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1.
Commun Biol ; 6(1): 50, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36641530

RESUMO

Psychiatric disorders, such as anxiety, are associated with inflammatory bowel disease (IBD), however, the neural mechanisms regulating this comorbidity are unknown. Here, we show that hypothalamic agouti-related protein (AgRP) neuronal activity is suppressed under chronic restraint stress (CRS), a condition known to increase anxiety and colitis susceptibility. Consistently, chemogenic activation or inhibition of AgRP neurons reverses or mimics CRS-induced increase of anxiety-like behaviors and colitis susceptibility, respectively. Furthermore, CRS inhibits AgRP neuronal activity by suppressing the expression of c-Jun. Moreover, overexpression of c-Jun in these neurons protects against the CRS-induced effects, and knockdown of c-Jun in AgRP neurons (c-Jun∆AgRP) promotes anxiety and colitis susceptibility. Finally, the levels of secreted protein thrombospondin 1 (THBS1) are negatively associated with increased anxiety and colitis, and supplementing recombinant THBS1 rescues colitis susceptibility in c-Jun∆AgRP mice. Taken together, these results reveal critical roles of hypothalamic AgRP neuron-derived c-Jun in orchestrating stress-induced anxiety and colitis susceptibility.


Assuntos
Colite , Hipotálamo , Camundongos , Animais , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Hipotálamo/metabolismo , Ansiedade/etiologia , Neurônios/fisiologia , Colite/genética , Colite/metabolismo
2.
Allergol. immunopatol ; 51(1): 159-167, ene. 2023. tab, graf
Artigo em Inglês | IBECS | ID: ibc-214032

RESUMO

Introduction: Inflammatory bowel disease (IBD), which mainly leads to diarrhea, fatigue, stool blood, abdominal pain, and cramping, is threatening public health. Tripartite motif-containing 52 (TRIM52) has been reported to play an important role in inflammatory responses via activating the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. However, the causes of IBD need to be elucidated, and the function of TRIM52 in IBD remains unclear. Here, we demonstrated that TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium (DSS)-induced IBD by activating TLR4/NF-κBs pathway. Methods: The colitis model was established on mice through DSS induction. For the TRIM52 knockdown, the mice were infected with a recombinant adenoviral vector expressing sgRNAs targeting TRIM52. RT-qPCR, western blot, and immunohistochemistry were performed to verify TRIM52 expression in DSS-induced IBD. The body weight, disease activity index, colon length, and H&E staining were used to assess the IBD symptoms in mice with TRIM52 knockdown. The inflammatory responses were examined by RT-qPCR and ELISA measuring tumor necrosis factor-α (TNF-α), inter-leukin 6 (IL-6), and interleukin 1β (IL-1β). Furthermore, the pyroptosis in colon tissue was detected by western blot. Finally, the TLR4/NF-κBs pathway activity was also examined by western blot. Results: TRIM52 expression was up-regulated in DSS-induced IBD, and knockdown of TRIM52 could alleviate the symptoms of IBD. TRIM52 knockdown retarded DSS-induced inflammatory response and inhibited DSS-induced pyroptosis in colon tissue. In addition, TRIM52 played a role in activating TLR4/NF-κBs pathway. Conclusion: Knockdown of TRIM52 alleviated inflammation and pyroptosis in IBD by regulating TLR4/NF-κBs pathway. TRIM52 is expected to be a novel diagnostic indicator for IBD and a target of therapeutic treatment (AU)


Assuntos
Animais , Camundongos , Proteínas com Motivo Tripartido/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Colite/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Transdução de Sinais , Camundongos Transgênicos , Sulfato de Dextrana
3.
Nutrients ; 15(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36678175

