RESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by continuous inflammation and ulcer formation in the intestinal mucosa.Its pathogenesis involves immune dysfunction,dysbiosis of gut microbiota,and mucosal damage caused by inflammation.Ferroptosis is an iron-dependent form of cell death regulated by disturbances in iron metabolism,lipid peroxidation,and depletion of glutathione (GSH).Studies have indicated that ferroptosis plays a crucial role in the pathogenesis of UC,particularly in regulating inflammatory responses and damaging intestinal epithelial cells.This article reviews the regulatory mechanisms and roles of ferroptosis in UC and discusses the potential therapeutic strategies to alleviate UC symptoms by modulating iron metabolism,reducing lipid peroxidation,and maintaining GSH levels,providing new targets and directions for the diagnosis and treatment of UC.
Asunto(s)
Colitis Ulcerosa , Ferroptosis , Humanos , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Hierro/metabolismo , Peroxidación de Lípido , Glutatión/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Microbioma Gastrointestinal , Inflamación , AnimalesRESUMEN
Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.
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Antibacterianos , Colon , Microbioma Gastrointestinal , Mucosa Intestinal , Moco , Animales , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Microbioma Gastrointestinal/efectos de los fármacos , Colon/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/microbiología , Moco/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/microbiología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Ratones Endogámicos C57BL , HumanosRESUMEN
Inflammatory bowel diseases (IBDs) are immune chronic diseases characterized by recurrent episodes, resulting in continuous intestinal barrier damage and intestinal microbiota dysbiosis. Safe strategies aimed at stabilizing and reducing IBDs recurrence have been vigorously pursued. Here, we constructed a recurrent intestinal injury Drosophila model and found that vitamin B12 (VB12), an essential co-factor for organism physiological functions, could effectively protect the intestine and reduce dextran sulfate sodium-induced intestinal barrier disruption. VB12 also alleviated microbial dysbiosis in the Drosophila model and inhibited the growth of gram-negative bacteria. We demonstrated that VB12 could mitigate intestinal damage by activating the hypoxia-inducible factor-1 signaling pathway in injured conditions, which was achieved by regulating the intestinal oxidation. In addition, we also validated the protective effect of VB12 in a murine acute colitis model. In summary, we offer new insights and implications for the potential supportive role of VB12 in the management of recurrent IBDs flare-ups.
Asunto(s)
Sulfato de Dextran , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Factor 1 Inducible por Hipoxia , Mucosa Intestinal , Transducción de Señal , Vitamina B 12 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Vitamina B 12/farmacología , Vitamina B 12/metabolismo , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Transducción de Señal/efectos de los fármacos , Sulfato de Dextran/toxicidad , Factor 1 Inducible por Hipoxia/metabolismo , Colitis/metabolismo , Colitis/inducido químicamente , Colitis/microbiología , Colitis/patología , Colitis/tratamiento farmacológico , Disbiosis/microbiología , Disbiosis/metabolismo , Ratones Endogámicos C57BL , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Drosophila/metabolismoRESUMEN
Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.
Asunto(s)
Cirrosis Hepática , Melatonina , Sirtuina 1 , Tioacetamida , Tioacetamida/toxicidad , Sirtuina 1/metabolismo , Melatonina/farmacología , Animales , Cirrosis Hepática/metabolismo , Cirrosis Hepática/inducido químicamente , Ratones , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Acetilación/efectos de los fármacos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patologíaRESUMEN
WSGP has demonstrated significant potential for various bioactive effects. However, limited research has explored their anti-ulcerative colitis (UC) effects and mechanism on the colonic system and gut microbial metabolites. We evaluated the ameliorative effects of WSGP on the UC mice model. Using H&E to assess histological injury of colon morphology, AB-PAS staining to detect mucin secretion from goblet cells and the mucous layer, IF to evaluate the expression of intercellular tight junction proteins, ELISA to measure inflammatory factors, WB analysis to measure protein expression of inflammatory signaling pathways, RT-qPCR to quantify gene transcription of inflammatory factors, and LC-MS to analyze metabolites in mouse cecum contents. WSGP supplementation increased food intake, body weight, and colon length while reducing disease activity and histological scores in colitis-afflicted mice. WSGP mitigated colonic tissue damage and restored intestinal barrier integrity by suppressing NF-κB/STAT3 signaling, thereby decreasing gene transcription, protein expression of proinflammatory factors, and nitric oxide production. Additionally, WSGP improved UC by altering the variety of intestinal microbial metabolites. This study demonstrates that WSGP supplementation attenuates UC mice by suppressing the NF-κB/STAT3 signaling pathway, enhancing mucosal barrier function, reducing pro-inflammatory cytokines, and modulating gut microbial metabolites.
