PPARγ attenuates cellular senescence of alveolar macrophages in asthma-COPD overlap.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) represents a complex condition characterized by shared clinical and pathophysiological features of asthma and COPD in older individuals. However, the pathophysiology of ACO remains unexplored. We aimed to identify the major inflammatory cells in ACO, examine senescence within these cells, and elucidate the genes responsible for regulating senescence. METHODS: Bioinformatic analyses were performed to investigate major cell types and cellular senescence signatures in a public single-cell RNA sequencing (scRNA-Seq) dataset derived from the lung tissues of patients with ACO. Similar analyses were carried out in an independent cohort study Immune Mechanisms Severe Asthma (IMSA), which included bulk RNA-Seq and CyTOF data from bronchoalveolar lavage fluid (BALF) samples. RESULTS: The analysis of the scRNA-Seq data revealed that monocytes/ macrophages were the predominant cell type in the lung tissues of ACO patients, constituting more than 50% of the cells analyzed. Lung monocytes/macrophages from patients with ACO exhibited a lower prevalence of senescence as defined by lower enrichment scores of SenMayo and expression levels of cellular senescence markers. Intriguingly, analysis of the IMSA dataset showed similar results in patients with severe asthma. They also exhibited a lower prevalence of senescence, particularly in airway CD206 + macrophages, along with increased cytokine expression (e.g., IL-4, IL-13, and IL-22). Further exploration identified alveolar macrophages as a major subtype of monocytes/macrophages driving cellular senescence in ACO. Differentially expressed genes related to oxidation-reduction, cytokines, and growth factors were implicated in regulating senescence in alveolar macrophages. PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) emerged as one of the predominant regulators modulating the senescent signature of alveolar macrophages in ACO. CONCLUSION: The findings suggest that senescence in macrophages, particularly alveolar macrophages, plays a crucial role in the pathophysiology of ACO. Furthermore, PPARγ may represent a potential therapeutic target for interventions aimed at modulating senescence-associated processes in ACO.Key words ACO, Asthma, COPD, Macrophages, Senescence, PPARγ.

Leptin/obR signaling exacerbates obesity-related neutrophilic airway inflammation through inflammatory M1 macrophages.

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.

Usefulness of candidate mRNAs and miRNAs as biomarkers for mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: To explore potential molecular mechanisms and novel biomarkers of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: The mRNA expression datasets GSE63060 and GSE63061 and the miRNA expression dataset GSE120584 were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and miRNA (DEmiRs) were identified in the normal, MCI, and AD groups. Mfuzz clustering and weighted correlation network analyses (WGCNA) were conducted, followed by pathway and functional enrichment analyses and miRNA-mRNA network construction. Furthermore, phenotypic correlation analysis and experimental verification were performed on key DEGs and DEmiRs. RESULTS: In total, 3,000 intersected DEGs from GSE63060/GSE63061 and 817 DEmiRs from GSE120584 were obtained. Mfuzz and WGCNA analyses revealed 106 DEGs including ribosomal protein L11 (RPL11) and 28 DEmiRs including miR-6764-5p. These DEGs and DEmiRs were mainly enriched in pathways like Ribosome. Moreover, 5 key DEGs including cytohesin 4 (CYTH4) and 6 crucial DEmiRs including miR-6734-3p were identified by miRNA-mRNA interaction network analysis. Phenotypic correlation analysis showed that CYTH4 and miR-6734-3p were correlated with patients' age. The results of quantitative polymerase chain reaction analysis confirmed that RPL11 expression was significantly downregulated in the MCI and AD groups compared to that in the normal group, while the expression of CYTH4, miR-6764-5p, and miR-6734-3p was remarkably upregulated in the MCI and AD groups. CONCLUSIONS: miR-6764-5p might contribute to MCI and AD by targeting RPL11 in the ribosome pathway. Therefore, miR-6734-3p and its target mRNA CYTH4 might be used as novel biomarkers for MCI and AD.

