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BACKGROUND: Frailty becomes more pronounced with advancing age, tightly intertwined with adverse clinical outcomes. Across diverse medical disciplines, frailty is now universally recognized as not only a risk factor but also a predictive indicator for unfavorable clinical prognosis. METHODS: This study was a retrospective cohort study that included clinical data from patients (aged ≥ 65 years) with esophageal cancer treated surgically at the First Affiliated Hospital of Anhui Medical University in 2021. For each patient, we calculated their 11-index modified frailty index(mFI-11) scores and categorized the patients into a frailty group (mFI-11hign) and a non-frailty group (mFI-11low) based on the optimal grouping cutoff value of 0.27 from a previous study. The primary study index was the incidence of postoperative pulmonary infection, arrhythmia, anastomotic fistula, chylothorax, and electrolyte disturbance complications. Secondary study indicators included postoperative ICU stay, total hospitalization time, readmission rate within 30 days of discharge, and mortality within 30 days after surgery. We performed univariate and multivariate analyses to assess the association between mFI-11 and adverse outcomes as well as postoperative complications. RESULTS: Five hundred and fifteen patients were included, including 64.9% (334/515) in the non-frailty group and 35.1% (181/515) in the frailty group. Comparing postoperative complication rates between the two groups revealed lower incidences of postoperative anastomotic fistula (21.5% vs. 4.5%), chylothorax (16.0% vs. 2.1%), cardiac arrhythmia (61.9% vs. 9.9%), pulmonary infections (85.1% vs. 26.6%), and electrolyte disturbance (84.5% vs. 15.0%) in patients of the non-frailty group was lower than that in the frailty group (p < 0.05). mFI-11 showed better prognostic results in predicting postoperative complications. anastomotic fistula (area under the ROC curve AUROC = 0.707), chylothorax (area under the ROC curve AUROC = 0.744), pulmonary infection (area under the ROC curve AUROC = 0.767), arrhythmia (area under the ROC curve AUROC = 0.793), electrolyte disturbance (area under the ROC curve AUROC = 0.832), and admission to ICU (area under the ROC curve AUROC = 0.700). CONCLUSION: Preoperative frail elderly patients with esophageal cancer have a high rate of postoperative complications. mFI-11 can be used as an objective indicator for identifying elderly patients at risk for esophageal cancer.
Subject(s)
Esophageal Neoplasms , Postoperative Complications , Humans , Esophageal Neoplasms/surgery , Male , Female , Aged , Postoperative Complications/epidemiology , Postoperative Complications/diagnosis , Retrospective Studies , China/epidemiology , Frailty/epidemiology , Frailty/diagnosis , Aged, 80 and over , Esophagectomy/adverse effects , Risk Factors , Geriatric Assessment/methods , Prognosis , Frail Elderly , East Asian PeopleABSTRACT
BACKGROUND: This study aimed to explore the efficacy of hookwire for computed tomography (CT)-guided pulmonary nodule (PN) localization before video-assisted thoracoscopic surgery (VATS) resection and determine the risk factors for localization-related complications. METHODS: We enrolled 193 patients who underwent preoperative CT-guided PN hookwire localization. The patients were categorized into groups A (103 patients had no complications) and B (90 patients had complications) according to CT and VATS. Uni- and multivariate logistic regression analyses were used to identify risk factors for localization-related complications. A numerical rating scale was used to evaluate hookwire localization-induced pain. RESULTS: We successfully performed localization in 173 (89.6%) patients. Pneumothorax was the main complication in 82 patients (42.5%). Patient gender, age, body mass index, tumor diameter, consolidation tumor ratio, pathologic diagnosis, position adjustment during location, lesion location, waiting time for surgery, and pleural adhesions were not significantly different between the two groups. The number of nodules, number of punctures, scapular rest position, and depth of insertion within the lung parenchyma were significant factors for successful localization. Multivariate regression analysis further validated the number of nodules, scapular rest position, and depth of insertion within the lung parenchyma as risk factors for hookwire-localization-related complications. Hookwire localization-induced pain is mainly mild or moderate pre- and postoperatively, and some patients still experience pain 7 days postoperatively. CONCLUSIONS: Hookwire preoperative PN localization has a high success rate, but some complications remain. Thus, clinicians should be vigilant and look forward to further improvement.
