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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: 115675, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36075275

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rheum palmatum L. (RP) and Coptis chinensis Franch. (CC), frequently used as herbal pair (HP) in clinical practicing of traditional Chinese medicine, exerted predominate efficacies in colitis treatment. However, the mechanism of their synergism lacks scientific explanation. AIM OF THE STUDY: By integrating network pharmacology and DSS-induced colitis model, the anti-colitis effects and synergistic molecular mechanisms of RP-CC combination was determined. MATERIALS AND METHODS: In vivo study, mice were divided into control, model, RP, CC and RP-CC (low, middle, high) groups, 2.5% DSS was administrated to induce colitis for consecutive 7 days, subsequently, the therapeutic effects were evaluated from body weight changes, disease activity index (DAI), and pathological conditions. After determining the shared and exclusive targets of RP and CC, respectively by network pharmacology, CETSA, WB, and qPCR were utilized to verify the action modes of RP and CC on specific targets. RESULTS: Compared to RP or CC used alone, RP-CC combination can significantly protect colon tissues from inflammatory damage in a dose-dependent manner via remarkably alleviating DAI and colon shortening. Network pharmacological analysis suggested that AKT1 would be the core target for RP-CC synergism since these two herbs could simultaneously but non-competitively bind to AKT1 at different sits. Furthermore, RP and CC could also influencing HIF and MAPK pathways, respectively, these additional actions attribute to more optimizing effectiveness towards colitis. CONCLUSION: In contrast to the mild therapeutic effects of RP or CC individually, RP-CC herb pair could exert strong and synergistic effects in treatment of colitis via non-competitive binding to AKT1 simultaneously, as well as exclusively influencing MAPK and HIF pathways. Our study not only provides the evidence for understanding the combined effect of RP and CC, but also brings up a new strategy and suggestive thoughts for the rationality of HP-based TCM formula.


Assuntos
Colite , Coptis , Medicamentos de Ervas Chinesas , Rheum , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Coptis/química , Coptis chinensis , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Camundongos , Farmacologia em Rede
3.
Food Chem ; 400: 133904, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36055136

RESUMO

Resveratrol is a dietary polyphenol that interacts with gut microbiota to possess various biological activities. To identify the microbial metabolites of resveratrol, fresh feces from 12 volunteers were cultured in vitro. Their urine samples were collected after taking a commercial capsule containing 600 mg of resveratrol. Metabolites were characterized and quantified by UPLC-Q-Exactive plus orbitrap MS/MS. The results showed that dihydroresveratrol, 3-(4-hydroxyphenyl)-propionic acid, and lunularin were the major microbial metabolites of RSV with interindividual differences. 3-(4-Hydroxyphenyl)-propionic acid significantly attenuated the inflammatory response of LPS-treated RAW264.7 cells and DSS-induced colitis in antibiotics-treated pseudo-germ-free mice by regulating MAPK and NF-κB pathways. In contrast, dihydroresveratrol did not exhibit significant anti-inflammatory effects, and lunularin exhibited pro-inflammatory effects in cells. This study may help to better understand the health effects of resveratrol and its microbial metabolites.


Assuntos
Anti-Inflamatórios , Colite , Resveratrol , Animais , Antibacterianos , Bibenzilas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Sulfato de Dextrana , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Fenóis , Fenilpropionatos , Polifenóis , Propionatos , Resveratrol/farmacologia , Estilbenos , Espectrometria de Massas em Tandem
4.
J Pharm Biomed Anal ; 223: 115115, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36332331

