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Background Metabolic syndrome (Mets) is prevalent in the general population and has been reported to be an independent risk factor for cognitive impairment. This study aimed to investigate the association of Mets with the risk of cognitive impairment. Methods We studied 5854 participants from the Jidong community. Cognitive function was assessed by the Mini-Mental State of Examination (MMSE) scale. Mets was diagnosed according to the International Diabetes Federation criteria. We used logistic regression analysis to investigate the association of metabolic syndrome with the risk of cognitive impairment. Result Among the 5854 adults included in the study, the age mean (SD) of age was 44 (13.57) years, and 2916 (50.34%) were male. There was a higher (56.03%) cognitive impairment incidence rate among participants with Mets than among those without Mets. In addition, there was a significant association between Mets and cognitive impairment (OR: 2.39, 95% CI: 2.00–2.86, P P P P Conclusion Our study suggested that Mets was associated with cognitive impairment and that abdominal obesity and hypertension were associated with an increased risk of cognitive impairment.

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.

Objective. The present study aimed to explore the association between SUA and NAFLD in women with different menstrual statuses. Methods. A total of 6043 women were selected from the Jidong and Kailuan communities for inclusion in the present study. The SUA levels of participants were divided into quartiles. NAFLD was determined by abdominal ultrasonography. Data from laboratory tests and clinical examination were collected, and basic information was obtained from standardized questionnaires. The menstrual status was stratified into menstrual period, menopause transition period, and postmenopause. Multivariate logistic regression models were used to determine the relationship between menstrual status, SUA, and NAFLD. Results. The levels of SUA in subjects with NAFLD in the menstrual period, menopause transition period, and postmenopause were 268.0 ± 71.1, 265.6 ± 67.8, and 286.7 ± 75.8 (mmol/L), respectively, and were higher than those in subjects without NAFLD. The adjusted odds ratios (ORs) with 95% confidence interval (CI) for NAFLD among participants in the menopause transition period and postmenopausal period were 1.10 (0.89–1.37) and 1.28 (1.04–1.58), respectively, compared with the menstrual period women. Compared to the lowest quartile of SUA, the adjusted ORs with 95% CI of the highest quartile for NAFLD were 2.24 (1.69–2.99) for females in the menstrual period, 1.92 (1.10–3.37) for females in the menopause transition period, and 1.47 (1.06–2.03) for females in postmenopause. Conclusions. Menstrual status was significantly correlated with NAFLD. High levels of SUA were associated with NAFLD in females during the three menstrual periods.

Background: Glioma is the most common primary tumor of the central nervous system and is associated with poor overall survival, creating an urgent need to identify survival-associated biomarkers. C1ORF112, an alpha-helical protein, is overexpressed in some cancers; however, its prognostic role has not yet been explored in gliomas. Thus, in this study, we attempted to address this by determining the prognostic value and potential function of C1ORF112 in low-grade gliomas (LGGs).Methods: The expression of C1ORF112 in normal and tumor tissues was analyzed using data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Oncomine, and Rembrandt databases. The genetic changes of C1ORF112 in LGG were analyzed using cBioPortal. Survival analysis was used to evaluate the relationship between C1ORF112 expression and survival in patients with LGG. Correlation between immune infiltration and C1ORF112 expression was determined using Timer software. Additionally, data from three online platforms were integrated to identify the co-expressed genes of C1ORF112. The potential biological functions of C1ORF112 were investigated by enrichment analysis.Results: C1ORF112 mRNA was highly expressed in LGGs (p < 0.01). Area under the ROC curve (AUC) showed that the expression of C1ORF112 in LGG was 0.673 (95% confidence interval [CI] = 0.618–0.728). Kaplan-Meier survival analysis showed that patients with high C1ORF112 expression had lower OS than patients with low C1ORF112 expression (p < 0.05). Multivariate analysis showed that high expression of C1ORF112 was an independent prognostic factor for the overall survival in patients from TCGA and CGGA databases. C1ORF112 expression was positively correlated with six immunoinfiltrating cells (all p < 0.001). The enrichment analysis suggested the enrichment of C1ORF112 and co-expressed genes in cell cycle and DNA replication.Conclusion: This study suggested that C1ORF112 may be a prognostic biomarker and a potential immunotherapeutic target for LGG.

BackgroundSystemic lupus erythematosus (SLE) affects many organs and systems of the human organism, at present, its specific pathogenesis is not completely clear, but inflammation is considered to be an important factor involved in the pathogenesis and progression of SLE. Gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) have different effects on inflammation: GGT has pro-inflammatory effects, on the contrary, TBIL has anti-inflammatory effects. Study has found that GGT and TBIL play opposite roles in metabolic diseases. However, the roles of them in SLE are unknown. Meanwhile, the relationship between GGT and SLE also remains unexplored.MethodWe recruited 341 SLE patients and 332 healthy individuals in Liaocheng People’s Hospital from August 2018 to May 2019. We diagnosed SLE using 2019 revised American College of Rheumatology (ACR) SLE criteria, and modeled the study outcomes using logistic regression to explore the respective relationship between GGT, TBIL and SLE. We also analyzed the interaction of GGT and TBIL in the progression of SLE.ResultsWe found that the levels of CRP, IL-6 and TNF-α in the aggravated group were significantly higher than those in the unaggravated group, the levels of C3 and C4 in the aggravated group were significantly lower than those in the unaggravated group. According to Spearman correlation analysis, GGT is proportional to CRP (rs=0.417) and IL-6 (rs=0.412), inversely proportional to C3 (rs=-0.177) and C4 (rs=0.-132). TBIL was inversely proportional to CRP (rs=-0.328) and TNF(rs=-0.360), and positively proportional to C3 (rs=0.174) and C4 (rs=0.172). In the fully adjusted model, compared to the lowest quartile, the highest quartile of GGT exhibited a positive association with the risk of SLE aggravation (OR=2.99, 95% CI: 1.42–6.31, PPP for interaction COMBINED=0.711) of high GGT level and TBIL were higher than their respective values (AUCGGT=0.612, AUCTBIL=0.614).ConclusionWe found that the effects of GGT and TBIL in the progression of SLE are opposite. High GGT level might be a risk factor for SLE aggravation, as GGT levels increased, so did the risk of SLE aggravation. At the same time, we found that low TBIL level might be a risk factor for SLE aggravation. Moreover, high GGT level and low TBIL level had a subadditive effect on the increased risk of SLE aggravation.

