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Previous reports have shown that histone deacetylase inhibitors (HDACi) can alter miRNA expression in a range of cancers. Both the 5p-arm and 3p-arm of mature miRNAs can be expressed from the same precursor and involved in cancer progress. Nevertheless, the detailed mechanism by which vorinostat (SAHA), a HDACi, triggers miR-769-5p/miR-769-3p-mediated suppression of proliferation and induces apoptosis in gastric cancer (GC) cells remains elusive. Here, we showed that the miRNA-seq analysis of GC cells treated with SAHA identified seven differentially expressed miRNAs with both strands of the miRNA duplex. miR-769-5p/miR-769-3p expression was downregulated in GC tissues compared with normal tissues. Functionally, high expression of miR-769-5p/miR-769-3p blocked the malignant abilities of GC cells. Mechanistically, miR-769-5p/miR-769-3p targeted IGF1R and IGF1R overexpression rescued the effects of miR-769-5p/miR-769-3p on GC cells growth and metastasis. Moreover, STAT3 bound to the promoter of miR-769. Furthermore, miR-769-5p/miR-769-3p expression was negatively regulated by the STAT3-IGF1R-HDAC3 complex. Besides, miR-769-5p/miR-769-3p synergized with SAHA to promote GC cells apoptosis. Our studies suggest that miR-769-5p/miR-769-3p acts as a tumor suppressor by the STAT3-IGF1R-HDAC3 complex. Moreover, SAHA triggers miR-769-5p/miR-769-3p-mediated inhibition of proliferation and induces apoptosis in GC cells.

Fanhai Lin,1,2,* Zhenming Yang,1,3,* Ye Qiu,4 Wen Zeng,3 Guangnan Liu,5 Jianquan Zhang1 1Department of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, Guangdong, 518000, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530016,People’s Republic of China; 3Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 4Department of Comprehensive Internal Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 5Department of Respiratory Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530005,People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianquan ZhangDepartment of Respiratory and Critical Medicine, The Eighth Affiliated Hospital, Sun Yat-Sen University, No. 3025, Shennan Middle Road, Shenzhen, 518000, Guangdong, People’s Republic of ChinaTel +8613978123845Fax +86755-23482484Email jqzhang2002@126.comBackground: Talaromyces marneffei is considered to commonly cause infection in individuals with human immunodeficiency virus (HIV) infection. However, the epidemiology of T. marneffei has changed, and an increasing number of HIV-negative but immunodeficient patients are infected with T. marneffei. The mechanisms of T. marneffei infection of HIV-negative hosts are complex and diverse. We report 2 cases of HIV-negative lung cancer with T. marneffei infection and positive anti-interferon-gamma autoantibodies (AIGAs) to provide clinical experience.Case Presentation: We report lung adenocarcinoma combined with T. marneffei infection in HIV-negative patients, and their AIGAs were measured. Both patients were male with a family history of cancer and presented with recurrent fever and cough. The patients were negative for HIV antibodies but positive for AIGAs. Chest computed tomography (CT) showed pulmonary nodules, exudative lesions and solid changes. The patients were diagnosed with lung adenocarcinoma and Talaromycosis marneffei (TSM) by pathological examination and tissue culture. Patient 1 received only antifungal treatment, refused antitumor treatment and died in February 2019, and Patient 2 unfortunately died in April 2019 after antifungal and antitumor treatments.Conclusion: An increasing number of HIV-negative but immunodeficient patients are infected with T. marneffei. The 2 patients in this report had lung cancer and positive AIGAs, causing immunodeficiencies, but the mechanism of T. marneffei infection in such patients is complex. Clinically, we should consider a comprehensive immunological examination to avoid the omission of other immunodeficiencies. We recommend routine testing for AIGA levels in HIV-negative marneffei patients. It is difficult to distinguish between lung cancer and disseminated TSM due to similar clinical characteristics and imaging, and multiple biopsies and cultures of diseased tissue are necessary. Early antifungal treatment and standard antitumor treatment can achieve satisfactory curative effects when a patient has both diseases.Keywords: Talaromyces marneffei, lung adenocarcinoma, adult immunodeficiency, anti-interferon-γ antibodies