RESUMO

Liandan Xiaoyan Formula (LDXYF) is a traditional Chinese medicine prescription (TCMP) consisting of Herba Andrographis (dried herb of Andrographis paniculata) and Picrasmae ramulus et folium (dried twiggeries and leaves of Picrasma quassioides). It is used to treat diarrhea, acute gastroenteritis, colitis, and dysentery, among other inflammatory gastrointestinal diseases. However, because of less research on the in vitro chemical composition and holistic metabolism of LDXYF, in vivo mechanisms of action and quality control of LDXYF have not yet been fully assessed due to the lack of studies into its bioactive components. In this study, ultra-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was established for comprehensive analysis of chemical compounds of LDXYF and their metabolites in serum and urine samples of control and colitis rats. As a result, totally 94 compounds in LDXYF were unambiguously identified or tentatively characterized. And a total of 91 LDXYF-related xenobiotics were characterized, including 61 (16 prototypes and 45 metabolites) in serum, and 72 (26 prototypes and 46 metabolites) in urine. Besides, we compared the exposure of metabolites in normal and colitis rats by chemometrics and summarize similarities and differences of metabolic pathways of mainly compounds in normal and colitis conditions, and found that in control and colitis conditions, alkaloids predominantly went through phase I reaction combined phase II reaction (hydroxylation and sulfation, hydroxylation and glucuronidation, demethylation and glucuronidation), while the major metabolic reaction of diterpene lactones were phase Ⅱ reactions (glucuronidation, sulfation). And there were no significant differences in metabolic pathways between control and colitis groups, just the exposure of prototype and their metabolites absorbed into serum or excreted through the urine were different, and 17 alkaloids and 6 diterpene lactone prototypes and their metabolites in serum could be considered as potential pharmacodynamic substances. A comprehensive analysis of the compounds and metabolic characteristics of LDXYF was conducted in our study, and the results laid the chemical foundation for further research into effective substances and the action mechanism of LDXYF.


Assuntos
Alcaloides , Colite , Medicamentos de Ervas Chinesas , Ratos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Medicamentos de Ervas Chinesas/química , Quimiometria , Ratos Sprague-Dawley , Metaboloma , Lactonas/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico
5.
Phytomedicine ; 108: 154490, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36332386

RESUMO

BACKGROUND: Ulcerative colitis (UC) progression is driven by the activation of immune cells that release pro-inflammatory mediators to disrupt intestinal epithelial barrier integrity. This study aimed to investigate the potential protective effects of Angelica oil (AO) on the intestinal epithelial barrier in mice with UC and the underlying mechanisms. METHODS: Improvement of the disease state and protective effect of AO on the intestinal epithelial barrier were observed in mice with dextran sulphate sodium salt (DSS)-induced UC. Protein microarrays were used to screen AO-affected cytokine pools and their recruited immune cells for accumulation in the tissues. Furthermore, quantitative proteomics was applied to search for AO-acting molecules and to verify in vitro the functions of key molecules between inflammation and the intestinal mucosal barrier. RESULTS: AO significantly alleviated intestinal inflammation, reduced intestinal permeability, and retained barrier function in mice with UC. Furthermore, cytokines inhibited by AO mainly promoted monocyte and neutrophil activation or chemotaxis. Moreover, proteomic screening revealed that S100A8/A9 was a key molecule significantly regulated by AO, and its mediated TLR4/NF-κB pathway was also inhibited. Finally, we verified that AO inhibited the activation of the S100A8/A9/TLR4 signalling pathway and enhanced the expression of tight junctions (TJs) proteins using a cellular model of intestinal barrier damage induced by S100A8/A9 or macrophage-derived medium. And the enhancement of TJs in intestinal epithelial cells and the inhibition of inflammatory signalling by AO were significantly attenuated due to the application of S100A8/A9 monoclonal antibody. CONCLUSION: These results demonstrated that AO improves intestinal mucosal barrier damage in the inflammatory environment of mice with UC by inhibiting the expression of S100A8/A9 and the activation of its downstream TLR4/NF-κB signalling pathway.


