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Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) have emerged as a new treatment strategy for inflammatory bowel disease (IBD) due to their immunoregulatory function. N6-methyladenosine (m6A) plays a crucial role in regulating intestinal immunity, especially in IBD where macrophages play an important role, although its mechanism is not yet fully understood. From this perspective, this research aimed to evaluate the effect of hucMSC-Ex on m6A modification of macrophages in IBD. In the process of alleviating inflammation, hucMSC-Ex promotes macrophage polarization toward the M2 type and regulates intracellular m6A levels by upregulating the expression of m6A "Writer" METTL3 and "Reader" YTHDF1. Solute Carrier Family 37 Member 2 (Slc37a2) was identified by Methylation RNA immunoprecipitation sequencing as the target molecule of the hucMSC-Ex. Mechanically, hucMSC-Ex promoted the binding of METTL3 to the Slc37a2 mRNA complex, and enhanced the binding of Slc37a2 to YTHDF1 to upregulate the intracellular expression of Slc37a2, thereby attenuating the pro-inflammatory function of macrophage. This study confirms the modulatory role of hucMSC-Ex on the m6A modification of macrophages in IBD, providing a new scientific basis for the treatment of IBD with hucMSC-Ex.
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Enfermedades Inflamatorias del Intestino , Macrófagos , Células Madre Mesenquimatosas , Metiltransferasas , Proteínas de Unión al ARN , Cordón Umbilical , Animales , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Humanos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Células Madre Mesenquimatosas/metabolismo , Cordón Umbilical/citología , Cordón Umbilical/metabolismo , Exosomas/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Ratones Endogámicos C57BL , Masculino , Activación de MacrófagosRESUMEN
Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.
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Enfermedades Inflamatorias del Intestino , Necroptosis , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Animales , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patologíaRESUMEN
Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acetylation, and glycolysis, have been implicated in IBD. An aberrant ubiquitination in IBD is often associated with dysregulated immune responses and inflammation. Mesenchymal stem cells (MSCs) play a crucial role in regulating ubiquitination modifications through the ubiquitin-proteasome system, a cellular machinery responsible for protein degradation. Specifically, MSCs have been shown to influence the ubiquitination of key signaling molecules involved in inflammatory pathways. This paper reviews the recent research progress in MSC-regulated ubiquitination in IBD, highlighting their therapeutic potential in treating IBD and offering a promising avenue for developing targeted interventions to modulate the immune system and alleviate inflammatory conditions.
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Enfermedades Inflamatorias del Intestino , Células Madre Mesenquimatosas , Ubiquitinación , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Animales , Trasplante de Células Madre Mesenquimatosas , Transducción de Señal , Procesamiento Proteico-PostraduccionalRESUMEN
OBJECTIVE: To explore the relationship between peripheral lymphocyte subsets and the survival of PCa patients. METHODS: Using the Kaplan-Meier curve and log-rank test, we compared the overall survival (OS) and progression-free survival (PFS) of 100 PCa patients with different levels of lymphocytes. Meanwhile, we investigated the prognostic factors by univariate and multivariate Cox regression analyses, and counted the peripheral lymphocyte subsets by flow cytometry. RESULTS: Both OS and PFS were significantly prolonged in the PCa patients with high levels of lymphocytes (≥747/µl), CD3+T cells (≥528/µl), CD4+T cells (≥315/µl), CD8+T cells (≥226/µl), B cells (≥105/µl) and NK cells (≥168/µl)(P < 0.001). Univariate and multivariate Cox regression analyses indicated that CD4+T cells ≤ 315/µl was an independent factor for the poor prognosis of PCa (HR=12.58, 95% CI: 3.00ï¼52.73). CONCLUSION: Decreased absolute count of peripheral lymphocyte subsets is associated with the poor prognosis of PCa.
