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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid subtype. However, unsatisfactory survival outcomes remain a major challenge, and the underlying mechanisms are poorly understood. N6-methyladenosine (m6A), the most common internal modification of eukaryotic mRNA, participates in cancer pathogenesis. In this study, m6A-associated long non-coding RNAs (lncRNA) were retrieved from publicly available databases. Univariate, LASSO, and multivariate Cox regression analyses were performed to establish an m6A-associated lncRNA model specific to DLBCL. Kaplan-Meier curves, principal component analysis, functional enrichment analyses and nomographs were used to study the risk model. The underlying clinicopathological characteristics and drug sensitivity predictions against the model were identified. Risk modelling based on the three m6A-associated lncRNAs was an independent prognostic factor. By regrouping patients using our model-based method, we could differentiate patients more accurately for their response to immunotherapy. In addition, prospective compounds that can target DLBCL subtypes have been identified. The m6A-associated lncRNA risk-scoring model developed herein holds implications for DLBCL prognosis and clinical response prediction to immunotherapy. In addition, we used bioinformatic tools to identify and verify the ceRNA of the m6A-associated lncRNA ELFN1-AS1/miR-182-5p/BCL-2 regulatory axis. ELFN1-AS1 was highly expressed in DLBCL and DLBCL cell lines. ELFN1-AS1 inhibition significantly reduced the proliferation of DLBCL cells and promoted apoptosis. ABT-263 inhibits proliferation and promotes apoptosis in DLBCL cells. In vitro and in vivo studies have shown that ABT-263 combined with si-ELFN1-AS1 can inhibit DLBCL progression.
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Adenina , Compuestos de Anilina , Linfoma de Células B Grandes Difuso , MicroARNs , ARN Largo no Codificante , Sulfonamidas , Humanos , Adenina/análogos & derivados , Biomarcadores , Linfoma de Células B Grandes Difuso/genética , MicroARNs/genética , Estudios Prospectivos , ARN Largo no Codificante/genéticaRESUMEN
Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition regarded as a major risk factor for colitis-associated cancer. However, the underlying mechanisms of IBD remain unclear. First, five GSE data sets available in GEO were used to perform 'batch correction' and Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs). Candidate molecules were identified using CytoHubba, and their diagnostic effectiveness was predicted. The CIBERSORT algorithm evaluated the immune cell infiltration in the intestinal epithelial tissues of patients with IBD and controls. Immune cell infiltration in the IBD and control groups was determined using the least absolute shrinkage selection operator algorithm and Cox regression analysis. Finally, a total of 51 DEGs were screened, and nine hub genes were identified using CytoHubba and Cytoscape. GSE87466 and GSE193677 were used as extra data set to validate the expression of the nine hub genes. CD4-naïve T cells, gamma-delta T cells, M1 macrophages and resting dendritic cells (DCs) are the main immune cell infiltrates in patients with IBD. Signal transducer and activator of transcription 1, CCR5 and integrin subunit beta 2 (ITGB2) were significantly upregulated in the IBD mouse model, and suppression of ITGB2 expression alleviated IBD inflammation in mice. Additionally, the expression of ITGB2 was upregulated in IBD-associated colorectal cancer (CRC). The silence of ITGB2 suppressed cell proliferation and tumour growth in vitro and in vivo. ITGB2 resting DCs may provide a therapeutic strategy for IBD, and ITGB2 may be a potential diagnostic marker for IBD-associated CRC.
