Effects of Different Exercise Intensities on the Rat Model of Heart Failure.

Heart failure (HF) is a clinical syndrome caused by the progression of various cardiac diseases to severe stages, and exercise training plays a positive role in the development of HF. This study aimed to investigate the impact of different intensities of exercise training on HF rats.In this study, we established two HF rat models by intraperitoneal injection of isoproterenol at 2.5 mg/kg/day and abdominal aortic coarctation. After exercise training for 4 weeks, the heart weight/body weight ratio and echocardiography results were measured. Moreover, the regulatory effect of different exercise intensities on myocardial function in HF model rats was verified using tissue staining, western blotting, and reagent kits.Exercise training had a bidirectional adjust effect on HF. A running training program of 20 minutes/time had the most significant effect on improving myocardial function in HF rats, whereas exercise intensity of 40 minutes/time or 50 minutes/time did not significantly improve myocardial function in HF rats. Moreover, exercise intensities of 20 minutes/time and 30 minutes/time could reduce the expression levels of the HF markers NT-proBNP and BNP in rats, but the effect was more significant at a duration of 20 minutes/time. We also found that compared with other exercise intensities, 20 minutes/time exercise intensity could significantly improve myocardial fibrosis, promote cardiomyocyte autophagy, and reduce apoptosis in combating HF.Furthermore, an exercise intensity of 20 minutes/time can significantly ameliorate the progression of HF. However, the degree of significance of increasing exercise intensity in improving HF progression is weakened or has no significant effect.

The causal relationship between physical activity, sedentary time and idiopathic pulmonary fibrosis risk: a Mendelian randomization study.

BACKGROUND: Several observational studies have found that physical inactivity and sedentary time are associated with idiopathic pulmonary fibrosis (IPF) risk. However, the causality between them still requires further investigation. Therefore, our study aimed to investigate the causal effect of physical activity (PA) and sedentary time on the risk of IPF via two-sample Mendelian randomization (MR) analysis. METHODS: Multiple genome-wide association study (GWAS) data involving individuals of European ancestry were analyzed. The datasets encompassed published UK Biobank data (91,105-377,234 participants) and IPF data (2018 cases and 373,064 controls) from FinnGen Biobank. The inverse variance weighting (IVW) method was the primary approach for our analysis. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger regression, MR-PRESSO global test, and leave-one-out analysis. RESULTS: Genetically predicted self-reported PA was associated with lower IPF risk [OR = 0.27; 95% CI 0.09-0.82; P = 0.02]. No causal effects of accelerometry-based PA or sedentary time on the risk of IPF were observed. CONCLUSIONS: Our findings supported a protective relationship between self-reported PA and the risk for IPF. The results suggested that enhancing PA may be an effective preventive strategy for IPF.

High neutrophil-lymphocyte ratio indicates a worse response to ursodeoxycholic acid in primary biliary cholangitis: a retrospective cohort study.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by inflammation of the interlobular bile ducts. Ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to 40% of patients with PBC have an incomplete response to UDCA. Neutrophil-to-lymphocyte (NLR) has been used to predict prognosis in various liver diseases. There is limited evidence on the treatment response to UDCA in PBC patients. Our study aimed to evaluate the relationship between NRL and the response to UDCA treatment in PBC patients. METHODS: A total of 257 primary biliary cholangitis (PBC) patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on alkaline phosphatase levels ≤1.67 times the upper limit of the normal value after 12 months of UDCA treatment. Multivariable logistic regression analysis was performed to investigate the association between NLR at baseline and the response to 12 months of UDCA treatment after adjusting for important confounding variables. The stability of the results was evaluated by unadjusted and adjusted models. RESULTS: The results of multiple regression analysis showed that NLR at baseline was positively associated with the nonresponse to UDCA treatment after adjustments for potential confounders (age, sex, BMI, hypertension, arterial plaque, thyroid disease, jaundice, albumin, globulin, total bile acid, ALP, GGT, LDLC, total cholesterol, hemoglobin, and APTT) (OR = 1.370, 95% CI 1.066-1.761). These results reveal that NLR is an independent risk factor for UDCA treatment nonresponse. CONCLUSIONS: Our results suggest that PBC patients with a high NLR had a worse response to UDCA therapy.

