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1.
Life Sci ; 241: 117164, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838135

RESUMO

AIMS: This study was to assess whether andrographolide derivative (AL-1) could restore mucosal homeostasis and regulate tight junctions through MLCK-dependent pathway in DSS-induced colitis mice. MAIN METHODS: Colitis mice model was induced by daily administration of 2.5% DSS for seven days. The therapeutic effect was determined by evaluating the histopathological changes and the pro-inflammatory cytokine level. In addition, the effects of AL-1 on tight junctions were examined by immunohistochemistry and Western blot. The expressions of factors in MLCK-dependent pathway were evaluated by immunofluorescence and Western blot. KEY FINDINGS: AL-1 protected the intestinal barrier function in DSS-induced colitis mice. These protective effects were achieved by maintaining the normal mucus secretion and preserving tight junctions via suppression of the MLCK-dependent pathway. SIGNIFICANCE: AL-1 could prevent the increase in the DSS-induced intestinal permeability. These data indicated that AL-1 could be a promising agent for UC treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Permeabilidade da Membrana Celular/fisiologia , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Diterpenos/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia
2.
Life Sci ; 242: 117220, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881230

RESUMO

BACKGROUND/AIMS: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism. MAIN METHODS: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot. KEY FINDINGS: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways. SIGNIFICANCE: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Oligossacarídeos/uso terapêutico , Panteteína/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Panteteína/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
3.
Life Sci ; 238: 116968, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628914

RESUMO

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.


Assuntos
Biomarcadores/metabolismo , Carcinogênese/patologia , Colite/complicações , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Azoximetano/toxicidade , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
4.
Appl Microbiol Biotechnol ; 103(19): 7931-7941, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456001

RESUMO

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD) characterized by superficial mucosal inflammation, rectal bleeding, diarrhea, and abdominal pain. Anti-inflammatory and immunosuppressive drugs have been used in the therapy of human UC. Interleukin (IL)-35, which functions as an anti-inflammatory cytokine, has been shown to play a potential therapeutic role in a UC-like mouse colitis induced by dextran sodium sulfate (DSS). However, the contribution of IL-35 via oral administration to colitis prevention has not been determined. In order to explore its preventative potentiality, a dairy Lactococcus lactis NZ9000 strain was engineered to express murine IL-35 (NZ9000/IL-35), and this recombinant bacteria was applied to prevent and limit the development of DSS-induced mouse colitis. We found that oral administration of NZ9000/IL-35 induced the accumulation of IL-35 in the gut lumen of normal mice. When administrated preventatively, NZ9000/IL-35-gavaged mice exhibited decreased weight loss, DAI score, colon shortening as well as colitis-associated histopathological changes in colon, indicating that the oral administration of NZ9000/35 contributed to the suppression of DSS-induced colitis progression. Moreover, much less Th17 cells and higher level of Treg cells in lamina propria, as well as increased colon and serum levels of IL-10 with a concomitant reduced pro-inflammatory cytokines, IL-6, IL-17A, IFN-γ, and TNF-α were apparently regulated by NZ9000/IL-35 in colitis mice. Together, we put forward direct evidence pinpointing the effectiveness of NZ9000/IL-35 in preventing UC-like mouse colitis, implying a potential candidate of this recombinant Lactococcus lactis that prevent the progression of IBD.


Assuntos
Colite Ulcerativa/prevenção & controle , Fatores Imunológicos/metabolismo , Interleucinas/metabolismo , Lactococcus lactis/metabolismo , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fatores Imunológicos/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Lactococcus lactis/genética , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Resultado do Tratamento
5.
Toxicol Lett ; 315: 23-30, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442584

