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Purpose: Impaired quality of life (QOL) is common in patients with inflammatory bowel disease (IBD). A tool to more quickly identify IBD patients at high risk of impaired QOL improves opportunities for earlier intervention and improves long-term prognosis. The purpose of this study was to use a machine learning (ML) approach to develop risk stratification models for evaluating IBD-related QOL impairments. Patients and Methods: An online questionnaire was used to collect clinical data on 2478 IBD patients from 42 hospitals distributed across 22 provinces in China from September 2021 to May 2022. Eight ML models used to predict the risk of IBD-related QOL impairments were developed and validated. Model performance was evaluated using a set of indexes and the best ML model was explained using a Local Interpretable Model-Agnostic Explanations (LIME) algorithm. Results: The support vector machine (SVM) classifier algorithm-based model outperformed other ML models with an area under the receiver operating characteristic curve (AUC) and an accuracy of 0.80 and 0.71, respectively. The feature importance calculated by the SVM classifier algorithm revealed that glucocorticoid use, anxiety, abdominal pain, sleep disorders, and more severe disease contributed to a higher risk of impaired QOL, while longer disease course and the use of biological agents and immunosuppressants were associated with a lower risk. Conclusion: An ML approach for assessing IBD-related QOL impairments is feasible and effective. This mechanism is a promising tool for gastroenterologists to identify IBD patients at high risk of impaired QOL.
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Metabolic-associated steatohepatitis (MASH) and ulcerative colitis (UC) exhibit a complex interconnection with immune dysfunction, dysbiosis of the gut microbiota, and activation of inflammatory pathways. This study aims to identify and validate critical butyrate metabolism-related shared genes between both UC and MASH. Clinical information and gene expression profiles were sourced from the Gene Expression Omnibus (GEO) database. Shared butyrate metabolism-related differentially expressed genes (sBM-DEGs) between UC and MASH were identified via various bioinformatics methods. Functional enrichment analysis was performed, and UC patients were categorized into subtypes using the consensus clustering algorithm based on sBM-DEGs. Key genes within sBM-DEGs were screened through Random Forest, Support Vector Machines-Recursive Feature Elimination, and Light Gradient Boosting. The diagnostic efficacy of these genes was evaluated using receiver operating characteristic (ROC) analysis on independent datasets. Additionally, the expression levels of characteristic genes were validated across multiple independent datasets and human specimens. Forty-nine shared DEGs between UC and MASH were identified, with enrichment analysis highlighting significant involvement in immune, inflammatory, and metabolic pathways. The intersection of butyrate metabolism-related genes with these DEGs produced 10 sBM-DEGs. These genes facilitated the identification of molecular subtypes of UC patients using an unsupervised clustering approach. ANXA5, CD44, and SLC16A1 were pinpointed as hub genes through machine learning algorithms and feature importance rankings. ROC analysis confirmed their diagnostic efficacy in UC and MASH across various datasets. Additionally, the expression levels of these three hub genes showed significant correlations with immune cells. These findings were validated across independent datasets and human specimens, corroborating the bioinformatics analysis results. Integrated bioinformatics identified three significant biomarkers, ANXA5, CD44, and SLC16A1, as DEGs linked to butyrate metabolism. These findings offer new insights into the role of butyrate metabolism in the pathogenesis of UC and MASH, suggesting its potential as a valuable diagnostic biomarker.
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Butiratos , Colite Ulcerativa , Biologia Computacional , Humanos , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Butiratos/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Curva ROC , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Bases de Dados Genéticas , Transcriptoma , Microbioma Gastrointestinal/genéticaRESUMO
Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.