Palmprint has a high application prospect due to the stability, uniqueness, difficulty of reproduction, easy acquisition and high user acceptance of its own texture characteristics. However, palmprint images acquired at long distances and in low light conditions lose a amount of significant palmprint texture features, which in turn will affect the accuracy of palmprint recognition. Combining traditional methods with deep learning methods, this paper proposes a low-illumination palmprint image enhancement method based on wavelet transform and improved UNet (insertion of integrated attention gate at the UNet jump connection, GUNet). Firstly, the input image is decomposed by wavelet transformation to obtain the decomposition result of the original image, that is the high-frequency image and the low-frequency image. Secondly,the high-frequency image is enhanced by the GUNet neural network to enhance the palmprint texture, and low-frequency images use weighted averaging to smooth low-frequency information other than palm texture information. After that, the palmprint image with a clear palmprint texture is obtained by the wavelet inverse transformation. Numerous experiments are carried out on palmprint databases such as Idiap, CASIA, IITD and a laboratory self-collection. Experimental results show that the proposed approach has higher PSNR, SSIM and VIF indicators than some existing methods, which suggest palmprint image with low-illumination can be significantly enhanced.

Background This study aims to establish a predictive risk model for deep vein thrombosis (DVT) in patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD) based on serum angiopoietin 2 (Ang-2) levels. Methods The research sample consisted of 650 patients with AECOPD admitted to the First Affiliated Hospital of Chengdu Medical College from January 2019 to January 2021, who were subsequently divided into a modeling group and a verification group. A univariate analysis was performed on the identified risk factors for DVT in AECOPD, and the significant factors were then incorporated into a multivariate logistic regression model to screen for the independent predictors of DVT. A nomogram was constructed, and a receiver operating characteristic curve (ROC), Hosmer-Lemeshow test, decision curve, and clinical impact curve in the modeling and validation cohort were used to analyze the discrimination power, calibration, and clinical validity of the predictive risk nomogram model of AECOPD with comorbid DVT. Results Univariate and multivariate logistic regression analyses showed that lower limb edema, BMI, diabetes, respiratory failure, D-dimer, and serum Ang-2 were risk factors for DVT in AECOPD. A nomogram model for predicting AECOPD with comorbid DVT was successfully established. The AUC values for the modeling group and the verification group were 0.844 (95% CI: 0.808-0.932) and 0.755 (95% CI: 0.679-0.861), respectively. According to the Hosmer-Lemeshow test, the P values of the nomogram in the modeling group and the verification group were 0.124 and 0.086, respectively. The decision curve and clinical impact curve suggested that most patients can benefit from this prediction model, and the predicted probability of the model was essentially the same as the actual clinical probability of DVT. Conclusions The predictive risk nomogram model of AECOPD with comorbid DVT based on serum Ang-2 levels has good discrimination power, calibration, and clinical influence. The model is a good fit and has a high predictive value, which helps clinicians identify AECOPD patients at high risk of DTV and formulate corresponding prevention and treatment measures.