RESUMO

Ulcerative colitis2 (UC) is an inflammatory bowel disease3 (IBD) that causes long-lasting inflammation and ulcers in the human digestive tract. The repair function of TLR4 in the intestinal epithelium is still unknown. Here, wild-type4 (WT) mice, TLR4-knockout mice5 (KO; TLR4-/-) and commensal-depleted mice were used as dextran sulfate sodium6 (DSS)-induced or radiation-induced colitis and injury models to explore the role of TLR4 signaling in intestinal injury. Exogenous lipopolysaccharide7 (LPS) promoted DSS-induced inflammatory cytokines and aggravated intestinal damage. TLR4 deficiency and commensal bacterial depletion inhibited the toxic effects of LPS, but these mice were more susceptible to DSS-induced and radiation-induced intestinal damage. Compared with WT mice, neither DSS nor radiation promoted production of more inflammatory cytokines in the guts of TLR4-KO and commensal-depleted mice. Introducing the cytokine repair factors, PGE2 and GM-CSF, increased the cytokine levels in the guts of DSS-induced colitis mice. We hypothesized that TLR4 and its ligands repaired the epithelium after DSS-induced and radiation-induced intestinal damage by upregulating PGE2 and GM-CSF. Transwell migration assays suggested that LPS, IL6, TNF, PGE2 and GM-CSF promoted intestinal cell migration, and cell viability analysis suggested that these factors protected against radiation-induced intestinal damage. Our data underscore the importance of the balancing role of TLR4 in intestinal injury and repair.


Assuntos
Linhagem Celular/efeitos da radiação , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Receptor 4 Toll-Like/efeitos da radiação , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
6.
Mediators Inflamm ; 2019: 5195134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467484

RESUMO

It has been described that the metalloprotease BmooMP-alpha-I purified from Bothrops moojeni snake venom is able to hydrolyze the TNF molecule. However, this observation has been based mainly on in vitro investigation, in addition to molecular modeling and docking approaches. Considering that there is no in vivo study to demonstrate the biological effects of this enzyme, the major aim to the present work was to investigate whether the BmooMP-alpha-I has any anti-inflammatory efficacy by setting up a murine experimental design of colitis induced by dextran sulfate sodium (DSS). For this purpose, C57BL/6 mice were divided into six groups, as follows: (i) animals without intestinal inflammation, (ii) animals without intestinal inflammation treated with BmooMP-alpha-I (50 µg/animal/day), and (iii) animals with intestinal inflammation induced by 3% of DSS, (iv) mice with intestinal inflammation induced by DSS and treated with BmooMP-alpha-I enzyme at the 50, 25, or 12.5 µg/animal/day dosages by intraperitoneal route. Clinical signs of colitis were observed daily for calculating the morbidity scores, cytokine measurements, and histological features. We observed that the animals treated with different doses of the enzyme presented a remarkable improvement of colitis signs, as confirmed by a significant increase of the intestine length in comparison to the DSS group. Also, no difference was observed between the groups treated with the enzyme or vehicle, as the colon length of these animals was slightly lower than that of the group of healthy animals, without induction of intestinal inflammation. The cytokine quantification in supernatants of intestinal tissue homogenates showed a significant reduction of 38% in IFN-gamma levels, when the animals were treated with 50 µg of the BmooMP-alpha-I compared to the animals receiving DSS only. A significant reduction of 39% in TNF levels was also observed in all doses of treatment with BmooMP-alpha-I, in addition to a significant reduction of 35% in the amount of IL-12p40. Histological examinations revealed that the BmooMP-alpha-I 50 µg treated group preserved colon architecture and goblet cells and reduced the ulcer area, when compared with DSS mice, which showed typical inflammatory changes in tissue architecture, such as ulceration, crypt dilation, loss of tissue architecture, and goblet cell depletion, accompanied by a significant cell infiltration. In conclusion, our results suggest that the improvement of clinical scores and histological findings related to BmooMP-alpha-I treatment in this experimental model could be attributed to the metalloprotease ability to modulate cytokine production locally at the inflamed intestine. These findings highlight the potential anti-inflammatory role and effectiveness of this enzyme as a therapeutic alternative in this type of immunopathological condition.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Metaloendopeptidases/uso terapêutico , Animais , Bothrops , Colite/metabolismo , Citocinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
7.
Anticancer Res ; 39(8): 4207-4213, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366507

