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1.
J Ethnopharmacol ; 300: 115741, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162543

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla decoction (PD), is an herbal formula commonly used for the treatment of ulcerative colitis (UC) in clinical practice, but the mechanism of PD alters the colitis remains elusive. AIM OF THE STUDY: To evaluate the intervention effect of PD on Dextran Sodium Sulfate (DSS)-induced UC based on gut microbiota and intestinal short-chain fatty acid (SCFAs) metabolism, and to investigate the mechanism of action of PD in treating UC. MATERIALS AND METHODS: A 3% (wt/vol) DSS-induced ulcerative colitis model in C57BL/6 male mice was used to evaluate the effect of oral PD in treating UC. The changes in gut microbiota in mice were analyzed by 16SrDNA gene sequencing, and the content of SCFAs in the intestinal contents of mice was determined by gas chromatography-mass spectrometry (GC-MS). Enzyme-linked immunosorbent assay (ELISA) was applied to analyze the expression of inflammatory cytokines in serum and colonic tissues, and western blotting (WB) was applied to analyze the expression of tight junction proteins in colonic tissues. RESULTS: PD can alleviate the symptoms of UC mice, Pulsatilla Decoction high dose treatment group (PDHT) shows the best effect. Compared with the DSS group, the PDHT had significantly lower body mass, disease activity index (DAI) score, colonic macroscopic damage index (CMDI) score, and pathological damage score, at the phylum level, the relative abundance of Bacteroidetes increased while that of Firmicutes and Proteobacteria decreased, at the Genus level, the abundance of Bacteroides and Lachnospiraceae.NK4A136.group increased while that of Clostridium. sensu.stricto。, Escherichia. shigella and Turicibacter decreased. Compared with the DSS group, acetate, propionate, and total SCFAs in the PDHT with significantly higher levels. The concentrations of interleukin-1ß (L-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin-17 (IL-17) decreased whereby the concentration of interleukin-10 (IL-10) increased in the PDHT group. The expression levels of Occludin, zonula occludens-1 (ZO-1), Claudin1, Claudin5, G protein-coupled receptor43 (GPR43) protein, and the relative expression of ZO-1 and Occludin mRNA were significantly increased PDHT group. CONCLUSIONS: PD has a good therapeutic effect on UC mice. The pharmacological mechanism is probably maintaining the homeostasis and diversity of gut microbiota, increasing the content of SCFAs, and repairing the colonic mucosal barrier.


Assuntos
Colite Ulcerativa , Colite , Pulsatilla , Animais , Bactérias/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Propionatos , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
J Ethnopharmacol ; 300: 115690, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36075274

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglian Pill (XLP) is a classical Chinese medicine prescription applied for controlling ulcerative colitis (UC). Whereas, the underlying mechanism remains unclear. AIM OF THE STUDY: The present work was aimed to investigate the mechanism of XLP in dextran sulfate sodium (DSS)-induced UC via the Toll Like Receptor 4 (TLR4)/Myeloid Differentiation factor 88 (MyD88)/Nuclear Factor kappa-B (NF-κB) signaling in mice. MATERIALS AND METHODS: The major components of XLP were detected by high-performance liquid chromatography-diode array detection (HPLC-DAD). The ulcerative colitis model was induced by DSS in mice. 5-Amino Salicylic Acid (5-ASA) group and XLP group were intragastrically treated. Disease activity index (DAI) and colon length were monitored and hematoxylin-eosin (HE) staining was conducted. Gasdermin D (GSDMD)-N and TLR4 expressions in colon tissues were visualized by immunofluorescence. TLR4 mRNA was measured by Real Time Quantitative PCR (RT-qPCR). The expressions of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), active-caspase-1, GSDMD-N, TLR4, MYD88, NF-κB, p-NF-κB, and the ubiquitination of TLR4 in colon tissues were detected by Western blot. Myeloperoxidase (MPO) enzyme activity was examined and serum inflammatory factors Interleukin (IL)-1ß, IL-6, Tumor Necrosis Factor-α (TNF-α), and IL-18 were determined by Enzyme-linked Immunosorbent Assay (ELISA). TLR4-/- mice were applied for verifying the mechanism of XLP attenuated DSS symptoms. RESULTS: The XLP treatment extended colon length, reduced DAI, and attenuated histopathological alteration in DSS-induced mice. XLP administration suppressed MPO activity and reduced the content of IL-1ß, IL-6, TNF-α and IL-18 in serum. XLP also inhibited the expression levels of GSDMD-N, TLR4, NLRP3, active-caspase-1, MyD88, p-NF-κB/NF-κB in colon tissues of DSS-induced mice. TLR4-/- mice proved that TLR4 was involved in XLP-mediated beneficial effect on DSS-induced ulcerative colitis. CONCLUSIONS: XLP might treat ulcerative colitis by regulating the TLR4/MyD88/NF-κB signaling pathway.


