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1.
J Sep Sci ; 44(10): 2065-2077, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33719176

RESUMO

Si Shen Wan is a classic traditional Chinese medicine formula, which has been used to treat chronic colitis for thousands of years. Many research and experience show that Si Shen Wan was developed by the combination of two sets of "Herb Pairs," Er Shen Wan and Fructus Schisandrae Chinensis Powder. This research aimed to revealing the effective substances, guide the clinical treatment, and represent the synergy effects from the view of pharmacokinetics. An ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for simultaneous quantification of 26 main bioactive compounds in normal and colitis rat plasma after oral administration of Si Shen Wan and its "Herb Pairs" extract. The method validation results illustrated that the experimental method was reliable and reproducible for quantitative determination of the biological samples. The pharmacokinetic behaviors in different groups were compared and discussed comprehensively, which indicated that the treatment of Si Shen Wan has a superiority in synthetic action of the "Herb Pairs" for the higher peak concentrations and bioavailability of some mainly components. Furthermore, the synergy effect was still existing backed up again for the longer eliminate time and a better bioavailability in colitis groups. The pharmacokinetics research of multiple components in Si Shen Wan and its "Herb Pairs" supplied a significant basis for better understanding the metabolic mechanism of these formulas in both normal and pathological state.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Colite/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Colite/sangue , Humanos , Masculino , Plasma/química , Ratos , Ratos Sprague-Dawley
2.
Cells ; 10(1)2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33418977

RESUMO

Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.


Assuntos
Colite/induzido quimicamente , DNA/metabolismo , Espaço Extracelular/metabolismo , Inflamação/patologia , Intestinos/patologia , Animais , Biomarcadores/metabolismo , Colite/sangue , Colite/patologia , DNA/sangue , DNA Mitocondrial/sangue , Desoxirribonucleases/metabolismo , Sulfato de Dextrana , Endoscopia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Inflamação/sangue , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ornitina/análogos & derivados , Ornitina/farmacologia , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Índice de Gravidade de Doença , Estreptonigrina/farmacologia
3.
Mediators Inflamm ; 2020: 6020247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029104

RESUMO

Liver disorder often occurs in patients with inflammatory bowel disease (IBD); however, the changes in IBD-induced liver disorder at the intrinsic molecular level (chiefly metabolites) and therapeutic targets are still poorly characterized. First, a refined and translationally relevant model of DSS chronic colitis in C57BL/6 mice was established, and cecropin A and antibiotics were used as interventions. We found that the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in the liver tissues of mice were highly increased in the context of DSS treatment but were lowered by cecropin A and antibiotics. Subsequently, an untargeted metabolomics analysis was performed by UPLC-Orbitrap-MS/MS to reveal the metabolic profile and attempt to find the potential therapeutic targets of the liver disorders that occur in IBD. Notably, 133 metabolites were identified by an integrated database. Metabolism network and pathway analyses demonstrated that the metabolic disturbance of the liver in IBD mice was mainly enriched in bile acid metabolism, arachidonic acid metabolism, amino acid metabolism, and steroid hormone biosynthesis, while those disturbances were regulated or reversed through cecropin A and antibiotic treatment. Furthermore, the top 20 metabolites, such as glutathione, maltose, arachidonic acid, and thiamine, were screened as biomarkers via one-way analysis of variance (one-way ANOVA, p < 0.05) coupled with variable importance for project values (VIP >1) of orthogonal partial least-squares discriminant analysis (OPLS-DA), which could be upregulated or downregulated with the cecropin A and antibiotics treatment. Spearman correlation analysis showed that the majority of the biomarkers have a significant correlation with cytokines (TNF-α, IL-1ß, IL-6, and IL-10), indicating that those biomarkers may act as potential targets to interact directly or indirectly with cecropin A and antibiotics to affect liver inflammation. Collectively, our results extend the understanding of the molecular alteration of liver disorders occurring in IBD and offer an opportunity for discovering potential therapeutic targets in the IBD process.


