RESUMO
Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.
Assuntos
Neoplasias Colorretais , Metformina , Humanos , Proteína com Valosina/genética , Proteína com Valosina/metabolismo , Processos Neoplásicos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ácidos Graxos/metabolismo , Metformina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , OxirreduçãoRESUMO
OBJECTIVE: This cohort study was to assess the association between serum calcium levels and the risk of acute kidney injury (AKI) in acute myocardial infarction (AMI) patients. METHODS: This study was analyzed using data of 1286 AMI patients aged ≥18 years who stayed in ICU more than 24 h in Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Univariable logistic regression model was established to identify potential covariates. Univariate and multivariable logistic regression models were used to analyze the association between serum calcium and the risk of AKI in patients with AMI. The association between serum calcium and the risk of AKI in patients with AMI was also shown by restricted cubic spline (RCS) plot. Odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: The median follow-up time was 1.61 (1.23, 2.30) days, and 436 (33.90%) participants had AKI at the end of follow-up. After adjusting for covariates, elevated level of serum calcium level was related to reduced risk of AKI in AMI patients (OR = 0.88, 95%CI: 0.80-0.98). Decreased risk of AKI was found in AMI patients with serum calcium level of 8.40-8.90 mg/dL (OR = 0.54, 95%CI: 0.34-0.86) or ≥8.90 mg/dL (OR = 0.60, 95%CI: 0.37-0.99). The RCS plot depicted that serum calcium level was negatively correlated with the risk of AKI in patients with AMI. CONCLUSIONS: AMI patients with AKI had lower serum calcium levels compared with those without AKI. Increased serum calcium level was associated with decreased risk of AKI in patients with AMI.
Assuntos
Injúria Renal Aguda , Cálcio , Bases de Dados Factuais , Infarto do Miocárdio , Humanos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/epidemiologia , Masculino , Feminino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Pessoa de Meia-Idade , Cálcio/sangue , Idoso , Fatores de Risco , Modelos Logísticos , Unidades de Terapia Intensiva/estatística & dados numéricos , Estudos de Coortes , Razão de Chances , Estudos RetrospectivosRESUMO
BACKGROUND: This study focused on the roles of lncRNA THRIL in coronary atherosclerotic heart disease (CAD) through regulating AKT signaling pathway and directly interacting with FUS. METHODS: QRT-PCR was conducted to detect the expression of THRIL in CAD blood samples and endothelial progenitor cells (EPCs). Cell autophagy of EPCs was examined through Cyto-ID Autophagy Detection Kit. CCK-8 assay and flow cytometry were carried out to assess cell viability and apoptosis under various interference conditions. Western blotting was conducted to detect the expression of interest proteins. The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were measured by qRT-PCR. The direct interactions between HCG18 and FUS was confirmed through RNA electrophoretic mobility shift assay (RNA EMSA) and RNA immunoprecipitation (RIP) assay. RESULTS: THRIL was upregulated in CAD blood samples and EPCs. Knockdown of THRIL in EPCs promoted cell viability, inhibited cell autophagy and further suppressed the development of CAD. Over-expression of THRIL induced inactivation of AKT pathway, while knockdown of THRIL played reversed effects. THRIL directly interacted with FUS protein and knockdown of FUS reversed the over-expressing effect of THRIL on cell proliferation, autophagy and the status of AKT pathway. CONCLUSION: THRIL inhibits the proliferation and mediates autophagy of endothelial progenitor cells via AKT pathway and FUS.
Assuntos
Autofagia/genética , Células Progenitoras Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Proteína FUS de Ligação a RNA/metabolismo , Apoptose/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Biomarcadores , Proliferação de Células , Sobrevivência Celular/genética , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Interferência de RNA , Transdução de SinaisRESUMO
OBJECTIVE: To evaluate the value of epicardial adipose tissue (EAT) thickness combined with serum ischemic modified albumin (IMA) concentration in the diagnosis of coronary heart disease. METHODS: A total of 180 patients with coronary heart disease from May 2017 to December 2018 were selected as the case group. After the examination of Judkins coronary angiography, they were grouped according to the results of angiography, including 60 patients in a single-vessel group, 60 patients in a double-vessel group, and 60 patients in a multi-vessel group. Sixty healthy people with physical examinations at our hospital at the same time were selected as the control group. All selected participants were tested for epicardial adipose tissue thickness by echocardiography and serum IMA concentration by albumin cobalt ion binding test. RESULTS: The EAT thickness and IMA concentration in the single-vessel disease group, double-vessel disease group, and multi-vessel disease group significantly were higher than those in the control group (P < .01). The ROC curve shows that the sensitivity is 53.33% and the specificity is 87.6%, when the EAT thickness is 6.12 mm. The sensitivity is 76.0% and the specificity is 72.3%, when the serum IMA concentration is 72 U/L. When the two were combined, the sensitivity was 40.15% and the specificity was 96.89%. In the parallel test, the sensitivity was 88.3% and the specificity was 65.44%. CONCLUSION: Ultrasound detection of EAT thickness and serum IMA concentration has certain reference value for the diagnosis of coronary heart disease. Combined diagnosis can significantly improve the diagnosis rate and accuracy of coronary heart disease.