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1.
J Cancer Res Clin Oncol ; 150(5): 243, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717677

RESUMO

Colitis-associated colorectal cancer has been a hot topic in public health issues worldwide. Numerous studies have demonstrated the significance of myeloid-derived suppressor cells (MDSCs) in the progression of this ailment, but the specific mechanism of their role in the transformation of inflammation to cancer is unclear, and potential therapies targeting MDSC are also unclear. This paper outlines the possible involvement of MDSC to the development of colitis-associated colorectal cancer. It also explores the immune and other relevant roles played by MDSC, and collates relevant targeted therapies against MDSC. In addition, current targeted therapies for colorectal cancer are analyzed and summarized.


Assuntos
Neoplasias Associadas a Colite , Neoplasias Colorretais , Células Supressoras Mieloides , Humanos , Células Supressoras Mieloides/imunologia , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/etiologia , Neoplasias Associadas a Colite/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Animais , Colite/complicações , Colite/imunologia
2.
Int J Biol Sci ; 20(7): 2507-2531, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725846

RESUMO

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.


Assuntos
Colite , Sulfato de Dextrana , Ferroptose , Inflamação , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Nucleotidiltransferases , Transdução de Sinais , Substância P , Animais , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Colite/metabolismo , Colite/induzido quimicamente , Substância P/metabolismo , Proteínas de Membrana/metabolismo , Ferroptose/efeitos dos fármacos , Inflamação/metabolismo , Sulfato de Dextrana/toxicidade , Masculino , Receptores da Neurocinina-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , DNA Mitocondrial/metabolismo
3.
Int J Biol Sci ; 20(7): 2491-2506, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725850

RESUMO

Colon inflammation is characterized by disturbances in the intestinal microbiota and inflammation. Melatonin (Mel) can improve colon inflammation. However, the underlying mechanism remains unclear. Recent studies suggest that m6A methylation modification may play an important role in inflammatory responses. This study aimed to explore the effects of melatonin and LPS-mediated m6A methylation on colon inflammation. Our study found that melatonin inhibits M1 macrophages, activates M2 macrophages, inhibit the secretion of pro-inflammatory factors, maintain colon homeostasis and improves colon inflammation through MTNR1B. In addition, the increased methylation level of m6A is associated with the occurrence of colon inflammation, and melatonin can also reduce the level of colon methylation to improve colon inflammation. Among them, the main methylated protein METTL3 can be inhibited by melatonin through MTNR1B. In a word, melatonin regulates m6A methylation by improving abnormal METTL3 protein level to reshape the microflora and activate macrophages to improve colon inflammation, mainly through MTNR1B.


Assuntos
Adenosina , Lipopolissacarídeos , Macrófagos , Melatonina , Melatonina/farmacologia , Melatonina/metabolismo , Animais , Camundongos , Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Metilação/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Metiltransferases/metabolismo , Metiltransferases/genética , Inflamação/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colite/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptor MT2 de Melatonina/genética , Células RAW 264.7
4.
Int J Mol Sci ; 25(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38731999

RESUMO

To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel activation as well as how these receptors' activity affects other systems. Moreover, there is a large volume of published studies describing the role of TRP channels in a number of pathological disorders, including inflammatory bowel disease (IBD) and sepsis. Nevertheless, the generalizability of these results is subject to certain limitations. For instance, the study of IBD relies on various animal models and experimental methods, which are unable to precisely imitate the multifactorial chronic disease. The diverse pathophysiological mechanisms and unique susceptibility of animals may account for the inconsistency of the experimental data collected. The main purpose of this study was to conduct a comprehensive review and analysis of existing studies on transient receptor potential (TRP) channels implicating specific models of colitis and sepsis, with particular emphasis on their involvement in pathological disorders such as IBD and sepsis. Furthermore, the text endeavors to evaluate the generalizability of experimental findings, taking into consideration the limitations posed by animal models and experimental methodologies. Finally, we also provide an updated schematic of the most important and possible molecular signaling pathways associated with TRP channels in IBD and sepsis.


