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1.
Prague Med Rep ; 122(3): 212-215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34606433

RESUMO

A fatal case of 67-year-old female with metastatic breast cancer on chemotherapy complicated with febrile neutropenia, colitis and sepsis due to Clostridium septicum is presented. Important clinical symptoms, laboratory and radiology findings together with therapy and outcome of neuropenic colitis are also discussed.


Assuntos
Bacteriemia , Neoplasias da Mama , Infecções por Clostridium , Clostridium septicum , Colite , Idoso , Bacteriemia/diagnóstico , Neoplasias da Mama/complicações , Infecções por Clostridium/complicações , Infecções por Clostridium/diagnóstico , Colite/diagnóstico , Colite/etiologia , Feminino , Humanos
2.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34548395

RESUMO

Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8 -/- mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8 -/- mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.


Assuntos
Adenosina Trifosfatases/fisiologia , Trifosfato de Adenosina/metabolismo , Colite/prevenção & controle , Glicólise , Células Mieloides/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Células Th17/imunologia , Animais , Células Cultivadas , Colite/etiologia , Colite/metabolismo , Colite/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/patologia , Receptores Purinérgicos P2X4/genética , Transdução de Sinais
3.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208517

RESUMO

Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.


Assuntos
Colite/etiologia , Colite/metabolismo , Mucosa Intestinal/metabolismo , Células-Tronco Mesenquimais/metabolismo , Superóxido Dismutase/genética , Junções Íntimas/metabolismo , Animais , Biomarcadores , Células CACO-2 , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Junções Íntimas/patologia
4.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201918

RESUMO

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) plays a critical role in the pathogenesis of inflammatory bowel diseases (IBD). Mice lacking PTPN2 in dendritic cells (DCs) develop skin and liver inflammation by the age of 22 weeks due to a generalized loss of tolerance leading to uncontrolled immune responses. The effect of DC-specific PTPN2 loss on intestinal health, however, is unknown. The aim of this study was to investigate the DC-specific role of PTPN2 in the intestine during colitis development. PTPN2fl/flxCD11cCre mice were subjected to acute and chronic DSS colitis as well as T cell transfer colitis. Lamina propria immune cell populations were analyzed using flow cytometry. DC-specific PTPN2 deletion promoted infiltration of B and T lymphocytes, macrophages, and DCs into the lamina propria of unchallenged mice and elevated Th1 abundance during acute DSS colitis, suggesting an important role for PTPN2 in DCs in maintaining intestinal immune cell homeostasis. Surprisingly, those immune cell alterations did not translate into increased colitis susceptibility in acute and chronic DSS-induced colitis or T cell transfer colitis models. However, macrophage depletion by clodronate caused enhanced colitis severity in mice with a DC-specific loss of PTPN2. Loss of PTPN2 in DCs affects the composition of lamina propria lymphocytes, resulting in increased infiltration of innate and adaptive immune cells. However, this did not result in an elevated colitis phenotype, likely because increased infiltration of macrophages in the intestine upon loss of PTPN2 loss in DCs can compensate for the inflammatory effect of PTPN2-deficient DCs.


Assuntos
Colite/etiologia , Colite/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/deficiência , Animais , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Transgênicos , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Fator de Transcrição STAT1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
5.
NPJ Biofilms Microbiomes ; 7(1): 58, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244520

RESUMO

The low viability during gastrointestinal transit and poor mucoadhesion considerably limits the effectiveness of Ligilactobacillus salivarius Li01 (Li01) in regulating gut microbiota and alleviating inflammatory bowel disease (IBD). In this study, a delivery system was designed through layer-by-layer (LbL) encapsulating a single Li01cell with chitosan and alginate. The layers were strengthened by cross-linking to form a firm and mucoadhesive shell (~10 nm thickness) covering the bacterial cell. The LbL Li01 displayed improved viability under simulated gastrointestinal conditions and mucoadhesive function. Almost no cells could be detected among the free Li01 after 2 h incubation in digestive fluids, while for LbL Li01, the total reduction was around 3 log CFU/mL and the viable number of cells remained above 6 log CFU/mL. Besides, a 5-fold increase in the value of rupture length and a two-fold increase in the number of peaks were found in the (bacteria-mucin) adhesion curves of LbL Li01, compared to those of free Li01. Oral administration with LbL Li01 on colitis mice facilitated intestinal barrier recovery and restoration of the gut microbiota. The improved functionality of Li01 by LbL encapsulation could increase the potential for the probiotic to be used in clinical applications to treat IBD; this should be explored in future studies.