Rapamycin attenuates the paraquat-induced pulmonary fibrosis through activating Nrf2 pathway.

Oxidative stress is a key regulator of idiopathic pulmonary fibrosis. Paraquat (PQ)-induced pulmonary fibrosis seriously endangers people's health. Rapamycin has been reported to alleviate PQ-induced pulmonary fibrosis, but its underlying mechanism is unclear. The nuclear factor E2-related factor 2 (Nrf2) plays an important regulatory role in the antioxidant therapy of PQ-induced pulmonary fibrosis. In this study, we tried to confirm that rapamycin attenuates PQ-induced pulmonary fibrosis by regulating Nrf2 pathway. In vivo, we proved that rapamycin could inhibit the degree of PQ-induced oxidant stress as well as enhanced the expression of Nrf2. In vitro, rapamycin decreased the upregulated effects of cell death and apoptosis, fibrosis-related factors expression and fibroblast-to-myofibroblast transformation by PQ treatment. In vivo, rapamycin treatment reduced fibrosis degree and the expression of fibrosis-related factors in lung tissues of rat treated PQ. Furthermore, we also found that Nrf2 knockdown reduced the inhibitory effect of rapamycin on PQ-induced pulmonary fibrosis, as well as decreased Nrf2 transfer from the cytoplasm into the nucleus. Our findings demonstrated that the protective effect of rapamycin is associated with the activation of the Nrf2 pathway in pulmonary fibrosis induced by PQ poisoning.

Inhibitory effect of circulating fibrocytes on injury repair in acute lung injury/acute respiratory distress syndrome mice model.

The study was aimed to explore the functions of circulating fibrocytes (CFs) on injury repair in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) mice model and its clinical value as a biomarker for ALI/ARDS. ALI/ARDS mice model was established by intratracheal instillation of lipopolysaccharide (LPS). Mononuclear cells were isolated from peripheral blood of ALI/ARDS model and flow cytometry was used to measure CFs defined as cells positive for CD45 and collagen-1. Histological changes of lung tissues were evaluated by H&E staining and Masson's trichrome staining. The correlations of CFs counts with damnification of lung tissue and the severity of pulmonary fibrosis were evaluated by Pearson correlation analyses. Western blot was used to detect the protein expression of collagen-1. ELISA was applied to determine cytokine CXCL12 concentration. Clinical relevance between CFs and ALI/ARDS was investigated. The greater number of CFs in the ALI/ARDS group implied higher degree of lung injury and more severe pulmonary fibrosis. The protein expression of collagen-1 and concentration of cytokine CXCL12 in ALI/ARDS group were higher than that in control group. Clinical and prognostic analysis revealed the higher injury degree and death rates in ALI/ARDS group than those in control group, and identified a greater severity and mortality for patients with ARDS than those with ALI. ROC curve analysis indicated the counts of CFs greater than 5.85% can predict death rates with AUC = 0.928. CFs had an inhibitory effect on injury repair in ALI/ARDS mice model. This might be unfavorable as a clinical marker for progression of ALI/ARDS.

Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung.

BACKGROUND/AIMS: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). METHODS: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. RESULTS: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). CONCLUSION: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

Rapamycin protects against paraquat-induced pulmonary fibrosis: Activation of Nrf2 signaling pathway.

Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ-induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway.

IL-27 inhibits the TGF-ß1-induced epithelial-mesenchymal transition in alveolar epithelial cells.