HOXA6 gene plays a role of the oncogene in various cancers. Nonetheless, its effect on gastric cancer (GC) occurrence and development is still unclear. We analysed whether HOXA6 interacts with the PBX2 protein using the STRING database. The molecular mechanism by which HOXA6 synergizes with PBX2 in GC metastasis is not fully understood. Here, we found that the expression of HOXA6 was increased in GC tissues and cell lines. The upregulation of HOXA6 was closely associated with differentiation, lymph node metastasis, AJCC stage, TNM stage, and poor survival outcome in GC patients based on tissue microarray (TMA) data. Moreover, the overexpression of HOXA6 promoted, whereas siRNA-mediated repression of HOXA6 inhibited, the cell proliferation, migration, and invasion of GC cells. Furthermore, HOXA6 could physically interact with and stabilize PBX2. In addition, HOXA6 and PBX2 expression was positively correlated in GC cells and tissue. HOXA6 and PBX2 suppression in GC cells also led to decreased migration and invasion potential in vitro. In vivo, HOXA6 was shown to cooperate with PBX2 to enhance cell metastasis via orthotopic implantation. These data indicate that HOXA6 promotes cell proliferation, migration, and invasion and that the HOXA6-PBX2 axis may be a useful biomarker for disease progression in GC.

Purpose Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. Methods To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. Results We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman’s correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. Conclusion Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells.

Previous studies have shown an association between coiled-coil domain-containing (CCDC) genes and different cancers. Our previous studies revealed that CCDC43 is highly expressed in colorectal cancer, but the expression and molecular mechanisms of CCDC43 in gastric cancer (GC) are yet to be determined. Here, we show that CCDC43 is overexpressed in gastric tissues. CCDC43 expression is closely related to tumor differentiation, lymph-node-metastasis, and prognosis of gastric cancer. Overexpression of CCDC43 promotes the proliferation, invasion, and metastasis of GC cells. CCDC43 may upregulate and stabilize ADRM1, resulting in the construction of the ubiquitin-mediated proteasome. In contrast, inhibition of ADRM1 could reverse the function of CCDC43 in GC both in vitro and in vivo. Our data demonstrate that transcription factor YY1 directly binds to CCDC43 and ADRM1 gene promoters, leading to over-expression of CCDC43 and ADRM1. Furthermore, in vitro experiments demonstrate that knock down of CCDC43 or ADRM1 attenuates the YY1-mediated malignant phenotypes. Finally, the association among YY1, CCDC43 and ADRM1 is validated in clinical samples. Our findings suggest that the CCDC43-ADRM1 axis regulated by YY1, promotes proliferation and metastasis of GC, and the axis may be a potential therapeutic target for GC.

Cigarette smoke is a major effector of chronic obstructive pulmonary disease (COPD), and Th17 cells and dendritic cells (DCs) involve in the pathogenesis of COPD. Previous studies have demonstrated the anti-inflammatory effects of macrolides. However, the effects of macrolides on the cigarette smoke extract- (CSE-) induced immune response are unclear. Accordingly, in this study, we evaluated the effects of erythromycin (EM) on CSE-exposed DCs polarizing naïve CD4+ T cells into Th17 cells. DCs were generated from bone marrow-derived mononuclear cells isolated from male BALB/c mice and divided into five groups: control DC group, CSE-exposed DC group, CD40-antibody-blocked CSE-exposed DC group, and EM-treated CSE-exposed DC group. The function of polarizing CD4+ T cells into Th17 cells induced by all four groups of DCs was assayed based on the mixed lymphocyte reaction (MLR) of naïve CD4+ T cells. CD40 expression in DCs in the CSE-exposed group increased significantly compared with that in the control group (P<0.05). The Th17 cells in the CSE-exposed DC/MLR group increased significantly compared with those in the control DC/MLR group (P<0.05). Moreover, Th17 cells in the CD40-blocked CSE-exposed DC/MLR group and EM-treated CSE-exposed DC/MLR group were reduced compared with those in the CSE-exposed DC/MLR group (P<0.05). Thus, these findings suggested that EM suppressed the CSE-exposed DC-mediated polarization of CD4+ T cells into Th17 cells and that this effect may be mediated through inhibition of the CD40/CD40L pathway.

