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1.
Drug Deliv ; 30(1): 2204207, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37139554

RESUMO

How to achieve stable co-delivery of multiple phytochemicals is a common problem. This study focuses on the development, optimization and characterization of Huanglian-HouPo extract nanoemulsion (HLHPEN), with multiple components co-delivery, to enhance the anti-ulcerative colitis (UC) effects. The formulation of HLHPEN was optimized by pseudo-ternary phase diagram combined with Box-Behnken design. The physicochemical properties of HLHPEN were characterized, and its anti-UC activity was evaluated in DSS-induced UC mice model. Based on preparation process optimization, the herbal nanoemulsion HLHPEN was obtained, with the droplet size, PDI value, encapsulation efficiency (EE) for 6 phytochemicals (berberine, epiberberine, coptisine, bamatine, magnolol and honokiol) of 65.21 ± 0.82 nm, 0.182 ± 0.016, and 90.71 ± 0.21%, respectively. The TEM morphology of HLHPEN shows the nearly spheroidal shape of particles. The optimized HLHPEN showed a brownish yellow milky single-phase and optimal physical stability at 25 °C for 90 days. HLHPEN exhibited the good particle stability and gradual release of phytochemicals in SGF and SIF, to resist the destruction of simulated stomach and small intestine environment. Importantly, the oral administration of HLHPEN significantly restored the shrunk colon tissue length and reduced body weight, ameliorated DAI value and colon histological pathology, decreased the levels of inflammatory factors in DSS-induced UC mice model. These results demonstrated that HLHPEN had a significant therapeutic effect on DSS-induced UC mice, as a potential alternative UC therapeutic agent.


Assuntos
Colite Ulcerativa , Colite , Medicamentos de Ervas Chinesas , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Colo , Compostos Fitoquímicos/efeitos adversos , Administração Oral , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colite/tratamento farmacológico
2.
Gut Microbes ; 15(1): 2205425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37131291

RESUMO

Emerging evidence implicates microbial proteolytic activity in ulcerative colitis (UC), but whether it also plays a role in Crohn's disease (CD) remains unclear. We investigated the effects of colonizing adult and neonatal germ-free C57BL/6 mice with CD microbiota, selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), or microbiota from healthy controls with LPA (HC-LPA) or HPA (HC-HPA). We then investigated colitogenic mechanisms in gnotobiotic C57BL/6, and in mice with impaired Nucleotide-binding Oligomerization Domain-2 (NOD2) and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice (Nod2-/-; R38E-PAR2 respectively). At sacrifice, total fecal proteolytic, elastolytic, and mucolytic activity were analyzed. Microbial community and predicted function were assessed by 16S rRNA gene sequencing and PICRUSt2. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity in germ-free mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with germ-free mice. CD-HPA mice had lower alpha diversity, distinct microbial profiles and higher fecal proteolytic activity compared with CD-LPA. C57BL/6 and Nod2-/- mice, but not R38E-PAR2, colonized with CD-HPA had higher colitis severity than those colonized with CD-LPA. Our results indicate that CD proteolytic microbiota is proinflammatory, increasing colitis severity through a PAR2 pathway.


Assuntos
Colite Ulcerativa , Colite , Doença de Crohn , Microbioma Gastrointestinal , Microbiota , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptor PAR-2/genética , RNA Ribossômico 16S/genética , Inflamação , Serina Proteases
3.
Arch Microbiol ; 205(6): 218, 2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37145326

RESUMO

The imbalance of Th17 and Treg cell differentiation, intestinal flora imbalance, and intestinal mucosal barrier damage may be important links in the occurrence and development of inflammatory bowel disease (IBD) since Th17 and Treg differentiation are affected by the intestinal flora. This study aimed to explore the effect of Escherichia coli (E. coli) LF82 on the differentiation of Th17 and Treg cells and the role of the intestinal flora in mouse colitis. The effects of E. coli LF82 infection on intestinal inflammation were evaluated by analyzing the disease activity index, histology, myeloperoxidase activity, FITC-D fluorescence value, and claudin-1 and ZO-1 expression. The effects of E. coli LF82 on the Th17/Treg balance and intestinal flora were analyzed by flow cytometry and 16S rDNA sequencing. Inflammatory markers, changes in the intestinal flora, and Th17/Treg cells were then detected after transplanting fecal bacteria from normal mice into colitis mice infected by E. coli LF82. We found that E. coli LF82 infection can aggravate the intestinal inflammation of mice colitis, destroy their intestinal mucosal barrier, increase intestinal mucosal permeability, and aggravate the imbalance of Th17/Treg differentiation and the disorder of intestinal flora. After improving the intestinal flora imbalance by fecal bacteria transplantation, intestinal inflammation and intestinal mucosal barrier damage were reduced, and the differentiation balance of Th17 and Treg cells was restored. This study showed that E. coli LF82 infection aggravates intestinal inflammation and intestinal mucosal barrier damage in colitis by affecting the intestinal flora composition and indirectly regulating the Th17 and Treg cell differentiation balance.