RESUMO

BACKGROUND/AIM: Oxaliplatin-induced chronic neuropathy is a prominent factor for dose reduction and not completing all cycles of chemotherapy for patients with colorectal cancer (CRC). The aim of the study was to investigate the pharmacokinetics and toxicodynamics of oxaliplatin-induced chronic neuropathy in CRC rats to ensure effective management. MATERIALS AND METHODS: A rat model of CRC was developed using 1,2-Dimethylhydrazine and dextran sulfate. Oxaliplatin (L-OHP) was administered intravenously to CRC rats every week. The pharmacokinetic profiles and tumor distribution of L-OHP and chronic neuropathies were investigated for over four weeks. RESULTS: The mean values of the area under the concentration-time curve for L-OHP showed a dose-dependent increase. Chronic neuropathy occurred from Day 14 in the 8 mg/kg group and Day 19 in the 3 and 5 mg/kg groups. CONCLUSION: These results provide preliminary information for the development of a pharmacokinetic and toxicodynamic model of L-OHP for CRC therapy cycles.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/patologia , 1,2-Dimetilidrazina/toxicidade , Animais , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Feminino , Humanos , Masculino , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacocinética , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos
8.
World J Gastroenterol ; 25(27): 3572-3589, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31367158

RESUMO

BACKGROUND: Mucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied. AIM: To document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis. METHODS: C57BL/6 male mice were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 d. They were euthanized 2 (day 7), 5 (day 10), 8 (day 13), and 23 (day 28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16S rRNA sequencing. RESULTS: The maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSS-treatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe (inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations (hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-ß, interleukin (Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction. CONCLUSION: This study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.


Assuntos
Colite Ulcerativa/imunologia , Colo/patologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/patologia , Regeneração/imunologia , Animais , Movimento Celular , Proliferação de Células , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/citologia , Colo/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , RNA Ribossômico 16S
9.
Chin Med J (Engl) ; 132(16): 1951-1958, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31335471

RESUMO

BACKGROUND: The effect and mechanism of Saccharomyces boulardii (Sb) in inflammatory bowel disease are unclear. The objective of the study was to evaluate the impact of Sb on intestinal mucosal barrier and intestinal flora in a colitis mouse model. METHODS: Forty C57BL/6J male mice were randomly assigned to five groups: normal control group (A), pathologic control group (B), Sb treatment group (C), mesalazine treatment group (D), and Sb combined with mesalazine treatment group (E). Colitis was induced by the addition of 2.5% (wt/vol) dextran sodium sulfate (DSS) in the drinking water ad libitum for 7 days. The general condition, weight change, stool property, and bloody stool level of mice were observed to evaluate the disease activity index. The expression of zona occludens-1 (ZO-1) and occludin in intestinal tissue were measured by immunohistochemistry. The level of tumor necrosis factor-α (TNF-α) and interleukin (IL)-8 in plasma was measured by enzyme linked immunosorbent assay. Inter-cellular tight junctions were observed by transmission electron microscopy. The feces and intestinal contents were collected sterilely, and intestinal flora was analyzed by 16S rRNA sequencing. RESULTS: Compared with group B, Sb reduced the disease activity index and histological score of group C (disease activity index: group B 2.708 ±â€Š0.628, group C 1.542 ±â€Š0.616, PBC = 0.005; histological score: group B 9.875 ±â€Š3.271, group C 4.750 ±â€Š1.832, PBC = 0.005) in DSS-induced colitis in mice. Sb exerted a protect effect on the expression of ZO-1 (group B 2.075 ±â€Š1.176, group C 4.225 ±â€Š1.316, PBC = 0.019) and occludin (group B 2.200 ±â€Š0.968, group C 3.525 ±â€Š1.047, PBC = 0.023). Compared with group B, Sb decreased the level of TNF-α and IL-8 of group C (TNF-α: group B 716.323 ±â€Š44.691 ng/L, group C 521.740 ±â€Š90.121 ng/L, PBC = 0.001; IL-8: group B 128.992 ±â€Š11.475 pg/mL, group C 106.283 ±â€Š15.906 pg/mL, PBC = 0.012). Treatment with Sb preserved the tight junctions and ameliorated microvilli and inter-cellular space. Treatment with Sb also showed its own characteristics: a higher percentage of Bacteroidetes and a lower percentage of Firmicutes, with significant differences or a significant trend. The proportion of the S24-7 family was increased significantly in the Sb treatment group. CONCLUSIONS: Sb shows an anti-inflammatory effect and has a protective effect on the intestinal mucosal mechanical barrier. Sb may up-regulate the abundance of family S24-7 specifically, and maybe a mechanism underlying its function.