Assuntos
Colite , Sepse , Canais de Potencial de Receptor Transitório , Sepse/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Colite/metabolismo , Colite/patologia , Transdução de Sinais , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Modelos Animais de Doenças
5.
Food Res Int ; 186: 114322, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729712

RESUMO

Lactobacillus delbrueckii subsp. lactis CIDCA 133 is a health-promoting bacterium that can alleviate gut inflammation and improve the epithelial barrier in a mouse model of mucositis. Despite these beneficial effects, the protective potential of this strain in other inflammation models, such as inflammatory bowel disease, remains unexplored. Herein, we examined for the first time the efficacy of Lactobacillus delbrueckii CIDCA 133 incorporated into a fermented milk formulation in the recovery of inflammation, epithelial damage, and restoration of gut microbiota in mice with dextran sulfate sodium-induced colitis. Oral administration of Lactobacillus delbrueckii CIDCA 133 fermented milk relieved colitis by decreasing levels of inflammatory factors (myeloperoxidase, N-acetyl-ß-D-glucosaminidase, toll-like receptor 2, nuclear factor-κB, interleukins 10 and 6, and tumor necrosis factor), secretory immunoglobulin A levels, and intestinal paracellular permeability. This immunobiotic also modulated the expression of tight junction proteins (zonulin and occludin) and the activation of short-chain fatty acids-related receptors (G-protein coupled receptors 43 and 109A). Colonic protection was effectively associated with acetate production and restoration of gut microbiota composition. Treatment with Lactobacillus delbrueckii CIDCA 133 fermented milk increased the abundance of Firmicutes members (Lactobacillus genus) while decreasing the abundance of Proteobacteria (Helicobacter genus) and Bacteroidetes members (Bacteroides genus). These promising outcomes influenced the mice's mucosal healing, colon length, body weight, and disease activity index, demonstrating that this immunobiotic could be explored as an alternative approach for managing inflammatory bowel disease.


Assuntos
Colite , Produtos Fermentados do Leite , Sulfato de Dextrana , Microbioma Gastrointestinal , Lactobacillus delbrueckii , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Colite/microbiologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/tratamento farmacológico , Lactobacillus delbrueckii/metabolismo , Produtos Fermentados do Leite/microbiologia , Camundongos , Probióticos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Inflamação , Colo/microbiologia , Colo/metabolismo , Lactobacillus
6.
Int Immunopharmacol ; 133: 112158, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38691917

RESUMO

BACKGROUND: The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Inflammatory cytokines and the kynurenine pathway (KP) play important roles in IBD and associated depression. Aripiprazole (ARP), an atypical antipsychotic, shows various anti-inflammatory properties and may be useful in treating major depressive disorder. This study aimed to evaluate the protective effects of ARP on TNBS-induced colitis and subsequent depression in rats, highlighting the role of the KP. MATERIAL AND METHODS: Fifty-six male Wistar rats were used, and all groups except for the normal and sham groups received a single dose of intra-rectal TNBS. Three different doses of ARP and dexamethasone were injected intraperitoneally for two weeks in treatment groups. On the 15th day, behavioral tests were performed to evaluate depressive-like behaviors. Colon ulcer index and histological changes were assessed. The tissue levels of inflammatory cytokines, KP markers, lipopolysaccharide (LPS), nuclear factor-kappa-B (NF-κB), and zonula occludens (ZO-1) were evaluated in the colon and hippocampus. RESULTS: TNBS effectively induced intestinal damages and subsequent depressive-like symptoms in rats. TNBS treatment significantly elevated the intestinal content of inflammatory cytokines and NF-κB expression, dysregulated the KP markers balance in both colon and hippocampus tissues, and increased the serum levels of LPS. However, treatment with ARP for 14 days successfully reversed these alterations, particularly at higher doses. CONCLUSION: ARP could alleviate IBD-induced colon damage and associated depressive-like behaviors mainly via suppressing inflammatory cytokines activity, serum LPS concentration, and affecting the NF-κB/kynurenine pathway.


