Ferroptosis is a kind of regulated cell death, supporting the pathological process of lung inflammation, including asthma. Quercetin (QCT), a kind of natural dietary flavonoid, exerts anti-inflammatory and anti-ferroptosis effects in various diseases. However, the role of QCT in ferroptosis-associated airway inflammation of neutrophilic asthma remains to be described. Our study aimed to investigate the therapeutic effects of QCT on neutrophilic airway inflammation of asthma. Ferrostatin-1 (Fer-1), as a kind of ferroptosis inhibitor, was used to demonstrate whether neutrophilic airway inflammation of asthma relied on ferroptosis. In our study, the alleviation effect of QCT on neutrophilic airway inflammation was similar to Fer-1. Moreover, the significantly decreased levels of ferroptosis anti-oxidant protein (GPX4 and SLC7A11), increased malondialdehyde (MDA) levels, upregulated levels of 4-hydroxynonenal (4-HNE) expression by immunohistochemistry, and distorted mitochondria morphological changes in the lung tissues suggested lung ferroptosis in neutrophilic airway inflammation, which could be reversed by QCT treatment. In vitro experiments showed that QCT reduced LPS-induced ferroptosis through upregulating cell viability and levels of ferroptosis anti-oxidant protein (SLC7A11 and GPX4), reducing inflammatory cytokines, and decreasing the levels of MDA. Furthermore, ferroptosis was accompanied by enhancing M1 phenotype in neutrophilic airway inflammation, and QCT suppressed ferroptosis by inhibiting the pro-inflammatory M1 profile in vitro and in vivo, just as Fer-1 did. In conclusion, our study found that QCT ameliorated ferroptosis-associated neutrophilic airway inflammation accompanied by inhibiting M1 macrophage polarization. QCT may be a promising ferroptosis inhibitor for neutrophilic airway inflammation.

Background: Obesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly elucidated. Among the adipokines related to obesity, leptin is related to the inflammatory response. However, little is understood about how leptin acts on the leptin receptor (obR) in neutrophilic airway inflammation in obesity-associated asthma. We explored the inflammatory effects of leptin/obR signaling in an obesity-related neutrophilic airway inflammation mouse model. Methods: We established a neutrophilic airway inflammation mouse model using lipopolysaccharide (LPS)/ovalbumin (OVA) sensitization and OVA challenge (LPS + OVA/OVA) in lean, obese, or db/db (obR deficiency) female mice. Histopathological, bronchoalveolar lavage fluid (BALF) inflammatory cell, and lung inflammatory cytokine analyses were used to analyze airway inflammation severity. Western blotting, flow cytometry, reverse transcription‐polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the underlying mechanisms. In vitro bone marrow‐derived macrophage (BMDM) and bone marrow-derived neutrophil experiments were performed. Results: We found that the serum leptin level was higher in obese than in lean female mice. Compared to LPS/OVA + OVA-treated lean female mice, LPS/OVA + OVA-treated obese female mice had higher peribronchial inflammation levels, neutrophil counts, Th1/Th17-related inflammatory cytokine levels, M1 macrophage polarization levels, and long isoform obR activation, which could be decreased by the obR blockade (Allo-Aca) or obR deficiency, suggesting a critical role of leptin/obR signaling in the pathogenesis of obesity-related neutrophilic airway inflammation in female mice. In in vitro experiments, leptin synergized with LPS/IFN-γ to promote the phosphorylation of the long isoform obR and JNK/STAT3/AKT signaling pathway members to increase M1 macrophage polarization, which was reversed by Allo-Aca. Moreover, leptin/obR-mediated M1 macrophage activity significantly elevated CXCL2 production and neutrophil recruitment by regulating the JNK/STAT3/AKT pathways. In clinical studies, obese patients with asthma had higher serum leptin levels and M1 macrophage polarization levels in induced sputum than non-obese patients with asthma. Serum leptin levels were positively correlated with M1 macrophage polarization levels in patients with asthma. Conclusions: Our results demonstrate leptin/obR signaling plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females by promoting M1 macrophage polarization. Graphical

In the phase 3 CheckMate 078 study, nivolumab showed significant overall survival (OS) benefit and superior tolerability versus docetaxel in a predominantly Chinese patient population with non-small cell lung cancer (NSCLC). However, data on long-term outcomes with immunotherapy in Asian patients are limited. We report 2-year efficacy and safety data. Patients with advanced/metastatic NSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks; n = 338) or docetaxel (75 mg/m2 every 3 weeks; n = 166) until progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was OS; secondary endpoints included progression-free survival, objective response rate, and safety. After 25.9 months minimum follow-up, 21 patients (6 %) remained on nivolumab versus 0 on docetaxel. Median OS was 11.9 months with nivolumab versus 9.5 months with docetaxel (HR: 0.75; 95 % CI: 0.61-0.93); 2-year OS rates were 28 % versus 18 %, respectively. Survival benefits were observed across a variety of predefined subgroups. At 2 years, 39 % and 0 % of responders had ongoing responses with nivolumab and docetaxel, respectively. Grade 3-4 treatment-related adverse events occurred in 12 % of patients with nivolumab versus 47 % with docetaxel, leading to discontinuation in 4 % and 5 % of patients, respectively. No new treatment-related deaths occurred. At 2 years, nivolumab maintained a favorable safety profile and continued to demonstrate superior OS versus docetaxel in this predominantly Chinese patient population with previously treated NSCLC. These data are consistent with long-term outcomes from the global CheckMate 017/057 studies.

Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho‐kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper‐responsiveness, β‐adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho‐kinase, cytokine and epigenetic regulation of RhoA/Rho‐kinase, and the role of RhoA/Rho‐kinase in regulating major features of asthma, such as airway hyper‐responsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho‐kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho‐kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho‐kinase signalling may be a promising therapeutic target for the treatment of asthma.

Objective: Germline alterations in the breast cancer susceptibility genes type 1 and 2, BRCA1 and BRCA2, predispose individuals to hereditary cancers, including breast, ovarian, prostate, pancreatic, and stomach cancers. Accumulating evidence suggests inherited genetic susceptibility to lung cancer. The present study aimed to survey the prevalence of pathogenic germline BRCA mutations (gBRCAm) and explore the potential association between gBRCAm and disease onset in Chinese advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 6,220 NSCLC patients were screened using capture-based ultra-deep targeted sequencing to identify patients harboring germline BRCA1/2 mutations. Results: Out of the 6,220 patients screened, 1.03% (64/6,220) of the patients harbored the pathogenic gBRCAm, with BRCA2 mutations being the most predominant mutations (49/64, 76.5%). Patients who developed NSCLC before 50 years of age were more likely to carry gBRCAm (P = 0.036). Among the patients harboring classic lung cancer driver mutations, those with concurrent gBRCAm were significantly younger than those harboring the wild-type gBRCA (P = 0.029). By contrast, the age of patients with or without concurrent gBRCAm was comparable to those of patients without the driver mutations (P = 0.972). In addition, we identified EGFR-mutant patients with concurrent gBRCAm who showed comparable progression-free survival but significantly longer overall survival (P = 0.002) compared to EGFR-mutant patients with wild-type germline BRCA. Conclusions: Overall, our study is the largest survey of the prevalence of pathogenic gBRCAm in advanced Chinese NSCLC patients. Results suggested a lack of association between germline BRCA status and treatment outcome of EGFR-TKI. In addition, results showed a positive correlation between pathogenic gBRCAm and an early onset of NSCLC.