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Colitis Ulcerosa , Ajo , Microbioma Gastrointestinal , Mucosa Intestinal , Polisacáridos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Polisacáridos/farmacología , Ajo/química , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Modelos Animales de Enfermedad , Masculino , Colon/metabolismo , Colon/patología , Colon/efectos de los fármacos , Colon/microbiología , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Agua , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: Aim: The purpose was to identify the morphological and functional features of the colonic mucus barrier in patients with symptomatic uncomplicated diverticular disease and acute uncomplicated diverticulitis. PATIENTS AND METHODS: Materials and Methods: In the research, three groups were formed. Group 1 included fragments of the mucous membrane of the large intestine, which were collected from 12 people during autopsies. The results of autopsies and histological examination of the material did not reveal any gastrointestinal pathology. Group 2 included biopsies of the mucous membrane of the large intestine from the area of the diverticulum of 34 patients with symptomatic uncomplicated diverticular disease. Group 3 included biopsies of the mucous membrane of the large intestine of 26 patients with acute uncomplicated diverticulitis. Histological (hematoxylin and eosin staining), histochemical (PAS reaction) and immunohistochemical (mouse monoclonal antibodies to Mucin 2 (MUC2) and Mucin 4 (MUC4)) staining methods were used. A morphometric study was also carried out. RESULTS: Results: In patients with diverticular disease, the authors identified disturbances in the morphofunctional state of the mucus barrier of the colon, the structure and function of goblet cells contained in its mucous membrane, characterized by a decrease in the thickness of the mucus layer covering the surface of the mucous membrane; a decrease in the size and number of goblet cells with a decrease in their mucus-producing ability; a change in the mucin profile, characterized by a violation of the content of MUC2 and MUC4. These changes were greatest in patients with acute uncomplicated diverticulitis compared with patients with symptomatic uncomplicated diverticular disease. CONCLUSION: Conclusions: The identified disturbances in the morphofunctional state of the mucus barrier of the colon, structural and functional changes in goblet cells may be one of the mechanisms for the development of acute uncomplicated diverticulitis and symptomatic uncomplicated diverticular disease.
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Mucosa Intestinal , Humanos , Masculino , Femenino , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Persona de Mediana Edad , Anciano , Moco/metabolismo , Colon/patología , Colon/metabolismo , Diverticulitis del Colon/patología , Diverticulitis del Colon/metabolismo , Enfermedad Aguda , Adulto , Mucina 2/metabolismo , Células Caliciformes/patología , Células Caliciformes/metabolismoRESUMEN
Incomplete resection rates vary among endoscopists performing cold snare polypectomy. Cold snare endoscopic mucosal resection (CS-EMR) is the technique of cold resection after submucosal injection to reduce incomplete resection. This study aimed to evaluate the efficacy and safety of CS-EMR for small colorectal polyps compared to hot snare endoscopic mucosal resection (HS-EMR). Preplanned sample size required 70 polyps to CS-EMR group or HS-EMR group, respectively. Patients with polyps sized 6-9 mm were randomly allocated to either the CS-EMR or the HS-EMR group. The primary outcome was residual or recurrent adenoma (RAA) rate. A total of 70 and 68 polyps were resected using CS-EMR and HS-EMR, respectively. In the intention-to-treat population, the RAA rate was 0% in the CS-EMR group and 1.5% in the HS-EMR group (risk difference [RD], - 1.47; 95% confidence interval [CI] - 4.34 to 1.39). En bloc resection rate was 98.6% and 98.5% (RD, - 0.04; 95% CI - 4.12 to 4.02); the R0 resection rate was 55.7% and 82.4% (RD, - 27.80; 95% CI - 42.50 to - 13.10). The total procedure time was 172 s (IQR, 158-189) in the CS-EMR group and 186 s (IQR, 147-216) in the HS-EMR group (median difference, - 14; 95% CI - 32 to 2). Delayed bleeding was 2.9% vs 1.5% (RD, 1.37; 95% CI - 3.47 to 6.21) in both groups, respectively. CS-EMR was non-inferior to HS-EMR for the treatment of small colorectal polyps. CS-EMR can be considered one of the standard methods for the removal of colorectal polyps sized 6-9 mm.