BackgroundDynamic D-dimer level is a key biomarker for the severity and mortality of COVID-19 (coronavirus disease 2019). How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists.MethodsWe performed meta-analysis and meta regression to analyze the associations of plasma D-dimer with 106 clinical variables to identify a panoramic view of the derangements of fibrinolysis in 14,862 patients of 42 studies. There were no limitations of age, gender, race, and country. Raw data of each group were extracted separately by two investigators. Individual data of case series, median and interquartile range, and ranges of median or mean were converted to SDM (standard deviation of mean).FindingsThe weighted mean difference of D-dimer was 0.97 µg/mL (95% CI 0.65, 1.29) between mild and severe groups, as shown by meta-analysis. Publication bias was significant. Meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels. Of these, 11 readouts were negatively related to the level of plasma D-dimer. Further, age and gender were confounding factors. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN (blood urea nitrogen), bilirubin, ALT (alanine aminotransferase), AST (aspartate aminotransferase), systolic blood pressure, and CK (creatine kinase).InterpretationThese findings support elevated D-dimer as an independent predictor for both mortality and complications. The identified D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and pulmonary hyperactive derangements of fibrinolysis, and the D-dimer-associated clinical biomarkers, and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.

Background. Extensive studies have been carried out to investigate the association between obesity and the risk of rheumatoid arthritis (RA); however, the results of the current reported original studies remain inconsistent. This study aimed to clarify the relationship between body mass index and rheumatoid arthritis by conducting an updated overall and dose-response meta-analysis. Methods. The relevant literature was searched using the PubMed and Embase databases (through 20 September 2018) to identify all eligible published studies. Random-effect models and dose-response meta-analyses were used to estimate the pooled risk ratio (RR) with a 95% confidence interval (CI). Subgroup analyses were also conducted based on the characteristics of the participants. Sensitivity analyses and publication bias tests were also performed to explore potential heterogeneity and bias in the meta-analysis. Results. Sixteen studies that included a total of 406,584 participants were included in the meta-analysis. Compared to participants with normal weight, the pooled RRs of rheumatoid arthritis were 1.12 (95% CI, 1.04-1.20) in overweight and 1.23 (95% CI, 1.09-1.39) in obese participants. There was evidence of a nonlinear relationship between body mass index (BMI) and RA (P for nonlinearity less than 0.001 in the overall meta-analysis, P for nonlinearity=0.025 in the case-control studies, P for nonlinearity=0.0029 in the cohort studies). No significant heterogeneity was found among studies (I2=10.9% for overweight and I2=45.5% for obesity). Conclusion. The overall and dose-response meta-analysis showed that increased BMI was associated with an increased risk for rheumatoid arthritis, which might present a prevention strategy for the prevention or control of rheumatoid arthritis. The nonlinear relationship between BMI and RA might present a personal prevention strategy for RA.

BACKGROUND AND PURPOSE The components of ideal cardiovascular health (CVH) metrics have been shown to be associated with non-alcoholic fatty liver disease (NAFLD). The present study aimed to determine the association between ideal CVH metrics and NAFLD. METHODS A total of 10,511 participants (47.26% men) aged 18 to 92 years were selected from the Jidong and Kailuan communities. Ideal CVH was based on 7 ideal CVH metrics: smoking, body mass index (BMI), physical activity, diet, total cholesterol, blood pressure and fasting blood glucose. NAFLD was determined by abdominal ultrasonography. All participants underwent questionnaire assessments and clinical and laboratory examinations. Logistic regression models were used to analyse the relationship of CVH metrics and the number of ideal CVH metrics with NAFLD. RESULTS The prevalence rates of NAFLD by CVH summary score quartiles were 64.38% (2,015/3,130), 50.16% (786/1,567), 33.28% (1,194/3,588) and 20.89% (465/2,226). Participants in the highest quartile showed a lower odds ratio (OR) than those in the lowest quartile (fully adjusted OR: 0.17, 95% CI: 0.17-0.20, P

Radiation-induced lung injury (RILI) is a common complication in radiotherapy of thoracic tumors and limits the therapeutic dose of radiation that can be given to effectively control tumors. RILI develops through a complex pathological process, resulting in induction and activation of various cytokines, infiltration by inflammatory cells, cytokine-induced activation of fibroblasts, and subsequent tissue remodeling by activated fibroblasts, ultimately leading to impaired lung function and respiratory failure. Increasing evidence shows that mesenchymal stem cells (MSCs) may play a main role in modulating inflammation and immune responses, promoting survival and repair of damaged resident cells and enhancing regeneration of damaged tissue through soluble paracrine factors and therapeutic extracellular vesicles. Therefore, the use of the MSC-derived secretome and exosomes holds promising potential for RILI therapy. Here, we review recent progress on the potential mechanisms of MSC therapy for RILI, with an emphasis on soluble paracrine factors of MSCs. Hypotheses on how MSC derived exosomes or MSC-released exosomal miRNAs could attenuate RILI are also proposed. Problems and translational challenges of the therapies based on the MSC-derived secretome and exosomes are further summarized and underline the need for caution on rapid clinical translation. Stem Cells Translational Medicine 2019;8:344–354

Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous recombinant human TRIM72 protein (rhT72) demonstrated tissue-mending properties in animal models of tissue injury. Here we examine the mechanisms of rhT72-mediated lung cell protection in vitro and test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator-induced lung injury. In vitro lung cell injury was induced by glass beads and stretching. Ventilator-induced lung injury was modeled by injurious ventilation at 30 ml/kg tidal volume. Affinity-purified rhT72 or control proteins were added into culture medium or applied through nebulization. Cellular uptake and in vivo distribution of rhT72 were detected by imaging and immunostaining. Exogenous rhT72 maintains membrane integrity of alveolar epithelial cells subjected to glass bead injury in a dose-dependent manner. Inhaled rhT72 decreases the number of fatally injured alveolar cells, and ameliorates tissue-damaging indicators and cell injury markers after injurious ventilation. Using in vitro stretching assays, we reveal that rhT72 improves both cellular resilience to membrane wounding and membrane repair after injury. Image analysis detected rhT72 uptake by rat alveolar epithelial cells, which can be inhibited by a cholesterol-disrupting agent. In addition, inhaled rhT72 distributes to the distal lungs, where it colocalizes with phosphatidylserine detection on nonpermeabilized lung slices to label wounded cells. In conclusion, our study showed that inhaled rhT72 accumulates in injured lungs and protects lung tissue from ventilator injury, the mechanisms of which include improving cell resilience to membrane wounding, localizing to injured membrane, and augmenting membrane repair.

