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1.
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
Colite , Espectrometria de Massas em Tandem , Animais , Antibacterianos/efeitos adversos , Anti-Inflamatórios , Bibenzilas , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Sulfato de Dextrana , Humanos , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Fenóis , Fenilpropionatos , Polifenóis , Propionatos , Resveratrol/farmacologia , Estilbenos
2.
Oxid Med Cell Longev ; 2022: 8543720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092152

RESUMO

Background: Bioactive compound such as interleukin-22 (IL-22) treatment is regarded as a sufficient treatment for ulcerative colitis (UC). It has been found that long noncoding RNAs (lncRNAs) expressed in many inflammatory diseases, including UC. We aimed to verify the treatment effect of bioactive compounds including IL-22 and lncRNAs in UC on colitis mice. Methods: UC mice were induced using DSS, followed by IL-22 or PBS intraperitoneally (i.p.) injection. Then, the histopathological parameters of the mice were determined. Then, RNA sequencing was performed to screen the differential lncRNAs. Quantitative real-time PCR (qRT-PCR) and lentivirus identified lncRNA-Ulcerative Colitis lncRNA (lncRNA-UCL) were regarded as the molecular regulator of the colitis mice. The correlation with lncRNA-UCL and mmu-miR-568 was validated using RNA-pulldown. Meanwhile, claudin-1 was predicted and confirmed as the target molecule of mmu-miR-568 using dual-luciferase assay. Results: IL-22 could significantly improve the histopathological features and decrease proinflammatory cytokine production in UC mice induced by DSS. It also can stimulate intestinal epithelial cell (IEC) reproduction and prevention of apoptosis. lncRNA-UCL was significantly downregulated in UC mice caused by DSS, while IL-22 treatment effectively reversed this effect. In terms of mechanism, lncRNA-UCL regulates intestinal epithelial homeostasis by sequestering mmu-miR-568 and maintaining close integrated protein expression, such as claudin-1. Conclusions: We have demonstrated the incredible role of bioactive compound, such as IL-22, in alleviating DSS-induced colitis symptoms via enhancing lncRNA-UCL expression. It can be regulated using tight junction (TJ) protein.


Assuntos
Colite Ulcerativa , Colite , MicroRNAs , RNA Longo não Codificante , Animais , Claudina-1/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Sulfato de Dextrana/toxicidade , Interleucinas , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Proteínas de Junções Íntimas/metabolismo , Regulação para Cima
3.
J Adv Res ; 40: 263-276, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36100331

RESUMO

INTRODUCTION: Ulcerative colitis (UC) is a chronic recurrent idiopathic disease characterized by damage to the colonic epithelial barrier and disruption of inflammatory homeostasis. At present, there is no curative therapy for UC, and the development of effective and low-cost therapies is strongly advocated. OBJECTIVES: Multiple lines of evidence support that tannic acid (TA) and berberine (BBR), two active ingredients derived from Chinese herb pair (Rhei Radix et Rhizoma and Coptidis Rhizoma), have promising therapeutic effects on colonic inflammation. This study aims to develop a targeted delivery system based on BBR/TA-based self-assemblies for the treatment of UC. METHODS: TA and BBR self-assemblies were optimized, and hyaluronic acid (HA) was coated to achieve targeted colon delivery via HA-cluster of differentiation 44 (CD44) interactions. The system was systematically characterized and dextran sodium sulfate (DSS)-induced mouse colitis model was further used to investigate the biodistribution behavior, effect and mechanism of the natural system. RESULTS: TA and BBR could self-assemble into stable particles (TB) and HA-coated TB (HTB) further increased cellular uptake and accumulation in inflamed colon lesions. Treatment of HTB inhibited pro-inflammatory cytokine levels, restored expression of tight junction-associated proteins and recovered gut microbiome alteration, thereby exerting anti-inflammatory effects against DSS-induced acute colitis. CONCLUSION: Our targeted strategy may provide a convenient and powerful platform for UC and reveal new modes of application of herbal combinations.