Assuntos
Colite Ulcerativa , Fator 88 de Diferenciação Mieloide , Animais , Caspases/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Interleucina-18/metabolismo , Interleucina-18/farmacologia , Interleucina-18/uso terapêutico , Interleucina-6/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peroxidase/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
PLoS One ; 17(11): e0276065, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36350879

RESUMO

BACKGROUND: The aim of the study was to determine the differences in terms of ghrelin presence in the colon between the patients with ulcerative colitis (UC) and control patients. METHODS: Sixty-one UC and 15 control patients were included in the study. Immunohistochemical staining for ghrelin was investigated in colonic biopsy samples of UC and control patients. UC patients were subdivided into Group A (absence of ghrelin staining) and Group B (presence of staining for ghrelin in biopsy samples). Disease activity scores, laboratory parameters and quantitative ghrelin staining were compared in both groups of UC patients, as well as with the observations in control patients. RESULTS: Cells in colonic mucosa stained for ghrelin were identified in twenty-three (37.7%) UC patients, while this proportion in control patients was 6/15(40%). A significant difference was found between Groups A and B for serum albumin concentration but not for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin concentration or leucocyte count. Mayo score/disease activity index (DAI) for UC were significantly higher in Group A than in Group B (p = 0.03). CONCLUSIONS: There were no differences in the amount of colonic ghrelin staining between healthy individuals and UC patients. Colonic ghrelin staining in UC patients seems to be associated with the increased activity of this disease.


Assuntos
Colite Ulcerativa , Humanos , Colite Ulcerativa/patologia , Grelina/metabolismo , Colo/patologia , Sedimentação Sanguínea , Mucosa Intestinal/metabolismo
4.
Front Immunol ; 13: 1021695, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341374

RESUMO

Atractylodes macrocephala Koidz. is one of the most frequently used traditional Chinese medicines for the treatment of ulcerative colitis (UC). The beneficial effect of polysaccharide from Atractylodes macrocephala Koidz. (PAMK) on UC has been reported, while the underlying mechanism and target remain unclear. In this study, we systematically investigated the therapeutic effect and the underlying mechanism of PAMK in UC based on a mouse model of dextran sodium sulfate (DSS)-induced colitis. PAMK treatment (100 mg/kg, 200 mg/kg and 400 mg/kg) significantly ameliorated DSS-induced colitis, manifested as a reduction in weight loss, disease activity index (DAI), colon shortening, spleen index and histological score. Moreover, PAMK treatment inhibited inflammation and improved the integrity of the intestinal barrier in colitis mice. Mechanistically, microarray analysis determined the critical role of the immunoregulatory effect of PAMK in alleviating UC. Flow cytometry analysis further demonstrated that PAMK treatment regulated the balance between T helper (Th) 17 and regulatory T (Treg) cells in the mesenteric lymph nodes (MLN) and spleen in mice with colitis. In addition, PAMK treatment downregulated the expression of IL-6 and suppressed the phosphorylation of STAT3. Together, these data revealed that PAMK treatment alleviated DSS-induced colitis by regulating the Th17/Treg cell balance, which may be dependent on the inhibition of the IL-6/STAT3 signaling pathway. Our study is the first to elucidate that the underlying mechanism by which PAMK treatment alleviates DSS-induced colitis is associated with an improved the Th17/Treg cell balance. Collectively, the study provides evidence for the potential of PAMK to treat UC.