Assuntos
Biomarcadores/sangue , Sulfato de Dextrana/toxicidade , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Colite/sangue , Colite/induzido quimicamente , Ensaio de Imunoadsorção Enzimática , Gentamicinas/uso terapêutico , Interleucina-10/sangue , Interleucina-6/sangue , Análise dos Mínimos Quadrados , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/sangue
4.
Cytokine ; 133: 155181, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32604005

RESUMO

Trefoil factor 3 (TFF3) is a small peptide secreted mainly by goblet cells in the gut, where it plays a key role in gastrointestinal defence and repair. Plasma TFF3 has been reported as a biomarker of intestinal injury and as such it has been evaluated as a marker of disease activity in colitis. Impaired gut barrier function has been postulated as the "motor" of critical illness. We here sought to determine the temporal dynamics of plasma TFF3 in adult patients admitted to intensive care unit with abdominal sepsis or after major abdominal surgery for a non-infectious condition (post-op GI patients). TFF3 was measured in plasma obtained from 143 patients with abdominal sepsis and 98 post-op GI patients on admission to the intensive care (day 0) and at days 2 and 4 thereafter. Abdominal sepsis patients showed sustained elevated plasma TFF3 levels from day 0 to 4 relative to healthy control values, while in post-op GI patients admission TFF3 levels were not increased, only rising at day 2 and 4. In both patient groups, the presence of shock was associated with higher TFF3 levels. Moreover, patients with 3 or more organs failing had higher plasma TFF3 concentrations. While plasma TFF3 was higher in sepsis patients who did not survive until day 30, TFF3 levels were not independently associated with 30-day mortality in a Cox regression analysis. These results could support the theory that intestinal injury contributes to the pathogenesis of critical illness. Future studies are needed to elucidate whether the proposed gut dysfunction precedes or supersedes organ dysfunction in time.


Assuntos
Abdome/patologia , Gastroenteropatias/sangue , Plasma/metabolismo , Sepse/sangue , Sepse/metabolismo , Fator Trefoil-3/sangue , Colite/sangue , Colite/metabolismo , Colite/patologia , Estado Terminal , Feminino , Gastroenteropatias/metabolismo , Gastroenteropatias/patologia , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Peptídeos/metabolismo , Estudos Prospectivos , Sepse/patologia
5.
Eur Rev Med Pharmacol Sci ; 24(13): 7345-7356, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706073

RESUMO

OBJECTIVE: To explore the effects of IFNG-AS1 and ANRIL on intestinal epithelial cells and their relationship with colitis. PATIENTS AND METHODS: From May 2017 to May 2019, 118 colitis patients admitted to our hospital were selected as the research group (RG), and 124 healthy controls were selected as the control group (CG). In addition, the normal intestinal epithelial cells HIEC and HIEC-6 were purchased to detect the IFNG-AS1 and ANRIL in the peripheral blood of patients in the two groups, and the effects of IFNG-AS1 and ANRIL on the intestinal epithelial cells were analyzed. RESULTS: IFNG-AS1 and ANRIL were highly expressed in colitis (p<0.050), and their combined detection had good diagnostic value for the occurrence of colitis and complications (p<0.050). In intestinal epithelial cells transfected with IFNG-AS1 and ANRIL, it was found that inhibition of IFNG-AS1 and ANRIL remarkably increased the proliferation and decreased the apoptosis of intestinal epithelial cells (p<0.050). CONCLUSIONS: IFNG-AS1 and ANRIL are highly expressed in colitis, and inhibiting their expression can promote the proliferation of intestinal epithelial cells and reduce apoptosis, which may be potential therapeutic targets for Crohn's colitis in the future.


Assuntos
Colite/metabolismo , Mucosa Intestinal/metabolismo , RNA Longo não Codificante/metabolismo , Adulto , Apoptose , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Colite/sangue , Colite/genética , Colite/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética
6.
Acta Cir Bras ; 35(4): e202000404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555936

RESUMO

PURPOSE: To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. METHODS: A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. RESULTS: Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). CONCLUSION: The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Calcitriol/uso terapêutico , Colite/tratamento farmacológico , Doença Aguda , Animais , Proteína C-Reativa/análise , Colite/sangue , Colite/patologia , Modelos Animais de Doenças , Peroxidação de Lipídeos , Masculino , Malondialdeído/sangue , Estresse Oxidativo/genética , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Componente Amiloide P Sérico/análise , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
7.
Biochim Biophys Acta Gen Subj ; 1864(10): 129668, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32553689