RESUMO

Our recent report illustrated the unitedly advantageous effects of postbiotic butyrate on active vitamin D3 (VD3)-orchestrated innate immunity in Salmonella colitis. There is growing awareness that aryl hydrocarbon receptor (AhR) can regulate intestinal immunity and barrier function, through modulating cecal inflammation and junction proteins expression. Hence, we researched the participation of AhR-regulated tight junction functions on the united effects of butyrate and VD3 on intestinal defense to Salmonella infection. Salmonella colitis model were elicited by oral gavage with 1 × 108 CFU of a S. typhimurium wild-type strain SL1344 in C57BL/6 mice. Before and after the colitis generation, mice were fed with butyrate and/or VD3 by oral gavage in the absence or presence of intraperitoneal injection of AhR inhibitor for 4 and 7 days, respectively. We observed that butyrate and VD3 could concert together to reduce the invasion of Salmonella in colitis mice by enhancing cecal cytokines and antimicrobial peptides expression and reducing zonulin and claudin-2 protein expressions in mucosal stain, compared to single treatment, which were counteracted by AhR inhibitor. It implies that AhR is involved in the united effects of butyrate and VD3 on the intestinal defense to Salmonella infection in colitis mice. This study discloses the promising alternative therapy of combining postbiotic and VD3 for invasive Salmonellosis and the pivotal role of AhR pathway.


Assuntos
Colite , Infecções por Salmonella , Camundongos , Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Colecalciferol/farmacologia , Junções Íntimas/metabolismo , Butiratos/farmacologia , Camundongos Endogâmicos C57BL , Colite/metabolismo , Infecções por Salmonella/tratamento farmacológico , Salmonella , Imunidade Inata , Proteínas de Junções Íntimas
4.
J Tradit Chin Med ; 43(1): 124-133, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36640003

RESUMO

OBJECTIVE: To elucidate the protective effect of Qingdai (, QD) on ulcerative colitis (UC) by means of and approaches. METHODS: A systems pharmacology analysis was per-formed to predict the active components of QD whereas the putative biological targets of QD against UC were obtained through target fishing, network cons-truction and enrichment analyses. Meanwhile, we examined the ameliorative effect of QD in a mouse model of dextran sulfate sodium (DSS)-induced colitis. During the 10-day experiment, the control and diseased mice were given with oral gavages of QD (1.3 g raw herbs·kg·d) or 5-aminosalicylic acid (5-ASA, 100 mg·kg·d) every day. The underlying pharma-cological mechanisms of QD in UC were determined using polymerase chain reaction tests, histological staining, enzyme-linked immunoassays, and Western blotting analysis. RESULTS: Searching from various network pharmacology databases, 29 compounds were identified in QD. According to the screening criteria suggested by TCMSP (i.e. OB ≥ 30% and DL ≥ 0.18), nine of them were considered the active ingredients that contribute to the ameliorative effects of QD on different mouse models of colitis. Most importantly, the protective effect of QD on DSS-induced colitis was significantly associated with modulations of the expression levels of glycogen synthase kinase 3-ß (Gsk3-ß) and forkhead box p3 (Foxp3), which are widely considered as important regulators of excessive inflammatory responses. CONCLUSIONS: The results of this study provide solid scientific evidence for the use of QD or its core active components in the clinical management of UC.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Farmacologia em Rede , Quinase 3 da Glicogênio Sintase/metabolismo , Colite/metabolismo , Colite/patologia , Mesalamina , Modelos Animais de Doenças , Colo
5.
Int J Mol Sci ; 24(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36614212

RESUMO

Short-chain fatty acids as well as their bacterial producers are of increasing interest in inflammatory bowel diseases. Although less studied compared to butyrate, acetate might also be of interest as it may be less toxic to epithelial cells, stimulate butyrate-producing bacteria by cross-feeding, and have anti-inflammatory and barrier-protective properties. Moreover, one of the causative factors of the probiotic potency of Saccharomyces cerevisae var. boulardii is thought to be its high acetate production. Therefore, the objective was to preclinically assess the effects of high acetate concentrations on inflammation and barrier integrity in organoid-based monolayer cultures from ulcerative colitis patients. Confluent organoid-derived colonic epithelial monolayers (n = 10) were exposed to basolateral inflammatory stimulation or control medium. After 24 h, high acetate or control medium was administered apically for an additional 48 h. Changes in TEER were measured after 48 h. Expression levels of barrier genes and inflammatory markers were determined by qPCR. Pro-inflammatory proteins in the supernatant were quantified using the MSD platform. Increased epithelial resistance was observed with high acetate administration in both inflamed and non-inflamed conditions, together with decreased expression levels of IL8 and TNFα and CLDN1. Upon high acetate administration to inflamed monolayers, upregulation of HIF1α, MUC2, and MKI67, and a decrease of the majority of pro-inflammatory cytokines was observed. In our patient-derived human epithelial cell culture model, a protective effect of high acetate administration on epithelial resistance, barrier gene expression, and inflammatory protein production was observed. These findings open up new possibilities for acetate-mediated management of barrier defects and inflammation in IBD.