Asunto(s)
Pólipos del Colon , Resección Endoscópica de la Mucosa , Humanos , Resección Endoscópica de la Mucosa/métodos , Masculino , Femenino , Persona de Mediana Edad , Pólipos del Colon/cirugía , Pólipos del Colon/patología , Anciano , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Colonoscopía/métodos , Resultado del Tratamiento , Adenoma/cirugía , Adenoma/patología , Recurrencia Local de Neoplasia/cirugía , Mucosa Intestinal/cirugía , Mucosa Intestinal/patologíaRESUMEN
Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.
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Fluorouracilo , Intestino Delgado , Melatonina , Mucositis , Organoides , Animales , Melatonina/farmacología , Ratas , Organoides/efectos de los fármacos , Fluorouracilo/efectos adversos , Fluorouracilo/farmacología , Ratones , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Mucositis/inducido químicamente , Mucositis/patología , Mucositis/prevención & control , Mucositis/tratamiento farmacológico , Masculino , Atrofia/inducido químicamente , Atrofia/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patologíaRESUMEN
The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn's disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.
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Enfermedad de Crohn , Mucosa Intestinal , Ustekinumab , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Ustekinumab/uso terapéutico , Femenino , Masculino , Alemania , Adulto , Persona de Mediana Edad , Estudios Prospectivos , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de los fármacos , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacosRESUMEN
PURPOSE: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. METHODS: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. RESULTS: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. CONCLUSIONS: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.
Asunto(s)
Colitis Ulcerosa , Colon , Oxazolona , Peroxidasa , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Masculino , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Peroxidasa/análisis , Peroxidasa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Sprague-Dawley , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Ratas , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento Epidérmico/análisis , Citocinas/metabolismo , Interleucina-13/análisis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/análisis , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis.
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Colitis , Sulfato de Dextran , Macrófagos , Proteínas de la Membrana , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Piroptosis/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Transducción de Señal/efectos de los fármacos , Inflamasomas/metabolismo , Citocinas/metabolismo , Masculino , Humanos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Recent evidence indicates that the gut microbiota (GM) has a significant impact on the inflammatory bowel disease (IBD) progression. Our aim was to investigate the GM profiles, the Microbial Dysbiosis Index (MDI) and the intestinal microbiota-associated markers in relation to IBD clinical characteristics and disease state. We performed 16S rRNA metataxonomy on both stools and ileal biopsies, metabolic dysbiosis tests on urine and intestinal permeability and mucosal immunity activation tests on the stools of 35 IBD paediatric patients. On the GM profile, we assigned the MDI to each patient. In the statistical analyses, the MDI was correlated with clinical parameters and intestinal microbial-associated markers. In IBD patients with high MDI, Gemellaceae and Enterobacteriaceae were increased in stools, and Fusobacterium, Haemophilus and Veillonella were increased in ileal biopsies. Ruminococcaceae and WAL_1855D were enriched in active disease condition; the last one was also positively correlated to MDI. Furthermore, the MDI results correlated with PUCAI and Matts scores in ulcerative colitis patients (UC). Finally, in our patients, we detected metabolic dysbiosis, intestinal permeability and mucosal immunity activation. In conclusion, the MDI showed a strong association with both severity and activity of IBD and a positive correlation with clinical scores, especially in UC. Thus, this evidence could be a useful tool for the diagnosis and prognosis of IBD.