Assuntos
Técnicas Bacteriológicas , Lactobacillus/fisiologia , Animais , Aderência Bacteriana , Biomarcadores , Linhagem Celular , Colite/etiologia , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Mediadores da Inflamação , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Camundongos , Viabilidade Microbiana , Probióticos/administração & dosagem
6.
Am J Clin Oncol ; 44(8): 395-401, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091476

RESUMO

BACKGROUND: Eosinophilic colitis (EoC) is a rare form of eosinophilic gastrointestinal disease characterized by diffuse eosinophilic infiltration in the deep lamina propria of colonic mucosa. The pathophysiology is unclear, but EoC has been associated with multiple known risk factors. AIM: The aim of this study was to characterize the clinical characteristics and disease course of patients with EoC at a major cancer center. MATERIAL AND METHODS: We retrospectively reviewed colonic samples obtained between January 2000 and December 2018 from our institutional database and included cases with significant colonic eosinophilia. Baseline clinical data and EoC-related clinical course and outcomes were documented. RESULTS: Forty-one patients were included. One fourth had coexisting autoimmune conditions. Seventy-eight percent had a cancer diagnosis. Half the patients received chemotherapy, with a median duration of 180 days between chemotherapy and EoC onset. Symptoms were present in 76% of patients. Diarrhea was more prevalent in patients who received chemotherapy (85% vs. 42%). Median duration of EoC symptoms was 30 days in patients with cancer and 240 days in those without cancer (P=0.03). Most patients (88%) had normal colonoscopy findings. Fifteen percent of patients required hospitalization. All-cause mortality was 37%, mostly related to underlying malignancy and organ failure. CONCLUSIONS: EoC in cancer patients appears to have more diarrhea-predominant symptoms, particularly in patients receiving chemotherapy, but a shorter disease duration compared with patients without cancer. Hospitalization can be required for serious cases. Treatment may be reserved for patients requiring symptom management, as most patients with EoC have good clinical outcomes regardless of treatment.


Assuntos
Colite/etiologia , Colite/patologia , Colite/terapia , Eosinofilia/etiologia , Neoplasias/fisiopatologia , Idoso , Colite/mortalidade , Colonoscopia , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/etiologia , Eosinofilia/mortalidade , Eosinofilia/terapia , Feminino , Hospitalização , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco
7.
BMJ Case Rep ; 14(6)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130968

RESUMO

A 65-year-old woman with a background of adult-onset Still's disease (AOSD) presented acutely to a general surgical unit with signs of bowel obstruction and sepsis. A CT scan was indicative of a mesenteric lymphadenopathy suspicious of malignancy. At the time of the surgery, a clinical diagnosis of lymphoma was made given the large number of lymph nodes; however, histological diagnosis was resulted as Crohn's colitis. There is only one other case of AOSD and Crohn's disease in the literature, and there is no clear pathological connection between the two inflammatory conditions. This case highlights the surgical management of an unusual presentation.


Assuntos
Colite , Doença de Crohn , Linfadenopatia , Doença de Still de Início Tardio , Adulto , Idoso , Colite/diagnóstico , Colite/etiologia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Feminino , Humanos , Linfonodos , Doença de Still de Início Tardio/complicações , Doença de Still de Início Tardio/diagnóstico
8.
Ann Hematol ; 100(7): 1685-1693, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34050373

RESUMO

Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC-MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 µmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.


Assuntos
5-Aminolevulinato Sintetase/antagonistas & inibidores , Acetilgalactosamina/análogos & derivados , Heme/deficiência , Hiper-Homocisteinemia/etiologia , Porfiria Aguda Intermitente/tratamento farmacológico , Pirrolidinas/uso terapêutico , Acetilgalactosamina/efeitos adversos , Acetilgalactosamina/uso terapêutico , Adulto , Arginina/uso terapêutico , Colite/etiologia , Colo Sigmoide/patologia , Ensaios Clínicos Controlados como Assunto , Hipersensibilidade a Drogas/etiologia , Feminino , Fibrose , Heme/análise , Heme/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Homocisteína/metabolismo , Humanos , Hidroximetilbilano Sintase/sangue , Hidroximetilbilano Sintase/genética , Masculino , Modelos Biológicos , Pancreatite/etiologia , Porfiria Aguda Intermitente/sangue , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/genética , Pirrolidinas/efeitos adversos
9.
Front Immunol ; 12: 618332, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986741