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Ácido Butírico , Proliferação de Células , Neoplasias Colorretais , Fluoruracila , Microbioma Gastrointestinal , Transdução de Sinais , Ubiquitina-Proteína Ligases , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ácido Butírico/farmacologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Camundongos Nus , Sinergismo Farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Background: This study aims to elucidate the role of mitochondrial autophagy in metabolic dysfunction-associated steatohepatitis (MASH) by identifying and validating key mitophagy-related genes and diagnostic models with diagnostic potential. Methods: The gene expression profiles and clinical information of MASH patients and healthy controls were obtained from the Gene Expression Omnibus database (GEO). Limma and functional enrichment analysis were used to identify the mitophagy-related differentially expressed genes (mito-DEGs) in MASH patients. Machine learning models were used to select key mito-DEGs and evaluate their efficacy in the early diagnosis of MASH. The expression levels of the key mito-DEGs were validated using datasets and cell models. A nomogram was constructed to assess the risk of MASH progression based on the expression of the key mito-DEGs. The mitophagy-related molecular subtypes of MASH were evaluated. Results: Four mito-DEGs, namely MRAS, RAB7B, RETREG1, and TIGAR were identified. Among the machine learning models employed, the Support Vector Machine demonstrated the highest AUC value of 0.935, while the Light Gradient Boosting model exhibited the highest accuracy (0.9189), kappa (0.7204), and F1-score (0.9508) values. Based on these models, MRAS, RAB7B, and RETREG1 were selected for further analysis. The logistic regression model based on these genes could accurately predict MASH diagnosis. The nomogram model based on these DEGs exhibited excellent prediction performance. The expression levels of the three mito-DEGs were validated in the independent datasets and cell models, and the results were found to be consistent with the findings obtained through bioinformatics analysis. Furthermore, our findings revealed significant differences in gene expression patterns, immune characteristics, biological functions, and enrichment pathways between the mitophagy-related molecular subtypes of MASH. Subtype-specific small-molecule drugs were identified using the CMap database. Conclusion: Our research provides novel insights into the role of mitophagy in MASH and uncovers novel targets for predictive and personalized MASH treatments.
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Background: Numerous studies have cast light on the relationship between the gastric microbiota and gastric carcinogenesis. In this study, we conducted a bibliometric analysis of the relevant literature in the field of gastric cancer and the gastric microbiota and clarified its research status, hotspots, and development trends. Materials and methods: Publications were retrieved from the Web of Science Core Collection on 18 July 2023. CiteSpace 6.2.R4, VOSviewer 1.6.19.0, and Biblioshiny were used for the co-occurrence and cooperation analyses of countries, institutions, authors, references, and keywords. A keyword cluster analysis and an emergence analysis were performed, and relevant knowledge maps were drawn. Results: The number of published papers in this field totaled 215 and showed an increasing trend. The analysis of funding suggested that the input in this field is increasing steadily. China had the highest number of publications, while the United States had the highest betweenness centrality. Baylor College of Medicine published the most articles cumulatively. Both Ferreira RM and Cooker OO had the highest citation frequency. The journal Helicobacter showed the most interest in this field, while Gut provided a substantial research foundation. A total of 280 keywords were obtained using CiteSpace, which were primarily focused on the eradication and pathogenic mechanisms of Helicobacter pylori, as well as the application of the gastric microbiota in the evaluation and treatment of gastric cancer. The burst analysis suggested that in the future, research may focus on the application of gastric microorganisms, particularly Fusobacterium nucleatum, in the diagnosis and treatment of gastric cancer, along with their pathogenic mechanisms. Conclusion: Current studies have been tracking the eradication of Helicobacter pylori and its pathogenic mechanisms, as well as changes in the gastric microbiota during gastric carcinogenesis. Future research may focus on the clinical application and pathogenesis of stomach microorganisms through bacteria such as Fusobacterium nucleatum.
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Objective: To explore the impact of common gastrointestinal (GI) symptoms on psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD). Methods: A unified questionnaire was developed to collect clinical data on the mental psychology and quality of life of IBD patients from 42 hospitals in 22 provinces in P. R. China from September 2021 to May 2022. The general clinical characteristics, psychological symptoms, sleep quality, and quality of life of IBD patients with different numbers of GI symptoms were analyzed by descriptive statistical analysis. Results: A total of 2,478 IBD patients were finally analysed in this study, including 365 without GI symptoms (14.7%), 752 with single symptoms (30.4%), 841 with double symptoms (33.9%), and 520 with three symptoms (21.0%). Compared with patients without GI symptoms, patients with only simple abdominalgia or diarrhea or hematochezia showed significantly higher levels of anxiety and depression and worse quality of life (all P < 0.05). Compared with asymptomatic patients, patients with double symptoms (e.g. abdominalgia plus hematochezia, diarrhea plus hematochezia, abdominalgia plus diarrhea) and patients with three symptoms (abdominalgia, diarrhea, and hematochezia) showed significantly higher levels of anxiety and depression and worse sleep quality and quality of life (all P < 0.05). Conclusion: Compared with IBD patients without gastrointestinal symptoms, patients with gastrointestinal symptoms were more likely to experience anxiety, depression, sleep disturbances, and poorer quality of life.