Yellowgenes are thought to be involved in the melanin biosynthetic pathway and play a crucial role in pigmentation reactions in insects. However, little research has been done onyellowgenes in lepidopteran pests. To clarify the function of one of theyellowgenes (yellow-y) inSpodoptera litura, we cloned the full-length ofyellow-y, and investigated its spatial and temporal expression profiles by quantitative real-time PCR (qPCR). It revealed thatyellow-ywas highly expressed in larva of fourth, fifth, and sixth instars, as well as in epidermis (Ep), fat bodies (FB), Malpighian tubes (MT), and midguts (MG) of the larvae; whereas it was expressed in very low levels in different tissues of adults, and was almost undetected in pupa. This expression profile suggests an important role ofyellow-yin larvae, minor role in adults, and no role in pupae. To confirm this, we disruptedyellow-yusing the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system, and obtained G0 insects with mutation inyellow-y. The mutation inyellow-yclearly rendered the larvae body, a color yellower than that of wide type insects, and in addition, the mutation resulted in abnormal segmentation and molting for older larvae. The mutation ofyellow-yalso made various adult tissues (antennae, proboscis, legs, and wings) yellowish. However, the mutation had no effect on pigmentation of the pupal cuticle. Taken together, our study clearly demonstrated the role ofyellow-ynot only in the body pigmentation of larvae and adults, and but also in segmentation and molting of larvae, providing new insights into the physiology of larval development, as well as a useful marker gene for genome editing based studies.

Gliomas are the most fatal malignant cerebral tumors. Temozolomide (TMZ), as the primary chemotherapy drug, has been widely used in clinics. However, resistance of TMZ still remains to poor defined. LncRNAs have been reported to play crucial roles in progression of various cancers and resistance of multiple drugs. However, the biological function and underlying mechanisms of most lncRNAs in glioma still remains unclear. Based on the TCGA database, a total of 94 differentially expressed lncRNAs, including 16 up-regulated genes and 78 downregulated genes were identified between gliomas and normal brain tissues. Subsequently, lncRNA DLEU1, HOTAIR, and LOC00132111 were tested to be significantly related to overall survival (OS) between high- and low-expression groups. Additionally, we verified that lncRNA DLEU1 was high expressed in 108 gliomas, compared with 19 normal brain tissues. And high expression of lncRNA DLEU1 predicted a poor prognosis (HR = 1.703, 95%CI: 1.133–2.917, p-value = 0.0159). Moreover, functional assays revealed that knockdown of lncRNA DLEU1 could suppress the proliferation by inducing cell cycle arrest at G1 phase and reducing the S phase by down-regulating the CyclinD1 and p-AKT, as the well as migration and invasion by inhibiting the epithelial–mesenchymal transition (EMT) markers, such as ZEB1, N-cadherin, β-catenin and snail in glioma cells. Furthermore, silencing lncRNA DLEU1 suppressed TMZ-activated autophagy via regulating the expression of P62 and LC3, and promoted sensitivity of glioma cells to TMZ by triggering apoptosis. Conclusively, our study indicated that lncRNA DLEU1 might perform as a prognostic potential target and underlying therapeutic target for sensitivity of glioma to TMZ.

Amine-looping-based CO2 mineralization is a promising technology for simultaneous CO2 absorption, mineralization, and carbonate crystallization in a single step. This paper performed a detailed investigation of the feasibility and underlying mechanism of the amine-looping process using industrial alkaline solid wastes, including one biomass ash (BA) and two coal-fired fly ashes named FA1 and FA2. The CO2 sequestration capacity and CO2 removal efficiency of selected ashes were investigated in five typical amine solutions, including monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), 2-amino-2-methy-1-propanol (AMP), and piperazine (PZ). The physicochemical property of ashes before and after carbonation and the dissolution of alkaline minerals in various amine solutions were systematically determined to explore the underlying mechanism involved in the amine-looping process. Results show that greater improvement in CO2 removal efficiencies and CO2 sequestration capacities were obtained by selected ashes in amine solutions compared to the traditional CO2 mineralization in the water-ash-CO2 system. It also revealed that amines played important roles in promoting CO2 mass transfer, enhancing Ca2+ leaching, and producing small-sized CaCO3. The largest CO2 sequestration capacity (102.9 g/kg) was achieved by FA1 in PZ solution which was suggested as the preferred solvent for the amine-looping process. In addition, the environmental risk of carbonated ashes for agricultural application in terms of amine loss and phytotoxicity was evaluated. Results implied that the phytotoxicity of carbonated BA could be neglected when a simple centrifugal wash was used to remove the absorbed amine on the surface of carbonated BA whilst the phytotoxicity of selected ashes can be significantly reduced after carbonation reactions.

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.

Glioblastoma multiforme (GBM) is the most malignant glioma with a high death rate. N6-methyladenosine (m6A) RNA methylation plays an increasingly important role in tumors. The current study aimed to determine the function of the regulators of m6A RNA methylation in GBM. We evaluated the difference, interaction, and correlation of these regulators with TCGA database. HNRNPC, WTAP, YTHDF2 and, YTHDF1 were significantly upregulated in GBM. To explore the expression characteristics of regulators in GBM, we defined two subgroups through consensus cluster. HNRNPC, WTAP, and YTHDF2 were significantly upregulated in the cluster2 which had a good overall survival (OS). To investigate the prognostic value of regulators, we used lasso cox regression algorithm to screen an independent prognostic risk characteristic based on the expression of HNRNPC, ZC3H13, and YTHDF2. The prognostic feature between the low and high-risk groups was significantly different (P < 0.05), which could predict significance of prognosis (area under the curve (AUC) = 0.819). Moreover, we used western blot, RT-PCR, and immunohistochemical staining to verify the expression of HNRNPC was associated with malignancy and development of gliomas. Similarly, the high expression of HNRNPC had a good prognosis. In conclusion, HNRNPC is a vital participant in the malignant progression of GBM and might be valuable for prognosis.

