RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases, is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. AIM OF THE STUDY: This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models. MATERIALS AND METHODS: The effect of SNS (1.5, 3, 6 g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques. RESULTS: SNS (1.5, 3, 6 g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6 g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury. CONCLUSIONS: This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.

Asunto(s)

Colesterol , Colitis Ulcerosa , Sulfato de Dextran , Medicamentos Herbarios Chinos , Animales , Medicamentos Herbarios Chinos/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Ratones , Masculino , Colesterol/sangre , Células Th17/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Farmacología en Red , Citocinas/metabolismo , Linfocitos T Reguladores/efectos de los fármacos

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 , Animales

RESUMEN

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.

Asunto(s)

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 C57BL

RESUMEN

BACKGROUND: Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. METHODS: A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. RESULTS: DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). CONCLUSIONS: Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

Asunto(s)

Colitis Ulcerosa , Ferroptosis , Ginsenósidos , MicroARNs , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Ginsenósidos/farmacología , MicroARNs/genética , Ratones , Ferroptosis/efectos de los fármacos , Humanos , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Regulación hacia Arriba/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Sulfato de Dextran/toxicidad , Apoptosis/efectos de los fármacos

RESUMEN

OBJECTIVE: To investigate the mechanism of sanguinarine (SA) for alleviating ulcerative colitis (UC) induced by dextran sodium sulfate (DSS) in mice. METHODS: Male C57BL/6 mouse models of 3.5% DSS-induced UC were randomized for treatment with 1, 5 and 10 mg/kg SA by gavage, 400 mg/kg sulfasalazine by gavage, or 10 mg/kg SA combined with intraperitoneal injection of 30 mg/kg ML385 (a Nrf2 inhibitor). The changes in intestinal inflammation was assessed by monitoring weight changes, disease activity index (DAI) score, colon length measurement, and HE staining. After the treatments, the colon tissues were collected for detection of malondialdehyde (MDA) content using colorimetry, mRNA expressions of inflammatory factors using RT-qPCR, and the expressions of Nrf2, HO-1, Keap-1, p-p65, p65, occludin, and ZO-1 proteins were detected using Western blotting. RESULTS: SA treatment obviously alleviated weight loss, colon length shortening and DAI score increase and ameliorated structural destruction of the colon glands and colonic crypts in mice with DSSinduced UC. SA intervention significantly decreased the levels of TNF-α, IL-1ß and IL-6 mRNA and lowered ROS and MDA levels in the colon tissue of UC mice. The mouse models receiving SA treatment showed significantly increased expressions of Nrf2, HO-1, occludin and ZO-1 and lowered expressions of Keap-1 and P-P65 in the colon tissue without significant changes of p65 expression, and these changes were SA dose-dependent. Treatment with ML385 obviously attenuated the effect of highdose SA for improving UC in the mouse models. CONCLUSION: SA can improve UC-like enteritis in mice possibly by activating the Nrf2 pathway and inhibiting the NF-κB pathway in the colon tissue.

Asunto(s)

Colitis Ulcerosa , Sulfato de Dextran , Modelos Animales de Enfermedad , Isoquinolinas , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , FN-kappa B , Transducción de Señal , Animales , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Colon/metabolismo , Colon/patología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ocludina/metabolismo , Malondialdehído/metabolismo , Interleucina-1beta/metabolismo , Benzofenantridinas