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BACKGROUND & AIMS: Although biologics were prescribed to achieve and maintain clinical remission of active Crohn's disease (CD), almost half of patients experienced a loss of response or intolerance. Here, we investigated the efficacy of combined treatment of biologics and 16-weeks exclusive enteral nutrition (EEN) in moderate-to-severe CD patients with small intestine lesions. METHODS: This was a real-world, multicenter retrospective study, from October 2016 to March 2023, medical records of patients registered at three IBD centers were reviewed for patients with ileal or ileocolonic CD in moderate-to-severe activity. All patients received treatment of biologics with concomitant 16-week EEN (BioEEN) or biologics alone (Bio). The clinical outcomes and endoscopic outcomes were assessed at week 16 and 52. RESULTS: There was no statistically significant difference between Bio (97 patients) and BioEEN group (100 patients) at baseline for demographic and clinical characteristics. Compared to treatment with biologics alone, patients with BioEEN treatment achieved higher rates of clinical response (95.0% vs. 66.0%), clinical remission (87.0% vs. 52.6%), endoscopic response (91.4% vs. 47.4%) including mucosal healing (85.7% vs. 23.7%) at week 16. The superiority of BioEEN sustained in maintenance, with 84.7% (vs. 49.1%) clinical response, 77.8% (vs. 38.6%) clinical remission, 69.2% (vs. 32.6%) endoscopic response and 51.9% (vs. 18.6%) mucosal healing at week 52. CONCLUSIONS: Combined treatment of biologics and 16-week EEN was an efficient therapeutic strategy with affirmative effectiveness for small intestine diseases of active CD.
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Produtos Biológicos , Doença de Crohn , Nutrição Enteral , Humanos , Doença de Crohn/terapia , Nutrição Enteral/métodos , Masculino , Feminino , Estudos Retrospectivos , Adulto , Produtos Biológicos/administração & dosagem , Produtos Biológicos/uso terapêutico , Resultado do Tratamento , Pessoa de Meia-Idade , Terapia Combinada/métodos , Íleo , Adulto Jovem , Indução de Remissão/métodosRESUMO
Portal vein tumor thrombosis (PVTT) frequently leads to malignant ascites (MA) in individuals with hepatocellular carcinoma (HCC), remaining a bottleneck in the treatment. This study aimed to explore the differences in microbes in paired groups and provide novel insights into PVTT and MA-related treatments. Formalin-fixed paraffin embedding ascite samples were collected from MA secondary to HCC and benign ascites (BA) secondary to liver cirrhosis (LC). Ascitic microbiota profiles were determined in the HCC and LC groups by 16S rRNA sequencing. Prognostic risk factors were screened using survival analysis. The correlation between the significantly different microbial signatures in the groups with PVTT (WVT) and non-PVTT (NVT) and clinical characteristics was explored. The expression of different immune cells was determined by labeling four markers in the MA tissue chips using multiplex immunohistochemistry. A total of 240 patients (196 with HCC with MA and 44 with LC with BA) were included in this study. Microbial profiles differed between the HCC and LC groups. PVTT and Barcelona Clinic Liver Cancer stage were shown to be prognostic risk factors. Significant differences in the alpha and beta diversities were observed between the WVT and NVT groups. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC MA. Differences in microbial signatures between the WVT and NVT groups were correlated with the level of C-reactive protein and apolipoprotein A1. This study revealed the microbial differences in the tumor microenvironment of MA secondary to HCC and BA secondary to LC.IMPORTANCEFirst, we explored the alteration of the ascites ecosystem through the microbiota in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Second, this is the first clinical study to investigate the differences between patients with HCC with and without portal vein tumor thrombosis via 16S rRNA sequencing. These results revealed a decreased microbial diversity and metabolic dysregulation in individuals with HCC and portal vein tumor thrombosis. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC malignant ascitic fluid. Our study provides a new perspective on treating malignant ascites secondary to HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Veia Porta , RNA Ribossômico 16S , Carcinoma Hepatocelular/microbiologia , Humanos , Neoplasias Hepáticas/microbiologia , Masculino , Feminino , Veia Porta/microbiologia , Veia Porta/patologia , Pessoa de Meia-Idade , Prognóstico , RNA Ribossômico 16S/genética , Idoso , Ascite/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Trombose Venosa/microbiologia , Cirrose Hepática/complicações , Cirrose Hepática/microbiologia , AdultoRESUMO
