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1.
PLoS Pathog ; 19(1): e1011096, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36693067

RESUMO

Fusobacterium nucleatum (Fn) is a critical colorectal cancer (CRC)-associated bacterium. DNA hunger/stationary phase protective proteins (Dps) are bacterial ferritins that protect DNA from oxidative stress. However, little is known about the regulatory roles of Fn-Dps towards host cellular functions. Here, we identified Fn-Dps from the culture supernatant of Fn by mass spectrometry, and prepared the recombinant of Fn-Dps protein. We show a novel virulence protein of Fn, Fn-Dps, which lyses and disrupts erythrocytes by the competition for iron acquisition. Also, Fn-Dps facilitates intracellular survival of Fn in macrophages by upregulating the expression of the chemokine CCL2/CCL7. In addition, Fn-Dps can elicit a strong humoral immune response, and mucosal immunization with Fn-Dps conferred protection against Fn in the intestinal tract. Moreover, a high level of anti-Fn-Dps antibody was prevalent in populations, and elevated anti-Fn-Dps antibody levels were observed in CRC patients. Furthermore, Fn-Dps promotes the migration of CRC cells via the CCL2/CCL7-induced epithelial-mesenchymal transition (EMT) and promotes CRC metastasis in vivo.


Assuntos
Neoplasias Colorretais , Fusobacterium nucleatum , Humanos , Fusobacterium nucleatum/genética , Fatores de Virulência/genética , Intestinos/patologia , Eritrócitos/metabolismo
2.
Cell Death Dis ; 14(1): 4, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604420

RESUMO

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain and the pathological accumulation of misfolded α-synuclein (α-syn) in the brain. A growing body of evidence suggests that the formation of misfolded α-syn and aggregation may begin in the peripheral nervous system, specifically the enteric nervous system, and then propagate to the central nervous system via the vagus nerve. However, the PD-like neuropathology induced by the intestine and vagus nerve extracts is rarely investigated. In this work, we injected lysates of the intestine and vagus obtained from a diagnosed PD patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection induced dopaminergic neurodegeneration and α-syn depositions in the striatum, substantia nigra, and other brain regions, including the frontal cortex, somatosensory cortex, hypothalamus, brain stem, and cerebellum. Moreover, significant activation of microglia and the development of astrogliosis were observed in the substantia nigra pars compacta of the injected rats. These findings provide essential information for our understanding of PD pathogenesis, as we established for the first time that the α-syn aggregates in the intestine and vagus of a PD patient were sufficient to induce prion-like propagation of endogenous α-syn pathology in wild-type rats.


Assuntos
Enteropatias , Doença de Parkinson , Sinucleinopatias , Ratos , Animais , Doença de Parkinson/patologia , Sinucleinopatias/patologia , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Substância Negra/metabolismo , Nervo Vago/metabolismo , Nervo Vago/patologia , Intestinos/patologia , Enteropatias/patologia , Neurônios Dopaminérgicos/metabolismo
3.
Oxid Med Cell Longev ; 2023: 3071610, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36691639

RESUMO

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease of the intestine, which is prone to recurrence and difficult to cure. Yiyi Fuzi Baijiang powder (YFBP), as a classic Chinese herbal formula, is commonly used in the clinical treatment of UC. However, its potential mechanism remains unclear. In this study, we investigated the mechanism by which YFBP exerts a therapeutic effect against UC. Firstly, we used network pharmacology to screen the active ingredients and potential targets of YFBP and constructed a "drug-ingredient-target" network. Based on bioinformatics, we searched for differentially expressed genes (DEGs) associated with UC and obtained common targets. The core targets of YFBP in the treatment of UC were identified using a protein-protein interaction (PPI) network, and molecular docking techniques were used to evaluate the binding energies of the core targets and corresponding ingredients. Enrichment analysis by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that YFBP exerted therapeutic effects by regulating multiple inflammatory pathways including TLR4, NF-κB, and TNF. Secondly, an experimental study was carried out in vivo for verification. Our results demonstrated that YFBP could effectively improve the symptoms and intestinal pathological of UC rats. Further study showed that YFBP could significantly downregulate the expressions of TLR4 and p-NF-κB p65 in UC rats, inhibit the activation of NLRP3 inflammasome, reduce the levels of IL-1ß and TNF-α, and then upregulate the expressions of tight junction proteins in intestinal epithelial cells. In addition, YFBP could improve the intestinal microbial community. In conclusion, our study revealed that YFBP had a good therapeutic effect on UC, and its mechanism might be related to the inhibition of the TLR4/NF-κB/NLRP3 inflammasome signaling pathway to repair intestinal epithelial barrier and the modulation of intestinal microbiota.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Ratos , Animais , Colite Ulcerativa/induzido quimicamente , NF-kappa B/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfato de Dextrana/efeitos adversos , Receptor 4 Toll-Like/metabolismo , Pós/efeitos adversos , Simulação de Acoplamento Molecular , Transdução de Sinais , Intestinos/patologia
4.
Carbohydr Polym ; 302: 120374, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36604052