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Biomarcadores , Disbiosis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Medicina de Precisión , Humanos , Disbiosis/microbiología , Niño , Femenino , Masculino , Enfermedades Inflamatorias del Intestino/microbiología , Adolescente , Medicina de Precisión/métodos , ARN Ribosómico 16S/genética , Heces/microbiología , Preescolar , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Íleon/microbiología , Íleon/patología , Colitis Ulcerosa/microbiologíaRESUMEN
This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 µg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway.
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Apoptosis , Lipopolisacáridos , Cofactor PQQ , Animales , Apoptosis/efectos de los fármacos , Porcinos , Cofactor PQQ/farmacología , Cofactor PQQ/uso terapéutico , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Modelos Animales de Enfermedad , MAP Quinasa Quinasa 3/metabolismo , Suplementos Dietéticos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Proteínas de Uniones Estrechas/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patologíaRESUMEN
BACKGROUND: Calprotectin, a damage-associated molecular pattern protein of the S100/calgranulin family, is a potential marker of gastrointestinal inflammation in dogs and mainly originates from activated macrophages and granulocytes. Increased calprotectin concentrations are reported in feces and serum samples from dogs with chronic inflammatory enteropathy (CIE), but mucosal calprotectin expression has not been extensively investigated in canine CIE. Thus, we aimed to evaluate gastrointestinal mucosal concentrations of calprotectin in 62 dogs (44 dogs with CIE compared to 18 healthy Beagles) using a particle-enhanced turbidimetric immunoassay method. Additionally, we assessed the relationship of gastric, duodenal, jejunal, ileal, and colonic mucosal calprotectin levels with the clinical disease severity (canine clinical inflammatory bowel disease activity index, CIBDAI), histopathologic findings, clinical outcome, and serum albumin concentrations to further evaluate the potential of calprotectin as a biomarker for CIE. RESULTS: Mucosal calprotectin concentrations in dogs with CIE were significantly higher in the duodenum (median: 276.2 µg/g) and colon (median: 298.2 µg/g) compared to healthy controls (median: 94.3 µg/g, P = 0.0039; and median: 112.0 µg/g, P = 0.0061). Similar numerical differences in the ileum and cecum were not statistically significant, and mucosal calprotectin concentrations correlated significantly among the different gastrointestinal segments. Histologic lesion severity was linked to mucosal calprotectin concentrations for inflammatory and structural histology criteria in the duodenum and colon (all P < 0.05). Higher mucosal calprotectin levels in the duodenum and across all segments correlated with lower serum albumin concentrations (both P < 0.05); duodenal mucosal calprotectin concentrations were more than sixfold higher in hypoalbuminemic dogs (median: 1441 µg/g, n = 4) than normoalbuminemic dogs (median: 227 µg/g, n = 40). There was no significant association of mucosal calprotectin levels with CIBDAI scores or individual clinical outcomes. CONCLUSIONS: These results show that duodenal and colonic mucosal calprotectin concentrations are increased in dogs with CIE, providing further supporting evidence for the diagnostic potential of fecal calprotectin (presumably reflecting mucosal) concentrations and in dogs with CIE. Further longitudinal research is needed to assess changes in mucosal calprotectin concentrations with clinical response to treatment vs. mucosal disease remission and to determine the clinical utility of fecal calprotectin concentrations to diagnose and monitor dogs with CIE in clinical practice.