Bisphenol F (BPF) is a widely used bisphenol A (BPA) substitute plastic additive that has attracted increasing public concerns due to its potential toxic effects on animal and human health. Although previous studies have indicated that BPF might have harmful effects on metabolic homeostasis, the systematic effects of BPF on glucose disorders remain controversial. In this study, mice fed a normal chow diet (ND) and high-fat diet (HFD) were administered BPF at a dose of 100 μg/kg of body weight, and glucose metabolism was monitored after both short- and long-term treatment. Little change in glucose metabolism was observed in BPF-treated ND mice, but improved glucose metabolism was observed in BPF-treated HFD mice. Consistently, BPF treatment led to increased insulin signalling in the skeletal muscle of HFD mice. Additionally, liver metabolite levels also revealed increased carbohydrate digestion and improved TCA cycle progression in BPF-treated HFD mice. Our results demonstrate that sustained BPF exposure at an environmentally relevant dosage may substantially improve glucose metabolism and enhance insulin sensitivity in mice fed a high-fat diet.

Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.

The coiled-coil domain-containing protein 43 (CCDC43) is essential to promote gastric cancer (GC) proliferation and invasion, while four and a half LIM domains 1 (FHL1) involves GC cells apoptosis. We attempted to address inter-relationship between CCDC43 and FHL1 in modulating GC cells growth and apoptosis. Levels of protein expression were assessed by western blot, immunofluorescence. Using EdU, plate colony formation, Matrigel invasion and animal models, we evaluated the function in vitro and in vivo. Apoptosis was evaluated by flow cytometry and Hoechst 33258 staining. Reciprocal co-immunoprecipitation (co-IP) analyses indicated that CCDC43 physically interacted with FHL1. The expression of CCDC43 was negatively correlated with FHL1. Moreover, up-regulation of CCDC43 resulted in FHL1 level decline, and the reverse is also true. CCDC43 expressed jointly with FHL1 group significantly decreases the ability of the growth, metastasis and invasion of GC cells compared with that of the CCDC43 group. Furthermore, siRNA-mediated repression of CCDC43 results in dissociation from FHL1 and causes suppression of GC cell proliferation and metastasis. CCDC43 repression mediates the stability of FHL1 protein. In addition, CCDC43 interacts with FHL1. Knockdown of CCDC43 plus FHL1 overexpression inhibits proliferation and migration and induces apoptosis of GC cells in vitro and vivo.

Background: dedicator of cytokinesis 2 is an atypical guanine exchange factor, which is particularly expressed in hematopoietic cells and modulates the activation along with the migration of immune cells by activating Ras--related C3 botulinum toxin substrate (Rac). Nevertheless, the role of DOCK2 in lung adenocarcinoma (LUAD) remains unclear.Methods: Herein, we performed bioinformatics analysis of lung adenocarcinoma data abstracted from TCGA (The Cancer Genome Altas) and GEO (Gene Expression Omnibus) data resources, and combined with web tools consisting of LinkedOmics, TIMER, and TISIDB. Finally, combined with clinical lung adenocarcinoma samples, we verified the expression of DOCK2 in tissue and its effect on the prognosis of lung adenocarcinoma.Results: In the TCGA lung adenocarcinoma data set, the expression of DOCK2 was down-regulated in tumor tissues and verified in multiple independent cohorts. In addition, the low expression of DOCK2 indicates a poor overall survival(OS) in both TCGA and other GEO data sets and in our clinical samples. COX regression data illustrated that the low expression of DOCK2 was an independent predictor for OS. Functional network analysis shows that DOCK2 participates in immune response through interleukin production, neuroinflammatory response, acquired immune response, leukocyte migration and activation of lymph node cells, and is related to multiple immune-related pathways. Besides, the expression of DOCK2 was remarkably related with many kinds of tumor infiltrating immune cells.Conclusion: combined with bioinformatics analysis and clinical sample verification, our study shows that DOCK2 can independently estimate the prognosis of lung adenocarcinoma and is related to immune infiltration. As a promising prognostic indicator and potential target of immunotherapy, the potential effect of DOCK2 on lung adenocarcinoma and its molecular mechanism are worthy of further discussion.

