RESUMEN
Recent research has uncovered a surprisingly high occurrence of aberrant expression and mutations in the genes that encode subunits of the SWI/SNF chromatin-remodeling complexes (SCRC). Nevertheless, the carcinogenic effects of aberrant expression and mutations in SWI/SNF genes have only been acknowledged in recent times, resulting in a comparatively limited understanding of these modifications. In this study, we comprehensively analyzed the expression difference, somatic mutation, potential biological pathways, stromal or immune cell infiltration, and drug sensitivity of SCRC-related genes (SCRGs) in pan-cancer. Furthermore, the evolutionary trend, prognostic signature, and immunotherapy response of SCRGs in kidney renal clear cell carcinoma (KIRC) were also evaluated. The expression of SCRGs was changed in 13 out of 14 tumor types, strongly linked to prognosis, and mutated in 30.9% of tumor patients. SCRGs were also closely associated with immune-related pathways and tumor metastasis pathways. The expression of SCRGs was positively associated with the immune score or stromal score but negatively correlated with Tumor purity. Three potential drugs (FK866, Ispinesib mesylate, and WZ3105) were identified to target the SCRGs. In KIRC, scRNA-seq analysis showed that the enrichment of SCRC and the communication frequency with immune cells were significantly declined during tumor cell progression. A prognostic signature was constructed in KIRC and was effective in predicting the prognosis for KIRC. Aberrant expression of eleven prognostic genes identified from the KIRC prognostic signature and the cytotoxicity of FK866 and Ispinesib mesylate to KIRC were verified by qRT-PCR and CCK-8 assay, respectively. Our study identified SCRGs as potential biomarker and therapeutic targets, providing new insights into SCRC for tumor-targeted therapy.
Asunto(s)
Biomarcadores de Tumor , Ensamble y Desensamble de Cromatina , Regulación Neoplásica de la Expresión Génica , Neoplasias , Humanos , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Pronóstico , Mutación , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Terapia Molecular Dirigida , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease, and to date, there are currently no effective pharmacological treatments to address this condition. Activation of cytosolic DNA sensing adaptor stimulator of interferon genes (STING) signaling is a crucial mechanism in AAA formation. PURPOSE: This study investigated pterostilbene (Pt), a naturally occurring polyphenol and resveratrol analogue, as a STING inhibitor for preventing AAA. METHODS: We evaluated the effect of Pt on AAA formation in angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mice. We used histological analysis, MMP activity measurement, western blot, and immunohistochemistry to detect AAA formation and development. We applied RNA sequencing, molecular docking, cellular thermal shift assay (CETSA) and functional studies to dissect the molecular mechanism of Pt-regulating KEAP1-Nrf2-STING signaling. We conditionally knocked down Nrf2 in vascular smooth muscle cells (VSMCs) in vivo to investigate its role in Pt-mediated protective effects on AAA. RESULTS: Pt effectively blocked the formation of AAA in AngII-infused ApoE-/- mice. Whole transcriptome sequencing analysis revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) and STING pathway in VSMCs were linked to the anti-AAA effects of pterostilbene. Mechanistically, Pt upregulated Nrf2 target genes (e.g., HO-1 and NQO1) through activation of the KEAP1/Nrf2 signaling, which restricted the immunostimulatory axis of mtDNA-STING-TBK1-NF-κB, thereby alleviating VSMC inflammation and preserving the VSMC contractile phenotype. Subsequently, molecular docking and CETSA revealed a binding mode between Pt and KEAP1/Nrf2. Intriguingly, the inhibitory effect of Pt on STING signaling and the protective role of Pt in AAA were largely abrogated by VSMC-specific Nrf2 knockdown in mice. CONCLUSION: Collectively, naturally derived Pt shows promising efficacy for the treatment of AAA by targeting the KEAP1-Nrf2-STING axis in VSMCs.
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Angiotensina II , Aneurisma de la Aorta Abdominal , Proteína 1 Asociada A ECH Tipo Kelch , Proteínas de la Membrana , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Estilbenos , Animales , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Masculino , Proteínas de la Membrana/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Apolipoproteínas E , Miocitos del Músculo Liso/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.