Assuntos
Colite , Infecções por Escherichia coli , Microbioma Gastrointestinal , Camundongos , Animais , Escherichia coli , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Colite/metabolismo , Colite/microbiologia , Colite/patologia , Infecções por Escherichia coli/microbiologia , Bactérias , Inflamação , Diferenciação Celular
4.
Int J Biol Sci ; 19(7): 2132-2149, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151884

RESUMO

The mechanism underlying inflammatory bowel disease (IBD) remains unclear. We aimed to identify early diagnostic biomarkers and understand their roles in the pathogenesis of IBD. Methods: We identified plasminogen activator inhibitor-1 (PAI-1) as a potential key gene that is upregulated in IBD based on published transcriptomic datasets. To further determine the role of PAI-1 in disease pathogenesis, we induced colitis in wild-type (WT) and PAI-1 knockout (KO) mice by administering dextran sulfate sodium (DSS). We used an RNA array of genes and 16S rRNA sequencing of the microbiome to analyze PAI-1 function. The colon and serum PAI-1 levels in humans were further evaluated for their diagnostic value. Results: PAI-1 expression was significantly increased in patients and DSS-induced WT mice but reduced in PAI-1 KO mice. These changes were associated with significantly decreased neutrophil infiltration in colonic tissues. The RNA array revealed that the CXC chemokines CXCL1 and CXCL5 and their common receptor CXCR2 were among the most significantly different genes between the PAI-1 KO mice with DSS-induced colitis and the WT mice. Mechanistically, PAI-1 deficiency led to blunted activation of the NF-κB pathway in the colon epithelium. The gut microbiome was altered in the PAI-1 KO mice, which showed enriched abundances of short-chain fatty acid-producing genera and diminished abundances of pathogenic genera. Receiver operating characteristic (ROC) curve analysis revealed the diagnostic value of PAI-1. Conclusions: Our data suggest a previously unknown function of PAI-1 inducing neutrophil-mediated chemokine expression by activating the NF-κB pathway and affecting the function of the gut microbiome. PAI-1 could be a potential diagnostic biomarker and a therapeutic target in IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Humanos , Camundongos , Colite/induzido quimicamente , Colite/metabolismo , Colo/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , NF-kappa B , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Ribossômico 16S
5.
Int J Biol Sci ; 19(7): 2150-2166, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151883

RESUMO

Background and Aims: Olfactomedin-4 is a glycoprotein that is upregulated in inflamed gastrointestinal tissues. This study aimed to investigate the role and underlying mechanisms of olfactomedin-4 in ulcerative colitis. Methods: C57BL/6 mice and olfactomedin-4 knockout mice were fed dextran sulfate sodium in drinking water to establish a colitis model. An in vitro inflammation model was constructed in HCT116 and NCM460 cells stimulated with lipopolysaccharide. The expression of olfactomedin-4 was detected by Western blotting, immunohistochemistry staining, and qRT‒PCR. The differences in the severity of colitis between olfactomedin-4 knockout mice and wild-type mice were compared, and the underlying mechanisms were explored. Results: Olfactomedin-4 expression was significantly upregulated in colonic tissues of active ulcerative colitis patients and in cellular and mouse models of colitis. Compared with wild-type littermates, olfactomedin-4 knockout mice were more susceptible to dextran sulfate sodium-induced colitis and produced higher levels of proinflammatory cytokines and chemokines. In addition, olfactomedin-4 deficiency significantly promoted intestinal epithelial cell apoptosis and increased intestinal permeability, which was mediated by the p53 pathway. Moreover, olfactomedin-4 directly interacted with and negatively regulated matrix metalloproteinase-9. Inhibiting matrix metalloproteinase-9 significantly decreased colonic p53 expression and ameliorated experimental colitis in olfactomedin-4 knockout mice, while overexpression of matrix metalloproteinase-9 aggravated colitis. Further experiments showed that matrix metalloproteinase-9 regulated p53 through the Notch1 signaling pathway to promote ulcerative colitis progression. Conclusions: Olfactomedin-4 is significantly upregulated in ulcerative colitis and may protect against colitis by directly inhibiting matrix metalloproteinase-9 and further decreasing p53-mediated apoptosis via Notch1 signaling.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Proteínas Reguladoras de Apoptose/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colite Ulcerativa/metabolismo , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
6.
Front Immunol ; 14: 1155090, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37180168