BACKGROUNDS: The Gustave Roussy Immune (GRIm) score predicts survival outcomes in several cancers. However, the prognostic significance of the GRIm score in patients with malignant ascites has not yet been investigated. METHODS: Clinical samples were collected from a cohort of patients with malignant ascites secondary to hepatocellular carcinoma (HCC). We calculated serum GRIm (sGRIm) and ascites GRIm (aGRIm) scores and divided the samples into low and high GRIm score groups. Survival analysis was used to compare the prognostic significance of the sGRIm and aGRIm scores. 16S rRNA sequencing was performed to determine the profiles of the intratumoral microbiota in the groups. A fluorescent multiplex immunohistochemistry (mIHC) assay was used to detect the expression of different immune cells by labeling seven markers of malignant ascites. RESULTS: 155 patients with HCC and malignant ascites were enrolled in this study. Survival analysis revealed that the aGRIm score showed a superior prognostic significance compared to the sGRIm score. Microbial analysis demonstrated that the bacterial richness and diversity were higher in the low aGRIm score group than in the high aGRIm score group. LefSe analysis revealed that certain bacteria were correlated with high aGRIm scores. Fluorescent mIHC displayed the tumor microenvironment of malignant ascites and found that the density of CD8 + T cells was significantly higher in the low aGRIm score group than in the high aGRIm score group. CONCLUSIONS: Our present study identified a novel scoring system (aGRIm score) that can predict the survival outcome of patients with malignant ascites secondary to HCC.
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Ascite , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Ascite/imunologia , Ascite/microbiologia , Feminino , Masculino , Pessoa de Meia-Idade , Microbiota/imunologia , Idoso , Prognóstico , Microambiente Tumoral/imunologia , Adulto , RNA Ribossômico 16S/genéticaRESUMO
Objective: Ulcerative colitis (UC) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely intertwined; however, the precise molecular mechanisms governing their coexistence remain unclear. Methods: We obtained UC (GSE75214) and MASLD (GSE151158) datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were acquired by the 'edgeR' and 'limma' packages of R. We then performed functional enrichment analysis of common DEGs. Hub genes were selected using the cytoHubba plugin and validated using GSE87466 for UC and GSE33814 for MASLD. Immunohistochemistry was employed to validate the hub genes' expression in clinical samples. Immune infiltration and gene set enrichment analyses of the hub genes were performed. Finally, we estimated the Spearman's correlation coefficients for the clinical correlation of the core genes. Results: Within a cohort of 26 differentially regulated genes in both UC and MASLD, pathways involving cytokine-mediated signaling, cell chemotaxis, and leukocyte migration were enriched. After further validation, CXCR4, THY1, CCL20, and CD2 were identified as the hub genes. Analysis of immune infiltration patterns highlighted an association between elevated pivotal gene expression and M1 macrophage activation. Immunohistochemical staining revealed widespread expression of pivotal genes in UC- and MASLD-affected tissues. Furthermore, significant correlations were observed between the increased expression of hub genes and biochemical markers, such as albumin and prothrombin time. Conclusion: This bioinformatics analysis highlights CXCR4, THY1, CCL20, and CD2 as crucial genes involved in the co-occurrence of UC and MASLD, providing insights into the underlying mechanisms of these two conditions.