Assuntos
Atractylodes , Colite Ulcerativa , Colite , Camundongos , Animais , Linfócitos T Reguladores/patologia , Interleucina-6/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/patologia
5.
Curr Microbiol ; 79(12): 393, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329273

RESUMO

Previously, we isolated a novel Phocaeicola strain, Phocaeicola faecalis FXJYN30E22, from the feces of a healthy human from China. Metagenomic analysis revealed that the distribution of FXJYN30E22 differed in the intestinal tract of different hosts. We aimed to determine whether FXJYN30E22 protects against ulcerative colitis by employing a mouse model. In this study, dextran sulfate sodium was used to construct the UC model. The disease activity index, colon length, body weight changes, and histological scores were used as the pathological indicators to assess the anti-inflammatory effect of P. faecalis FXJYN30E22. Further, cytokine levels, tight junction mRNA expression levels, and short-chain fatty acid (SCFA) concentrations were also analyzed. Phocaeicola faecalis FXJYN30E22 could reduce the DSS-induced increase in DAI score, and enhance the colon length and body weight. Phocaeicola faecalis FXJYN30E22 could enhance TJ protein concentration and modulate the level of cytokines to reach levels close to those of the control group. FXJYN30E22 could also upregulate the concentrations of SCFA, which include acetate and butyrate. Based on the correlation analysis, four factors, including interleukin (IL)-6, IL-10, IL-1ß levels, and propionate concentration, were related to the protective roles of FXJYN30E22 in UC mice to different degrees. According to an analysis of the genomic information, the potential protective effects of strain FXJYN30E22 may be associated with the secretion of SCFA by specific genes. These findings suggest that oral P. faecalis FXJYN30E22 could help maintain the epithelial barrier by regulating cytokine levels and secreting SCFA.


Assuntos
Colite Ulcerativa , Colite , Humanos , Camundongos , Animais , Sulfato de Dextrana/toxicidade , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Peso Corporal , Camundongos Endogâmicos C57BL
6.
World J Gastroenterol ; 28(40): 5845-5864, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36353202

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) constitutes a substantial risk factor for colorectal cancer. Connexin 43 (Cx43) is a protein that forms gap junction (GJ) complexes involved in intercellular communication, and its expression is altered under pathological conditions, such as IBD and cancer. Recent studies have implicated epigenetic processes modulating DNA methylation in the pathogenesis of diverse inflammatory and malignant diseases. The ten-eleven translocation-2 (TET-2) enzyme catalyzes the demethylation, hence, regulating the activity of various cancer-promoting and tumor-suppressor genes. AIM: To investigate Cx43 and TET-2 expression levels and presence of 5-hydroxymethylcytosine (5-hmC) marks under inflammatory conditions both in vitro and in vivo. METHODS: TET-2 expression was evaluated in parental HT-29 cells and in HT-29 cells expressing low or high levels of Cx43, a putative tumor-suppressor gene whose expression varies in IBD and colorectal cancer, and which has been implicated in the inflammatory process and in tumor onset. The dextran sulfate sodium-induced colitis model was reproduced in BALB/c mice to evaluate the expression of TET-2 and Cx43 under inflammatory conditions in vivo. In addition, archived colon tissue sections from normal, IBD (ulcerative colitis), and sporadic colon adenocarcinoma patients were obtained and evaluated for the expression of TET-2 and Cx43. Expression levels were reported at the transcriptional level by quantitative real-time polymerase chain reaction, and at the translational level by Western blotting and immunofluorescence. RESULTS: Under inflammatory conditions, Cx43 and TET-2 expression levels increased compared to non-inflammatory conditions. TET-2 upregulation was more pronounced in Cx43-deficient cells. Moreover, colon tissue sections from normal, ulcerative colitis, and sporadic colon adenocarcinoma patients corroborated that Cx43 expression increased in IBD and decreased in adenocarcinoma, compared to tissues from non-IBD subjects. However, TET-2 expression and 5-hmC mark levels decreased in samples from patients with ulcerative colitis or cancer. Cx43 and TET-2 expression levels were also investigated in an experimental colitis mouse model. Interestingly, mice exposed to carbenoxolone (CBX), a GJ inhibitor, had upregulated TET-2 levels. Collectively, these results show that TET-2 levels and activity increased under inflammatory conditions, in cells downregulating gap junctional protein Cx43, and in colon tissues from mice exposed to CBX. CONCLUSION: These results suggest that TET-2 expression levels, as well as Cx43 expression levels, are modulated in models of intestinal inflammation. We hypothesize that TET-2 may demethylate genes involved in inflammation and tumorigenesis, such as Cx43, potentially contributing to intestinal inflammation and associated carcinogenesis.


