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1.
Int J Mol Sci ; 24(18)2023 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-37762228

RESUMEN

Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis, including lung adenocarcinoma (LUAD). However, the functional and regulatory mechanisms of lncRNAs in LUAD remain poorly understood. In this study, we investigated the role of lncRNA ZBED5-AS1 in LUAD. We found that ZBED5-AS1 was upregulated in LUAD specimens and overexpressed in LUAD cell lines. ZBED5-AS1 promoted LUAD cell proliferation, migration, and invasion in vitro and promoted LUAD cell growth in vivo. ZBED5-AS1 promoted ZNF146 expression, activating the ATR/Chk1 pathway and leading to LUAD progression. We observed that exosomes from LUAD cells have a higher expression of ZBED5-AS1 compared with exosomes from the normal cell line BEAS-2B. Coculture experiments with exosomes showed that ZBED5-AS1 expression was downregulated after coculture with Si-ZBED5-AS1 exosomes, and coculture with exosomes with low ZBED5-AS1 expression inhibited proliferation and invasion of LUAD cells. Our results indicate that ZBED5-AS1 functions as an oncogenic factor in LUAD cells by targeting the ZNF146/ATR/Chk1 axis.


Asunto(s)
Adenocarcinoma , ARN Largo no Codificante , Humanos , Adenocarcinoma/genética , Proteínas de la Ataxia Telangiectasia Mutada , Carcinogénesis , Transformación Celular Neoplásica , Pulmón , ARN Largo no Codificante/genética
2.
Pharmacol Res ; 183: 106389, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35934193

RESUMEN

Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo. Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo. High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Animales , Biomarcadores , Proliferación Celular/fisiología , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Medicina de Precisión , Pronóstico , Receptores Acoplados a Proteínas G
3.
Drug Dev Res ; 81(1): 85-92, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31693211

RESUMEN

Acute lung injury (ALI) is a clinical syndrome characterized by respiratory failure and acute inflammatory response. Myeloid differentiation protein 2 (MD2) has been reported to play a pivotal role in the recognition of LPS and LPS-mediates inflammatory response. There have been no clinically effective therapeutic drugs for ALI. L6H9, an inhibitor of MD2, showed anti-inflammatory effects and cardiac protective activity. However, its effect on ALI has not been elucidated. In this study, intratracheal instillation of LPS was employed to induce ALI in rats. L6H9 pretreatment attenuates LPS-induced pathological variations in lung tissue and pulmonary edema. LPS instillation enhanced lung microvascular permeability, thereby causing inflammatory cells flow into bronchoalveolar lavage fluid (BALF). However, L6H9 inhibited the LPS-induced upregulation of total protein concentration and the number of inflammatory cells in BALF. In the meantime, macrophages infiltration in lung tissue induced by LPS was also mitigated by L6H9 treatment. Furthermore, L6H9 suppressed LPS-induced inflammatory cytokines expression in BALF, serum, and lung tissue. It is noteworthy that LPS-induced MD2/TLR4 complex formation was inhibited by L6H9 in lung tissue. On the whole, these results show that L6H9 can attenuate LPS-induced ALI in vivo by targeting MD2. Our study provide new candidate for the treatment of ALI.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Chalconas/administración & dosificación , Lipopolisacáridos/efectos adversos , Antígeno 96 de los Linfocitos/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Chalconas/química , Chalconas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Instilación de Medicamentos , Masculino , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento
5.
Biochem Biophys Res Commun ; 496(2): 245-252, 2018 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-29180018

RESUMEN

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/farmacología , Chalconas/farmacología , Pulmón/efectos de los fármacos , Sepsis/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Animales , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Lipopolisacáridos , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Pulmón/inmunología , Pulmón/patología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/inmunología , Cultivo Primario de Células , Sepsis/inducido químicamente , Sepsis/inmunología , Sepsis/patología
6.
BMC Complement Altern Med ; 18(1): 330, 2018 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-30541517