BACKGROUND: IL-27 is a multifunctional cytokine that has both pro-inflammatory and anti-inflammatory functions. Although IL-27 has been shown to potently inhibit lung fibrosis, the detailed mechanism of IL-27 in this process is poorly understood. Epithelial-mesenchymal transition (EMT) is one of the key mechanisms involved in pulmonary fibrosis. We assessed the effects of IL-27 on TGF-ß1-induced EMT in alveolar epithelial cells. METHODS: A549 cells (a human AEC cell line) were incubated with TGF-ß1, IL-27, or both TGF-ß1 and IL-27, and changes in E-cadherin, ß-catenin, vimentin and a-SMA levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT and TGF-ß/Smad signalling pathways were examined by western blot. RESULTS: IL-27 increased the expression of epithelial phenotypic markers, including E-cadherin and ß-catenin, and inhibited mesenchymal phenotypic markers, including vimentin and a-SMA in A549 cells. Moreover, TGF-ß1-induced EMT was attenuated by IL-27. Furthermore, we found that TGF-ß1 activated the phosphorylation of JAK1, STAT1, STAT3, STAT5, Smad1, Smad3 and Smad5, and IL-27 partially inhibited these changes in this process. When cells were treated with the STAT3 specific inhibitor wp1006 and the Smad3 specific inhibitor SIS3, the inhibition of EMT by IL-27 was significantly strengthened. CONCLUSION: Our results suggest that IL-27 attenuates epithelial-mesenchymal transition in alveolar epithelial cells in the absence or presence of TGF-ß1 through the JAK/STAT and TGF-ß/Smad signalling pathways.

Ethnic and geographic variations in HPV prevalence and genotype distribution in north-western Yunnan, China.

The prevalence and genotype distribution of human papillomavirus (HPV) vary throughout the world. To assess the prevalence and genotype distribution of HPV among three ethnic groups in two geographic locations in north-western Yunnan, we recruited 522 women in Shangri-le (n = 255) and Lijiang (n = 267). PCR amplification of HPV DNA was performed on cervical cells from these women using two consensus primer systems (MY09/11 and GP5/6). Amplified-HPV DNA was genotyped using the HPV GenoArray test. Geographically, the HPV prevalence was significantly higher (P = 0.002) among Shangri-le women than among Lijiang women. Infections with high-risk (HR)-HPV and with multiple HPV genotypes were also significantly more common (P = 0.001) among women in Shangri-le than women in Lijiang. Additionally, the prevalence of overall, HR-HPV, and single genotype HPV infections was significantly higher (P = 0.001) among Tibetan women than among Naxi and Han women. HPV-16 and HPV-33 were significantly more frequent in Shangri-le women compared with Lijiang (P = 0.006) women. In addition, HPV-16 (9.81%) and HPV-33 (5.88%) were significantly more prevalent in Tibetan women than in Naxi and Han women. Here, for the first time, we highlight the significant variation in the prevalence and genotype distribution of HPV in various populations in the north-western region of Yunnan Province.

Epidemiologic characterization of human papillomavirus (HPV) infection in various regions of Yunnan Province of China.

BACKGROUND: This study was designed to determine the Human papillomavirus (HPV) prevalence and its distribution of genotypes in various regions of Yunnan Province, China. METHOD: In this study, participants were recruited during routine gynecologic examination between Oct 2013 and Feb 2015. A total of 17,898 women were recruited. Polymerase chain reaction was used for detecting the HPV positive samples and HPV geno-array test was used for genotyping. RESULTS: The overall HPV infection rate (19.9 %) among the south-western women was significantly higher (P = 0.001) than that among the north-western (18.0 %), south-eastern (13.3 %), north-eastern (11.1 %) and central women (12.9 %). The high-risk (HR) (18.1 %, P = 0.001) and single genotype (16.7 %, P = 0.001) infection rates among the South-western women were also significantly higher than those of among the north-western (13.9 %, 11.3 %), south-eastern (11.6 %, 10.5 %), north-eastern (9.6 %, 9.1 %) and central women (10.5 %, 10.0 %), respectively. While, the infections with multiple HPV (4.2 %) genotypes were significantly more common (P = 0.001) among women in north-western Yunnan than women in the south-western (1.3 %, 3.1 %), south-eastern (1.7 %, 2.7 %), north-eastern (1.5 %, 2.0 %) and central Yunnan (2.4 %, 2.9 %). A total of 30 HPV genotypes were detected; among them 13 were HR-HPV, 3 were PHR-HPV (Potential High risk), 8 were LR-HPV (Low risk) and six were unclassified. The most common HPV genotypes were HPV-52, 16, 58, 53 in control group, HPV-16, 52, 58, 39 and 53 in CINI (Cervical intraepithelial Neoplasia), HPV-52, 16, 58, 33, 53 and 81 in CINII, HPV16, 58, 18, 52, 81 in CINIII and HPV-16 18, 58, 52 in cervical cancer (CC), respectively. Such variation has also been observed about distribution of HPV genotypes distribution among single and multiple infections. CONCLUSION: This study gives an epidemiological estimate of HPV prevalence and different genotype distribution in various region of Yunnan province and further explains its prevalence in different neoplastic lesions. Overall HPV-16, 52, 58, and 18 are the leading HR-HPV genotypes.

