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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) bears high mortality due to unclear pathogenesis and limited therapeutic options. Therefore, identifying novel regulators is required to develop alternative therapeutic strategies. METHODS: The lung fibroblasts from IPF patients and Reticulocalbin 3 (RCN3) fibroblast-selective knockdown mouse model were used to determine the importance of Rcn3 in IPF; the epigenetic analysis and protein interaction assays, including BioID, were used for mechanistic studies. RESULTS: Reticulocalbin 3 (RCN3) upregulation is associated with the fibrotic activation of lung fibroblasts from IPF patients and Rcn3 overexpression blunts the antifibrotic effects of pirfenidone and nintedanib. Moreover, repressing Rcn3 expression in mouse fibroblasts ameliorates bleomycin-induced lung fibrosis and pulmonary dysfunction in vivo. Mechanistically, RCN3 promotes fibroblast activation by maintaining persistent activation of TGFß1 signalling via the TGFß1-RCN3-TGFBR1 positive feedback loop, in which RCN3 upregulated by TGFß1 exposure detains EZH2 (an epigenetic methyltransferase) in the cytoplasm through RCN3-EZH2 interaction, leading to the release of the EZH2-H3K27me3 epigenetic repression of TGFBR1 and the persistent expression of TGFBR1. CONCLUSIONS: These findings introduce a novel regulating mechanism of TGFß1 signalling in fibroblasts and uncover a critical role of the RCN3-mediated loop in lung fibrosis. RCN3 upregulation may cause resistance to IPF treatment and targeting RCN3 could be a novel approach to ameliorate pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , Animais , Camundongos , Receptor do Fator de Crescimento Transformador beta Tipo I , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Bleomicina/toxicidade , Modelos Animais de Doenças , Fibroblastos , Proteínas de Ligação ao CálcioRESUMO
BACKGROUND: Gene variants have been identified in patients with familial or sporadic idiopathic pulmonary fibrosis (IPF). These variants may partially account for the genetic risk of IPF. The aim of this study was to identify potential genes involved in both familial and sporadic IPF. METHODS: A Han family in northern China with four members diagnosed with IPF was investigated in this observational study. Whole-exome sequencing (WES) was used to identify germline variants underlying disease phenotypes in five members of this family. Candidate rare variants were validated by Sanger sequencing in samples from 16 family members and 119 patients with sporadic IPF. The plasma levels of proteins encoded by the above candidate genes were also examined in 16 family members, 119 other patients with sporadic IPF and 120 age- and sex-matched healthy controls. RESULTS: In a Chinese Han family, MMP19 c.1222 C > T was identified in all familial IPF patients and six offspring from generations III and IV. This variant introduces a premature stop codon, which may damage protein function. Sanger sequencing revealed that 7.6% (9/119) of sporadic IPF patients harbored three MMP19 variants. The genetic risk analysis for pulmonary fibrosis showed that MMP19 c.1499 C > T and c.1316G > A were significantly associated with an increased risk of IPF (OR 3.66, p = 0.028 and OR 8.64, p < 0.001, respectively). The plasma levels of MMP19 were significantly higher in patients with sporadic or familial IPF than in healthy controls (all p < 0.001). CONCLUSIONS: MMP19 variants were identified in familial or sporadic IPF, thus providing a potential new clue into IPF pathogenesis.
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Fibrose Pulmonar Idiopática , Humanos , China/epidemiologia , Fibrose Pulmonar Idiopática/genética , Fatores de RiscoRESUMO
PURPOSE: To explore in myeloperoxidase-antineutrophil cytoplasmic autoantibody-associated vasculitis (MPO-AAV) the value of circulating oncomarkers in identifying interstitial lung disease (ILD) and predicting prognosis. METHODS: Newly diagnosed MPO-AAV patients were evaluated retrospectively at a single center. The serum levels of carbohydrate antigen (CA) 19-9, CA125, cytokeratin fraction 21-1 (CYFRA21-1), carcinoembryonic antigen, squamous cell carcinoma antigen, and neuron-specific enolase were compared between patients with and without ILD. The strength of the oncomarkers in identifying ILD was assessed through logistic regression and receiver operating characteristic (ROC) curves. Correlation analysis was applied to detect the associations between oncomarkers and ILD severity. The significance of serum oncomarkers as prognosis predictors for MPO-AAV associated ILD was evaluated by survival analysis. RESULTS: 169 MPO-AAV patients were included and ILD was found in 101 patients. Serum CA125, CA19-9, and CYFRA21-1 were significantly higher in patients with ILD than those without ILD. The area under the ROC curve of CA19-9, CA125, and CYFRA21-1 for identifying ILD was 0.701, 0.660, and 0.711, respectively. A specificity of 98.5% for diagnosing ILD was found for CA19-9 at the recommended normal level. CA19-9 was positively correlated with HRCT fibrosis score (r = 0.498, p < 0.001) and CYFRA21-1 was correlated with ground-glass score (r = 0.316, p = 0.002). Both CA19-9 and CYFRA21-1 were independent risk factors for all-cause mortality in patients with ILD. CONCLUSION: Serum CA19-9 and CYFRA21-1 might be useful markers in the diagnosis, disease severity evaluation, and prognosis prediction of MPO-AAV-associated ILD.