RESUMEN

BACKGROUND: Baicalin is a flavonoid compound that exerts specific pharmacological effect in attenuating the proliferation, migration, and apoptotic resistance of hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanism has not been fully elucidated yet. Although our previous studies had indicated that activation of A2aR attenuates CXCR expression, little is known about the relationship between A2aR and SDF-1/CXCR4 axis in hypoxic PASMCs. In this study, we aimed to investigate the effect of A2aR on the SDF-1/CXCR4 axis in hypoxic PASMCs, the mechanism underlying this effect, and whether baicalin exerts its protective functions though A2aR. METHODS: Rat PASMCs were cultured under normoxia/hypoxia and divided into nine groups: normoxia, hypoxia, hypoxia + AMD3100 (a CXCR4 antagonist), hypoxia + baicalin, hypoxia + negative virus, normoxia + A2aR knockdown, hypoxia + A2aR knockdown, hypoxia + CGS21680 (an A2aR agonist), and hypoxia + A2aR knockdown + baicalin. Lentiviral transfection methods were used to establish the A2aR knockdown model in PASMCs. Cells were incubated under hypoxic conditions for 24 h. Expression levels of A2aR, SDF-1, and CXCR4 were detected using RT-qPCR and western blot. The proliferation and migration rate were observed via CCK-8 and Transwell methods. Cell cycle distribution and cell apoptosis were measured by flow cytometry (FCM) and the In-Situ Cell Death Detection kit (Fluorescein). RESULTS: Under hypoxic conditions, levels of A2aR, SDF-1, and CXCR4 were significantly increased compared to those under normoxia. The trend of SDF-1 and CXCR4 being inhibited when A2aR is up-regulated was more obvious in the baicalin intervention group. Baicalin directly enhanced A2aR expression, and A2aR knockdown weakened the function of baicalin. SDF-1 and CXCR4 expression levels were increased in the hypoxia + A2aR knockdown group, as were the proliferation and migration rates of PASMCs, while the apoptotic rate was decreased. Baicalin and CGS21680 showed opposite effects. CONCLUSIONS: Our data indicate that baicalin efficiently attenuates hypoxia-induced PASMC proliferation, migration, and apoptotic resistance, as well as SDF-1 secretion, by up-regulating A2aR and down-regulating the SDF-1/CXCR4 axis.


Asunto(s)
Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Quimiocina CXCL12/metabolismo , Flavonoides/farmacología , Receptor de Adenosina A2A/metabolismo , Receptores CXCR4/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CXCL12/análisis , Quimiocina CXCL12/genética , Masculino , Miocitos del Músculo Liso , Arteria Pulmonar/citología , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A/análisis , Receptor de Adenosina A2A/genética , Receptores CXCR4/análisis , Receptores CXCR4/genética , Regulación hacia Arriba/efectos de los fármacos
7.
J Mol Cell Cardiol ; 82: 153-66, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25772255

RESUMEN

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway.


Asunto(s)
Apoptosis/efectos de los fármacos , Glucósidos/farmacología , Hipertensión Pulmonar/metabolismo , Hipoxia/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fenoles/farmacología , Receptor de Adenosina A2A/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Expresión Génica , Glucósidos/administración & dosificación , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/etiología , Pulmón/metabolismo , Pulmón/patología , Pulmón/ultraestructura , Masculino , Ratones , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Fenoles/administración & dosificación , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Adenosina A2A/genética , Remodelación Vascular
8.
Sleep Breath ; 19(2): 677-84, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25395264