RESUMEN

OBJECTIVE: To explore the targets and pathways of Cynanchum wilfordii for treatment of ulcerative colitis (UC). METHODS: UPLC-QE-MS was used to identify the components of Cynanchum wilfordii ethanol extract, and their targets were screened using public databases for construction of the core protein-protein interaction (PPI) network and GO and KEGG enrichment analyses. Forty male C57 mice were randomized into normal control group, model group, mesalazine group and Cynanchum wilfordii group (n=10), and in the latter 3 groups, mouse UC models were established by treatment with 2.5% DSS and the latter 2 groups drug interventions by gavage. The therapeutic effect was evaluated by recording body weight changes and DAI score. Pathological changes of the colon tissue were observed with HE and AB-PAS staining, and JAK2 and STAT3 protein expressions were detected with Western blotting. The metabolites and metabolic pathways were identified by metabonomics analysis. RESULTS: We identified 240 chemical components in Cynanchum wilfordii alcoholic extracts, including 19 steroids. A total of 177 Cynanchum wilfordii targets, 5406 UC genes, and 117 intersection genes were obtained. JAK2 and STAT3 were the core targets and significantly enriched in lipid and atherosclerosis pathways. Cynanchum wilfordii treatment significantly increased the body weight and decreased DAI score of UC mice (P < 0.05), alleviated intestinal pathologies, and decreased JAK2 and STAT3 protein expressions in the colon tissues. Most of the 83 intersecting differential metabolites between the control, model and Cynanchum wilfordii groups were identified as glycerophospholipids, arachidonic acid, and amino acids involving glycerophospholipid metabolism and other pathways. Correlation analysis suggested that the core targets of Cynanchum wilfordii for UC participated in regulation of the metabolites. CONCLUSION: Cynanchum wilfordii alleviates lipid and amino acid metabolism disorders to lessen UC in mice by regulating the core targets including JAK2 and STAT3 and the levels of endogenous metabolites.

Asunto(s)

Colitis Ulcerosa , Cynanchum , Metabolómica , Ratones Endogámicos C57BL , Farmacología en Red , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Ratones , Masculino , Cynanchum/química , Factor de Transcripción STAT3/metabolismo , Modelos Animales de Enfermedad , Extractos Vegetales/farmacología , Janus Quinasa 2/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Cromatografía Líquida de Alta Presión , Mapas de Interacción de Proteínas

RESUMEN

Ulcerative colitis (UC) is a typical inflammatory bowel disease (IBD), impairing the quality of life of patients. Dehydroevodiamine (DHE) is an active alkaloid isolated from Tetradium ruticarpum that exerts significant anti-inflammatory effects in gastrointestinal diseases. However, the effect and mechanisms of DHE on UC remain unclear. We performed a DSS-induced experimental UC rat model to reveal the efficacy and potential mechanisms of DHE on UC. HE and AB-PAS staining were used for the evaluation of pathologies, and 16S rRNA sequencing was used to detect changes in gut microbes. Metabolomics was used to detect changes in serum metabolites. Network pharmacology and transcriptomics were conducted to reveal the underlying mechanisms of DHE for UC. HuProt proteome microarrays, molecular docking, and SPR were used to reveal the targets of action of DHE. WB, RT-qPCR, and IHC were used to assess the action effects of DHE. DHE demonstrated significant alleviation of DSS-induced colitis symptoms in rats by suppressing inflammatory and oxidative stress responses, amending colonic barrier injury, and inhibiting apoptosis. In terms of gut microbial modulation, DHE decreased the abundance of Allobaculum, Clostridium, Escherichia, Enterococcus, and Barnesiella and increased the abundance of Lactobacillus, Bifidobacterium, and SMB5. Moreover, metabolomics suggested that the regulation of DHE in DSS-induced UC rats mainly involved aminoacyl-tRNA biosynthesis, vitamin B6 metabolism, phenylalanine, tyrosine, and so on. Mechanically, DHE alleviated UC in rats by targeting AKT1, thereby inhibiting the PI3K/AKT/NF-κB signaling pathway.

