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1.
Nutrients ; 13(8)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34444730

RESUMO

Micronutrient deficiencies can arise in various conditions, including inflammatory bowel diseases (IBD), and diagnosing these deficiencies can be challenging in the absence of specific clinical signs. The aim of this study was to evaluate the status of various trace elements hair concentration in IBD patients compared to a healthy control group and to identify potential correlations between the micronutrient status and relevant parameters related to disease activity. The concentrations of iron, magnesium, calcium, zinc, copper, manganese, selenium and sulfur in the hair of 37 IBD patients with prior diagnosed IBD (12 Crohn's disease and 25 ulcerative colitis) and 31 healthy controls were evaluated by Energy Dispersive X-Ray spectroscopy (EDX). Significant differences in hair concentration profile of studied trace elements were identified for IBD patients compared to healthy controls. A significantly decreased hair concentration of iron, magnesium, calcium and selenium and a significantly increased sulfur hair concentration were observed in IBD patients at the time of evaluation. A decreased hair calcium concentration (r = -0.772, p = 0.003) and an increased sulfur concentration (r = 0.585, p = 0.046) were significantly correlated with disease activity. Conclusion: Hair mineral and trace elements evaluation may contribute to a proper evaluation of their status in IBD patients and improving the management of nutritional status of IBD patients.


Assuntos
Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Cabelo/química , Micronutrientes/análise , Adulto , Cálcio/análise , Cobre/análise , Feminino , Humanos , Ferro/análise , Magnésio/análise , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Selênio/análise , Espectrometria por Raios X , Enxofre/sangue , Oligoelementos/análise , Zinco/análise
2.
Theranostics ; 11(16): 7797-7812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335965

RESUMO

Rationale: Corticosteroid resistance (CR) is a serious drawback to steroid therapy in patients with ulcerative colitis (UC); the underlying mechanism is incompletely understood. Twist1 protein (TW1) is an apoptosis inhibitor and has immune regulatory functions. This study aims to elucidate the roles of TW1 in inducing and sustaining the CR status in UC. Methods: Surgically removed colon tissues of patients with ulcerative colitis (UC) were collected, from which neutrophils were isolated by flow cytometry. The inflammation-related gene activities in neutrophils were analyzed by RNA sequencing. A CR colitis mouse model was developed with the dextran sulfate sodium approach in a hypoxia environment. Results: Higher TW1 gene expression was detected in neutrophils isolated from the colon tissues of UC patients with CR and the CR mouse colon tissues. TW1 physically interacted with glucocorticoid receptor (GR)α in CR neutrophils that prevented GRα from interacting with steroids; which consequently abrogated the effects of steroids on regulating the cellular activities of neutrophils. STAT3 (Signal Transducer and Activator of Transcription-3) interacted with Ras protein activator like 1 to sustain the high TW1 expression in colon mucosal neutrophils of CR patients and CR mice. Inhibition of TW1 restored the sensitivity to corticosteroid of neutrophils in the colon tissues of a CR murine model. Conclusions: UC patients at CR status showed high TW1 expression in neutrophils. TW1 prevented steroids from regulating neutrophil activities. Inhibition of TW1 restored the sensitivity to corticosteroids in the colon tissues at the CR status.


Assuntos
Colite Ulcerativa/metabolismo , Resistência a Medicamentos/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Corticosteroides/farmacologia , Adulto , Animais , China , Colite , Colite Ulcerativa/genética , Colo/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteínas Nucleares/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 Relacionada a Twist/genética
3.
Biomed Pharmacother ; 138: 111535, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311533