Eleven previously uncharacterized steroids, along with three analogs were isolated from Aglaia lawii leaves. Their structures were definitely characterized by the methods of NMR, MS, IR, ECD and X-ray crystallography study. Among these unreported compounds, 3-epi-dyscusin C, 3-epi-lansisterone E and (Z)-2α-hydroxyaglawone were C-21 pregnane steroids incorporating a highly oxygenated ring A, while others were Δ5-3β-hydroxy-7-ketosteroids bearing different ring D and C-17 aliphatic chains. All isolates were evaluated for nitric oxide (NO) inhibitory activities. 3-Epi-dyscusin C, 3-epi-lansisterone E, (Z)-2α-hydroxyaglawone and 17(20)E-dyscusin B showed significant anti-inflammatory activities with IC50 values of NO inhibition less than 10 μM (in the range from 4.47 ± 0.36 to 7.67 ± 0.46 μM).

BACKGROUND AND PURPOSE: Lung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. Here, we have tested whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid. EXPERIMENTAL APPROACH: Human lungs and airway acid‐instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, and protein docking were combined for identifying plasmin cleavage sites. KEY RESULTS: Plasmin improved lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin activated αβγENaC channels in oocytes in a time‐dependent manner. Deletion of four consensus proteolysis tracts (αΔ432‐444, γΔ131‐138, γΔ178‐193, and γΔ410‐422) eliminated plasmin‐induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin‐cleaved C‐terminal fragments and full‐length human γENaC proteins. In addition, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage‐induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal. CONCLUSION AND IMPLICATIONS: Plasmin can cleave ENaC to improve blood‐gas exchange by resolving oedema fluid and could be a potent therapy for oedematous lungs.

Background Chronic tissue injury was shown to induce progressive scarring in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), while an array of repair/regeneration and stress responses come to equilibrium to determine the outcome of injury at the organ level. In the lung, type I alveolar epithelial (ATI) cells constitute the epithelial barrier, while type II alveolar epithelial (ATII) cells play a pivotal role in regenerating the injured distal lungs. It had been demonstrated that eukaryotic cells possess repair machinery that can quickly patch the damaged plasma membrane after injury, and our previous studies discovered the membrane-mending role of Tripartite motif containing 72 (TRIM72) that expresses in a limited number of tissues including the lung. Nevertheless, the role of alveolar epithelial cell (AEC) repair in the pathogenesis of IPF has not been examined yet. Method In this study, we tested the specific roles of TRIM72 in the repair of ATII cells and the development of lung fibrosis. The role of membrane repair was accessed by saponin assay on isolated primary ATII cells and rat ATII cell line. The anti-fibrotic potential of TRIM72 was tested with bleomycin-treated transgenic mice. Results We showed that TRIM72 was upregulated following various injuries and in human IPF lungs. However, TRIM72 expression in ATII cells of the IPF lungs had aberrant subcellular localization. In vitro studies showed that TRIM72 repairs membrane injury of immortalized and primary ATIIs, leading to inhibition of stress-induced p53 activation and reduction in cell apoptosis. In vivo studies demonstrated that TRIM72 protects the integrity of the alveolar epithelial layer and reduces lung fibrosis. Conclusion Our results suggest that TRIM72 protects injured lungs and ameliorates fibrosis through promoting post-injury repair of AECs.

Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.

Background One of most important concerns of postmenopausal women is obesity. The relationships between menstruation status and obesity phenotypes are unclear. This study aimed to assess the associations between menstrual status and different obesity phenotypes in women. Methods In total, 5373 women aged ≥40 years were recruited from the Jidong and Kailuan communities. Basic information was collected via clinical examination, laboratory testing and standardized questionnaires. The women were stratified into the following three groups: menstrual period, menopausal transition period and postmenopausal period. General obesity was defined as a body mass index (BMI) of ≥28 kg/m2. Central obesity was defined as a waist-to-hip ratio (WHR) of > 0.85. Visceral obesity was defined as the presence of nonalcoholic fatty liver disease (NAFLD) and increased pericardial fat volume (PFV). Results The numbers of women in the menstrual, menopausal transition, and postmenopausal periods were 2807 (52.2%), 675 (12.6%) and 1891 (35.2%), respectively. The adjusted odds ratio (OR) and 95% confidence interval (CI) for central obesity among women in the menopausal transition and postmenopausal periods compared with women in the menstrual period were 0.99 (0.82–1.19) and 1.52 (1.26–1.84), respectively. The OR for NAFLD among postmenopausal women was 1.78 (1.44–2.20). The adjusted β-coefficient (standard error, SE) for PFV among postmenopausal women was 41.25 (7.49). The adjusted OR for general obesity among postmenopausal women was 1.01 (0.77–1.34). Conclusions This study demonstrated that menopause is an independent risk factor for central and visceral obesity but not general obesity.

Smoke inhalation injury is the leading cause of death in firefighters and victims. Inhaled hot air and toxic smoke are the predominant hazards to the respiratory epithelium. We aimed to analyze the effects of thermal stress and smoke aldehyde on the permeability of the airway epithelial barrier. Transepithelial resistance (RTE) and short-circuit current (ISC) of mouse tracheal epithelial monolayers were digitized by an Ussing chamber setup. Zonula occludens-1 tight junctions were visualized under confocal microscopy. A cell viability test and fluorescein isothiocyanate-dextran assay were performed. Thermal stress (40°C) decreased RTEin a two-phase manner. Meanwhile, thermal stress increased ISCfollowed by its decline. Na+depletion, amiloride (an inhibitor for epithelial Na+channels [ENaCs]), ouabain (a blocker for Na+/K+-ATPase) and CFTRinh-172 (a blocker of cystic fibrosis transmembrane regulator [CFTR]) altered the responses of RTEand ISCto thermal stress. Steady-state 40°C increased activity of ENaCs, Na+/K+-ATPase, and CFTR. Acrolein, one of the main oxidative unsaturated aldehydes in fire smoke, eliminated RTEand ISC. Na+depletion, amiloride, ouabain, and CFTRinh-172 suppressed acrolein-sensitive ISC, but showed activating effects on acrolein-sensitive RTE. Thermal stress or acrolein disrupted zonula occludens-1 tight junctions, increased fluorescein isothiocyanate-dextran permeability but did not cause cell death or detachment. The synergistic effects of thermal stress and acrolein exacerbated the damage to monolayers. In conclusion, the paracellular pathway mediated by the tight junctions and the transcellular pathway mediated by active and passive ion transport pathways contribute to impairment of the airway epithelial barrier caused by thermal stress and acrolein.Graphical HeadlightsThermal stress and acrolein are two essential determinants for smoke-inhalation injury, impairing airway epithelial barrier.Transcellular ion transport pathways via the ENaC, CFTR, and Na/K-ATPase are interrupted by both thermal stress and acrolein, one of the most potent smoke toxins.Heat and acrolein damage the integrity of the airway epithelium through suppressing and relocating the tight junctions.