RESUMO

BACKGROUND: Alternative glycosylation of serum IgG has been shown to be closely associated with colorectal cancer (CRC). Currently, a dynamic study which can not only minimize the influence of genetic background, environment and other interfering factors during cancer development, but also focus on investigating carcinogenic characteristics of IgG glycan is lacking. METHODS: Serum IgG N-glycans were characterized at four stages of CRC development by ultra-performance liquid chromatography in a typical colitis-related CRC mouse model induced by azoxymethane-dextran sodium sulfate. Furthermore, the expression of related glycosyltransferases in splenic B lymphocytes at the corresponding time was also assessed. RESULTS: The relative abundance of seven IgG glycans, which can be classified as monoantennary, core fucose, sialic acid, galactose and bisecting, was changed during tumor growth. The abundance of some glycans was altered during the first stage of cancer induction. Correspondingly, the expression of glycosyltransferases in splenic B lymphocytes and different tissues in cancer groups was also decreased compared to that in controls. CONCLUSIONS: This study represents the comprehensive analysis of IgG glycosylation in the dynamic process of colitis-associated CRC. To our knowledge, this is the first report that the expression of glycosyltransferases in mouse splenic B lymphocytes is consistent or inconsistent with the alterations of IgG N-glycans, and the variation tendency is tissue nonspecific. GENERAL SIGNIFICANCE: Providing a novel approach to identify the IgG glycans related to the development of CRC and laying a foundation for research on structure and function of glycans using mouse.


Assuntos
Colite/sangue , Neoplasias Colorretais/sangue , Imunoglobulina G/sangue , Polissacarídeos/análise , Animais , Colite/complicações , Colite/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Glicômica , Glicosilação , Imunoglobulina G/análise , Camundongos , Polissacarídeos/sangue
8.
J Agric Food Chem ; 68(29): 7641-7647, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32594738

RESUMO

Dietary intake of linoleic acid (LA, 18:2ω-6) has risen dramatically in recent decades. Previous studies have suggested a high intake of LA could increase tissue concentrations of proinflammatory and protumorigenic ω-6-series eicosanoid metabolites, increasing risks of inflammation and associated diseases. However, the effects of a LA-rich diet on in vivo profiles of eicosanoids and development of inflammatory diseases are understudied. Here, we treated spontaneous colitis-prone (Il-10-/-) mice with a control diet (∼3 Cal% LA) or a LA-rich diet (∼9 Cal% LA) for 18 weeks and analyzed the effects of the LA-rich diet on profiles of eicosanoids and development of colitis. We found that treatment with the LA-rich diet increased the tissue level of LA: the liver levels of LA were 5.8 ± 0.6% in the control diet-treated mice versus 11.7 ± 0.7% in the LA-rich diet-treated mice (P < 0.01). The plasma concentrations of a series of LA-derived metabolites, including 9-hydroxyoctadecadienoic acid (HODE), 9,10-dihydroxyoctadecenoic acid (DiHOME), 12,13-DiHOME, and 13-HODE were significantly increased by treatment with the LA-rich diet (P < 0.05). However, the LA-rich diet had little effect on the severity of colitis in the treated Il-10-/- mice. These results suggest a limited role of increased consumption of dietary LA on promoting colitis in the Il-10-/- model.


Assuntos
Colite/sangue , Colite/dietoterapia , Eicosanoides/sangue , Interleucina-10/deficiência , Ácido Linoleico/metabolismo , Animais , Colite/genética , Humanos , Interleucina-10/genética , Ácido Linoleico/química , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout
9.
Int Immunopharmacol ; 85: 106610, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32473571