MASH1 induces neuron transdifferentiation of adrenal medulla chromaffin cells. / MASH1ä»‹å¯¼è‚¾ä¸Šè ºé«“è´¨å—œé“¬ç»†èƒžå‘ç”Ÿç¥žç»å ƒè½¬åˆ†åŒ–.

OBJECTIVES: Nerve growth factor (NGF) induces neuron transdifferentiation of adrenal medulla chromaffin cells (AMCCs) and consequently downregulates the secretion of epinephrine (EPI), which may be involved in the pathogenesis of bronchial asthma. Mammalian achaete scute-homologous 1 (MASH1), a key regulator of neurogenesis in the nervous system, has been proved to be elevated in AMCCs with neuron transdifferentiation in vivo. This study aims to explore the role of MASH1 in the process of neuron transdifferentiation of AMCCs and the mechanisms. METHODS: Rat AMCCs were isolated and cultured. AMCCs were transfected with siMASH1 or MASH1 overexpression plasmid, then were stimulated with NGF and/or dexamethasone, PD98059 (a MAPK kinase-1 inhibitor) for 48 hours. Morphological changes were observed using light and electron microscope. Phenylethanolamine-N-methyltransferase (PNMT, the key enzyme for epinephrine synthesis) and tyrosine hydroxylase were detected by immunofluorescence. Western blotting was used to test the protein levels of PNMT, MASH1, peripherin (neuronal markers), extracellular regulated protein kinases (ERK), phosphorylated extracellular regulated protein kinases (pERK), and JMJD3. Real-time RT-PCR was applied to analyze the mRNA levels of MASH1 and JMJD3. EPI levels in the cellular supernatant were measured using ELISA. RESULTS: Cells with both tyrosine hydroxylase and PNMT positive by immunofluorescence were proved to be AMCCs. Exposure to NGF, AMCCs exhibited neurite-like processes concomitant with increases in pERK/ERK, peripherin, and MASH1 levels (all P<0.05). Additionally, impairment of endocrine phenotype was proved by a signifcant decrease in the PNMT level and the secretion of EPI from AMCCs (all P<0.01). MASH1 interference reversed the effect of NGF, causing increases in the levels of PNMT and EPI, conversely reduced the peripherin level and cell processes (all P<0.01). MASH1 overexpression significantly increased the number of cell processes and peripherin level, while decreased the levels of PNMT and EPI (all P<0.01). Compared with the NGF group, the levels of MASH1, JMJD3 protein and mRNA in AMCCs in the NGF+PD98059 group were decreased (all P<0.05). After treatment with PD98059 and dexamethasone, the effect of NGF on promoting the transdifferentiation of AMCCs was inhibited, and the number of cell processes and EPI levels were decreased (both P<0.05). In addition, the activity of the pERK/MASH1 pathway activated by NGF was also inhibited. CONCLUSIONS: MASH1 is the key factor in neuron transdifferentiation of AMCCs. NGF-induced neuron transdifferentiation is probably mediated via pERK/MASH1 signaling.

Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with poor prognosis and treatment options are scarce. Immunotherapy has shown robust clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with standard chemotherapy as a first-line treatment for ES-SCLC. METHODS: The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18-75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305. FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI 0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death). INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals.

MicroRNA Expression Profiles of Epicardial Adipose Tissue-Derived Exosomes in Patients with Coronary Atherosclerosis.