Background and PurposeLung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. We aimed to test whether plasmin cleaves epithelial sodium channels (ENaC) to resolve lung oedema fluid.Experimental ApproachesHuman lungs and airway acid-instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, protein docking, and alveolar fluid clearance were combined for identifying plasmin specific cleavage sites and benefits.Key ResultsPlasmin led to a marked increment in lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin specifically activated αβγENaC channels in oocytes in a time-dependent manner. Deletion of four consensus proteolysis tracts (αΔ432-444, γΔ131-138, γΔ178-193, and γΔ410-422) eliminated plasmin-induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin-cleaved C-terminal fragments and full-length human γENaC proteins. In addition to confirming the 7 cleavage sites, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin with mass spectrometry. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage-induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal.Conclusion and ImplicationsWe demonstrate that plasmin could cleave ENaC to benefit the blood-gas exchange by resolving oedema fluid as a potent fibrinolytic therapy for oedematous pulmonary diseases.Bullet point summaryWhat is already knowSerine proteases proteolytically cleave epithelial sodium channels, including plasmin and uPA acutely.Activity of epithelial sodium channels is increased post proteolysis.What this study addsPlasmin cleaves up to 16 sites composed of two proteolytic centres in both full-length and furin-cleaved human γ subunit of epithelial sodium channels in hours.Non-proteolytic sites in both α and γ subunits interrupt the plasmin cleavage-induced channel gating.Intratracheally instilled plasmin facilitates alveolar fluid clearance in normal human and injured mouse lungs.Clinical significanceActivation of human lung epithelial sodium channels by plasmin may benefit lung oedema resolution as a novel therapy for ARDS.

Background: The World Health Organization (WHO) recommends monitoring changes in seroprevalence of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) over time from the beginning of an epidemic to predict and plan accordingly for public health responses. At present, few domestic and foreign reports exist on the diagnosis of COVID-19 patients through serological tests. To detect and assess asymptomatic infections of COVID-19 among people in Wuhan, the epicenter of the COVID-19 pandemic in China, and provide a basis for planning an adequate public health response, we analyzed the records in a Wuhan general hospital of medical examinations mandatory for 16- to 64-year-old asymptomatic people to resume their job-related work. This retrospective study estimated the seroprevalence of IgM and IgG and compared the epidemiological characteristics of asymptomatic SARS-CoV-2- infected workers. Methods: Medical examination data were collected from the Wuhan General Hospital between March 26 and April 28, 2020. Serological tests for the presence of antibodies (IgM and IgG) against SARS-CoV-2 used a colloidal gold method. Nucleic acid sequence of viruses were detected with a fluorescent PCR method. Demographical and radiological data were collected. Statistical analyses were conducted using SPSS 20.0 software. Findings: Between March 26 and April 28, 2020, a total of 18,391 asymptomatic back-to-work participants were enrolled. Among them, 89 had positivity for IgM (0·48%, 95% confidence interval (CI): 0·38–0·58%); 620 cases had IgG positivity (3·37%, 95% CI: 3·11–3·64%), and 650 cases had either IgG positivity or IgM positivity (3·53%, 95% CI: 3·26–3·80%). After standardizing for the genders and ages in the population of Wuhan, the overall standardized seroprevalence of IgG was 3·33% (95% CI: 3·07–3·59%) and the standardized seroprevalence of IgG was 3·01% (95% CI: 2·69–3·33%) among males and 3·66% (95 % CI: 3·23–4·09%) among females. The standardized seroprevalence of IgG was higher in women than in men with a significant difference (x 2 = 2060·3, p < 0·01). By a detection method adjustment, the seroprevalence of IgG was 1·57% (95% CI: 1·39–1·75%) in all medical records, of which males were 1·96% (95% CI: 1·64–2·28%), and females were 1·19% (95% CI: 0·99–1·39%). The assayadjusted seroprevalence of IgG was higher in women than in men, and the difference was significant (x 2 = 5871·0, p < 0·01). The differences were significant for seroprevalence of IgG among people who went back to work in different categories of work place (x 2 = 198·44, p < 0·01). The differences in seroprevalence for IgG positivity or IgM positivity among people who went back to work in different urban and rural areas was also significant (x 2 = 45·110, p < 0·01). Calculated as IgG and/or IgM antibody positivity, the number of new infections was reduced by 64·8% from March 26 to April 28, 2020. Based on the census population aged 16–64 years in Wuhan in 2017, we estimated that 172,340 (95% CI: 157,568–187,112) asymptomatic people aged 16–64 years were infected with SARS-CoV-2 in Wuhan between March 25 and April 28 2020. This estimate was 3·4-times higher than the officially reported 50,333 infections on April 28. Interpretation: The seropositivity rate in Wuhan indicated that RT-PCR-confirmed patients only represented a small part of the total number of cases. Seropositivity progressively decreased in the Wuhan population from March 26 to April 28, 2020, comparable to Japan and Denmark, but well below the level reported in New York, Iran, Italy, and Germany. The prevalence of asymptomatic infection was higher in women than in men among people who went back to work in Wuhan. The low seroprevalence suggests that most of the population remains susceptible to COVID19. Funding: Emergency Management Project of the National Natural Science Foundation of China (81842035) ; Advisory Research Project of the Chinese Academy of Engineering in 2019 (2019-XZ-70) Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of the Hubei Provincial Hospital of Integrated Chinese & Western Medicine. This was a retrospective and observational study and informed consent was obtained.

The aim of this study was to evaluate the role of bamboo shoot fiber (BSF) in regulating insulin sensitivity in mice. Two BSFs were obtained from D. hamiltonii and D. latiforus. C57BL/6 mice were fed a low-fat diet or a high-fat diet with 10% fiber as cellulose (HFC), or two BSFs (HFDH or HFDL) for 13 weeks. Compared with the HFC group, HFDH and HFDL groups exhibited considerably less body weight gain, lower levels of fasting glucose and insulin, and lower values of glucose areas under the curve during glucose and insulin tolerance tests. BSF groups also had lower glucoses stimulated insulin concentrations. In addition, more phosphorylation of Akt in insulin target tissues was associated with higher protein expression levels of PGC-1α and phosphorylated AMPK and p38 in BSF fed mice. These results indicated that BSF improved insulin sensitivity in high-fat diet-fed mice through enhancing insulin signaling and activating PGC-1α.