RESUMO

Carrageenan is a common additive, but mounting studies have reported that it may cause or aggravate inflammation in the intestines. The safety of carrageenan remains controversial and its inflammatory mechanisms are unclear. In this review, the pathogenesis of colitis by carrageenans was discussed. We analyzed the pathogenesis of inflammatory bowel disease, followed that line of thought, the existing evidence of carrageenans causing colitis in cellular and animal models was summarized to draw its colitis pathogenesis. Two pathways were described including: 1) carrageenan changed the composition of intestinal microbiota, especially Akkermansia muciniphila, which destroyed the mucosal barrier and triggered the inflammatory immune response; and 2) carrageenan directly contacted with receptors on epithelial cells and activated the NF-κB inflammatory pathway. This review aim to provide guidance for exploring the treatment of colitis caused by carrageenan, and safe processing and utilization of carrageenan in food industry, which is worthy of study in the future.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Carragenina , Colite/induzido quimicamente , Colite/patologia , Intestinos/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia
5.
Pediatr Surg Int ; 39(1): 80, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631569

RESUMO

PURPOSE: Nowadays, the standard therapy for patients with short bowel syndrome is parenteral nutrition (PN). Various growth factors have been tested to achieve weaning from prolonged PN administration. We evaluated the effect of hepatocyte growth factor (HGF) on structural intestinal adaptation and cell proliferation in a rat model of SBS. METHODS: Thirty Sprague-Dawley rats were divided into three groups; group A rats (sham) underwent bowel transection, group B rats underwent a 75% bowel resection, and group C rats underwent the same procedure but were treated postoperatively with HGF. Histopathologic parameters of intestinal adaptation were determined, while microarray and rt-PCR analyses of ileal RNA were also performed. RESULTS: Treatment with HGF resulted in significant increase in body weight, while the jejunal and ileal villus height and crypt depth were increased in HGF rats (36%, p < 0.05 and 27%, p < 0.05 respectively). Enterocyte proliferation was also significantly increased in HGF rats (21% p < 0.05). Microarray and quantitative rt-PCR analyses showed that the genes hgfac, rac 1, cdc42, and akt 1 were more than twofold up-regulated after HGF treatment. CONCLUSION: HGF emerges as a growth factor that enhances intestinal adaptation. The future use of HGF may potentially reduce the requirement for PN in SBS patients.


Assuntos
Síndrome do Intestino Curto , Ratos , Animais , Síndrome do Intestino Curto/tratamento farmacológico , Síndrome do Intestino Curto/metabolismo , Ratos Sprague-Dawley , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/farmacologia , Intestinos/patologia , Mucosa Intestinal/metabolismo , Adaptação Fisiológica , Modelos Teóricos , Modelos Animais de Doenças
6.
ACS Nano ; 17(1): 811-824, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36521055

RESUMO

Oral drug delivery is a common route for management of inflammatory bowel disease (IBD) but suffers from low bioavailability and systemic side effects during passage through the alimentary canal. Here, we present a therapeutic nano reagent of a ferulic acid-derived lignin nanoparticle (FALNP). We showed that FALNP with favorable antioxidant activity can regulate IBD. More importantly, the intestinal pH-responsive degradability of FALNP allows it to withstand the harsh gastric acid environment, bypass physiological barriers, and target the intestine for gastrointestinal delivery. In vivo experiments showed that oral administration of FALNP markedly relieved pathological symptoms in a mouse model of acute colitis by reducing oxidative stress and regulating the gut microbiome. By integrating anti-inflammatory medicine, FALNP also can be used as a bioactive carrier to exert a potent synergistic therapeutic effect. In addition to colitis, FALNP can be readily adaptable for use as a carrier platform for therapy of many other intestinal diseases.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Portadores de Fármacos/uso terapêutico , Lignina/uso terapêutico , Indicadores e Reagentes , Ácido Gástrico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos/patologia , Concentração de Íons de Hidrogênio
7.
J Cell Mol Med ; 27(2): 246-258, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36579449