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Doenças Pulmonares Intersticiais , Vasculite , Anticorpos Anticitoplasma de Neutrófilos , Antígenos de Neoplasias , Antígeno Ca-125 , Antígeno CA-19-9 , Humanos , Queratina-19 , Doenças Pulmonares Intersticiais/etiologia , Peroxidase , Prognóstico , Estudos Retrospectivos , Vasculite/complicaçõesRESUMO
BACKGROUND: Asbestosis and fibrotic hypersensitivity pneumonitis (FHP) share the pathogenetic mechanisms induced bronchiolocentric fibrotic process secondary to inhalation exposure. Under the occupational and environmental mixed exposures, asbestosis and FHP are needed to make the differential diagnoses on high-resolution computed tomography (HRCT), especially in the countries still using asbestos. The study aimed to analyze the HRCT features of asbestosis versus FHP. METHODS: The patients with asbestosis or with HP were sequentially recruited in this comparative study at Beijing Chaoyang Hospital between January 2006 and December 2016. Patients' clinical data were obtained from a predesigned charts. The international classification of HRCT for occupational and environmental respiratory diseases was used to categorize chest imaging findings in patients. The calculation of test statistics was used to compare the imaging features of asbestosis and FHP. RESULTS: 341 patients with asbestosis and 158 patients with HP were sequentially recruited, among which 204 patients with asbestosis and 74 patients with FHP were eligible for data analysis. Patients with asbestosis were older and had a longer latent period until disease manifestation than those with FHP. Asbestosis was characterized by irregular and/or linear opacities, with lower lung preponderance, accompanied by ground-glass opacities and mosaic attenuation. Notably, 98.5% of patients with asbestosis showed benign pleural abnormalities, and 39.7% of these patients had diffuse pleural thickening with parenchymal bands and/or rounded atelectasis. Abnormalities of the mediastinal and diaphragmatic pleura were observed only in cases of asbestosis, and this finding showed high specificity for the diagnosis for asbestosis compared with that for FHP. Subpleural dots or diaphragmatic pleural abnormalities showed moderate sensitivity and high specificity for diagnosis of asbestosis compared with that for FHP. Interobserver reliability was good for evaluation of imaging findings including honeycombing, pleural calcification, lymphadenectasis, and lymph node calcification. CONCLUSIONS: HRCT-based imaging findings can distinguish between asbestosis and FHP to a certain extent, particularly with regard to subpleural dots and diaphragmatic pleural abnormalities that characterize the former.
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Alveolite Alérgica Extrínseca , Amianto , Asbestose , Doenças Pleurais , Alveolite Alérgica Extrínseca/diagnóstico por imagem , Amianto/efeitos adversos , Asbestose/diagnóstico por imagem , Fibrose , Humanos , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/métodosRESUMO
Consumption of dietary fiber and anthocyanin has been linked to a lower incidence of colorectal cancer (CRC). This study scrutinizes the potential antitumorigenic attributes of a black rice diet (BRD), abundantly rich in dietary fiber and anthocyanin. Our results demonstrate notable antitumorigenic effects in mice on BRD, indicated by a reduction in both the size and number of intestinal tumors and a consequent extension in life span, compared to control diet-fed counterparts. Furthermore, fecal transplants from BRD-fed mice to germ-free mice led to a decrease in colonic cell proliferation, coupled with maintained integrity of the intestinal barrier. The BRD was associated with significant shifts in gut microbiota composition, specifically an augmentation in probiotic strains Bacteroides uniformis and Lactobacillus. Noteworthy changes in gut metabolites were also documented, including the upregulation of indole-3-lactic acid and indole. These metabolites have been identified to stimulate the intestinal aryl hydrocarbon receptor pathway, inhibiting CRC cell proliferation and colorectal tumorigenesis. In summary, these findings propose that a BRD may modulate the progression of intestinal tumors by fostering protective gut microbiota and metabolite profiles. The study accentuates the potential health advantages of whole-grain foods, emphasizing the potential utility of black rice in promoting health.