High‐sensitivity C‐reactive protein (hs‐CRP) and lipoprotein‐associated phospholipase A2 (Lp‐PLA2) have been reported to be independent predictors of atherosclerosis. However, whether the combination of these two markers can improve the prediction of atherosclerosis is unknown. This study aimed to evaluate the association between combining hs‐CRP and Lp‐PLA2 and predicting carotid atherosclerosis. A total of 1982 participants aged ≥40 years were included in this study. Hs‐CRP and Lp‐PLA2 were measured by a high‐sensitivity nephelometry assay and quantitative sandwich enzyme‐linked immunosorbent assay, respectively. Ultrasonography was performed on the bilateral carotid arteries to evaluate stenosis and plaques. Multivariable logistic regression models were used to analyse the association between the combination of the hs‐CRP and Lp‐PLA2 levels and carotid plaques and stenosis. A total of 1579 (79.7%) and 181 (9.1%) subjects had carotid plaques and carotid stenosis, respectively. The group with high hs‐CRP and Lp‐PLA2 levels had the highest prevalence of carotid plaques (90.6%) and stenosis (20.8%). A significant association was found between high hs‐CRP and Lp‐PLA2 levels and carotid stenosis (adjusted odds ratio [OR]: 2.39; 95% confidence interval [CI]: 1.13‐5.09), but this combination was not associated with carotid plaques (OR: 2.62, 95% CI: 0.93‐7.38). The results suggested that the combination of hs‐CRP and Lp‐PLA2 were better predictors than either protein alone with regard to carotid atherosclerosis.

Respiratory diseases, which are leading causes of mortality and morbidity in the world, are dysfunctions of the nasopharynx, the trachea, the bronchus, the lung and the pleural cavity. Symptoms of chronic respiratory diseases, such as cough, sneezing and difficulty breathing, may seriously affect the productivity, sleep quality and physical and mental well-being of patients, and patients with acute respiratory diseases may have difficulty breathing, anoxia and even life-threatening respiratory failure. Respiratory diseases are generally heterogeneous, with multifaceted causes including smoking, ageing, air pollution, infection and gene mutations. Clinically, a single pulmonary disease can exhibit more than one phenotype or coexist with multiple organ disorders. To correct abnormal function or repair injured respiratory tissues, one of the most promising techniques is to correct mutated genes by gene editing, as some gene mutations have been clearly demonstrated to be associated with genetic or heterogeneous respiratory diseases. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems are three innovative gene editing technologies developed recently. In this short review, we have summarised the structure and operating principles of the ZFNs, TALENs and CRISPR/Cas9 systems and their preclinical and clinical applications in respiratory diseases.

Four new limonoids, named as trichiconlide G (1), 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), 21-oxo-23-hydroxyltrijugin F (4), along with sixteen known analogues (5–20) were isolated from the leaves and twigs of Trichilia connaroides. Their structures and absolute configurations were determined by spectroscopic analyses, X-ray diffraction analysis, and TD-DFT-ECD calculations. Trichiconlide G (1) is one rare naturally occurring 1,2-seco phragmalin-type limonoid bearing a C-7/28 δ-lactone ring. Additionally, 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), and 21-oxo-23-hydroxyltrijugin F (4) are three naturally occurring limonoids with a rare C-16/8 δ-lactone ring. All isolates were evaluated for their cytotoxic and anti-inflammatory activities. None of compounds exhibited cytotoxicity against five human cancer cell lines A-549, HepG2, 5-8F, Siha, and SCC-4 at the concentration of 40 μM. Compounds 16 and 17 showed moderate anti-inflammatory activity with IC50 values of 28.45 ± 2.51 and 22.66 ± 2.01 μM, respectively.

Integrated CO2 absorption and mineralisation (IAM) is a promising technology for rapidly CO2 absorption and sequestration. However, the traditional IAM using alkanolamines as CO2 solvents and solid wastes as carbonation feedstocks still suffers from the utilization difficulty of low value products and environmental risks of amine degradation. In this study, the green solvent, amino acid salts (AAS), including potassium l -argininate (ArgK), potassium glycinate, potassium sarcosinate, potassium l -alaninate, potassium β-alaninate, were selected for IAM using rejected brine as the carbonation feedstock. Results shows that compared to amines (monoethanolamine, diethanolamine, N-methyldiethanolamine, triethanolamine, piperazine, 2-amino-2-methy-1-propanol), the selected AASs in IAM were not only more effective CO2 carriers that passed CO2 to calcium ions to form CaCO3, but also better CaCO3 growth regulators to tune morphology properties of products. CO2 desorption efficiencies in CO2-loaded AASs (nearly 100 %) were much higher than those of in CO2-loaded amines especially than in MEA (38 %). ArgK stood out in regulating the morphology of crystal with smallest particle size. Then ArgK was selected for optimization experiments at various conditions (temperature, Ca2+/CO2 ratio, reactant concentration and chelating agent) to further investigate effects of operating conditions on CaCO3 properties and to provide some basic information for the polymorph and morphology regulation of CaCO3. Ethylene diamine tetraacetic acid (EDTA) as a chelating agent was found a notable influence on controlling the polymorph of CaCO3, where the amorphous CaCO3 and new structures of calcite appeared. However, the effect of EDTA on CO2 absorption step was not clear and required further investigation.

