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1.
Cell Signal ; 117: 111075, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38311302

RESUMO

OBJECTIVE: To confirm the mechanism of dynamic-related protein 1 (Drp1)-mediated mitochondrial fission through ROS/HIF-1α-mediated regulation of lipid metabolic reprogramming in the progression of pulmonary fibrosis (PF). METHODS: A mouse model of PF was established by intratracheal instillation of bleomycin (BLM) (2.5 mg/kg). A PF cell model was constructed by stimulating MRC-5 cells with TGF-ß (10 ng/mL). Pathological changes in the lung tissue and related protein levels were observed via tissue staining. The indicators related to lipid oxidation were detected by a kit, and lipid production was confirmed through oil red O staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR, Western blotting and immunofluorescence staining were used to detect the expression of genes and proteins related to the disease. We used CCK-8 and EdU staining to confirm cell proliferation, flow cytometry was used to confirm apoptosis and ROS levels, α-SMA expression was detected by immunofluorescence staining, and mitochondria were observed by MitoTracker staining. RESULTS: The BLM induced lung tissue structure and alveolar wall thickening in mice. Mitochondrial fission was observed in MRC-5 cells induced by TGF-ß, which led to increased cell proliferation; decreased apoptosis; increased expression of collagen, α-SMA and Drp1; and increased lipid oxidation and inflammation. Treatment with the Drp1 inhibitor mdivi-1 or transfection with si-Drp1 attenuated the induction of BLM and TGF-ß. For lipid metabolism, lipid droplets were formed in BLM-induced lung tissue and in TGF-ß-induced cells, fatty acid oxidation genes and lipogenesis-related genes were upregulated, ROS levels in cells were increased, and the expression of HIF-1α was upregulated. Mdivi-1 treatment reversed TGF-ß induction, while H2O2 treatment or OE-HIF-1α transfection reversed the effect of mdivi-1. CONCLUSION: In PF, inhibition of Drp1 can prevent mitochondrial fission in fibroblasts and regulate lipid metabolism reprogramming through ROS/HIF-1α; thus, fibroblast activation was inhibited, alleviating the progression of PF.


Assuntos
Fibrose Pulmonar , Animais , Camundongos , Peróxido de Hidrogênio/farmacologia , Reprogramação Metabólica , Dinâmica Mitocondrial , Fibrose Pulmonar/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Metabolismo dos Lipídeos
2.
J Immunol Res ; 2023: 9439536, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38023615

RESUMO

Pulmonary fibrosis (PF) can lead to chronic inflammation, the destruction of alveoli and irreversible lung damage. Sestrin2 is a highly protective stress-inducible protein that is involved in the cell response to various stress factors and the regulation of homeostasis and has a certain protective effect against PF. In this study, TGF-ß1 was used to establish a PF cell model. Bleomycin was used to induce PF in mice, and the expression levels of related proteins were detected by western blotting. The levels of the inflammatory cytokine, TNF-α, IL-6, and IL-1ß were detected by enzyme-linked immunosorbent assays. Immunoprecipitation was used to verify the interaction between ATF4 and NRF2 and between Sestrin2 and NRF2 to explore the specific mechanism by which Sestrin2 affects PF. The results showed that Sestrin2 inhibited fibroblast-to-myofibroblast transition (FMT), improved inflammation, promoted cell proliferation, and alleviated PF. Activating transcription factor 4/nuclear factor erythroid 2-related factor 2 (NRF2/ATF4) signaling pathway activation could alleviate endoplasmic reticulum stress, inhibit ferroptosis and FMT, and reduce reactive oxygen species levels, thereby alleviating PF. Overexpression of ATF4 and the addition of a ferroptosis inducer reversed Sestrin2-mediated alleviation of PF. In conclusion, Sestrin2 alleviates PF and endoplasmic reticulum stress-dependent ferroptosis through the NRF2/ATF4 pathway.


Assuntos
Ferroptose , Fibrose Pulmonar , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Estresse do Retículo Endoplasmático , Inflamação
3.
Molecules ; 27(4)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35208999

RESUMO

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP's activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4-YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Via de Sinalização Hippo/efeitos dos fármacos , Humanos , Camundongos , Modelos Biológicos , Estrutura Molecular , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Open Life Sci ; 14: 201-207, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33817152

RESUMO

To investigate how long non-coding RNAs DUXAP8 (LncRNA DUXAP8) influence the cell proliferation and invasion of non-small-cell lung cancer (NSCLC), we detected the expression levels of LncRNA DUXAP8 in lung cancer (LC) tissues, 4 LC-related cell lines (A549, SPC-A1, SK-MES-1 and NCI-H1299) and normal lung tissues via quantitative real-time PCR (qRT-PCR). Compared with normal lung tissue, LncRNA DUXAP8 was significantly up-regulated in NSCLC, especially in stage III / IV and diameter ≥ 3cm of lung cancer. Among 4 lung cancer cell lines, LncRNA DUXAP8 in A549 cells was the highest (P<0.001). Construction of LncRNA DUXAP8 overexpression and LncRNA DUXAP8 knockout in A549 cell lines was further performed and subsequently injected into nude mice to build an in vivo tumor xenograft model. The results indicated that LncRNA DUXAP8 overexpression significantly promoted the A549 cells' proliferation, enhanced invasion and induced tumor growth. Conversely, LncRNA DUXAP8 knockout significantly suppressed A549 cells' proliferation, weakened invasion and inhibited tumor growth. Taken together, our results imply that LncRNA DUXAP8 is a potential regulatory molecular marker in non-small-cell lung cancer.

5.
Mol Med Rep ; 14(2): 1132-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27279494

RESUMO

In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy. The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC). After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation. Triptolide, a top compound identified by this vigorous in silico screening, was then tested in vitro on the H2347 cell line carrying wild-type EGFR, revealing an anti-proliferative potency similar to that of known drugs against NSCLC.


Assuntos
Antineoplásicos/química , Desenho de Fármacos , Medicamentos de Ervas Chinesas/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Simulação por Computador , Medicamentos de Ervas Chinesas/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Humanos , Ligação de Hidrogênio , Neoplasias Pulmonares , Modelos Moleculares , Conformação Molecular , Ligação Proteica
6.
Ann Thorac Surg ; 98(3): 1109-11, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25193202

RESUMO

This report describes the first totally thoracoscopic tracheoplasty for a squamous cell carcinoma at the mediastinal trachea. The surgical procedure was conducted with five access incisions. A segment of the trachea was resected circumferentially, and the tracheal stumps were joined by an end-to-end anastomosis. The patient recovered rapidly and was discharged on the 12th postoperative day.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Toracoscopia , Traqueia/cirurgia , Neoplasias da Traqueia/cirurgia , Idoso , Humanos , Masculino , Mediastino
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