Subject(s)
Lung Neoplasms , Solitary Pulmonary Nodule , Thoracic Surgery, Video-Assisted , Tomography, X-Ray Computed , Humans , Male , Female , Middle Aged , Risk Factors , Tomography, X-Ray Computed/methods , Thoracic Surgery, Video-Assisted/methods , Thoracic Surgery, Video-Assisted/adverse effects , Aged , Lung Neoplasms/surgery , Solitary Pulmonary Nodule/surgery , Solitary Pulmonary Nodule/diagnostic imaging , Adult , Multiple Pulmonary Nodules/surgery , Multiple Pulmonary Nodules/diagnostic imaging , Retrospective Studies , Postoperative Complications/etiology , Preoperative Care/methodsABSTRACT
Background: Open thoracotomy has been the traditional surgical approach for patients with bronchogenic cysts (BCs). This study aimed to evaluate the safety and efficacy of video-assisted thoracoscopic surgery (VATS) compared to open surgery for the treatment of BCs in adults. Methods: This single-institution, retrospective cohort study included 117 consecutive adult patients who underwent VATS (group A) or open surgery (group B) for BC resection between February 2019 and January 2023. Data regarding clinical history, operation duration, length of hospital stay, 30-day mortality, and recurrence during follow-up were collected and analyzed. Results: Of the total cohort, 103 (88.0%) patients underwent VATS, while 14 (12.0%) patients underwent open surgery. Patients' age in group B were much older than group A (P=0.014), and no significant differences in other demographic and baseline clinical characteristics were observed between the groups. The VATS group had shorter median operation duration (96 vs. 149.5 min, P<0.001) and shorter mean length of hospital stay (5.0±5.5 vs. 8.6±4.0 days, P<0.001). One death occurred in the open surgery group. During a median follow-up of 34 (interquartile range, 20.8-42.5) months, no instances of BC recurrence were observed in either group. Conclusions: Compared to open surgery, VATS is also a safe and efficacious approach for treating BCs in adults. What's more, VATS offered shorter operative times and hospital stays. Considering the minimally invasive, VATS may be a better choice in most patients with bronchial cysts.
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AIM: Some studies have reported that body composition profiles affect clinical outcomes of multidisciplinary treatments in several types of cancers; however, a paucity of data exists on the association in neoadjuvant immunotherapy. In the present study, we aimed to investigate the effect of body composition on the clinical outcomes of patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy plus chemotherapy (nICT). METHODS: Clinicopathological data and computed tomography (CT) images of 85 patients with locally advanced ESCC who underwent esophagectomy after nICT were collected. At diagnosis and before surgery, the CT scan of the third lumbar vertebra was chosen to evaluate the skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), the subcutaneous and the visceral adiposity index. The relationships between body composition and tumor response after nICT and postoperative complications were analyzed. RESULTS: The clinical stage (Odds Ratio (OR) 0.345, 95% confidence interval (CI) 0.141-0.844, p = 0.020) and change in SMI (∆SMI, OR 1.394, 95% CI 1.061-1.832, p = 0.017) were associated with tumor remission after nICT. Moreover, the multivariate logistic analysis revealed that ∆SMI (OR 0.598, 95% CI 0.433-0.828, p = 0.002) was associated with the incidence of postoperative complications. Patients with ∆SMI <-1 had a higher rate of postoperative complications (56% vs 15%, p < 0.001). CONCLUSIONS: For ESCC, ∆SMI is associated with the pathological response after nICT and postoperative complications. Further analysis is needed to clarify whether nutritional intervention during neoadjuvant therapy increases SMI and thus improves clinical outcomes.