Assuntos
Adenocarcinoma , Colite Ulcerativa , Colite , Neoplasias do Colo , Dioxigenases , Doenças Inflamatórias Intestinais , Animais , Camundongos , Adenocarcinoma/patologia , Carcinogênese/patologia , Colite/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/patologia , Conexina 43/genética , Conexina 43/metabolismo , Sulfato de Dextrana/toxicidade , Dioxigenases/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia
7.
Dis Colon Rectum ; 65(S1): S50-S56, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36399768

RESUMO

BACKGROUND: Pouchitis is the most common inflammatory complication in ulcerative colitis patients undergoing postoperative construction of an IPAA. Pouchitis refers to a spectrum of diseases, and as such, it lacks a universally accepted definition as well as validated instruments to measure disease activity and treatment response. Assessing pouchitis activity is challenging, and methods for diagnosis and classification of severity of pouchitis are not universally agreed upon. CLINICAL FEATURES: Pouchitis is characterized by a constellation of clinical symptoms, including increased stool frequency, urgency, incontinence, bleeding, and rarely constitutional symptoms such as malaise and low-grade fever. However, these symptoms are subjective, and similar symptoms can be caused by noninflammatory conditions including anal sphincter dysfunction, anastomotic strictures, occult leaks, pouch inlet obstruction, and cuffitis. Objective scores that include endoscopic and histologic criteria have been developed for subjects with an IPAA. However, these instruments are not validated for measuring pouchitis disease activity and are associated with a number of challenges. In addition, the clinical components of the scores correlate poorly with endoscopic and histologic findings. CONCLUSION AND FUTURE DIRECTIONS: There is a need for prospective studies to facilitate the development and validation of novel instruments that are valid, reliable, and responsive to change that would facilitate the development of therapeutic agents for the treatment of pouchitis.


Assuntos
Colite Ulcerativa , Pouchite , Proctocolectomia Restauradora , Humanos , Pouchite/diagnóstico , Pouchite/etiologia , Proctocolectomia Restauradora/efeitos adversos , Proctocolectomia Restauradora/métodos , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Colite Ulcerativa/patologia , Canal Anal/cirurgia , Estudos Prospectivos
8.
BMC Med Inform Decis Mak ; 22(Suppl 6): 300, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401328

RESUMO

BACKGROUND: The SI-CURA project (Soluzioni Innovative per la gestione del paziente e il follow up terapeutico della Colite UlceRosA) is an Italian initiative aimed at the development of artificial intelligence solutions to discriminate pathologies of different nature, including inflammatory bowel disease (IBD), namely Ulcerative Colitis (UC) and Crohn's disease (CD), based on endoscopic imaging of patients (P) and healthy controls (N). METHODS: In this study we develop a deep learning (DL) prototype to identify disease patterns through three binary classification tasks, namely (1) discriminating positive (pathological) samples from negative (healthy) samples (P vs N); (2) discrimination between Ulcerative Colitis and Crohn's Disease samples (UC vs CD) and, (3) discrimination between Ulcerative Colitis and negative (healthy) samples (UC vs N). RESULTS: The model derived from our approach achieves a high performance of Matthews correlation coefficient (MCC) > 0.9 on the test set for P versus N and UC versus N, and MCC > 0.6 on the test set for UC versus CD. CONCLUSION: Our DL model effectively discriminates between pathological and negative samples, as well as between IBD subgroups, providing further evidence of its potential as a decision support tool for endoscopy-based diagnosis.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/patologia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Inteligência Artificial , Endoscopia
9.
Folia Biol (Praha) ; 68(2): 50-58, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36384262

RESUMO

Ulcerative colitis is caused by various external factors and is an inflammatory disease that causes decreased intestinal function. Tenebrio molitor larvae contain more than 30 % fat, and the fat component consists of 45 % oleic acid, 20 % linoleic acid and 20 % polyunsaturated fatty acids. In this study, after administering Tenebrio molitor larva oil (TMLO) in a dextran sodium sulphate (DSS)-induced ulcerative colitis mouse model, the pathological findings and inflammatory markers of colitis were analysed to assess whether a colitis mitigation effect was achieved. In the TMLO-administered group, the colon length increased, the spleen weight decreased, and the body weight increased compared with that in the DSS group. In addition, the disease activity index level decreased, the mRNA expression level of inflammatory cytokines in the colon decreased, and the myeloperoxidase activity level significantly decreased. Also, the activity of the NF-κB pathway involved in the regulation of the inflammatory response was lower in the TMLO group than in the DSS group. Taken together, these results suggest that TMLO suppresses occurrence of acute ulcerative colitis in the DSS mouse model. Therefore, TMLO has the potential to be developed as a health food for the prevention and treatment of ulcerative colitis.