Assuntos
Colite Ulcerativa , Colite , Humanos , Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Butiratos/farmacologia , Acetatos/farmacologia , Acetatos/metabolismo , Organoides/metabolismo , Colite/metabolismo
6.
Allergol Immunopathol (Madr) ; 51(1): 159-167, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36617836

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD), which mainly leads to diarrhea, fatigue, stool blood, abdominal pain, and cramping, is threatening public health. Tripartite motif-containing 52 (TRIM52) has been reported to play an important role in inflammatory responses via activating the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. However, the causes of IBD need to be elucidated, and the function of TRIM52 in IBD remains unclear. Here, we demonstrated that TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium (DSS)-induced IBD by activating TLR4/NF-κBs pathway. METHODS: The colitis model was established on mice through DSS induction. For the TRIM52 knockdown, the mice were infected with a recombinant adenoviral vector expressing sgRNAs targeting TRIM52. RT-qPCR, western blot, and immunohistochemistry were performed to verify TRIM52 expression in DSS-induced IBD. The body weight, disease activity index, colon length, and H&E staining were used to assess the IBD symptoms in mice with TRIM52 knockdown. The inflammatory responses were examined by RT-qPCR and ELISA measuring tumor necrosis factor-α (TNF-α), inter-leukin 6 (IL-6), and interleukin 1ß (IL-1ß). Furthermore, the pyroptosis in colon tissue was detected by western blot. Finally, the TLR4/NF-κBs pathway activity was also examined by western blot. RESULTS: TRIM52 expression was up-regulated in DSS-induced IBD, and knockdown of TRIM52 could alleviate the symptoms of IBD. TRIM52 knockdown retarded DSS-induced inflammatory response and inhibited DSS-induced pyroptosis in colon tissue. In addition, TRIM52 played a role in activating TLR4/NF-κBs pathway. CONCLUSION: Knockdown of TRIM52 alleviated inflammation and pyroptosis in IBD by regulating TLR4/NF-κBs pathway. TRIM52 is expected to be a novel diagnostic indicator for IBD and a target of therapeutic treatment.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Piroptose , Proteínas com Motivo Tripartido , Animais , Camundongos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inflamação , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Proteínas com Motivo Tripartido/metabolismo
7.
Food Funct ; 14(2): 720-733, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36598450

RESUMO

As potential candidates for treating ulcerative colitis (UC), polysaccharides have been attracting extensive interest in recent years. Cordyceps sinensis (C. sinensis) is a kind of traditional Chinese edible food, and its polysaccharide fractions have been found to be effective in regulating immunity and protecting the kidneys. To determine the potential function of polysaccharides from natural C. sinensis on UC, their effects in terms of histological, serological, biochemical, and immunological aspects on dextran sulphate sodium (DSS)-induced colitis mice model were investigated. Results showed that the polysaccharides significantly alleviated colitis by increasing the colon length, alleviating colon tissue damage, and inhibiting the activation of the NF-κB pathway. In addition, polysaccharides reduced the contents of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the serum, increased the number of goblet cells, and improved the expression of intestinal tight junction proteins (Occludin and Claudin-1). They also evidently enhanced the formation of IgA-secretory cells and sIgA contents. Furthermore, the polysaccharides modulated the gut microbiota by decreasing the relative abundance of Bilophila and increasing the relative abundance of Dehalobacterium, Coprococcus, Oscillospira, and Desulfovibrio, which is accompanied by an increase in the short chain fatty acids' (SCFAs) concentrations in cecal contents. These results suggested that C. sinensis polysaccharides possessed promising intervening effects on experimental acute UC in mice.


