Pristimerin alleviates cigarette smoke-induced inflammation in chronic obstructive pulmonary disease via inhibiting NF-κB pathway.

Cigarette smoke (CS) is a risk factor for chronic obstructive pulmonary disease (COPD), which can exacerbate inflammation and oxidative stress. Pristimerin (Pris) is a natural compound with antioxidant and anti-inflammatory effects. We managed to evaluate the protective effects of Pris on CS-induced COPD. The CS-induced COPD mice model and cell model were constructed. The effects of Pris treatment on lung function, inflammatory cell infiltration, myeloperoxidase (MPO), and pathological changes of lung tissues in mice model were evaluated. The impacts of Pris treatment on inflammatory factors, chemokines, and oxidative stress parameters in mice lung tissues and cells were determined by kits. The viability of human bronchial epithelial cells after Pris treatment was tested by CCK-8. The activation of NF-κB pathway was confirmed by Western blot and immunofluorescence. CS treatment impaired lung function, reduced weight of mice, and enhanced inflammatory cell infiltration, MPO, and lung tissue damage, but these effects of CS were reversed by Pris treatment. Furthermore, Pris treatment downregulated the levels of malondialdehyde, IL-6, IL-1ß, TNF-α, CXCL1, and CXLC2, but upregulated superoxide dismutase and catalase levels. Pris treatment could overturn CS-induced activation of the NF-κB pathway. Pris alleviates CS-induced COPD by inactivating NF-κB pathway.

Salt-inducible kinases inhibitor HG-9-91-01 targets RIPK3 kinase activity to alleviate necroptosis-mediated inflammatory injury.

Receptor-interacting protein kinase 3 (RIPK3) functions as a central regulator of necroptosis, mediating signaling transduction to activate pseudokinase mixed lineage kinase domain-like protein (MLKL) phosphorylation. Increasing evidences show that RIPK3 contributes to the pathologies of inflammatory diseases including multiple sclerosis, infection and colitis. Here, we identified a novel small molecular compound Salt-inducible Kinases (SIKs) inhibitor HG-9-91-01 inhibiting necroptosis by targeting RIPK3 kinase activity. We found that SIKs inhibitor HG-9-91-01 could block TNF- or Toll-like receptors (TLRs)-mediated necroptosis independent of SIKs. We revealed that HG-9-91-01 dramatically decreased cellular activation of RIPK3 and MLKL. Meanwhile, HG-9-91-01 inhibited the association of RIPK3 with MLKL and oligomerization of downstream MLKL. Interestingly, we found that HG-9-91-01 also trigger RIPK3-RIPK1-caspase 1-caspase 8-dependent apoptosis, which activated cleavage of GSDME leading to its dependent pyroptosis. Mechanistic studies revealed that SIKs inhibitor HG-9-91-01 directly inhibited RIPK3 kinase activity to block necroptosis and interacted with RIPK3 and recruited RIPK1 to activate caspases leading to cleave GSDME. Importantly, mice pretreated with HG-9-91-01 showed resistance to TNF-induced systemic inflammatory response syndrome. Consistently, HG-9-91-01 treatment protected mice against Staphylococcus aureus-mediated lung damage through targeting RIPK3 kinase activity. Overall, our results revealed that SIKs inhibitor HG-9-91-01 is a novel inhibitor of RIPK3 kinase and a potential therapeutic target for the treatment of necroptosis-mediated inflammatory diseases.

High Expression of lncRNA HEIH is Helpful in the Diagnosis of Non-Small Cell Lung Cancer and Predicts Poor Prognosis.

BACKGROUND: This study aims to investigate the expression and clinical value of long non-coding RNA (lncRNA) HEIH in peripheral blood of patients with non-small cell lung cancer (NSCLC). METHODS: Healthy subjects (N=70), patients with lung squamous cell carcinoma (LUSC, N=70) and patients with lung adenocarcinoma (LUAD, N=80) were included. LncRNA HEIH expression in peripheral blood of included subjects was detected using RT-qPCR. According to the median expression of lncRNA HEIH, LUSC and LUAD patients were allocated into lncRNA HEIH high/low expression groups. The correlation between lncRNA HEIH and clinical indicators of patients was analyzed; Logistic multifactor regression was used to analyze the independent risk factors influencing lncRNA HEIH level. Receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of lncRNA HEIH and carcinoembryonic antigen (CEA) in LUSC/LUAD patients. MedCalc-Comparison of ROC curves was used to compare the area under ROC curve. The cumulative survival rates of lncRNA HEIH high/low expression group were analyzed by Kaplan-Meier curve. COX multivariate analysis was used to assess the independent factors affecting prognosis of NSCLC. RESULTS: LncRNA HEIH in peripheral blood of LUSC/LUAD patients was higher than that in healthy controls, with no evident difference between LUSC and LUAD groups. In LUSC/LUAD patients, TNM stage, lymph node metastasis, distal metastasis, and CEA were independent risk factors affecting lncRNA HEIH; patients with high lncRNA HEIH expression had larger pack-years and tumor size, higher CEA level and tumor stage, and higher risk of lymph node metastasis and distal metastasis. LncRNA HEIH had higher diagnostic efficiency than CEA in NSCLC patients. High expression of lncRNA HEIH predicted poor prognosis in patients with NSCLC and was an independent risk factor for prognosis of NSCLC. CONCLUSION: High expression of lncRNA HEIH is helpful in the diagnosis of NSCLC and predicts poor prognosis.

Analysis of the expression levels and clinical value of miR-365 and miR-25 in serum of patients with non-small cell lung cancer.

The present study aimed to investigate the expression levels and clinical value of miR-365 and miR-25 in serum of patients with non-small cell lung cancer (NSCLC). Patients (180) diagnosed with NSCLC at the Affiliated Hospital of Guangdong Medical University from July 2011 to December 2013 were used as the experimental group. Volunteers (90) undergoing health examinations were used as the control group. The serum of the patients was collected after fasting in the morning. The expression levels of miR-365 and miR-25 in the serum of patients was assessed by quantitative real-time PCR (qRT-PCR), and the relationship among miR-365, miR-25 and the postoperative survival rate of NSCLC patients was analyzed. The relative expression level of miR-25 of patients with peripheral infiltration was significantly higher than that of patients without peripheral infiltration (P<0.05). There were significant differences in the relative expression level of miR-25 in different pathological grades and TNM stages, as well as with lymph node metastasis (P<0.05). The survival rate of NSCLC patients with high expression of miR-25 was significantly lower than that of NSCLC patients with low expression of miR-25 (P<0.05). The relative expression level of miR-365 of patients with peripheral infiltration was significantly lower than that of patients without peripheral infiltration (P<0.05). There were significant differences in the relative expression level of miR-365 in different pathological grades and TNM stages, as well as with lymph node metastasis (P<0.05). The survival rate of NSCLC patients with high expression of miR-365 was significantly higher than that of NSCLC patients with low expression of miR-365 (P<0.05). In conclusion, the expression levels of miR-25 and miR-365 were different in the serum of NSCLC patients, and they were closely related to certain clinical characteristics such as peripheral infiltration, pathological grade, tumor diameter, TNM stage and lymph node metastasis. Moreover, it was revealed that miR-25 and miR-365 affected the 5-year survival rate of patients. miR-25 and miR-365 could be used as important tumor markers to evaluate the prognosis of NSCLC patients.