Assuntos
Angelica , Colite Ulcerativa , Colite , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteômica , Mucosa Intestinal/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Sulfato de Dextrana/efeitos adversos , Colite/induzido quimicamente , Camundongos Endogâmicos C57BL
6.
J Nutr Biochem ; 111: 109155, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36162566

RESUMO

Inflammatory bowel disease (IBD) patients are particularly vulnerable to infection with Clostridium difficile infection (CDI).Available treatments of IBD with CDI have not effective. Butyrate, the metabolites of microbiota, plays a vital role in maintaining immune homeostasis and potential drugs for treatment of IBD with CDI. The aim of this study was to investigate the effect of butyrate on IBD with CDI. Mice were given dextran sulfate sodium (DSS) and were infected with C. difficile (CD). Butyrate was treated during the study period. Butyrate protected from DSS+CD induced colitis by improving weight loss, survival, colon shorten, activity index score, and suppressing the expression of proinflammatory cytokines including IL-6, IL-17, TNF-α, IL-1ß as well as regulating Th17/Treg balance through activation of SIRT1/mTOR. Besides, SR1001, an inhitor of the orphan nuclear receptors retinoic acid-related receptor γt, which is a transcription factor specific to the formation of Th17 cells can suppress the Th17 development and alleviate the DSS+CD induced colitis in mice. Notably, the therapeutic effect of butyrate was revered when disease mice treated with butyrate and Ex-527, a SIRT1 inhibitor. Taken together, we demonstrate that butyrate alleviates dextran sulfate sodium and clostridium difficile induced colitis by preventing Th17 through activation of SIRT1/mTOR.


Assuntos
Clostridioides difficile , Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Células Th17 , Sulfato de Dextrana/toxicidade , Sirtuína 1/metabolismo , Butiratos/metabolismo , Modelos Animais de Doenças , Colite/induzido quimicamente , Colite/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Colo/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Camundongos Endogâmicos C57BL
7.
Phytomedicine ; 108: 154518, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36403513

RESUMO

BACKGROUND: Chios mastic gum (CMG) is a traditional Greek medicine used to treat a variety of gastrointestinal disorders, including inflammatory bowel disease (IBD). However, the bioactive compounds of CMG and the mechanisms of action for controlling of IBD remain unknown. PURPOSE: Masticadienonic acid (MDA) is one of the most abundant constituents isolated from CMG. This study aims to investigate the potential effects and underlying mechanisms of MDA in the pathogenesis of colitis. METHODS: The effects of MDA were evaluated using a dextran sulphate sodium (DSS)-induced acute colitis mouse model. The body and spleen weight and colon length and weight were measured and the clinical symptoms were analysed. Blood samples were collected to analyse the level of serum inflammatory markers. Colon tissues were processed for histopathological examination, evaluation of the epithelial barrier function, and investigation of the probable mechanisms of action. The gut microbiota composition was also studied to determine the mechanism for the beneficial effects of MDA on IBD. RESULTS: MDA could ameliorate the severity of IBD by increasing the body weight and colon length, reducing spleen weight, disease activity index, and histological score. MDA treatments reduce the release of serum inflammatory cytokines tumour necrosis factor-alpha (TNFα), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) via inhibiting the MAPK and NF-κB signalling pathways. MDA supplementation could also improve the intestinal barrier function by activating the NF-E2-related factor-2 (Nrf2) signalling pathway and restoring the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin. In addition, MDA administration modulates the gut microbiota composition in DSS-induced colitis mice. CONCLUSION: The results indicate that MDA attenuated experimental colitis by restoring intestinal barrier integrity, reducing inflammation, and modulating the gut microbiota. The present study provides novel insights into CMG-mediated remission of IBD and may facilitate the development of preventive and therapeutic strategies for IBD.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Camundongos , Animais , Sulfato de Dextrana/efeitos adversos , Resina Mástique/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Interleucina-6/farmacologia
8.
World J Gastroenterol ; 28(39): 5750-5763, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36338892

RESUMO

BACKGROUND: Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients. AIM: To determine the association of IMC with OS and PFS and identify clinical predictors of IMC. METHODS: We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC. RESULTS: IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07). CONCLUSION: IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.