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Biología Computacional , Enfermedades Inflamatorias del Intestino , Humanos , Animales , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Biología Computacional/métodos , Ratones , Perfilación de la Expresión Génica , Modelos Animales de Enfermedad , Antígenos CD18/genética , Antígenos CD18/metabolismo , Mapas de Interacción de Proteínas , Receptores CCR5/genética , Receptores CCR5/metabolismoRESUMEN
Type 2 diabetes mellitus (T2D) and osteoporosis (OP) are systemic metabolic diseases and often coexist. The mechanism underlying this interrelationship remains unclear. We downloaded microarray data for T2D and OP from the Gene Expression Omnibus (GEO) database. Using weighted gene co-expression network analysis (WGCNA), we identified co-expression modules linked to both T2D and OP. To further investigate the functional implications of these associated genes, we evaluated enrichment using ClueGO software. Additionally, we performed a biological process analysis of the genes unique in T2D and OP. We constructed a comprehensive miRNA-mRNA network by incorporating target genes and overlapping genes from the shared pool. Through the implementation of WGCNA, we successfully identified four modules that propose a plausible model that elucidates the disease pathway based on the associated and distinct gene profiles of T2D and OP. The miRNA-mRNA network analysis revealed co-expression of PDIA6 and SLC16A1; their expression was upregulated in patients with T2D and islet ß-cell lines. Remarkably, PDIA6 and SLC16A1 were observed to inhibit the proliferation of pancreatic ß cells and promote apoptosis in vitro, while downregulation of PDIA6 and SLC16A1 expression led to enhanced insulin secretion. This is the first study to reveal the significant roles of PDIA6 and SLC16A1 in the pathogenesis of T2D and OP, thereby identifying additional genes that hold potential as indicators or targets for therapy.
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Diabetes Mellitus Tipo 2 , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , MicroARNs , Osteoporosis , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Osteoporosis/genética , Osteoporosis/metabolismo , MicroARNs/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regulación de la Expresión Génica , Apoptosis/genética , Transcriptoma/genética , Proliferación Celular/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Insulina/metabolismoRESUMEN
With the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), coronaviruses have begun to attract great attention across the world. Of the known human coronaviruses, however, Middle East respiratory syndrome coronavirus (MERS-CoV) is the most lethal. Coronavirus proteins can be divided into three groups: nonstructural proteins, structural proteins, and accessory proteins. While the number of each of these proteins varies greatly among different coronaviruses, accessory proteins are most closely related to the pathogenicity of the virus. We found for the first time that the ORF3 accessory protein of MERS-CoV, which closely resembles the ORF3a proteins of severe acute respiratory syndrome coronavirus and SARS-CoV-2, has the ability to induce apoptosis in cells in a dose-dependent manner. Through bioinformatics analysis and validation, we revealed that ORF3 is an unstable protein and has a shorter half-life in cells compared to that of severe acute respiratory syndrome coronavirus and SARS-CoV-2 ORF3a proteins. After screening, we identified a host E3 ligase, HUWE1, that specifically induces MERS-CoV ORF3 protein ubiquitination and degradation through the ubiquitin-proteasome system. This results in the diminished ability of ORF3 to induce apoptosis, which might partially explain the lower spread of MERS-CoV compared to other coronaviruses. In summary, this study reveals a pathological function of MERS-CoV ORF3 protein and identifies a potential host antiviral protein, HUWE1, with an ability to antagonize MERS-CoV pathogenesis by inducing ORF3 degradation, thus enriching our knowledge of the pathogenesis of MERS-CoV and suggesting new targets and strategies for clinical development of drugs for MERS-CoV treatment.
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Apoptosis , Infecciones por Coronavirus/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Proteínas no Estructurales Virales/metabolismo , Células A549 , Línea Celular , Biología Computacional , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/virología , Células Epiteliales/fisiología , Células Epiteliales/virología , Células HEK293 , Interacciones Huésped-Patógeno , HumanosRESUMEN