RESUMO

LST1 is a small adaptor protein expressed in leukocytes of myeloid lineage. Due to the binding to protein tyrosine phosphatases SHP1 and SHP2 it was thought to have negative regulatory function in leukocyte signaling. It was also shown to be involved in cytoskeleton regulation and generation of tunneling nanotubes. LST1 gene is located in MHCIII locus close to many immunologically relevant genes. In addition, its expression increases under inflammatory conditions such as viral infection, rheumatoid arthritis and inflammatory bowel disease and its deficiency was shown to result in slightly increased sensitivity to influenza infection in mice. However, little else is known about its role in the immune system homeostasis and immune response. Here we show that similar to humans, LST1 is expressed in mice in the cells of the myeloid lineage. In vivo, its deficiency results in alterations in multiple leukocyte subset abundance in steady state and under inflammatory conditions. Moreover, LST1-deficient mice show significant level of resistance to dextran sodium sulphate (DSS) induced acute colitis, a model of inflammatory bowel disease. These data demonstrate that LST1 regulates leukocyte abundance in lymphoid organs and inflammatory response in the gut.


Assuntos
Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Colite/etiologia , Colite/metabolismo , Colite/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Genótipo , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Fosforilação
11.
Commun Biol ; 4(1): 585, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990686

RESUMO

G protein-coupled receptor (GPR)35 is highly expressed in the gastro-intestinal tract, predominantly in colon epithelial cells (CEC), and has been associated with inflammatory bowel diseases (IBD), suggesting a role in gastrointestinal inflammation. The enterotoxigenic Bacteroides fragilis (ETBF) toxin (BFT) is an important virulence factor causing gut inflammation in humans and animal models. We identified that BFT signals through GPR35. Blocking GPR35 function in CECs using the GPR35 antagonist ML145, in conjunction with shRNA knock-down and CRISPRcas-mediated knock-out, resulted in reduced CEC-response to BFT as measured by E-cadherin cleavage, beta-arrestin recruitment and IL-8 secretion. Importantly, GPR35 is required for the rapid onset of ETBF-induced colitis in mouse models. GPR35-deficient mice showed reduced death and disease severity compared to wild-type C57Bl6 mice. Our data support a role for GPR35 in the CEC and mucosal response to BFT and underscore the importance of this molecule for sensing ETBF in the colon.


Assuntos
Toxinas Bacterianas/administração & dosagem , Bacteroides fragilis/patogenicidade , Colite/patologia , Colo/patologia , Células Epiteliais/patologia , Trato Gastrointestinal/patologia , Metaloendopeptidases/administração & dosagem , Receptores Acoplados a Proteínas G/fisiologia , Animais , Bacteroides fragilis/genética , Bacteroides fragilis/metabolismo , Colite/etiologia , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/microbiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL
12.
Methods Mol Biol ; 2299: 385-403, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34028756

RESUMO

Mouse models are essential for investigation of underlying disease mechanisms that drive intestinal fibrosis, as well as assessment of potential therapeutic approaches to either prevent or resolve fibrosis. Here we describe several common mouse models of intestinal inflammation and fibrosis, including chemically driven colitis models, a bacterially triggered colitis model, and spontaneous intestinal inflammation in genetically susceptible mouse strains. Detailed protocols are provided for dextran sodium sulfate (DSS) colitis, 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis, adherent-invasive Escherichia coli (AIEC)-triggered colitis, the interleukin-10 knockout (IL-10KO) mouse model of spontaneous colitis, and the SAMP/YitFc model of spontaneous ileocolitis.


Assuntos
Colite/etiologia , Colite/patologia , Interleucina-10/genética , Animais , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Escherichia coli/patogenicidade , Humanos , Masculino , Camundongos , Camundongos Knockout , Ácido Trinitrobenzenossulfônico/efeitos adversos
13.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946346

RESUMO

Colitis causes destruction of the intestinal mucus layer and increases intestinal inflammation. The use of antioxidants and anti-inflammatory agents derived from natural sources has been recently highlighted as a new approach for the treatment of colitis. Oxyresveratrol (OXY) is an antioxidant known to have various beneficial effects on human health, such as anti-inflammatory, antibacterial activity, and antiviral activity. The aim of this study was to investigate the therapeutic effect of OXY in rats with dextran sulfate sodium (DSS)-induced acute colitis. OXY ameliorated DSS-induced colitis and repaired damaged intestinal mucosa. OXY downregulated the expression of pro-inflammatory cytokine genes (TNF-α, IL-6, and IL-1ß) and chemokine gene MCP-1, while promoting the production of anti-inflammatory cytokine IL-10. OXY treatment also suppressed inflammation via inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in the colon, as well as the activity of myeloperoxidase (MPO). OXY exhibited anti-apoptotic effects, shifting the Bax/Bcl-2 balance. In conclusion, OXY might improve DSS-induced colitis by restoring the intestinal mucus layer and reducing inflammation within the intestine.