RESUMEN

PURPOSE: Obstructive sleep apnea syndrome (OSAS) has been recognized as an important risk factor for cardiovascular morbidity and mortality. However, the underlying mechanisms are poorly understood. Present study aimed to investigate the role of NF-κB-dependent inflammation pathways in pathophysiological responses of cardiovascular system in OSAS. METHODS: Thirty male specific pathogen-free (SPF) Sprague-Dawley rats were randomly assigned to normoxia (N) group, continual hypoxia (CH) group, and intermittent hypoxia (IH) group (n = 10) and were exposed to N (21% O2), CH (8% O2), or IH (6-11% O2 for 10 s and 21% O2 for 80 s in every 90 s) for 8 h/day for 35 days. The hemodynamic and pathomorphologic effects of IH and CH exposure were investigated as well as the expression of NF-κB-dependent inflammation factors. RESULTS: Chronic IH or CH significantly increased mean pulmonary arterial pressure (mPAP) in rats, while no significant changes occurred in mean carotid arterial pressure (mCAP). The ratio of right ventricle (RV) to left ventricle (LV) + septum (S) was significantly increased by both IH and CH, suggesting RV hypertrophy was induced by IH or CH. Elastic fiber staining showed an irregular pattern of elastic fiber distribution after hypoxia, and aortic tunica media thickness was increased. Both chronic IH and CH upregulated the expressions of transcription factor NF-κB and related pro-inflammatory cytokines and adhesion molecules. CONCLUSIONS: The current study expands our understanding that both IH and CH could activate the expression of NF-κB and related inflammatory factors as well as cause pathophysiologic damage to the cardiovascular system in OSAS. All these results provide further support to an emerging hypothesis that activation of NF-κB-dependent inflammation may play a central role in the pathophysiology of cardiovascular dysfunction in OSAS.


Asunto(s)
Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Hipoxia/patología , Hipoxia/fisiopatología , Mediadores de Inflamación/sangre , FN-kappa B/sangre , Apnea Obstructiva del Sueño/fisiopatología , Animales , Aorta/patología , Modelos Animales de Enfermedad , Ventrículos Cardíacos/patología , Hemodinámica/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Apnea Obstructiva del Sueño/patología
9.
Comput Biol Med ; 171: 108038, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38442552

RESUMEN

Radial endobronchial ultrasonography (R-EBUS) has been a surge in the development of new ultrasonography for the diagnosis of pulmonary diseases beyond the central airway. However, it faces challenges in accurately pinpointing the location of abnormal lesions. Therefore, this study proposes an improved machine learning model aimed at distinguishing between malignant lung disease (MLD) from benign lung disease (BLD) through R-EBUS features. An enhanced manta ray foraging optimization based on elite perturbation search and cyclic mutation strategy (ECMRFO) is introduced at first. Experimental validation on 29 test functions from CEC 2017 demonstrates that ECMRFO exhibits superior optimization capabilities and robustness compared to other competing algorithms. Subsequently, it was combined with fuzzy k-nearest neighbor for the classification prediction of BLD and MLD. Experimental results indicate that the proposed modal achieves a remarkable prediction accuracy of up to 99.38%. Additionally, parameters such as R-EBUS1 Circle-dense sign, R-EBUS2 Hemi-dense sign, R-EBUS5 Onionskin sign and CCT5 mediastinum lymph node are identified as having significant clinical diagnostic value.


Asunto(s)
Enfermedades Pulmonares , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Mediastino/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Ultrasonografía/métodos , Enfermedades Pulmonares/patología
10.
Comput Biol Med ; 178: 108638, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38897152