Within the past 2 decades, three highly pathogenic human coronaviruses have emerged, namely, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The health threats and economic burden posed by these tremendously severe coronaviruses have paved the way for research on their etiology, pathogenesis, and treatment. Compared to SARS-CoV and SARS-CoV-2, MERS-CoV genome encoded fewer accessory proteins, among which the ORF4b protein had anti-immunity ability in both the cytoplasm and nucleus. Our work for the first time revealed that ORF4b protein was unstable in the host cells and could be degraded by the ubiquitin proteasome system. After extensive screenings, it was found that UBR5 (ubiquitin protein ligase E3 component N-recognin 5), a member of the HECT E3 ubiquitin ligases, specifically regulated the ubiquitination and degradation of ORF4b. Similar to ORF4b, UBR5 can also translocate into the nucleus through its nuclear localization signal, enabling it to regulate ORF4b stability in both the cytoplasm and nucleus. Through further experiments, lysine 36 was identified as the ubiquitination site on the ORF4b protein, and this residue was highly conserved in various MERS-CoV strains isolated from different regions. When UBR5 was knocked down, the ability of ORF4b to suppress innate immunity was enhanced and MERS-CoV replication was stronger. As an anti-MERS-CoV host protein, UBR5 targets and degrades ORF4b protein through the ubiquitin proteasome system, thereby attenuating the anti-immunity ability of ORF4b and ultimately inhibiting MERS-CoV immune escape, which is a novel antagonistic mechanism of the host against MERS-CoV infection. IMPORTANCE ORF4b was an accessory protein unique to MERS-CoV and was not present in SARS-CoV and SARS-CoV-2 which can also cause severe respiratory disease. Moreover, ORF4b inhibited the production of antiviral cytokines in both the cytoplasm and the nucleus, which was likely to be associated with the high lethality of MERS-CoV. However, whether the host proteins regulate the function of ORF4b is unknown. Our study first determined that UBR5, a host E3 ligase, was a potential host anti-MERS-CoV protein that could reduce the protein level of ORF4b and diminish its anti-immunity ability by inducing ubiquitination and degradation. Based on the discovery of ORF4b-UBR5, a critical molecular target, further increasing the degradation of ORF4b caused by UBR5 could provide a new strategy for the clinical development of drugs for MERS-CoV.
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Infecciones por Coronavirus , Interacciones Microbiota-Huesped , Coronavirus del Síndrome Respiratorio de Oriente Medio , Proteolisis , Ubiquitina-Proteína Ligasas , Ubiquitinación , Proteínas Virales , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Citocinas/inmunología , Humanos , Inmunidad Innata , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Terapia Molecular Dirigida , Complejo de la Endopetidasa Proteasomal/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , SARS-CoV-2 , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinas/metabolismo , Proteínas Virales/química , Proteínas Virales/metabolismo , Replicación ViralRESUMEN
BACKGROUND: Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown. METHODS: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms. RESULTS: Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (ß-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models. CONCLUSIONS: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Circular/genética , ARN Interferente Pequeño , Regulación hacia ArribaRESUMEN
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally to over 200 countries with more than 23 million confirmed cases and at least 800,000 fatalities as of 23 August 2020. Declared a pandemic on March 11 by World Health Organization, the disease caused by SARS-CoV-2 infection, called coronavirus disease 2019 (COVID-19), has become a global public health crisis that challenged all national healthcare systems. This review summarized the current knowledge about virologic and pathogenic characteristics of SARS-CoV-2 with emphasis on potential immunomodulatory mechanism and drug development. With multiple emerging technologies and cross-disciplinary approaches proving to be crucial in our global response against COVID-19, the application of PROteolysis TArgeting Chimeras strategy, CRISPR-Cas9 gene editing technology, and Single-Nucleotide-Specific Programmable Riboregulators technology in developing antiviral drugs and detecting infectious diseases are proposed here. We also discussed the available but still limited epidemiology of COVID-19 as well as the ongoing efforts on vaccine development. In brief, we conducted an in-depth analysis of the pathogenesis of SARS-CoV-2 and reviewed the therapeutic options for COVID-19. We also proposed key research directions in the future that may help uncover more underlying molecular mechanisms governing the pathology of COVID-19.