Traumatic tracheal stenosis (TS) is a serious respiratory disease characterized by hyperplasia of airway granulation. Plumbagin (PLB) is a natural naphthoquinone component with anti-fibrotic properties. This research aimed to explore the roles of PLB in alleviating TS and the underlying mechanisms. For in vitro studies, lung fibroblasts (IMR-90 cells), with/without PLB treatment or TGF-β1 induction, were used. The viability and proliferation of IMR-90 cells were examined by CCK-8 and EdU incorporation assays. The differentiation of IMR-90 cells was assessed by detecting the mRNA and protein expression levels of collagen (COL)-1 and alpha-smooth muscle actin (α-SMA). Besides, immunofluorescence assay was conducted to evaluate the localization of α-SMA in TGF-β1-induced IMR-90 cells. Moreover, the combination of PLB with/without TβRI (SB-431,542), PI3K/Akt (Ly294002) or mTOR (rapamycin) inhibitor was pretreated on IMR-90 cells after TGF-β1 induction. For in vivo studies, a rat model of TS was established. The pathological features and severity of TS were determined by hematoxylin and eosin staining. The protein levels of TGF-β1/Smad and Akt/mTOR pathways were detected for both in vitro and in vivo models. PLB effectively inhibited the proliferation and differentiation of TGF-β1-induced IMR-90 cells, and suppressed TGF-β1/Smad and Akt/mTOR signaling pathways both in vivo and in vitro. Furthermore, PLB reduced the degree of TS in rats. Taken together, our results indicate that PLB regulates lung fibroblast activity and attenuates TS in rats by inhibiting TGF-β1/Smad and Akt/mTOR signaling pathways. In conclusion, this study implies that PLB may serve as a promising therapeutic compound for TS., Graphical abstract, GRAPHICAL ABSTRACT

Through a bottom-up strategy, CdS quantum dots (QDs) doped with 12 gold atoms in each nanocrystal (NC) were prepared by cation exchange reactions. The (Au12) dopants inside the CdS matrix were directly observed using Cs-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) images and quantitatively confirmed using the inductively coupled plasma atomic emission spectroscopy (ICP-AES) data. With a photoluminescence quantum yield (PLQY) of 37.5%, the as-prepared (Au12)@CdS QDs emitted light at 635 nm. Due to the injection of excited electrons from the lowest unoccupied molecular orbital (LUMO) of dopants to the conduction band (CB) of CdS, multiple fine peaks were observed in the photoluminescence excitation (PLE) spectra. By using clusters as starting materials, we demonstrate a universal approach for the precise tailoring of dopants and provide a pathway for band energy engineering of doped QDs.

BACKGROUND Primary pulmonary mucosa-associated lymphoma tissue lymphoma is rare and is often misdiagnosed because of its diverse and nonspecific clinical features. The aim of this study was to raise awareness among clinicians and to share our experience of treating and managing such patients. MATERIAL AND METHODS This retrospective study was conducted between 1 January 2009 and 31 October 2017 at the First Affiliated Hospital of Guangxi Medical University. All cases were confirmed via pathology and immunohistochemistry. In addition, we reviewed all relevant literature. RESULTS Altogether, 21 patients (7 female, 14 male) with a median age of 54 (range, 19-84) years were diagnosed with primary pulmonary mucosa-associated lymphoma. Expiratory dyspnea, repeated cough and expectoration, and weight loss were the most common symptoms. Pulmonary lesions were found via physical examination in 10 patients who had no obvious symptoms. Chest computed tomography showed nodules, pulmonary consolidation, bronchial bronchogram, ground-glass opacity, and mediastinal lymph node enlargement. Some patients were misdiagnosed with tuberculosis and pneumonia, while others were initially diagnosed with cancer. Tumor pathology and immunocytochemistry indicated primary pulmonary mucosa-associated lymphoma tissue lymphoma. Six patients underwent chemotherapy, 5 underwent surgery, 4 underwent surgery and chemotherapy, 3 were only observed, and 3 refused treatment. CONCLUSIONS The development of primary pulmonary mucosa-associated lymphoid tissue lymphoma is slow and insidious. Having no specific clinical symptoms and imaging findings, it is easily misdiagnosed. Final diagnosis is made via pathologic evaluation and immunohistochemistry. Surgery and chemotherapy are the primary treatment modalities and yield a good prognosis.