Assuntos
Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/microbiologia , Saccharomyces boulardii/fisiologia , Animais , Colite/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocludina/metabolismo , Distribuição Aleatória , Proteína da Zônula de Oclusão-1/metabolismo
10.
Biomed Res Int ; 2019: 8020785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317039

RESUMO

The intestinal microbiome plays a crucial role in promoting intestinal health, and perturbations to its constitution may result in chronic intestinal inflammation and lead to colorectal cancer (CRC). α-Ketoglutarate is an important intermediary in the NF-κB-mediated inflammatory pathway that maintains intestinal homeostasis and prevents initiation of intestinal inflammation, a known precursor to carcinoma development. The objective of this study was to assess the potential protective effects of α-ketoglutarate intervention against CRC development, which may arise due to its known anti-inflammatory and antitumour effects. CRC was induced in C57BL/6 mice using azoxymethane (AOM) and dextran sulfate sodium (DSS). Tumour frequency, histological rating, and colonic microbiota were assessed in colonic samples. The findings demonstrated that α-ketoglutarate offered significant protection against CRC development in mice. Furthermore, α-ketoglutarate also exhibited immunomodulatory effects mediated via downregulation of interleukin (IL)-6, IL-22, tumour necrosis factor (TNF)-α, and IL-1ß cytokines. Finally, intervention with α-ketoglutarate tended to minimise the frequency of opportunistic pathogens (Escherichia and Enterococcus) while increasing the populations of Akkermansia, Butyricicoccus, Clostridium, and Ruminococcus. Taken together, our findings show that dietary α-ketoglutarate intervention may protect against inflammation-related CRC.


Assuntos
Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácidos Cetoglutáricos/farmacologia , Animais , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/microbiologia , Citocinas/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/microbiologia , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-6/genética , Interleucinas/genética , Camundongos , NF-kappa B/genética
11.
Phytomedicine ; 63: 153011, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301538

RESUMO

BACKGROUND: Ilexgenin A (IA), the main bioactive compound from Ilex hainanensis Merr., has significant hypolipidemic activities. However, the effects of IA on colitis-associated colorectal cancer (CRC) and its mechanisms are still unknown. PURPOSE: The study was designed to evaluate the effect of IA on CRC and explore its underlying mechanisms. STUDY DESIGN: The effect of IA on colitis related CRC were evaluated in azoxymethane (AOM)/dextran sulfate sodium (DSS) mice and the underlying mechanisms were revealed by metabolomics, which were further validated in vivo and in vitro. METHODS: The Balb/c mice were treated with AOM/DSS to induce CRC model and fed with normal diet with or without 0.02% IA. After the experimental period, samples of plasma were collected and analyzed by ultra-high-performance liquid chromatography/quadrupole time off light mass spectrometry (UHPLC-Q-TOF). Multivariate statistical tools were used to identify the changes of serum metabolites associated with CRC and responses to IA treatment. HT 29 and HCT 116 cells were stimulated by palmitate (PA) and cultured under hypoxia. Western blot, Q-PCR, and Immunofluorescence staining were performed to confirm the molecular pathway in vivo and in vitro. RESULTS: Our results showed IA significantly inhibited the inflammatory colitis symptoms such as disease activity index score, shortening of colon tissues and the increase of inflammatory cytokines. In metabolomic study, 31 potential metabolites associated with CRC were identified and 24 of them were reversed by IA treatment. Most of biomarkers were associated with arachidonic acid metabolism, glycerophospholipid catabolism, and phospholipid metabolism, suggesting lipid metabolism might be involved in the beneficial effect of IA on CRC. Furthermore, we also found IA could decrease the expressions of SREBP-1 and its target gene in the colon tissues of AOM/DSS mice. It could down-regulate the triglyceride (TG) content and the expressions of HIF1α, SREBP-1, FASN, and ACC in HT 29 and HCT 116 cells. The inhibitory effect of IA on SREBP-1 was also attenuated by desferrioxamine (DFX), suggesting HIF1α is involved in the regulation of IA on SREBP-1. CONCLUSION: IA prevents early colonic carcinogenesis in AOM/DSS mice and reprogramed lipid metabolism partly through HIF1α/SREBP-1.