Assuntos
Colite Ulcerativa , Colite , Cordyceps , Animais , Camundongos , Cordyceps/metabolismo , Dextranos/metabolismo , Camundongos Endogâmicos C57BL , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , NF-kappa B/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças
8.
Food Funct ; 14(1): 181-194, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36477762

RESUMO

Probiotics have been evaluated as alternative approaches for preventing the relapse of Crohn's disease (CD). Previously, we observed strain-specific anti-inflammatory properties of Bifidobacterium bifidum in 2,4,6-trinitrobenzene sulfonic acid (TNBS) acute colitis models. In this study, we further assessed the effects of several B. bifidum strains on colonic damage, fibrosis, inflammatory factors, intestinal microbial and metabolic profiles, and peripheral regulatory T cells (Tregs) in the context of TNBS chronic colitis in mice. These results indicated that B. bifidum FJSWX19M5, but not FXJWS17M4, ameliorated body weight loss, reduced colonic shortening and injury, decreased markers of gut inflammation, and rebalanced colonic metabolism in TNBS-treated mice. FJSWX19M5 supplementation also promoted Treg cell differentiation and intestinal barrier restoration compared to other strains. All living B. bifidum strains (FJSWX19M5, FXJWS17M4 and FHENJZ3M6) seemed to restore the disruption of the gut microbiota caused by TNBS. The co-culture of B. bifidum strains and mesenteric lymph node cells from TNBS-treated mice showed that those strains with anti-colitis could induce higher IL-10 levels and a lower ratio of IL-22/IL-10 and IL-17/IL-10 when compared to those strains that were not protective. Furthermore, heat-killed FJSWX19M5 exhibited a relief effect on colitis-related symptoms (including body weight loss, colonic shortening and injury). These data imply that specific B. bifidum strains or their lysates may be the current therapeutic alternatives for CD.


Assuntos
Bifidobacterium bifidum , Colite , Doença de Crohn , Animais , Camundongos , Linfócitos T Reguladores , Interleucina-10/genética , Interleucina-10/metabolismo , Bifidobacterium bifidum/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Citocinas/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Redução de Peso , Modelos Animais de Doenças
9.
Int Immunopharmacol ; 114: 109532, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36508925

RESUMO

Inflammatory bowel diseases (IBD) are chronic debilitating inflammatory disorders of the gastrointestinal tract that is characterized by intestinal epithelial barrier dysfunction and excessive activation of the mucosal immune system. Isosteviol (IS) has been reported to possess anti-inflammatory properties. In this study, we aimed to investigate effects and mechanisms of IS against intestinal inflammation. C57BL/6 mice were randomly divided into Sham, IS, dextran sodium sulfate (DSS), and DSS + IS groups. In vivo colitis model was established using 3.0 % DSS. In vitro, tumor necrosis factor-α (TNF-α)-treated Caco-2 cells were used as an inflammatory model. Clinical characteristics, histological performance, proinflammatory cytokine expression, and intestinal barrier function were measured. In addition, activation of the pyruvate dehydrogenase kinase 1/protein kinase B/nuclear factor-κB (PDK1/AKT/NF-κB) signaling pathway was determined by western blotting and quantitative polymerase chain reaction. The results showed that IS mitigated DSS-induced colitis by reducing body weight loss, colonic shortening, and disease activity index score, and by inhibiting expressions of proinflammatory cytokines IL-1ß, IL-6, and TNF-α. IS restored impaired barrier function by regulating tight junctions and intestinal epithelial permeability. Furthermore, we found that IS ameliorated intestinal barrier injury by regulating PDK1/AKT/NF-κB signaling pathway. In conclusion, our results demonstrate that IS attenuates experimental colitis by preserving intestinal barrier function, probably mediated by PDK1/AKT/NF-κB signaling pathway. These findings highlight the potential of IS as a therapeutic agent for IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Humanos , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células CACO-2 , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Transdução de Sinais , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Mucosa Intestinal
10.
Eur J Pharmacol ; 939: 175469, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36528071

