RESUMO
The tumor suppressor LKB1 gene encodes a serine-threonine kinase that regulates cell proliferation and polarity. Inactivation of LKB1 by mutations in LKB1 or loss of its expression is highly correlated with lung, ovarian, and pancreatic cancers, and WNT/ß-catenin pathway is also known to be involved in many human malignancies. However, the relationship between LKB1 and WNT signaling pathway in esophageal carcinoma remains unknown. The expression of LKB1 in 62 cases of esophageal cancer patients was determined by quantitative real-time PCR. It was found that LKB1 mRNA level was significantly lower than the adjacent normal epithelium and that the LKB1 downregulation was correlating with TNM stages. Moreover, the expression of WNT target genes such as Cyclin D1, C-MYC, MMP2, and FZD2 was significantly upregulated in esophageal cancer tissues. LKB1 overexpression in TE10 cells inhibited TOPFlash luciferase reporter activity and WNT target gene expression even in the presence of WNT3A. Conversely, LKB1 knockdown enhanced WNT signaling activity in esophageal cancer cells. It was also found that LKB1 antagonized WNT signaling pathway through interaction with GSK3ß to downregulate ß-catenin expression level. Functional investigation revealed that LKB1 suppressed the promotion effects of WNT3A on the cell growth of TE10 cells. The LKB1 functions in regulating cell growth and WNT target genes expression were impaired by GSK3ß inhibition, suggesting that LKB1 antagonized WNT-induced cell proliferation through enhancement of GSK3ß activity. Together, the interaction between LKB1 and GSK3ß upregulates GSK3ß activity to suppress WNT-induced cell proliferation in esophageal carcinoma cells. Loss of LKB1 expression may result in the deregulation of WNT/ß-catenin pathway to promote malignant progression of esophageal cancer.
Assuntos
Neoplasias Esofágicas/genética , Quinase 3 da Glicogênio Sintase/genética , Proteínas Serina-Treonina Quinases/metabolismo , Via de Sinalização Wnt/genética , Quinases Proteína-Quinases Ativadas por AMP , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/biossíntese , beta Catenina/biossíntese , beta Catenina/metabolismoRESUMO
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an important enzyme which can catalyze the two-electron reduction of quinoid compounds into hydroquinones. NQO1 Pro187Ser polymorphism can change the enzymatic activity of NQO1, and it has been proposed to be associated with risk of esophageal cancer. We performed a meta-analysis to examine the association between NQO1 Pro187Ser polymorphism and esophageal cancer. Odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the association. Twelve case-control studies with 1,725 cases with esophageal cancer and 2,341 controls were finally included in the meta-analysis. Overall, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer (allele model: OR = 1.24, 95% CI 1.06-1.46, P OR = 0.009; homozygote model: OR = 1.59, 1195% CI 1.10-2.30, P OR = 0.013; dominant model: OR = 1.31, 95% CI 1.05-1.64, P OR = 0.018). In the subgroup analysis by ethnicity, there was an obvious association between NQO1 Pro187Ser polymorphism and esophageal cancer in Asians but not in Caucasians. Therefore, the meta-analysis suggests that NQO1 Pro187Ser polymorphism is associated with esophageal cancer risk.
Assuntos
Neoplasias Esofágicas/genética , Predisposição Genética para Doença/genética , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático/genética , Estudos de Casos e Controles , Humanos , Razão de Chances , População Branca/genéticaRESUMO
INTRODUCTION: Ultrasound-guided thoracic paravertebral block (UTPB) is widely used for postoperative analgesia in thoracic surgery. However, it has many disadvantages. Thoracoscopy-guided thoracic paravertebral block (TTPB) is a new technique for thoracic paravertebral block (TPB). In this study, we compared the use of TTPB and UTPB for pain management after thoracoscopic radical surgery for lung cancer. METHODS: In total, 80 patients were randomly divided 1:1 into the UTPB group and the TTPB group. The surgical time of TPB, the success rate of the first puncture, block segment range, visual analog scale (VAS) scores at 2, 6, 12, 24, and 48 h post operation, and the incidence of postoperative adverse reactions were compared between the two groups. RESULTS: The surgical time of TPB was significantly shorter in the TTPB group than in the UTPB group (2.2 ± 0.3 vs. 5.7 ± 1.7 min, t = - 12.411, P < 0.001). The success rate of the first puncture and the sensory block segment were significantly higher in the TTPB group than in the UTPB group (100% vs. 76.9%, χ2 = 8.309, P < 0.001; 6.5 ± 1.2 vs. 5.1 ± 1.3 levels, t = - 5.306, P < 0.001, respectively). The VAS scores were significantly higher during rest and coughing at 48 h post operation than at 2, 6, 12, and 24 h post operation in the TTPB group. The VAS scores were significantly lower during rest and coughing at 12 and 24 h post operation in the TTPB group than in the UTPB group (rest: 2.5 ± 0.4 vs. 3.4 ± 0.6, t = 7.325, P < 0.001; 2.5 ± 0.5 vs. 3.5 ± 0.6, t = 7.885, P < 0.001; coughing: 3.4 ± 0.6 vs. 4.2 ± 0.7, t = 5.057, P < 0.001; 3.4 ± 0.6 vs. 4.2 ± 0.8, t = 4.625, P < 0.001, respectively). No significant difference was observed in terms of postoperative adverse reactions between the two groups. CONCLUSIONS: Compared with UTPB, TTPB shows advantages, such as simpler and more convenient surgery, shorter surgical time, a higher success rate of the first puncture, wider block segments, and superior analgesic effect. TTPB can effectively reduce postoperative pain due to thoracoscopic lung cancer radical surgery. TRIAL REGISTRATION: https://www.chictr.org.cn , identifier ChiCTR2300072005, prospectively registered on 31/05/2023.