RESUMO

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) are the major risk factor for developing colitis associated cancer (CAC). Previously, we have reported that Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was overexpressed in colorectal cancer (CRC), but we don't know the role of PIK3R3 in IBD. METHODS: We investigated the differential expression of PIK3R3 and ZO-1 in IBD patients by using Immunohistochemical (IHC) and Gene Expression Omnibus (GEO) database analysis. Caco-2 cells were exposed to different conditions to assess protein level changes of PIK3R3 and ZO-1. Caco-2 cell monolayers were transfected with PIK3R3/siPIK3R3 to assess transepithelial electrical resistance. Tight junction protein integrity was assessed by immunoblot and immunofluorescence. For further, intestinal permeability and tight junction protein integrity were assessed in animal study to assess the treatment role of PIK3R3 specific inhibitor TAT-N 15 (N15). RESULTS: PIK3R3 was increased in IBD patients, and negatively controlled the expression of ZO-1. In vitro, PIK3R3 regulates ZO-1 by activating NF-kB pathway. Overexpression of PIK3R3 in Caco-2 cells decreased transepithelial electrical resistance (TEER), an opposite result was observed in siPIK3R3 cells. In animal study, inhibition of PIK3R3 by N15 contributed to amelioration of DSS-induced intestinal permeability. Mice treated with N15 exhibited less disruption of TJs in colon tissues. CONCLUSIONS: PIK3R3 was increased in clinical IBD patients with accompanying disruption of ZO-1 expression. Inhibition of PIK3R3 attenuated DSS-induced IBD symptoms in a mouse model. These findings indicated that PIK3R3 could be a therapeutic target for IBD.


Assuntos
Doenças Inflamatórias Intestinais/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Células CACO-2 , Colite/sangue , Colite/induzido quimicamente , Colite/imunologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Ácidos Sulfônicos/administração & dosagem , Ácidos Sulfônicos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
10.
Neurogastroenterol Motil ; 32(6): e13825, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32115817

RESUMO

BACKGROUND: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms. METHODS: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz-210 µs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed. KEY RESULTS: Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION & INFERENCES: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function.


Assuntos
Colite/prevenção & controle , Terapia por Estimulação Elétrica/métodos , Plexo Lombossacral/fisiologia , Animais , Colite/sangue , Citocinas/sangue , Masculino , Norepinefrina/sangue , Polipeptídeo Pancreático/sangue , Ratos Sprague-Dawley
11.
Int J Biol Macromol ; 149: 1252-1261, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035958

RESUMO

The aim of this study is to investigate whether Flammuliana Velutipes Polysaccharide (FVP) could aid in the prevention of colitis. Effect of FVP on colitis was evaluated using dextran sulfate sodium (DSS)-induced colitis in rats. Influence of FVP on the expression of inflammation related biomarkers and signal pathway element of TLR4\NF-κB were assessed. The composition and taxonomy of colonic microbiota were analyzed by 16S rDNA high throughput sequencing, and the concentrations of caecal short fatty chain acids were assessed by chromatography-mass spectrometry. Our results showed that FVP treatment could regulate the colonic microbial dysbiosis and promote the levels of caecal short fatty chain acids, leading to down-regulation of TLR4\NF-κB signal pathway, which finally ameliorate the colitis. Thus, the present study is the first attempt to elucidate the effect of FVP on colitis and support the potential application of FVP as a functional food ingredient or preventive drugs for colitis.


Assuntos
Colite/tratamento farmacológico , Colite/microbiologia , Colo/patologia , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Flammulina/química , Inflamação/tratamento farmacológico , Polissacarídeos/uso terapêutico , Amina Oxidase (contendo Cobre)/sangue , Animais , Ceco/química , Colite/sangue , Colite/complicações , Colo/microbiologia , Sulfato de Dextrana , Disbiose/sangue , Disbiose/complicações , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/sangue , Inflamação/complicações , Mucosa Intestinal/patologia , Masculino , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Polissacarídeos/farmacologia , Análise de Componente Principal , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Receptores Toll-Like/metabolismo
12.
Int J Biol Macromol ; 149: 1180-1188, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014479

RESUMO

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology with increasing incidence world widely. Previous studies have indicated that the α-D-glucan YCP purified from the mycelium of the marine fungus Phoma herbarum YS4108 had certain immunomodulatory activities in animal and cell models. In the study, the therapeutic effect and intestinal regulatory activity of YCP (40 mg/kg, intraperitoneal injection) on UC were investigated in dextran sulfate sodium (DSS)-induced colitis mice. The results showed YCP could improve the general symptoms, reestablish the intestinal immune balance, and repair the mucosal barrier in colitis mice. The administration of YCP also significantly increased butyrate and isovaleric acid levels. In addition, YCP resulted in prominent alterations on specific microbiota including Firmicutes, Bacteroidetes, Proteobacteria, Clostridiales, and Lachnospiraceae which are closely related to immune regulation and mucus repair. Therefore, YCP may be a candidate for curing UC because of its conspicuous effects comparable to 5-aminosalicylic acid (5-ASA).