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Subgrupos Linfocitarios , Neoplasias de la Próstata , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata/sangre , Estimación de Kaplan-Meier , Linfocitos T CD4-Positivos/inmunología , Recuento de Linfocitos , Citometría de Flujo , Modelos de Riesgos Proporcionales , Células Asesinas Naturales , Linfocitos T CD8-positivosRESUMEN
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex disorder with an unknown cause. However, the dysbiosis of the gut microbiome has been found to play a role in IBD etiology, including exacerbated immune responses and defective intestinal barrier integrity. The gut microbiome can also be a potential biomarker for several diseases, including IBD. Currently, conventional treatments targeting pro-inflammatory cytokines and pathways in IBD-associated dysbiosis do not yield effective results. Other therapies that directly target the dysbiotic microbiome for effective outcomes are emerging. We review the role of the gut microbiome in health and IBD and its potential as a diagnostic, prognostic, and therapeutic target for IBD. This review also explores emerging therapeutic advancements that target gut microbiome-associated alterations in IBD, such as nanoparticle or encapsulation delivery, fecal microbiota transplantation, nutritional therapies, microbiome/probiotic engineering, phage therapy, mesenchymal stem cells (MSCs), gut proteins, and herbal formulas.
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Endometrial cancer (EC) is the most common cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound 33 showed excellent antiproliferative activities against both progesterone-sensitive ISK cells and progesterone-resistant KLE cells. Moreover, 33 could significantly inhibit colony formation and migration of EC cells and induce cell apoptosis. Remarkably, 33 significantly suppressed KLE xenograft tumor growth without influencing body weights or key organs. In addition, 33 exhibited good pharmacokinetic properties and low extrapyramidal side effects. Mechanism research indicated that 33 reduced Ca2+ levels in mitochondria by targeting GRP75 and disrupting its interaction with IP3R. Overall, 33 showed promising potential as an anti-EC candidate agent.
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Antineoplásicos , Calcio , Proliferación Celular , Neoplasias Endometriales , Receptores de Inositol 1,4,5-Trifosfato , Mitocondrias , Fenotiazinas , Humanos , Femenino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Animales , Fenotiazinas/farmacología , Fenotiazinas/síntesis química , Fenotiazinas/química , Fenotiazinas/uso terapéutico , Calcio/metabolismo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/metabolismo , Proliferación Celular/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Línea Celular Tumoral , Homeostasis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones Desnudos , Proteínas HSP70 de Choque Térmico/metabolismo , Descubrimiento de Drogas , Relación Estructura-Actividad , Ratones Endogámicos BALB C , Proteínas de la MembranaRESUMEN
Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4-nitroquinoline 1-oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single-cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor-promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor-promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment-associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.
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BACKGROUND: Diabetic nephropathy (DN) is a severe complication of diabetes that affects the kidneys. Disulfidptosis, a newly defined type of programmed cell death, has emerged as a potential area of interest, yet its significance in DN remains unexplored. METHODS: This study utilized single-cell sequencing data GSE131882 from GEO database combined with bulk transcriptome sequencing data GSE30122, GSE30528 and GSE30529 to investigate disulfidptosis in DN. Single-cell sequencing analysis was performed on samples from DN patients and healthy controls, focusing on cell heterogeneity and communication. Weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were employed to identify disulfidptosis-related gene sets and pathways. A diagnostic model was constructed using machine learning techniques based on identified genes, and immunocorrelation analysis was conducted to explore the relationship between key genes and immune cells. PCR validation was performed on blood samples from DN patients and healthy controls. RESULTS: The study revealed significant disulfidptosis heterogeneity and cell communication differences in DN. Specific targets related to disulfidptosis were identified, providing insights into the pathogenesis of DN. The diagnostic model demonstrated high accuracy in distinguishing DN from healthy samples across multiple datasets. Immunocorrelation analysis highlighted the complex interactions between immune cells and key disulfidptosis-related genes. PCR validation supported the differential expression of model genes VEGFA, MAGI2, THSD7A and ANKRD28 in DN. CONCLUSION: This research advances our understanding of DN by highlighting the role of disulfidptosis and identifying potential biomarkers for early detection and personalized treatment.
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Nefropatías Diabéticas , Análisis de la Célula Individual , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/diagnóstico , Humanos , Análisis de la Célula Individual/métodos , Transcriptoma , Perfilación de la Expresión Génica , Estudios de Casos y Controles , Redes Reguladoras de Genes , Aprendizaje AutomáticoRESUMEN
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive system and includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stress markers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlate with the severity of the disease. Thus, oxidative stress markers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD.