RESUMO

Dysregulation of intestinal immune response plays a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD). Mastiha's anti-inflammatory properties are well established. Our aim was to investigate Mastiha's regulatory effect on IL-17A serum levels in IBD patients. Alterations of the faecal metabolome as a functional readout of microbial activity were explored. A randomized, double-blind, placebo-controlled, parallel-group design was applied for a total of 3 months in active and 6 months in inactive IBD patients. Serum IL-17A increased significantly in Mastiha group (p = 0.006), and the mean change differed significantly between Mastiha and placebo (p = 0.003) even after adjusting for age, sex and BMI (p = 0.001) in inactive patients. In inactive UC patients IL-17A decreased significantly only in placebo (p = 0.033). No significant differences were detected in active disease. Faecal metabolomics indicated that intervention with Mastiha influenced considerably the metabolic profile of IBD patients in remission exhibiting, in between others, increased levels of glycine and tryptophan. Glycine has been proposed to have a therapeutic effect against IBD, while tryptophan derivatives are involved in immunoregalutory mechanisms, such as the Th17 cells differentiation. Thus, it is quite possible that the immunoregulatory role of Mastiha in quiescent IBD involves the regulation of Th17 cells function and differentiation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fezes/química , Interleucina-17/sangue , Resina Mástique/uso terapêutico , Metaboloma , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/isolamento & purificação , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Método Duplo-Cego , Feminino , Grécia , Humanos , Masculino , Resina Mástique/efeitos adversos , Pessoa de Meia-Idade , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
4.
Int J Biol Macromol ; 185: 804-812, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34229016

RESUMO

Aloe polysaccharides (APs) are acetyl polysaccharides. It has been reported APs could protect mice from ulcerative colitis (UC), but the complex interactions between APs and the intestinal barrier were unclear. Here, we investigated the relationship between APs and UC, and determined the synergistic effects of Nrf2/HO-1 signaling pathway and short-chain fatty acids (SCFAs) metabolism on protecting intestinal barrier in acute UC mice. Results showed APs could scavenge free radicals in vitro. In vivo, APs had the antioxidant and anti-inflammatory effect both in serum and colon. Besides, the pathological results showed APs could alleviate colonic lesions. Furthermore, our study indicated treatment with APs effectively increased SCFAs production. The inhibition of acute UC in mice was correlated with the APs-mediated effects on improving the expression of ZO-1, occludin, Nrf2, HO-I, and NQO1. Thus, APs effectively promoted the intestinal barrier via Nrf2/HO-1 signaling pathway and SCFAs metabolism, effectively ameliorating acute colitis in mice.


Assuntos
Aloe/química , Colite Ulcerativa/tratamento farmacológico , Ácidos Graxos Voláteis/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Polissacarídeos/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacologia , Sequência de Carboidratos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana/síntese química , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Polissacarídeos/química , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
5.
Chem Biodivers ; 18(7): e2100130, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34080308

RESUMO

The polysaccharides of the Chinese herbal medicine Dendrobium huoshanense exhibit anti-inflammatory effects in multiple organs through regulating the immune responses. In the present study, we constructed ulcerative colitis (UC) model rats using dextran sulfate sodium to investigate the anti-inflammatory effects of D. huoshanense polysaccharides (DHP). After oral administration of DHP for two weeks, the indices of UC symptoms, including the ratio of colon weight to length, Disease Activity Index (DAI), and Colon Mucosal Damage Index (CMDI), all decreased significantly compared with the UC model group. The histological sections also revealed better cell orders in DHP treatments than in the UC model rats. Moreover, in treatment with high dose of DHP (200 mg/kg), the treatment efficacy arrived the similar levels to those in the treatment with 300 mg/kg sulfasalazine, which is a typical medicine to treat UC. These results indicated that DHP has a high efficacy to treat UC in model rats. Furthermore, serum levels of interleukin-1ß, tumor necrosis factor-α, interleukin-17, and transforming growth factor-ß were assessed using the enzyme linked immunosorbent assay (ELISA) method, and the levels of nuclear factor-κB in colon tissue sections were determined using the immunohistochemical method. The results showed that all these indices decreased significantly after administration of DHP in UC model rats, which might be the mechanisms underlying the DHP-suppressed UC inflammation. Overall, this study indicated that DHP might be directly used to treat UC and is a promising source to develop novel drugs against UC.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Dendrobium/química , Inflamação/prevenção & controle , NF-kappa B/antagonistas & inibidores , Polissacarídeos/farmacologia , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Feminino , Masculino , NF-kappa B/metabolismo , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G157-G170, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132111

RESUMO

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Leptina/metabolismo , Lipopolissacarídeos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Calgranulina A/metabolismo , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/etiologia , Colite Ulcerativa/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Zucker , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Fator de Transcrição STAT3/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Am J Physiol Gastrointest Liver Physiol ; 321(2): G232-G242, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34133236