RESUMO

Background: The disruption of intestinal barrier functions and the dysregulation of mucosal immune responses, mediated by aberrant purinergic metabolism, are involved in the pathogenesis of inflammatory bowel diseases (IBD). A novel mesenchymal-like endometrial regenerative cells (ERCs) has demonstrated a significant therapeutic effect on colitis. As a phenotypic marker of ERCs, CD73 has been largely neglected for its immunosuppressive function in regulating purinergic metabolism. Here, we have investigated whether CD73 expression on ERCs is a potential molecular exerting its therapeutic effect against colitis. Methods: ERCs either unmodified or with CD73 knockout (CD73-/-ERCs), were intraperitoneally administered to dextran sulfate sodium (DSS)-induced colitis mice. Histopathological analysis, colon barrier function, the proportion of T cells, and maturation of dendritic cells (DCs) were investigated. The immunomodulatory effect of CD73-expressing ERCs was evaluated by co-culture with bone marrow-derived DCs under LPS stimulation. FACS determined DCs maturation. The function of DCs was detected by ELISA and CD4+ cell proliferation assays. Furthermore, the role of the STAT3 pathway in CD73-expressing ERCs-induced DC inhibition was also elucidated. Results: Compared with untreated and CD73-/-ERCs-treated groups, CD73-expressing ERCs effectively attenuated body weight loss, bloody stool, shortening of colon length, and pathological damage characterized by epithelial hyperplasia, goblet cell depletion, the focal loss of crypts and ulceration, and the infiltration of inflammatory cells. Knockout of CD73 impaired ERCs-mediated colon protection. Surprisingly, CD73-expressing ERCs significantly decreased the populations of Th1 and Th17 cells but increased the proportions of Tregs in mouse mesenteric lymph nodes. Furthermore, CD73-expressing ERCs markedly reduced the levels of pro-inflammatory cytokines (IL-6, IL-1ß, TNF-α) and increased anti-inflammatory factors (IL-10) levels in the colon. CD73-expressing ERCs inhibited the antigen presentation and stimulatory function of DCs associated with the STAT-3 pathway, which exerted a potent therapeutic effect against colitis. Conclusions: The knockout of CD73 dramatically abrogates the therapeutic ability of ERCs for intestinal barrier dysfunctions and the dysregulation of mucosal immune responses. This study highlights the significance of CD73 mediates purinergic metabolism contributing to the therapeutic effects of human ERCs against colitis in mice.


Assuntos
Colite , Humanos , Animais , Camundongos , Camundongos Knockout , Colite/induzido quimicamente , Colite/terapia , Intestinos/patologia , Citocinas/metabolismo
7.
Lipids Health Dis ; 22(1): 63, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37189092

RESUMO

BACKGROUND: Gut microbiota are involved in the onset and development of chronic intestinal inflammation. The recently described endocannabinoidome (eCBome), a diverse and complex system of bioactive lipid mediators, has been reported to play a role in various physio-pathological processes such as inflammation, immune responses and energy metabolism. The eCBome and the gut microbiome (miBIome) are closely linked and form the eCBome - miBIome axis, which may be of special relevance to colitis. METHODS: Colitis was induced in conventionally raised (CR), antibiotic-treated (ABX) and germ-free (GF) mice with dinitrobenzene sulfonic acid (DNBS). Inflammation was assessed by Disease Activity Index (DAI) score, body weight change, colon weight-length ratio, myeloperoxidase (MPO) activity and cytokine gene expression. Colonic eCBome lipid mediator concentrations were measured by HPLC-MS /MS. RESULTS: GF mice showed increased levels of anti-inflammatory eCBome lipids (LEA, OEA, DHEA and 13- HODE-EA) in the healthy state and higher MPO activity. DNBS elicited reduced inflammation in GF mice, having lower colon weight/length ratios and lower expression levels of Il1b, Il6, Tnfa and neutrophil markers compared to one or both of the other DNBS-treated groups. Il10 expression was also lower and the levels of several N-acyl ethanolamines and 13-HODE-EA levels were higher in DNBS-treated GF mice than in CR and ABX mice. The levels of these eCBome lipids negatively correlated with measures of colitis and inflammation. CONCLUSIONS: These results suggest that the depletion of the gut microbiota and subsequent differential development of the gut immune system in GF mice is followed by a compensatory effect on eCBome lipid mediators, which may explain, in part, the observed lower susceptibility of GF mice to develop DNBS-induced colitis.