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COVID-19 , SARS-CoV-2 , Antivirales/uso terapéutico , Humanos , Pandemias , Salud Pública , SARS-CoV-2/genéticaRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem- and progenitor-cell origin. AML features massive proliferation of abnormal blasts and leukemia cells in the bone marrow and the inhibition of normal hematopoiesis at onset. Exosomes containing proteins or nucleic acids are secreted by cells; they participate in intercellular communication and serve as key modulators of hematopoiesis. The purpose of this study was to investigate the effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the regulation of AML and the underlying mechanisms mediated by microRNA (miRNA). METHODS: Dysregulated miR-7-5p in AML patients was identified using qRT-PCR and its clinical significance was explored. Bioinformatic analysis revealed the target gene OSBPL11 that could be regulated by miR-7-5p. The findings were validated using a dual-luciferase reporter assay and western blotting. The functional genes of the PI3K/AKT/mTOR signaling pathway were identified, and the functional significance of miR-7-5p in AML cells was determined using a functional recovery assay. AML cells were co-cultured with exosomes originating from BMSCs overexpressing miR-7-5p to determine cell-cell regulation by Exo-miR-7-5p, as well as in vitro and in vivo functional validation via gain- and loss-of-function methods. RESULTS: Expression of miR-7-5p was decreased in AML patients and cells. Overexpression of miR-7-5p curbed cellular proliferation and promoted apoptosis. Overexpression of OSBPL11 reversed the tumorigenic properties of miR-7-5p in AML cells in vitro. Exo-miR-7-5p derived from BMSCs induced formation of AML cells prone to apoptosis and a low survival rate, with OSBPL11 expression inhibited through the PI3K/AKT/mTOR signaling pathway. Exo-miR-7-5p derived from BMSCs exhibited tumor homing effects in vitro and in vivo, and inhibited AML development. CONCLUSIONS: Exo-miR-7-5p derived from BMSCs negatively regulates OSBPL11 by suppressing the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting AML proliferation and promoting apoptosis. The data will inform the development of AML therapies based on BMSC-derived exosomes.
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Exosomas/química , Leucemia Mieloide Aguda , Células Madre Mesenquimatosas/química , MicroARNs/genética , Receptores de Esteroides/genética , Animales , Línea Celular Tumoral , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Phosphoribosylformylglycinamidine synthase (PFAS) is an essential enzyme in de novo synthesis of purine. Previously, PFAS has been reported to modulate RIG-I activation during viral infection via deamidation. In this study, we sought to identify potential substrates that PFAS can deamidate. Flag-PFAS was transfected into HEK-293T cells and PFAS associated proteins were purified with anti-Flag M2 magnetic beads. PFAS associated proteins were identified using mass spectrometry and were analyzed using bioinformatics tools including KEGG pathway analysis, gene ontology annotation, and protein interaction network analysis. A total of 441 proteins is suggested to potentially interact with PFAS. Of this number, 12 were previously identified and 429 are newly identified. The interactions of PFAS with CAD, CCT2, PRDX1, and PHGDH were confirmed by co-immunoprecipitation and western blotting. This study is first to report the interaction of PFAS with several proteins which play physiological roles in tumor development including CAD, CCT2, PRDX1, and PHGDH. Furthermore, we show here that PFAS is able to deamidate PHGDH, and induce other posttranslational modification into CAD, CCT2 and PRDX1. The present data provide insight on the biological function of PFAS. Further study to explore the role of these protein interactions in tumorigenesis and other diseases is recommended.
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Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/metabolismo , Mapas de Interacción de Proteínas , Cromatografía Liquida , Electroforesis en Gel Bidimensional , Células HEK293 , Humanos , Mapeo de Interacción de Proteínas , Espectrometría de Masas en TándemRESUMEN
Immunotherapy has recently attracted considerable attention. However, currently, a thorough analysis of the trends associated with the epithelial-mesenchymal transition (EMT) and immunotherapy is lacking. In this study, we used bibliometric tools to provide a comprehensive overview of the progress in EMT-immunotherapy research. A total of 1,302 articles related to EMT and immunotherapy were retrieved from the Web of Science Core Collection (WOSCC). The analysis indicated that in terms of the volume of research, China was the most productive country (49.07%, 639), followed by the United States (16.89%, 220) and Italy (3.6%, 47). The United States was the most influential country according to the frequency of citations and citation burstiness. The results also suggested that Frontiers in Immunotherapy can be considered as the most influential journal with respect to the number of articles and impact factors. "Immune infiltration," "bioinformatics analysis," "traditional Chinese medicine," "gene signature," and "ferroptosis" were found to be emerging keywords in EMT-immunotherapy research. These findings point to potential new directions that can deepen our understanding of the mechanisms underlying the combined effects of immunotherapy and EMT and help develop strategies for improving immunotherapy.