Assuntos
Antineoplásicos , Berberina , Colite Ulcerativa , Colite , Animais , Antineoplásicos/uso terapêutico , Benzopiranos/efeitos adversos , Berberina/efeitos adversos , China , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos , Salicilatos , Taninos/efeitos adversos , Taninos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Distribuição Tecidual
4.
Biochem Biophys Res Commun ; 628: 147-154, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36087511

RESUMO

Expression of mucin MUC2, a component of the colonic mucus layer, plays a crucial role in intestinal homeostasis. Here, we describe a new regulator of MUC2 expression, the deubiquitinase ZRANB1 (Trabid). A ZRANB1 mutation changing cysteine to serine in amino acid position 443, affects ubiquitination. To analyze ZRANB1 function in the intestine, we generated Zranb1 C443S mutant knock-in (Zranb1C443S/C443S) mice using the CRISPR/Cas9 system. Zranb1C443S/C443S mice exhibited decreased mRNA expression and MUC2 production. Colonic organoids from Zranb1C443S/C443S mice displayed decreased Muc2 mRNA expression following differentiation into goblet cells. Finally, we analyzed dextran sulfate sodium-induced colitis to understand ZRANB1's role in intestinal inflammation. Zranb1C443S/C443S mice with colitis exhibited significant weight loss, reduced colon length, and worsening clinical and pathological scores, indicating that ZRANB1 contributes to intestinal homeostasis. Together, these results suggest that ZRANB1 regulates MUC2 expression and intestinal inflammation, which may help elucidating the pathogenesis of inflammatory bowel disease and developing new therapeutics targeting ZRANB1.


Assuntos
Colite , Cisteína , Animais , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Cisteína/metabolismo , Enzimas Desubiquitinantes/metabolismo , Sulfato de Dextrana/toxicidade , Inflamação/patologia , Mucosa Intestinal/metabolismo , Camundongos , Mucinas/metabolismo , Muco/metabolismo , RNA Mensageiro/genética , Serina/metabolismo
5.
Microbiome ; 10(1): 149, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114582

RESUMO

BACKGROUND: The pathogenesis of inflammatory bowel diseases (IBD) is multifactorial, and diagnostic and treatment strategies for IBD remain to be developed. RhoB regulates multiple cell functions; however, its role in colitis is unexplored. RESULTS: Here, we found RhoB was dramatically increased in colon tissues of ulcerative colitis (UC) patients and mice with DSS-induced colitis. Compared with wild type mice, RhoB+/- and RhoB-/- mice developed milder DSS-induced colitis and increased goblet cell numbers and IEC proliferation. Decreased RhoB promoted goblet cell differentiation and epithelial regeneration through inhibiting Wnt signaling pathway and activating p38 MAPK signaling pathway. Moreover, increased SCFA-producing bacteria and SCFA concentrations were detected in intestinal microbiome of both RhoB+/- and RhoB-/- mice and upregulated SCFA receptor expression was also observed. CONCLUSIONS: Taken together, a higher level of RhoB is associated with UC, which also contributes to UC development through modulating cell signaling and altering intestinal bacterial composition and metabolites. These observations suggest that RhoB has potential as a biomarker and a treatment target for UC. Video Abstract.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Biomarcadores , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Camundongos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Cell Mol Biol Lett ; 27(1): 75, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064319

RESUMO

BACKGROUND: Ulcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear. METHODS: In vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1. RESULTS: Pou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown. CONCLUSION: Overall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.


Assuntos
Neoplasias Associadas a Colite , Fator 6 de Transcrição de Octâmero/metabolismo , Animais , Carcinogênese , Sulfato de Dextrana/toxicidade , Inflamação , Camundongos , Fatores de Transcrição NFATC
7.
Sci Data ; 9(1): 549, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071055

RESUMO

An inappropriate diet is a risk factor for inflammatory bowel disease (IBD). It is established that the consumption of spicy food containing capsaicin is strongly associated with the recurrence and worsening of IBD symptoms. Moreover, capsaicin can induce neutrophil accumulation in the lamina propria, contributing to disease deterioration. To uncover the potential signaling pathway involved in capsaicin-induced relapse and the effects of capsaicin on neutrophil activation, we performed proteomic analyses of intestinal tissues from chronic colitis mice following capsaicin administration and transcriptomic analyses of dHL-60 cells after capsaicin stimulation. Collectively, these multiomic analyses identified proteins and genes that may be involved in disease flares, thereby providing new insights for future research.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Capsaicina , Doença Crônica , Colite/genética , Colite/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , RNA-Seq , Transcriptoma
8.
Pak J Biol Sci ; 25(9): 843-851, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36098087