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Colite Ulcerativa , Fígado Gorduroso , Doenças Metabólicas , Humanos , Colite Ulcerativa/genética , Albuminas , Movimento CelularRESUMO
This study investigates HRas-dependent mechanisms in the disruption of regulatory T (Treg) cells and T helper 17 (Th17) cells balance in ulcerative colitis (UC). Comprehensive RNA sequencing and bioinformatics analyses revealed elevated HRas and MAPK pathway-related protein expression in UC samples. Using a murine UC model induced by dextran sulfate sodium (DSS), HRas silencing was found to promote Treg cell differentiation and suppress Th17 cell production, effectively restoring balance. Inactivation of the MAPK pathway played a pivotal role in this rebalancing effect. In vivo experiments further confirmed that HRas silencing mitigated colon tissue damage in DSS-induced mice, emphasizing its potential as a therapeutic strategy for UC.
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Colite Ulcerativa , Colite , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/tratamento farmacológico , Colo , Células Th17 , Linfócitos T Reguladores , Diferenciação Celular , Sulfato de Dextrana/farmacologia , Colite/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Gastric cancer (GC) represents a significant health burden with dire prognostic implications upon metastasis and recurrence. Pterostilbene (PTE) has been proven to have a strong ability to inhibit proliferation and metastasis in other cancers, while whether PTE exhibits anti-GC activity and its potential mechanism remain unclear. PURPOSE: To explore the efficacy and potential mechanism of PTE in treating GC. METHODS: We employed a comprehensive set of assays, including CCK-8, EdU staining, colony formation, flow cytometry, cell migration, and invasion assays, to detect the effect of PTE on the biological function of GC cells in vitro. The xenograft tumor model was established to evaluate the in vivo anti-GC activity of PTE. Network pharmacology was employed to predict PTE's potential targets and pathways within GC. Subsequently, Western blotting, immunofluorescence, and immunohistochemistry were utilized to analyze protein levels related to the cell cycle, EMT, and the JAK2/STAT3 pathway. RESULTS: Our study demonstrated strong inhibitory effects of PTE on GC cells both in vitro and in vivo. In vitro, PTE significantly induced cell cycle arrest at G0/G1 and S phases and suppressed proliferation, migration, and invasion of GC cells. In vivo, PTE led to a dose-dependent reduction in tumor volume and weight. Importantly, PTE exhibited notable safety, leaving mouse weight, liver function, and kidney function unaffected. The involvement of the JAK2/STAT3 pathway in PTE's anti-GC effect was predicted utilizing network pharmacology. PTE suppressed JAK2 kinase activity by binding to the JH1 kinase structural domain and inhibited the downstream STAT3 signaling pathway. Western blotting confirmed PTE's inhibition of the JAK2/STAT3 pathway and EMT-associated protein levels. The anti-GC effect was partially reversed upon STAT3 activation, validating the pivotal role of the JAK2/STAT3 signaling pathway in PTE's activity. CONCLUSION: Our investigation validates the potent inhibitory effects of PTE on the proliferation and metastasis of GC cells. Importantly, we present novel evidence implicating the JAK2/STAT3 pathway as the key mechanism through which PTE exerts its anti-GC activity. These findings not only establish the basis for considering PTE as a promising lead compound for GC therapeutics but also contribute significantly to our comprehension of the intricate molecular mechanisms underlying its exceptional anti-cancer properties.
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Movimento Celular , Proliferação de Células , Janus Quinase 2 , Camundongos Nus , Fator de Transcrição STAT3 , Transdução de Sinais , Estilbenos , Neoplasias Gástricas , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Estilbenos/farmacologia , Animais , Humanos , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Farmacologia em Rede , Masculino , Metástase Neoplásica , Transição Epitelial-Mesenquimal/efeitos dos fármacosRESUMO
In recent years, there has been a global trend of aging, which has resulted in significant changes to the burden of gastritis and duodenitis (GD). Using the global burden of disease (GBD) database spanning 1990 to 2019, we evaluated the temporal trends of age-standardized incidence rates (ASIR), age-standardized death rates (ASDR), and age-standardized disability-adjusted life years (AS-DALYs) for GD using estimated annual percentage changes (EAPC). Additionally, we examined the burden of GD across various strata, including social demographic index (SDI), age, and sex. Finally, the risk factors linked to the incidence and mortality of GD, utilizing Pearson correlation analysis. In 2019, there were 31 million GD patients globally, a notable increase of 12 million from 1990, while the ASIR, ASDR, and AS-DALYs for GD all showed a decrease. Correlation analysis showed a significant negative relationship between ASIR and SDI. Factors like hand hygiene and vitamin A deficiency had significant positive correlations with ASIR and ASDR in 2019. Over the past thirty years, the burden of GD has increased alongside global population aging. Future efforts should focus on exploring prevention for GD, with special attention to the elderly population in low SDI regions.