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Enfermedades Inflamatorias del Intestino , Estrés Oxidativo , Humanos , Estrés Oxidativo/fisiología , Enfermedades Inflamatorias del Intestino/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Biomarcadores/metabolismo , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Especies de Nitrógeno Reactivo/metabolismo , AnimalesRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease that poses challenges in terms of treatment. The precise mechanism underlying the role of human umbilical cord mesenchymal stem cell-derived exosome (HucMSC-Ex) in the inflammatory repair process of IBD remains elusive. Mucosal mast cells accumulate within the intestinal tract and exert regulatory functions in IBD, thus presenting a novel target for addressing this intestinal disease. METHODS: A mouse model of Dextran Sulfate Sodium (DSS)-induced colitis was established and hucMSC-Ex were administered to investigate their impact on the regulation of intestinal mast cells. An in vitro co-culture model using the human clonal colorectal adenocarcinoma cell line (Caco-2) and human mast cell line (LAD2) was also established for further exploration of the effect of hucMSC-Ex. RESULTS: We observed the accumulation of mast cells in the intestines of patients with IBD as well as mice. In colitis mice, there was an upregulation of mast cell-related tryptase, interleukin-33 (IL-33), and suppression of tumorigenicity 2 receptor (ST2 or IL1RL1), and the function of the intestinal mucosal barrier related to intestinal tight junction protein was weakened. HucMSC-Ex treatment significantly reduced mast cell infiltration and intestinal damage. In the co-culture model, a substantial number of mast cells interact with the epithelial barrier, triggering activation of the IL-33/IL1RL1 (ST2) pathway and subsequent release of inflammatory factors and trypsin. This disruption leads to aberrant expression of tight junction proteins, which can be alleviated by supplementation with hucMSC-Ex. CONCLUSION: Our results suggest that hucMSC-Ex may reduce the release of mast cell mediators via the IL-33/IL1RL1 (ST2) axis, thereby mitigating its detrimental effects on intestinal barrier function.
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The relentless pursuit of effective cancer diagnosis and treatment strategies has led to the rapidly expanding field of nanotechnology, with a specific focus on nanocomposites. Nanocomposites, a combination of nanomaterials with diverse properties, have emerged as versatile tools in oncology, offering multifunctional platforms for targeted delivery, imaging, and therapeutic interventions. Nanocomposites exhibit great potential for early detection and accurate imaging in cancer diagnosis. Integrating various imaging modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), and fluorescence imaging, into nanocomposites enables the development of contrast agents with enhanced sensitivity and specificity. Moreover, functionalizing nanocomposites with targeting ligands ensures selective accumulation in tumor tissues, facilitating precise imaging and diagnostic accuracy. On the therapeutic front, nanocomposites have revolutionized cancer treatment by overcoming traditional challenges associated with drug delivery. The controlled release of therapeutic agents from nanocomposite carriers enhances drug bioavailability, reduces systemic toxicity, and improves overall treatment efficacy. Additionally, the integration of stimuli-responsive components within nanocomposites enables site-specific drug release triggered by the unique microenvironment of the tumor. Despite the remarkable progress in the field, challenges such as biocompatibility, scalability, and long-term safety profiles remain. This article provides a comprehensive overview of recent developments, challenges, and prospects, emphasizing the transformative potential of nanocomposites in revolutionizing the landscape of cancer diagnostics and therapeutics. In Conclusion, integrating nanocomposites in cancer diagnosis and treatment heralds a new era for precision medicine.
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Nanocompuestos , Neoplasias , Humanos , Nanocompuestos/química , Neoplasias/diagnóstico por imagen , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Animales , Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Imagen por Resonancia Magnética/métodos , Medios de Contraste/química , Nanomedicina/métodos , Tomografía Computarizada por Rayos X , Portadores de Fármacos/químicaRESUMEN
Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.