Asunto(s)

Colitis Ulcerosa , Microbioma Gastrointestinal , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Ratas , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Modelos Animales de Enfermedad , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Sulfato de Dextran

RESUMEN

OBJECTIVE: The present study aimed to compare measured and estimated resting metabolic rate (RMR) predicted by selected equations in patients with nonactive inflammatory bowel disease (IBD) on an outpatient university clinic regimen. RESEARCH METHODS & PROCEDURES: Seventy-two adult (≥20 years) IBD patients (45 with Crohn's disease-CD) had RMR measured (mRMR) by indirect calorimetry and also estimated by predictive equations (Cunningham, Henry, Anjos et al., and Marra et al.). Body composition was assessed by DXA. Absolute Bias (estimated - mRMR) and % Bias (Bias/mRMR) were calculated. Agreement was assessed as the limit of agreement (LoA) in the Bland & Altman approach. RESULTS: There was no difference in age, body composition and mRMR between individuals with CD (5414.2 ± 1023.7 kJ/day) and ulcerative colitis (5443.9 ± 1008.9 kJ/day). Among the equations, only the Anjos et al.'s population-specific equation (-52.1 [642.0] kJ/day, P = 0.493; LoA: -1311; 1206 kJ/d) accurately estimated RMR. The equations of Marra et al. produced the highest % Bias (24.1 ± 14.8%). The Bland & Altman plots showed that the range of the LoA was relatively similar for all equations. In the simple regression analysis, the model with FFM resulted in a higher coefficient of determination (R2 = 0.51 for DC 0.74 for UC) compared to the model that included BM (R2 = 0.35 for DC and 0.65 for UC). CONCLUSIONS: Among the equations analyzed, only Anjos et al.'s accurately estimated RMR in outpatients with nonactive IBD. However, caution is advised when applying it at the individual level, due to the wide observed LoA.

Asunto(s)

Metabolismo Basal , Composición Corporal , Calorimetría Indirecta , Enfermedades Inflamatorias del Intestino , Humanos , Metabolismo Basal/fisiología , Masculino , Femenino , Adulto , Calorimetría Indirecta/métodos , Persona de Mediana Edad , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/fisiopatología , Colitis Ulcerosa/fisiopatología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/fisiopatología , Adulto Joven

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is defined by persistent inflammatory processes within the gastrointestinal tract of uncertain etiology. Current therapeutic approaches are limited in their ability to address oxidative stress, inflammation, barrier function restoration, and modulation of gut microbiota in a coordinated manner to maintain intestinal homeostasis. RESULTS: This study involves the construction of a metal-phenolic nanozyme (Cur-Fe) through a ferric ion-mediated oxidative coupling of curcumin. Cur-Fe nanozyme exhibits superoxide dismutase (SOD)-like and •OH scavenging activities, demonstrating significant anti-inflammatory and anti-oxidant properties for maintaining intracellular redox balance in vitro. Drawing inspiration from Escherichia coli Nissle 1917 (EcN), a biomimetic Cur-Fe nanozyme (CF@EM) is subsequently developed by integrating Cur-Fe into the EcN membrane (EM) to improve the in vivo targeting ability and therapeutic effectiveness of the Cur-Fe nanozyme. When orally administered, CF@EM demonstrates a strong ability to colonize the inflamed colon and restore intestinal redox balance and barrier function in DSS-induced colitis models. Importantly, CF@EM influences the gut microbiome towards a beneficial state by enhancing bacterial diversity and shifting the compositional structure toward an anti-inflammatory phenotype. Furthermore, analysis of intestinal microbial metabolites supports the notion that the therapeutic efficacy of CF@EM is closely associated with bile acid metabolism. CONCLUSION: Inspired by gut microbes, we have successfully synthesized a biomimetic Cur-Fe nanozyme with the ability to inhibit inflammation and restore intestinal homeostasis. Collectively, without appreciable systemic toxicity, this work provides an unprecedented opportunity for targeted oral nanomedicine in the treatment of ulcerative colitis.

Asunto(s)

Colitis Ulcerosa , Microbioma Gastrointestinal , Homeostasis , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Animales , Homeostasis/efectos de los fármacos , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Curcumina/farmacología , Curcumina/química , Ratones Endogámicos C57BL , Escherichia coli/efectos de los fármacos , Administración Oral , Biomimética/métodos , Masculino , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Antioxidantes/farmacología , Antioxidantes/química

RESUMEN

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.