Assuntos
Antineoplásicos Imunológicos , Colite , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Estudos Retrospectivos , Estudos de Casos e Controles , Melanoma/tratamento farmacológico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Vitamina D
9.
Korean J Parasitol ; 60(5): 309-315, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36320107

RESUMO

Inflammatory bowel disease (IBD) is a chronic and recurrent illness of the gastrointestinal tract. Treatment of IBD traditionally involves the use of aminosalicylic acid and steroids, while these drugs has been associated with untoward effects and refractoriness. The absence of effective treatment regimen against IBD has led to the exploration of new targets. Parasites are promising as an alternative therapy for IBD. Recent studies have highlighted the use of parasite-derived substances, such as excretory secretory products, extracellular vesicles (EVs), and exosomes, for the treatment of IBD. In this report, we examined whether EVs secreted by Giardia lamblia could prevent colitis in a mouse model. G. lamblia EVs (GlEVs) were prepared from in vitro cultures of Giardia trophozoites. Clinical signs, microscopic colon tissue inflammation, and cytokine expression levels were detected to assess the effect of GlEV treatment on dextran sulfate sodium (DSS)-induced experimental murine colitis. The administration of GlEVs prior to DSS challenge reduced the expression levels of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1 beta, and interferon gamma. Our results indicate that GlEV can exert preventive effects and possess therapeutic properties against DSS-induced colitis.


Assuntos
Colite , Vesículas Extracelulares , Giardia lamblia , Doenças Inflamatórias Intestinais , Camundongos , Animais , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Camundongos Endogâmicos C57BL , Giardia lamblia/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Modelos Animais de Doenças , Colo/patologia
10.
J Immunother Cancer ; 10(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36323433

RESUMO

BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. METHODS: The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. RESULTS: Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. CONCLUSIONS: This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.


Assuntos
Produtos Biológicos , Colite , Neoplasias do Colo , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Camundongos , Azoximetano , Antígeno B7-H1/genética , Colite/induzido quimicamente , Di-Iodotirosina/genética , Interleucina-15/genética , Antígenos de Histocompatibilidade Menor/genética , Acúmulo de Mutações , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral
11.
Sci Rep ; 12(1): 20169, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418891

RESUMO

Gastrointestinal tract (gut) inflammation increases stress and threat-coping behaviors, which are associated with altered activity in fear-related neural circuits, such as the basolateral amygdala and hippocampus. It remains to be determined whether inflammation from the gut affects neural activity by altering dendritic spines. We hypothesized that acute inflammation alters dendritic spines in a brain region-specific manner. Here we show that acute gut inflammation (colitis) evoked by dextran sodium sulfate (DSS) did not affect the overall spine density in the CA1 region of hippocampus, but increased the relative proportion of immature spines to mature spines on basal dendrites of pyramidal neurons. In contrast, in animals with colitis, no changes in spine density or composition on dendrites of pyramidal cells was observed in the basolateral amygdala. Rather, we observed decreased spine density on dendrites of stellate neurons, but not the relative proportions of mature vs immature spines. We used cFos expression evoked by the forced swim task as a measure of neural activity during stress and found no effect of DSS on the density of cFos immunoreactive neurons in basolateral amygdala. In contrast, fewer CA1 neurons expressed cFos in mice with colitis, relative to controls. Furthermore, CA1 cFos expression negatively correlated with active stress-coping in the swim task and was negatively correlated with gut inflammation. These data reveal that the effects of acute gut inflammation on synaptic remodeling depend on brain region, neuronal phenotype, and dendrite location. In the hippocampus, a shift to immature spines and hypoactivity are more strongly related to colitis-evoked behavioral changes than is remodeling in basolateral amygdala.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Colite , Animais , Camundongos , Hipocampo , Células Piramidais , Inflamação , Colite/induzido quimicamente
12.
Front Immunol ; 13: 960329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36420263