RESUMO

<b>Background and Objective:</b> Ulcerative colitis (UC) is inflammation of the large intestine with ulceration but can also cause extraintestinal manifestations (EIM) by damaging surrounding organs such as the liver. <i>Garcinia mangostana</i> (GM) pericarp and α-mangostin (MGS) have been reported to have anti-inflammatory activity. This study evaluated the effects of GM pericarp extract and MGS on the expression of hepatic cytochrome P450 (CYP) enzymes as an EIM of UC. <b>Materials and Methods:</b> Male ICR mice were orally administered GM pericarp extract (40, 200 and 1000 mg/kg/day), MGS (30 mg/kg/day) or sulfasalazine (SUL) (100 mg/kg/day) daily for 7 days. On days 4-7, UC was induced by dextran sulfate sodium (DSS 40 kDa, 6 g/kg/day). Profiles of CYP mRNA expression were determined by RT/qPCR. Alkoxyresorufin <i>O</i>-dealkylation (including ethoxy-, methoxy-, pentoxy- and benzyloxy-resorufin), aniline hydroxylation and erythromycin <i>N</i>-demethylation CYP responsive activities were also examined. <b>Results:</b> The DSS-induced UC mice showed suppressed expression<i> </i>of <i>Cyp1a1</i>, <i>Cyp1a2</i>, <i>Cyp2b9/10</i>, <i>Cyp2e1</i>, <i>Cyp2c29</i>, <i>Cyp2d9</i>, <i>Cyp3a11</i> and <i>Cyp3a13</i> mRNAs. The GM pericarp extract and MGS restored expression of all investigated CYPs and their responsive enzyme activities in DSS-induced UC mice to levels comparable to the control and parallel to the effects of the anti-inflammatory control SUL. <b>Conclusion:</b> The GM is a promising therapy to restore UC-modified hepatic CYP profiles.


Assuntos
Colite Ulcerativa , Garcinia mangostana , Animais , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/efeitos adversos , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sulfato de Dextrana/efeitos adversos , Garcinia mangostana/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/farmacologia , Xantonas
9.
Biomed Pharmacother ; 154: 113651, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36081290

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory life-threatening and premalignant disorder with no cure that even might end up with surgical removal of a large section or even all of the colon. It is characterized by relapsing-remitting courses of intestinal inflammation and mucosal damage in which oxidative stress and exaggerated inflammatory response play a significant role. Most of the current medications to maintain remission are symptomatic and have many adverse reactions. Therefore, the potential for improved management of patients with UC continues to increase. Yet, the benefits of using the antiarthritic agent diacetylrhein to counteract inflammation in UC are still obscure. Hence, our study was designed to explore its potential role in UC using a model of dextran sodium sulfate-induced acute colitis in rats. Our results revealed that diacetylrhein targeted the NLRP3 and inhibited the inflammasome assembly. Consequently, caspase-1 activity and the inflammatory cytokines IL-1ß and IL-18 were inhibited leading to a curbed pyroptosis process. Additionally, diacetylrhein revealed a significant antiapoptotic potential as revealed by the levels of pro-apoptotic and anti-apoptotic proteins. Concomitant to these effects, diacetylrhein also interrupted NFκB signals leading to improved microscopic features of inflamed colon and decreased colon weight to length ratio, indices of disease activity, and macroscopic damage. Additionally, a reduction in the myeloperoxidase activity, IL-6, and TGF-ß alongside an increase in the gene expression of Ocln and ZO-1 were detected. To conclude diacetylrhein showed a significant antioxidant and anti-inflammatory potential and therefore might represent a promising agent in the management of acute UC.


Assuntos
Colite Ulcerativa , Colite , Animais , Antraquinonas/farmacologia , Antraquinonas/uso terapêutico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Inflamação/metabolismo , Ratos , Sulfatos
10.
Int J Mol Sci ; 23(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36077084

RESUMO

Recent studies have shown dysbiosis is associated with inflammatory bowel disease (IBD). However, trying to restore microbial diversity via fecal microbiota transplantation (FMT) or probiotic intervention fails to achieve clinical benefit in IBD patients. We performed a probiotic intervention on a simulated IBD murine model to clarify their relationship. IBD was simulated by the protocol of azoxymethane and dextran sodium sulfate (AOM/DSS) to set up a colitis and colitis-associated neoplasm model on BALB/c mice. A single probiotic intervention using Clostridium butyricum Miyairi (CBM) on AOM/DSS mice to clarify the role of probiotic in colitis, colitis-associated neoplasm, gut microbiota, and immune cytokines was performed. We found dysbiosis occurred in AOM/DSS mice. The CBM intervention on AOM/DSS mice failed to improve colitis and colitis-associated neoplasms but changed microbial composition and unexpectedly increased expression of proinflammatory IL-17A in rectal tissue. We hypothesized that the probiotic intervention caused dysbiosis. To clarify the result, we performed inverse FMT using feces from AOM/DSS mice to normal recipients to validate the pathogenic effect of dysbiosis from AOM/DSS mice and found mice on inverse FMT did develop colitis and colon neoplasms. We presumed the probiotic intervention to some extent caused dysbiosis as inverse FMT. The role of probiotics in IBD requires further elucidation.