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Background: Cutaneous melanoma is a highly heterogeneous cancer, and understanding the role of inflammation-related genes in its progression is crucial. Methods: The cohorts used include the TCGA cohort from TCGA database, and GSE115978, GSE19234, GSE22153 cohort, and GSE65904 cohort from GEO database. Weighted Gene Coexpression Network Analysis (WGCNA) identified key inflammatory modules. Machine learning techniques were employed to construct prognostic models, which were validated across multiple cohorts, including the TCGA cohort, GSE19234, GSE22153, and GSE65904. Immune cell infiltration, tumor mutation load, and immunotherapy response were assessed. The hub gene STAT1 was validated through cellular experiments. Results: Single-cell analysis revealed heterogeneity in inflammation-related genes, with NK cells, T cells, and macrophages showing elevated inflammation-related scores. WGCNA identified a module highly associated with inflammation. Machine learning yielded a CoxBoost + GBM prognostic model. The model effectively stratified patients into high-risk and low-risk groups in multiple cohorts. A nomogram and Receiver Operating Characteristic (ROC) curves confirmed the model's accuracy. Low-risk patients exhibited increased immune cell infiltration, higher Tumor Mutational Burden (TMB), and potentially better immunotherapy response. Cellular experiments validated the functional role of STAT1 in melanoma progression. Conclusion: Inflammation-related genes play a critical role in cutaneous melanoma progression. The developed prognostic model, nomogram, and validation experiments highlight the potential clinical relevance of these genes and provide a basis for further investigation into personalized treatment strategies for melanoma patients.
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Inflammatory bowel disease (IBD) is marked by persistent inflammation, and its development and progression are linked to environmental, genetic, immune system and gut microbial factors. DNA methylation (DNAm), as one of the protein modifications, is a crucial epigenetic process used by cells to control gene transcription. DNAm is one of the most common areas that has drawn increasing attention recently, with studies revealing that the interleukin (IL)23/IL12, winglessrelated integration site, IL6associated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3 and apoptosis signaling pathways are involved in DNAm and in the pathogenesis of IBD. It has emerged that DNAmassociated genes are involved in perpetuating the persistent inflammation that characterizes a number of diseases, including IBD, providing a novel therapeutic strategy for exploring their treatment. The present review discusses DNAmassociated genes in the pathogenesis of IBD and summarizes their application as possible diagnostic, prognostic and therapeutic biomarkers in IBD. This may provide a reference for the particular form of IBD and its related methylation genes, aiding in clinical decisionmaking and encouraging therapeutic alternatives.
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Metilación de ADN , Enfermedades Inflamatorias del Intestino , Humanos , Metilación de ADN/genética , Enfermedades Inflamatorias del Intestino/genética , Epigénesis Genética , Animales , Biomarcadores , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Stratifying patient risk and exploring the tumor microenvironment are critical endeavors in prostate cancer research, essential for advancing our understanding and management of this disease. METHODS: Single-cell sequencing data for prostate cancer were sourced from the pradcellatlas website, while bulk transcriptome data were obtained from the TCGA database. Dimensionality reduction cluster analysis was employed to investigate heterogeneity in single-cell sequencing data. Gene set enrichment analysis, utilizing GO and KEGG pathways, was conducted to explore functional aspects. Weighted gene coexpression network analysis (WGCNA) identified key gene modules. Prognostic models were developed using Cox regression and LASSO regression techniques, implemented in R software. Validation of key gene expression levels was performed via PCR assays. RESULTS: Through integrative analysis of single-cell and bulk transcriptome data, key genes implicated in prostate cancer pathogenesis were identified. A prognostic model focused on sphingolipid metabolism (SRSR) was constructed, comprising five genes: "FUS," "MARK3," "CHTOP," "ILF3," and "ARIH2." This model effectively stratified patients into high-risk and low-risk groups, with the high-risk cohort exhibiting significantly poorer prognoses. Furthermore, distinct differences in the immune microenvironment were observed between these groups. Validation of key gene expression, exemplified by ILF3, was confirmed through PCR analysis. CONCLUSION: This study contributes to our understanding of the role of sphingolipid metabolism in prostate cancer diagnosis and treatment. The identified prognostic model holds promise for improving risk stratification and patient outcomes in clinical settings.
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Neoplasias de la Próstata , Análisis de la Célula Individual , Esfingolípidos , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Masculino , Pronóstico , Esfingolípidos/metabolismo , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Redes Reguladoras de GenesRESUMEN
Hepatocellular carcinoma (HCC) is a common type of cancer that ranks first in cancer-associated death worldwide. Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key components of the pyrimidine pathway, which promotes cancer development. However, the function of CAD in HCC needs to be clarified. In this study, the clinical and transcriptome data of 424 TCGA-derived HCC cases were analyzed. The results demonstrated that high CAD expression was associated with poor prognosis in HCC patients. The effect of CAD on HCC was then investigated comprehensively using GO annotation analysis, KEGG enrichment analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT algorithm. The results showed that CAD expression was correlated with immune checkpoint inhibitors and immune cell infiltration. In addition, low CAD levels in HCC patients predicted increased sensitivity to anti-CTLA4 and PD1, while HCC patients with high CAD expression exhibited high sensitivity to chemotherapeutic and molecular-targeted agents, including gemcitabine, paclitaxel, and sorafenib. Finally, the results from clinical sample suggested that CAD expression increased remarkably in HCC compared with non-cancerous tissues. Loss of function experiments demonstrated that CAD knockdown could significantly inhibit HCC cell growth and migration both in vitro and in vivo. Collectively, the results indicated that CAD is a potential oncogene during HCC metastasis and progression. Therefore, CAD is recommended as a candidate marker and target for HCC prediction and treatment.