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Duodenite , Gastrite , Humanos , Idoso , Duodenite/epidemiologia , Fatores de Risco , Gastrite/epidemiologia , Envelhecimento , Bases de Dados Factuais , Produtos Finais de Glicação Avançada , Saúde Global , IncidênciaRESUMO
BACKGROUND: The currently available clinical therapeutic drugs for ulcerative colitis (UC) are considered inadequate owing to certain limitations. There have been reports on the anti-inflammatory effects of 2'-hydroxycinnamaldehyde (HCA). However, whether HCA can improve UC is still unclear. Here, we aimed to investigate the pharmacological effects of HCA on UC and its underlying molecular mechanisms. METHODS: The pharmacological effects of HCA were comprehensively investigated in 2 experimental setups: mice with dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-treated fetal human colon (FHC) cells. Furthermore, the interaction between HCA and signal transducer and activator of transcription 3 (STAT3) was investigated using molecular docking. The FHC cells with STAT3 knockdown or overexpression and mice with intestinal epithelium-specific STAT3 deletion (STAT3ΔIEC) were used to evaluate whether STAT3 mediated the pharmacological effects of HCA. RESULTS: 2'-Hydroxycinnamaldehyde attenuated dysregulated expression of inflammatory cytokines in a dose-dependent manner while increasing the expression of tight junction proteins, reducing the apoptosis of intestinal epithelial cells, and effectively alleviating inflammation both in vivo and in vitro. 2'-Hydroxycinnamaldehyde bound directly to STAT3 and inhibited its activation. The modulation of STAT3 activation levels due to STAT3 knockdown or overexpression influenced the mitigating effects of HCA on colitis. Further analysis indicated that the remission effect of HCA was not observed in STAT3ΔIEC mice, indicating that STAT3 mediated the anti-inflammatory effects of HCA. CONCLUSIONS: We present a novel finding that HCA reduces colitis severity by attenuating intestinal mucosal barrier damage via STAT3. This discovery holds promise as a potential new strategy to alleviate UC.
The current clinical therapeutic drugs for ulcerative colitis (UC) remain inadequate owing to certain adverse events. Administration of 2ʹ-hydroxycinnamaldehyde (HCA) significantly reduces colitis severity via direct inhibition of STAT3 to attenuate intestinal mucosal barrier damage. Hence, HCA may be a potential new strategy in UC.
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Sulfato de Dextrana , Mucosa Intestinal , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/metabolismo , Animais , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Humanos , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Masculino , Colite/tratamento farmacológico , Colite/induzido quimicamente , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Cinamatos/farmacologia , Simulação de Acoplamento Molecular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos , Citocinas/metabolismoRESUMO
AIMS: To investigate the current situation of mental psychology and quality of life (QoL) in patients with inflammatory bowel disease (IBD) in China, and analyze the influencing factors. METHODS: A unified questionnaire was developed to collect clinical data on IBD patients from 42 hospitals in 22 provinces from September 2021 to May 2022. Multivariate Logistic regression analysis was conducted, and independent influencing factors were screened out to construct nomogram. The consistency index (C-index), receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, accuracy, and clinical utility of the nomogram model. RESULTS: A total of 2478 IBD patients were surveyed, including 1371 patients with ulcerative colitis (UC) and 1107 patients with Crohn's disease (CD). Among them, 25.5%, 29.7%, 60.2%, and 37.7% of IBD patients had anxiety, depression, sleep disturbance and poor QoL, respectively. The proportion of anxiety, depression, and poor QoL in UC patients was significantly higher than that in CD patients (all p < 0.05), but there was no difference in sleep disturbance between them (p = 0.737). Female, higher disease activity and the first visit were independent risk factors for anxiety, depression and sleep disturbance in IBD patients (all p < 0.05). The first visit, higher disease activity, abdominal pain and diarrhea symptoms, anxiety, depression and sleep disturbance were independent risk factors for the poor QoL of patients (all p < 0.05). The AUC value of the nomogram prediction model for predicting poor QoL was 0.773 (95% CI: 0.754-0.792). The calibration diagram of the model showed that the calibration curve fit well with the ideal curve, and DCA showed that the nomogram model could bring clinical benefits. CONCLUSION: IBD patients have higher anxiety, depression, and sleep disturbance, which affect their QoL. The nomogram prediction model we constructed has high accuracy and performance when predicting QoL.