Assuntos
Neoplasias Associadas a Colite , Colite , Doenças Inflamatórias Intestinais , Probióticos , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/terapia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/terapia , Doenças Inflamatórias Intestinais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Probióticos/farmacologia , Sulfatos
11.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077356

RESUMO

Hemp (Cannabis sativa L.) is used for medicinal purposes owing to its anti-inflammatory and antioxidant activities. We evaluated the protective effect of nanovesicles isolated from hemp plant parts (root, seed, hemp sprout, and leaf) in dextran sulfate sodium (DSS)-induced colitis in mice. The particle sizes of root-derived nanovesicles (RNVs), seed-derived nanovesicles (SNVs), hemp sprout-derived nanovesicles (HSNVs), and leaf-derived nanovesicles (LNVs) were within the range of 100-200 nm as measured by nanoparticle tracking analysis. Acute colitis was induced in C57BL/N mice by 5% DSS in water provided for 7 days. RNVs were administered orally once a day, leading to the recovery of both the small intestine and colon lengths. RNVs, SNVs, and HSNVs restored the tight (ZO-1, claudin-4, occludin) and adherent junctions (E-cadherin and α-tubulin) in DSS-induced small intestine and colon injury. Additionally, RNVs markedly reduced NF-κB activation and oxidative stress proteins in DSS-induced small intestine and colon injury. Tight junction protein expression and epithelial cell permeability were elevated in RNV-, SNV-, and HSNV-treated T84 colon cells exposed to 2% DSS. Interestedly, RNVs, SNVs, HSNVs, and LNVs reduced ALT activity and liver regeneration marker proteins in DSS-induced liver injury. These results showed for the first time that hemp-derived nanovesicles (HNVs) exhibited a protective effect on DSS-induced gut leaky and liver injury through the gut-liver axis by inhibiting oxidative stress marker proteins.


Assuntos
Cannabis , Colite , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sulfatos , Junções Íntimas/metabolismo
12.
Gut Microbes ; 14(1): 2107387, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36050867

RESUMO

Although post-cholecystectomy (PC) patients usually have gastrointestinal complications and a higher risk of colorectal cancer, previous studies undetected a heightened risk of inflammatory bowel disease. Thus, we tried to investigate cholecystectomy's impact and pathophysiological mechanism on murine colitis models and clarify the association among fecal bile acids (BAs), mucosal bacterial microbiota, and immune cells in the PC patients. One month or three months after cholecystectomy, mice have induced colitis and tested BAs and fecal microbiota analysis. Next, mice were treated with various cholecystectomy-accumulated bile acids in drinking water for three months before inducing colitis. All 14 paired PC patients and healthy subjects were enrolled for BAs and mucosal microbiota analysis. Cholecystectomy ameliorated DSS-induced murine colitis, accelerated mucosal repair, and induced a significant shifting of fecal microbiota and BAs profiles under colitis status, which featured a higher relative abundance of species involved in BAs metabolism and increased secondary BAs concentrations. Cholecystectomy-associated secondary BAs (LCA, DCA, and HDCA) also ameliorated DSS-induced colitis and accelerated mucosal repair in mice. Cholecystectomy and specific secondary BAs treatments inhibited monocytes/macrophages recruitment in colitis mice. In vitro, cholecystectomy-associated secondary BAs also downregulated monocytes chemokines in the THP-1 derived macrophages through activation of the LXRα-linked signaling pathway. The alterations of mucosal microbiota and fecal BAs profiles were found in the PC patients, characterized as increased species with potential immuno-modulating effects and secondary BAs, which were negatively associated with peripheral monocytes levels. Cholecystectomy-induced secondary bile acids accumulation ameliorated colitis through inhibiting monocyte/macrophage recruitment, which might be mediated by the LXRα-related signaling pathway. Cholecystectomy, after 3 months follow-up, has an immune-regulatory role in murine colitis, preliminarily explaining that no increased risk of IBD had been reported in the PC patients, which still warrants further studies.