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Ferroptosis is an emerging mode of programmed cell death fueled by iron buildup and lipid peroxidation. Recent evidence points to the function of ferroptosis in the aetiology and development of cancer and other disorders. Consequently, harnessing iron death for disease treatment has diverted the interest of the researchers in the field of basic and clinical research. The ubiquitin-proteasome system (UPS) represents a primary protein degradation pathway in eukaryotes. It involves labelling proteins to be degraded by ubiquitin (Ub), followed by recognition and degradation by the proteasome. Dysfunction of the UPS can contribute to diverse pathological processes, emphasizing the importance of maintaining organismal homeostasis. The regulation of protein stability is a critical component of the intricate molecular mechanism underlying iron death. Moreover, the intricate involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for targeted treatment strategies. Besides, it highlights the potential of ferroptosis as a promising target for cancer therapy, emphasizing the combination between ferroptosis and the UPS. The molecular mechanisms underlying ferroptosis, including key regulators such as glutathione peroxidase 4 (GPX4), cysteine/glutamate transporter (system XC-), and iron metabolism, are thoroughly examined, alongside the role of the UPS in modulating the abundance and activity of crucial proteins for ferroptotic cell death, such as GPX4, and nuclear factor erythroid 2-related factor 2 (NRF2). As a pivotal regulatory system for macromolecular homeostasis, the UPS substantially impacts ferroptosis by directly or indirectly modulating iron death-related molecules or associated signaling pathways. This review explores the involvement of the UPS in regulating iron death-related molecules and signaling pathways, providing valuable insights for the targeted treatment of diseases associated with ferroptosis.
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Neutrophil-mediated immunotherapy is a promising strategy for treating Candida albicans infection due to its potential in dealing with drug-resistant events. Our previous study found that ACT001 exhibited good antifungal immunotherapeutic activity by inhibiting PD-L1 expression in neutrophils, but its strong cytotoxicity and high BBB permeability hindered its antifungal application. To address these deficiencies, a series of novel sulfide derivatives were designed and synthesized based on a slow-release prodrug strategy. Among these derivatives, compound 16 exhibited stronger inhibition of PD-L1 expression, less cytotoxicity to neutrophils, and lower BBB permeability than ACT001. Compound 16 also significantly enhanced neutrophil-mediated antifungal immunity in C. albicans infected mice, with acceptable pharmacokinetic properties and good oral safety. Moreover, pharmacological mechanism studies demonstrated that ACT001 and compound 16 reduced PD-L1 expression in neutrophils by directly targeting STAT3. Briefly, this study provided a novel prototype compound 16 which exhibited great potential in neutrophil-mediated antifungal immunotherapy.
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Antifúngicos , Furanos , Neutrófilos , Animales , Ratones , Antifúngicos/farmacología , Antifúngicos/metabolismo , Neutrófilos/metabolismo , Antígeno B7-H1 , Reposicionamiento de Medicamentos , Candida albicans/metabolismoRESUMEN
The electronic and magnetic properties of d0 dilute magnetic semiconductors formed by rock-salt structured magnesium oxide (MgO) doped with C are systematically studied based on first-principles calculations and the Ising model. It is shown that the electronic holes of p states are generated due to the impurity carbon replacing oxygen in MgO, and the magnetic moment of 2µB is introduced by each C impurity. The polarization energy and formation energy of C-doped MgO are calculated, and the magnetization energy of C-doped MgO is also calculated which is used to obtain the exchange constant between C impurities. By means of the Ising model, we simulated the magnetization and the susceptibility of the doped system with increasing temperature and obtained the Curie temperature of C-doped MgO.
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Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.