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Bibliometría , Biología Computacional , China , Transición Epitelial-Mesenquimal , InmunoterapiaRESUMEN
The ORF9b protein, derived from the nucleocapsid's open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response. Despite its significance, the precise regulatory mechanisms underlying its function remain elusive. In the present study, we unveil that the ORF9b protein of SARS-CoV-2, including emerging mutant strains like Delta and Omicron, can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway, despite certain mutations present among these strains. Moreover, our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70 (TOM70) as a substrate receptor, bridging ORF9b with heat shock protein 90 alpha (HSP90α) and Cullin 5 (CUL5) to form a complex. Within this complex, CUL5 triggers the ubiquitination and degradation of ORF9b, acting as a host antiviral factor, while HSP90α functions to stabilize it. Notably, treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b, leading to a pronounced inhibition of SARS-CoV-2 replication. Single-cell sequencing data revealed an up-regulation of HSP90α in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90α to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90α complex as a critical regulator of ORF9b protein stability, shedding light on the intricate host-virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.
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COVID-19 , Proteínas Cullin , Proteínas HSP90 de Choque Térmico , SARS-CoV-2 , Ubiquitinación , Replicación Viral , Humanos , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Replicación Viral/genética , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , COVID-19/virología , COVID-19/genética , COVID-19/metabolismo , COVID-19/inmunología , Ubiquitinación/genética , Células HEK293 , Benzoquinonas/farmacología , Estabilidad Proteica , Células Vero , Proteínas Virales/genética , Proteínas Virales/metabolismo , Lactamas MacrocíclicasRESUMEN
OBJECTIVE: To investigate the relationship between serum sex hormone levels, liver function, and pathogenic mechanisms related to cutaneous lesions involving the facial skin in male patients with liver cirrhosis. METHODS: Fifty male cirrhotic patients with facial skin lesions, including spider angiomas, angiotelectasis and special type rash, (mean age: 48.1 +/- 12.2 years) were randomly selected for study and enrolled as the case group. Thirty cirrhotic male patients without facial skin lesions (mean age: 44.5 +/- 11.7 years) were enrolled as the control group. Serum levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), prolactin (PRL), estradiol (E2), progesterone (PRGE), and testosterone (T) were detected and compared between cases and controls by the t-test. All patients were sub-categorized according to severity of cirrhosis (Child-Pugh classification) and comparisons between cases and controls were carried out by single factor analysis of variance. Logistic regression modeling was used to evaluate whether the presence of skin lesions is related to changes in markers of liver impairment, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), serum albumin (Alb), prothrombin time (PT-SEC), creatinine (CREA), platelet count (PLT), and alcoholism. RESULTS: In the cases with spider veins, LH level was significantly elevated (t = 2.01) and T level was significantly decreased (t = -2.20) (both, P less than 0.05 vs. controls). In the cases with telangiectasia, the LH level (t = 3.76, E2 (t = 2.08) and E2/T ratio (t = 2.98) were significantly elevated and T level was significantly decreased (t = -3.77) (all, P less than 0.05 vs. controls). In the cases with special type rash, FSH level was significantly elevated (t = 2.03) and T level was significantly decreased (t = -2.01) (both, P less than 0.05 vs. controls). In the case group, E2 levels decreased as severity of liver damage increased, while in the control group, E2 levels increased as severity of liver damage increased; however, the difference in average E2 values of the two groups did not reach statistical significance (P more than 0.05). In both cases and controls, the T levels were decreased as the severity of liver damage increased (F = 3.70, P less than 0.05). Multivariate logistic regression analysis showed that increased incidence of facial skin lesions is associated with alcoholism (odds ratio (OR) = 4.46, 95% confidence interval (CI) = 1.45-13.7, P less than 0.05) and elevated serum levels of AST (OR = 11.87, 95% CI = 1.24-113.1, P less than 0.05). CONCLUSION: Alcoholism, impaired liver function, and perturbed levels of circulating sex hormones are associated with cirrhosis-related facial lesions and may play important roles in the pathogenesis of cutaneous lesions in patients with cirrhosis.
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Hormonas Esteroides Gonadales/sangre , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Piel/patología , Adulto , Alcoholismo/fisiopatología , Estudios de Casos y Controles , Cara/patología , Humanos , Cirrosis Hepática/sangre , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.