Assuntos
Colite , Microbioma Gastrointestinal , Animais , Ácidos e Sais Biliares , Colecistectomia , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos
13.
Mol Med ; 28(1): 104, 2022 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058917

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is a common chronic remitting disease with no satisfactory treatment. The aim of this study was to investigate the protective effect of α7 nicotinic acetylcholine receptor (α7nAChR), and to determine the underlying mechanism of its activity. METHODS: The expression and distribution of α7nAChR in the intestinal tissue of patients with ulcerative colitis and Crohn's disease were analyzed. The effects of vagal excitation on murine experimental colitis were investigated. The colitis model was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). The therapeutic group received treatment with the α7nAChR agonist PNU-282987 by intraperitoneal injection. RESULTS: Our results showed that there was significantly increased expression of α7nAChR in colitis and Crohn's disease intestinal tissue, and its expression was mainly located in macrophages and neutrophils, which were extensively infiltrated in the disease status. Treatment with an α7nAChR agonist potently ameliorated the DSS-induced illness state, including weight loss, stool consistency, bleeding, colon shortening, and colon histological injury. α7nAChR agonist exerted anti-inflammatory effects in DSS colitis mice by suppressing the secretion of multiple types of proinflammatory factors, such as IL6, TNFα, and IL1ß, and it also inhibited the colonic infiltration of inflammatory cells by blocking the DSS-induced overactivation of the NF-κB and MAPK signaling pathways. Mechanistically, activation of α7nAChR decreased the number of infiltrated M1 macrophages in the colitis intestine and inhibited the phagocytosis ability of macrophages, which were activated in response to LPS stimulation. CONCLUSION: Thus, an α7nAChR agonist ameliorated colonic pathology and inflammation in DSS-induced colitis mice by blocking the activation of inflammatory M1 macrophages.


Assuntos
Colite , Doença de Crohn , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colo/patologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
14.
Wei Sheng Yan Jiu ; 51(4): 624-644, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-36047269

RESUMO

OBJECTIVE: To explore the protective effect and mechanism of Bifidobacterium bifidum TMC3115 of improving the gut microbiota disorder caused by antibiotic exposurein early life, and the possible protection of inflammatory bowel disease in adulthood in mice. METHODS: 80 newborn mice were randomly divided into 3 groups, a blank control group(n=40), a ceftriaxone exposure group(n=20), a Bifidobacterium bifidum TMC3115 intervention group(n=20). After birth, they were respectively treated with saline, ceftriaxone(100 mg/kg), and ceftriaxone(100 mg/kg) + TMC3115(1×10~9CFU/d) for 3 weeks. After 3 weeks, half of each group was randomly sacrificed, and the rest were normally fed to 6 weeks. At 6 weeks, the blank control group was randomly divided into a negative control group(n=10) and a colitis model group(n=10). The negative control group drunk pure water freely, and the other three groups were added 3% DSS to the drinking water for 4 days to induce colitis. At 6 weeks and 4 days, the remaining mice were sacrificed. The weight change, spleen coefficient, gut microbiota analysis based on second-generation sequencing and serum tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-10(IL-10)levels of the mice at 3 weeks and after DSS intervention were recorded. In addition, the colon length and inflammation pathology score of the mice after DSS intervention were also measured. RESULTS: At 3 weeks, compared with the control, antibiotic exposure in the early life inhibited the weight gain and reduced the diversity and uniformity of the gut microbiota of the mice(P<0.05). The intervention of TMC3115 under antibiotic exposure during this period increased the relative abundance of Bifidobacterium in the intestines(P<0.05), and the effect still existed after DSS stimulation in adulthood, laying the foundation for TMC3115 to exert long-term benefits. After DSS stimulation in adulthood, mice showed significant weight gain inhibition, colon length shorteningand inflammation pathology scoreincrease compared with the negative control(P<0.05), showed the inflammatory bowel disease(IBD)model was successfully constructed. The relative abundance of beneficial bacteria such as Lactobacillus in the Bifidobacterium bifidum TMC3115 intervention group increased compared with the ceftriaxone exposure group(P<0.05), while the relative abundance of harmful bacteria such as Staphylococcus, Clostridium, and Desulfovibrio decreased(P<0.05). Furthermore, the mice exposed to antibiotic in early life produced a stronger immune response, but the mice which received TMC3115 intervention at the same time had a significant decrease in serum TNF-α and IL-6 levels and increase in IL-10 level compared with the mice which only interfered with antibiotics(P<0.05). CONCLUSION: Antibiotic exposure in early life is a negative factor for long-term inflammatory bowel disease, and TMC3115 has preventive significance for long-term inflammatory bowel disease under the background of antibiotic exposure. The mechanism of TMC3115 may be to adjust the gut microbiota and balance the immune system.