RESUMO

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract (GI). Currently, the treatment options for IBD are limited. It has been reported that a novel bioactive mitochondrial-derived peptide (MOTS-c) encoded in the mitochondrial 12S rRNA, suppresses inflammatory response by enhancing the phagocytosis of macrophages. The aim of this study was to investigate the protective effects of MOTS-c against dextran sulfate sodium (DSS)-induced colitis. The results showed that intraperitoneal (i.p.) administration of MOTS-c significantly ameliorated the symptoms of DSS-induced experimental colitis, such as body weight loss, colon length shortening, diarrhea, and histological damage. MOTS-c down-regulated the expression of pro-inflammatory cytokines, decreased the plasma levels of myeloperoxidase, and inhibited the activation of macrophages and recruitment of neutrophils. Moreover, treatment with MOTS-c exhibited anti-apoptotic effects and significantly suppressed the phosphorylation of AMPKα1/2, ERK, and JNK. Notably, oral administration of MOTS-c did not result in any significant improvements. Screening of cell penetrating peptides was performed, (PRR)5 was linked to the C-terminus of MOTS-c through a linker to synthesize a new molecule (termed MP) with better penetration into the colon epithelium. In vitro experiments revealed the longer half-life of MP than MOTS-c, and in vivo experiments showed that oral administration of MP significantly ameliorated DSS-induced colitis. CONCLUSION: The present results demonstrate a protective role of MOTS-c in experimental IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Sulfato de Dextrana/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Colo , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fatores de Transcrição/metabolismo , Apoptose , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
11.
Artigo em Inglês | MEDLINE | ID: mdl-36273507

RESUMO

Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mice exhibit IBD- and depressive-like phenotypes. A disturbed intestinal environment causes a decrease in serotonin and abnormal myelination in the brain, along with depressive-like behavior in rodents. However, the involvement of these factors in DSS-induced depressive-like behavior in mice remains unclear. In this study, we examined whether myelin proteins in the prefrontal cortex (PFC) and hippocampi were altered in DSS-treated mice, along with the changes in the serotonergic system in the PFC by western blotting and HPLC. The effects of brexpiprazole (Brx), a serotonin modulator, on DSS-induced depressive-like behavior using the tail-suspension test were evaluated. Subsequently, we investigated Brx's effects on the levels of myelin, nodal proteins, and neurotrophic molecules in the PFC with western blotting, and examined the altered node of Ranvier formation by immunohistochemistry. DSS-treated mice showed a reduction in myelin and nodal proteins, dysfunction of the serotonergic system, and impaired formation of the nodes of Ranvier in the PFC. Brx administration prevented the DSS-induced depressive-like behavior and demyelination in the PFC. However, the Brx-mediated effects were inhibited by the selective 5-HT1A antagonist, WAY100635, or the selective TrkB antagonist, ANA-12. Brx decreased the phosphorylation of ERK, CREB, and TrkB along with the expression of BDNF in the PFC of DSS-treated mice. Moreover, the effects of Brx were blocked by WAY100635. These findings indicated that myelination regulated by the activation of the ERK1/2-CREB-BDNF-TrkB pathway in the PFC may be involved in mediating the antidepressant effects of Brx.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Serotonina/metabolismo , Córtex Pré-Frontal/metabolismo , Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Modelos Animais de Doenças , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Depressão/metabolismo
12.
Int J Biol Macromol ; 227: 872-883, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563806

RESUMO

Plant polysaccharides act as prebiotics by modulating gut microbiota. However, the functional characteristics of buckwheat Fagopyrum tataricum polysaccharides (FTP) and F. esculentum polysaccharides (FEP) on colitis prevention are not valid. This study evaluated the ameliorative effects of FTP and FEP against TNBS-induced colitis via gut microbiota modulation in rats. The characterizations of FTP and FEP were analyzed, including FTIR, TGA, DSC, and monosaccharide composition. In addition, the pathological features of colon length and symptoms in TNBS-induced colitis were improved via the intragastric preadministration of FTP and FEP. The results showed that prefeeding with FTP and FEP decreased inflammatory cytokines (IL-6, IL-1ß, and TNF-α), ß-glucuronidase, and mucinase, as well as increasing superoxide dismutase, catalase, and glutathione peroxidase levels, in TNBS-induced rats. A decrease in inflammatory signaling-associated proteins (NF-κB, MAPK, COX-2, and iNOS) improved the treatment of TNBS-induced colitis by buckwheat polysaccharides. Moreover, prefeeding with buckwheat polysaccharides increased the Firmicutes/Bacteroidetes ratio and short-chain fatty acid (SCFA) production and decreased the abundance of inflammation-related bacteria (Oscillospiraceae and Oscillibacter). In conclusion, FTP and FEP strongly improved TNBS-induced colitis through antioxidant, anti-inflammatory, and microbiota modulation properties, especially in the high-dose FEP group. Buckwheat polysaccharides have the potential for utilization in functional ingredients or food development.