RESUMO

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT). Current strategies to prevent GvHD with immunosuppressive drugs carry significant morbidity and may affect the graft-versus-tumor (GVT) effect. Inflammatory bowel disease (IBD) is an intestinal inflammatory condition that affects more than 2 million people in the United States. Current strategies to prevent colitis with immunosuppressive drugs carry significant morbidity. Recently, Repulsive Guidance Molecule b (RGMb) has been identified as part of a signaling hub with neogenin and BMP receptors in mice and humans. In addition, RGMb binds BMP-2/4 in mice and humans as well as PD-L2 in mice. RGMb is expressed in the gut epithelium and by antigen presenting cells, and we found significantly increased expression in mouse small intestine after total body irradiation HCT conditioning. We hypothesized that RGMb may play a role in GvHD and IBD pathogenesis by contributing to mucosal inflammation. Using major-mismatched HCT mouse models, treatment with an anti-RGMb monoclonal antibody (mAb) that blocks the interaction with BMP-2/4 and neogenin prevented GvHD and improved survival compared to isotype control (75% versus 30% survival at 60 days after transplantation). The GVT effect was retained in tumor models. Using an inflammatory bowel disease dextran sulfate sodium model, treatment with anti-RGMb blocking monoclonal antibody but not isotype control prevented colitis and improved survival compared to control (73% versus 33% at 21 days after treatment) restoring gut homeostasis. Anti-RGMb mAb (9D1) treatment decreased IFN-γ and significantly increased IL-5 and IL-10 in the gut of the treated mice compared to the isotype control treated mice.


Assuntos
Colite , Doença Enxerto-Hospedeiro , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , Inflamação , Doenças Inflamatórias Intestinais/terapia , Colite/induzido quimicamente , Imunossupressores , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Moléculas de Adesão Celular Neuronais
13.
J Agric Food Chem ; 70(46): 14718-14731, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36375817

RESUMO

Ulcerative colitis (UC), one of the foremost common forms of inflammatory bowel disease, poses a serious threat to human health. Currently, safe and effective treatments are not available. This study investigated the protective effect of ginkgolide C (GC), a terpene lactone extracted from Ginkgo biloba leaves, on UC and its underlying mechanism. The results showed that GC remarkably mitigated the severity of DSS-induced colitis in mice, as demonstrated by decreased body weight loss, reduced disease activity index, mitigated tissue damage, and increased colon length. Furthermore, GC inhibited DSS-induced hyperactivation of inflammation-related signaling pathways (NF-κB and MAPK) to reduce the production of inflammatory mediators, thereby mitigating the inflammatory response in mice. GC administration also restored gut barrier function by elevating the number of goblet cells and boosting the levels of tight junction-related proteins (claudin-3, occludin, and ZO-1). In addition, GC rebalanced the intestinal flora of DSS-treated mice by increasing the diversity of the flora, elevating the abundance of beneficial bacteria, such as Lactobacillus and Allobaculum, and decreasing the abundance of harmful bacteria, such as Bacteroides, Oscillospira, Ruminococcus, and Turicibacter. Taken together, these results suggest that GC administration effectively alleviates DSS-induced colitis by inhibiting the inflammatory response, maintaining mucosal barrier integrity, and regulating intestinal flora. This study may provide a scientific basis for the rational use of GC in preventing colitis and other related diseases.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Camundongos , Humanos , Animais , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Lactonas/metabolismo , Colite Ulcerativa/metabolismo , Colo/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Camundongos Endogâmicos C57BL
14.
Front Immunol ; 13: 1034648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389671

RESUMO

Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183, known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18. Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn's disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag-/- recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag-/- mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine.


Assuntos
Colite , Estudo de Associação Genômica Ampla , Camundongos , Humanos , Animais , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/genética , Modelos Animais de Doenças , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T CD4-Positivos/metabolismo
15.
Front Immunol ; 13: 1001623, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389768

RESUMO

Immune checkpoint inhibitors (ICIs) have become a promising therapeutic strategy for malignant tumors, improving patient prognosis, along with a spectrum of immune-related adverse events (irAEs), including gastrointestinal toxicity, ICI-related colitis (IRC), and diarrhea. The gut microbiota has been suggested as an important regulator in the pathogenesis of IRC, and microbiota modulations like probiotics and fecal microbiota transplantation have been explored to treat the disease. This review discusses the interaction between the gut microbiota and IRC, focusing on the potential pathogenic mechanisms and promising interventions.