Assuntos
Bifidobacterium bifidum , Colite , Doenças Inflamatórias Intestinais , Animais , Antibacterianos , Bifidobacterium bifidum/fisiologia , Ceftriaxona , Colite/induzido quimicamente , Colite/microbiologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Inflamação , Doenças Inflamatórias Intestinais/patologia , Interleucina-10 , Interleucina-6 , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa , Aumento de Peso
15.
Zhongguo Zhong Yao Za Zhi ; 47(16): 4418-4427, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046871

RESUMO

Cold-heat combination is a common method in the treatment of ulcerative colitis, which is represented by classic drug pair, Coptidis Rhizoma and Zingiberis Rhizoma.The present study explored the synergetic effects of berberine and 6-shogaol, the primary components of Coptidis Rhizoma and Zingiberis Rhizoma, respectively, on intestinal inflammation and intestinal flora in mice with ulcerative colitis to reveal the effect and mechanism of cold-heat combination in the treatment of ulcerative colitis.The ulcerative colitis model was induced by dextran sulfate sodium(DSS) in mice.The model mice were administered with berberine(100 mg·kg~(-1)), 6-shogaol(100 mg·kg~(-1)), and berberine(50 mg·kg~(-1)) combined 6-shogaol(50 mg·kg~(-1)) by gavage, once per day.After 20 days of drug administration, mouse serum, colon tissues, and feces were sampled.Hematoxylin-eosin(HE) staining was used to observe histopathological changes in colon tissues.Alcian blue/periodic acid-Schiff(AB/PAS) staining was used to observe the changes in the mucus layer of colon tissues.Enzyme-linked immunosorbent assay(ELISA) was employed to detect the serum content of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interleukin-6(IL-6).Immunohistochemical method was adopted to detect the protein expression of macrophage surface markers F4/80, mucin-2, claudin-1, and zonula occludens-1(ZO-1) in colon tissues.High-throughput Meta-amplicon library sequencing was used to detect changes in the intestinal flora of mice.The results indicated that the 6-shogaol group, the berberine group, and the combination group showed significantly relieved intestinal injury, reduced number of F4/80-labeled positive macrophages in colon tissues, increased protein expression of mucin-2, claudin-1, and ZO-1, and decreased serum le-vels of TNF-α, IL-1ß, and IL-6.Shannon, Simpson, Chao, and Ace indexes of the intestinal flora of mice in the 6-shogaol group and the combination group significantly increased, and Chao and Ace indexes in the berberine group significantly increased.As revealed by the bioinformatics analysis of intestinal flora sequencing, the relative abundance of Verrucomicrobia at the phylum, class, and order levels decreased significantly in all treatment groups after drug administration, while that of Bacillibacteria gradually increased.In the 6-shogaol group and the combination group, Akkermansia muciniphila completely disappeared, but acid-producing bacillus still existed in large quantities.As concluded, both 6-shogaol and berberine can inhibit intestinal inflammation, reduce the infiltration and activation of macrophages, relieve intestinal damage, reduce intestinal permeability, improve the structure of flora, and promote intestinal microecological balance.The combined application of berberine and 6-shogaol has a significant synergistic effect.


Assuntos
Berberina , Colite Ulcerativa , Colite , Medicamentos de Ervas Chinesas , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Catecóis , Claudina-1/metabolismo , Claudina-1/farmacologia , Claudina-1/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucina-2/metabolismo , Mucina-2/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
16.
Biol Pharm Bull ; 45(9): 1312-1320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36047200