Assuntos
Colite , Dinitrobenzenos , Camundongos , Animais , Dinitrobenzenos/efeitos adversos , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Inflamação , Lipídeos
8.
Front Immunol ; 14: 1117828, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153611

RESUMO

In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs. Conversely, the absence of STAT5 tetramers results in a switch to a functionally distinct monocyte-derived macrophage population. In the dextran sulfate sodium (DSS) model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression of arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and sustained supplementation of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. This study suggests that STAT5 tetramers protect against severe intestinal inflammation through the regulation of arginine metabolism.


Assuntos
Colite , Monócitos , Fator de Transcrição STAT5 , Animais , Camundongos , Arginase/metabolismo , Diferenciação Celular , Sulfato de Dextrana/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inflamação , Óxido Nítrico/metabolismo , Fator de Transcrição STAT5/metabolismo
9.
J Ethnopharmacol ; 313: 116534, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37127140

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional oriental medicine, the dried seeds of Psoralea corylifolia L. (PC) have been used to treat various diseases, including gastrointestinal, urinary, orthopedic, diarrheal, ulcer, and inflammatory disorders. AIM OF THE STUDY: Although its various biological properties are well-known, there is no information on the therapeutic effects and bioavailable components of PC against inflammatory bowel disease. Therefore, we focused on the relationship between hydroethanolic extract of PC (EPC) that ameliorates colitis in mice and bioactive constituents of EPC that suppress pro-inflammatory cytokines in macrophages. MATERIALS AND METHODS: We investigated the therapeutic effects of EPC in a dextran sulfate sodium-induced colitis mouse model and identified the orally absorbed components of EPC using UPLC-MS/MS analysis. In addition, we evaluated and validated the mechanism of action of the bioavailable constituents of EPC using network pharmacology analysis. The effects on nitric oxide (NO) and inflammatory cytokines were measured by Griess reagent and enzyme linked immunosorbent assay in lipopolysaccharide (LPS)-induced macrophages. RESULTS: In experimental colitis, EPC improved body weight loss, colon length shortening, and disease activity index. Moreover, EPC reduced the serum levels of pro-inflammatory cytokines and histopathological damage to the colon. Network pharmacological analysis identified 13 phytochemicals that were bioavailable following oral administration of EPC, as well as their potential anti-inflammatory effects. 11 identified EPC constituents markedly reduced the overproduction of NO, tumor necrosis factor-α, and/or interleukin-6 in macrophages induced by LPS. The LPS-induced expression of the nuclear factor kappa-light-chain-enhancer of activated B cells reporter gene was reduced by the 4 EPC constituents. CONCLUSIONS: The results indicate that the protective activity of EPC against colitis is a result of the additive effects of each constituent on the expression of inflammatory cytokines. Therefore, it suggests that 11 bioavailable phytochemicals of EPC could aid in the management of intestinal inflammation, and also provides useful insights into the clinical application of PC for the treatment of inflammatory bowel diseases.