Assuntos
Organismos Aquáticos/química , Ascomicetos/química , Colite/tratamento farmacológico , Glucanos/uso terapêutico , Homeostase , Mucosa Intestinal/patologia , Animais , Colite/sangue , Colite/microbiologia , Colite/patologia , Citocinas/sangue , Ácidos Graxos/metabolismo , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Glucanos/farmacologia , Mediadores da Inflamação/sangue , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Filogenia
13.
Toxicol Mech Methods ; 30(2): 107-114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31532267

RESUMO

In standard nonclinical drug safety evaluation studies, limitations exist in predicting the clinical risk of a drug based only on data from healthy animals. To obtain more comprehensive toxicological information on norisoboldine (NOR), we conducted an exploratory study using C57BL/6 mice in addition to healthy mice as models of dextran sodium sulfate (DSS) colitis to evaluate the safety of NOR. The healthy mice and DSS colitis mice were exposed to 30 or 90 mg NOR/kg body weight or water for 15 days. Compared with the model control group, 90 mg/kg of NOR aggravated the symptoms and colonic lesions of the DSS colitis mice and even caused death in two animals. No significant adverse effects were observed in the healthy mice. These different toxic reactions to NOR in the healthy and DSS colitis mice indicate that NOR toxicity varies by status among animals and suggests that the DSS colitis mouse model may be more susceptible, accurate and comprehensive in evaluating the safety of NOR. In conclusion, 90 mg/kg of NOR may be safe for healthy mice but not for DSS colitis mice. The DSS colitis mouse model, with many features similar to those of human colitis patients, may be a novel choice to counteract the deficiencies of using healthy mice to evaluate the safety of anti-inflammatory bowel disease (IBD) drugs, and further research is required.


Assuntos
Alcaloides/toxicidade , Colite/induzido quimicamente , Colo/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Colite/sangue , Colite/patologia , Colo/imunologia , Colo/patologia , Relação Dose-Resposta a Droga , Marcação In Situ das Extremidades Cortadas , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Análise de Sobrevida
14.
Gut ; 69(3): 578-590, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31792136

RESUMO

OBJECTIVE: The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. DESIGN: To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. RESULTS: As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn's disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. CONCLUSIONS: Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. TRIAL REGISTRATION NUMBER: NCT02749630.


Assuntos
Colite/genética , Doença de Crohn/fisiopatologia , Estresse do Retículo Endoplasmático/genética , Células Epiteliais/fisiologia , Interleucinas/farmacologia , Transcrição Genética , Animais , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Doença Crônica , Colite/sangue , Colite/tratamento farmacológico , Colite/patologia , Colo/patologia , Doença de Crohn/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Interleucina-17/farmacologia , Interleucina-23/antagonistas & inibidores , Interleucinas/sangue , Interleucinas/genética , Mucosa Intestinal/patologia , Camundongos , Organoides , Gravidade do Paciente , Fenilbutiratos/farmacologia , Proteínas Recombinantes/farmacologia , Transcrição Genética/efeitos dos fármacos , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas , Ustekinumab/farmacologia , Ustekinumab/uso terapêutico
15.
Oxid Med Cell Longev ; 2019: 6138723, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687082

RESUMO

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-κB p65 and IκBα, downregulated the expression of iNOS and COX-2, and attenuated the expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), ERK, and JNK. In conclusion, AL-1 alleviated DSS-induced murine colitis by inhibiting activation of the NF-κB and MAPK signaling pathways. Our data suggest that AL-1 could be a potential new treatment for UC.