Assuntos
Colite , Fagopyrum , Microbioma Gastrointestinal , Ratos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Polissacarídeos/metabolismo , Modelos Animais de Doenças
13.
Food Funct ; 14(1): 500-515, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36519687

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic disorder, manifested as oxidative stress, lipid accumulation, and inflammation of the liver. Tetrastigma hemsleyanum leaves (THL), which are rich in flavonoids and phenolic acids, have good anti-inflammatory, antioxidant, and hepatoprotective effects. However, it is unknown whether THL extracts can improve NAFLD and the underlying mechanisms are unknown. Hence, this study was designed to investigate the effects of THL extracts on NAFLD and perform a preliminary inquiry into the underlying mechanism based on the gut-liver axis. The results showed that THL extracts could reverse NAFLD-related oxidative stress, lipid accumulation, and inflammation. Additionally, the protective effect of THL extracts on the gut includes the maintenance of the intestinal barrier and the regulation of gut microbiota, which may be one of the mechanisms by which THL improves NAFLD. To be specific, in our study, THL extracts alleviated hepatic lipid accumulation and oxidative stress by regulating the expression of lipid synthesis/catabolism and the oxidative stress genes (SREBP-1c/ACC-1/PPAR-α/PPAR-γ/Keap1/Nrf2). In addition, THL extracts reduced damage to the intestinal barrier (ZO-1/Mucin2/occludin) and increased the relative abundance of Lactobacillales, Ruminococcaceae, and Bifidobacteriales in NAFLD mice. In short, THL extracts alleviated NAFLD-related oxidative stress, lipid accumulation, and inflammation in NAFLD mice which may be via the gut-liver axis (gut barrier integrity and gut microbiota).


Assuntos
Colite , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Colite/tratamento farmacológico , Colite/metabolismo , Dieta Hiperlipídica , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipídeos/farmacologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Folhas de Planta/química , Intestinos/metabolismo , Extratos Vegetais
14.
Biomed Pharmacother ; 158: 114136, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36535201

RESUMO

The gut-liver axis is a bidirectional relationship between the gut with its microbiota and the hepatic. Ulcerative colitis (UC) disrupts the intestinal barrier and influx of intestinal microorganisms and their products into the liver, which trigger liver injury. Tea consumption is associated with a low incidence of UC in Asian countries. In this study, we revealed the mechanisms of six types of tea water extracts (TWEs) obtained from the leaves of Camellia sinensis on the dextran sodium sulfate (DSS)-induced colitis and liver injury in mice. The TWEs significantly restored mucin production and increased the expression levels of tight junction (TJ) proteins such as zonula occludens-1 (ZO-1), occluding, and claudin-1. In addition, TWEs also reduced the levels of pro-inflammatory cytokines in the colon and liver tissue by inactivating the NF-κB/NLRP3. Moreover, TEWs treatment promoted the integrity of the intestinal barrier to reduce serum lipopolysaccharide (LPS) levels, thereby reducing liver injury caused by intestinal microbial translocation and LPS induction. Analysis of 16 S rRNA microbial sequencing revealed that tea water extracts (TWEs) restored the DSS-induced gut dysbiosis. Interestingly, our results showed that the degree of fermentation of tea leaves was negatively associated with the alleviation of DSS-induced colitis effects, and there was also an overall negative trend with colitis-induced liver injury, except for black tea. Taken together, tea consumption mitigated DSS-induced colitis and liver injury in mice via inhibiting the TLR4/NF-κB/NLRP3 inflammasome pathway.


Assuntos
Camellia sinensis , Colite Ulcerativa , Colite , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Inflamassomos/metabolismo , Lipopolissacarídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Chá , Proteínas de Junções Íntimas/metabolismo , Receptor 4 Toll-Like
15.
Food Funct ; 14(2): 1048-1061, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36562464