Assuntos
Anti-Inflamatórios/farmacologia , Sulfato de Dextrana/efeitos adversos , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Animais , Biomarcadores , Colite/tratamento farmacológico , Colite/etiologia , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
15.
Front Immunol ; 12: 619366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708211

RESUMO

Ulcerative colitis is an inflammatory disease of the colon that is associated with colonic neutrophil accumulation. Recent evidence indicates that diet alters the composition of the gut microbiota and influences host-pathogen interactions. Specifically, bacterial fermentation of dietary fiber produces metabolites called short-chain fatty acids (SCFAs), which have been shown to protect against various inflammatory diseases. However, the effect of fiber deficiency on the key initial steps of inflammation, such as leukocyte-endothelial cell interactions, is unknown. Moreover, the impact of fiber deficiency on neutrophil recruitment under basal conditions and during inflammation in vivo is unknown. Herein, we hypothesized that a fiber-deficient diet promotes an inflammatory state in the colon at baseline and predisposes the host to more severe colitis pathology. Mice fed a no-fiber diet for 14 days showed significant changes in the gut microbiota and exhibited increased neutrophil-endothelial interactions in the colonic microvasculature. Although mice fed a no-fiber diet alone did not have observable colitis-associated symptoms, these animals were highly susceptible to low dose (0.5%) dextran sodium sulphate (DSS)-induced model of colitis. Supplementation of the most abundant SCFA, acetate, prevented no-fiber diet-mediated enrichment of colonic neutrophils and colitis pathology. Therefore, dietary fiber, possibly through the actions of acetate, plays an important role in regulating neutrophil recruitment and host protection against inflammatory colonic damage in an experimental model of colitis.


Assuntos
Quimiotaxia de Leucócito/imunologia , Colite/etiologia , Fibras na Dieta/deficiência , Microbioma Gastrointestinal , Infiltração de Neutrófilos/imunologia , Animais , Biomarcadores , Adesão Celular , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Dieta , Modelos Animais de Doenças , Células Endoteliais , Contagem de Leucócitos , Masculino , Metagenômica/métodos , Camundongos , RNA Ribossômico 16S
16.
Front Immunol ; 12: 609319, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679744

RESUMO

Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1ß and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.


Assuntos
Azepinas/farmacologia , Colite/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Piroptose/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Animais , Biomarcadores , Colite/tratamento farmacológico , Colite/etiologia , Colite/patologia , Modelos Animais de Doenças , Endotoxemia/complicações , Endotoxemia/etiologia , Imuno-Histoquímica , Inflamassomos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Fosforilação , Junções Íntimas/metabolismo
17.
Front Immunol ; 12: 615803, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33633749

RESUMO

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ2 on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ2 on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ2 hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ2 accelerated the resolution of experimentally induced colitis. 15d-PGJ2 treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ2 treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ2, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Fatores Imunológicos/farmacologia , Prostaglandina D2/análogos & derivados , Animais , Biomarcadores , Colite/etiologia , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Prostaglandina D2/farmacologia , Fator de Transcrição STAT3 , Resultado do Tratamento
18.
Eur J Immunol ; 51(6): 1461-1472, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33548071

RESUMO

Blocking the mevalonate pathway for cholesterol reduction by using statin may have adverse effects including statin-induced colitis. Moreover, one of the predisposing factors for colitis is an imbalanced CD4+ T cell, which can be observed on the complete deletion of HMG-CoA reductase (HMGCR), a target of statins. In this study, we inquired geranylgeranyl pyrophosphate (GGPP) is responsible for maintaining the T-cell homeostasis. Following dextran sulfate sodium (DSS)-induced colitis, simvastatin increased the severity of disease, while cotreatment with GGPP, but not with cholesterol, reversed the disease magnitude. GGPP ameliorated DSS-induced colitis by increasing Treg cells. GGPP amplified Treg differentiation through increased IL-2/STAT 5 signaling. GGPP prenylated Ras protein, a prerequisite for extracellular signal-regulated kinase (ERK) pathway activation, leading to increased IL-2 production. Higher simvastatin dose increased the severity of colitis. GGPP ameliorated simvastatin-increased colitis by increasing Treg cells. Treg cells, which have the capacity to suppress inflammatory T cells and were generated through IL-2/STAT5 signaling, increased IL-2 production through prenylation and activation of the Ras/ERK pathway.