RESUMEN

Lung cancer is categorized into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer. Of these, NSCLC accounts for approximately 85% of all cases and encompasses varieties such as squamous cell carcinoma and adenocarcinoma. For patients with advanced NSCLC that do not have oncogene addiction, the preferred treatment approach is a combination of immunotherapy and chemotherapy. However, the progression-free survival (PFS) typically ranges only from about 6 to 8 months, accompanied by certain adverse events. In order to carry out individualized treatment more effectively, it is urgent to accurately screen patients with PFS for more than 12 months under this treatment regimen. Therefore, this study undertook a retrospective collection of pulmonary CT images from 60 patients diagnosed with NSCLC treated at the First Affiliated Hospital of Wenzhou Medical University. It developed a machine learning model, designated as bSGSRIME-SVM, which integrates the rime optimization algorithm with self-adaptive Gaussian kernel probability search (SGSRIME) and support vector machine (SVM) classifier. Specifically, the model initiates its process by employing the SGSRIME algorithm to identify pivotal image features. Subsequently, it utilizes an SVM classifier to assess these features, aiming to enhance the model's predictive accuracy. Initially, the superior optimization capability and robustness of SGSRIME in IEEE CEC 2017 benchmark functions were validated. Subsequently, employing color moments and gray-level co-occurrence matrix methods, image features were extracted from images of 60 NSCLC patients undergoing immunotherapy combined with chemotherapy. The developed model was then utilized for analysis. The results indicate a significant advantage of the model in predicting the efficacy of immunotherapy combined with chemotherapy for NSCLC, with an accuracy of 92.381% and a specificity of 96.667%. This lays the foundation for more accurate PFS predictions and personalized treatment plans.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Aprendizaje Automático , Tomografía Computarizada por Rayos X , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Femenino , Masculino , Tomografía Computarizada por Rayos X/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Máquina de Vectores de Soporte , Radiómica
11.
Comput Biol Med ; 180: 108776, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39089116

RESUMEN

Inflammatory response is a crucial factor that affects prognosis and therapeutic effect in tumor cells. Although some studies have shown that inflammation could make DNA more vulnerable to external attacks, resulting in serious DNA damage, the underlying mechanism remains unknown. Then, using tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS), this research elevated the level of inflammation in cancer cells, and hydrogen peroxide (H2O2) and ultraviolet (UV) were utilized as common reactive oxygen species (ROS)-induced DNA damage agents. We show that either H2O2 or UV achieved a more substantial antiproliferative effect in the inflammation environment compared with H2O2 or UV treatment alone. The inflammation environment enhanced H2O2- or UV-induced cell apoptosis and ROS production. Although the phenomenon that inflammation itself could trigger ROS-dependent DNA damage was well known, the underlying mechanism for the sensitization of inflammation to trigger intense DNA damage via ROS in cancer cells remains unclear. In this study, the inflammation-related genes and the corresponding expression information were obtained from the TCGA and fetched genes associated with inflammatory factors. Screening of thirteen inflammatory-related, including ATM, and prognostic genes. In addition, KEGG analysis of prognostic genes shows that biological processes such as DNA replication. ATM and ATR, which belong to the PI3/PI4-kinase family, can activate p53. Inflammation promotes the vulnerability of DNA by activating the ATM/ATR/p53 pathway, while not affecting the DNA damage repair pathway. In brief, this research suggested that inflammation made DNA vulnerable due to the amplifying H2O2- or UV-induced ROS production and the motoring ATM/ATR/p53 pathway. In addition, our findings revealed that inflammation's motoring of the ATM/ATR/p53 pathway plays a crucial role in DNA damage. Therefore, exploring the mechanism between inflammation and ROS-dependent DNA damage would be extremely valuable and innovative. This study would somewhat establish a better understanding of inflammation, DNA damage, and cancer.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Inflamación , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína p53 Supresora de Tumor/metabolismo , Inflamación/metabolismo , Neoplasias/metabolismo , Neoplasias/inmunología , Línea Celular Tumoral , Daño del ADN , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/metabolismo
12.
Phytomedicine ; 128: 155538, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38552432