// Yue Li 1, * , Jianjun Chang 1, * , Yong Cui 2 , Runzhen Zhao 3 , Yan Ding 1 , Yapeng Hou 1 , Zhiyu Zhou 1 , Hong-Long Ji 3, 4 and Hongguang Nie 1 1 Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang 110122, Liaoning, China 2 Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China 3 Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas 75708, USA 4 Texas Lung Injury Institute, University of Texas Health Northeast, Tyler, Texas 75708, USA * These authors have contributed equally to this work Correspondence to: Hongguang Nie, email: hgnie@cmu.edu.cn Hong-Long Ji, email: james.ji@uthct.edu Keywords: epithelial sodium channels, crotonaldehyde, lung injury, alveolar fluid clearance, reactive oxygen species Received: March 17, 2017 Accepted: April 25, 2017 Published: May 12, 2017 ABSTRACT Background: Crotonaldehyde is a highly noxious α,β-unsaturated aldehyde in cigarette smoke that causes edematous acute lung injury. Objective: To understand how crotonaldehyde impairs lung function, we examined its effects on human epithelial sodium channels (ENaC), which are major contributors to alveolar fluid clearance. Methods: We studied alveolar fluid clearance in C57 mice and ENaC activity was examined in H441 cells. Expression of α- and γ-ENaC was measured at protein and mRNA levels by western blot and real-time PCR, respectively. Intracellular ROS levels were detected by the dichlorofluorescein assay. Heterologous αβγ-ENaC activity was observed in an oocyte model. Results: Our results showed that crotonaldehyde reduced transalveolar fluid clearance in mice. Furthermore, ENaC activity in H441 cells was inhibited by crotonaldehyde dose-dependently. Expression of α- and γ-subunits of ENaC was decreased at the protein and mRNA level in H441 cells exposed to crotonaldehyde, which was probably mediated by the increase in phosphorylated extracellular signal-regulated protein kinases 1 and 2. ROS levels increased time-dependently in cells exposed to crotonaldehyde. Heterologous αβγ-ENaC activity was rapidly eliminated by crotonaldehyde. Conclusion: Our findings suggest that crotonaldehyde causes edematous acute lung injury by eliminating ENaC activity at least partly via facilitating the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 signal molecules. Long-term exposure may decrease the expression of ENaC subunits and damage the cell membrane integrity, as well as increase the levels of cellular ROS products.

// Runzhen Zhao 1,* , Zhenlei Su 2,* , Jing Wu 2 and Hong-Long Ji 1 1 Texas Lung Injury Institute, University of Texas Health Northeast, Tyler, Texas, USA 2 Institute of Lung and Molecular Therapy, Xinxiang Medical University, Xinxiang, Henan, China * These authors have contributed equally to this work Correspondence to: Hong-Long Ji, email: // Keywords : serious adverse events, cell therapy, respiratory diseases, systematic review, meta-analysis Received : January 17, 2017 Accepted : February 08, 2017 Published : February 16, 2017 Abstract Background: Cell therapy holds the most promising for acute and chronic deleterious respiratory diseases. However, the safety and tolerance for lung disorders are controversy. Methods: We undertook a systematic review and meta-analyses of all 23 clinical studies of cell therapy. The outcomes were odds ratio (OR), risk difference (RD), Peto OR, relative risk, and mean difference of serious adverse events. Results: 342 systemic infusions and 57 bronchial instillations (204 recipients) of cells were analyzed for acute respiratory distress syndrome (ARDS), bronchopulmonary dysplasia, pulmonary arterial hypertension, silicosis, sarcoidosis, extensively drug-resistant tuberculosis, chronic obstructive pulmonary diseases (COPD), and idiopathic pulmonary fibrosis. The frequency of death in adults from any causes was 71 and 177 per 1,000 for cell therapy and controls, respectively, with an OR of 0.31 (95% CI: 0.03, 3.76) and RD of -0.22 (95% CI: -0.53, 0.09). No significant difference was found for ARDS and COPD. The frequency of deaths and non-fatal serious adverse events of 17 open studies were similar to those of randomized controlled trials. Moreover, serious adverse events of allogenic cells were greater than autologous preparations, as shown by frequency, OR and RD. Conclusions: We conclude that either infusion or instillation of mesenchymal stem stromal or progenitor cells are well tolerated without serious adverse events causally related to cell treatment. Cell therapy has not been associated with significant changes in spirometry, immune function, cardiovascular activity, and the quality of life.

Epithelial sodium channels (ENaC) play an important role in re-absorbing excessive luminal fluid by building up an osmotic Na+ gradient across the tight epithelium in the airway, the lung, the kidney, and the colon. The ENaC is a major pathway for retention of salt in kidney too. MicroRNAs (miRs), a group of non-coding RNAs that regulate gene expression at the post-transcriptional level, have emerged as a novel class of regulators for ENaC. Given the ENaC pathway is crucial for maintaining fluid homeostasis in the lung and the kidney and other cavities, we summarized the cross-talk between ENaC and miRs and recapitulated the underlying regulatory factors, including aldosterone, transforming growth factor-β1, and vascular endothelial growth factor-A in the lung and other epithelial tissues/organs. We have compared the profiling of miRs between normal and injured mice and human lungs, which showed a significant alteration in numerous miRs in mouse models of LPS and ventilator induced ARDS. In addition, we reiterated the potential regulation of the ENaC by miRs in stem/ progenitor cell-based re-epithelialization, and identified a promising pharmaceutic target of ENaC for removing edema fluid in ARDS by mesenchymal stem cells-released paracrine. In conclusion, it seems that the interactions between miRs and scnn1s/ENaCs are critical for lung development, epithelial cell turnover in adult lungs, and re-epithelialization for repair.

Smoke inhalation injury is the leading cause of death in firefighters and victims. Inhaled hot air and toxic smoke are the predominant hazards to the respiratory epithelium. We aimed to analyze the effects of thermal stress and smoke aldehyde on the permeability of the airway epithelial barrier. Transepithelial resistance (R(TE)) and short-circuit current (I(SC)) of mouse tracheal epithelial monolayers were digitized by an Ussing chamber setup. Zonula occludens-1 tight junctions were visualized under confocal microscopy. A cell viability test and fluorescein isothiocyanate-dextran assay were performed. Thermal stress (40°C) decreased R(TE) in a two-phase manner. Meanwhile, thermal stress increased I(SC) followed by its decline. Na(+) depletion, amiloride (an inhibitor for epithelial Na(+) channels [ENaCs]), ouabain (a blocker for Na(+)/K(+)-ATPase) and CFTRinh-172 (a blocker of cystic fibrosis transmembrane regulator [CFTR]) altered the responses of R(TE) and I(SC) to thermal stress. Steady-state 40°C increased activity of ENaCs, Na(+)/K(+)-ATPase, and CFTR. Acrolein, one of the main oxidative unsaturated aldehydes in fire smoke, eliminated R(TE) and I(SC). Na(+) depletion, amiloride, ouabain, and CFTRinh-172 suppressed acrolein-sensitive I(SC), but showed activating effects on acrolein-sensitive R(TE). Thermal stress or acrolein disrupted zonula occludens-1 tight junctions, increased fluorescein isothiocyanate-dextran permeability but did not cause cell death or detachment. The synergistic effects of thermal stress and acrolein exacerbated the damage to monolayers. In conclusion, the paracellular pathway mediated by the tight junctions and the transcellular pathway mediated by active and passive ion transport pathways contribute to impairment of the airway epithelial barrier caused by thermal stress and acrolein.