Assuntos
Anti-Inflamatórios , Aripiprazol , Colite , Citocinas , Depressão , Cinurenina , NF-kappa B , Ratos Wistar , Ácido Trinitrobenzenossulfônico , Animais , Masculino , Cinurenina/metabolismo , Cinurenina/sangue , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Aripiprazol/uso terapêutico , Aripiprazol/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Ratos , NF-kappa B/metabolismo , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Colo/patologia , Colo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Modelos Animais de Doenças , Humanos
7.
BMJ Case Rep ; 17(5)2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719255

RESUMO

A man in his 80s was undergoing immunotherapy with pembrolizumab, an anti-PD-1 monoclonal antibody, following his diagnosis of adenocarcinoma of primary lung origin. 24 weeks into treatment, the patient reported experiencing loose stools associated with malaise and poor appetite but no further symptoms. This progressed in frequency and a clinical diagnosis of grade 2 immune checkpoint inhibitor colitis was made. Management with oral prednisolone was commenced but symptoms persisted. Common enteric infections had been ruled out, as were coeliac disease and hyperthyroidism. Flexible sigmoidoscopy and colonoscopy results were not in keeping with colitis, having revealed normal looking mucosa. Following this, a faecal elastase level was found to be low. A diagnosis of pembrolizumab-induced pancreatic exocrine insufficiency was made, and stool frequency and consistency swiftly improved following the use of pancreatic enzyme replacement therapy.


Assuntos
Anticorpos Monoclonais Humanizados , Diarreia , Inibidores de Checkpoint Imunológico , Humanos , Masculino , Inibidores de Checkpoint Imunológico/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso de 80 Anos ou mais , Neoplasias Pulmonares/tratamento farmacológico , Insuficiência Pancreática Exócrina/induzido quimicamente , Insuficiência Pancreática Exócrina/tratamento farmacológico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico
9.
Commun Biol ; 7(1): 527, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714733

RESUMO

Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.


Assuntos
Colite , Macrófagos , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Colite/patologia , Colite/induzido quimicamente , Camundongos , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Camundongos Knockout , Fenótipo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Índice de Gravidade de Doença , Masculino , Inflamação/genética , Inflamação/metabolismo
10.
Arch Iran Med ; 27(5): 277-286, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690795

RESUMO

Human cytomegalovirus (HCMV) is classified within the Herpesvirales order and is prevalent in 50%‒80% of the general population. Most carriers experience this infection without noticeable clinical symptoms. HCMV causes a lifelong latent infection that can be reactivated due to immune disorders and inflammation. The reactivation of HCMV becomes particularly significant when it coincides with inflammatory bowel disease (IBD). While cytomegalovirus (CMV) colitis in IBD patients was identified years ago, the role of CMV in triggering flare-ups, acute severe colitis, treatment resistance, and other outcomes in IBD patients experiencing CMV reactivation remains a subject of ongoing debate. In this review, we aim to address an updated insight into aspects related to the CMV colitis in IBD patients including epidemiology, risk factors, clinical features, diagnostic tests, histology, place of immunosuppressants and indications for antiviral treatment. We suggest for personalized and thorough assessment based on the disease phase and colitis severity when prescribing drugs to these patients. Furthermore, we emphasize the importance of regular patient follow-up to monitor drug side effects, ensuring treatment success, and minimizing the risk of colectomy.


Assuntos
Antivirais , Infecções por Citomegalovirus , Doenças Inflamatórias Intestinais , Humanos , Infecções por Citomegalovirus/complicações , Doenças Inflamatórias Intestinais/complicações , Antivirais/uso terapêutico , Fatores de Risco , Citomegalovirus , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Adulto , Colite/virologia
11.
Front Immunol ; 15: 1374425, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745644