Assuntos
Colite Ulcerativa , Colite , Fabaceae , Psoralea , Camundongos , Animais , Psoralea/metabolismo , Lipopolissacarídeos/farmacologia , Cromatografia Líquida , Farmacologia em Rede , Espectrometria de Massas em Tandem , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Anti-Inflamatórios/efeitos adversos , Colo , Citocinas/metabolismo , Sulfato de Dextrana , Colite Ulcerativa/tratamento farmacológico , NF-kappa B/metabolismo
10.
Biosci Rep ; 43(5)2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37128889

RESUMO

An inclusion complex formation with cyclodextrin is a promising method to improve the bioavailability of water-insoluble drugs. The pharmacokinetic characteristics of Hyperoside-2-hydroxypropyl-ß-cyclodextrin inclusion complex in rats were evaluated. Compared with Hyperoside, the results showed that maximum plasma concentration and AUC0-t indexes of Hyperoside inclusion complex in rat plasma were increased, the value of half-life time was prolonged, and the value of apparent clearance was decreased, which proved that Hyperoside complexed with 2-hydroxypropyl-ß-cyclodextrin could improve its bioavailability and increase its blood concentration. Secondly, the therapeutic effect of Hyperoside before and after complexing was further compared through the dextran sodium sulfate-induced colitis in mice. The experimental results showed that under the same dose, the Hyperoside inclusion complex had a better therapeutic effect, which could significantly increase the body weight of mice, improve the disease activity index, alleviate colon shortening, improve pathological colon changes, and have a better protective effect on colitis mice. According to 16S rDNA sequencing analyses, Hyperoside-2-hydroxypropyl-ß-cyclodextrin may have an anti-inflammatory effect by increasing the abundance of beneficial bacteria (e.g. Firmicuria) and decreasing the proportion of harmful bacteria (e.g. Bacteroidetes) to balance the colon's microbiota.


Assuntos
Colite , Camundongos , Ratos , Animais , 2-Hidroxipropil-beta-Ciclodextrina/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Quercetina , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
11.
J Ethnopharmacol ; 313: 116557, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37142141

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. AIM OF THE STUDY: To evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. MATERIALS AND METHODS: Colitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. RESULTS: Oral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARγ signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARγ signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-γ induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARγ dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. CONCLUSION: Our findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARγ, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , PPAR gama/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Quercetina/metabolismo , Leucócitos Mononucleares/metabolismo , Camundongos Endogâmicos C57BL , Colo , Colite/tratamento farmacológico , Macrófagos , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fator de Transcrição STAT1/metabolismo
12.
Microbiome ; 11(1): 96, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37131223

RESUMO

BACKGROUND: The Western dietary pattern, characterized by high consumption of fats and sugars, has been strongly associated with an increased risk of developing Crohn's disease (CD). However, the potential impact of maternal obesity or prenatal exposure to a Western diet on offspring's susceptibility to CD remains unclear. Herein, we investigated the effects and underlying mechanisms of a maternal high-fat/high-sugar Western-style diet (WD) on offspring's susceptibility to 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced Crohn's-like colitis. METHODS: Maternal dams were fed either a WD or a normal control diet (ND) for eight weeks prior to mating and continued throughout gestation and lactation. Post-weaning, the offspring were subjected to WD and ND to create four groups: ND-born offspring fed a normal diet (N-N) or Western diet (N-W), and WD-born offspring fed a normal (W-N) or Western diet (W-W). At eight weeks of age, they were administered TNBS to induce a CD model. RESULTS: Our findings revealed that the W-N group exhibited more severe intestinal inflammation than the N-N group, as demonstrated by a lower survival rate, increased weight loss, and a shorter colon length. The W-N group displayed a significant increase in Bacteroidetes, which was accompanied by an accumulation of deoxycholic acid (DCA). Further experimentation confirmed an increased generation of DCA in mice colonized with gut microbes from the W-N group. Moreover, DCA administration aggravated TNBS-induced colitis by promoting Gasdermin D (GSDMD)-mediated pyroptosis and IL-1beta (IL-1ß) production in macrophages. Importantly, the deletion of GSDMD effectively restrains the effect of DCA on TNBS-induced colitis. CONCLUSIONS: Our study demonstrates that a maternal Western-style diet can alter gut microbiota composition and bile acid metabolism in mouse offspring, leading to an increased susceptibility to CD-like colitis. These findings highlight the importance of understanding the long-term consequences of maternal diet on offspring health and may have implications for the prevention and management of Crohn's disease. Video Abstract.