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Senescencia Celular , Cilostazol , Inflamación , Proteínas de la Membrana , Ratones Endogámicos C57BL , Mitocondrias , Animales , Proteínas de la Membrana/metabolismo , Cilostazol/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Senescencia Celular/efectos de los fármacos , Ratones , Envejecimiento/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Citosol/metabolismo , ADN/metabolismo , Masculino , Células Endoteliales de la Vena Umbilical Humana , Fenotipo Secretor Asociado a la Senescencia , Células CultivadasRESUMEN
The SARS-CoV-2 virus, also known as the severe acute respiratory syndrome coronavirus 2, has raised great threats to humans. The connection between the SARS-CoV-2 virus and cancer is currently unclear. In this study, we thus evaluated the multi-omics data from the Cancer Genome Atlas (TCGA) database utilizing genomic and transcriptomic techniques to fully identify the SARS-CoV-2 target genes (STGs) in tumor samples from 33 types of cancers. The expression of STGs was substantially linked with the immune infiltration and may be used to predict survival in cancer patients. STGs were also substantially associated with immunological infiltration, immune cells, and associated immune pathways. At the molecular level, the genomic changes of STGs were frequently related with carcinogenesis and patient survival. In addition, pathway analysis revealed that STGs were involved in the control of signaling pathways associated with cancer. The prognostic features and nomogram of clinical factors of STGs in cancers have been developed. Lastly, by mining the cancer drug sensitivity genomics database, a list of potential STG-targeting medicines was compiled. Collectively, this work demonstrated comprehensively the genomic alterations and clinical characteristics of STGs, which may offer new clues to explore the mechanisms on a molecular level between SARS-CoV-2 virus and cancers as well as provide new clinical guidance for cancer patients who are threatened by the COVID-19 epidemic.
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COVID-19 , Neoplasias , Humanos , SARS-CoV-2 , Multiómica , GenómicaRESUMEN
BACKGROUND AND OBJECTIVE: SIRT6, an NAD+-dependent protein deacetylase, is a key modulator of various biological functions. However, the precise role of SIRT6 in the regulation of endothelial function is still not fully understood. The current study sought to determine whether SIRT6 modulates NOS3 activity to regulate endothelium-dependent relaxations in the arterial wall and, if so, to investigate the potential underlying mechanism (s). METHODS: ApoE-/- mice and Sprague-Dawley rats had their aortic rings isolated for a vascular reactivity assay. Endothelial cells were cultured before qRT-PCR, western blot, immunoprecipitation, NO bioavailability, and acetylation/deacetylation assays were performed. RESULTS: SIRT6 expression was significantly reduced in the aorta of ApoE-/- mice fed a high-cholesterol diet, as was endothelium-dependent relaxation. Endothelial dysfunction could be corrected by delivering a SIRT6 overexpression construct via an adenovirus. In cultured endothelial cells, siRNA knockdown of SIRT6 decreased NOS3 catalytic activity, whereas adenoviral overexpression of SIRT6 increased NOS3-derived nitric oxide (NO) generation. SIRT6 interacted with and deacetylated human NOS3 at lysines 494, 497, and 504 of the calmodulin-binding domain, allowing calmodulin to bind to NOS3 and stimulate NOS3 activity. SIRT6 knockdown also reduced NOS3 expression by inhibiting Kruppel-Like Factor 2 (KLF2). CONCLUSIONS: We identified SIRT6 as a new regulator of the activity of NOS3, with functional implications for endothelial-dependent relaxation.
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Células Endoteliales , Sirtuinas , Animales , Humanos , Ratones , Ratas , Apolipoproteínas E/metabolismo , Calmodulina , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Sprague-Dawley , Sirtuinas/genética , Sirtuinas/metabolismoRESUMEN
Citri Reticulatae Pericarpium (CRP) has been utilized as a versatile medicinal herb with wide cardiovascular benefits in Asian nations for centuries. Accumulating evidence suggests that CRP and its components are effective in preventing cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, myocardial ischemia, arrhythmia, cardiac hypertrophy, heart failure, and hypertension. Studies show that the two most bioactive components of CRP are flavonoids and volatile oils. The cardiovascular protective effects of CRP have attracted considerable research interest due to its hypolipidemic, antiplatelet activity, antioxidant and anti-inflammatory effects. Hereby, we provide a rigorous and up-to-date overview of the cardiovascular protective properties and the potential molecular targets of CRP, and finally highlight the pharmacokinetics and the therapeutic potential of the main pharmacologically active components of CRP to treat CVDs.