RESUMO

Various gut bacteria, including Lactobacillus plantarum, possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo-cis-6,trans-11-octadecadienoic acid (γKetoC), a γ-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with γKetoC significantly suppressed proliferation of CD4+ T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c+ cells isolated from the spleen. γKetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of γKetoC on DCs. We also found that γKetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of γKetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2-/- BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2+/- mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2-/- mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in γKetoC-mediated anti-inflammatory responses.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Camundongos Knockout , Citocinas/metabolismo , Modelos Animais de Doenças , Sulfato de Dextrana , Ácidos Oleicos/farmacologia , Lactobacillus plantarum , Colite/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Masculino
12.
Clin Transl Sci ; 17(5): e13821, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38742709

RESUMO

Inflammatory bowel disease (IBD) is characterized by a chronically dysregulated immune response in the gastrointestinal tract. Bone marrow multipotent mesenchymal stromal cells have an important immunomodulatory function and support regeneration of inflamed tissue by secretion of soluble factors as well as through direct local differentiation. CXCR4 is the receptor for CXCL12 (SDF-1, stromal-derived factor-1) and has been shown to be the main chemokine receptor, required for homing of MSCs. Increased expression of CXCL12 by inflamed intestinal tissue causes constitutive inflammation by attracting lymphocytes but can also be used to direct MSCs to sites of injury/inflammation. Trypsin is typically used to dissociate MSCs into single-cell suspensions but has also been shown to digest surface CXCR4. Here, we assessed the regenerative effects of CXCR4high and CXCR4low MSCs in an immune-deficient mouse model of DSS-induced colitis. We found that transplantation of MSCs resulted in clinical improvement and histological recovery of intestinal epithelium. In contrary to our expectations, the levels of CXCR4 on transplanted MSCs did not affect their regenerative supporting potential, indicating that paracrine effects of MSCs may be largely responsible for their regenerative/protective effects.


Assuntos
Colite , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Receptores CXCR4 , Regeneração , Animais , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Células-Tronco Mesenquimais/metabolismo , Colite/induzido quimicamente , Colite/patologia , Colite/imunologia , Colite/terapia , Colite/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Sulfato de Dextrana , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/imunologia , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Células da Medula Óssea/metabolismo
13.
FASEB J ; 38(10): e23667, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38742812

RESUMO

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.


Assuntos
Colite , Janus Quinase 2 , Fator de Transcrição STAT3 , Transdução de Sinais , Linfócitos T Reguladores , Células Th17 , Ácido Trinitrobenzenossulfônico , Animais , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Janus Quinase 2/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Transcrição STAT3/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico/toxicidade , Masculino , Camundongos Endogâmicos BALB C , Diferenciação Celular/efeitos dos fármacos
14.
Cancer Cell ; 42(5): 797-814.e15, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38744246

RESUMO

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.


Assuntos
Colite , Inibidores de Checkpoint Imunológico , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Animais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos dos fármacos , Interferon gama/metabolismo , Feminino , Análise de Célula Única , Camundongos
15.
J Agric Food Chem ; 72(19): 10923-10935, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38691832

RESUMO

This study aimed to explore the ameliorative effects and potential mechanisms of Huangshan Umbilicaria esculenta polysaccharide (UEP) in dextran sulfate sodium-induced acute ulcerative colitis (UC) and UC secondary liver injury (SLI). Results showed that UEP could ameliorate both colon and liver pathologic injuries, upregulate mouse intestinal tight junction proteins (TJs) and MUC2 expression, and reduce LPS exposure, thereby attenuating the effects of the gut-liver axis. Importantly, UEP significantly downregulated the secretion levels of TNF-α, IL-1ß, and IL-6 through inhibition of the NF-κB pathway and activated the Nrf2 signaling pathway to increase the expression levels of SOD and GSH-Px. In vitro, UEP inhibited the LPS-induced phosphorylation of NF-κB P65 and promoted nuclear translocation of Nrf2 in RAW264.7 cells. These results revealed that UEP ameliorated UC and SLI through NF-κB and Nrf2-mediated inflammation and oxidative stress. The study first investigated the anticolitis effect of UEP, suggesting its potential for the treatment of colitis and colitis-associated liver disease.