Assuntos
Colite , Doença de Crohn , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Camundongos , Animais , Doença de Crohn/induzido quimicamente , Dieta Ocidental/efeitos adversos , Colite/induzido quimicamente , Dieta Hiperlipídica/efeitos adversos , Ácido Desoxicólico , Camundongos Endogâmicos C57BL
13.
PLoS One ; 18(5): e0280232, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37159460

RESUMO

Entamoeba histolytica is a disease-causing parasitic amoeba which affects an estimated 50 million people worldwide, particularly in socioeconomically vulnerable populations experiencing water sanitation issues. Infection with E. histolytica is referred to as amoebiasis, and can cause symptoms such as colitis, dysentery, and even death in extreme cases. Drugs exist that are capable of killing this parasite, but they are hampered by downsides such as significant adverse effects at therapeutic concentrations, issues with patient compliance, the need for additional drugs to kill the transmissible cyst stage, and potential development of resistance. Past screens of small and medium sized chemical libraries have yielded anti-amoebic candidates, thus rendering high-throughput screening a promising direction for new drug discovery in this area. In this study, we screened a curated 81,664 compound library from Janssen pharmaceuticals against E. histolytica trophozoites in vitro, and from it identified a highly potent new inhibitor compound. The best compound in this series, JNJ001, showed excellent inhibition activity against E. histolytica trophozoites with EC50 values at 0.29 µM, which is better than the current approved treatment, metronidazole. Further experimentation confirmed the activity of this compound, as well as that of several structurally related compounds, originating from both the Janssen Jump-stARter library, and from chemical vendors, thus highlighting a new structure-activity relationship (SAR). In addition, we confirmed that the compound inhibited E. histolytica survival as rapidly as the current standard of care and inhibited transmissible cysts of the related model organism Entamoeba invadens. Together these results constitute the discovery of a novel class of chemicals with favorable in vitro pharmacological properties. The discovery may lead to an improved therapy against this parasite and in all of its life stages.


Assuntos
Amebíase , Amoeba , Colite , Cistos , Disenteria Amebiana , Disenteria , Humanos
14.
Front Cell Infect Microbiol ; 13: 1178714, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153156

RESUMO

The success rate of azomethane-dextran sodium sulfate (AOM-DSS) model in mice has been a long-standing problem. Treatment of AOM and the first round DSS induces acute colitis and is of great significance for the success of AOM-DSS model. In this study, we focused on the role of gut microbiota in the early stage of AOM-DSS model. Few mice with obvious weight loss and high disease-activity score survived from double strike of AOM and the first round DSS. Different ecological dynamics of gut microbiota were observed in AOM-DSS treated mice. Pseudescherichia, Turicibacter, and Clostridium_XVIII were of significance in the model, uncontrolled proliferation of which accompanied with rapid deterioration and death of mice. Akkermansia and Ruthenibacterium were significantly enriched in the alive AOM-DSS treated mice. Decrease of Ligilactobacillus, Lactobacillus, and Limosilactobacillus were observed in AOM-DSS model, but significant drop of these genera could be lethal. Millionella was the only hub genus of gut microbiota network in dead mice, which indicated dysbiosis of the intestinal flora and fragility of microbial network. Our results will provide a better understanding for the role of gut microbiota in the early stage of AOM-DSS model and help improve the success rate of model construction.


Assuntos
Colite , Microbioma Gastrointestinal , Animais , Camundongos , Dextranos , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Colo/microbiologia
15.
J Agric Food Chem ; 71(19): 7299-7311, 2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37132503

RESUMO

The pharmacological values of marine algal polysaccharides on gut health are being recognized in recent research. However, the protective effect of degraded polysaccharides from Porphyra haitanensis (PHP-D) on the colonic mucosal barrier damaged in ulcerative colitis is poorly understood. The purpose of this study was to investigate how PHP-D could maintain the integrity of colonic mucosal layer mediated by microbiota in a dextran sulfate sodium (DSS)-induced colitis mouse model. Structural analysis revealed that PHP-D had a typical porphyran structure having a backbone of alternating (1 → 3)-linked ß-d-galactopyranose units linked to either (1 → 4)-3,6-anhydro-α-l-galactopyranose units or (1 → 4)-linked α-l-galactose-6-sulfate units. An in vivo study demonstrated that PHP-D treatment reduced the severity of DSS-induced ulcerative colitis. 16S rRNA phylogenetic sequencing revealed that PHP-D affected the diversity of gut microbiota with an increase of Bacteroides, Muribaculum, and Lactobacillus species. Similarly, PHP-D increased levels of short-chain fatty acids. Furthermore, PHP-D restored mucus thickness and improved the expression of tight junction proteins. This work demonstrates that PHP-D is capable of enhancing a colonic mucosal barrier. These outcomes offer unique perspectives on the potential application of P. haitanensis as a promising natural product for the management of ulcerative colitis.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Sulfato de Dextrana/metabolismo , Galactose/metabolismo , RNA Ribossômico 16S/genética , Filogenia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Polissacarídeos/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
16.
J Nanobiotechnology ; 21(1): 145, 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37127609