RESUMO

Enteropathogenic E. coli (EPEC) is a causal agent for diarrheal diseases and contributes to morbidity and mortality in children under the age of five years. The emergence and rapid spread of antibiotic resistant EPEC strains necessitate the search for novel alternatives to antibiotics. In this study, we used Citrobacter rodentium, a natural mouse pathogen that mimics many aspects of human EPEC infections, to investigate the antimicrobial properties of the blueberry anthocyanin malvidin 3-glucoside (MG) using a multi-omics approach. MG supplementation reversed the bodyweight loss induced by C. rodentium infection and improved colonic hyperplasia and histopathological scores. In the colon tissue, MG supplementation significantly increased the expression of Hace1, a key regulator of TNFα-driven signaling, and impacted multiple pathways, such as TGFß signaling. MG partially restored C. rodentium-induced microbial dysbiosis and significantly enhanced the abundance of the probiotic Bifidobacterium animalis. Moreover, MG disrupted the interactions of E. coli with other gut microbes. MG significantly mediated several host- and microbiota-derived metabolites, such as cytosine, ureidopropionic acid, and glutaric acid. MG normalized the bioactive lipid oleoylethanolamine, a member of the endocannabinoid system, from the dysregulated level in infected mice, directly contributing to its overall beneficial effects. Our findings provided novel insights into molecular processes via which the flavonoid malvidin exerts its biological effects in the gastrointestinal tract.


Assuntos
Colite , Escherichia coli Enteropatogênica , Criança , Humanos , Animais , Camundongos , Pré-Escolar , Citrobacter rodentium , Antocianinas/metabolismo , Colite/metabolismo , Colo/metabolismo , Camundongos Endogâmicos C57BL , Ubiquitina-Proteína Ligases/metabolismo
16.
Nat Commun ; 13(1): 7617, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36539404

RESUMO

Chemicals in food are widely used leading to significant human exposure. Allura Red AC (AR) is a highly common synthetic colorant; however, little is known about its impact on colitis. Here, we show chronic exposure of AR at a dose found in commonly consumed dietary products exacerbates experimental models of colitis in mice. While intermittent exposure is more akin to a typical human exposure, intermittent exposure to AR in mice for 12 weeks, does not influence susceptibility to colitis. However, exposure to AR during early life primes mice to heightened susceptibility to colitis. In addition, chronic exposure to AR induces mild colitis, which is associated with elevated colonic serotonin (5-hydroxytryptamine; 5-HT) levels and impairment of the epithelial barrier function via myosin light chain kinase (MLCK). Importantly, chronic exposure to AR does not influence colitis susceptibility in mice lacking tryptophan hydroxylase 1 (TPH1), the rate limiting enzyme for 5-HT biosynthesis. Cecal transfer of the perturbed gut microbiota by AR exposure worsens colitis severity in the recipient germ-free (GF) mice. Furthermore, chronic AR exposure elevates colonic 5-HT levels in naïve GF mice. Though it remains unknown whether AR has similar effects in humans, our study reveals that chronic long-term exposure to a common synthetic colorant promotes experimental colitis via colonic 5-HT in gut microbiota-dependent and -independent pathway in mice.


Assuntos
Colite , Corantes de Alimentos , Humanos , Animais , Camundongos , Serotonina/metabolismo , Corantes de Alimentos/toxicidade , Corantes de Alimentos/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Intestinos , Colo/metabolismo , Camundongos Endogâmicos C57BL , Mucosa Intestinal/metabolismo , Sulfato de Dextrana
17.
Folia Histochem Cytobiol ; 60(4): 311-322, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36504132

RESUMO

INTRODUCTION: Ulcerative colitis (UC) is a nonspecific intestinal inflammatory disease. Dexmedetomidine (DEX) is a selective alpha 2-adrenergic receptor agonist commonly used for analgesia and sedation in intensive care units. Herein, the role and mechanism of DEX in dextran sulfate sodium (DSS)-induced colitis was explored. MATERIALS AND METHODS: A murine model of DSS-induced colitis was established by adding 3.5% (w/v) DSS in drinking water to C57BL/6J female mice. The severity of colitis was measured by the disease activity index (DAI) score, colon length and body weight of mice. The serum concentration and mRNA levels of inflammatory cytokines in colon tissues were assessed by ELISA and RT-qPCR, respectively. Protein levels of apoptotic markers, tight junction proteins and genes involved in the TLR4/MyD88/NF-κB signaling were quantified utilizing Western blotting. The pathological changes of colon tissues were evaluated by hematoxylin-eosin (HE) staining and histological score. Intestinal permeability in vivo was assessed by fluorescein isothiocyanate (FITC)-dextran (FITC-D) administration. TUNEL assay was used to determine cell apoptosis in the intestinal epithelium. RESULTS: DSS administration resulted in weight loss, shortening of the colon, increased DAI score, histological abnormalities, and increased serum FITC-D levels in mice, all of which were reversed by DEX injection. Moreover, DEX attenuated DSS-triggered inflammatory response, intestinal barrier injury and intestinal epithelial cell apoptosis. Mechanically, DEX inactivated the TLR4/MyD88/NF-κB signaling in the colon tissues. CONCLUSIONS: DEX exerts beneficial effects against the intestinal barrier dysfunction, inflammatory response, and apoptosis of intestinal epithelial cells via inactivation of the TLR4/MyD88/NF-κB signaling in mice with DSS-induced colitis.