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Colon , Enfermedades de los Perros , Mucosa Intestinal , Complejo de Antígeno L1 de Leucocito , Animales , Perros , Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/patología , Complejo de Antígeno L1 de Leucocito/análisis , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Masculino , Femenino , Colon/patología , Colon/metabolismo , Duodeno/patología , Duodeno/metabolismo , Biomarcadores/metabolismo , Enfermedades Inflamatorias del Intestino/veterinaria , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Grifola frondosa polysaccharide (GFP) is a consumable fungus recognized for its potential health advantages. The present study aimed to investigate the development and potential etiologies of ulcerative colitis (UC) utilizing oxazolone (OXZ) as an inducer in mice, along with assessing the therapeutic effects of GFP at varying doses in UC mice, with sulfasalazine (SASP) serving as the positive control. The obtained results indicated that OXZ intervention in mice induced numerous physical manifestations of UC, including increased disease activity index (DAI), decreased goblet cell division, enhanced fibrosis, reduced expression of Claudin1 and Zona encludens protein1 (ZO-1), decreased proliferative activity of colonic mucosal epithelial cells, disturbed oxidation balance, and alterations in intestinal flora. Nonetheless, GFP intervention significantly ameliorated or even resolved these abnormal indicators to a considerable extent. Consequently, this study suggests that GFP might serve as a prebiotic to regulate intestinal flora, mitigate enterotoxin production, restore oxidative balance, thereby reducing the generation of inflammatory mediators, restoring the intestinal barrier, and ultimately improving OXZ-induced UC in mice. GFP demonstrates promising potential as a candidate drug for colitis treatment and as a dietary supplement for alleviating intestinal inflammatory issues.
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Colitis Ulcerosa , Grifola , Oxazolona , Animales , Oxazolona/toxicidad , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Ratones , Grifola/química , Masculino , Polisacáridos Fúngicos/farmacología , Polisacáridos Fúngicos/química , Polisacáridos/farmacología , Polisacáridos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Microbioma Gastrointestinal/efectos de los fármacos , Sulfasalazina/farmacologíaRESUMEN
2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800â¯mg/kg), M(1600â¯mg/kg), H(3200â¯mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry.
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Pollos , Duodeno , Retardadores de Llama , Estrés Oxidativo , Animales , Estrés Oxidativo/efectos de los fármacos , Duodeno/efectos de los fármacos , Duodeno/patología , Duodeno/metabolismo , Masculino , Retardadores de Llama/toxicidad , Inflamación/inducido químicamente , Inflamación/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Compuestos Organofosforados/toxicidad , Organofosfatos/toxicidadRESUMEN
OBJECTIVE: This study will explore the function of WTAP, the critical segment of m6A methyltransferase complex, in UC and its regulation on immune response. METHODS: The expression levels of key proteins were detected in colon tissues which were derived from UC patients and mice. Macrophage polarization and CD4+ T cell infiltration were detected by flow cytometry and IF staining. ELISA assay was utilized to analyze the level of the inflammatory cytokines. m6A-RIP-PCR, actinomycin D test, and RIP assays were utilized to detect the m6A level, stability, and bound proteins of CES2 mRNA. A dual luciferase reporter assay was conducted to confirm the transcriptional interactions between genes. A co-culture system of intestinal epithelium-like organs was constructed to detect the primary mouse intestinal epithelial cells (PMIEC) differentiation. The interaction between proteins was detected via Co-IP assay. RESULTS: The expression of WTAP and CES2 in UC tissues was increased and decreased, respectively. Knockdown of WTAP inhibited the progression of UC in mice by inhibiting M1 macrophage polarization and CD4+ T cell infiltration. WTAP combined YTHDF2 to promote the m6A modification of CES2 mRNA and inhibited its expression. CES2 co-expressed with EPHX2 and overexpression of CES2 promoted the differentiation of PMIEC. The inhibitory effect of WTAP knockdown on the progress of UC was partially abrogated by CES2 knockdown. CONCLUSION: WTAP/YTHDF2 silences CES2 by promoting its m6A modification and then promotes the progression of UC. WTAP could be a promoting therapy target of UC.