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Exosomes can help to effectively regulate the crosstalk between cancer cells and normal cells in the tumor microenvironment. They also regulate cancer cell proliferation and apoptosis by virtue of their cargo molecules. Transmission electron microscopy (TEM) together with differential ultracentrifugation served for verifying the presence of exosomes. In vivo and in vitro assays served for determining the role of exosomal circ_001264. RNA pull-down and dual-luciferase reporter assays assisted in the classification of the mechanism of exosomal circ_001264-mediated regulation of the crosstalk between Acute myeloid leukemia (AML) cells and M2 macrophages. Furthermore, we adopted a programmed death ligand 1 antibody (aPD-L1) in combination with exosomal circ_001264 siRNA for antitumor treatment in vitro and in vivo mouse models served for validating the in vivo outcomes. Out study illustrated the aberrant overexpression of circ_001264 in AML patients and its correlation with poor patient prognosis. AML cell-derived exosomal circ_001264 regulated the RAF1 expression and activated the p38-STAT3 signaling pathway, thereby inducing the M2 macrophage polarization. Polarized M2 macrophages can induce PD-L1 overexpression by secreting PD-L1. Here, a programmed death ligand (aPD-L1) was adopted for preventing the immunosuppression, which was able to achieve the desired therapeutic effect at the tumor site. Indeed, in the mouse model, leukemia tumor load decreased remarkably in the exosomal circ_001264 siRNA plus aPD-L1 combination group. Taken together, our study contributed to a theoretical basis for AML treatment. The co-administration of exosomal circ_001264 siRNA and aPD-L1 exhibited an obvious anti-cancer effectiveness in AML.
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Leucemia Mieloide Aguda , MicroARNs , Humanos , Animales , Ratones , ARN Circular/genética , Antígeno B7-H1/genética , Terapia de Inmunosupresión , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Macrófagos , ARN Interferente Pequeño/genética , Proliferación Celular , Línea Celular Tumoral , Microambiente Tumoral/genéticaRESUMEN
Cuproptosis is a novel type of cell death that may play a vital role in preventing various types of cancer. Studies examining cuproptosis are limited, and the cuproptosis-related lncRNAs (long non-Coding ribonucleic acids) involved in the regulation of colon cancer remain unclear. This study aimed to identify the prognostic signature of cupronosis-related lncRNAs and explore their potential molecular functions in colon cancer. Data on the clinical correlation were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed cuproptosis-related long non-coding ribonucleic acids (lncRNAs) were analyzed using the "limma" package. Then, the prognostic cuproptosis-related lncRNA signature (CupRLSig) was identified through univariate Cox and co-expression analyses, and a prognostic model was constructed based on CupRLSig using the least absolute shrinkage selection operator (LASSO) algorithm and Cox regression analysis. The Kaplan-Meier survival curve and receiver operating characteristic (ROC) curve were used for evaluating the model's capacity for prognosis prediction. In addition, the immune landscape, and drug sensitivity of CupRLSig were analyzed. Finally, the functions of AL512306.3 and ZEB1-AS1 were verified through in vitro experiments. The high- or low-risk groups were classified according to the risk score. The signature-based risk score showed a stronger ability to predict patient's survival compared with the traditional clinicopathological features. In addition, immune responses, such as inflammation-promoting response and T-cell co-inhibition, were significantly different between the two groups. Moreover, chemotherapy drugs or inhibitors, such as axitinib, cisplatin, doxorubicin, and elesclomol, may be considered as potential therapeutic drugs for patients in high-risk groups. Finally, inhibition of AL512306.3 and ZEB1-AS1 significantly suppressed the cell proliferation in colon cancer cells. These results provide novel insights into the pathogenesis of colon cancer and offer promising biomarkers with the potential to guide research on carcinogenesis and cancer treatment.
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Recent studies have demonstrated epigenetic regulation of immune responses. Nevertheless, the underlying effect of RNA N6-methyladenosine (m6A) modifications on tumor microenvironment cell infiltration remains elusive. In this study, we thoroughly assessed m6A modification patterns of 255 myeloid leukemia specimens based on 23 m6A regulators. Consensus clustering of the 23 m6A regulators was performed to determine three distinct m6A modification patterns that were remarkably consistent with three immunophenotypes of tumors: immunorejection, immune activation, and immune inertness. Further evaluation and prognostic analysis of the m6A modification patterns of individual tumors revealed that low m6A score was characterized by increased mutational burden, immune activation, and survival rates, whereas high m6A score was characterized by poorer survival rates and the absence of effective immune infiltration. In addition, this study investigated the association between m6A regulators and antitumor immune responses and discovered higher expression of the immune regulators PD-L1, PD-L2, MRP1, and MRP2 in low m6A scores. Generally, the expression pattern of m6A regulators was remarkably associated with prognostic results and antitumor immune responses in acute myeloid leukemia and may be an underlying target and biological marker for immune therapies.