Background and Aims: Epicardial adipose tissue, exosomes, and miRNAs have important activities in atherosclerosis. The purpose of this study was to establish miRNA expression profiles of epicardial adipose tissue-derived exosomes in patients with coronary atherosclerosis. Methods: Biopsies of epicardial adipose tissue were obtained from patients with and without coronary artery disease (CAD, n = 12 and NCAD, n = 12) during elective open-heart surgeries. Tissue was incubated with DMEM-F12 for 24 hours. Exosomes were isolated, then nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting were performed to confirm the existence of exosomes. Total RNA in exosomes was subjected to high-throughput sequencing to identify differentially expressed miRNAs. MicroRNA target gene prediction was performed, and target genes were analyzed by Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and mirPath to identify function. Reverse transcription quantitative PCR was performed to confirm the differentially expressed miRNAs. Results: Fifty-three unique miRNAs were identified (adjusted p < 0.05, fold of change > 2), among which 32 miRNAs were upregulated and 21 miRNAs were downregulated in coronary artery disease patients. Reverse transcription quantitative PCR validated the results for seven miRNAs including miR-141-3p, miR-183-5p, miR-200a-5p, miR-205-5p, miR-429, miR-382-5p and miR-485-3p, with the last two downregulated. GO and KEGG analysis by mirPath indicated that these differentially expressed miRNAs were enriched in cell survival, apoptosis, proliferation, and differentiation. Conclusions: Coronary artery disease patients showed differential epicardial adipose tissue exosomal miRNA expression compared with patients without coronary artery disease. The results provide clues for further studies of mechanisms of atherosclerosis.

Overexpression of the SARS-CoV-2 receptor ACE2 is induced by cigarette smoke in bronchial and alveolar epithelia.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a target for disease prevention. However, the relationship between ACE2 expression and its clinical implications in SARS-CoV-2 pathogenesis remains unknown. Here, we explored the location and expression of ACE2, and its correlation with gender, age, and cigarette smoke (CS), in a CS-exposed mouse model and 224 non-malignant lung tissues (125 non-smokers, 81 current smokers, and 18 ex-smokers) by immunohistochemistry. Moreover, the correlations of ACE2 with CS-induced oxidative stress-related markers, hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), and 4-hydroxynonenal (4-HNE) were investigated. Chromatin immunoprecipitation and luciferase reporter assays identified the cause of ACE2 overexpression in human primary lung epithelial cells. We demonstrated that ACE2 was predominantly overexpressed on the apical surface of bronchial epithelium, while reduced in alveolar epithelium, owing to the dramatically decreased abundance of alveolar type II pneumocytes in CS-exposed mouse lungs. Consistent with this, ACE2 was primarily significantly overexpressed in human bronchial and alveolar epithelial cells in smokers regardless of age or gender. Decreased ACE2 expression was observed in bronchial epithelial cells from ex-smokers compared with current smokers, especially in those who had ceased smoking for more than 10 years. Moreover, ACE2 expression was positively correlated with the levels of HIF-1α, iNOS, and 4-HNE in both mouse and human bronchioles. The results were further validated using a publicly available dataset from The Cancer Genome Atlas (TCGA) and our previous integrated data from Affymetrix U133 Plus 2.0 microarray (AE-meta). Finally, our results showed that HIF-1α transcriptionally upregulates ACE2 expression. Our results indicate that smoking-induced ACE2 overexpression in the apical surface of bronchial epithelial cells provides a route by which SARS-CoV-2 enters host cells, which supports clinical relevance in attenuating the potential transmission risk of COVID-19 in smoking populations by smoking cessation. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD-L1-positive locally advanced or metastatic non-small-cell lung cancer: KEYNOTE-042 China Study.

In the global KEYNOTE-042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD-L1)-positive locally advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE-042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD-L1 tumor proportion score [TPS] ≥50% vs 1%-49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty-two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow-up, 33.0 [range, 25.6-41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD-L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43-0.94]), TPS ≥20% (0.66 [0.47-0.92]) and TPS ≥1% (0.67 [0.50-0.89]). Grade 3 to 5 treatment-related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE-042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD-L1 TPS ≥1%, supporting first-line pembrolizumab monotherapy for PD-L1-positive advanced/metastatic NSCLC in China.

Triglyceride-glucose index is associated with in-stent restenosis in patients with acute coronary syndrome after percutaneous coronary intervention with drug-eluting stents.