IL-27 alleviates the bleomycin-induced pulmonary fibrosis by regulating the Th17 cell differentiation.

BACKGROUND: Interleukin-27 (IL-27) is a multifunctional cytokine with both pro-inflammatory and immunoregulatory functions. At present, the role of IL-27 in pulmonary fibrosis remains unknown. METHODS: In this study, we observed the expression of IL-27/IL-27R in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We verified the role of IL-27 using hematoxylin and eosin as well as Masson's staining methods and measuring the content of hydroxyproline as well as collagen I and III. We assessed the differentiation of T lymphocytes in the spleen and measured the concentration of cytokines in bronchoalveolar lavage fluid (BALF) and the expression level of relevant proteins in the JAK/STAT and TGF-ß/Smad signaling pathways in lung tissue. RESULTS: Increased IL-27 expression in BLM-induced pulmonary fibrosis was noted. IL-27 treatment may alleviate pulmonary fibrosis and increase the survival of mice. IL-27 inhibited the development of CD4(+) IL-17(+), CD4(+) IL-4(+) T, and CD4(+) Foxp3(+) cells and the secretion of IL-17, IL-4, IL-6, and TGF-ß. IL-27 induced the production of CD4(+) IL-10(+) and CD4(+) INF-γ(+) T cells. IL-27 decreased the levels of phosphorylated STAT1, STAT3, STAT5, Smad1, and Smad3 but increased the level of SOCS3. CONCLUSIONS: This study demonstrates that IL-27 potentially attenuates BLM-induced pulmonary fibrosis by regulating Th17 differentiation and cytokine secretion.

Reasons why women are more likely to develop primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune disease of biliary stasis in which immune factors cause the gradual destruction of small bile ducts, biliary stasis, and eventually the development of liver fibrosis, cirrhosis, and even liver failure. One of the main characteristics of PBC is that it primarily affects middle-aged women, but the precise cause is still unknown. This article analyzes the unique causes and mechanisms of the female predominance of PBC and summarizes the potential causes.The female domination of PBC is reported to be primarily caused by sex hormones, environmental circumstances, and epigenetic changes, each of which has a different subtle impact on patients' gender disparities.

ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC), a typical autoimmune liver disease, is characterized by an increased infiltration of immune cells. However, the specific molecular mechanisms regulating immune cell migration in PBC are unknown. Engulfment and cell motility 1 (ELMO1) plays an important function in cellular dynamics. In view of this, the aim of this study was to explore the expression of ELMO1 in PBC, its effects on the proliferation, migration, and secretion of inflammatory factors by the mainly regulated immune cells and the specific molecular mechanisms behind it. METHODS: To determine the expression of ELMO1 in PBC and its major regulatory immune cells in PBC. The migratory and proliferative capacities of ELMO1-deficient macrophages were measured, and their pro-inflammatory cytokine secretion was also detected and explored mechanistically. RESULTS: ELMO1 expression was up-regulated in the PBC patients and positively correlated with alkaline phosphatase (ALP). ELMO1 mainly regulated macrophages in the liver of PBC patients. Knockdown of ELMO1 did not affect macrophage proliferation, however,knockdown of ELMO1 significantly inhibited macrophage migration,downstream RAC1 activity was diminished, and reduced F-actin synthesis. Knockdown of ELMO1 reduced macrophage inflammatory factor secretion and NF-κB signaling pathway activity was decreased. CONCLUSIONS: ELMO1 regulates macrophage directed migration and attenuates inflammation via NF-κB signaling pathway in primary biliary cholangitis.