Assuntos
Colite , Sulfato de Dextrana , Fator 2 Relacionado a NF-E2 , NF-kappa B , Polissacarídeos , Animais , Camundongos , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/administração & dosagem , Sulfato de Dextrana/efeitos adversos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Humanos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Células RAW 264.7 , NF-kappa B/metabolismo , NF-kappa B/genética , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Estresse Oxidativo/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-6/imunologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Mucina-2/genética , Mucina-2/metabolismo
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(4): 765-772, 2024 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-38708511

RESUMO

OBJECTIVE: To investigate the expression level of Kruppel-like transcription factor family member KLF11 in intestinal mucosal tissues of Crohn's disease (CD) and its regulatory effect on intestinal inflammation in CD-like colitis. METHODS: We examined KLF11 expression levels in diseased and normal colon mucosal tissues from 12 CD patients and 12 patients with colorectal cancer using immunofluorescence staining. KLF11 expression was also detected in the colon mucosal tissues of a mouse model of 2, 4, 6-trinitrobenesulfonic acid (TNBS)-induced colitis. A recombinant adenoviral vector was used to upregulate KLF11 expression in the mouse models and the changes in intestinal inflammation was observed. A Caco-2 cell model with stable KLF11 overexpression was constructed by lentiviral infection. The effect of KLF11 overexpression on expressions of JAK2/STAT3 signaling pathway proteins was investigated using immunoblotting in both the mouse and cell models. The mouse models were treated with coumermycin A1, a JAK2/STAT3 signaling pathway agonist, and the changes in intestinal inflammatory responses were observed. RESULTS: The expression level of KLF11 was significantly lowered in both the clinical specimens of diseased colon mucosal tissues and the colon tissues of mice with TNBS-induced colitis (P < 0.05). Adenovirus-mediated upregulation of KLF11 significantly improved intestinal inflammation and reduced the expression levels of inflammatory factors in the intestinal mucosa of the colitis mouse models (P < 0.05). Overexpression of KLF11 significantly inhibited the expression levels of p-JAK2 and p-STAT3 in intestinal mucosal tissues of the mouse models and in Caco-2 cells (P < 0.05). Treatment with coumermycin A1 obviously inhibited the effect of KLF11 upregulation for improving colitis and significantly increased the expression levels of inflammatory factors in the intestinal mucosa of the mouse models (P < 0.05). CONCLUSION: KLF11 is downregulated in the intestinal mucosa in CD, and upregulation of KLF11 can improve intestinal inflammation and reduce the production of inflammatory factors probably by inhibiting the JAK2/STAT3 signaling pathway.


Assuntos
Proteínas Reguladoras de Apoptose , Colite , Mucosa Intestinal , Janus Quinase 2 , Proteínas Repressoras , Fator de Transcrição STAT3 , Transdução de Sinais , Ácido Trinitrobenzenossulfônico , Animais , Camundongos , Colite/induzido quimicamente , Colite/metabolismo , Humanos , Fator de Transcrição STAT3/metabolismo , Janus Quinase 2/metabolismo , Células CACO-2 , Mucosa Intestinal/metabolismo , Modelos Animais de Doenças , Doença de Crohn/metabolismo , Inflamação/metabolismo , Regulação para Cima , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
17.
Nat Commun ; 15(1): 3784, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710716

RESUMO

Probiotic and engineered microbe-based therapeutics are an emerging class of pharmaceutical agents. They represent a promising strategy for treating various chronic and inflammatory conditions by interacting with the host immune system and/or delivering therapeutic molecules. Here, we engineered a targeted probiotic yeast platform wherein Saccharomyces boulardii is designed to bind to abundant extracellular matrix proteins found within inflammatory lesions of the gastrointestinal tract through tunable antibody surface display. This approach enabled an additional 24-48 h of probiotic gut residence time compared to controls and 100-fold increased probiotic concentrations within the colon in preclinical models of ulcerative colitis in female mice. As a result, pharmacodynamic parameters including colon length, colonic cytokine expression profiles, and histological inflammation scores were robustly improved and restored back to healthy levels. Overall, these studies highlight the potential for targeted microbial therapeutics as a potential oral dosage form for the treatment of inflammatory bowel diseases.