BACKGROUND: The triglyceride-glucose (TyG) index is an alternative marker of insulin resistance (IR) and is closely associated with the prevalence and prognosis of atherosclerotic cardiovascular disease (ASCVD). However, the association between the TyG index and in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with acute coronary syndrome (ACS) remains unknown. METHODS: The present study retrospectively recruited patients who were admitted for ACS and underwent coronary angiography at 6 to 24 months after successful DES-based percutaneous coronary intervention (PCI). In addition, we calculated the TyG index with the following formula: Ln(fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2) and divided patients into 3 groups according to the tertile of the TyG index. Most importantly, multivariate logistic regression analysis models were also constructed to assess the association between the TyG index and DES-ISR in patients with ACS. RESULTS: A total of 1574 patients with ACS (58.4 ± 9.4 years, 77.4% male) were included in this study. At the median follow-up time of 12 (9-14) months, the prevalence of DES-ISR increased stepwise with the increasing tertile of the TyG index (11.6% vs 17.3% vs 19.4%, p = 0.002), and the TyG index was also higher in the ISR group than in the non-ISR group (9.00 ± 0.58 vs 8.84 ± 0.61, p < 0.001). In addition, the positive association between the TyG index and the prevalence of DES-ISR was also determined in the fully adjusted model (TyG, per 1-unit increase: OR 1.424, 95% CI 1.116 to 1.818, p = 0.005; tertile of TyG, the OR (95% CI) values for tertile 2 and tertile 3 were 1.454 (1.013 to 2.087) and 1.634 (1.125 to 2.374), respectively, with tertile 1 as a reference). The association was also reflected in most subgroups. Moreover, adding the TyG index to the predictive model for DES-ISR in patients with ACS could contribute to an increase in C-statistics (0.675 vs 0.659, p = 0.010), categorical net reclassification improvement (0.090, p < 0.001), and integrated discrimination improvement (0.004, p = 0.040). CONCLUSION: An elevated TyG index was independently and positively associated with DES-ISR in patients with ACS who underwent PCI. However, the incremental predictive value of the TyG index for DES-ISR was slight. To further confirm our findings, future studies are needed.

Neutrophil Extracellular Trapping Network Promotes the Pathogenesis of Neutrophil-associated Asthma through Macrophages.

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-1ß 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-1ß, 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.

Profilin 1 Protein and Its Implications for Cancers.

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes. PFN1 was first identified as a G-actin sequestering molecule, and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed. In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain, a poly-L-proline (PLP)-binding domain, and a phosphoinositide-binding domain. PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis) and some chronic (eg, hypertension). In the past 10 years, PFN1's role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Association between the triglyceride glucose index and coronary collateralization in coronary artery disease patients with chronic total occlusion lesions.

BACKGROUND: Recent studies have substantiated the role of the triglyceride glucose (TyG) index in predicting the prognosis of coronary artery disease (CAD) patients, while no relevant studies have revealed the association between the TyG index and coronary collateralization in the event of coronary chronic total occlusion (CTO). The current study intends to explore whether, or to what extent, the TyG index is associated with impaired collateralization in CAD patients with CTO lesions. METHODS: The study enrolled 1093 CAD patients undergoing cardiac catheterization for at least one CTO lesion. Data were collected from the Beijing Anzhen Hospital record system. The degree of collaterals was determined according to the Rentrop classification system. The correlation between the TyG index and coronary collateralization was assessed. RESULTS: Overall, 318 patients were included in a less developed collateralization (Rentrop classification 0-1) group. The TyG index was significantly higher in patients with impaired collateralization (9.3±0.65 vs. 8.8±0.53, P<0.001). After adjusting for various confounding factors, the TyG index remained correlated with the occurrence of impaired collateralization, with odds ratios (ORs) of 1.59 and 5.72 in the T2 and T3 group compared with the first tertile group (P<0.001). In addition, subgroup analysis showed that higher TyG index values remained strongly associated with increased risk of less developed collateralization. To compare the risk assessment efficacy for the formation of collateralization between the TyG index and other metabolic abnormality indicators, an area under the receiver-operating characteristic (ROC) curve (AUC) was obtained. A significant improvement in the risk assessment performance for impaired collateralization emerged when adding the TyG index into a baseline model. CONCLUSIONS: The increased TyG index is strongly associated with less developed collateralization in CAD patients with CTO lesions and its risk assessment performance is better than single metabolic abnormality indicators.