Subject(s)
Body Composition , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Neoadjuvant Therapy , Humans , Esophageal Neoplasms/therapy , Esophageal Neoplasms/pathology , Male , Female , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/pathology , Middle Aged , Aged , Treatment Outcome , Esophagectomy , Immunotherapy , Retrospective Studies , Tomography, X-Ray Computed , Postoperative Complications/epidemiology , Postoperative Complications/etiologyABSTRACT
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy with a high morbidity and mortality rate. TMEM100 has been shown to be suppressor gene in a variety of tumors, but there are no reports on the role of TMEM100 in esophageal cancer (EC). AIM: To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion. METHODS: Firstly, we found the expression of TMEM100 in EC through The Cancer Genome Atlas database. The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis. We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification. To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100. Finally, we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases (MAPK) pathway. RESULTS: In the present study, by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects. Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC. Then, we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells [quantitative real-time PCR (qRT-PCR) and western blotting]. Subsequently, we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells (qRT-PCR and western blotting). Overexpression of TMEM100 also inhibited proliferation, invasion and migration of ESCC cells (cell counting kit-8 and clone formation assays). Next, by enrichment analysis, we found that the gene set was significantly enriched in the MAPK signaling pathway. The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting. CONCLUSION: TMEM100 is a suppressor gene in ESCC, and its low expression may lead to aberrant activation of the MAPK pathway. Promoter methylation may play a key role in regulating TMEM100 expression.
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Influence maximization problem has received significant attention in recent years due to its application in various domains, such as product recommendation, public opinion dissemination, and disease propagation. This paper proposes a theoretical analysis framework for collective influence in hypergraphs, focusing on identifying a set of seeds that maximize influence in threshold models. First, we extend the message passing method from pairwise networks to hypergraphs to accurately describe the activation process in threshold models. Then, we introduce the concept of hypergraph collective influence (HCI) to measure the influence of nodes. Subsequently, we design an algorithm, HCI-TM, to select the influence maximization set, taking into account both node and hyperedge activation. Numerical simulations demonstrate that HCI-TM outperforms several competing algorithms in synthetic and real-world hypergraphs. Furthermore, we find that HCI can be used as a tool to predict the occurrence of cascading phenomena. Notably, we find that the HCI-TM algorithm works better for larger average hyperdegrees in Erdös-Rényi hypergraphs and smaller power-law exponents in scale-free hypergraphs.
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BACKGROUND: The role of Acyl-CoA dehydrogenase long chain (ACADL) in different tumor types had different inhibiting or promoting effect. However, its role in non-small cell lung cancer (NSCLC) carcinogenicity is not clear. METHOD: In this study, we utilized The Cancer Genome Atlas (TCGA) database to analyze ACADL expression in NSCLC and its correlation with overall survival. Furthermore, we investigated the function of ACADL on cellular proliferation, invasion, colony, apoptosis, cell cycle in vitro with NSCLC cells. Mechanistically, we evaluated the regulatory effect of ACADL expression on its downstream factor yes-associated protein (YAP) by assessing YAP phosphorylation levels and its cellular localization. Finally, we verified the tumorigenic effect of ACADL on NSCLC cells through xenograft experiments in vivo. RESULTS: Compared to adjacent non-cancerous samples, ACADL significantly down-regulated in NSCLC. Overexpression of ACADL, effectively reduced the proliferative, colony, and invasive capabilities of NSCLC cells, while promoting apoptosis and inducing cell cycle arrest. Moreover, ACADL overexpression significantly enhanced YAP phosphorylation and hindered its nuclear translocation. However, the inhibitory effect of the overexpression of ACADL in NSCLC cells mentioned above can be partially counteracted by YAP activator XMU-MP-1 application both in vitro and in vivo. CONCLUSION: The findings suggest that ACADL overexpression could suppress NSCLC development by modulating YAP phosphorylation and limiting its nuclear shift. This role of ACADL-YAP axis provided novel insights into NSCLC carcinogenicity and potential therapeutic strategies.