Tracheal stenosis following injury cannot be effectively treated. The current study compared the protective effects of different anti-inflammatory drugs on tracheal stenosis and investigated their possible mechanisms. Rabbit tracheal stenosis models following injury were constructed and confirmed using hematoxylin and eosin (H&E) staining. A total of 30 rabbits were divided into the control (CON), penicillin (PEN), erythromycin (ERY), budesonide (BUD) and PEN + ERY + BUD groups (n=6). Stenotic tracheal tissue, serum and bronchoalveolar lavage fluid (BALF) were collected 10 days after continuous treatment. Pathological changes in the tracheas were observed by H&E staining. Histone deacetylase 2 (HDAC2) expression in tracheal tissues was detected by immunofluorescence. Immunohistochemistry was performed to detect collagen I (Col-I) and collagen III (Col-III) levels in tracheal tissues. Transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8) levels in serum and BALF samples were determined using ELISA kits. Western blotting detected HDAC2, IL-8, TGF-β1 and VEGF levels in tracheal tissues. H&E staining demonstrated that tracheal epithelial hyperplasia and fibroblast proliferation in the ERY and PEN + ERY + BUD groups markedly improved compared with the CON group. Furthermore, in tracheal tissues, HDAC2 expression was significantly increased and IL-8, TGF-β1, VEGF, Col-I and Col-III levels were significantly decreased in the ERY and PEN + ERY + BUD groups compared with the CON group. Additionally, the results for the PEN + ERY + BUD were more significant compared with the ERY group. In serum and BALF samples, IL-8, TGF-β1 and VEGF levels in the ERY and PEN + ERY + BUD groups were significantly lower compared with the CON group, with the results of the PEN + ERY + BUD group being more significant compared with the ERY group. There were no significant differences between the PEN, BUD and CON groups. ERY inhibited tracheal granulation tissue proliferation and improved tracheal stenosis following injury and synergistic effects with PEN and BUD further enhanced these protective effects. The mechanism may involve HDAC2 upregulation and inhibition of local airway and systemic inflammatory responses.

Bisphenol S (BPS), an industrial chemical that is a structural analogue of bisphenol A, has been widely reported to be involved in various biological processes. Epidemiological studies have demonstrated that exposure to BPS is associated with dysglycaemia-related health outcomes. The role of BPS in glucose metabolism, however, remains controversial. In this study, we aimed to investigate the effects of chronic exposure to environmentally relevant concentrations of BPS on glucose metabolism in different nutritionally conditioned mice. Our results revealed that 1-month exposure to a BPS dosage of 100 μg/kg bw slightly increased the insulin sensitivity of normal diet-fed mice, and that this effect was enhanced after 3-month exposure. It was also found that BPS exposure attenuated insulin resistance and reduced gluconeogenesis in high-fat diet-fed mice. Consequently, the concentrations of hepatic metabolites related to glucose metabolism were altered in both groups of mice. Moreover, thyroid hormone signalling was disrupted after BPS administration in both groups of mice. Taken together, our results demonstrated that chronic exposure to environmentally relevant concentrations of BPS exerted an unexpected hypoglycaemic effect in mice of different nutritional statuses, and that this was partly attributable to disrupted thyroid hormone signalling.