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Colitis Ulcerosa , Progresión de la Enfermedad , Macrófagos , Animales , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Ratones , Humanos , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/inmunología , Masculino , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Regulación de la Expresión Génica , Metiltransferasas/metabolismo , Metiltransferasas/genética , FemeninoRESUMEN
Deoxynivalenol (DON) is a kind of widespread traditional Fusarium mycotoxins in the environment, and its intestinal toxicity has received considerable attention. Recently, the emerging Fusarium mycotoxin enniatins (ENNs) have also been shown to frequently coexist with DON in animal feed and food with large consumption. However, the mechanism of intestinal damage caused by the two mycotoxins co-exposure remains unclear. In this study, Caco-2 cell line was used to investigate the combined toxicity and potential mechanisms of four representative ENNs (ENA, ENA1, ENB, and ENB1) and DON. The results showed that almost all mixed groups showed antagonistic effects, particularly ENB at 1/4 IC50 (CI = 6.488). Co-incubation of ENNs mitigated the levels of signaling molecule levels disrupted by DON, including reactive oxygen species (ROS), calcium mobilization (Ca2+), adenosine triphosphate (ATP). The differentially expressed genes (DEGs) between the mixed and ENB groups were significantly enriched in the Ras/PI3K/Akt signaling pathway, including 28 up-regulated genes and 40 down-regulated genes. Quantitative real-time PCR further confirmed the lower expression of apoptotic gene in the mixed group, thereby reducing the cytotoxic effects caused by DON exposure. This study emphasizes that co-exposure of ENNs and DON reduces cytotoxicity by regulating the Ras/PI3K/Akt signaling pathway. Our results provide the first comprehensive evidence about the antagonistic toxicity of ENNs and DON on Caco-2 cells, and new insights into mechanisms investigated by transcriptomics.
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Depsipéptidos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Tricotecenos , Proteínas ras , Tricotecenos/toxicidad , Humanos , Células CACO-2 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Depsipéptidos/toxicidad , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas ras/metabolismo , Proteínas ras/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Especies Reactivas de Oxígeno/metabolismo , Intestinos/efectos de los fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver diseases (CLD) are liver disorders resulting from abnormal bile formation, secretion, and excretion from various causes. Due to the lack of suitable and safe medications, liver transplantation is the ultimate treatment for CLD patients. Isoastragaloside I (IAS I) is one of the main saponin found in Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge, which has been demonstrated to obviously alleviate CLD. Nevertheless, the IAS I's specific anti-CLD mechanism remains undecipherable. AIM OF THE STUDY: This study's purpose was to elucidate the protective consequence of IAS I on 0.1% 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet-induced CLD mice, and to reveal its potential mechanism. MATERIALS AND METHODS: In this study, mice with CLD that had been fed a 0.1% DDC diet were distributed two doses of IAS I (20 mg/kg, 50 mg/kg). The effects of IAS I on CLD models were investigated by assessing blood biochemistry, liver histology, and Hyp concentrations. We investigated markers of liver fibrosis and ductular reaction using immunohistochemistry, Western blot, and qRT-PCR. Liver inflammation indicators, arachidonic acid (ARA), and ω-3 fatty acid (FA) metabolites were also analyzed. Quantitative determination of 39 bile acids (BAs) in different organs employing UHPLC-Q-Exactive Orbitrap HRMS technology. Additionally, the H&E and Western blot analysis were used to evaluate differences in intestinal barrier function in DDC-induced mice before and after administering IAS I. RESULTS: After treatment with IAS I, serum biochemical indicators and liver hydroxyproline (Hyp) increased in a dose-dependent manner in CLD mice. The IAS I group showed significant improvement in indicators of liver fibrosis and ductular response, including as α-smooth muscle actin (α-SMA) and cytokeratin 19 (CK19), and transforming growth factor-ß (TGF-ß)/Smads signaling pathway. And inflammatory factors: F4/80, tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), ARA and ω-3 FA metabolites showed significant improvement following IAS I treatment. Moreover, IAS I significantly ameliorated liver tau-BAs levels, particularly TCA, THCA, THDCA, TCDCA, and TDCA contents, which were associated with enhanced expression of hepatic farnesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (Cyp7a1), and bile-salt export pump (BSEP). Furthermore, IAS I significantly improved pathological changes and protein expression related to intestinal barrier function, including zonula occludens protein 1 (ZO-1), Muc2, and Occludin. CONCLUSIONS: IAS I alleviated cholestatic liver injury, relieved inflammation, improved the altered tau-BAs metabolism and restored intestinal barrier function to protect against DDC-induced cholestatic liver diseases.