RESUMO

We previously demonstrated that per os administration and ad libitum ingestion of a magnesium chloride (MgCl2) solution had a prophylactic effect on dextran sulfate sodium (DSS)-induced colitis in mice, magnesium being considered to play a role in this preferable action. Magnesium oxide (MgO) is a commercially available magnesium formulation, but whether or not it prevents development of colitis is unknown. In this study, we investigated the effect of MgO administration on development of colitis in DSS-treated male C57BL/6J mice. Experimental colitis was induced by ad libitum ingestion of 1% (w/v) DSS, and the colitis severity was evaluated by disease activity index (DAI) scores, histological assessment and colonic expression of inflammatory cytokines. A 1 mg/mL MgO solution was administered to mice through ad libitum ingestion from a day before DSS treatment to the end of the experimental period of 12 d. In addition, the effects of DSS, MgO and their combination on the gut microbiota were investigated by 16S ribosomal RNA metagenome analysis. DSS-induced elevation of DAI scores was partially but significantly decreased by MgO administration, while MgO administration had no apparent effect on the shortened colonic length, elevated mRNA expression of colonic interleukin-1ß and tumor necrosis factor-α, increased accumulation of colonic mast cells, or altered features of the gut microbiota in DSS-treated mice. Overall, we demonstrated that MgO had a prophylactic effect on the development of colitis in DSS-treated mice by preventing histological colonic damage, but not colonic inflammation or alteration of the gut microbiota.


Assuntos
Colite , Óxido de Magnésio , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/prevenção & controle , Sulfato de Dextrana , Modelos Animais de Doenças , Magnésio , Óxido de Magnésio/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Front Cell Infect Microbiol ; 12: 960208, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118029

RESUMO

Background: Mesenchymal stem cell (MSC) therapy has emerged as a promising novel therapeutic strategy for managing inflammatory bowel disease (IBD) mainly via dampening inflammation, regulating immune disorders, and promoting mucosal tissue repair. However, in the process, the associated changes in the gut microbiota and the underlying mechanism are not yet clear. Methods: In the present study, dextran sulfate sodium (DSS) was used to induce colitis in mice. Mice with colitis were treated with intraperitoneal infusions of MSCs from human umbilical cord mesenchymal stem cells (HUMSCs) and evaluated for severity of inflammation including weight reduction, diarrhea, bloody stools, histopathology, and mortality. The proportion of regulatory T cells (Tregs) and immunoglobulin A-positive (IgA+) plasmacytes in gut-associated lymphoid tissue were determined. The intestinal and fecal levels of IgA were tested, and the proportion of IgA-coated bacteria was also determined. Fecal microbiome was analyzed using 16S rRNA gene sequencing analyses. Results: Treatment with HUMSCs ameliorated the clinical abnormalities and histopathologic severity of acute colitis in mice. Furthermore, the proportion of Tregs in both Peyer's patches and lamina propria of the small intestine was significantly increased. Meanwhile, the proportion of IgA+ plasmacytes was also substantially higher in the MSCs group than that of the DSS group, resulting in elevated intestinal and fecal levels of IgA. The proportion of IgA-coated bacteria was also upregulated in the MSCs group. In addition, the microbiome alterations in mice with colitis were partially restored to resemble those of healthy mice following treatment with HUMSCs. Conclusions: Therapeutically administered HUMSCs ameliorate DSS-induced colitis partially via regulating the Tregs-IgA response, promoting the secretion of IgA, and facilitating further the restoration of intestinal microbiota, which provides a potential therapeutic mechanism for HUMSCs in the treatment of IBD.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Células-Tronco Mesenquimais , Animais , Bactérias , Colite/tratamento farmacológico , Colite/terapia , Sulfato de Dextrana/toxicidade , Humanos , Imunoglobulina A Secretora , Inflamação , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Cordão Umbilical/patologia
18.
Food Funct ; 13(18): 9324-9339, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36069282

RESUMO

The ameliorative effects on ulcerative colitis (UC) as well as the related mechanisms of the essential oil derived from the edible herb Zanthoxylum bungeanum Maxim (ZBEO) have been demonstrated herein. Based on GC-MS analysis, 45 volatile compounds in ZBEO were determined for its quality control. In vitro studies showed that after pretreatment with ZBEO, the disordered expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and an anti-inflammatory cytokine (IL-10) on colon epithelial NCM460 cells induced by lipopolysaccharide (LPS) could be reversed. Additionally, oral administration of ZBEO significantly alleviated colitis in dextran sulfate sodium (DSS)-induced UC mice, including body weight loss, colon length shortening, disease activity index and colonic pathological damage. Furthermore, to uncover the anti-UC mechanisms of ZBEO, analysis of transcriptomes by next-generation sequencing technology was performed to explore the RNA genetic variation on colon tissues. Based on GO analysis and KEGG pathway analysis, a series of genetic pathways involved in the protective role of ZBEO against UC were determined. As a result, ZBEO treatment could decrease the expression of VCAM-1, TLR8, IL-1ß and IL-11 mRNA as verified by qRT-PCR, which are involved in these potential genetic pathways. In conclusion, ZBEO administration would be a medicinal or dietary supplementation strategy for ulcerative colitis treatment.