RESUMO

The Western diet has been suggested to contribute to the rising incidence of inflammatory bowel diseases. This has led to the hypothesis that fructose, a component of the Western diet, could play a role in the pathogenesis of inflammatory bowel diseases. A high-fructose diet is known to exacerbate experimental colitis. This study tested whether the expression of GLUT5, the fructose transporter, is a determinant of the severity of experimental colitis during elevated fructose consumption and whether ileal inflammation is associated with altered GLUT5 expression in Crohn's disease. Studies in genetically engineered mice showed that in comparison to Glut5+/+ mice, feeding a 15 kcal% fructose diet to Glut5-/- mice led to worse dextran sodium sulfate (DSS)-induced colitis. This effect was associated with elevated levels of colonic fructose and a shift in the fecal microbiota in Glut5-/- mice. Importantly, treatment with broad-spectrum antibiotics protected against the worsening of colitis mediated by dietary fructose in Glut5-/- mice. Gene expression analysis revealed that GLUT5 levels are reduced in the intestines of patients with ileal Crohn's disease. Moreover, levels of GLUT5 negatively correlated with expression of proinflammatory mediators in these samples. Collectively, these results demonstrate that dietary constituent (fructose)-host gene (GLUT5) interactions can shape the colonic microbiota, thereby impacting the severity of colitis.NEW & NOTEWORTHY This study provides the first evidence that reduced levels of GLUT5, the fructose transporter, worsen experimental colitis upon fructose feeding, an effect mediated by changes in the gut microbiota. Moreover, GLUT5 expression is reduced in Crohn's ileitis. Overall, these findings demonstrate the importance of interactions between dietary fructose and host GLUT5 as determinants of both the composition of colonic microbiota and severity of experimental colitis.


Assuntos
Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Frutose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Animais , Colite Ulcerativa/etiologia , Açúcares da Dieta/efeitos adversos , Açúcares da Dieta/metabolismo , Frutose/efeitos adversos , Microbioma Gastrointestinal , Transportador de Glucose Tipo 5/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Dodecilsulfato de Sódio/toxicidade
8.
Front Immunol ; 12: 611256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079536

RESUMO

Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.


Assuntos
Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Imunomodulação/efeitos dos fármacos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Gerenciamento Clínico , Suscetibilidade a Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Terapia de Alvo Molecular , Resultado do Tratamento , Ustekinumab/farmacologia , Ustekinumab/uso terapêutico
9.
AAPS PharmSciTech ; 22(5): 180, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34129135

RESUMO

Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor-α (TNF-α), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-ΚB), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Celecoxib/síntese química , Celecoxib/farmacocinética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Sulfato de Dextrana/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , NF-kappa B/metabolismo , Compostos Orgânicos/síntese química , Compostos Orgânicos/farmacocinética , Compostos Orgânicos/uso terapêutico , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
10.
Eur J Med Chem ; 222: 113583, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119832

RESUMO

Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNFα activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNFα activity in vitro (IC50 = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4bvia molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (ß) (Ki = 760.86 nM) vs. alpha (α) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Descoberta de Drogas , Oxazóis/farmacologia , Fenóis/farmacologia , Quinolonas/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazóis/química , Fenóis/química , Quinolonas/síntese química , Quinolonas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
11.
Biomed Pharmacother ; 140: 111770, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34119929