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Animal models are extensively used in all aspects of biomedical research, with substantial contributions to our understanding of diseases, the development of pharmaceuticals, and the exploration of gene functions. The field of genome modification in rabbits has progressed slowly. However, recent advancements, particularly in CRISPR/Cas9-related technologies, have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases, including cardiovascular disorders, immunodeficiencies, aging-related ailments, neurological diseases, and ophthalmic pathologies. These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice. This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine, underscoring their impact and future potential in translational medicine.
Subject(s)
Biomedical Research , Veterinary Drugs , Humans , Rabbits , Animals , Mice , CRISPR-Cas Systems , Gene Editing/veterinary , Models, AnimalABSTRACT
OBJECTIVE: This study aims to report the 2-year outcomes of patients with clinical stage N2-3 esophageal squamous cell carcinoma who received neoadjuvant chemotherapy and immunotherapy followed by surgery from a phase 2 NICE trial. METHODS: Eligible patients with clinical stage N2-3 esophageal squamous cell carcinoma were screened and enrolled, then treated with regimen of nab-paclitaxel (100 mg/m2, days 1, 8, 15), carboplatin (area under the curve = 5, day 1), camrelizumab (200 mg, day 1) of two 21-day cycles and esophagectomy 4 to 6 weeks after the last chemotherapy. Oncologic outcomes, recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) were explored. RESULTS: From November 20, 2019, to December 22, 2020, 60 patients were recruited. After a median follow-up of 27.4 months, disease recurrence was observed in 19 (37.3%) patients, with 5 (9.8%) locoregional recurrence, 9 (17.6%) distant metastasis, and 5 (9.8%) combined recurrence. Lung was the most commonly involved metastatic site. The median time to recurrence was 10.8 months (interquartile range, 7.5-12.7 months). The 2-year OS and RFS rates were 78.1% and 67.9%, respectively. Patients who achieved major pathologic response (MPR) had a significantly greater 2-year OS rate (91.4% vs 47.7%; P < .001) and RFS rate (77.1% vs 45.9%; P = .003). On multivariable analysis, MPR was indicated as an independent prognostic factor for disease recurrence (hazard ratio, 0.39; 95% confidence interval, 0.21-0.82; P = .029). CONCLUSIONS: In patients receiving neoadjuvant chemotherapy and immunotherapy, distant metastasis remains the predominant recurrence pattern. MPR is associated with lower recurrence and better survival. Long-term results derived from randomized controlled trials are further required. TRIAL REGISTRATION NUMBER: ChiCTR1900026240.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Neoplasms/therapy , Esophageal Neoplasms/pathology , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/methods , Cisplatin , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/pathology , ImmunotherapyABSTRACT
INTRODUCTION: Parietal pleurectomy with bullectomy has been established as an effective method for preventing the recurrence of primary spontaneous pneumothorax (PSP). Our center introduced enhanced technical measures in uniportal thoracoscopic parietal pleurectomy with bullectomy for patients with PSP, aiming to document our initial experience and assess the procedure's effectiveness in preventing the recurrence of PSP. METHODS: We analyzed the clinical data of 86 patients with PSP who underwent the improved uniportal thoracoscopic parietal pleurectomy with bullectomy between July 2019 and August 2022. During the procedure, the parietal pleura above the second intercostal space was stripped but not removed. Instead, it was retained in the thoracic cavity using a piece of pedunculated pleura. Subsequently, the stumps of the lung were covered by the preserved parietal pleura. RESULTS: The results of the study showed that the mean operative time was 59.87 ± 16.93 min, and the postoperative drainage duration averaged 3.94 ± 2.17 days. The mean intraoperative blood loss was 24.33 ± 48.91 ml, and the mean postoperative drainage volume was 289.00 ± 170.03 ml. Prolonged air leakage for more than 5 days was observed in five patients (5.81%), but no other postoperative complications were recorded. During the follow-up, one patient (1.16%) experienced a recurrence of pneumothorax. CONCLUSIONS: The perioperative results of bullectomy with the improved pleurectomy technique are deemed satisfactory. The various technical steps attempted at our center are found to be feasible and safe, and they may contribute to reducing the rates of recurrence in PSP.