Assuntos
Neoplasias Colorretais/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triterpenos/farmacologia , Animais , Anticarcinógenos/farmacologia , Azoximetano/toxicidade , Colite/induzido quimicamente , Colite/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/toxicidade , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , beta Catenina/genética
12.
Mediators Inflamm ; 2019: 6953963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275059

RESUMO

Mesenchymal stem cells (MSCs) exert powerful immunosuppression in inflammatory bowel disease (IBD). Macrophages are the dominant inflammatory cells in enteritis regulated via MSCs. However, the roles of macrophages in the process of MSCs attenuating IBD and the mechanisms of MSCs regulating macrophages are largely unknown. In this study, DSS- (dextran sulfate sodium salt-) induced IBD in macrophage-depleted models of CD11b-DTR mice was used to study the relationship between hucMSCs (human umbilical cord mesenchymal stromal cells) and macrophage. Body weights, disease activities, and pathological changes were documented to assess the therapeutic effects of hucMSCs. Furthermore, hucMSCs transfected with miR148b-5p mimics and miR148b-5p inhibitors were cocultured with LPS-induced RAW264.7 cells to investigate the role of miR148b-5p in hucMSC-regulated colitis. The outcome indicated that hucMSCs attenuated the IBD by downregulating 15-lox-1 expression in macrophages. Further findings pointed out that hucMSCs transfected with miR148b-5p mimics could be elevated to promote the tissue repair and inhibit the expression of 15-lox-1 but failed to perform the function of easing enteritis when treated with miR148b-5p inhibitors. In conclusions, we propose that hucMSCs attenuate IBD by releasing miR148b-5p to inhibit the expression of 15-lox-1 in macrophages.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Sulfato de Dextrana/toxicidade , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Animais , Araquidonato 15-Lipoxigenase/genética , Western Blotting , Imunofluorescência , Humanos , Inibidores de Lipoxigenase/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Células RAW 264.7 , Reação em Cadeia da Polimerase em Tempo Real
13.
Chin Med J (Engl) ; 132(15): 1833-1842, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31268903

RESUMO

BACKGROUND: Imbalance of intestinal microbiota was closely related to colitis. Under these circumstances, regulation of enteric flora may be beneficial to the repair of inflammation. We aimed to investigate the effects of probiotics (Bifidobacterium and Lactobacillus), prebiotics and their combination on inflammation, and microflora in mice of acute colitis. METHODS: C57BL/6J mice were divided into six groups randomly (blank control group, model control group, probiotics group, synbiotics group, lactitol group and probiotics + lactitol group). Each group was given 2.5% dextran sulfate sodium drinking water for 5 days other than the blank control group. Except for the model control group, the other four groups were intervened with probiotics, synbiotics (probiotics and inulin), lactitol, and probiotics + lactitol. Mice were sacrificed after 1 week of gavage, and pathologic scores were calculated. The feces of different periods and intestinal mucosa samples were collected to analyze the differences of intestinal microbiota by 16S rRNA sequencing. Differences of two groups or multiple groups were statistically examined through unpaired Student t test and analysis of variance (ANOVA), respectively. ANOVA, Tukey, Anosim, and metastats analysis were used to compare differences of microbiota among different groups. RESULTS: After gavage for 1 week, the pathologic scores of groups with the intervention were significantly lower than those in the model control group, and the difference was statistically significant (P < 0.05). The model control group was higher in the genus of Bacteroides (relative abundance: 0.3679 vs. 0.0099, P = 0.0016) and lower in Lactobacillus (relative abundance: 0.0020 vs. 0.0122, P = 0.0188), Roseburia (relative abundance: 0.0004 vs. 0.0109, P = 0.0157), compared with the blank control group. However, the same phenomenon was not found in groups gavaged with probiotics and lactitol. Compared with model control group, mice with intervention were increased with Bifidobacterium (relative abundance: 0.0172 vs. 0.0039, P = 0.0139), Lachnospiraceae_NK4A136_group (relative abundance: 0.1139 vs. 0.0320, P = 0.0344), Lachnospiraceae_UCG-006 (relative abundance: 0.0432 vs. 0.0054, P = 0.0454), and decreased with Alistipes (relative abundance: 0.0036 vs. 0.0105, P = 0.0207) in varying degrees. The mucosal flora was more abundant than the fecal flora, and genus of Mucispirillum (relative abundance: 0.0207 vs. 0.0001, P = 0.0034) was more common in the mucosa. Lactitol group showed higher level of Akkermansia than model control group (relative abundance: 0.0138 vs. 0.0055, P = 0.0415), probiotics group (relative abundance: 0.0138 vs. 0.0022, P = 0.0041), and synbiotics group (relative abundance: 0.0138 vs. 0.0011, P = 0.0034), while probiotics + lactitol group had more abundant Akkermansia than synbiotics group (relative abundance: 0.0215 vs. 0.0013, P = 0.0315). CONCLUSIONS: Probiotics and prebiotics reduce the degree of inflammation in acute colitis mice obviously. Mice with acute colitis show reduced beneficial genera and increased harmful genera. Supplementation of probiotics and prebiotics display the advantage of increasing the proportion of helpful bacteria and regulating the balance of intestinal microbiota. Lactitol might promote the proliferation of Akkermansia.