RESUMEN

OBJECTIVE: The effect of solamargine on lung adenocarcinoma and its effect on STAT1 signaling pathway mediated immune escape were studied through network pharmacology and in vitro and in vivo experiments. METHODS: The solamargine targets were screened using the TCMSP and the LUAD targets were screened using the GeneCard, OMIM, PharmGkb, TTD and DrugBank databases. PPI network analysis and target prediction were performed using GO and KEGG. Colony formation assay, EDU staining, wound healing, transwell assay, Hoechst and flow cytometry were used to detect the effects of solamargine on the proliferation, migration and apoptosis of LUAD. Western blotting (WB) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect P-STAT1 and PD-L1 expression. And immunofluorescence was used to detect P-STAT1 expression. In vivo experiments, C57BL/6 mice were divided into control group, low concentration group, high concentration group, positive control group and combination group. Every other day, following seven consecutive doses, the size of the tumor was assessed. Finally, the expressions of P-STAT1, STAT1, PD-L1 and apoptosis index proteins were detected by WB. RESULTS: The anti-LUAD effect of solamargine was found by wound healing, colony formation assay, transwell assay, hoechst and EdU staining. The results of network pharmacological analysis showed that solamargine could suppress STAT1 expression level. Further enrichment assay of STAT1 showed that STAT1 was associated with immune-related pathways. In addition, molecular signal analysis by WB and RT-qPCR indicated that solamargine could reduce the expression levels of P-STAT1 and PD-L1 in a concentration-dependent manner. According to the results of in vivo assays, combination of solamargine and immune checkpoint inhibitors (ICIs) durvalumab could significantly inhibit the growth of Lewis transplanted tumors in C57BL/6 mice, and no toxic side effect was recoded. CONCLUSION: These results indicated that solamargine could inhibit the proliferation and promote the apoptosis of LUAD. It also could reduce the expression level of P-STAT1 protein and inhibit the expression level of PD-L1. At the same time, the combination with the ICIs can better block the expression of PD-L1 in cells, thereby inhibiting the immune escape pathway of tumor cells and achieving anti-tumor effects. This study proposed a novel combined therapeutic approach, involving the inhibition of STAT1 by solamargine in conjunction with ICIs.


Asunto(s)
Adenocarcinoma del Pulmón , Apoptosis , Antígeno B7-H1 , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Factor de Transcripción STAT1 , Factor de Transcripción STAT1/metabolismo , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Antígeno B7-H1/metabolismo , Humanos , Apoptosis/efectos de los fármacos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Ratones , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Células A549 , Inhibidores de Puntos de Control Inmunológico/farmacología
13.
Front Cell Dev Biol ; 12: 1252064, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38550378

RESUMEN

N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotic cells. It is a post-transcriptional modification of mRNA, a dynamic reversible process catalyzed by methyltransferase, demethylase, and binding proteins. Ferroptosis, a unique iron-dependent cell death, is regulated by various cell metabolic events, including many disease-related signaling pathways. And different ferroptosis inducers or inhibitors have been identified that can induce or inhibit the onset of ferroptosis through various targets and mechanisms. They have potential clinical value in the treatment of diverse diseases. Until now, it has been shown that in several cancer diseases m6A can be involved in the regulation of ferroptosis, which can impact subsequent treatment. This paper focuses on the concept, function, and biological role of m6A methylation modification and the interaction between m6A and ferroptosis, to provide new therapeutic strategies for treating malignant diseases and protecting the organism by targeting m6A to regulate ferroptosis.

14.
Front Neuroinform ; 16: 1078685, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36601381

RESUMEN

Introduction: Although tuberculous pleural effusion (TBPE) is simply an inflammatory response of the pleura caused by tuberculosis infection, it can lead to pleural adhesions and cause sequelae of pleural thickening, which may severely affect the mobility of the chest cavity. Methods: In this study, we propose bGACO-SVM, a model with good diagnostic power, for the adjunctive diagnosis of TBPE. The model is based on an enhanced continuous ant colony optimization (ACOR) with grade-based search technique (GACO) and support vector machine (SVM) for wrapped feature selection. In GACO, grade-based search greatly improves the convergence performance of the algorithm and the ability to avoid getting trapped in local optimization, which improves the classification capability of bGACO-SVM. Results: To test the performance of GACO, this work conducts comparative experiments between GACO and nine basic algorithms and nine state-of-the-art variants as well. Although the proposed GACO does not offer much advantage in terms of time complexity, the experimental results strongly demonstrate the core advantages of GACO. The accuracy of bGACO-predictive SVM was evaluated using existing datasets from the UCI and TBPE datasets. Discussion: In the TBPE dataset trial, 147 TBPE patients were evaluated using the created bGACO-SVM model, showing that the bGACO-SVM method is an effective technique for accurately predicting TBPE.