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Transtornos do Sono-Vigília , Feminino , Humanos , China/epidemiologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/psicologia , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Doença de Crohn/psicologia , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/psicologia , Qualidade de Vida , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/diagnóstico , MasculinoRESUMO
The Western diet, characterized by its high content of long-chain fatty acids (LCFAs), is widely recognized as a significant triggering factor for inflammatory bowel disease (IBD). While the link between a high-fat diet and colitis has been observed, the specific effects and mechanisms remain incompletely understood. Our study provides evidence that the diet rich in LCFAs can disrupt the integrity of the intestinal barrier and exacerbate experimental colitis in mice. Mechanistically, LCFAs upregulate the signal transducer and activator of transcription-3 (STAT3) pathway in the inflammatory model, and STAT3 knockout effectively counters the pro-inflammatory effects of LCFAs on colitis. Specifically, palmitic acid (PA), a representative LCFA, enters intestinal epithelial cells via the cluster of differentiation 36 (CD36) pathway and participates in the palmitoylation cycle of STAT3. Inhibiting this cycle using pharmacological inhibitors like 2-Bromopalmitate (2-BP) and ML349, as well as DHHC7 knockdown, has the ability to alleviate inflammation induced by PA. These findings highlight the significant role of dietary LCFAs, especially PA, in the development and progression of IBD. Diet adjustments and targeted modulation offer potential therapeutic strategies for managing this condition. Model of LCFAs involvement in the palmitoylation cycle of STAT3 upon internalization into cells. Following cellular uptake through CD36, LCFAs are converted to palmitoyl-CoA. In the presence of DHHC7, palmitoyl-CoA binds to STAT3 at the C108 site, forming palmitoylated STAT3. Palmitoylation further promotes phosphorylation at the Y705 site of STAT3. Subsequently, palmitoylated STAT3 undergoes depalmitoylation by APT2 and translocates to the nucleus to exert its biological functions.
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Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Colite/induzido quimicamente , Dieta Hiperlipídica/efeitos adversos , Endocitose , Ácidos Graxos/metabolismo , Lipoilação , Fator de Transcrição STAT3/metabolismoRESUMO
Purpose: Immune infiltration plays a pivotal role in the pathogenesis of mucosal damage in ulcerative colitis (UC). The objective of this study was to systematically analyze and identify genetic characteristics associated with immune infiltration in UC. Patients and Methods: Gene expression data from three independent datasets obtained from the Gene Expression Omnibus (GEO) were utilized. By employing the ssGSEA and CIBERSORT algorithms, we estimated the extent of immune cell infiltration in UC samples. Subsequently, Weighted Correlation Network Analysis (WGCNA) was performed to identify gene modules exhibiting significant associations with immune infiltration, and further identification of hub genes associated with immune infiltration was accomplished using least absolute shrinkage and selection operator (LASSO) regression analysis. The relationship between the identified hub genes and clinical information was subsequently investigated. Results: Our findings revealed significant activation of both innate and adaptive immune cells in UC. Notably, the expression levels of CD44, IL1B, LYN, and ITGA5 displayed strong correlations with immune cell infiltration within the mucosa of UC patients. Immunohistochemical analysis confirmed the significant upregulation of CD44, LYN, and ITGA5 in UC samples, and their expression levels were found to be significantly associated with common inflammatory markers, including the systemic immune inflammation indices, C-reactive protein, and erythrocyte sedimentation rate. Conclusion: CD44, LYN, and ITGA5 are involved in the immune infiltration pathogenesis of UC and may be potential therapeutic targets for UC.