Assuntos
Colite Ulcerativa , Colite , Tenebrio , Camundongos , Animais , Sulfato de Dextrana/toxicidade , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Larva , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
10.
Am J Gastroenterol ; 117(11): 1858-1870, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36327438

RESUMO

INTRODUCTION: Patients with inflammatory bowel diseases (IBDs) of the colon are at an increased risk of colorectal cancer (CRC). This study investigates the epidemiology of IBD-CRC and its outcomes. METHODS: Using population data from the English National Health Service held in the CRC data repository, all CRCs with and without prior diagnosis of IBD (Crohn's, ulcerative colitis, IBD unclassified, and IBD with cholangitis) between 2005 and 2018 were identified. Descriptive analyses and logistic regression models were used to compare the characteristics of the 2 groups and their outcomes up to 2 years. RESULTS: Three hundred ninety thousand six hundred fourteen patients diagnosed with CRC were included, of whom 5,141 (1.3%) also had a previous diagnosis of IBD. IBD-CRC cases were younger (median age at CRC diagnosis [interquartile range] 66 [54-76] vs 72 [63-79] years [ P < 0.01]), more likely to be diagnosed with CRC as an emergency (25.1% vs 16.7% [ P < 0.01]), and more likely to have a right-sided colonic tumor (37.4% vs 31.5% [ P < 0.01]). Total colectomy was performed in 36.3% of those with IBD (15.4% of Crohn's, 44.1% of ulcerative colitis, 44.5% of IBD unclassified, and 67.7% of IBD with cholangitis). Synchronous (3.2% vs 1.6% P < 0.01) and metachronous tumors (1.7% vs 0.9% P < 0.01) occurred twice as frequently in patients with IBD compared with those without IBD. Stage-specific survival up to 2 years was worse for IBD-associated cancers. DISCUSSION: IBD-associated CRCs occur in younger patients and have worse outcomes than sporadic CRCs. There is an urgent need to find reasons for these differences to inform screening, surveillance, and treatment strategies for CRC and its precursors in this high-risk group.


Assuntos
Colangite , Colite Ulcerativa , Neoplasias Colorretais , Doença de Crohn , Doenças Inflamatórias Intestinais , Idoso , Humanos , Colite Ulcerativa/complicações , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/patologia , Neoplasias Colorretais/diagnóstico , Doença de Crohn/complicações , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/patologia , Fatores de Risco , Medicina Estatal , Pessoa de Meia-Idade
11.
PLoS One ; 17(10): e0276195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36301950

RESUMO

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBD) of unknown cause characterized by a relapsing-remitting behavior. Growing evidence supports the idea that the epithelial barrier plays a central role in the pathogenesis of IBD as well as in its evolution over time, thus representing a potential target for novel therapeutic options. In the last decade, the introduction of 3D epithelial cultures from ex vivo-expanded intestinal adult stem cells (ASCs) has impacted our ability to study the function of the epithelium in several gastrointestinal disorders, including IBD. Here, we describe in detail a reproducible protocol to generate Matrigel-embedded epithelial organoids from ASCs of non-IBD and IBD donors using small colonic biopsies, including steps for its optimization. A slightly modified version of this protocol is also provided in case surgical samples are used. With this method, epithelial organoids can be expanded over several passages, thereby generating a large quantity of viable cells that can be used in multiple downstream analyses including genetic, transcriptional, proteomic and/or functional studies. In addition, 3D cultures generated using our protocol are suitable for the establishment of 2D cultures, which can model relevant cell-to-cell interactions that occur in IBD mucosa.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Adulto , Humanos , Organoides/patologia , Mucosa Intestinal/patologia , Proteômica , Doenças Inflamatórias Intestinais/patologia , Colo/patologia , Colite Ulcerativa/patologia
12.
World J Gastroenterol ; 28(36): 5300-5312, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36185628