RESUMO

Our study has renewed interest in the genus Jasmine for the treatment of chronic inflammatory conditions. Aerial parts of Jasminum grandiflorum L. subsp. floribundum total methanolic extract (JTME) were tested for its therapeutic potential as an anti-inflammatory agent using two experimental models in rats; acetic acid (AA) induced ulcerative colitis and adjuvant induced arthritis. The administration of JTME showed anti-inflammatory activity in a dose dependent manner. JTME, 400 mg/kg was like prednisolone, 2 mg/kg p.o. (the reference drug), since it improved the tissues of the colon clinically, macro and microscopically (ulcer index), and histopathological (scoring). It reduced the intestinal expression of pro-inflammatory cytokines in the colonic mucosa; IFNγ, TNFα, IL-6, IL-1, and MPO. It also preserved tight junctions in intestinal epithelial cells by counter-regulating claudin-5 and occludin levels additionally, it had a potent antioxidant activity. The expressions of NF-κB p65, TNF-α and caspase-3 in rats administered AA (2 mL of 4% solution, once, intrarectally) were significantly increased, where the lowest expression was scored in JTME, 400 mg/kg group. In the adjuvant induced model of rheumatoid arthritis, the TJME, 400 mg/kg reduced the levels of cathepsin D, iNOS, NO, RF, CRP, CPP and elevated the total antioxidant capacity of tissues. Additionally, it maintained bones without histopathological lesions, articular cartilage damage, and inflammation of the synovial membrane and periarticular tissues, in contrast to arthritic rats. Finally, we report a new detailed study to validate the medicinal importance of Jasminum for the chronic inflammatory disorders with immune dysfunction with anti-inflammatory and antioxidant effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Jasminum , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Artrite Experimental/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
12.
J Cell Mol Med ; 25(12): 5707-5720, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34002930

RESUMO

To investigate the therapeutic effects of phellodendrine in ulcerative colitis (UC) through the AMPK/mTOR pathway. Volunteers were recruited to observe the therapeutic effects of Compound Cortex Phellodendri Liquid (Huangbai liniment). The main components of Compound Cortex Phellodendri Liquid were analysed via network pharmacology. The target of phellodendrine was further analysed. Caco-2 cells were cultured, and H2 O2 was used to stimulate in vitro cell model. Expression levels of LC3, AMPK, p-AMPK, mTOR and p-mTOR were detected via Western blotting and through immunofluorescence experiments. The therapeutic effects of phellodendrine were analysed via expression spectrum chip sequencing. The sequencing of intestinal flora further elucidated the therapeutic effects of phellodendrine. Compared with the control group, Compound Cortex Phellodendri Liquid could substantially improve the healing of intestinal mucosa. Network pharmacology analysis revealed that phellodendrine is the main component of Compound Cortex Phellodendri Liquid. Moreover, this alkaloid targets the AMPK signalling pathway. Results of animal experiments showed that phellodendrine could reduce the intestinal damage of UC compared with the model group. Findings of cell experiments indicated that phellodendrine treatment could activate the p-AMPK /mTOR signalling pathway, as well as autophagy. Expression spectrum chip sequencing showed that treatment with phellodendrine could promote mucosal healing and reduce inflammatory responses. Results of intestinal flora detection demonstrated that treatment with phellodendrine could increase the abundance of flora and the content of beneficial bacteria. Phellodendrine may promote autophagy by regulating the AMPK-mTOR signalling pathway, thereby reducing intestinal injury due to UC.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Colite Ulcerativa/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Quinolizinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Adulto , Animais , Estudos de Casos e Controles , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
13.
Exp Cell Res ; 404(2): 112638, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34015312

RESUMO

Ulcerative colitis (UC) is a disease characterized by inflammation and disruption of the intestinal epithelial barrier. Necroptosis plays a critical role in disease progression. Indole-3-carbinol (I3C), a natural dietary agonist of aryl hydrocarbon receptor (AHR), has shown alleviating effects on UC. However, its mechanisms of action have not been comprehensively elucidated. Therefore, we aimed at investigating the protective role of I3C in DSS-induced colitis mice models. I3C significantly ameliorated body weight loss, colon length shortening and colonic pathological damage in colitis mice, reduced disease activity index (DAI) and histological (HI) scores, as well as alleviated colonic necroptosis and inflammation. In vitro, I3C attenuated necroptosis and inflammation of colonoids and NCM460 cells. AHR, activated by I3C, inhibits activation of receptor-interacting protein kinase 1 (RIPK1) and the subsequent assembly of necrosome in a time-dependent manner, as well as suppressing NF-κB activation and decreasing TNF-α, IL-1ß, IL-6 and IL-8 expression. Silencing of AHR aggravated necroptosis and inflammation of NCM460 cells, and did not be ameliorated by I3C. Furthermore, AHR activation induces the expression of inhibitor of apoptosis proteins (IAPs) and the ubiquitination of RIPK1. In conclusion, I3C exerts a protective effect in DSS-induced colitis mice models by alleviating the necroptosis and inflammation of IECs through activating AHR.