Assuntos
Anticolesterolemiantes/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Colite/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-2/metabolismo , Fosfatos de Poli-Isoprenil/uso terapêutico , Sinvastatina/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticolesterolemiantes/efeitos adversos , Diferenciação Celular , Células Cultivadas , Colite/etiologia , Sulfato de Dextrana , Modelos Animais de Doenças , Homeostase , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Ativação Linfocitária , Ácido Mevalônico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Sinvastatina/efeitos adversos
19.
J Cell Mol Med ; 25(5): 2679-2690, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33491282

RESUMO

Integrins, as a large family of cell adhesion molecules, play a crucial role in maintaining intestinal homeostasis. In inflammatory bowel disease (IBD), homeostasis is disrupted. Integrin αvß6, which is mainly regulated by the integrin ß6 subunit gene (ITGB6), is a cell adhesion molecule that mediates cell-cell and cell-matrix interactions. However, the role of ITGB6 in the pathogenesis of IBD remains elusive. In this study, we found that ITGB6 was markedly upregulated in inflamed intestinal tissues from patients with IBD. Then, we generated an intestinal epithelial cell-specific ITGB6 transgenic mouse model. Conditional ITGB6 transgene expression exacerbated experimental colitis in mouse models of acute and chronic dextran sulphate sodium (DSS)-induced colitis. Survival analyses revealed that ITGB6 transgene expression correlated with poor prognosis in DSS-induced colitis. Furthermore, our data indicated that ITGB6 transgene expression increased macrophages infiltration, pro-inflammatory cytokines secretion, integrin ligands expression and Stat1 signalling pathway activation. Collectively, our findings revealed a previously unknown role of ITGB6 in IBD and highlighted the possibility of ITGB6 as a diagnostic marker and therapeutic target for IBD.


Assuntos
Colite/etiologia , Colite/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica , Cadeias beta de Integrinas/genética , Mucosa Intestinal/metabolismo , Animais , Biomarcadores , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Marcação de Genes , Vetores Genéticos/genética , Humanos , Mediadores da Inflamação/metabolismo , Cadeias beta de Integrinas/metabolismo , Mucosa Intestinal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Transgênicos
20.
Nutrients ; 13(1)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451114

RESUMO

This study aimed to investigate the effects of Clostridium tyrobutyricum (C. tyrobutyricum) on colonic immunity and the role of IL-22 in the protective function of C. tyrobutyricum. Mice were supplemented with 108 CFU/mL C. tyrobutyricum daily for 20 days, followed by injecting with LPS for 24 h. In vivo interference of IL-22 via injecting with an adeno-associated virus was conducted to elucidate the role of IL-22 in C. tyrobutyricum attenuating colonic inflammation. The results showed that C. tyrobutyricum decreased the mRNA expression of IL-6 and IL-1ß. C. tyrobutyricum enhanced the mRNA expression of IL-22 and the expression of MUC2 in the colon. The in vivo interference results showed that C. tyrobutyricum enhanced the mRNA expression of IL-6 and IL-1ß while decreased the expression of MUC2 after knocking down IL-22. The flow cytometric analysis showed that C. tyrobutyricum decreased the proportions of macrophages, DCs, and mast cells and effectively regulated the proportion of Th17 cells, indicating that C. tyrobutyricum may stimulate the expression of IL-22 via regulating Th17 cells. Our study concluded that C. tyrobutyricum protected against LPS-induced colonic barrier dysfunction and inflammation via IL-22 signaling, suggesting that C. tyrobutyricum could be a potential probiotic in regulating colonic health.


Assuntos
Clostridium tyrobutyricum/fisiologia , Colite/etiologia , Colite/metabolismo , Interleucinas/metabolismo , Lipopolissacarídeos/efeitos adversos , Transdução de Sinais , Animais , Colite/prevenção & controle , Células Dendríticas , Modelos Animais de Doenças , Imunomodulação , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Probióticos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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