siRNA-Act1 inhibits the function of IL-17 on lung fibroblasts via the NF-κB pathway.

BACKGROUND: Interleukin (IL)-17-producing T lymphocytes play a role in pulmonary fibrosis, but the possible mechanism of IL-17 on lung fibroblasts remains uncertain. OBJECTIVES: To explore the role and possible mechanism of IL-17 on lung fibroblasts. METHODS: A mouse model of pulmonary fibrosis was established by intratracheal administration of 5 mg/kg bleomycin. At 14 days following bleomycin administration the pulmonary fibroblasts were isolated, cultured and identified. siRNA for activator 1 (Act1) were transfected into lung fibroblasts, which were cocultured with IL-17. The NF-κB pathway was detected for IL-17 on the lung fibroblasts. RESULTS: IL-17R was increased significantly at 14 days in the bleomycin-induced pulmonary fibroblast model, exogenous IL-17 significantly promoted the proliferation of the pulmonary fibroblasts in primary culture and obviously increased the expression of α-smooth muscle actin and type I and type III collagen in the fibroblasts. We found that IL-17 rapidly activated the NF-κB signaling pathway through activated phosphorylated p65 and IκB, and all roles of IL-17 on lung fibroblasts were inhibited under the interference for the expression of Act1 in lung fibroblasts. CONCLUSION: IL-17 may directly promote the proliferation, transformation and collagen synthesis of lung fibroblasts via the NF-kB signaling pathway, which can be inhibited by the interference for the expression of Act1.

PU.1 negatively regulates tumorigenesis in non-small-cell lung cancer.

PU.1 is a key transcription factor that modulates hematopoietic cell differentiation and is involved in various physiological and pathological processes. PU.1 has been described to have multiple roles in a diverse range of cancers, but its contribution in non-small-cell lung cancer (NSCLC) has not been clearly elucidated. Fifty pairs of lung adenocarcinoma (LUAD) tissues and paraneoplastic tissues were collected. RT-qPCR assay was used to test PU.1 expression. Expression of PU.1 in LUAD cell lines and control cell lines was detected by RT-qPCR, and the role of PU.1 in LUAD was investigated by in vitro experiment. Levels of the major proteins in the apoptotic pathway were also detected by Western blot. The expression of PU.1 was remarkably downregulated in LUAD. Overexpression of PU.1 impaired the viability of LUAD cells as well as their metastatic function. In addition, PU.1 promoted apoptosis of LUAD cells by decreasing Bcl2 and increasing Bax/Bak1 expression. PU.1 plays an inhibitory role in LUAD, mainly promoting the apoptosis of LUAD cells.

Transcriptomic and metabolomic analysis of liver cirrhosis.

BACKGROUND: Liver cirrhosis is one of the leading causes of decreased life expectancy worldwide. However, the molecular mechanisms underlying liver cirrhosis remain unclear. In this study, we performed a comprehensive analysis using transcriptome and metabolome sequencing to explore the genes, pathways, and interactions associated with liver cirrhosis. METHODS: We performed transcriptome and metabolome sequencing of blood samples from patients with cirrhosis and healthy controls (1:1 matched for sex and age). We validated the differentially expressed microRNA (miRNA) and mRNAs using real-time quantitative polymerase chain reaction. RESULTS: For transcriptome analysis, we screened for differentially expressed miRNAs and mRNAs, analyzed mRNAs to identify possible core genes and pathways, and performed co-analysis of miRNA and mRNA sequencing results. In terms of the metabolome, we screened five pathways that were substantially enriched in the differential metabolites. Next, we identified the metabolites with the most pronounced differences among these five metabolic pathways. We performed receiver operating characteristic (ROC) curve analysis of these five metabolites to determine their diagnostic efficacy for cirrhosis. Finally, we explored possible links between the transcriptome and metabolome. CONCLUSION: Based on sequencing and bioinformatics, we identified miRNAs and genes that were differentially expressed in the blood of patients with liver cirrhosis. By exploring pathways and disease-specific networks, we identified unique biological mechanisms. In terms of metabolomes, we identified novel biomarkers and explored their diagnostic efficacy. We identified possible common pathways in the transcriptome and metabolome that could serve as candidates for further studies.