Serum adropin level is associated with endothelial dysfunction in patients with obstructive sleep apnea and hypopnea syndrome.

OBJECTIVE: Adropin is a recently discovered peptide hormone that plays a vital role in metabolism and cardiovascular-cerebrovascular function. The purpose of this study is to investigate the role of circulating adropin levels in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and further determine the relationship between serum adropin concentration and endothelial dysfunction in patients with OSAHS. METHODS: Forty polysomnography-diagnosed patients with OSAHS and 21 age and sex-matched healthy controls were enrolled in the current study. Serum adropin level, endothelial function parameters including flow-mediated dilatation (FMD) of brachial artery, endothelin-1 (ET-1), and nitric oxide (NO) were measured in all participants. RESULTS: Serum adropin levels were significantly lower in patients with OSAHS compared to the control subjects. FMD was lower and serum ET-1 levels were higher in patients with OSAHS compared to control subjects. No significant difference was seen in serum NO levels between the two groups. Multivariate linear regression analysis revealed that serum adropin level was positively associated with FMD and negatively correlated with AHI. Additionally, serum adropin levels were lower in patients with OSAHS who had endothelial dysfunction compared with those patients without endothelial dysfunction. The receiver operating characteristic (ROC) analysis showed that area under the curve (AUC) for serum adropin in predicting endothelial dysfunction status in patients with OSAHS was 0.815 (95% CI 0.680-0.951, p = 0.001). The cutoff value of serum adropin level was less than 235.0 pg/mL, which provided the sensitivity and specificity of 81% and 75%, respectively, for the detection of endothelial dysfunction in patients with OSAHS. CONCLUSION: Lower circulating adropin levels are closely associated with endothelial dysfunction in patients with OSAHS. Circulating adropin level may serve as an early biomarker to predict the development of endothelial dysfunction before the emergence of clinical symptoms in patients with OSAHS.

Correlation between sleep characteristics and cognitive decline in the elderly people: A cross-sectional study in China.

STUDY OBJECTIVES: In this study, we conducted a cross-sectional analysis of the sleep characteristics in the elderly Chinese people to comprehensively investigate the association between sleep and cognitive function in the elderly people. We aimed to evaluate the most important demographic factors, conventional physiological indices and living habits that may influence sleep. METHODS: We surveyed 2901 elderly people (age ≥60 years old) face-to-face from 1 July to 31 December 2017, who were recruited from 17 communities of the Pudong New Area (Shanghai, China) by probability proportional to size. The Pittsburgh sleep quality index (PSQI) scale was used to describe the sleep features of each participant. Cognitive assessment was performed using the mini-mental state examination (MMSE) scale, Montreal cognitive assessment (MoCA) and the clinical dementia rating (CDR) scale. Those factors which potentially influence sleep and consequentially may impact cognition in the elderly people were evaluated, and the correlations of sleep characteristics and cognitive function were explored by the linear regression analysis. RESULTS: Altogether, there were 1287 (44.4%) people taking part in the investigation. Sleep quality was significantly correlated with MMSE and MoCA total scores. Healthy sleep (especially enough sleep) was correlated with better cognitive functions. Besides recognised relative factors (such as age, sex and living alone), the number of children was found to be a strong risk factor of poor sleep. Anxiety before sleep and light/noise interference significantly damaged sleep while an exercise routine was associated with better sleep. Moderate levels of reading, watching TV and household work were correlated with superior sleep quality. CONCLUSION: In conclusion, sleep characteristics correlate with cognitive decline in the elderly people, and they can be influenced by multiple demographic factors and living habits. To improve sleep quality, it may be important to change sleep environment, to be relax, to increase physical exercise and recreational activities moderately.