RESUMO

Colon-targeted oral drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC), which is a disease with high relapse and remission rates associated with immune system inflammation and dysregulation localized within the lining of the large bowel. However, the success of current available approaches used for colon-targeted therapy is limited. Budesonide (BUD) is a corticosteroid drug, and its rectal and oral formulations are used to treat UC, but the inconvenience of rectal administration and the systemic toxicity of oral administration restrict its long-term use. In this study, we designed and prepared colon-targeted solid lipid nanoparticles (SLNs) encapsulating BUD to treat UC by oral administration. A negatively charged surfactant (NaCS-C12) was synthesized to anchor cellulase-responsive layers consisting of polyelectrolyte complexes (PECs) formed by negatively charged NaCS and cationic chitosan onto the SLNs. The release rate and colon-specific release behavior of BUD could be easily modified by regulating the number of coated layers. We found that the two-layer BUD-loaded SLNs (SLN-BUD-2L) with a nanoscale particle size and negative zeta potential showed the designed colon-specific drug release profile in response to localized high cellulase activity. In addition, SLN-BUD-2L exhibited excellent anti-inflammatory activity in a dextran sulfate sodium (DSS)-induced colitis mouse model, suggesting its potential anti-UC applications.


Assuntos
Celulases , Colite Ulcerativa , Colite , Nanopartículas , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Budesonida , Colo , Colite/induzido quimicamente , Celulases/uso terapêutico , Modelos Animais de Doenças
17.
Front Immunol ; 14: 1127785, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37205093

RESUMO

Background: Atractylodes macrocephala Koidz. (AM) is a functional food with strong ant-colitis activity. AM volatile oil (AVO) is the main active ingredient of AM. However, no study has investigated the improvement effect of AVO on ulcerative colitis (UC) and the bioactivity mechanism also remains unknown. Here, we investigated whether AVO has ameliorative activity on acute colitis mice and its mechanism from the perspective of gut microbiota. Methods: Acute UC was induced in C57BL/6 mice by dextran sulfate sodium and treated with the AVO. Body weight, colon length, colon tissue pathology, and so on were assessed. The gut microbiota composition was profiled using 16s rRNA sequencing and global metabolomic profiling of the feces was performed. The results showed that AVO can alleviate bloody diarrhea, colon damage, and colon inflammation in colitis mice. In addition, AVO decreased potentially harmful bacteria (Turicibacter, Parasutterella, and Erysipelatoclostridium) and enriched potentially beneficial bacteria (Enterorhabdus, Parvibacter, and Akkermansia). Metabolomics disclosed that AVO altered gut microbiota metabolism by regulating 56 gut microbiota metabolites involved in 102 KEGG pathways. Among these KEGG pathways, many metabolism pathways play an important role in maintaining intestine homeostasis, such as amino acid metabolism (especially tryptophan metabolism), bile acids metabolism, and retinol metabolism. Conclusion: In conclusion, our study indicated that AVO can be expected as novel prebiotics to treat ulcerative colitis, and modulating the composition and metabolism of gut microbiota may be its pharmacological mechanism.


Assuntos
Actinobacteria , Atractylodes , Besouros , Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , RNA Ribossômico 16S
18.
Front Immunol ; 14: 1165667, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37215126