METTL3 regulatory TROAP can regulate the progression of non-small cell lung cancer through PI3K/AKT and EMT signaling pathway.

TROAP, interacts with trophinin and bystin, polys a key role in embryo implantation. TROAP is required for spindle assembly and centrosome integrity during the mitosis. TROAP has been described to promote tumorigenesis in a diverse range of cancer. We performed this study to assess the biological and clinical significance of TROAP in Non-small cell lung cancer. Forty-eight pairs of lung adenocarcinoma (LUAD) tissues and paraneoplastic tissues were collected. RT-qPCR, western bolt and immunohistochemistry assay was used to test TROAP RNA and protein expression not in LUAD tissues and paraneoplastic tissues but in LUAD cell lines and control cell lines. TROAP knockdown and overexpression vector were constructed and transfected into lung cancer cells. CCK-8, transwell, and wound healing assays were used to assess cell viability, migration, and invasion. The expression of PI3K/AKT and EMT signaling proteins and METTL3 were determined by western blot. We found the TROAP was enriched in NSCLC tissues and cell lines. TROAP knockdown inhibited cell proliferation, migration, invasion compared with control group in NSCLC. Mechanism analysis revealed that TROAP activated PI3K/AKT and EMT signaling pathway. To a certain extent, TROAP was regulated by METTL3. In a word, TROAP accelerated the progression of NSCLC through PI3K/AKT and EMT pathway, and TROAP might be considered as a novel target for NSCLC therapy.

The role of all-trans retinoic acid in bleomycin-induced pulmonary fibrosis in mice.

Much evidence suggests that immune imbalance in the lung plays a crucial role in the development of pulmonary fibrosis. Recently, all-trans retinoic acid (ATRA) shifting the regulatory T/T-helper 17 (Treg/Th17) profile had been proven in some diseases. However, to date, the effect of ARTA of pulmonary fibrosis has not been examined from this aspect. The objective of this study was to study the effect of ATRA on bleomycin-induced pulmonary fibrosis in mice and its possible mechanism. Pulmonary fibrosis was induced in C57BL/6 male mice by intratracheal instillation of bleomycin (5 mg.kg(-1)), which were randomly divided into control, bleomycin, and ATRA groups. Five mice in each group were sacrificed on day 28 after intratracheal instillation. Hemotoxylin and eosin (H&E) and Masson staining were used for pathological examination, and hydroxyproline in lung tissue was measured. Interleukin (IL)-17A protein expression was observed in lung with immunohistochemistry. The expression of IL-17A, IL-10, IL-6, and transforming growth factor (TGF)-ß mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Th17 and Treg expression in spleen lymphocytes were measured by flow cytometry. H&E and masson staining and expression of hydroxyproline showed that ATRA significantly alleviated lung fibrosis than in the bleomycin group. The expression of IL-17A, IL-10, IL-6, and TGF-ß mRNAs were higher in the bleomycin group than in the normal group. ATRA can decrease these cytokines except for IL-10. CD4+CD25+ Treg cell ratio in the bleomycin group was significantly lower than normal, but CD4+IL-17+ T cells was higher; ARTA reversed this kind of expression. ATRA may ease the bleomycin-induced pulmonary fibrosis by inhibiting the expression of IL-6 and TGF-ß, shifting the Treg/Th17 ratio and reducing the secretion of IL-17A.