Assuntos
Colite Ulcerativa , Óleos Voláteis , Zanthoxylum , Animais , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Interleucina-10/metabolismo , Interleucina-11/metabolismo , Interleucina-11/farmacologia , Interleucina-11/uso terapêutico , Interleucina-6/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Óleos Voláteis/uso terapêutico , RNA/farmacologia , RNA Mensageiro/metabolismo , Receptor 8 Toll-Like/metabolismo , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular
19.
Food Funct ; 13(18): 9169-9182, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36069409

RESUMO

Milt is an underutilized fish processing by-product containing valuable nutrients for human health. Here, a gastrointestinal hydrolysate of degreased yellowtail (Seriola quinqueradiata) milt contained 70.6% arginine-rich protein, 20% nucleic acids, 7.1% minerals and 2.3% carbohydrates. Yellowtail milt hydrolysates (YMH) effectively attenuated the H2O2-induced burst of intracellular reactive oxygen species, plasma membrane impairment, loss of cell viability, interleukin 8 production and the expression of claudin-4 and occludin in Caco-2 cells with its protein fraction playing a greater antioxidant role than its nucleic acid fraction. YMH also significantly counteracted the tumor necrosis factor α- and interleukin 1ß-stimulated interleukin 8 production and cyclooxygenase-2 and inducible nitric oxide synthase expression in Caco-2 cells and inhibited the production of nitric oxide and proinflammatory mediators in lipopolysaccharide-stimulated RAW 264.7 cells depending on its protein fraction, rather than its nucleic acid fraction. YMH and a positive drug 5-aminosalicylic acid were intragastrically administered to C57BL/6 mice daily for 7 days during and after 4-day dextran sodium sulphate exposure. Based on clinical signs, colon histopathology and biochemical analysis of colonic tight junction proteins, mucus compositions and goblet cells, YMH ameliorated mouse colitis symptoms and intestinal epithelial barrier dysfunction more effectively than 5-aminosalicylic acid. According to myeloperoxidase activity, proinflammatory cytokines and NF-κB, YMH and 5-aminosalicylic acid exerted equivalent inhibitory effects on colonic and systemic inflammation. Overall, YMH have considerable antioxidant and anti-inflammatory efficacies to maintain gut health.


Assuntos
Colite , Ácidos Nucleicos , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Arginina , Células CACO-2 , Claudina-4/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana/efeitos adversos , Humanos , Peróxido de Hidrogênio/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/efeitos adversos , Mesalamina/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ácidos Nucleicos/efeitos adversos , Ocludina/metabolismo , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sulfatos , Fator de Necrose Tumoral alfa/metabolismo
20.
J Agric Food Chem ; 70(37): 11678-11688, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36095239

RESUMO

Bifidobacteria are important mediators of immune system development within the gastrointestinal system and immunological homeostasis. The present study explored the anti-colitic activity of Bifidobacterium bifidum H3-R2 in a murine dextran sulfate sodium (DSS)-induced model of ulcerative colitis (UC). Moreover, this study offers novel insight regarding the molecular basis for the probiotic properties of B. bifidum H3-R2 by analyzing the underlying mechanisms whereby B. bifidum H3-R2-derived proteins affect the intestinal barrier. B. bifidum H3-R2 administration was sufficient to alleviate clinical manifestations consistent with DSS-induced colitis, restoring aberrant inflammatory cytokine production, enhancing tight junction protein expression, and positively impacting overall intestinal microecological homeostasis in these animals. Moreover, the bifidobacteria-derived GroEL and transaldolase (TAL) proteins were found to regulate tight junction protein expression via the NF-κB, myosin light chain kinase (MLCK), RhoA/Rho-associated protein kinase (ROCK), and mitogen-activated protein kinase (MAPK) signaling pathways, preventing the lipopolysaccharide (LPS)-mediated disruption of the intestinal epithelial cell barrier.


Assuntos
Bifidobacterium bifidum , Colite Ulcerativa , Colite , Animais , Bifidobacterium/metabolismo , Bifidobacterium bifidum/genética , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas de Junções Íntimas/metabolismo , Transaldolase/metabolismo
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