Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Postoperative clinical outcomes of patients with thymic epithelial tumors after over-3-year follow-up at a single-center.

BACKGROUND: To evaluate postoperative clinical outcomes and analyze influencing factors for patients with thymic epithelial tumors over 3 years after operation. METHODS: Patients with thymic epithelial tumors (TETs) who underwent surgical treatment in the Department of Thoracic Surgery at Beijing Hospital from January 2011 to May 2019 were retrospectively enrolled in the study. Basic patient information, clinical, pathological, and perioperative data were collected. Patients were followed up by telephone interviews and outpatient records. Statistical analyses were performed using SPSS version 26.0. RESULTS: A total of 242 patients (129 men, 113 women) with TETs were included in this study, of which 150 patients (62.0%) were combined with myasthenia gravis (MG) and 92 patients (38.0%) were not. 216 patients were successfully followed up and their complete information was available. The median follow-up period was 70.5 months (range, 2-137 months). The 3-year overall survival (OS) rate of the whole group was 93.9%, and the 5-year OS rate was 91.1%. The 3-year relapse-free survival (RFS) rate of the whole group was 92.2%, and the 5-year relapse-free survival rate was 89.8%. Multivariable COX regression analysis indicated that recurrence of thymoma was an independent risk factor for OS. Younger age, Masaoka-Koga stage III + IV, and TNM stage III + IV were independent risk factors for RFS. Multivariable COX regression analysis indicated that Masaoka-Koga staging III + IV, WHO type B + C were independent risk factors for postoperative improvement of MG. For patients with MG, the postoperative complete stable remission (CSR) rate was 30.5%. And the result of multivariable COX regression analysis showed that thymoma patients with MG with Osserman staging IIA + IIB + III + IV were not prone to achieving CSR. Compared with patients without MG, MG was more likely to develop in patients with WHO classification type B, and patients with myasthenia gravis were younger, with longer operative duration, and more likely to develop perioperative complications. CONCLUSIONS: The 5-year overall survival rate of patients with TETs was 91.1% in this study. Younger age and advanced stage were independent risk factors for RFS of patients with TETs, and recurrence of thymoma were independent risk factors for OS. In patients with MG, WHO classification type B and advanced stage were independent predictors of poor outcomes of MG treatment after thymectomy.

Surgical treatment of intermediate to high grade thymic neuroendocrine neoplasms: case series of five patients and literature review.

Background: Thymic neuroendocrine neoplasms (Th-NENs) are extremely rare. Th-NENs are divided into four pathological subtypes: typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC). The latter three subtypes are highly aggressive with poor prognosis. There are limited reports on the optimal surgical strategies for Th-NENs. This study aims to report a case series of Th-NENs after surgical treatment and review the literatures. Methods: We report a case series of five patients diagnosed with Th-NENs and summarize their clinical characteristics. Literatures related to surgical treatment of Th-NENs were reviewed. Results: There were three males and two females, and mean age was 53.6 years. No myasthenia gravis or neuroendocrine symptoms were found. Three patients were diagnosed with AC and the other two were diagnosed with LCNEC. Two patients were stage II-b, one patient was stage III-a, and two patients were stage IV-b. One patient received preoperative chemotherapy, one patient received preoperative chemoradiotherapy, and three patients underwent surgery directly. Two patients underwent extended thymectomy via video-assisted thoracoscopic surgery (VATS), two patients underwent extended thymectomy via median sternotomy, and one patient underwent resection of anterior mediastinal tumor, sternal metastases, superior vena cava and partial right atrium via median sternotomy and cardiopulmonary bypass. R0 resection was achieved in 80% (4/5) of patients. There was no postoperative 90-day complication and death. One patient had no recurrence. One patient had lymph node metastases and was still alive after somatostatin analogue therapy. One patient had no recurrence of Th-NENs but died of other tumors. Two patients had distant metastases. Median overall survival (mOS) was 49 (range, 4-134) months. A total of 22 original studies related to surgical treatment of Th-NENs were retrieved. Conclusions: Th-NENs is a very rare and extremely aggressive malignancy. Early diagnosis and surgical resection are the most important methods to improve prognosis. Radical resection and lymph node dissection are recommended for accurate staging and better prognosis. Currently, there are few clinical data on Th-NENs and several important surgical issues remain unresolved. In the future, multi-center, large-sample database and clinical studies are urgently needed to explore better treatment modality.

CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in acute lung injury induced by sepsis through modulating miR-21.

Acute lung injury (ALI) induced by sepsis is characterized by an inflammatory process related to the up-regulation of inflammatory cytokines and chemokines. In the present study, we explored the role of circC3P1 in sepsis-induced ALI in vitro and in vivo. The caecal ligation and puncture (CLP)-induced sepsis model was established through CLP surgery. Forty adult male C57BL/6 mice were randomly assigned into sham, CLP, CLP + vector and CLP + circC3P1 (each n = 10). Primary murine pulmonary microvascular endothelial cells (MPVECs) were transfected with circC3P1 or empty vector 24 hours prior to LPS treatment via Lipofectamine 2000. The expressions of circC3P1, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1ß were evaluated after 6-h LPS treatment. Cell apoptosis was evaluated via flow cytometry. The CLP group demonstrated pulmonary morphological abnormalities, increased concentrations of TNF-α, IL-6 and IL-1ß in the lung tissue, compared with the sham group. MPVECs treated with LPS significantly elevated TNF-α, IL-6 and IL-1ß levels and increased cell apoptosis than that in the control group. The circC3P1 overexpression in sepsis-induced ALI mice attenuated pulmonary injury, inflammation and apoptosis. Besides, circC3P1 revealed anti-inflammatory and anti-apoptotic effect in MPVEC-treated LPS. CircC3P1 overexpression reduced cell apoptosis and pro-inflammatory cytokines levels via down-regulating miR-21. CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in ALI induced by sepsis through modulating miR-21, indicating that circC3P1 is a promising therapeutic biomarker for sepsis-induced ALI.