Assuntos
Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Prebióticos , Probióticos/farmacologia , Probióticos/uso terapêutico , Análise de Variância , Animais , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Microbioma Gastrointestinal/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Distribuição Aleatória , Álcoois Açúcares/farmacologia , Álcoois Açúcares/uso terapêutico
14.
World J Gastroenterol ; 25(21): 2603-2622, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210713

RESUMO

BACKGROUND: Given the complex pathogenesis of ulcerative colitis (UC), the conventional therapeutic methods are not fully curative. As a sort of systematic complementary and alternative medicine, traditional Chinese medicine (TCM) provides new options for the standard therapy. Nevertheless, there are still numerous problems with the promotion of TCM attributed to its complexity, and consequently, new research approaches are urgently needed. Thus, we explored the protective effects of Jian-Pi Qing-Chang (JPQC) decoction on UC based on systems pharmacology approach, which might fill the current innovation gap in drug discovery and clinical practice pertaining to TCM. AIM: To investigate the protective mechanisms of JPQC decoction on UC based on systems pharmacology approach. METHODS: We performed systems pharmacology to predict the active ingredients, the matched targets, and the potential pharmacological mechanism of JPQC on UC. In vivo, we explored the effects of JPQC in a colitis model induced by dextran sulfate sodium. In vitro, we adopted the bone marrow-derived macrophages (BMDMs) as well as BMDMs co-cultured with Caco2 cells to verify the underlying mechanisms and effects of JPQC on UC under TNF-α stimulation. RESULTS: Systems pharmacology revealed 170 targets for the 107 active ingredients of JPQC and 112 candidate targets of UC. Protein-protein interaction networks were established to identify the underlying therapeutic targets of JPQC on UC. Based on enrichment analyses, we proposed our hypothesis that JPQC might have a protective effect on UC via the NF-κB/HIF-1α signalling pathway. Subsequent experimental validation revealed that treatment with TNFα activated the NF-κB/HIF-1α signalling pathway in BMDMs, thereby damaging the epithelial barrier permeability in co-cultured Caco2 cells, while JPQC rescued this situation. The findings were also confirmed in a dextran sulfate sodium-induced colitis model. CONCLUSION: JPQC could improve the mucosal inflammatory response and intestinal epithelial barrier function via the NF-κB/HIF-1α signalling pathway, which provides new perspectives on the pharmaceutical development and clinical practice of TCM.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Biologia de Sistemas , Animais , Células CACO-2 , Técnicas de Cocultura , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Descoberta de Drogas , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Macrófagos , Camundongos , NF-kappa B/imunologia , NF-kappa B/metabolismo , Cultura Primária de Células , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
EBioMedicine ; 45: 495-510, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253515

RESUMO

BACKGROUND: Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis. METHODS: Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry. FINDINGS: TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80+α7nAChR+ macrophages in wild type mice suggest CAIP activation. INTERPRETATION: These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.