Investigation of risk factors for the conversion of mild cognitive impairment to dementia.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia and is characterized by pathological cognitive decline. The study aimed at revealing the risk of MCI progressing to dementia through a follow-up investigation. METHODS: In 2011, 441 MCI subjects were recruited, and the disease status was tracked by the follow-up survey in 2017. Subjects with MCI stable (MCIs; N = 356) and MCI progressed into dementia (MCIp; N = 77) were analysed in our study. Community-dwelling old people of age ≥ 55 were recruited from 30 streets and 24 committees (or communities) of the Pudong New District (Shanghai, China). Neuropsychological tests of MMSE, MoCA, 17-item HAMD-17, ADL and HIS were performed. Additionally, the correlations of neuropsychological items and MCIp were explored by univariate and multivariate regression analyses. RESULTS: MCIp patients had the lower MMSE and MoCA total scores, whereas the ADL, and HIS total score in MCIp group were higher than in MCIs group. The univariate analysis revealed age, attention (MoCA), visuospatial/executive, number of births, marital status and attention and calculation were significant predictors of MCI progression. In multivariate analysis, age was an independent risk factor of MCI aggravating, while attention (MoCA) was independent protective factor for MCI progression. CONCLUSIONS: Age and worsening attention but not depression in MCI patients were independently associated with the progression of dementia in a 6-year follow-up period.

Discordance between the triglyceride glucose index and fasting plasma glucose or HbA1C in patients with acute coronary syndrome undergoing percutaneous coronary intervention predicts cardiovascular events: a cohort study from China.

BACKGROUND: Previous studies have investigated the relationship of the triglyceride glucose (TyG) index with the incidence of cardiovascular events. However, to date, there have been no studies comparing the predictive values of fasting plasma glucose (FPG), glycosylated hemoglobin A (HbA1C) and the TyG index for the risk of cardiovascular events. This study aimed to use discordance analysis to evaluate and compare the effectiveness of FPG, HbA1C and the TyG index to predict the risk of cardiovascular events. METHODS: Patients diagnosed with acute coronary disease (ACS) undergoing percutaneous coronary intervention (PCI) were enrolled in this study. The TyG index was computed using the following formula: ln [fasting triglycerides (mg/dL) × FPG (mg/dL)/2]. We categorized patients into 4 concordance/discordance groups. Discordance was defined as a TyG index equal to or greater than the median and an FPG or HbA1C less than the median, or vice versa. The primary outcome was the composite of death, nonfatal myocardial infarction, nonfatal stroke and unplanned repeat revascularization. A Cox proportional hazards regression model was performed to estimate the risk of cardiovascular events according to the concordance/discordance groups. Sensitivity analysis was performed on each patient group divided into high or low categories for HbA1C or FPG and were repeated according to diabetes status. RESULTS: In total, 9285 patients were included in the final statistical analysis (male: 75.3%, age: 59.9 ± 10.05 years, BMI: 26.2 ± 9.21 kg/m2, diabetes: 43.9% and dyslipidemia: 76.8%). The medians defining concordance/discordance were 6.19 mmol/L for FPG, 6.1% for HbA1C and 8.92 for the TyG index. The TyG index was strongly related to triglycerides and HDL-C (r = 0.881 and -0.323, respectively; both P < 0.001). During the 17.4 ± 2.69 months of follow-up, there were 480 (5.1%) incident cardiovascular events. Among patients with a lower HbA1C or FPG, 15.6% and 16.3%, respectively, had a discordantly high TyG index and a greater risk of cardiovascular events compared with patients with a concordantly low TyG index after full adjustment (HR: 1.92, 95% CI 1.33-2.77; HR: 1.89, 95% CI 1.38-2.59; for HbA1C and FPG, respectively). Repeat risk estimation using high or low categories for FPG or HbA1C and diabetes status confirmed the results. CONCLUSIONS: Patients with a discordantly high TyG index had a significantly greater risk of cardiovascular events regardless of diabetes status. The TyG index might be a better predictor of cardiovascular risk than FPG or HbA1C for patients with ACS undergoing PCI. This discordance may support better cardiovascular risk management regardless of diabetes status.

miR-155 Modulates Cockroach Allergen- and Oxidative Stress-Induced Cyclooxygenase-2 in Asthma.