RESUMO

Radiation-induced intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal, or retroperitoneal tumours. Recently, in the model of DSS (Dextran Sulfate Sodium Salt) -induced intestinal inflammatory injury, it has been found in the study that transgenic mice expressing hVDR in IEC (Intestinal Epithelial Cell) manifest highly anti-injury properties in colitis, suggesting that activated VDR in the epithelial cells of intestine may inhibit colitis by protecting the mucosal epithelial barrier. In this study, we investigated the effect of the expression and regulation of VDR on the protection of RIII, and the radiosensitivity in vitro experiments, and explored the initial mechanism of VDR in regulating radiosensitivity of IEC. As a result, we found that the expression of VDR in intestinal tissues and cells in mice can be induced by ionizing radiation. VDR agonists are able to prolong the average survival time of mice after radiation and reduce the radiation-induced intestinal injury. For lack of vitamin D, the radiosensitivity of intestinal epithelial cells in mice increased, which can be reduced by VDR activation. Ensuing VDR activation, the radiation-induced intestinal stem cells damage is decreased, and the regeneration and differentiation of intestinal stem cells is promoted as well. Finally, on the basis of sequencing analysis, we validated and found that VDR may target the HIF/PDK1 pathway to mitigate RIII. We concluded that agonism or upregulation of VDR expression attenuates radiation-induced intestinal damage in mice and promotes the repair of epithelial damage in intestinal stem cells.


Assuntos
Colite , Receptores de Calcitriol , Animais , Camundongos , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Lesões Experimentais por Radiação
8.
Int Immunopharmacol ; 114: 109531, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36513023

RESUMO

To investigate the characteristics and functions of yak ß-defensin 124 (DEFB124), prokaryotic expression, analysis of gut microbiological and other methods were used in this study. The results showed that the sequence of yak DEFB124 gene was 306 bp in length and 207 bp in open reading frame, which encoded 68 amino acids. Yak DEFB124 protein was highly conserved and had the closest relationship with cattle. Yak DEFB124 protein was a secreted cationic ß-defensin. The recombinant expression plasmid pET32a-DEFB124 was constructed, and an about 24 kDa protein was successfully expressed. Yak DEFB124 protein had inhibitory activity against Staphylococcus aureus (S. aureus), and its MIC value was 64 µg/mL. After treating with yak DEFB124 protein, the activities of alkaline phosphatase (AKP) and total superoxide dismutase (T-SOD) were higher (P < 0.01) in the jejunum tissue, but the activity of lysozyme (LZM) was lower (P < 0.01). The number of goblet cells in the duodenum, jejunum, and ileum of the mice in the DEFB124 group was increased (P < 0.01). Besides, the expressions of MUC2 mRNA and protein were increased (P < 0.05) after the treatment with yak DEFB124 protein. Furthermore, the relative abundance of Lactobacillus in jejunum of mice in DEFB124 group was also increased. In summary, yak DEFB124 protein could increase the number of goblet cells in mice intestine and the abundance of intestinal probiotics Lactobacillus, thereby protecting the intestinal tract and alleviating intestinal damage.


Assuntos
Infecções Estafilocócicas , beta-Defensinas , Animais , Bovinos , Camundongos , beta-Defensinas/genética , beta-Defensinas/imunologia , Células Caliciformes , Probióticos , Infecções Estafilocócicas/imunologia , Staphylococcus aureus , Intestinos/imunologia , Intestinos/patologia
9.
J Immunol ; 210(3): 271-282, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36548460

RESUMO

Swine coronavirus-porcine epidemic diarrhea virus (PEDV) with specific susceptibility to pigs has existed for decades, and recurrent epidemics caused by mutant strains have swept the world again since 2010. In this study, single-cell RNA sequencing was used to perform for the first time, to our knowledge, a systematic analysis of pig jejunum infected with PEDV. Pig intestinal cell types were identified by representative markers and identified a new tuft cell marker, DNAH11. Excepting enterocyte cells, the goblet and tuft cells confirmed susceptibility to PEDV. Enrichment analyses showed that PEDV infection resulted in upregulation of cell apoptosis, junctions, and the MAPK signaling pathway and downregulation of oxidative phosphorylation in intestinal epithelial cell types. The T cell differentiation and IgA production were decreased in T and B cells, respectively. Cytokine gene analyses revealed that PEDV infection downregulated CXCL8, CXCL16, and IL34 in tuft cells and upregulated IL22 in Th17 cells. Further studies found that infection of goblet cells with PEDV decreased the expression of MUC2, as well as other mucin components. Moreover, the antimicrobial peptide REG3G was obviously upregulated through the IL33-STAT3 signaling pathway in enterocyte cells in the PEDV-infected group, and REG3G inhibited the PEDV replication. Finally, enterocyte cells expressed almost all coronavirus entry factors, and PEDV infection caused significant upregulation of the coronavirus receptor ACE2 in enterocyte cells. In summary, this study systematically investigated the responses of different cell types in the jejunum of piglets after PEDV infection, which deepened the understanding of viral pathogenesis.