RESUMO
The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.
Assuntos
Lesão Pulmonar Aguda , Pulmão , Nanoestruturas , Ácido Oleanólico , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Ácido Oleanólico/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/química , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Nanoestruturas/química , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Portadores de Fármacos/química , Masculino , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Pneumonia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Endogâmicos C57BL , Lipídeos/química , Anticorpos/farmacologia , Líquido da Lavagem Broncoalveolar/química , Humanos , Sistemas de Liberação de Medicamentos/métodos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacosRESUMO
AIM: To observe the therapeutic efficacy of Baicalin in rats with severe acute pancreatitis (SAP) and explore its therapeutic mechanisms. METHODS: The SAP rat models were randomly divided into the model control group, Baicalin treatment group, octreotide treatment group and sham operation group. All groups were randomly subdivided into 3 h, 6 h and 12 h groups with 15 rats in each group. The survival, ascites volume and pathological changes of pancreas in all rats were observed at different time points after operation. The plasma amylase content and serum TNF-alpha, IL-6, malonaldehyde (MDA) and PLA(2) contents were also determined. RESULTS: The survival was not obviously different between the treated groups, and was significantly higher in treated groups at 12 h compared to the model control group (P < 0.05, 15 vs 10). The ascites/body weight ratio at 3 h and 6 h was significantly lower in Baicalin treatment group compared to the model control group and octreotide treatment group (P < 0.05, 1.00 vs 2.02 and 1.43 and P < 0.001, 2.29 (1.21) vs 2.70 (0.80) and 2.08 (2.21), respectively). The contents of amylase, TNF-alpha, IL-6, MDA and PLA(2) were significantly lower in the treated groups than in the model control group (P < 0.05, 4342 vs 5303, 5058 vs 6272 in amylase, P < 0.01, 21.90 vs 36.30, 23.80 vs 39.70, 36 vs 54.35 in MDA and 56.25 vs 76.10 in PlA(2), or P < 0.001, 65.10 and 47.60 vs 92.15 in TNF-alpha, 3.03 vs 5.44, 2.88 vs 6.82, 2.83 vs 5.36 in IL-6, respectively). The pathological scores of pancreas in the treated groups were significantly lower than that in the model control group (P < 0.05, 9.00 vs 10.05, 6.00 vs 9.00, 8.00 vs 10.05), but no marked difference was found between the treated groups. CONCLUSION: The Baicalin injection has significant therapeutic effects on SAP rats, its effects are similar to those of octreotide. The Baicalin injection is also cheap and has a big application range, quite hopefully to be used in clinical treatment of SAP.
Assuntos
Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Masculino , Pancreatite/patologia , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To investigate the therapeutic effect of phacoemulsification for primary closed-angle glaucoma complicated with cataract. METHODS: Phacoemulsification with posterior chamber foldable intraocular lens implantation was performed in 55 cases (58 eyes) of acute or chronic primary closed-angle glaucoma complicated with cataract. The changes of visual acuity, intraocular pressure, central anterior chamber depth and anterior chamber angle were observed after operation and the patients were followed up for 6 months. RESULTS: Compared with those before operation, the postoperative best corrected visual acuity and anterior chamber depth were improved, the intraocular pressure was reduced, and the closed chamber angle was partially reopened. CONCLUSION: Phacoemulsification with posterior chamber foldable intraocular lens implantation not only improves the visual acuity but also controls the intraocular pressure, and can be a valuable method for treating primary closed-angle glaucoma with cataract.