Exposure to cockroach allergen is a strong risk factor for developing asthma. Asthma has been associated with allergen-induced airway epithelial damage and heightened oxidant stress. In this study, we investigated cockroach allergen-induced oxidative stress in airway epithelium and its underlying mechanisms. We found that cockroach extract (CRE) could induce reactive oxygen species (ROS) production, particularly mitochondrial-derived ROS, in human bronchial epithelial cells. We then used the RT2 Profiler PCR array and identified that cyclooxygenase-2 (COX-2) was the most significantly upregulated gene related to CRE-induced oxidative stress. miR-155, predicted to target COX-2, was increased in CRE-treated human bronchial epithelial cells, and was showed to regulate COX-2 expression. Moreover, miR-155 can bind COX-2, induce COX-2 reporter activity, and maintain mRNA stability. Furthermore, CRE-treated miR-155-/- mice showed reduced levels of ROS and COX-2 expression in lung tissues and PGE2 in bronchoalveolar lavage fluid compared with wild-type mice. These miR-155-/- mice also showed reduced lung inflammation and Th2/Th17 cytokines. In contrast, when miR-155-/- mice were transfected with adeno-associated virus carrying miR-155, the phenotypic changes in CRE-treated miR-155-/- mice were remarkably reversed, including ROS, COX-2 expression, lung inflammation, and Th2/Th17 cytokines. Importantly, plasma miR-155 levels were elevated in severe asthmatics when compared with nonasthmatics or mild-to-moderate asthmatics. These increased plasma miR-155 levels were also observed in asthmatics with cockroach allergy compared with those without cockroach allergy. Collectively, these findings suggest that COX-2 is a major gene related to cockroach allergen-induced oxidative stress and highlight a novel role of miR-155 in regulating the ROS-COX-2 axis in asthma.

Diminished stimulator of interferon genes production with cigarette smoke-exposure contributes to weakened anti-adenovirus vectors response and destruction of lung in chronic obstructive pulmonary disease model.

Cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD) and dampens antiviral response, which increases viral infections and leads to COPD acute exacerbation (AECOPD). Adenovirus, a nonenveloped DNA virus, is linked with AECOPD, whose DNAs trigger innate immune response via interacting with pattern recognition receptors (PRRs). Stimulator of interferon genes (STING), as a cytosolic DNA sensor, participates in adenovirus-induced interferon ß (IFNß)-dependent antiviral response. STING is involved in various pulmonary diseases, but role of STING in pathogenesis of AECOPD is not well documented. In the present study, we explored relationship between STING and AECOPD induced by recombinant adenovirus vectors (rAdVs) and CS in wild type (WT) and STING-/- mice; and also characterized the inhibition of STING- IFNß pathway in pulmonary epithelium exposed to cigarette smoke extract (CSE). We found that CS or CSE exposure alone dramatically inhibited STING expression, but not significantly effected IFNß production. Moreover, CS or CSE-exposed significantly suppressed activation of STING-IFNß pathway induced by rAdVs and suppressed clearance of rAdVs DNA. Inflammation, fibrosis and emphysema of lung tissues were exaggerated when treated with CS plus rAdVs, which further deteriorate in absences of STING. In A549 cells with knockdown of STING, we also observed enhancing apoptosis related to emphysema, especially CSE and adenovirus vectors in combination. Therefore, STING may play a protective role in preventing the progress of COPD.

NETs promote ALI/ARDS inflammation by regulating alveolar macrophage polarization.

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.