Assuntos
Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Suínos , Animais , Vírus da Diarreia Epidêmica Suína/genética , Transcriptoma , Intestino Delgado/patologia , Intestinos/patologia , Análise de Sequência de RNA
10.
BMC Pediatr ; 22(1): 723, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36536313

RESUMO

BACKGROUND: In the validation of new imaging technology for children with Hirschsprung's disease (HSCR), basic anatomical parameters of the bowel wall must be established specifically for this patient group. AIM: To explore differences in histoanatomical layers of bowel wall, comparing ganglionic and aganglionic bowel walls, and to examine if the bowel wall thickness is linked to patient weight. METHODS: This was an observational study of bowel specimens from children weighing 0-10 kg, operated on consecutively during 2018-2020. Ganglionic and aganglionic bowel walls were measured in digitalized microscopy images from 10 sites per trans-sectional specimen and compared regarding the thickness of their histoanatomical layers. RESULTS: Bowel walls were measured in 21 children. Full bowel wall thickness did not differ between aganglionic and ganglionic bowel (2.20 vs 2.04; p = 0.802) while weight at surgery correlated positively with both ganglionic and aganglionic bowel wall thickness (r = 0.688 and 0.849, respectively), and age at surgery with ganglionic bowel wall thickness (r = 0.517). In aganglionic segments, the muscularis externa layer was thicker compared to that in ganglionosis (0.45 vs 0.31 mm, p = 0.012) whereas the muscularis interna was thinner (0.45 vs 0.62 mm, p < 0.001). A diagnostic index was identified whereby a lower ratio of muscularis interna/externa thickness followed by a thinner muscularis interna differed between aganglionic and ganglionic bowel in all specimens. CONCLUSION: Thicknesses of the bowel wall's muscle layers differ between aganglionic and ganglionic bowel walls in children with HSCR. These findings support a diagnostic index that could be validated for transfer to instant diagnostic imaging techniques. LEVEL OF EVIDENCE: Diagnostic: 3.


Assuntos
Doença de Hirschsprung , Criança , Humanos , Lactente , Doença de Hirschsprung/genética , Intestinos/patologia , Gânglios/patologia
11.
Mucosal Immunol ; 15(6): 1181-1187, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36380094

RESUMO

Rapid development of the fetal and neonatal intestine is required to meet the growth requirements of early life and form a protective barrier against external insults encountered by the intestinal mucosa. The fetus receives nutrition via the placenta and is protected from harmful pathogens in utero, which leads to intestinal development in a relatively quiescent environment. Upon delivery, the intestinal mucosa is suddenly tasked with providing host defense and meeting nutritional demands. To serve these functions, an array of specialized epithelial cells develop from intestinal stem cells starting in utero and continuing postnatally. Intestinal disease results when these homeostatic processes are interrupted. For preterm neonates, the most common pathology resulting from epithelial barrier dysfunction is necrotizing enterocolitis (NEC). In this review, we discuss the normal development and function of the intestinal epithelium in early life as well as how disruption of these processes can lead to NEC.


Assuntos
Enterocolite Necrosante , Mucosa Intestinal , Recém-Nascido , Humanos , Mucosa Intestinal/patologia , Enterocolite Necrosante/patologia , Intestinos/patologia , Células Epiteliais/patologia
12.
Genes (Basel) ; 13(11)2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36360243

RESUMO

Radiation-induced toxicity to healthy/normal intestinal tissues, especially during radiotherapy, limits the radiation dose necessary to effectively eradicate tumors of the abdomen and pelvis. Although the pathogenesis of intestinal radiation toxicity is highly complex, understanding post-irradiation alterations in protein profiles can provide crucial insights that make radiotherapy safer and more efficient and allow for increasing the radiation dose during cancer treatment. Recent preclinical and clinical studies have advanced our current understanding of the molecular changes associated with radiation-induced intestinal damage by assessing changes in protein expression with mass spectrometry-based approaches and 2-dimensional difference gel electrophoresis. Studies by various groups have demonstrated that proteins that are involved in the inflammatory response, the apoptotic pathway, reactive oxygen species scavenging, and cell proliferation can be targeted to develop effective radiation countermeasures. Moreover, altered protein profiles serve as a crucial biomarkers for intestinal radiation damage. In this review, we present alterations in protein signatures following intestinal radiation damage as detected by proteomics approaches in preclinical and clinical models with the aim of providing a better understanding of how to accomplish intestinal protection against radiation damage.