RESUMO

Advances in diagnostics of inflammatory bowel diseases (IBD) and improved treatment strategies allowed the establishment of new therapeutic endpoints. Currently, it is desirable not only to cease clinical symptoms, but mainly to achieve endoscopic remission, a macroscopic normalization of the bowel mucosa. However, up to one-third of IBD patients in remission exhibit persisting microscopic activity of the disease. The evidence suggests a better predictive value of histology for the development of clinical complications such as clinical relapse, surgical intervention, need for therapy escalation, or development of colorectal cancer. The proper assessment of microscopic inflammatory activity thus became an important part of the overall histopathological evaluation of colonic biopsies and many histopathological scoring indices have been established. Nonetheless, a majority of them have not been validated and no scoring index became a part of the routine bioptic practice. This review summarizes a predictive value of microscopic disease activity assessment for the subsequent clinical course of IBD, describes the most commonly used scoring indices for Crohn's disease and ulcerative colitis, and comments on current limitations and unresolved issues.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colite Ulcerativa/patologia , Doença de Crohn/tratamento farmacológico , Endoscopia/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/complicações , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia
13.
Int J Mol Sci ; 23(19)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36232412

RESUMO

Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut-immune-brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut-immune-brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Animais , Encéfalo/patologia , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Inflamação , Doenças Inflamatórias Intestinais/patologia , Camundongos , Morbidade
14.
Biomed Res Int ; 2022: 7025634, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36262975

RESUMO

Dendritic cells (DCs) are the most important antigen-presenting cells and are pivotal in initiating effective adaptive immune responses to induce immune tolerance and maintain immune homeostasis. Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is chronic, intestinal inflammatory and autoimmune disorder. DCs participate in IBD pathogenesis. This review is aimed at briefly discussing the role of DCs in IBD and the relationship between them and highlighting the prominent role of these cells in the treatment of these disorders.


Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/patologia , Doença de Crohn/patologia , Colite Ulcerativa/patologia , Células Dendríticas
15.
Am J Physiol Gastrointest Liver Physiol ; 323(6): G554-G561, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36283090

RESUMO

Ulcerative colitis (UC) is a chronic disease that is characterized by diffuse inflammation of the colonic and rectal mucosa. The burden of UC is rising globally with significant disparities in levels and trends of disease in different countries. The pathogenesis of UC involves the presence of pathogenic factors including genetic, environmental, autoimmune, and immune-mediated components. Evidence suggests that disturbed interactions between the host immune system and gut microbiome contribute to the origin and development of UC. Current medications for UC include antibiotics, corticosteroids, and biological drugs, which can have deleterious off-target effects on the gut microbiome, contributing to increased susceptibility to severe infections and chronic immunosuppression. Alternative, nonpharmacological, and behavioral interventions have been proposed as safe and effective treatments to alleviate UC, while also holding the potential to improve overall life quality. This mini-review will discuss the interactions between the immune system and the gut microbiome in the case of UC. In addition, we suggest nonpharmacological and behavioral strategies aimed at restoring a proper microbial-immune relationship.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Humanos , Colite Ulcerativa/patologia , Homeostase , Imunidade
16.
Phytomedicine ; 107: 154468, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209702

RESUMO

BACKGROUND: Ulcerative colitis (UC) has affected an increasing number of people globally, with still limited clinical success. Huanglian Decoction (HLD) is a famous classical prescription documented for alleviating gastrointestinal disorders with unexplored therapeutic effects and mechanisms. PURPOSE: This study aimed to investigate the therapeutic effect and underlying mechanism of HLD in dextran sodium sulfate (DSS)-induced colitis mice. METHODS: The efficacy and safety of HLD were evaluated in a well-established DSS-induced colitis mice model. Disease progression was monitored via clinical symptoms, histopathological examination, biochemical assays, and epithelial barrier function evaluation. RESULTS: HLD alleviated DSS-induced colitis symptoms, reversed colon length reduction, reduced histological injury, downregulated the level of pro-inflammatory cytokines, maintained the tight distribution of ZO-1/occludin-1 and the normal level of ß-catenin, concurrent with apoptosis reduction in the colonic epithelium. After HLD treatment, the DSS-induced gut dysbiosis was modulated, and the gut microbiota achieved a new equilibrium state. CONCLUSION: This study demonstrates that HLD may present a potential remedy for UC treatment, providing evidence for further developing Chinese classical prescriptions.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/patologia , Citocinas , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Camundongos , Camundongos Endogâmicos C57BL , Ocludina , Prescrições , beta Catenina
17.
Front Immunol ; 13: 1020902, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275703