Acquired tracheal stenosis is a common disease occurring after endotracheal intubation or tracheotomy. Currently, surgery is the main option to treat the stenosis. This study investigated therapeutic effect and possible mechanism of nintedanib on tracheal stenosis. The rabbit models of tracheal stenosis were established and were administered with nintedanib and budesonide. The damage and repair of the tracheal tissue were determined using hematoxylin and eosin (HE) staining. The expression of histone deacetylase 2 (HDAC2), interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western Blot and immunofluorescence assay. The expression of collagens I and III was assayed immunohistochemically. Remarkable tracheal stenosis was observed after the trachea was brushed in the rabbit model. Compared with control, the stenosis was improved after nintedanib treatment. The mRNA of HDAC2 was increased and that of IL-8 and VEGF was decreased significantly in the tracheal tissue following nintedanib treatment. Western blot analysis showed that HDAC2 increased to the level similar to that of control while VEGF remained unchanged following nintedanib treatment. Budesonide treatment also resulted in increased HDAC2 expression and decreased IL-8 and VEGF expression. Immunofluorescence assays also showed an increased HDAC2 expression following nintedanib treatment. Collagens I and III decreased significantly after nintedanib treatment in the tracheal tissues of models. Therefore, it is concluded that nintedanib alleviates the acquired tracheal stenosis by activating HDAC2 expression and suppressing IL-8 and VEGF expression, and may offer new option to medical treatment for the disease.

Background Long-term observations and studies have found that the occurrence and development of lung adenocarcinoma (LUAD) is associated with certain metabolic changes and that metabolic disorders are directly related to carcinogenic gene mutations. We attempted to establish a prognostic model for LUAD based on the expression profiles of metabolic genes. Method We analyzed the gene expression profiles of patients with LUAD obtained from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to assess the correlation between each metabolic gene and survival. The survival-related metabolic genes were fit into the least absolute shrinkage and selection operator (LASSO) to establish a prognostic model for LUAD. After 100,000 times of calculations and model construction, we successfully established a prognostic model consisting of 16 genes that can classify patients with LUAD into high-risk and low-risk groups. Further, the protein-protein interaction (PPI) network was built to determine the hub gene from16 metabolic genes. Finally, the top one hub gene was validated by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in our 50 paired LUAD and adjacent tissues, and the prognostic performance of 16 metabolic genes was validated in GEO LUAD cohorts. Results Univariate Cox regression analysis and LASSO regression analysis results showed that the prognostic model established based on 16 metabolic genes could differentiate patients with LUAD with significantly different overall survival (OS) and that the prognosis of the high-risk group was worse than that of the low-risk group. In addition, the model can independently predict the OS of patients in both the training cohort and the validation cohort (training cohort: HR =2.44, 95% CI: 1.58–3.74, P

Objective. This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis. Methods. The rabbit model of tracheal stenosis was established. The rabbits were randomly divided into 8 groups. Histone deacetylase-2 (HDAC2) expression was detected by immunofluorescence. The expression of type I collagen and type III collagen was detected by immunohistochemical method. The expression of TGF-β1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-β1, VEGF and IL-8 in bronchi of each group was detected by Western blotting method. Results. In Erythromycin (ERY) group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group, the degree of bronchial stenosis was alleviated, and the mucosal epithelium was still slightly proliferated. The effect of ERY combined with other drugs was more obvious. The HDAC2 protein expression increased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group and decreased significantly in Vorinostat group, the expression of collagen I and III decreased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group (P<0.05). The TGF-β1, IL-8 and VEGF levels decreased significantly in ERY group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group (P<0.05). Conclusions. Erythromycin inhibited inflammation and excessive proliferation of granulation tissue after tracheobronchial mucosal injury by up-regulating the expression of HDAC2, it promoted wound healing and alleviated tracheobronchial stenosis. When combined with budesonide, penicillin and other glucocorticoids and antibiotics, it had a good synergistic effect. However, vorinostat could attenuate erythromycin’s effect by down-regulating the expression of HDAC2. It may have good clinical application prospects in the treatment of tracheal stenosis.