Subject(s)
Pneumothorax , Thoracic Surgical Procedures , Humans , Pneumothorax/surgery , Retrospective Studies , Pleura/surgery , Postoperative Complications , Recurrence , Thoracic Surgery, Video-Assisted/methods , Treatment OutcomeABSTRACT
Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are crucially implicated in the cancer progression. The current study intends to excavate and clarify the mechanisms of the key IGF2BPs in non-small cell lung cancer (NSCLC). The expression of IGF2BPs and kinesin family member 2A (KIF2A) was examined using immunohistochemistry, real-time quantitative polymerase chain reaction, and western blot in NSCLC tissue samples or cell lines. NSCLC cell viability was examined using a cell counting kit-8 assay. Cell apoptotic rate was assessed using flow cytometry analysis. The migration and invasion of H1299 cells were subject to scratch test and Transwell assays, respectively. Starbase 2.0 was used to detect the downstream factors of the IGF2BP1 protein. The binding of IGF2BP with KIF2A was detected using RNA binding protein immunoprecipitation assays. Ki-67 immunohistochemistry assay and TUNEL assays were applied for the evaluation of proliferation and apoptosis in vivo, respectively. IGF2BP1 was upregulated in NSCLC tissue samples and cells. Functionally, IGF2BP1 overexpression promoted the proliferative ability, migration, and invasiveness of H1299 cells, while inhibiting cell apoptosis in vitro. In vivo studies revealed that overexpression of IGF2BP1 promoted tumor growth of NSCLC. Mechanistically, IGF2BP1 was involved in KIF2A mRNA stabilization. KIF2A exerted the same functions as IGF2BP1 via the Wnt/ß-catenin signaling. In conclusion, IGF2BP1 enhances NSCLC malignant progression by stabilizing KIF2A to modulate the Wnt/ß-catenin pathway.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , MicroRNAs , Humans , beta Catenin/genetics , beta Catenin/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Kinesins/genetics , Kinesins/metabolism , Lung Neoplasms/pathology , RNA, Messenger , Wnt Signaling Pathway/geneticsABSTRACT
The traditional prognostic model may induce the possibility of incorrect assessment of mortality risk under the assumption of linearity. It is urgent to develop a non-linearity precise prognostic model for achieving personalized medicine in lung cancer. In our study, we develop and validate a prognostic model "Modified-DeepSurv" for patients with lung carcinoma based on deep learning and evaluate its value for prognosis, while Cox proportional hazard regression was used to develop another model "CPH." The C-index of the Modified-DeepSurv and CPH was 0.956 (95% confidence interval [CI]: 0.946-0.974) and 0.836 (95% CI: 0.774-0.896), respectively, in the training cohort, while the C-index of the Modified-DeepSurv and CPH was 0.932 (95%CI: 0.908-0.964) and 0.777 (95%CI: 0.633-0.919), respectively, in the test dataset. The Modified-DeepSurv model visualization was realized by a user-friendly graphic interface. Modified-DeepSurv can effectively predict the survival of lung cancer patients and is superior to the conventional CPH model.
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Background: Mediastinal haemangioma is a rare type of tumour and accounts for ≤0.5% of all mediastinal tumours. Mediastinal haemangioma is often nonspecific upon examination by imaging. Mediastinal haemangioma diagnosis is difficult to confirm before surgery because the characteristic features of diagnostic imaging are poor, and these lesions are extremely rarely encountered in clinical practice. Case Description: We herein report a case of thoracoscopic resection of a cavernous haemangioma in the anterior mediastinum. A 40-year-old man was referred to our hospital for a health examination. A chest computed tomography scan showed a mass with irregular contrast enhancement and a smooth surface. Using video-assisted thoracoscopic surgery, the tumour was completely extirpated and confirmed histologically to be a cavernous haemangioma. The patient recovered well, was discharged, he has since had no recurrences, and continues to be closely monitored as an outpatient. Conclusions: Mediastinal haemangiomas, a rare type of mediastinal tumour, are typically benign and located in the anterior mediastinum, and lack specific symptoms and relevant imaging features. We found that minimally invasive thoracoscopic resection provided a satisfactory view and facilitated correct handling of a mediastinal cavernous haemangioma. Although such tumours are mostly benign and the prognosis is good, we recommend aggressive surgical management to avoid missing malignant lesions.