Asunto(s)
Adenosina/análogos & derivados , Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/genética , Procesamiento Postranscripcional del ARN , ARN Neoplásico/genética , Microambiente Tumoral , Adenosina/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Bases de Datos Genéticas , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Metilación , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/genética , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Mutación , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , ARN Neoplásico/metabolismo , Transducción de SeñalRESUMEN
COVID-19 is mainly associated with respiratory distress syndrome, but a subset of patients often present gastrointestinal (GI) symptoms. Imbalances of gut microbiota have been previously linked to respiratory virus infection. Understanding how the gut-lung axis affects the progression of COVID-19 can provide a novel framework for therapies and management. In this study, we examined the gut microbiota of patients with COVID-19 (n = 47) and compared it to healthy controls (n = 19). Using shotgun metagenomic sequencing, we have identified four microorganisms unique in COVID-19 patients, namely Streptococcus thermophilus, Bacteroides oleiciplenus, Fusobacterium ulcerans, and Prevotella bivia. The abundances of Bacteroides stercoris, B. vulgatus, B. massiliensis, Bifidobacterium longum, Streptococcus thermophilus, Lachnospiraceae bacterium 5163FAA, Prevotella bivia, Erysipelotrichaceae bacterium 6145, and Erysipelotrichaceae bacterium 2244A were enriched in COVID-19 patients, whereas the abundances of Clostridium nexile, Streptococcus salivarius, Coprococcus catus, Eubacterium hallii, Enterobacter aerogenes, and Adlercreutzia equolifaciens were decreased (p < 0.05). The relative abundance of butyrate-producing Roseburia inulinivorans is evidently depleted in COVID-19 patients, while the relative abundances of Paraprevotella sp. and the probiotic Streptococcus thermophilus were increased. We further identified 30 KEGG orthology (KO) modules overrepresented, with 7 increasing and 23 decreasing modules. Notably, 15 optimal microbial markers were identified using the random forest model to have strong diagnostic potential in distinguishing COVID-19. Based on Spearman's correlation, eight species were associated with eight clinical indices. Moreover, the increased abundance of Bacteroidetes and decreased abundance of Firmicutes were also found across clinical types of COVID-19. Our findings suggest that the alterations of gut microbiota in patients with COVID-19 may influence disease severity. Our COVID-19 classifier, which was cross-regionally verified, provides a proof of concept that a set of microbial species markers can distinguish the presence of COVID-19.
RESUMEN
SARS-CoV-2 is the etiological agent responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19). The main protease of SARS-CoV-2, 3CLpro, is an attractive target for antiviral inhibitors due to its indispensable role in viral replication and gene expression of viral proteins. The search of compounds that can effectively inhibit the crucial activity of 3CLpro, which results to interference of the virus life cycle, is now widely pursued. Here, we report that epigallocatechin-3-gallate (EGCG), an active ingredient of Chinese herbal medicine (CHM), is a potent inhibitor of 3CLpro with half-maximum inhibitory concentration (IC50) of 0.874 ± 0.005 µM. In the study, we retrospectively analyzed the clinical data of 123 cases of COVID-19 patients, and found three effective Traditional Chinese Medicines (TCM) prescriptions. Multiple strategies were performed to screen potent inhibitors of SARS-CoV-2 3CLpro from the active ingredients of TCMs, including network pharmacology, molecular docking, surface plasmon resonance (SPR) binding assay and fluorescence resonance energy transfer (FRET)-based inhibition assay. The SPR assay showed good interaction between EGCG and 3CLpro with KD ~6.17 µM, suggesting a relatively high affinity of EGCG with SARS-CoV-2 3CLpro. Our results provide critical insights into the mechanism of action of EGCG as a potential therapeutic agent against COVID-19.