Assuntos
Colite/terapia , Inflamação/terapia , Doenças Inflamatórias Intestinais/terapia , Terapia por Ultrassom , Animais , Colite/induzido quimicamente , Colite/patologia , Citocinas/genética , Citocinas/efeitos da radiação , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Macrófagos/efeitos da radiação , Camundongos , Camundongos Knockout , Peroxidase/química , Proteômica , Receptor Nicotínico de Acetilcolina alfa7/genética
16.
Nat Commun ; 10(1): 2427, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160593

RESUMO

Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.


Assuntos
Colite/imunologia , Colo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Doenças Inflamatórias Intestinais/imunologia , Células Supressoras Mieloides/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/etiologia , Sulfato de Dextrana/toxicidade , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Hematopoéticas/citologia , Código das Histonas , Histonas/metabolismo , Técnicas In Vitro , Indazóis/farmacologia , Indóis/farmacologia , Metilação , Camundongos , Células Supressoras Mieloides/citologia , Piridonas/farmacologia
17.
Poult Sci ; 98(10): 4449-4456, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162611

RESUMO

Butyric acid is a beneficial feed additive used in animal production, including poultry production. However, there are few reports on butyric acid as a prophylactic treatment against intestinal inflammation in broilers. The current study explored the effect of sodium butyrate (SB) as a prophylactic treatment on the intestinal health and gut microbiota of broilers with intestinal inflammation induced by dextran sulfate sodium (DSS) by monitoring changes in intestinal histopathology, gut leakiness indicators, inflammatory cytokines, and gut microbiota composition. Sodium butyrate supplementation prior to DSS administration significantly reduced the lesion scores of intestinal bleeding (P < 0.05) and increased villus height and the total mucosa of the ileum (P < 0.05). Regardless of intestinal inflammation, supplementation with SB at 300 mg/kg significantly decreased the levels of D (-)-lactate (P < 0.05), interleukin-6, and interleukin-1ß (P < 0.05) but increased the level of interleukin-10 (P < 0.05). The SB treatment did not affect the alpha diversity of intestinal microbiota during intestinal inflammation progression but altered their composition, and the microbial community structure of treated broilers was similar to that of control broilers. Taken together, our results reveal the importance of SB in improving intestinal development, inducing an anti-inflammatory effect during intestinal inflammation progression, and modulating the microbial community in broilers. Sodium butyrate seems to be optimized for anti-inflammatory effects at higher doses (300 mg/kg SB).


Assuntos
Anti-Inflamatórios/farmacologia , Ácido Butírico/farmacologia , Galinhas , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Intestinos/fisiologia , Doenças das Aves Domésticas/tratamento farmacológico , Ração Animal/análise , Animais , Anti-Inflamatórios/administração & dosagem , Ácido Butírico/administração & dosagem , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/imunologia , Sulfato de Dextrana/toxicidade , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Feminino , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/veterinária , Doenças das Aves Domésticas/induzido quimicamente , Doenças das Aves Domésticas/imunologia
18.
J Biomed Sci ; 26(1): 46, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189465

RESUMO

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) is highly expressed on macrophages in inflamed intestines and reportedly promotes inflammatory bowel disease (IBD) by augmenting pro-inflammatory responses. To study the mechanism mediated by TREM-1 on macrophages, we generated an independent TREM-1 deficient mouse. METHODS: Acute colitis was induced in C57BL/6 and TREM-1-deficient mice by the administration of dextran sodium sulfate (DSS). Colonic lamina propria immune cell composition and cytokines were analyzed. An innate lymphoid cell (ILC) co-culture experiment with macrophages was used to analyze IL-22 levels. Exogenous IL-22 and TREM-1-expressing macrophages were supplied to TREM-1-deficient mice for examining their effects on intestinal barrier integrity. RESULTS: In inflamed colons, TREM-1 loss compromised the activation of ILC3 and their production of IL-22, which is required for intestinal barrier integrity. ILC3-mediated IL-22 production depends on IL-1ß secreted by M1-polarized macrophages, and we found that TREM-1 deficiency results in a decreased number of IL-1ß producing-M1 macrophages in colons exposed to DSS. Accordingly, DSS-mediated damage was ameliorated by supplying exogenous IL-22 and TREM-1-expressing macrophages to TREM-1-deficient mice. CONCLUSIONS: TREM-1 plays a crucial role in regulating IL-22 production by ILC3 through modulating M1-macrophage polarization during DSS-induced acute colitis.