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Undetected infections fuel the dissemination of many infectious agents. However, identification of unobserved infectious individuals remains challenging due to limited observations of infections and imperfect knowledge of key transmission parameters. Here, we use an ensemble Bayesian inference method to infer unobserved infections using partial observations. The ensemble inference method can represent uncertainty in model parameters and update model states using all ensemble members collectively. We perform extensive experiments in both model-generated and real-world networks in which individuals have differential but unknown transmission rates. The ensemble method outperforms several alternative approaches for a variety of network structures and observation rates, despite that the model is mis-specified. Additionally, the computational complexity of this algorithm scales almost linearly with the number of nodes in the network and the number of observations, respectively, exhibiting the potential to apply to large-scale networks. The inference method may support decision-making under uncertainty and be adapted for use for other dynamical models in networks.
Subject(s)
Algorithms , Gene Regulatory Networks , Humans , Bayes TheoremABSTRACT
Primary mediastinal choriocarcinoma, also known as non-pregnant choriocarcinoma, is a rare malignancy unrelated to pregnancy, with a higher incidence in males. And primary mediastinal choriocarcinoma is mostly associated with organ and lymph node metastasis, with rapid progression and poor prognosis. Here, we report an extremely rare case of the primary anterior mediastinal choriocarcinoma that occurred in an 18-year-old man with multiple metastases of the lung and brain.
Subject(s)
Brain Neoplasms , Choriocarcinoma , Mediastinal Neoplasms , Testicular Neoplasms , Male , Pregnancy , Female , Humans , Adolescent , Choriocarcinoma/pathology , Choriocarcinoma/secondary , Testicular Neoplasms/complications , Mediastinal Neoplasms/pathology , Lung/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/complicationsABSTRACT
OBJECTIVE: Acute lung injury (ALI) is featured as excessive inflammatory response and oxidative damage, and results in high death rate of septic patients. This research intends to determine the function of multiple EGF like domains 6 (MEGF6) in sepsis-induced ALI. METHODS: Mice were intratracheally treated with adenovirus to knock down or overexpress MEGF6 in lung tissues, and then were subjected to cecum ligation and puncture (CLP) operation to induce ALI. Primary peritoneal macrophages were isolated, and were knocked down or overexpressed with MEGF6, and then, were stimulated with lipopolysaccharide (LPS) to confirm its role in vitro. RESULTS: Serum and lung MEGF6 levels were significantly elevated in septic mice. MEGF6 knockdown exacerbated, while MEGF6 overexpression prevented inflammation, oxidative damage and ALI in CLP mice. Meanwhile, LPS-elicited inflammatory response and oxidative damage in primary macrophages were reduced by MEGF6 overexpression, but were further aggravated by MEGF6 knockdown. Mechanistic studies revealed that MEGF6 reduced cluster of differentiation 38 (CD38) expression and subsequently elevated intracellular nicotinamide adenine dinucleotide levels, thereby activating sirtuin 1 (SIRT1) without affecting the protein expression. SIRT1 suppression or CD38 overexpression with either genetic or pharmacologic methods remarkably blunted the lung protective effects of MEGF6 in CLP mice. CONCLUSION: MEGF6 prevents CLP-induced ALI through CD38/SIRT1 pathway, and it might be a valuable therapeutic candidate for the management of sepsis-induced ALI.
