GLP-1R activation attenuates the progression of pulmonary fibrosis via disrupting NLRP3 inflammasome/PFKFB3-driven glycolysis interaction and histone lactylation.

BACKGROUND: Pulmonary fibrosis is a serious interstitial lung disease with no viable treatment except for lung transplantation. Glucagon-like peptide-1 receptor (GLP-1R), commonly regarded as an antidiabetic target, exerts antifibrotic effects on various types of organ fibrosis. However, whether GLP-1R modulates the development and progression of pulmonary fibrosis remains unclear. In this study, we investigated the antifibrotic effect of GLP-1R using in vitro and in vivo models of pulmonary fibrosis. METHODS: A silica-induced pulmonary fibrosis mouse model was established to evaluate the protective effects of activating GLP-1R with liraglutide in vivo. Primary cultured lung fibroblasts treated with TGF-ß1 combined with IL-1ß (TGF-ß1 + IL-1ß) were used to explore the specific effects of liraglutide, MCC950, and 3PO on fibroblast activation in vitro. Cell metabolism assay was performed to determine the glycolytic rate and mitochondrial respiration. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which liraglutide affects fibroblast activation. ChIP‒qPCR was used to evaluate histone lactylation at the promoters of profibrotic genes in TGF-ß1 + IL-1ß- or exogenous lactate-stimulated lung fibroblasts. RESULTS: Activating GLP-1R with liraglutide attenuated pulmonary inflammation and fibrosis in mice exposed to silica. Pharmacological inhibition of the NLRP3 inflammasome suppressed PFKFB3-driven glycolysis and vice versa, resulting in decreased lactate production in TGF-ß1 + IL-1ß-stimulated lung fibroblasts. Activating GLP-1R inhibited TGF-ß1 + IL-1ß-induced fibroblast activation by disrupting the interaction between the NLRP3 inflammasome and PFKFB3-driven glycolysis and subsequently prevented lactate-mediated histone lactylation to reduce pro-fibrotic gene expression. In addition, activating GLP-1R protected mitochondria against the TGF-ß1 + IL-1ß-induced increase in oxidative phosphorylation in fibroblasts. In exogenous lactate-treated lung fibroblasts, activating GLP-1R not only repressed NLRP3 inflammasome activation but also alleviated p300-mediated histone lactylation. Finally, GLP-1R activation blocked silica-treated macrophage-conditioned media-induced lung fibroblast activation. CONCLUSIONS: The antifibrotic effects of GLP-1R activation on pulmonary fibrosis could be attributed to the inhibition of the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis, and histone lactylation in lung fibroblasts. Thus, GLP-1R is a specific therapeutic target for the treatment of pulmonary fibrosis.

Protein tyrosine phosphatase PTPRO represses lung adenocarcinoma progression by inducing mitochondria-dependent apoptosis and restraining tumor metastasis.

Emerging evidence indicates that protein activities regulated by receptor protein tyrosine phosphatases (RPTPs) are crucial for a variety of cellular processes, such as proliferation, apoptosis, and immunological response. Protein tyrosine phosphatase receptor type O (PTPRO), an RPTP, has been revealed as a putative suppressor in the development of particular tumors. However, the function and the underlying mechanisms of PTPRO in regulating of lung adenocarcinoma (LUAD) are not well understood. In this view, the present work investigated the role of PTPRO in LUAD. Analysis of 90 pairs of clinical LUAD specimens revealed significantly lower PTPRO levels in LUAD compared with adjacent non-tumor tissue, as well as a negative correlation of PTPRO expression with tumor size and TNM stage. Survival analyses demonstrated that PTPRO level can help stratify the prognosis of LUAD patients. Furthermore, PTPRO overexpression was found to suppress the progression of LUAD both in vitro and in vivo by inducing cell death via mitochondria-dependent apoptosis, downregulating protein expression of molecules (Bcl-2, Bax, caspase 3, cleaved-caspase 3/9, cleaved-PARP and Bid) essential in cell survival. Additionally, PTPRO decreased LUAD migration and invasion by regulating proteins involved in the epithelial-to-mesenchymal transition (E-cadherin, N-cadherin, and Snail). Moreover, PTPRO was shown to restrain JAK2/STAT3 signaling pathways. Expression of PTPRO was negatively correlated with p-JAK2, p-STAT3, Bcl-2, and Snail levels in LUAD tumor samples. Furthermore, the anti-tumor effect of PTPRO in LUAD was significant but compromised in STAT3-deficient cells. These data support the remarkable suppressive role of PTPRO in LUAD, which may represent a viable therapeutic target for LUAD patients.

SARS-CoV-2 in the pancreas and the impaired islet function in COVID-19 patients.

Diabetes mellitus (DM) is one of the most common underlying diseases that may aggravates COVID-19. In the present study, we explored islet function, the presence of SARS-CoV-2 and pathological changes in the pancreas of patients with COVID-19. Oral glucose tolerance tests (OGTTs) and the C-peptide release test demonstrated a decrease in glucose-stimulated C-peptide secretory capacity and an increase in HbA1c levels in patients with COVID-19. The prediabetic conditions appeared to be more significant in the severe group than in the moderate group. SARS-CoV-2 receptors (ACE2, CD147, TMPRSS2 and neuropilin-1) were expressed in pancreatic tissue. In addition to SARS-CoV-2 virus spike protein and virus RNA, coronavirus-like particles were present in the autophagolysosomes of pancreatic acinar cells of a patient with COVID-19. Furthermore, the expression and distribution of various proteins in pancreatic islets of patients with COVID-19 were altered. These data suggest that SARS-CoV-2 in the pancreas may directly or indirectly impair islet function.