Objective. The exact shape of the dose-response relationship between maternal body mass index (BMI) and the risk of congenital heart defects (CHDs) in infants has not been clearly defined yet. This study aims to further clarify the relationship between maternal obesity and the risk of CHDs in infants by an overall and dose-response meta-analysis. Methods. PubMed, Embase, and Web of Science databases were searched to identify all related studies. The studies were limited to human cohort or case-control studies in English language. Random-effect models and dose-response meta-analysis were used to synthesize the results. Heterogeneity, subgroup analysis, sensitivity analysis, and publication bias were also assessed. Results. Nineteen studies with 2,416,546 participants were included in our meta-analysis. Compared with the mothers with normal weight, the pooled relative risks (RRs) of infants with CHDs were 1.08 (95% CI=1.03-1.13) in overweight and 1.23 (95% CI=1.17-1.29) in obese mothers. According to the findings from the linear meta-analysis, we observed an increased risk of infants with CHDs (RR=1.07, 95% CI=1.06-1.08) for each 5 kg/m2 increase in maternal BMI. A nonlinear relationship between maternal BMI and risk of infants with CHDs was also found (p=0.012). Conclusion. The results from our meta-analysis indicate that increased maternal BMI is related to increased risk of CHDs in infants.

Smoke-inhalation-induced acute lung injury (SI-ALI) is a leading cause of morbidity and mortality in victims of fire tragedies. SI-ALI contributes to an estimated 30% of burn-caused patient deaths, and recently, more attention has been paid to the specific interventions for this devastating respiratory illness. In the last decade, much progress has been made in the understanding of SI-ALI patho-mechanisms and in the development of new therapeutic strategies in both preclinical and clinical studies. This article reviews the recent progress in the treatment of SI-ALI, based on pathophysiology, thermal damage, airway obstruction, the nuclear-factor kappa-B signaling pathway, and oxidative stress. Preclinical therapeutic strategies include use of mesenchymal stem cells, hydrogen sulfide, peroxynitrite decomposition catalysts, and proton-pump inhibitors. Clinical interventions include high-frequency percussive ventilation, perfluorohexane, inhaled anticoagulants, and nebulized epinephrine. The animal model, dose, clinical application, and pharmacology of these medications are summarized. Future directions and further needs for developing innovative therapies are discussed. The reviews of this paper are available via the supplementary material section.

Influenza virus has a significant impact on the respiratory system. The mechanism of how influenza virus impairs the fluid transport in airway is not fully understood. We examined its effects on epithelial sodium channels (ENaC), which are very important for water and salt transport in the respiratory system. We focused on the impacts of influenza virus on ENaC activity in mouse tracheal epithelial cells (MTECs) and applied Ussing chamber apparatus for recording the short-circuit currents in primary cultured MTECs. Expressions of α and γ-ENaC were measured at the protein and mRNA levels by western blot and quantitative real-time polymerase chain reaction, respectively. Roles of the with-no-lysine-kinase-4 (WNK4) pathway were considered in participating influenza virus-involved ENaC regulation by using siRNA to knockdown WNK4 and the physical properties of airway surface liquid (ASL) were detected by confocal microscopy. Our results showed that influenza virus reduced ENaC activity, and the expressions of α and γ-ENaC were decreased at the protein and mRNA levels, respectively. WNK4 expression increased time-dependently at the protein level after influenza virus infection, while knockdown of WNK4 rescued the impact of influenza virus on ENaC and ASL height increased obviously after MTECs were treated with influenza virus. Taken together, these results suggest that influenza virus causes the changes of biophysical profile in the airway by altering the ENaC activity at least partly via facilitating the expression of WNK4.

MicroRNAs (miRNAs), a series of small noncoding RNAs that regulate gene expression at the post-transcriptional/translational level, are pivotal in cell differentiation, biological development, occurrence, and development of diseases, especially in cancers. Early studies have shown that miRNA-335 (miR-335) is widely dysregulated in human cancers and play critical roles in tumorigenesis and tumor progression. In this review, we aim to summarize the regulation of miR-335 expression mechanisms in cancers. We focus on the target genes regulated by miR-335 and its downstream signaling pathways involved in the biological effects of tumor growth, invasion, and metastasis both in vitro and in vivo, and analyze the relationships between miR-335 expression and the clinical characteristics of tumors as well as its effects on prognosis. The collected evidences support the potential use of miR-335 in prognosis and diagnosis as well as the therapeutic prospects of miR-335 in cancers.

The high resistant rate of Adriamycin (Adr) is associated with a poor prognosis of breast cancer in women worldwide. Since miR-222 might contribute to chemoresistance in many cancer types, in this study, we aimed to investigate its efficacy in breast cancer through PTEN/Akt/p27 kip1 pathway. Firstly, in vivo, we verified that miR-222 was upregulated in chemoresistant tissues after surgery compared with the paired preneoadjuvant samples of 21 breast cancer patients. Then, human breast cancer Adr-resistant cell line (MCF-7/Adr) was constructed to validate the pathway from the parental sensitive cell line (MCF-7/S). MCF-7/Adr and MCF-7/S were transfected with miR-222 mimics, miR-222 inhibitors, or their negative controls, respectively. The results showed that inhibition of miR-222 in MCF-7/Adr significantly increased the expressions of PTEN and p27 kip1 and decreased phospho-Akt (p-Akt) both in mRNA and protein levels (p < 0.05) by using quantitative real-time PCR (qRT-PCR) and western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased the IC50 of MCF-7/Adr cells. Additionally, immunofluorescence demonstrated that the subcellular location of p27 kip1 was dislocated resulting from the alteration of miR-222. Conversely, in MCF-7/S transfected with miR-222 mimics, upregulation of miR-222 is associated with decreasing PTEN and p27 kip1 and increasing Akt accompanied by less apoptosis and higher IC50. Importantly, Adr resistance induced by miR-222 overexpression through PTEN/Akt/p27 was completely blocked by LY294002, an Akt inhibitor. Taken together, these data firstly elucidated that miR-222 could reduce the sensitivity of breast cancer cells to Adr through PTEN/Akt/p27 kip1 signaling pathway, which provided a potential target to increase the sensitivity to Adr in breast cancer treatment and further improved the prognosis of breast cancer patients.