RESUMO

Background: Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated. Methods: The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines. Wild-type and MMP-7-null mice treated with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid were used for determining the pro-inflammatory function(s) of MMP-7 in vivo. Results: MMP-7 was highly expressed in patients with UC and in rodents with experimental colitis. IL-1ß, IL-4, IL-13, TNFα, or lipopolysaccharide enhanced MMP-7 expression in human colonic epithelial cells, rat colonic smooth muscle cells, and THP-1-derived macrophages. Active MMP-7 degraded tight junction protein Claudin-7 in epithelial cells, cleaved recombinant Claudin-7 in cell-free system, and increased Caco-2 monolayer permeability. Immunostaining of colon biopsies revealed up-regulation of MMP-7 and reduction of Claudin-7 in UC patients. Compared to wild-type mice, Mmp7 -/- mice had significantly less inflammation in the colon upon DSS insult. DSS-induced alterations in junction proteins were mitigated in Mmp7 -/- mice, suggesting that MMP-7 disrupts the intestinal barrier. MMP-7 antibody significantly ameliorated colonic inflammation and Claudin-7 reduction in 2 different rodent models of colitis. Summary: MMP-7 impairs intestinal epithelial barrier by cleavage of Claudin-7, and thus aggravating inflammation. These studies uncovered Claudin-7 as a novel substrate of MMP-7 in the intestinal epithelium and reinforced MMP-7 as a potential therapeutic target for IBD.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Ratos , Animais , Proteínas de Junções Íntimas/metabolismo , Sulfato de Dextrana/toxicidade , Metaloproteinase 7 da Matriz/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-13/metabolismo , Junções Íntimas/metabolismo , Células CACO-2 , Lipopolissacarídeos/efeitos adversos , Interleucina-4/metabolismo , Colite/patologia , Doenças Inflamatórias Intestinais/metabolismo , Colite Ulcerativa/patologia , Inflamação/metabolismo , Camundongos Knockout , Citocinas/metabolismo , Claudinas/genética , Claudinas/metabolismo , Trinitrobenzenos/metabolismo , Trinitrobenzenos/uso terapêutico , Ácidos Sulfônicos/efeitos adversos , Ácidos Sulfônicos/metabolismo
18.
J Gastroenterol ; 57(12): 962-970, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36184701

RESUMO

BACKGROUND: Mucin depletion is one of the histological indicators of clinical relapse among patients with ulcerative colitis (UC). Mucin depletion is evaluated semiquantitatively by pathologists using histological images. Therefore, the interobserver concordance is not extremely high, and an objective evaluation method is needed. This study was conducted to demonstrate that our automated quantitative method using a deep learning-based model is useful in predicting the prognosis of patients with UC. METHODS: Deep learning-based models were trained to detect goblet cell mucus area from whole slide images of biopsy specimens. This study involved 114 patients with UC in endoscopic remission with a partial Mayo score of ≤ 1. Biopsy specimens were collected during colonoscopy, and the ratio of goblet cell mucus area to the epithelial cell and goblet cell mucus area was calculated as goblet cell ratio (GCR). The follow-up time was 12 months, and the primary outcome was the relapse rate. Clinical relapse was defined as partial Mayo score of ≥ 3. RESULTS: Sixteen patients (14%) experienced clinical relapse. In the relapsed group, the GCRs of specimens obtained from the cecum, ascending colon, and rectum were significantly lower than those of specimens in the relapse-free group (p = 0.010, p = 0.027, p < 0.01). In the rectum, patients with a GCR of ≤ 12% had a significantly higher relapse rate than those with a GCR of > 12% (45% [10/22] vs. 6.5% [6/92]; p < 0.01). CONCLUSIONS: Quantifying goblet cell mucus areas using a deep learning-based model is useful in predicting the clinical relapse in patients with UC in clinical and endoscopic remission.