Assuntos
Colite Ulcerativa/metabolismo , Células Epiteliais/metabolismo , Inflamação/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Colite Ulcerativa/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Intestinos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
14.
Food Funct ; 12(14): 6403-6415, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34057171

RESUMO

Selenium (Se) is an essential micronutrient that has implications in human diseases, including inflammatory bowel disease (IBD), especially with respect to Se deficiencies. Recently, selenium nanoparticles (SeNPs) have attracted significant attention due to their diversity of biological activities and unique advantages including low toxicity and high biological availability. In this study, an eco-friendly, efficient and low-cost method for synthesis of SeNPs by Kluyveromyces lactis GG799 (K. lactis GG799) was established, and the SeNPs were investigated for their physicochemical properties and anti-inflammatory activities in vivo. K. lactis GG799 was able to successfully transform sodium selenite into bright-red SeNPs with particle sizes of 80 and 150 nm and the nanoparticles accumulated intracellularly. Upon isolation, the SeNPs were found to be mainly capped by proteins and polysaccharides by components analysis. Dietary supplementation with 0.6 mg kg-1 Se (in the form of biogenic SeNPs) effectively attenuated dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice by alleviating oxidative stress and intestinal inflammation. These findings suggested that SeNPs synthesized by K. lactis GG799 may be a promising and safe Se supplement for the prevention and treatment of IBD.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Kluyveromyces , Nanopartículas/química , Selênio/farmacologia , Animais , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Colite Ulcerativa/metabolismo , Suplementos Nutricionais , Humanos , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nanopartículas/administração & dosagem , Estresse Oxidativo , Tamanho da Partícula , Selênio/química
15.
Biomed Res Int ; 2021: 6483860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055987

RESUMO

Mucosal healing comprises a key goal of ulcerative colitis (UC) treatment. Anterior gradient protein 2 (AGR2) plays an important role in maintaining intestinal homeostasis in UC. However, the role of AGR2 in the repair of mucosal injury is not yet clear. This study is aimed at investigating the expression of AGR2 in the intestinal tissues of children with UC and its role in repairing mucosal injury. Forty UC patients who were hospitalized in the Pediatric Gastroenterology Ward of Shengjing Hospital affiliated with China Medical University between July 1, 2013, and May 31, 2020, and 20 children who had normal colonoscopy results during the same period (control group) made up the study sample. The disease activity of UC was evaluated based on the pediatric ulcerative colitis activity index, and the ulcerative colitis endoscopic index was evaluated according to the Rachmilewitz score. Immunohistochemical staining was employed to examine the differences in AGR2 expression in the intestinal mucosa between groups. The protective effect of AGR2 in a model of tumor necrosis factor-alpha- (TNF-α-) induced intestinal mucosal barrier injury and the underlying molecular mechanism were explored through in vitro experiments. The results showed that compared with the normal control group, UC patients in the remission or active period had significantly higher expression of AGR2 in the intestine. AGR2 expression was positively correlated with Ki67, an intestinal epithelial cell proliferation marker, but negatively correlated with the degree of endoscopic mucosal injury. In an in vitro model, AGR2 overexpression promoted cell proliferation and migration and inhibited TNF-α-induced intestinal epithelial barrier damage by activating yes-associated protein (YAP). Collectively, our study suggests that AGR2 might serve as a valuable biomarker to help assess the condition and mucosal healing status of UC patients. In vitro, AGR2 promoted the repair of intestinal mucosal barrier injury by activating YAP.


Assuntos
Colite Ulcerativa/metabolismo , Mucosa Intestinal/metabolismo , Chaperonas Moleculares/metabolismo , Mucoproteínas/metabolismo , Proteínas Oncogênicas/metabolismo , Biomarcadores/metabolismo , Criança , China , Colonoscopia , Feminino , Humanos , Masculino , Mucoproteínas/genética , Proteínas Oncogênicas/genética , Fator de Necrose Tumoral alfa
16.
Carbohydr Polym ; 265: 118041, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33966825