Assuntos
Colite , Microbioma Gastrointestinal , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Colite/induzido quimicamente , Colite/terapia , Transplante de Microbiota Fecal
16.
BMC Gastroenterol ; 22(1): 469, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401221

RESUMO

BACKGROUND: Triclosan, an antimicrobial agent in personal care products, could be absorbed into the human body through the digestive tract. This animal experiment aimed to clarify the effects of triclosan exposure on the microbiome and intestinal immune functions in healthy and ulcerative colitis models. METHODS: Balb/c mice were maintained on an AIN-93G diet containing 80ppm triclosan dissolved in polyethylene as vehicle or vehicle alone for 1 week or 4 weeks. In the end, the mice were sacrificed, blood samples and colon tissues were collected for analysis of inflammation, and fecal samples were collected for 16 S rRNA sequencing of gut microbiota. To establish ulcerative colitis mice model, at the beginning of the 4th week, mice maintained on the diet with or without triclosan were treated with 2% Dextran sulfate sodium(DSS) in drinking water for 1 week. Then mice were sacrificed for analysis of colitis and gut microbiota. RESULTS: Triclosan exposure to common mice enhanced the levels of p-NF-κb and Toll-like receptor 4 (TLR4), and decreased the Occludin in the colon. Triclosan exposure to DSS-induced mice increased the level of inflammatory cytokines, reduced the levels of Occludin, and exacerbated the degree of damage to intestinal mucosa and crypt, infiltration of inflammatory cells and atypia of glandular cells. Low-grade intraepithelial neoplasia appeared. Both in common and DSS-induced mice, triclosan exposure changed the diversity and composition of gut microbiota. Fecal samples showed higher enrichment of sulfate-reducing bacteria and Bacteroides, and less butyrate-producing bacteria. CONCLUSION: Triclosan exposure induced disturbance of gut microbiota and exaggerated experimental colitis in mice. And changes in the composition of gut microbiota were characterized by the increase of harmful bacteria, including sulfate-reducing bacteria and Bacteroides, and the reduction of protective probiotics, butyrate-producing bacteria.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Triclosan , Humanos , Camundongos , Animais , Microbioma Gastrointestinal/genética , Triclosan/efeitos adversos , Sulfato de Dextrana/efeitos adversos , Colite Ulcerativa/induzido quimicamente , Ocludina , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/microbiologia , Sulfatos/efeitos adversos , Butiratos/farmacologia
17.
Int J Nanomedicine ; 17: 5303-5314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406639

RESUMO

Aim: This study focuses on constructing of an anti-inflammatory drug delivery system by encapsulation of berberine in the ß-glucan nanoparticles and evaluates its effect on treating ulcerative colitis. Methods: ß-Glucan and the anti-inflammatory drug berberine (BER) are self-assembled into nanoparticles to construct a drug delivery system (GLC/BER). The interaction between the drug and the carrier was characterized by circular dichroism, ultraviolet-visible spectroscopy, and dynamic light scattering. The anti-inflammatory effect of the GLC/BER was evaluated through a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammation model and a sodium sulfate (DSS)-induced C57BL/6 mouse ulcerative colitis model. Results: The GLC/BER nanoparticles have a particle size of 80-120 nm and a high encapsulation efficiency of 37.8±4.21%. In the LPS-induced RAW264.7 macrophage inflammation model, GLC/BER significantly promoted the uptake of BER by RAW264.7 cells. RT-PCR and ELISA assay showed that it could significantly inhibit the inflammatory factors including IL-1ß, IL-6 and COX-2. Furthermore, GLC/BER shows inhibiting effect on the secretion of pro-inflammatory factors such as IL-1ß and IL-6, down-regulating the production of nitrite oxide; in animal studies, GLC/BER was found to exert a relieving effect on mice colitis. Conclusion: The study found that GLC/BER has an anti-inflammatory effect in vitro and in vivo, and the GLC carrier improves the potency and bioavailability of BER, providing a new type of nanomedicine for the treatment of colitis.