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Background: Usual interstitial pneumonia (UIP) is a pattern of interstitial pneumonia that is caused by different etiologies. This study aimed to investigate the transplant-free survival (TFS) and the decline in forced vital capacity (FVC) of the patients with UIP and probable UIP patterns on CT caused by various underlying conditions. Methods: A retrospective cohort study was conducted, enrolling patients with interstitial lung disease exhibiting a CT pattern consistent with UIP or probable UIP. Clinical and prognostic data of patients categorized by the etiology were compared. Results: A total of 591 patients were included and classified into the following groups: idiopathic pulmonary fibrosis (IPF) (n = 320), connective tissue disease (CTD)-UIP (n = 229), asbestosis-UIP (n = 28), and hypersensitivity pneumonitis (HP)-UIP (n = 14). Advanced age, elevated levels of serum cytokeratin fraction 21-1 and percentage of neutrophils in bronchoalveolar lavage were observed in all groups. IPF patients showed a more rapid decline in FVC (133.9 mL/year) compared to CTD-UIP (24.5 mL/year, p = 0.001) and asbestosis-UIP (61.0 mL/year, p = 0.008) respectively. Sub-analysis of CTD-UIP revealed that patients with rheumatoid arthritis (RA)-UIP (88.1 mL/year) or antineutrophil cytoplasmic antibody-associated vasculitis (AAV)-UIP (72.9 mL/year) experienced a faster deterioration in FVC compared to those with primary Sjögren's syndrome (pSS)-UIP (25.9 mL/year, p < 0.05). Kaplan-Meier curves showed that IPF had the poorest TFS (median 55.9 months), followed by HP-UIP (57.5 months), CTD-UIP (66.7 months), and asbestosis-UIP (TFS not reached). RA-UIP or AAV-UIP did not exhibit any prognostic advantages compared to IPF, while asbestosis-UIP and pSS-UIP showed better survival rates. Conclusion: Patients with UIP caused by different underlying conditions share certain common features, but the trajectories of disease progression and survival outcomes differ.
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This study aimed to investigate the effects of dynamic high-pressure homogenization (DHPH), dynamic high-pressure microfluidization (DHPM), and wet media milling (WMM) processes on the particle size, microstructure, triple helix structure, wettability and suspension stability of insoluble undenatured type II collagen (IUC-II). The structural and powdery properties were regulated by different processes and parameters. By contrast, WMM-treated IUC-II showed smallest particle size (15.70 µm), highest wetting rate (216.94 mm/h) and best suspension stability. However, individual mechanical processes caused partial disruption of IUC-II triple helix structure. Low-acyl gellan gum (LAGG) could bind to IUC-II through hydrogen bonds and hydrophobic interactions, which protected the triple helix structure and further enhanced powdery properties of IUC-II treated by WMM process, but restrained the soluble transition during digestion. These results demonstrated that WMM process was more suitable for enhancing powdery properties of IUC-II, while the triple helix structure of IUC-II could be effectively protected by LAGG.
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Fenômenos Mecânicos , Colágeno Tipo II , Ligação de HidrogênioRESUMO
Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex-biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/ + mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo-germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo-germ mice receiving fecal sample from male mice. Sex-biased gut metabolites in pseudo-germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex-biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex-biased gut microbiota and metabolites could be a potential sex-targeting therapeutic strategy of CRC.