Assuntos
Colite/tratamento farmacológico , Colite/enzimologia , Diterpenos/uso terapêutico , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Colite/sangue , Colite/induzido quimicamente , Citocinas/sangue , Sulfato de Dextrana , Modelos Animais de Doenças , Diterpenos/farmacologia , Feminino , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/sangue , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
16.
J Ethnopharmacol ; 245: 112186, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31472273

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived mainly from plants that exhibit anti-inflammatory and antitumor activities being one of the key mechanism of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- α. AIM OF THE STUDY: The overall objective of the present study was to evaluate the anti-inflammatory action of a sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. and parthenolide (PTH) in Balb-c mice with DSS-induced colitis. MATERIALS AND METHODS: The anti-inflammatory effects of Intraperitonial administration of DPC (5 mg/kg/day) were evaluated in Balb/c mice with DSS-induced colitis, and further the body weight measurement, TNF-α and TGF-ß level was determined. RESULTS: After intraperitoneal treatment for one week, DSS-induced colitis was significantly reduced in mice treated with either of both sesquiterpenes lactones, as witnessed by reduced cellular infiltration, tissue damage, TNF-α production, and enhanced production of TGF-ß. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed anti-inflammatory activity, in this experimental model of colitis the sesquiterpene lactones DPC and PTH exhibit equal anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Lactonas/uso terapêutico , Sesquiterpenos/uso terapêutico , Vernonia , Animais , Colite/sangue , Colite/induzido quimicamente , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Sulfato de Dextrana , Flores , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos BALB C , Folhas de Planta , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
17.
J Transl Med ; 17(1): 253, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387598

RESUMO

BACKGROUND: Noninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored. Inflammation is known to play an important role in the tumor microenvironment of CRC. Therefore, the aim of this study was to elucidate novel inflammatory biomarkers related to early diagnosis and prognosis of CRC. METHODS: Based on the results from a multiplex assay and a pan-cancer screening of TCGA data with 18 cancer types, we identified several targeted biomarkers. We further confirmed these results using a trial cohort of 112 CRC patients and 151 controls (59 healthy donors, 52 colitis and 40 colorectal adenoma patients) by Elisa and immunohistochemistry (IHC). The biomarkers expression levels in CRC patients of different clinical stages were compared. The targeted biomarkers panel was developed using logistic regression model and was then validated using an independent cohort including 75 CRC patients and 90 controls (35 healthy donors, 20 colitis and 35 colorectal adenoma patients). Diagnostic accuracy was evaluated using area under the receiver-operating characteristic (ROC) curve and overall survival analysis was used for prognosis. Gene ontology (GO) analyses and Gene set enrichment analyses (GSEA) were performed to predict the function of the candidate biomarkers. RESULTS: CCL20 and IL-17A were identified as candidate biomarkers using multiplex assay and pan-cancer screening of TCGA data. Elisa and IHC demonstrated that both CCL20 and IL-17A levels were highly expressed in CRC patients, more especially in patients with advanced stage disease. A signature expression of the two biomarkers showed high diagnostic accuracy of CRC. Importantly, the diagnostic sensitivity and specificity were still satisfactory in the early stage and low carcinoembryonic antigen (CEA) level groups. Bioinformatics analysis revealed that CCL20 and IL-17A may be involved in CRC progression. In addition, the diagnostic performance of CCL20 and IL-17A in combination was superior to that of either marker alone. CONCLUSIONS: Serum CCL20 and IL-17A levels were identified as independent prognostic markers for CRC. The CCL20-IL-17A panel exhibited a good performance in the diagnosis of early stage CRC.


Assuntos
Adenoma/sangue , Biomarcadores Tumorais/sangue , Quimiocina CCL20/sangue , Neoplasias Colorretais/sangue , Interleucina-17/sangue , Idoso , Área Sob a Curva , Estudos de Casos e Controles , Análise por Conglomerados , Colite/sangue , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC
18.
DNA Cell Biol ; 38(11): 1338-1345, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31464523

RESUMO

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease, which often affects colon or rectum or both. It is now well recognized that sphingosine kinases-1/sphingosine-1-phosphate (S1P) signaling may have a very significant potential as targets for therapeutic intervention in UC. Compared with the pure dextran sodium sulfate group, administration of PF543 significantly reduced clinical symptoms with less weight loss, diarrhea, and shortening of the colon. The severity of colitis was improved with reduced disease activity index and degree of histological damage in colon. Moreover, treatment with PF543 not only decreased S1P but also inhibited mRNA expression of proinflammatory factors such as interleukin (IL)-1ß and IL-6. This suggests that PF543 might exhibit an anti-inflammatory function against colitis through inhibition of expression of proinflammatory factors.