Assuntos
Berberina , Colite Ulcerativa , Colite , Nanopartículas , beta-Glucanas , Camundongos , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Lipopolissacarídeos , Interleucina-6 , Camundongos Endogâmicos C57BL , Macrófagos , Colite/induzido quimicamente , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico
18.
Biochem Biophys Res Commun ; 636(Pt 2): 48-54, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36343490

RESUMO

Inflammatory bowel disease (IBD) is a non-specific inflammatory disease of the intestine with the pathogenesis to be largely unknown. We found that microRNA (miR)-10b knock-out mice displayed mild IBD symptoms, suggesting that miR-10b may be involved in the onset and development of IBD. This study focuses on elucidating the role of miR-10b in IBD. The colitis model was induced by feeding the mice with 2.5% dextran sodium sulfate (DSS), and the expression levels of miR-10b in colon tissue and blood samples were examined. The severity of colitis was assessed by disease activity index, colon length, histopathological damage, intestinal permeability and ELISA. Then, after transfection of Caco-2 cells with miR-10b mimic and inhibitor, qRT-PCR was used to detect the expression levels of intestinal barrier related genes in colon tissues and cells. miR-10b levels were significantly reduced in mice with DSS-induced acute colitis. Compared with wild-type (WT) mice, miR-10b knockout mice were more sensitive to DSS-induced colitis characterized by increased inflammatory cell infiltration and more severe disruption of colonic barrier function. In addition, by inhibiting miR-10b and thus increasing intestinal barrier gene expression in Caco-2 cells, we found that miR-10b suppressed inflammatory responses and enhanced intestinal barrier function both in vivo and in vitro. miR-10b inhibits the inflammatory response in DSS-induced acute colitis mice in vivo and enhances intestinal barrier function in vitro, suggesting that miR-10b plays a key role in the developmental process of IBD. Thus, miR-10b may be expected to be a new target for the treatment of IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , MicroRNAs , Animais , Humanos , Camundongos , Células CACO-2 , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo
19.
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
20.
BMC Vet Res ; 18(1): 405, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384756

RESUMO

BACKGROUND: Uncertain effects of probiotics and/or prebiotics have been reported in experimental and clinical colitis. This study aims to examine the effects of a synbiotic combination comprising Bacillus licheniformis DSM 17236 and Saccharomyces cerevisiae cell wall extract on dextran sulfate sodium (DSS)-induced colitis in Sprague Dawley rats. METHODS: Acute colitis was induced in rats by oral administration of DSS 3.5% for 7 days. Fifty rats were divided equally into five groups; one control group and the other groups were induced with colitis and treated with or without the tested synbiotic, mixed with diet, for 28 days and sulfasalazine (100 mg/kg) via intragastric tube once daily for 14 days. RESULTS: Symptomatically, the synbiotic administration raised the disease activity index (DAI) to comparable scores of the DSS group, specially from the 2nd to 7th days post DSS intoxication. It also induced a significant (p < 0.05) amplification of WBCs, myeloperoxidase (MPO), malondialdehyde (MDA), nuclear factor kappa B (NF-kB) expression and proinflammatory cytokines tumor necrosis factor alpha (TNFα), interferon gamma (INFγ), and interleukin-1 beta (IL-1ß) while depressed the antioxidant enzymes glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) when compared with the DSS and control groups. The DSS intoxicated and Synbiotic+DSS groups showed desquamations of the covering epithelium, noticeable diffuse leukocytic infiltrations, sever catarrhal enteritis, ischemic colitis with diffuse coagulative necrosis of the entire colonic mucosa. Contrarily, sulfasalazine proved to be effective in the reduction of the tested inflammatory markers and the pathological degenerative changes of the DSS ulcerative colitis. CONCLUSION: The examined synbiotic did not ameliorate but aggravated the DSS-induced colitis, so it should be subjected to intensive experimental and clinical testing before their use in animals and human.


Assuntos
Bacillus licheniformis , Colite , Doenças dos Roedores , Simbióticos , Humanos , Ratos , Animais , Sulfato de Dextrana/toxicidade , Saccharomyces cerevisiae , Sulfassalazina/efeitos adversos , Ratos Sprague-Dawley , Colite/induzido quimicamente , Colite/terapia , Colite/metabolismo , Colite/veterinária
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