RESUMO

Aloe polysaccharides (APs) are indigestible bioactive polysaccharides, while can be fermented by colonic microbiota. Although plant polysaccharides can alleviate subacute ulcerative colitis (SUC), the mechanisms APs regulated SUC via colonic microbiota have not been fully explored. Hence, to elucidate the complex interactions between the novel APs, colonic microbiota, SCFAs, and inflammation, the SUC mouse model and in-depth analysis were performed, including multiple bioinformatics analysis and structural equation modeling (SEM). After APs intervention, SCFAs and SCFAs-producing genus, including Akkermansia and Blautia, were increased in colon, and the colonic inflammation and barrier dysfunction were alleviated significantly in SUC mice. Spearman analysis found positive correlations between microbiota and SCFAs. PICRUSt2 and KEGG analysis revealed 6-pyruvoyltetra hydropterin synthase in folate biosynthesis metabolism pathway was activated, while phosphotransferase system was inhibited. SEM results further proved APs was beneficial to gut micro-ecological balance in mice via SCFAs metabolism and anti-inflammatory functions. Together, APs could be exploited to alleviate SUC as dietary therapeutics.


Assuntos
Aloe/química , Colite Ulcerativa/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Akkermansia/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Biologia Computacional/métodos , Sulfato de Dextrana/efeitos adversos , Ácidos Graxos Voláteis/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Análise de Classes Latentes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fósforo-Oxigênio Liases/metabolismo , Polissacarídeos/química
17.
Ann Clin Lab Sci ; 51(2): 245-254, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941565

RESUMO

OBJECTIVE: Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease. To date, the pathogenesis of UC has not been fully understood. This study aimed to identify crucial genes and related transcription factors in UC by bioinformatic methods. METHODS: Datasets GSE75214 and GSE48958 were used to identify the common differentially expressed genes (DEGs). GO and KEGG pathway enrichment analyses were performed using the STRING database. The protein-protein interaction (PPI) network was constructed to screen hub genes using the STRING database and Cytoscape software. The expressions of the identified hub genes were verified using dataset GSE73661, and their correlations with Mayo scores were analyzed using dataset GSE92415. The transcriptional factor (TF) regulatory network of the hubgenes was constructed by Network Analyst. RESULTS: A total of 147 common DEGs, including 114 up-regulated and 33 down-regulated genes, were screened out, among which CXCL9, TIMP1, PTGS2, ICAM1, CXCL1, MMP9, IL1B, CXCL8, and IL6 were identified as hub genes with high degrees in the PPI network. Correlation analysis showed that the expressions of these hub genes were significantly correlated with Mayo scores in UC patients. Finally, RELA, FLI1, and BACH1 were predicted to be the key TFs regulating these nine hub genes. CONCLUSIONS: This study systematically analyzed the differential gene expression pattern and associated key TFs in UC, which may provide new insights into the pathogenesis and offer opportunities for discovering novel biomarkers and therapeutic targets for UC.


Assuntos
Colite Ulcerativa/genética , Fatores de Transcrição/genética , Colite Ulcerativa/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Mapas de Interação de Proteínas/genética , Fatores de Transcrição/metabolismo
18.
Carbohydr Polym ; 263: 117998, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33858583

RESUMO

Herein, dual-bioresponsive of Rhein (RH) in promoting colonic mucous damage repair and controlling inflammatory reactions were combined by the dual-targeting (intestinal epithelial cells and macrophages) oral nano delivery strategy for effective therapy of ulcerative colitis (UC). Briefly, two carbohydrates, calcium pectinate (CP) and hyaluronic acid (HA) were used to modify lactoferrin (LF) nanoparticles (NPs) to encapsulate RH (CP/HA/RH-NPs). CP layer make CP/HA/RH-NPs more stable and protect against the destructive effects of the gastrointestinal environment and then release HA/RH-NPs to colon lesion site. Cellular uptake evaluation confirmed that NPs could specifically target and enhance the uptake rate via LF and HA ligands. in vivo experiments revealed that CP/HA/RH-NPs significantly alleviated inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway and accelerated colonic healing. Importantly, with the help of CP, this study was the first to attempt for LF as a targeting nanomaterial in UC treatment and offers a promising food-based nanodrug in anti-UC.