Assuntos
Colite Ulcerativa , Colite , Dexmedetomidina , Animais , Feminino , Camundongos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Modelos Animais de Doenças , Fluoresceína-5-Isotiocianato/metabolismo , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Modelos Teóricos , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
18.
JCI Insight ; 7(22)2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36509284

RESUMO

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3-/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.


Assuntos
Neoplasias Associadas a Colite , Colite , Animais , Camundongos , Azoximetano , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/metabolismo , Células Epiteliais/metabolismo , Prolil Hidroxilases/metabolismo
19.
Molecules ; 27(23)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36500233

RESUMO

M10, a novel myricetin derivative, is an anti-inflammatory agent designed for treatment of colitis. Here, we aim to investigate its pharmacokinetic behavior and tissue distribution in a mouse model with colitis. Pharmacokinetics and tissue distribution of M10 and its metabolite myricetin were compared in normal mice and in dextran-sodium-sulfate (DSS)-induced colitis mice. The role of fecal microbiota was also analyzed during metabolism of M10 in vitro. After oral administration, M10 was very low in the plasma of both normal and diseased mice. However, both M10 and myricetin were mainly distributed in the gastrointestinal tract, including the stomach, colon and small intestine, in physiological and pathological conditions. Significantly, M10 and myricetin were found in higher levels in gastrointestinal tracts with inflamed tissues than in normal tissues of mice. An in vitro assay revealed that 80% of M10 was metabolized to myricetin via fecal microbiota. After oral administration, M10 was not absorbed into circulation but mainly distributed in the inflamed submucosal tissues of colitic mice, where it was metabolized into myricetin to prevent colitis development.


Assuntos
Colite Ulcerativa , Colite , Camundongos , Animais , Sulfato de Dextrana/efeitos adversos , Colite Ulcerativa/induzido quimicamente , Distribuição Tecidual , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Modelos Animais de Doenças , Sulfatos/metabolismo , Sódio/metabolismo , Camundongos Endogâmicos C57BL
20.
Molecules ; 27(24)2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36557879

RESUMO

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that include Crohn's disease (CD) and ulcerative colitis (UC). The incidence of IBD is rising globally. However, the etiology of IBD is complex and governed by multiple factors. The current clinical treatment for IBD mainly includes steroids, biological agents and need-based surgery, based on the severity of the disease. Current drug therapy is often associated with adverse effects, which limits its use. Therefore, it necessitates the search for new drug candidates. In this pursuit, phytochemicals take the lead in the search for drug candidates to benefit from IBD treatment. ß-myrcene is a natural phytochemical compound present in various plant species which possesses potent anti-inflammatory activity. Here we investigated the role of ß-myrcene on colon inflammation to explore its molecular targets. We used 2% DSS colitis and TNF-α challenged HT-29 adenocarcinoma cells as in vivo and in vitro models. Our result indicated that the administration of ß-myrcene in dextran sodium sulfate (DSS)-treated mice restored colon length, decreased disease activity index (DAI), myeloperoxidase (MPO) enzyme activity and suppressed proinflammatory mediators. ß-myrcene administration suppressed mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways to limit inflammation. ß-myrcene also suppressed mRNA expression of proinflammatory chemokines in tumor necrosis factor-α (TNF-α) challenged HT-29 adenocarcinoma cells. In conclusion, ß-myrcene administration suppresses colon inflammation by inhibiting MAP kinases and NF-κB pathways.


Assuntos
Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Colo/metabolismo , Doenças Inflamatórias Intestinais/patologia , Inflamação/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças
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