Assuntos
Colite/patologia , Colo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Metanol/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/farmacologia , Animais , Colite/sangue , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Lisofosfolipídeos/sangue , Masculino , Metanol/farmacologia , Metanol/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Pirrolidinas/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/sangue , Baço/efeitos dos fármacos , Baço/patologia , Especificidade por Substrato
19.
Biomed Pharmacother ; 118: 109247, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351432

RESUMO

AIM: Fish oil (FO) and mesalazine have well-known anti-inflammatory and antioxidant effects; on the other hand, information related to combined intrarectal administration of FO and mesalazine is limited. The present study was conducted to make comparison on therapeutic effectiveness of rectally administered FO and mesalazine in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis. METHODS: Wistar rats were randomly assigned to 5 groups as (1) Control, (2) Colitis, (3) Colitis + Mesalazine (Colitis + M), (4) Colitis + Fish Oil (Colitis + F), and (5) Colitis + Mesalazine + Fish Oil (Colitis + M + F). Intrarectally administered TNBS induced colitis. At the end of the trial, the rats' macroscopic and histopathologic lesions were rated and tumour necrosis factor (TNF)-α, Interleukin 6 (IL6), glutathione reductase (GR), glutathione peroxidase (GP), myeloperoxidase (MPO), malondialdehyde (MDA), Superoxide dismutase (SOD), Total nitrate and nitrite, and catalase (CAT) in serum and tissue were detected. RESULTS: As a result of macroscopic and microscopic examination, although separate administrations of FO and mesalazine partly decreased the damage, their combined administration decreased the damage scores significantly (p < 0.01). It was observed that separate and combined administrations of FO and mesalazine decreased the increase in the serum and tissue TNF-α and IL-6 levels caused by colitis (p < 0.05). It was observed that the serum MPO, serum GR, tissue SOD, tissue nitrite/nitrate values of both Colitis + M and Colitis + F groups were close to the control in terms of all the parameter values in Colitis + M + F group (p > 0.05). Also based on the histological results, the inflammation damage in the tissue caused by colitis in the Colitis + M + F group recovered significantly. CONCLUSIONS: We found that microscopic and macroscopic damage, serum IL-6 level decreased and increased serum and tissue GP and tissue GR values in Colitis + M + F group compared to Colitis + M and Colitis + F groups. Combined intrarectal administration of FO and mesalazine may bring a new insight concerning the treatment of ulcerative colitis.


Assuntos
Colite/tratamento farmacológico , Colite/patologia , Óleos de Peixe/administração & dosagem , Óleos de Peixe/uso terapêutico , Mesalamina/administração & dosagem , Mesalamina/uso terapêutico , Animais , Colite/sangue , Citocinas/sangue , Óleos de Peixe/farmacologia , Mucosa Intestinal/patologia , Mesalamina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Resultado do Tratamento , Ácido Trinitrobenzenossulfônico
20.
J Clin Immunol ; 39(5): 494-504, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31172380

RESUMO

PURPOSE: Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. METHODS: We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. RESULTS: MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p < 0.0001; for CDMI R2 0.83, p = 0.0006; for MaRIA R2 0.89, p = 0.0002). MRI was better tolerated and generally preferred, quicker, and visualized the entire large bowel whereas colonoscopy did not reach the terminal ileum in 3 participants. Elevated FCP accurately differentiated patients with colitis from those without, and log(calprotectin) correlated well with disease activity (R2 0.71, p = 0.009). Serum interleukin (IL)-12 concentration correlated with colitis activity but IL-1ß and TNF did not. Harvey-Bradshaw index did not correlate with colitis activity. CONCLUSIONS: MRI and fecal calprotectin are useful methods for monitoring CGD colitis and should reduce the need for colonoscopy in these patients. IL-12 may represent an appropriate target for treatment.


Assuntos
Colite/diagnóstico , Fezes/química , Doença Granulomatosa Crônica/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Adulto , Colite/sangue , Colite/etiologia , Colonoscopia , Citocinas/sangue , Feminino , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
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