Subject(s)
Acute Lung Injury , Sepsis , Animals , Humans , Mice , Acute Lung Injury/drug therapy , Acute Lung Injury/etiology , ADP-ribosyl Cyclase 1 , Lipopolysaccharides , Sepsis/complications , Sirtuin 1ABSTRACT
AMP-activated protein kinase (AMPK) activation plays crucial roles in the treatment of many oxidative stress- and inflammation-induced diseases, including acute lung injury (ALI). Limonin is a naturally occurring tetracyclic triterpenoid extracted from the plants of Rutaceae and Meliaceae. Limonin also serves as an AMPK activator with anti-inflammatory and anti-oxidation effects. However, the potential beneficial effects of limonin on ALI and the possible mechanisms have never been disclosed till now. Here, the effects of limonin on lipopolysaccharide (LPS)-induced ALI in C57 BL/6 mice, plus bone marrow-derived macrophages (BMDM) stimulated with LPS to induce in vitro ALI model were investigated. Limonin significantly improved pulmonary function and alleviated lung pathological injury in LPS-induced mice. Meanwhile, limonin also markedly decreased inflammation and oxidative stress in lung tissues from LPS-treated mice. In vitro experiments also unveiled that limonin could decrease inflammation and oxidative stress in LPS-induced BMDM in a concentration-dependent manner. Mechanically, limonin could promote the activation of AMPKα and upregulate the expression of nuclear factor erythroid 2-related factor 2 (NRF2) in lung tissues and BMDM. Pharmacological inhibition of AMPKα by Compound C or AMPKα knockout could abolish the pulmonary protection from limonin during ALI. In conclusion, limonin mediates the activation of AMPKα/NRF2 pathway, providing an attractive therapeutic target for ALI in the future.
Subject(s)
Acute Lung Injury , Limonins , Animals , Mice , Lipopolysaccharides/pharmacology , AMP-Activated Protein Kinases/metabolism , Limonins/pharmacology , Limonins/therapeutic use , NF-E2-Related Factor 2/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Lung/pathology , Inflammation/pathology , Mice, Inbred C57BLABSTRACT
BACKGROUND: Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor-associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear. METHODS: Proteins and mRNA expression were determined by western blot and RT-qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo. RESULTS: First, we determined that lactate upgraded the M2-type polarization marker levels of macrophages. Cell function assays confirmed that lactate-activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor - oxamate hampered the level of lactate in TE-1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate-stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate-induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization. CONCLUSION: EC-secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC.
Subject(s)
Esophageal Neoplasms , Proto-Oncogene Proteins c-akt , Animals , Mice , Humans , Proto-Oncogene Proteins c-akt/metabolism , MAP Kinase Signaling System , Lactic Acid/metabolism , Lactic Acid/pharmacology , Cell Line, Tumor , Macrophages/metabolism , Esophageal Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
Pulmonary fibrosis is a chronic progressive disease which steadily causes a critical public health concern. Nesfatin-1, a novel energy-regulating peptide discovered in 2006, could increase the level of AMPK phosphorylation. Previous studies have unveiled that Nesfatin-1 possessed many pharmacological effects including anti-inflammation, anti-oxidative stress, anti-fibrosis, and the regulation of lipid metabolism. Here, we investigated the impact of Nesfatin-1 on pulmonary fibrosis. Male C57BL/6J mice were intraperitoneally injected with Nesfatin-1 (10 µg·kg-1·day-1) for 21 days since mice were intratracheally administrated with bleomycin (BLM) (2 U/kg). Primary murine lung fibroblasts were stimulated with TGF-ß1 (10 ng/ml) for 48 h. The results showed that Nesfatin-1 treatment significantly improved pulmonary function and decreased the production of collagen in BLM-treated mice. Meantime, Nesfatin-1 treatment also inhibited oxidative stress and inflammation in lung tissues from BLM-treated mice. Mechanically, Nesfatin-1 blocked the activation of TGF-ß1/Smad2/3 signaling pathway in lung tissues challenged with BLM. In addition, we found that Nesfatin-1 enhanced the phosphorylation of AMPKα during pulmonary fibrosis. However, pharmacological inhibition or genetic deletion of AMPKα could both offset the pulmonary protection mediated by Nesfatin-1 during pulmonary fibrosis. Our experimental results firstly show Nesfatin-1 might serve as a novel treatment or adjuvant against pulmonary fibrosis by blocking TGF-ß1/Smad pathway in an AMPKα-dependent manner.