15.
Artículo en Inglés | MEDLINE | ID: mdl-33280587

RESUMEN

AIM AND OBJECTIVE: Lung cancer is the most commonly occurring cancer, which contributes to the majority of death caused by cancer, where non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. To treat NSCLC, STAT3 has been identified as a target with therapeutic potential. The neobavaisoflavone (NBIF) is one of the flavonoids of traditional Chinese medicine Psoralea corylifolial. MATERIALS AND METHODS: Human NSCLC cell lines, PC-9, H460, and A549, were applied to determine NBIF's anti-proliferative effects through cell viability and colony formation detection. The effect of NBIF on cell apoptosis was determined through flow cytometry-based assay. Western blotting was used in this study to confirm the levels of P-STAT3, Bcl-2, and Bax, which are apoptotic proteins. RESULTS: It was observed that NBIF could decrease the cell viability and its migration and induce apoptosis in human NSCLC cell lines dose-dependently. Levels of P-STAT3, as well as the downstream signals of the STAT3 pathway, were downregulated, suggesting that the tumorsuppression effects of NBIF might be related to the inhibition of STAT3 signaling. Furthermore, NBIF could contribute to the upregulation of BAX and downregulation of BCL2. CONCLUSION: NBIF might perform the anti-NSCLC efficacy as a result of the inhibition of the STAT3 pathway. Besides, our work suggests that NBIF could provide therapeutic alternatives for NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Isoflavonas , Neoplasias Pulmonares , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Humanos , Isoflavonas/farmacología , Neoplasias Pulmonares/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/farmacología , Factor de Transcripción STAT3/uso terapéutico
16.
Am J Transl Res ; 13(6): 7420-7421, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34306516

RESUMEN

[This corrects the article on p. 1884 in vol. 11, PMID: 30972212.].

17.
Front Cell Dev Biol ; 9: 761758, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34746153

RESUMEN

Lung squamous cell carcinoma (LUSC) is a leading cause of mobidity and mortality worldwide. Recently, there was a shift in the treatment pattern of immune therapy in LUSC patients; merely a small number of patients with non-small cell lung cancer (NSCLC) at advanced stages respond well to immune checkpoint blockade (ICB) therapy, and tumor mutation burden (TMB) is a valuable independent indicator of response to immune therapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immunocytes in LUSC are still unclear. In the present paper, our team analyzed the somatically mutated genes from the ICGC (International Cancer Genome Consortium) and TCGA (The Cancer Genome Atlas) datasets and discovered that 15 frequent gene mutations occurred in both cohorts, including ZFHX4, MUC16, FLG, TP53, LRP1B, TTN, SYNE1, RYR2, CSMD3, USH2A, MUC17, DNAH5, FAM135B, COL11A1, and RYR3. Interestingly, only mutated TTN was related to higher TMB and prognostic outcomes among the 15 mutated genes. Moreover, according to the CIBERSORT algorithm, we revealed that TTN mutation enhanced the antitumor immune response. In conclusion, TTN may have important clinical implications for relevant immune therapy of lung squamous carcinoma.