Assuntos
Proteoma , Lesões por Radiação , Humanos , Proteoma/genética , Lesões por Radiação/genética , Lesões por Radiação/patologia , Intestinos/patologia , Espécies Reativas de Oxigênio , Proteômica
13.
Nature ; 611(7936): 578-584, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323778

RESUMO

Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites<sup>1,2</sup>, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.


Assuntos
Ácidos e Sais Biliares , Fibras na Dieta , Microbioma Gastrointestinal , Inflamação , Inulina , Animais , Humanos , Camundongos , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/farmacologia , Fibras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Imunidade Inata , Inflamação/induzido quimicamente , Inflamação/classificação , Inflamação/patologia , Inulina/farmacologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Metabolômica , Pulmão/efeitos dos fármacos , Pulmão/patologia , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Interleucina-33/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia
14.
Transl Neurodegener ; 11(1): 44, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253844

RESUMO

BACKGROUND: Aberrant aggregation of α-synuclein (α-syn) is a key pathological feature of Parkinson's disease (PD), but the precise role of intestinal α-syn in the progression of PD is unclear. In a number of genetic Drosophila models of PD, α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology. METHOD: We investigated the potential role of intestinal α-syn in PD pathogenesis using a Drosophila model. Human α-syn was overexpressed in Drosophila guts, and life span, survival, immunofluorescence and climbing were evaluated. Immunofluorescence, Western blotting and reactive oxygen species (ROS) staining were performed to assess the effects of intestinal α-syn on intestinal dysplasia. High-throughput RNA and 16S rRNA gene sequencing, quantitative RT-PCR, immunofluorescence, and ROS staining were performed to determine the underlying molecular mechanism. RESULTS: We found that the intestinal α-syn alone recapitulated many phenotypic and pathological features of PD, including impaired life span, loss of dopaminergic neurons, and progressive motor defects. The intestine-derived α-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing. Moreover, intestinal expression of α-syn induced dysbiosis, while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD. Intestinal α-syn triggered ROS, and eventually led to the activation of the dual oxidase (DUOX)-ROS-Jun N-terminal Kinase (JNK) pathway. In addition, α-syn from both the gut and the brain synergized to accelerate the progression of PD. CONCLUSIONS: The intestinal expression of α-syn recapitulates many phenotypic and pathologic features of PD, and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila. Our findings provide new insights into the role of intestinal α-syn in PD pathophysiology.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Drosophila/genética , Drosophila/metabolismo , Oxidases Duais , Disbiose/complicações , Disbiose/genética , Humanos , Intestinos/patologia , Proteínas Quinases JNK Ativadas por Mitógeno , Doença de Parkinson/metabolismo , RNA Ribossômico 16S , Espécies Reativas de Oxigênio , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
15.
Front Immunol ; 13: 1034570, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36311796

RESUMO

Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using in vitro culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.


Assuntos
Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Proteínas de Transporte/metabolismo , Colo , Citocinas/metabolismo , Intestinos/patologia
16.
Nature ; 611(7937): 801-809, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36266581

RESUMO

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.


Assuntos
Meio Ambiente , Herbicidas , Inflamação , Doenças Inflamatórias Intestinais , Intestinos , Animais , Camundongos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Peixe-Zebra , Aprendizado de Máquina , Bases de Dados Factuais , Modelos Animais de Doenças , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/metabolismo , Intestinos/patologia , NF-kappa B , Proteína beta Intensificadora de Ligação a CCAAT , Receptores de Hidrocarboneto Arílico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Herbicidas/efeitos adversos
17.
Ter Arkh ; 94(7): 920-926, 2022 Aug 12.
Artigo em Russo | MEDLINE | ID: mdl-36286953