Assuntos
Colite Ulcerativa , Colo , Modelos Animais de Doenças , Matriz Extracelular , Probióticos , Saccharomyces boulardii , Animais , Probióticos/administração & dosagem , Feminino , Camundongos , Matriz Extracelular/metabolismo , Colite Ulcerativa/terapia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Colo/microbiologia , Colo/metabolismo , Colo/patologia , Camundongos Endogâmicos C57BL , Colite/terapia , Colite/microbiologia , Colite/patologia , Citocinas/metabolismo , Humanos
18.
J Clin Invest ; 134(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690730

RESUMO

The gut microbiota is an integral part of the human metaorganism that is required to shape physiologic host immune responses including host defense against pathogens. Disease-associated gut dysbiosis has been characterized by blooms of pathobionts, which are bacterial species that can drive disease under certain conditions. Pathobionts like Enterobacteriaceae often bloom during flares of inflammatory bowel disease (IBD) and are causally linked with IBD in murine models. In this issue of the JCI, Hecht and colleagues investigated how simple carbohydrates are causally linked to the bloom of the gut pathobiont Klebsiella pneumoniae, which belong to the Enterobacteriaceae family. Notably, the presence of fiber reduced the dissemination of K. pneumoniae into the blood and liver in a colitis model. Their findings provide a diet-related mechanism for gut dysbiosis, which has implications in the management of IBD and other conditions in which gut dysbiosis is an underlying factor.


Assuntos
Disbiose , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Klebsiella pneumoniae , Humanos , Animais , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Carboidratos da Dieta/efeitos adversos , Infecções por Klebsiella , Colite/induzido quimicamente , Colite/microbiologia , Fibras na Dieta
19.
World J Gastroenterol ; 30(16): 2258-2271, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38690023

RESUMO

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most frequent and debilitating conditions leading to gastroenterological referrals. However, recommended treatments remain limited, yielding only limited therapeutic gains. Chitin-glucan (CG) is a novel dietary prebiotic classically used in humans at a dosage of 1.5-3.0 g/d and is considered a safe food ingredient by the European Food Safety Authority. To provide an alternative approach to managing patients with IBS, we performed preclinical molecular, cellular, and animal studies to evaluate the role of chitin-glucan in the main pathophysiological mechanisms involved in IBS. AIM: To evaluate the roles of CG in visceral analgesia, intestinal inflammation, barrier function, and to develop computational molecular models. METHODS: Visceral pain was recorded through colorectal distension (CRD) in a model of long-lasting colon hypersensitivity induced by an intra-rectal administration of TNBS [15 milligrams (mg)/kilogram (kg)] in 33 Sprague-Dawley rats. Intracolonic pressure was regularly assessed during the 9 wk-experiment (weeks 0, 3, 5, and 7) in animals receiving CG (n = 14) at a human equivalent dose (HED) of 1.5 g/d or 3.0 g/d and compared to negative control (tap water, n = 11) and positive control (phloroglucinol at 1.5 g/d HED, n = 8) groups. The anti-inflammatory effect of CG was evaluated using clinical and histological scores in 30 C57bl6 male mice with colitis induced by dextran sodium sulfate (DSS) administered in their drinking water during 14 d. HT-29 cells under basal conditions and after stimulation with lipopolysaccharide (LPS) were treated with CG to evaluate changes in pathways related to analgesia (µ-opioid receptor (MOR), cannabinoid receptor 2 (CB2), peroxisome proliferator-activated receptor alpha, inflammation [interleukin (IL)-10, IL-1b, and IL-8] and barrier function [mucin 2-5AC, claudin-2, zonula occludens (ZO)-1, ZO-2] using the real-time PCR method. Molecular modelling of CG, LPS, lipoteichoic acid (LTA), and phospholipomannan (PLM) was developed, and the ability of CG to chelate microbial pathogenic lipids was evaluated by docking and molecular dynamics simulations. Data were expressed as the mean ± SEM. RESULTS: Daily CG orally-administered to rats or mice was well tolerated without including diarrhea, visceral hypersensitivity, or inflammation, as evaluated at histological and molecular levels. In a model of CRD, CG at a dosage of 3 g/d HED significantly decreased visceral pain perception by 14% after 2 wk of administration (P < 0.01) and reduced inflammation intensity by 50%, resulting in complete regeneration of the colonic mucosa in mice with DSS-induced colitis. To better reproduce the characteristics of visceral pain in patients with IBS, we then measured the therapeutic impact of CG in rats with TNBS-induced inflammation to long-lasting visceral hypersensitivity. CG at a dosage of 1.5 g/d HED decreased visceral pain perception by 20% five weeks after colitis induction (P < 0.01). When the CG dosage was increased to 3.0 g/d HED, this analgesic effect surpassed that of the spasmolytic agent phloroglucinol, manifesting more rapidly within 3 wk and leading to a 50% inhibition of pain perception (P < 0.0001). The underlying molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved, at least in part, a significant induction of MOR, CB2 receptor, and IL-10, as well as a significant decrease in pro-inflammatory cytokines IL-1b and IL-8. CG also significantly upregulated barrier-related genes including muc5AC, claudin-2, and ZO-2. Molecular modelling of CG revealed a new property of the molecule as a chelator of microbial pathogenic lipids, sequestering gram-negative LPS and gram-positive LTA bacterial toxins, as well as PLM in fungi at the lowesr energy conformations. CONCLUSION: CG decreased visceral perception and intestinal inflammation through master gene regulation and direct binding of microbial products, suggesting that CG may constitute a new therapeutic strategy for patients with IBS or IBS-like symptoms.