18.
Front Cell Dev Biol ; 9: 680600, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34513827

RESUMEN

Non-small cell lung carcinoma (NSCLC) is a major neoplastic disease with a high mortality worldwide; however, effective treatment of this disease remains a challenge. Flubendazole, a traditional anthelmintic drug, possesses potent antitumor properties; however, the detailed molecular mechanism of flubendazole activity in NSCLC needs to be further explored. In the present study, flubendazole was found to exhibit valid antitumor activity in vitro as well as in vivo. Flubendazole blocked phosphorylation of STAT3 in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptotic proteins. Further, flubendazole inhibited STAT3 activation by inhibiting its phosphorylation and nuclear localization induced by interleukin-6 (IL-6). Notably, the autophagic flux of NSCLC cell lines was increased after flubendazole treatment. Furthermore, flubendazole downregulated the expression of BCL2, P62, and phosphorylated-mTOR, but it upregulated LC3-I/II and Beclin-1 expression, which are the main genes associated with autophagy. Collectively, these data contribute to elucidating the efficacy of flubendazole as an anticancer drug, demonstrating its potential as a therapeutic agent via its suppression of STAT3 activity and the activation of autophagy in NSCLC.

19.
IEEE Access ; 9: 45486-45503, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34786313

RESUMEN

This paper has proposed an effective intelligent prediction model that can well discriminate and specify the severity of Coronavirus Disease 2019 (COVID-19) infection in clinical diagnosis and provide a criterion for clinicians to weigh scientific and rational medical decision-making. With indicators as the age and gender of the patients and 26 blood routine indexes, a severity prediction framework for COVID-19 is proposed based on machine learning techniques. The framework consists mainly of a random forest and a support vector machine (SVM) model optimized by a slime mould algorithm (SMA). When the random forest was used to identify the key factors, SMA was employed to train an optimal SVM model. Based on the COVID-19 data, comparative experiments were conducted between RF-SMA-SVM and several well-known machine learning algorithms performed. The results indicate that the proposed RF-SMA-SVM not only achieves better classification performance and higher stability on four metrics, but also screens out the main factors that distinguish severe COVID-19 patients from non-severe ones. Therefore, there is a conclusion that the RF-SMA-SVM model can provide an effective auxiliary diagnosis scheme for the clinical diagnosis of COVID-19 infection.

20.
Neurosci Lett ; 714: 134563, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31678372

RESUMEN

Cigarette smoking is associated with a higher risk of Alzheimer's disease (AD), but the underlying mechanisms remain to be clarified. In this study, we aimed to examine the effects of cigarette smoking on multiple AD biomarkers among older individuals with normal cognition (NC). Among 415 older individuals with NC from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, we examined the associations between smoking status (non-smokers vs smokers) and global cognition, verbal memory, hippocampal volumes, cerebral glucose metabolism and CSF AD pathologies. The primary findings of this study were: (1) In NC, smokers showed worse performance on verbal memory tests [Rey Auditory Verbal Learning Test (RAVLT) total learning score and delayed recall] than non-smokers; (2) Compared with non-smokers, smokers had significantly lower HpVR; (3) Smokers, relative to non-smokers, demonstrated lower levels of cerebral glucose metabolism as measured by FDG-PET; and (4) there were no significant differences in CSF AD pathologies (CSF Aß42, t-tau or p-tau) between non-smokers and smokers. Longitudinal studies are needed to investigate the relationship between cigarettes smoking and changes in AD-related markers over time. Further, ADNI participants were highly educated and predominantly white. This may limit the generalizability of our results. In summary, among individuals with NC, cigarette smoking was associated with memory impairment, hippocampal atrophy and cerebral glucose hypometabolism, but not CSF AD pathologies.


Asunto(s)
Encéfalo/diagnóstico por imagen , Fumar Cigarrillos/psicología , Cognición , Hipocampo/diagnóstico por imagen , Memoria , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Encéfalo/metabolismo , Estudios de Casos y Controles , Fumar Cigarrillos/líquido cefalorraquídeo , Fumar Cigarrillos/metabolismo , Fumar Cigarrillos/patología , Glicoles de Etileno , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Voluntarios Sanos , Hipocampo/patología , Humanos , Masculino , Tamaño de los Órganos , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/metabolismo , Tomografía de Emisión de Positrones , Radiofármacos , Proteínas tau/líquido cefalorraquídeo
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