Abnormal Coagulation Function of Patients With COVID-19 Is Significantly Related to Hypocalcemia and Severe Inflammation.

This study aimed to detect, analyze, and correlate the clinical characteristics, blood coagulation functions, blood calcium levels, and inflammatory factors in patients with mild and severe COVID-19 infections. The enrolled COVID-19 infected patients were from Wuhan Jin Yin-tan Hospital (17 cases, Wuhan, China), Suzhou Infectious Disease Hospital (87 cases, Suzhou, China), and Xuzhou Infectious Disease Hospital (14 cases, Xuzhou, China). After admission, basic information was collected; X-ray and chest CT images were obtained; and data from routine blood tests, liver and kidney function, myocardial enzymes, electrolytes, blood coagulation function, (erythrocyte sedimentation rate) ESR, C-reactive protein (CRP), IL-6, procalcitonin (PCT), calcitonin, and other laboratory tests were obtained. The patients were grouped according to the clinical classification method based on the pneumonia diagnosis and treatment plan for new coronavirus infection (trial version 7) in China. The measurements from mild (56 cases) and severe cases (51 cases) were compared and analyzed. Most COVID-19 patients presented with fever. Chest X-ray and CT images showed multiple patchy and ground glass opacities in the lungs of COVID 19 infected patients, especially in patients with severe cases. Compared with patients with mild infection, patients with severe infection were older (p = 0.023) and had a significant increase in AST and BUN. The levels of CK, LDH, CK-MB, proBNP, and Myo in patients with severe COVID-19 infection were also increased significantly compared to those in patients with mild cases. Patients with severe COVID-19 infections presented coagulation dysfunction and increased D-dimer and fibrin degradation product (FDP) levels. Severe COVID-19 patients had low serum calcium ion (Ca2+) concentrations and high calcitonin and PCT levels and exhibited serious systemic inflammation. Ca2+ in COVID-19 patients was significantly negatively correlated with PCT, calcitonin, D-dimer, PFDP, ESR, CRP and IL-6. D-dimer in COVID-19 patients was a significantly positively correlated with CRP and IL-6. In conclusion, patients with severe COVID-19 infection presented significant metabolic dysfunction and abnormal blood coagulation, a sharp increase in inflammatory factors and calcitonin and procalcitonin levels, and a significant decrease in Ca2+. Decreased Ca2+ and coagulation dysfunction in COVID-19 patients were significantly correlated with each other and with inflammatory factors.

Carcinoembryonic Antigen: A Potential Biomarker to Evaluate the Severity and Prognosis of COVID-19.

Background and Objectives: Corona Virus Disease 2019 (COVID-19) has become a serious pandemic disease worldwide. Identification of biomarkers to predict severity and prognosis is urgently needed for early medical intervention due to high mortality of critical cases with COVID-19. This retrospective study aimed to indicate the values of carcinoembryonic antigen (CEA) in evaluating the severity and prognosis of COVID-19. Methods: We included 46 death cases from intensive care unit and 68 discharged cases from ordinary units with confirmed COVID-19 of Wuhan Jin Yin-tan Hospital from January 1 to March 22, 2020. Laboratory and radiologic data were analyzed retrospectively. All patients were followed up until April 10, 2020. Results: COVID-19 patients in the death group had significantly higher CEA levels (ng/ml) than discharged group (14.80 ± 14.20 vs. 3.80 ± 2.43, P < 0.001). The risk of COVID-19 death increased 1.317 times for each additional 1 ng/ml CEA level (OR = 1.317, 95% CI: 1.099-1.579). The standardized and weighted receiver operating characteristic curve (ROC) analysis adjusted to age, sex, and ferritin levels suggested that the area under the curve (AUC) of the serum CEA levels was 0.808 in discrimination between death cases and discharged cases with COVID-19 (P < 0.001). We found mortality of COVID-19 is associated with elevated CEA levels increased (HR = 1.023, 95% CI: 1.005-1.042), as well as age (HR = 1.050, 95% CI: 1.016-1.086) and ferritin levels (HR = 1.001, 95% CI: 1.001-1.002) by survival analysis of Cox regression model. Among discharged patients, CEA levels were significant lower in moderate cases compared to the severe and critical cases (P = 0.005; OR = 0.488, 95% CI: 0.294-0.808) from binary logistic regression analysis. The AUC of CEA levels was 0.79 in distinguishing moderate cases from discharged COVID-19 patients by standardized and weighted ROC analysis (P < 0.001). A positive correlation between CEA levels and CT scores existed in discharged patients (Correlation Coefficient: 0.687; P < 0.001). Conclusions: Elevated CEA levels increased the risk of death from COVID-19 and CEA levels were related to CT scores of the discharged patients positively.

Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway.

BACKGROUND: Duguelin is a rotenoid extracted from plants and has potent antitumor effects in vitro and in vivo. However, the mechanism underlying the antitumor effect remains unclear. Our preliminary study showed that Deguelin is effective to stimulate the generation of Reactive Oxygen Species (ROS). In the current study, we evaluated the in vitro cytotoxicity of Deguelin against lung cancer cells and studied whether a ROS scavenger, N-acetyl-cysteine (NAC), can reverse the inhibitory effect of Deguelin. RESULTS: We showed that the dose-dependent apoptotic inducing effect of Deguelin could be partially reversed by the co-administration of NAC. Moreover, Deguelin reduced the phosphorylation of Akt protein and induced the apoptotic protein Caspase-3 in a dose-dependent manner. Co-treatment with NAC partially attenuated this effect and rescued some cells from apoptosis. CONCLUSION: Deguelin induces the apoptosis of cancer cells through a ROS driven Akt pathway, which could translate into a promising therapeutic for lung cancer.