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Albuminas/metabolismo , Doença das Coronárias/diagnóstico , Pericárdio/diagnóstico por imagem , Ultrassonografia Doppler em Cores/métodos , Biomarcadores/sangue , Angiografia Coronária/métodos , Doença das Coronárias/sangue , Ecocardiografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine the effect and mechanism of gamma-secretase inhibitor DAPT on the growth and apoptosis of human ovarian carcinoma SKOV3 cells. METHODS: The effect of gamma-secretase inhibitor DAPT was tested in vitro using SKOV3 cells. Its inhibition effect on cell proliferation was determined by CCK-8 assay. The cell apoptosis was detected by AO/EB double staining and flow cytometry. The expression of Notch1 mRNA and protein was detected by RT-PCR and Western blot. RESULTS: Compared with controls, 5 micromol/L, 10 micromol/L and 20 micromol/L of DAPT showed an effect of cell growth inhibition in a dose-dependent manner, with 19.87%, 28.38%, and 46.67% of 24 h inhibitory rates, respectively. Dose-dependent effect of DAPT on cell apoptosis was also evident, with (5.80 +/- 0.98)%, (12.96 +/- 4.99)%, (30.88 +/- 7.63)%, and (42.98 +/- 1.46)% apoptosis rates for the control, 5 micromol/L, 10 micromol/I, and 20 micromol/L DAPT groups, respectively. RT-PCR analysis demonstrated that the expression of Notch1 mRNA decreased significantly in the DAPT groups, with an inhibition rate of 10.23%, 20.50%, and 38.83% for the three DAPT groups, respectively. Western blot results demonstrated that the expression of Notch1 protein decreased significantly, with an inhibition rate of 12.89%, 27.47%, and 49.84% for the three DAPT groups, respectively. CONCLUSION: Gamma-secretase inhibitor DAPT can block Notch signaling pathway, inhibit proliferation, and induce apoptosis of SKOV3 cells through down-regulation of the expression of Notch1.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Receptor Notch1/metabolismo , Transdução de Sinais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Dipeptídeos/farmacologia , Regulação para Baixo , Feminino , Humanos , Neoplasias Ovarianas/metabolismoRESUMO
Microalgae are a group of microorganisms containing chlorophyll A, which are highly photosynthetic and rich in nutrients. And they can produce multiple bioactive substances (peptides, proteins, polysaccharides, and fatty acids) for biomedical applications. Despite the unique advantages of microalgae-based biotherapy, the insufficient treatment efficiency limits its further application. With the development of nanotechnology, the combination of microalgae and biomaterials can improve therapeutic efficacies, which has attracted increasing attention. In this microalgal-biomaterials hybrid system, biomaterials with excellent optical and magnetic properties play an important role in biological therapy. Microalgae, as a natural vehicle, can increase oxygen content and alleviate hypoxia in diseased areas, further enhancing therapeutic effects. In this review, the synergistic therapeutic effects of microalgal-biomaterials hybrid system in different diseases (cancer, myocardial infarction, ischemia stroke, chronic infection, and intestinal diseases) are comprehensively summarized.
Assuntos
Materiais Biocompatíveis , Microalgas , Materiais Biocompatíveis/química , Humanos , AnimaisRESUMO
The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
Assuntos
Fator de Ligação a CCCTC , Transtornos do Neurodesenvolvimento , Organoides , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Humanos , Animais , Camundongos , Transtornos do Neurodesenvolvimento/genética , Organoides/metabolismo , Mutação , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Masculino , Cromatina/metabolismo , Cromatina/genética , Feminino , Encéfalo/metabolismo , Encéfalo/patologia , Mutação Puntual , Células-Tronco Embrionárias Humanas/metabolismoRESUMO
The nucleosome is the fundamental subunit of chromatin. Nucleosome structures are formed by the combination of histone octamers and genomic DNA. Through a systematic and precise process of folding and compression, these structures form a 30-nm chromatin fibre that is further organized within the nucleus in a hierarchical manner, known as the 3D genome. Understanding the intricacies of chromatin structure and the regulatory mode governing chromatin interactions is essential for unravelling the complexities of cellular architecture and function, particularly in relation to cell fate determination, regeneration, and the development of diseases. Here, we provide a general overview of the hierarchical structure of chromatin as well as of the evolution of chromatin conformation capture techniques. We also discuss the dynamic regulatory changes in higher-order chromatin structure that occur during stem cell lineage differentiation and somatic cell reprogramming, potential regulatory insights at the chromatin level in organ regeneration, and aberrant chromatin regulation in diseases.
Assuntos
Cromatina , Nucleossomos , Cromatina/genética , DNA/genética , Diferenciação Celular/genética , RegeneraçãoRESUMO
IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Feminino , Humanos , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Glioma/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Metilação , Mutação , Vírus Oncolíticos/genética , Vírus Oncolíticos/metabolismoRESUMO
Sex determining region Y-box 2 (SOX2) is a transcription factor that serves a role in numerous different types of malignant cancer. Altered expression of chloride channel proteins has been described in a variety of malignancies. However, the association between SOX2 and chloride channel proteins is not yet fully understood. The present study investigated the association between SOX2 and chloride voltage-gated channel 3 (CLC-3) in prostate cancer. Flow cytometry demonstrated that the inactivation of CLC-3 or SOX2 arrested cell cycle progression in the G0/G1 phase. Furthermore, CLC-3 was observed to bind to SOX2, and vice versa, by co-immunoprecipitation. SOX2 appears to initiate and maintain prostate cancer tumorigenesis, in part, by modulating the cell cycle. These findings indicate the potential of SOX2 and CLC-3 as targets for the development of multi-targeted therapeutics.
RESUMO
OBJECTIVES: The aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model. Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot. RESULT: Tet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages. CONCLUSIONS: Tet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.