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.
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.
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.
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.
MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that ate involved in the transcriptional and post-transcriptional regulation of gene expression. Recently, miRNAs were demonstrated to be ...effectively delivered to a target cell or tissue from a host cell via extracellular vesicles (EVs). These EVs can be detected in blood, urine, exhaled breath condensates, bronchoalveolar lavage fluid (BALF), and other fluids. miRNAs are generated by donor cells and then packaged into EVs and delivered with intact functionality. After being delivered to the target cells, they regulate the translation of their target genes and the function of the target cells. Thus, EV transported miRNAs have become a new method for intercellular communication. EV miRNA transfer is well-documented in various pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary hypertension, and acute lung injury (ALI). In this review, we summarize the novel findings of EV miRNA transfer, focusing on the roles of miR-210, miR-200, miR-17, miR-146a, miR-155, and other miRNAs that are transported from primary human bronchial epithelial cells (HBECs), BALF, mesenchymal stem cells, and dendritic cells.
It has been reported that up to 42% of the population aged over 60 are affected by mild cognitive impairment (MCI) worldwide. This study aims to investigate the prevalence and progression of MCI ...through a meta-analysis.
We searched Embase and PubMed for relevant literature. Stable disease rate (SR), reversion rate (RR), dementia rate (DR), and Alzheimer's disease rate (AR) were used to evaluate the progression of MCI. The prevalence and progression rates were both obtained by reported percentile and indirect data analysis. Additionally, we carried out sensitivity analysis of each index by excluding some studies due to influence analysis with the most publication bias.
Effect size (ES) was used to present adjusted overall prevalence (16%) and progression rates including SR (45%), RR (15%), DR (34%), and AR (28%) of MCI. Compared with clinic-based outcomes, MCI prevalence, SR, and RR are significantly higher in community, while DR and AR are lower. Despite significant heterogeneity found among the studies, no publication bias was observed.
Age and gender were observed to be associated with MCI, in which age was considered as an impact factor for DR. The strong heterogeneity may result from variations in study design and baselines. Standardized MCI criteria were suggested to systematically evaluate MCI in the future.
The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti–programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has ...revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP.
ORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People’s Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee.
Between September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 95% confidence interval: 0.422–0.681, p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively.
Regarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.
Lung cancer is one of the most lethal malignant tumors in the world. The high recurrence and mortality rate make it urgent for scientists and clinicians to find new targets for better treatment of ...lung cancer. Early studies indicated that estrogen receptor β (ERβ) might impact the progression of non-small-cell lung cancer (NSCLC). However, the detailed mechanisms, especially its linkage to the CXCR4-mediated cell invasion, remain unclear. Here we found that ERβ could promote NSCLC cell invasion via increasing the circular RNA (circRNA), circ-TMX4, expression via directly binding to the 5' promoter region of its host gene TMX4. ERβ-promoted circ-TMX4 could then sponge and inhibit the micro RNA (miRNA, miR), miR-622, expression, which can then result in increasing the CXCR4 messenger RNA translation via a reduced miRNA binding to its 3' untranslated region (3'UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of NSCLC cells confirmed the in vitro data, and the human NSCLC database analysis and tissue staining also confirmed the linkage of ERβ/miR-622/CXCR4 signaling to the NSCLC progression. Together, our findings suggest that ERβ can promote NSCLC cell invasion via altering the ERβ/circ-TMX4/miR-622/CXCR4 signaling, and targeting this newly circ-TMX4/miR-622/CXCR4 signaling may help us find new treatment strategies to better suppress NSCLC progression.
Neutrophil extracellular traps (NETs) facilitate the extracellular killing of pathogens. However, excessive NETs formation and poor degradation are associated with exacerbated immune responses and ...tissue injury. In this study, we investigated the role of NETs in lipopolysaccharide (LPS)-mediated acute lung injury (ALI) and assessed the use of DNase I, for the treatment of ALI. Additionally, we focused on the controversial issue of whether LPS directly induces NETs release in vitro. NETs formation was detected in murine ALI tissue in vivo and was associated with increased NETs markers, citrullinated-histone H3 tissue levels and NET-DNA levels in BALF. Treatment with DNase I significantly degraded NETs and reduced citrullinated-histone H3 levels, which protected against ALI and ameliorated pulmonary oedema and total protein in BALF. In addition, DNase I significantly reduced IL-6 and TNF-α levels in plasma and BALF. In vitro, LPS-activated platelets rather than LPS alone efficiently induced NETs release. In conclusion, NETs formed during LPS-induced ALI, caused organ damage and initiated the inflammatory response. NETs degradation by DNase I promoted NET-protein clearance and protected against ALI in mice; thus, DNase I may be a new potential adjuvant for ALI therapy. Specifically, LPS induced NETs formation in an indirect manner via platelets activation.