RESUMO
BACKGROUND & AIMS: 2'-Fucosyllactose (2'-FL), the primary constituent of human milk oligosaccharides, has been identified as a potential regulator of inflammation in inflammatory bowel disease. Despite this recognition, the specific mechanisms through which 2'-FL alleviates ulcerative colitis (UC) remain ambiguous. This study seeks to investigate the potential anti-inflammatory properties of 2'-FL concerning intestinal inflammation and uncover the associated mechanisms. METHODS: C57BL/6J mice were orally administered a daily dose of 500 mg/kg 2'-FL for 11 consecutive days, followed by the induction of colitis using 3 % (wt/vol) dextran sulfate sodium (DSS) for the final 6 days. Subsequently, a comprehensive range of techniques, including an Acyl-biotin exchange assay, fluorescein-isothiocyanate-labeled dextran assay, histopathology, ELISA, quantitative real-time PCR, Western blot, immunofluorescence staining, immunohistochemistry staining, Alcian blue-periodic acid schiff staining, TdT-mediated dUTP nick end labeling, transmission electron microscopy, iTRAQ quantitative proteomics, bioinformatics analysis, and the generation of signal transducer and activator of transcription 3 (STAT3) knockout mice, were employed to explore the relevant molecular mechanisms. RESULTS: Administration of 2'-FL significantly ameliorated DSS-induced colitis in mice and enhanced the integrity of the intestinal mucosal barrier. 2'-FL downregulated the phosphorylation of STAT3 and inhibited STAT3-related signaling pathways in colon tissues, which, in turn, reduced inflammatory responses. Interestingly, knockdown of STAT3 attenuated the protective effects of 2'-FL, highlighting that 2'-FL-mediated inflammatory attenuation is dependent on STAT3 expression. Additionally, 2'-FL could influence STAT3 activation by modulating the palmitoylation and depalmitoylation of STAT3. CONCLUSIONS: 2'-FL promotes the recovery of the intestinal mucosal barrier and suppresses inflammation in ulcerative colitis by inhibiting the palmitoylation and phosphorylation of STAT3.
Assuntos
Colite Ulcerativa , Colite , Trissacarídeos , Humanos , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/metabolismo , Fator de Transcrição STAT3/metabolismo , Fosforilação , Lipoilação , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Inflamação/metabolismo , Sulfato de Dextrana , Modelos Animais de DoençasRESUMO
BACKGROUND: Most studies have primarily focused on assessing the association between diet or exercise patterns and metabolic dysfunction-associated steatotic liver disease (MASLD). This study adopted a more comprehensive approach by introducing the oxidative balance score (OBS) to evaluate the combined effects of diet and lifestyle on the body's antioxidant ability. Our main objective was to investigate the association between OBS and the burden of MASLD in the United States. METHODS: Participants with complete information from 2001 to 2018 were included. In the absence of other definite liver injury factors, the United States fatty liver index (us-FLI) ≥ 30 was used as the diagnostic criterion for MASLD. We first calculated the weighted prevalence for each cycle and stratified it according to demographic and metabolic-related disease characteristics. Subsequently, weighted multiple logistic regression was used to evaluate the relationship between OBS and MASLD. In addition, we explored the body's inflammatory state and the level of insulin resistance (IR) in mediating OBS and MASLD. RESULTS: From 2001 to 2018, the prevalence of MASLD in the U.S. population as a whole increased from 29.76% to 36.04%, and the rate was higher in people with metabolic-related diseases. Notably, OBS exhibited a negative correlation with MASLD. Participants in the highest tertile of OBS had a significantly lower prevalence of MASLD compared to those in the lowest tertile [OR: 0.72, 95%CI: (0.57, 0.92), p < 0.001]. Moreover, a high OBS is associated with a lower inflammatory state and level of IR. The body's inflammatory state and IR level mediated the association between OBS and MASLD by 5.2% and 39.7%, respectively (both p < 0.001). CONCLUSIONS: In this study, we observed an increasing prevalence of MASLD over the years. A higher OBS was associated with a lower risk of MASLD, especially when OBS ≥ 25. The body's inflammatory state and IR level mediate the association between OBS and MASLD, but the mechanism needs to be further investigated.