Assuntos
Colite Ulcerativa , Aprendizado Profundo , Células Caliciformes , Mucinas , Humanos , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/patologia , Colonoscopia , Células Caliciformes/patologia , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Mucinas/deficiência , Muco , Recidiva , Indução de Remissão , Índice de Gravidade de Doença
19.
Mol Med Rep ; 26(6)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36281914

RESUMO

Ulcerative colitis (UC) is a significant burden on human health, and the elucidation of the mechanism by which it develops has potential for the prevention and treatment of UC. It has been reported that acteoside (ACT) exhibits strong anti­inflammatory activity. In the present study, it was hypothesized that ACT may exert a protective effect against UC. The effects of ACT on inflammation, oxidative stress and apoptosis were evaluated using dextran sulphate sodium (DSS)­treated mice and DSS­treated human colorectal adenocarcinoma Caco­2 cells, which have an epithelial morphology. The results demonstrated that the ACT­treated mice with DSS­induced UC exhibited significantly reduced colon inflammation, as demonstrated by a reversal in body weight loss, colon shortening, disease activity index score, inflammation, oxidative stress and colonic barrier dysfunction. Further in vivo experiments demonstrated that ACT inhibited DSS­induced apoptosis in colon tissues, as demonstrated by the results of the TUNEL assay and the altered protein expression levels of Bax, cleaved caspase­3 and Bcl­2. Furthermore, DSS significantly stimulated the protein expression levels of high mobility group box 1 protein (HMGB1), which serves a central role in the initiation and progression of UC, an effect which was markedly inhibited by ACT. Finally, DSS significantly decreased the protein expression levels of heme oxygenase­1 (HO­1) in colon tissues and the effect of ACT on GSH, apoptotic proteins and HMGB1 was markedly attenuated in the presence of the HO­1 inhibitor tin protoporphyrin. In conclusion, ACT ameliorated colon inflammation through HMGB1 inhibition in a HO­1­dependent manner.


Assuntos
Colite Ulcerativa , Colite , Proteína HMGB1 , Camundongos , Humanos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Sulfato de Dextrana/toxicidade , Heme Oxigenase-1/metabolismo , Proteína HMGB1/metabolismo , Caspase 3/metabolismo , Protoporfirinas/farmacologia , Células CACO-2 , Estanho/efeitos adversos , Proteína X Associada a bcl-2 , Colite/patologia , Transdução de Sinais , Inflamação , Anti-Inflamatórios/farmacologia
20.
Biomed Pharmacother ; 155: 113645, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36115109

RESUMO

Oral colon-targeting preparation can achieve targeted drug release in the lesion site and have a great application prospect. In this study, we presented the principle of particle design in the field of materials science into the preparation of colon-targeting preparation. Enzymatic Pulsatilla saponins Colon-targeting composite Microparticles (EPCM) were prepared by mechanical grinding without any organic solvent. Firstly, Response Surface Methodology (RSM) designed by Box-Behnken was used to optimize the preparation process of EPCM, and the structure of EPCM was characterized. All-Atomic and Molecular Dynamics (AAMD) was used to calculate the compatibility between drugs and coating materials before and after release, so as to explain the principle of colon- targeted drug release in this method. Then, colon-targeting characteristics of EPCM in vitro and in vivo were investigated by experiments. Finally, the pharmacodynamics effects of this composite microparticles on Ulcerative Colitis (UC) induced by DSS in C57BL/6 mice were evaluated. The results demonstrated that the colon-targeting composite microparticles could be prepared by mechanical grinding based on particle design principle. The composite microparticles have appropriate colon-targeting drug release performance in vitro and in vivo, and have good anti-ulcerative colitis effect. This study provides a new idea for the preparation of oral colon-targeting preparation of Traditional Chinese medicine, and has evident reference value for the study of coating isolation and powder modification of traditional Chinese medicine for other purposes.


Assuntos
Colite Ulcerativa , Pulsatilla , Saponinas , Camundongos , Animais , Pulsatilla/química , Saponinas/química , Solventes , Pós/farmacologia , Camundongos Endogâmicos C57BL , Colo , Colite Ulcerativa/patologia , Tecnologia
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