Talaromyces marneffei (TM) is an important opportunistic pathogenic fungus capable of causing disseminated lethal infection. In our previous study, we identified host lncRNAs and mRNAs that are dysregulated in TM-infected bronchial epithelial cells. In this report, we verified that IL-6, a key factor in acute inflammatory response, is down-regulated in TM pathogenesis. To elucidate the mechanism of IL-6 regulation, we analyzed the coding/non-coding network, and identified lncSSBP1, a novel lncRNA that is up-regulated by TM. Our results demonstrate that overexpression of lncSSBP1 decreases IL-6 mRNA expression, whereas knockdown of lncSSBP1 enhances IL-6 mRNA expression. Though lncSSBP1 is primarily localized to the nucleus, bioinformatics analysis suggests that it is unlikely to function as competing endogenous RNA or to interact with IL-6 transcription factors. Instead, RNA pull down and RNA immunoprecipitation assays showed that lncSSBP1 binds specifically to heterogenous nuclear ribonucleoprotein K (hnRNPK), which is involved in IL-6 mRNA processing. Our findings suggest that lncSSBP1 may affect IL-6 mRNA expression during TM infection through interaction with hnRNPk in bronchial epithelial cells. Our results suggest a novel pathway by which TM may suppress the immune response to its advantage.

In human gastric cancer (GC), the upregulation of FOXK1 and vimentin is frequently observed in cancer cells and correlates with increased malignancy. We report that FOXK1 synergizes with vimentin to promote GC invasion and metastasis via the induction of epithelial-mesenchymal transition (EMT). We showed that higher expression levels of FOXK1 were significantly associated with GC development. FOXK1 can physically interact with and stabilize vimentin. Moreover, a positive correlation between the expression of FOXK1 and vimentin was found in GC cells. Higher expression levels of these two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage, and poorer prognosis. Furthermore, the coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of EMT in GC cells. However, the siRNA-mediated repression of vimentin in FOXK1-overexpressing cells reversed the EMT-like phenotype and reduced GC cell migration and invasion in vitro and in vivo. Altogether, our findings suggest that the vimentin-FOXK1 axis provides new insights into the molecular mechanisms underlying EMT regulation during GC progression and metastasis.

Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-α, IL-6 and IL-12, subsequently inducing differentiation of IFN-γ producing CD8+T cells and IL-17-producing CD8+T cells from mouse naive CD8+T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-γ producing CD8+T and IL-17-producing CD8+T cell-mediated immune responses.

Background Lung adenocarcinoma is characterized by early asymptomatic progression and metastasis. Appearance of respiratory symptoms usually means the disease is aggravated. The aim of this study was to identify the protein profile in plasma of lung adenocarcinoma of stages I-IV, and look for novel diagnostic biomarkers. Methods Isobaric tags for relative and absolute quantification (iTRAQ) coupled with two dimensional liquid chromatography - tandem mass spectrometry technology (2D LC-MS/MS) was applied to separate and identify differential expression of proteins in plasma specimens from 10 healthy individuals, 10 patients with pneumonia, 7 patients with lung adenocarcinoma of stages I-II, respectively, and 10 patients with lung adenocarcinoma of stages III-IV, then analyze the functions of the differential expression of proteins by bioinformatics. Results ADAMTS-like protein 4, Fibrinogen-like protein 1 precursor, secretoglobin family 3A member 2 and haptoglobin were up-regulated in patients with lung adenocarcinoma by proteomics analysis, and the expression levels of SCGB3A2 and Hp by ELISA were consistent. Pathway analysis of identified differential expression of proteins showed they were mainly involved in chemokine/p53/TGF-beta signaling pathway. Conclusions Plasma SCGB3A2 is a potential maker for diagnosis of primary pulmonary adenocarcinoma. Abnormal post-translational protein modification may be associated with the progression of lung cancer.