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Neoplasias Colorretais , Microbioma Gastrointestinal , Masculino , Feminino , Animais , Camundongos , Neoplasias Colorretais/patologia , Sulfato de Dextrana , Carcinogênese , Transformação Celular NeoplásicaRESUMO
OBJECTIVES: This study aimed to explore differences in clinical features and prognosis among patients with varied myeloperoxidase (MPO) antineutrophil cytoplasmic antibody-associated vasculitis (MPO-AAV) associated lung diseases. METHODS: Patients with MPO-AAV-associated lung diseases were enrolled in this retrospective cohort study at a single center. Clinical features and laboratory data at the time of diagnosis were compared among patients with various lung disease patterns. Kaplan-Meier and Cox regression analyses were performed to analyze overall survival. RESULTS: A total of 155 patients were finally included and categorized into five groups, as follows: 72 had a usual interstitial pneumonia (UIP) pattern, 40 had non-UIP interstitial pneumonia, 18 had bronchiectasis (BR), 13 had necrotizing granuloma (NG), and 12 had diffuse alveolar hemorrhage (DAH). Among the five groups, patients with DAH had higher dyspnea and hemoptysis frequencies, lower PaO2/FiO2 levels, elevated C-reactive protein levels, and the poorest prognosis. The overall survival (OS) in the DAH group (median OS: 3.2 months) was significantly poorer than that in the NG group (median OS: not reached, log rank P < 0.001), the BR group (median OS: not reached, log rank P < 0.001), and the non-UIP IP group (median OS: 61.1 months, log rank P = 0.001). The UIP group had significantly more ex-smokers than the other groups (P < 0.001) and the second poorest survival (median OS: 39.1 months). The NG group tended to have female predominance, a higher incidence of ENT involvement, less severe renal involvement, and the best survival. After adjusting for multi-model Cox regression analysis, DAH and UIP (hazard ratio: 19.301 and 9.940, respectively, compared with NG) were independent predictors of all-cause mortality. CONCLUSIONS: Various patterns of lung disease-associated MPO-AAV may potentially predict patient survival. Key Point ⢠The present study described the clinical and prognostic features of various lung diseases-associated MPO-AAV, indicating the potential prediction for the survival of MPO-AAV patients.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Pneumopatias , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Feminino , Humanos , Pneumopatias/complicações , Peroxidase , Estudos RetrospectivosRESUMO
The purpose of the present work is to fabricate emulsions with excellent stability to deliver ß-carotene using a novel biomacromolecule. ß-Lactoglobulin-ferulic acid-chitosan ternary conjugate (BFCC), which was synthesized based on the carbodiimide-mediated coupling reaction and laccase induction, was confirmed by Fourier transform infrared (FTIR) and proton nuclear magnetic resonance (1H NMR) spectra. Also, BFCC was used to stabilize ß-carotene emulsions. The results indicated that the concentration of BFCC affected the physical stability of ß-carotene emulsions. Compared with the emulsions stabilized by ß-lactoglobulin (ß-LG), chitosan-ferulic acid conjugate (CFC), and ß-LG-CFC mixture (BFCM), the emulsion stabilized by BFCC exhibited better stability under various environmental stresses. Moreover, the emulsion stabilized by BFCC had higher ß-carotene retention during storage at 25 and 55 °C or under ultraviolet (UV) light exposure. The knowledge acquired in the current research offered an effective way to develop novel biomacromolecular emulsifiers and could find potential in fabricating delivery systems for bioactive compounds with markedly enhanced physiochemical properties.
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Quitosana/química , Ácidos Cumáricos/química , Lactoglobulinas/química , beta Caroteno/química , Fenômenos Químicos , Emulsões/químicaRESUMO
The purpose of current research is to design and acquire novel biological macromolecule materials with enhanced functional properties. Chitosan-ferulic acid binary conjugate (CFC) was synthesized based on the carbodiimide-mediated coupling reaction, and then ß-lactoglobulin-ferulic acid-chitosan ternary conjugate (BFCC) was fabricated by laccase induction. Furthermore, the impact of laccase concentration on the formation mechanism of BFCC was investigated by the analyses of reaction group content, ultraviolet-visible (UV-vis) absorption, circular dichroism (CD), and fluorescence spectroscopy. Results showed that hetero- and homo-conjugates between CFC and ß-lactoglobulin (ß-LG) were achievable at the low concentration (≤4 U/mL) and high concentration (≥6 U/mL) of laccase, respectively. The CD spectrum indicated that the interaction with CFC made ß-LG more disorderly. Functional evaluation results revealed that the antioxidant activity and thermal stability of BFCC were improved compared with ß-LG. The knowledge obtained in the present study provided an effective method to acquire innovative biological macromolecule materials with desirable functional characteristics.