutics. Ferroptosis is an iron-dependent form of cell death. It is characterized by intracellular lipid peroxide accumulation and redox imbalance. In this review, we summarized the current findings of ferroptosis regulation in GC. We also tackled on the action of different potential drugs and genes in inducing ferroptosis for treating GC and solving drug resistance. Furthermore, we also explored the relationship between ferroptosis and the tumor microenvironment in GC. Finally, we discussed areas for future studies on the role of ferroptosis in GC to accelerate the clinical utility of ferroptosis induction as a treatment strategy for GC.
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As a critical regulator of bone resorption. osteoclastogenesis is closely associated with osteoporosis (OP) and commonly induced by receptor activator of nuclear factor-κB ligand (RANKL), suggesting that suppression of inflammation may improve OP. Urolithin A (UroA), an active metabolite of ellagic acid, is known to exert anti-inflammatory and antioxidative effects. However, whether UroA attenuates osteoclastogenesis remains unclear. Using a lipopolysaccharide (LPS)-induced bone loss model, we evaluated the effects of UroA on inflammatory osteoclastogenesis in mice and explored the potential mechanism from RANKL-related signaling pathway. UroA significantly improved LPS-induced bone loss and rescued the imbalance in bone microarchitecture parameters. Hematoxylin&eosin (H&E) and tartrate resistant acid phosphatase (TRAP) staining of femurs showed that UroA suppressed LPS-induced osteoclastogenesis accompanied by the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling. In RANKL-triggered mouse bone marrow-derived macrophages (BMDMs), UroA inhibited the formation of osteoclasts and Fibrous actin rings (F-actin rings), and decreased TRAP activity. Moreover, UroA significantly decreased mRNA and protein expression of major inflammatory cytokines in LPS-challenged RAW264.7 cells by decreasing the phosphorylation of NF-κB p65, c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase1/2 (Erk1/2), and p38. Furthermore, UroA may activate the Nrf2 signaling pathway by increasing mRNA and protein expression of antioxidant proteins. We conclude that UroA attenuated RANKL-induced osteoclastogenesis by suppressing the p38 mitogen-activated protein kinase (MAPK) pathway and inducing Nrf2 nuclear translocation. Thus, supplementation with UroA may help alleviate inflammation-induced bone loss and bone resorption.
Assuntos
Reabsorção Óssea , Ligante RANK , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Diferenciação Celular , Cumarínicos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Osteoclastos , Osteogênese , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Remote ischemic conditioning (RIC) displays a cardioprotective role in acute myocardial infarction (AMI). Since interruption of blood vessel is not an essential trigger of remote cardioprotection, tissue compression may play a prominent part in the effect. The purpose of this study was to confirm the protective effect of tissue compression on AMI and the underlying mechanisms. METHODS AND RESULTS: Rat model of AMI was induced by ligation of the left anterior descending coronary artery. Remote cyclic compression (RCC) on forelimb was applied to AMI rats for 3 days after the operation. RCC postconditioning displayed cardioprotective effects against AMI injury by limiting infarct size, alleviating cardiac dysfunction, and suppressing cardiomyocyte apoptosis. In addition, RCC postconditioning induced myocardial autophagy as evidenced by increased LC3-II and Beclin-1 and reduced mTOR levels. Furthermore, RCC treatment upregulated AMPK phosphorylation in the context of AMI hearts. AMPK inhibitor Compound C administration markedly abrogated RCC-mediated cardioprotective effect, as evidenced by decreased infarct size and cardiac function. CONCLUSION: Our results indicated that RCC postconditioning could attenuate AMI injury through inhibiting apoptosis and promoting autophagy via AMPK signaling pathway. The research provided a novel perspective for studying the cardioprotection of RIC and possible therapeutic strategy for managing AMI injury.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Infarto do Miocárdio , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , RatosRESUMO
Background: Parkinson's disease (PD) is a common neurological degenerative disease that cannot be completely cured, although drugs can improve or alleviate its symptoms. Optogenetic technology, which stimulates or inhibits neurons with excellent spatial and temporal resolution, provides a new idea and approach for the precise treatment of Parkinson's disease. However, the neural mechanism of photogenetic regulation remains unclear. Objective: In this paper, we want to study the nonlinear features of EEG signals in the striatum and globus pallidus through optogenetic stimulation of the substantia nigra compact part. Methods: Rotenone was injected stereotactically into the substantia nigra compact area and ventral tegmental area of SD rats to construct rotenone-treated rats. Then, for the optogenetic manipulation, we injected adeno-associated virus expressing channelrhodopsin to stimulate the globus pallidus and the striatum with a 1 mW blue light and collected LFP signals before, during, and after light stimulation. Finally, the collected LFP signals were analyzed by using nonlinear dynamic algorithms. Results: After observing the behavior and brain morphology, 16 models were finally determined to be successful. LFP results showed that approximate entropy and fractal dimension of rats in the control group were significantly greater than those in the experimental group after light treatment (p < 0.05). The LFP nonlinear features in the globus pallidus and striatum of rotenone-treated rats showed significant statistical differences before and after light stimulation (p < 0.05). Conclusion: Optogenetic technology can regulate the characteristic value of LFP signals in rotenone-treated rats to a certain extent. Approximate entropy and fractal dimension algorithm can be used as an effective index to study LFP changes in rotenone-treated rats.
Assuntos
Gânglios da Base/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Optogenética/métodos , Rotenona/farmacologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Desacopladores/farmacologiaRESUMO
Background: Remote ischemic conditioning (RIC) is a cardioprotective phenomenon, yet transient ischemia is not a requisite trigger for remote cardioprotection. In fact, RIC is a stimulus compound containing interruption of the blood vessel and tissue compression. In this study, we evaluate the effects of remote tissue compression on infarct size after myocardial infarction and explore its preliminary mechanisms. Methods and Results: We used a murine model of myocardial infarction to assess ischemia injury and identified remote conditioning by rhythmic compression on forelimb as a novel cardioprotective intervention. We show that the cardioprotective signal transduction of remote conditioning from the trigger limb to the heart involves the release of adenosine. Our results demonstrate that A2a and A2b receptors are indispensable parts for cardioprotection of remote conditioning, which is linked to its anti-inflammatory properties by the subsequent activation of cAMP/PKA/NF-κB axis. Conclusion: Our results establish a new connection between remote tissue compression and cardiovascular diseases, which enhances our cognition about the role of tissue compression on RIC cardioprotection.