CDKN2B antisense RNA 1 expression alleviates idiopathic pulmonary fibrosis by functioning as a competing endogenouse RNA through the miR-199a-5p/Sestrin-2 axis.

Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial lung disease. At present, the pathogenesis of IPF has not been fully elucidated, which has affected the development of effective treatment methods. Here, we explored the function and potential mechanism of long noncoding RNA (lncRNA) CDKN2B antisense RNA 1 (CDKN2B-AS1) in IPF.Transforming growth factor-ß (TGF-ß) and bleomycin (BLM) were used to induce IPF in cells and animal models. Real Time quantitative Polymerase Chain Reaction (RT-qPCR) showed the expression of CDKN2B-AS1, miR-199a-5p and Sestrin-2 (SESN2) in cells and tissues. The double luciferase reporter gene assay confirmed the targeting relationship among CDKN2B-AS1, miR-199a-5p, and SESN2. Related protein levels were detected by Western blot combined with Cell Counting Kit-8 (CCK-8), wound healing, and flow cytometry to analyze cell proliferation, migration, and apoptosis. The pathological characteristics of mouse lung tissue were determined by Hematoxylin-eosin (HE) and Masson staining. We found that the expression of CDKN2B-AS1 was decreased in TGF-ß-treated cells and BLM-treated mice. Overexpression of CDKN2B-AS1 inhibited cell proliferation and migration, promoted apoptosis, decreased the expression of fibrosis-related proteins and promoted autophagy. In addition, overexpression of CDKN2B-AS1 alleviated pulmonary fibrosis in BLM-treated mice. Mechanistically, CDKN2B-AS1 acts as a miR-199a-5p sponge to regulate SESN2 expression. Our results indicate the importance of the CDKN2B-AS1/miR-199a-5p/SESN2 axis.

Emergence of Carbapenem-Resistant ST244, ST292, and ST2446 Pseudomonas aeruginosa Clones in Burn Patients in Yunnan Province.

Introduction: The prevalence of carbapenem-resistant Pseudomonas aeruginosa is increasing persistently, particularly in burn ward isolates. Here, we investigate the prevalence of carbapenem-resistant Pseudomonas aeruginosa in a burn ward of a provincial-level hospital at Kunming, Yunnan province, China. Methods: A total of 118 P. aeruginosa strains were isolated from 57 hospitalized patients, and their MICs were measured. Carbapenem-resistant isolates were selected for multilocus sequence typing (MLST). Carbapenem-resistance mechanisms were identified by examining carbapenemase genes and OprD protein and Carba-NP testing. Representative isolates were further characterized by de novo sequencing for carbapenemase molecular background. Results: Among 118 P. aeruginosa isolates, 54 (54/118,45.8%) were carbapenem-resistant Pseudomonas aeruginosa, and 3 genotypes were found (ST292, ST244, and ST2446). Non-carbapenemase-producing ST292 was the most prevalent ST, followed by ST2446 and ST244. A novel 13-bp oprD deletion was found in the ST292 clone, which formed the truncated outer membrane protein and may cause carbapenem resistance. ST244 and ST2446 harbored blaIMP-45 and blaIMP-87, respectively. blaIMP-45 is located in a megaplasmid, together with aac(6')-Ib3, blaOXA-1, catB3, qnrVC6, armA, msr(E), mph(E), aph(3')-Ia, tetC/tetR, aac(6')-Ib3, floR, mexC-mexD-oprJ, fosA and lead to extensive drug resistance. ST2446 contains a carbapenem-resistant gene blaIMP-87 on the chromosome and is acquired by a novel gene cassette array (blaIMP-87-ant(2")-Ia-blaOXA-10-aac(6')-Ib3) of class 1 integron. Discussion: For the first time, ST244, ST292 and ST2446 are reported emerging in burn patients, with distinctive carbapenem-resistance mechanisms, respectively. The obtained results highlight the need to surveillance carbapenem-resistant isolates in burn patients.