Assuntos
Quitina , Colo , Modelos Animais de Doenças , Glucanos , Síndrome do Intestino Irritável , Ratos Sprague-Dawley , Dor Visceral , Animais , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Humanos , Colo/efeitos dos fármacos , Colo/patologia , Ratos , Dor Visceral/tratamento farmacológico , Dor Visceral/fisiopatologia , Dor Visceral/metabolismo , Dor Visceral/etiologia , Quitina/farmacologia , Glucanos/farmacologia , Glucanos/administração & dosagem , Camundongos , Prebióticos/administração & dosagem , Ácido Trinitrobenzenossulfônico/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/fisiopatologia , Colite/patologia , Células HT29
20.
Nutrients ; 16(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38732527

RESUMO

Ulcerative colitis (UC) is characterized by chronic inflammation and ulceration of the intestinal inner lining, resulting in various symptoms. Sea buckthorn berries contain a bioactive compound known as sea buckthorn polysaccharide (SBP). However, the precise mechanisms underlying the impact of SBP on UC remain unclear. In this study, we investigated the effects of pretreatment with SBP on colitis induced by DSS. Our findings demonstrate that SBP pretreatment effectively reduces inflammation, oxidative stress, and intestinal barrier damage associated with colitis. To further elucidate the role of SBP-modulated gut microbiota in UC, we performed fecal microbiota transplantation (FMT) on DSS-treated mice. The microbiota from SBP-treated mice exhibits notable anti-inflammatory and antioxidant effects, improves colonic barrier integrity, and increases the abundance of beneficial bacteria, as well as enhancing SCFA production. Collectively, these results strongly indicate that SBP-mediated amelioration of colitis is attributed to its impact on the gut microbiota, particularly through the promotion of SCFA-producing bacteria and subsequent elevation of SCFA levels. This study provides compelling evidence supporting the efficacy of pre-emptive SBP supplementation in alleviating colitis symptoms by modulating the gut microbiota, thereby offering novel insights into the potential of SBP as a regulator of the gut microbiota for colitis relief.


Assuntos
Microbioma Gastrointestinal , Hippophae , Polissacarídeos , Animais , Hippophae/química , Polissacarídeos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/microbiologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transplante de Microbiota Fecal , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/metabolismo , Sulfato de Dextrana , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Frutas/química , Ácidos Graxos Voláteis/metabolismo
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