RESUMO

Toll-like receptors (TLRs) have a crucial role not only in triggering innate responses against microbes but in orchestrating an appropriate adaptive immunity. However, deregulated activation of TLR signaling leads to chronic inflammatory conditions such as inflammatory bowel disease (IBD). In this study, we evaluated the immunomodulatory potential of a TLR inhibitor in the form of a cell-penetrating peptide using an ulcerative colitis animal model. A peptide derived from the TIR domain of the TLR adaptor molecule TIRAP that was conjugated with a cell-penetrating sequence (cpTLR-i) suppressed the induction of pro-inflammatory cytokines such as TNF-α and IL-1ß in macrophages. In DSS-induced colitis mice, cpTLR-i treatment ameliorated colitis symptoms, colonic tissue damage, and mucosal inflammation. Intriguingly, cpTLR-i attenuated the induction of TNF-α-expressing proinflammatory macrophages while promoting that of regulatory macrophages expressing arginase-1 and reduced type 17 helper T cell (Th17) responses in the inflamed colonic lamina propria. An in vitro study validated that cpTLR-i enhanced the differentiation of monocyte-driven macrophages into mature macrophages with a regulatory phenotype in a microbial TLR ligand-independent manner. Furthermore, the cocultivation of CD4 T cells with macrophages revealed that cpTLR-i suppressed the activation of Th17 cells through the functional modulation of macrophages. Taken together, our data show the immunomodulatory potential of the TLR inhibitor peptide and suggest cpTLR-i as a novel therapeutic candidate for the treatment of IBD.


Assuntos
Peptídeos Penetradores de Células , Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Peptídeos Penetradores de Células/farmacologia , Fator de Necrose Tumoral alfa , Macrófagos
19.
Front Immunol ; 14: 1186892, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37215145

RESUMO

A growing body of research suggests that short-chain fatty acids (SCFAs), metabolites produced by intestinal symbiotic bacteria that ferment dietary fibers (DFs), play a crucial role in the health status of symbiotes. SCFAs act on a variety of cell types to regulate important biological processes, including host metabolism, intestinal function, and immune function. SCFAs also affect the function and fate of immune cells. This finding provides a new concept in immune metabolism and a better understanding of the regulatory role of SCFAs in the immune system, which impacts the prevention and treatment of disease. The mechanism by which SCFAs induce or regulate the immune response is becoming increasingly clear. This review summarizes the different mechanisms through which SCFAs act in cells. According to the latest research, the regulatory role of SCFAs in the innate immune system, including in NLRP3 inflammasomes, receptors of TLR family members, neutrophils, macrophages, natural killer cells, eosinophils, basophils and innate lymphocyte subsets, is emphasized. The regulatory role of SCFAs in the adaptive immune system, including in T-cell subsets, B cells, and plasma cells, is also highlighted. In addition, we discuss the role that SCFAs play in regulating allergic airway inflammation, colitis, and osteoporosis by influencing the immune system. These findings provide evidence for determining treatment options based on metabolic regulation.


Assuntos
Colite , Ácidos Graxos Voláteis , Humanos , Ácidos Graxos Voláteis/metabolismo , Inflamação , Inflamassomos/metabolismo , Sistema Imunitário/metabolismo
20.
Food Funct ; 14(10): 4777-4791, 2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37128780

RESUMO

Inflammatory bowel disease (IBD) is continuously increasing globally and caused by intestinal barrier dysfunction. Although protocatechuic acid (PCA) has a protective effect on colitis, the molecular mechanisms underlying its contribution to intestinal barrier function remain unknown. Transepithelial electrical resistance (TEER) and FITC-dextran permeability measurements reveled that PCA suppresses lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α-induced increase in intestinal permeability; zonula occludens (ZO)-1 and claudin-2 redistribution was also suppressed in the epithelial cell membranes of differentiated Caco-2 cells. PCA was found to directly bind Rho-associated coiled-coil containing protein kinase (ROCK), subsequently suppressing myosin light chain (MLC) phosphorylation. Notably, PCA binds ROCK to a similar degree as Y27632, a selective ROCK inhibitor. Orally administering PCA (5 or 25 mg per kg per day) to C57BL/6 mice alleviated the 3% dextran sulfate sodium (DSS)-induced colitis symptoms including reduced colon length, disrupted intestinal barrier structure, and increased proinflammatory cytokines expressions, such as interleukin (IL)-1ß, TNF-α, and IL-6. Furthermore, orally administering PCA suppressed DSS-induced ZO-1 and claudin-2/4 redistribution in mice colon membrane fractions. Therefore, PCA may serve as a promising nutraceutical to improve gut health and alleviate IBD by maintaining intestinal barrier function in vitro and in vivo.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , Células CACO-2 , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/farmacologia , Proteínas de Junções Íntimas/metabolismo , Claudina-2/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Junções Íntimas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Mucosa Intestinal/metabolismo , Sulfato de Dextrana/efeitos adversos
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