Steroid-resistant asthma is a troublesome clinical problem in public health. The pathogenesis of steroid-resistant asthma is complex and remains to be explored. In our work, the online Gene ...Expression Omnibus microarray dataset GSE7368 was used to explore differentially expressed genes (DEGs) between steroid-resistant asthma patients and steroid-sensitive asthma patients. Tissue-specific gene expression of DEGs was analyzed using BioGPS. The enrichment analyses were performed using GO, KEGG, and GSEA analysis. The protein-protein interaction network and key gene cluster were constructed using STRING, Cytoscape, MCODE, and Cytohubba. A steroid-resistant neutrophilic asthma mouse model was established using lipopolysaccharide (LPS) and ovalbumin (OVA). An LPS-stimulated J744A.1 macrophage model was prepared to validate the underlying mechanism of the interesting DEG gene using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 66 DEGs were identified, most of which were present in the hematologic/immune system. Enrichment analysis displayed that the enriched pathways were the IL-17 signaling pathway, MAPK signal pathway, Toll-like receptor signaling pathway, and so on. DUSP2, as one of the top upregulated DEGs, has not been clearly demonstrated in steroid-resistant asthma. In our study, we observed that the salubrinal administration (DUSP2 inhibitor) reversed neutrophilic airway inflammation and cytokine responses (IL-17A, TNF-α) in a steroid-resistant asthma mouse model. We also found that salubrinal treatment reduced inflammatory cytokines (CXCL10 and IL-1β) in LPS-stimulated J744A.1 macrophages. DUSP2 may be a candidate target for the therapy of steroid-resistant asthma.
Neutrophils activated during acute lung injury (ALI) form neutrophil extracellular traps (NETs) to capture pathogens. However, excessive NETs can cause severe inflammatory reactions. Macrophages are ...classified as M1 macrophages with proinflammatory effects or M2 macrophages with anti-inflammatory effects. During ALI, alveolar macrophages (AMs) polarize to the M1 phenotype. This study tested the hypothesis that NETs may aggravate ALI or acute respiratory distress syndrome (ARDS) inflammation by promoting alveolar macrophage polarization to the M1 type. Our research was carried out in three aspects: clinical research, animal experiments and in vitro experiments. We determined that NET levels in ARDS patients were positively correlated with M1-like macrophage polarization. NET formation was detected in murine ALI tissue and associated with increased M1 markers and decreased M2 markers in BALF and lung tissue. Treatment with NET inhibitors significantly inhibitor NETs generation, downregulated M1 markers and upregulated M2 markers. Regardless of LPS pre-stimulation, significant secretion of proinflammatory cytokines and upregulated M1 markers were detected from bone marrow-derived macrophages (M0 and M2) cocultured with high concentrations of NETs; conversely, M2 markers were downregulated. In conclusion, NETs promote ARDS inflammation during the acute phase by promoting macrophage polarization to the M1 phenotype. We propose that NETs play an important role in the interaction between neutrophils and macrophages during the early acute phase of ALI.
Asthma is a complex airway inflammatory disease that can be roughly classified into eosinophilic phenotype and non-eosinophilic phenotype. Most of the latter manifested as airway inflammation ...dominated by neutrophil infiltration, namely neutrophil-dominated asthma (NA). Neutrophil extracellular trapping (NETs) is a newly discovered antimicrobial mechanism of neutrophils; however, NETs can not only resist killing pathogenic microorganisms, but also promote tissue damage and autoimmune response. In the present study, we successfully established NA model in C57BL/6 mice and observed the increased formation of NETs. In NA mice, the free DNA abundance, the airway resistance, the cell numbers (total cell number, macrophage number, and neutrophil number), and inflammatory cytokine levels were significantly increased while the lung dynamic compliance was significantly reduced. After DNase I treatment, the above indexes in NA mice were all improved. In NA mice, either treatment with macrophage scavenger or IL-1β neutralizing antibody also improved the above-described indexes. In vitro, in human peripheral blood-derived neutrophils, PMA treatment significantly increased the formation of NETs. Furthermore, in macrophages differentiated from THP-1 monocytes, LPS or isolated NETs both significantly increased the levels of cytokines. In conclusion, NETs can stimulate macrophages to secrete IL-1β, which promotes neutrophils infiltration in the airway; infiltrated neutrophils, in turn, generates NETs, which can amplify the tissue damage caused by NETs and macrophages, inducing and aggravating NA.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Curcumin is a major yellow pigment and active component of turmeric widely used as dietary spice and herbal medicine. This compound has been reported to be a promising antitumor agent, although the ...underlying molecular mechanisms are not fully understood yet. In this study, we reported that curcumin inhibited growth of lung adenocarcinoma cells, but had no cytotoxic activity to IMR-90 normal lung fibroblast cells. Curcumin induced autophagy in the A549 human lung adenocarcinoma cell line, evidenced by LC3 immunofluorescence analysis and immunoblotting assays on LC3 and SQSTM1. Moreover, the autophagy inhibitor 3-MA partly blocked the inhibitory effect of curcumin on the growth of A549 cells. Curcumin markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetylCoA carboxylase in A549 cells. At last, pharmacological blockade of the AMPK signaling pathway by compound C and genetic disruption of the AMPK signaling pathway with siRNA-mediated AMPKα1 knockdown impaired the autophagy-inducing effect of curcumin. Collectively, our data suggests that curcumin induces autophagy via activating the AMPK signaling pathway and the autophagy is important for the inhibiting effect of curcumin in lung adenocarcinoma cells.
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