Assuntos
Antraquinonas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Ácido Hialurônico/química , Lactoferrina/química , Nanopartículas/química , Pectinas/química , Animais , Antraquinonas/química , Transporte Biológico , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Inibidores Enzimáticos/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/antagonistas & inibidores , Nanopartículas/uso terapêutico , Receptores de Superfície Celular/metabolismo , Proteínas de Junções Íntimas/metabolismo , Distribuição Tecidual , Receptor 4 Toll-Like/antagonistas & inibidores
19.
Life Sci ; 276: 119433, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794250

RESUMO

AIM: Ulcerative colitis (UC) is a common intestinal problem characterized by the diffusion of colon inflammation and immunity dysregulation. Nifuroxazide, a potent STAT-3 inhibitor, exhibits diverse pharmacological properties. The present study aimed to elucidate a novel anti-colitis mechanism of nifuroxazide against the acetic acid-induced UC model. METHODS: Rats were grouped into control (received vehicle), UC (2 ml of 5% acetic acid by intrarectal infusion), UC plus sulfasalazine (100 mg/kg/day, P.O.), UC plus nifuroxazide (25 mg/kg/day, P.O.), and UC plus nifuroxazide (50 mg/kg/day, P.O.) and lasted for 6 days. RESULTS: The present study revealed that nifuroxazide significantly reduced UC measures, hematological changes, and histological alteration. In addition, treatment with nifuroxazide significantly down-regulated serum CRP as well as the colonic expressions of MPO, IL-6, TNF-α, TLR-4, NF-κB-p65, JAK1, STAT-3, DKK1 in a dose-dependent manner. Besides, our results showed that the colonic Wnt expression was up-regulated with nifuroxazide treatment. In a dose-dependent manner, nifuroxazide markedly alleviated acetic acid-induced cellular infiltration and improved ulcer healing by increasing intestinal epithelial cell regeneration. SIGNIFICANCE: Our results collectively indicate that nifuroxazide is an effective anti-colitis agent through regulation of colon inflammation and proliferation via modulation IL-6/STAT-3/Wnt signaling pathway.


Assuntos
Ácido Acético/toxicidade , Colite Ulcerativa/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Interleucina-6/metabolismo , Nitrofuranos/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteína Wnt1/metabolismo , Animais , Antibacterianos/toxicidade , Anti-Infecciosos/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Modelos Animais de Doenças , Interleucina-6/genética , Masculino , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Proteína Wnt1/genética
20.
Ecotoxicol Environ Saf ; 215: 112161, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33812202

RESUMO

Recent studies have revealed that neutrophil extracellular traps (NETs) may contribute directly to the initiation of ulcerative colitis (UC), a typical inflammatory bowel disease (IBD) characterized by mucosal damage. Staphylococcal nuclease (SNase), a nonspecific phosphodiesterase, has a strong ability to degrade DNA. Here we investigate whether intestinal NET degradation with an oral preparation of SNase can ameliorate dextran sulfate sodium (DSS)-induced UC in mice. SNase encapsulated with calcium alginate (ALG-SNase) was formulated using crosslinking technology with sodium alginate and calcium chloride. ALG-SNase were orally administered to DSS-induced UC mice, and their therapeutic efficacy was evaluated. The expression of inflammatory cytokines and biomarkers of NETs was also assessed, as well as the intestinal permeability in mice. The results showed that ALG-SNase nanoparticles were successfully prepared and delivered to the colon of UC mice. In addition, oral administration of ALG-SNase nanoparticles decreased NET levels in the colon and effectively alleviated the clinical colitis index and tissue inflammation in UC mice. Moreover, the SNase nanoparticles reduced intestinal permeability and regulated the expression of proinflammatory cytokines. Furthermore, the markers of NETs were strongly correlated with the expression levels of tight junction proteins in colon tissue. In conclusion, our data showed that oral administration of ALG-SNase can effectively ameliorate colitis in UC mice via NET degradation and suggested SNase as a candidate therapy for the treatment of UC.


Assuntos
Armadilhas Extracelulares/metabolismo , Nuclease do Micrococo/administração & dosagem , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Intestinos , Masculino , Camundongos , Nuclease do Micrococo/metabolismo , Proteínas de Junções Íntimas/metabolismo
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