RESUMO

COVID-19 infection may present with gastrointestinal lesions in up to 25% of patients. One of the target organs of the SARS-CoV-2 virus is the intestine. The pathogenesis of intestinal damage in a new coronavirus infection remains unclear and requires further in-depth study. Possible mechanisms include a direct cytotoxic effect of the virus, a persistent reduction in butyrate-producing bacteria, side effects of drugs, Clostridioides difficile infection, microvascular thrombosis, and the immune-mediated inflammatory reactions in the intestine. The most common symptom of intestinal damage during coronavirus infection, both in the acute phase and in the post-COVID period, is diarrhea. The impact of many aggressive factors on the intestines can form both long-term functional disorders and be the cause of the onset of organic diseases. Treatment should be aimed at possible causes of intestinal damage (Clostridioides difficile), as well as reducing inflammation, restoring intestinal permeability, cytoprotection of mucosal cells, replenishing butyric acid deficiency. When choosing a therapy for intestinal disorders, preference should be given to drugs with a pleiotropic effect in order to influence various possible pathogenetic mechanisms.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Ácido Butírico , Diarreia , Intestinos/patologia , Inflamação
18.
Front Immunol ; 13: 981502, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189238

RESUMO

Behçet's syndrome (BS) is a chronic form of relapsing multisystem vasculitis, characterized by recurrent oral and genital ulcers. Intestinal BS is a special type of BS. Volcano-shaped ulcers in the ileocecum are a typical finding of intestinal BS, and punched-out ulcers can be observed in the intestine or esophagus. At present, there is no recognized radical treatment for intestinal BS. Glucocorticoids and immunosuppressants are currently the main drugs used to improve the condition. Although it has been reported that monoclonal anti-TNF antibodies may be effective for some refractory intestinal BS, further randomized, prospective trials are necessary to confirm these findings. Some patients are restricted from using biological agents because of serious allergic reactions of drugs, inconvenient drug injections or the impact of the novel coronavirus epidemic. If endoscopic remission (endoscopic healing) is not achieved for a prolonged period of time, serious complications, such as perforation, fistula formation, and gastrointestinal bleeding can be induced. Therefore, it is necessary to develop new treatment methods for controlling disease progression. We reviewed the relevant literature, combined with the analysis of the correlation between the pathogenesis of BS and the mechanism of Janus kinase (JAK) inhibition, and considered that tofacitinib (TOF) may be effective for managing refractory intestinal BS. We report for the first time that four patients with severe refractory intestinal BS were successfully treated with TOF. We hope to provide valuable information on JAK inhibitors as potential therapeutic targets for the treatment of severe refractory intestinal BS.


Assuntos
Síndrome de Behçet , Inibidores de Janus Quinases , Piperidinas , Pirimidinas , Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Fatores Biológicos/uso terapêutico , COVID-19/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Intestinos/patologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases , Piperidinas/uso terapêutico , Estudos Prospectivos , Pirimidinas/uso terapêutico , Inibidores do Fator de Necrose Tumoral , Úlcera/tratamento farmacológico
19.
Sci Rep ; 12(1): 15256, 2022 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088483

RESUMO

A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.


Assuntos
Celulas de Paneth , Sepse , Animais , Estresse do Retículo Endoplasmático , Intestinos/patologia , Camundongos , Celulas de Paneth/metabolismo , Sepse/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
20.
Eur J Immunol ; 52(10): 1547-1560, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35985020

RESUMO

Tissue-resident memory T cells (Trm), and particularly the CD8+ subset, have been shown to play a pivotal role in protection against infections and tumors. Studies in animal models and human tissues have highlighted that, while a core functional program is shared by Trm at all anatomical sites, distinct tissues imprint unique features through specific molecular cues. The intestinal tissue is often the target of pathogens for local proliferation and penetration into the host systemic circulation, as well as a prominent site of tumorigenesis. Therefore, promoting the formation of Trm at this location is an appealing therapeutic option. The various segments composing the gastrointestinal tract present distinctive histological and functional characteristics, which may reflect on the imprinting of unique functional features in the respective Trm populations. What these features are, and whether they can effectively be harnessed to promote local and systemic immunity, is still under investigation. Here, we review how Trm are generated and maintained in distinct intestinal niches, analyzing the required molecular signals and the models utilized to uncover them. We also discuss evidence for a protective role of Trm against infectious agents and tumors. Finally, we integrate the knowledge obtained from animal models with that gathered from human studies.


Assuntos
Memória Imunológica , Neoplasias , Animais , Linfócitos T CD8-Positivos , Humanos , Intestinos/patologia , Células T de Memória
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