Assuntos
Colite/patologia , Interleucinas/metabolismo , Mucosa Intestinal/fisiologia , Linfócitos/imunologia , Macrófagos/fisiologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Colite/induzido quimicamente , Colite/fisiopatologia , Sulfato de Dextrana/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout
19.
Nat Microbiol ; 4(10): 1737-1749, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182797

RESUMO

Products derived from bacterial members of the gut microbiota evoke immune signalling pathways of the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. We recently demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities following depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and interleukin (IL)-22-producing innate lymphoid cells, which in turn promote pSTAT3 signalling in intestinal epithelial cells and protection from intestinal injury. In addition, we demonstrate that MNV provides a striking IL-22-dependent protection against early-life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.


Assuntos
Microbioma Gastrointestinal/imunologia , Interferon Tipo I/metabolismo , Interleucinas/metabolismo , Intestinos/imunologia , Intestinos/virologia , Animais , Antibacterianos/toxicidade , Proliferação de Células , Citrobacter rodentium/fisiologia , Colo/citologia , Colo/imunologia , Colo/metabolismo , Colo/virologia , Sulfato de Dextrana/toxicidade , Infecções por Enterobacteriaceae/prevenção & controle , Interleucinas/genética , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Norovirus/imunologia , Norovirus/fisiologia , Transdução de Sinais/genética , Organismos Livres de Patógenos Específicos , Proteínas não Estruturais Virais/genética , Replicação Viral
20.
PLoS One ; 14(5): e0217642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141554

RESUMO

BACKGROUND AND AIM: Various drugs have been developed for inflammatory bowel disease (IBD), but still there are limitations in the treatment due to the insufficient responses and significant adverse effects of immunosuppressant. Apocynin is an NADPH-oxidase inhibitor with established safety profiles. We aimed to investigate the protective efficacy of apocynin in IBD using chemical-induced mouse colitis model. METHOD: We induced experimental colitis by administrating 5% dextran sulfate sodium (DSS) to 8-week old BALB/c mouse for 11 days. Apocynin (400 mg/kg) or sulfasalazine (150 mg/kg) were administeredduring7 days. We monitored bodyweight daily and harvested colon and spleen at day 11 to check weight and length. We also examined histopathologic change and pro-, anti-inflammatory cytokines and enzymes from harvested colons (iNOS, COX-2, TNF-α, MCP-1, p-NrF2, and HO-1). RESULT: Apocynin significantly alleviated weight reduction induced by DSS treatment (21.64 ± 0.55 for Apocynin group vs. 20.33 ± 0.90 for DSS group, p = 0.005). Anti-inflammatory efficacy of apocynin was also shown by the recovery of colon weight and length. Histopathologic examination revealed significantly reduced inflammatory foci and erosions by apocynin treatment. Colonic expression of iNOS, COX-2, TNF-α, and MCP-1 was decreased significantly in the apocynin treated group. Anti-inflammatory mediators Nrf2 and HO-1 were activated significantly in apocynin treated mouse. CONCLUSION: Apocynin showed significant anti-inflammatory efficacy against chemically induced colonic inflammation. This study also revealed the unique action of apocynin compared to the currently prescribed drug, sulfasalazine. Given its excellent safety profile and potent efficacy with novel action mechanism, apocynin can be a new therapeutic molecule for the IBD treatment, which can be added to the currently available drugs.


Assuntos
Acetofenonas/farmacologia , Colite/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/farmacologia , Camundongos
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