Asunto(s)

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 , Femenino

RESUMEN

Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract with unknown definitive etiology. Polysaccharides are among the most important active components of Abelmoschi Corolla, exhibitings various pharmacological activities such as antioxidation and immunomodulation. However, no studies have yet reported the application of Abelmoschi Corolla Polysaccharides (ACP) in treating UC. This study aims to highlight the therapeutic efficacy of ACP in UC and reveal the underlying mechanism. The potential therapeutic effect is initially verified using a dextran sodium sulfate (DSS)-induced colitis model. 16S rRNA sequencing is performed using feces samples and untargeted metabolomics using serum samples to further reveal that ACP reprograms the dysbiosis triggered by UC progression, increases the abundance of Bacteroides spp., Blautia spp., and Parabacteroides spp. at the genus level and enriches the serum concentration of 7-ketodeoxycholic acid (7-KDA). Furthermore, using the FXR-/- mouse model, it is revealed that Farnesoid X Receptor (FXR) is a key target for ACP and the metabolite 7-KDA to block STAT3 phosphorylation by repairing the intestinal barrier to attenuate UC. Taken together, this work highlights the therapeutic potential of ACP against UC, mainly exerting its effects via modulating gut microbiota and regulating the FXR/STAT3 signaling pathway.

Asunto(s)

Abelmoschus , Microbioma Gastrointestinal , Polisacáridos , Receptores Citoplasmáticos y Nucleares , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Polisacáridos/farmacología , Polisacáridos/química , Transducción de Señal/efectos de los fármacos , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo , Abelmoschus/química , Sulfato de Dextran , Modelos Animales de Enfermedad , Masculino , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Ratones Endogámicos C57BL

RESUMEN

Inflammatory bowel disease is a chronic inflammatory disease that encompasses entities such as Crohn's disease and ulcerative colitis. Its incidence has risen in newly industrialised countries over time, turning it into a global disease. Lately, studies on inflammatory bowel disease have focused on finding non-invasive and specific biomarkers. Long non-coding RNAs may play a role in the pathophysiology of inflammatory bowel disease and therefore they may be considered as potential biomarkers for this disease. In the present article, we review information in the literature on the relationship between long non-coding RNAs and inflammatory bowel disease. We especially focus on understanding the potential function of these RNAs as non-invasive biomarkers, providing information that may be helpful for future studies in the field.

Asunto(s)

Biomarcadores , Enfermedades Inflamatorias del Intestino , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Animales , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/diagnóstico

RESUMEN

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure.

Asunto(s)

Bacteroides , Colitis Ulcerosa , Trasplante de Microbiota Fecal , Heces , Mucosa Intestinal , Humanos , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/terapia , Colitis Ulcerosa/metabolismo , Masculino , Femenino , Heces/microbiología , Bacteroides/genética , Adulto , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Persona de Mediana Edad , Microbioma Gastrointestinal , Insuficiencia del Tratamiento , ARN Ribosómico 16S/genética , Metaboloma

RESUMEN

Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.

Asunto(s)

Enfermedades Inflamatorias del Intestino , Necroptosis , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Animales , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología

RESUMEN

Background: Previous observational studies have revealed the strong relationship between fatty acids (FA) and inflammatory bowel disease (IBD). Nonetheless, due to the inherent limitations of retrospective research, the causality between the two has not been clearly established. Methods: Genetic variants associated with the 17 FA indicators were derived from genome-wide association studies. Summary statistics for the discovery cohort and testing cohort for IBD, including ulcerative colitis (UC) and Crohn's disease (CD), were available from IIBDGC and FinnGen, respectively. Bidirectional MR analysis and sensitivity analysis with multiple measures were applied to comprehensively investigate the causal link between FA and IBD. Results: Combining the results of various MR methods, the validation of testing cohort, and the merging of meta-analysis, we demonstrated that genetically predicted Omega-3 FA levels, Ratio of Omega-3 FA to total FA, Docosahexaenoic acid (DHA) levels, and Ratio of DHA to total FA reduced the risk of IBD, UC, and CD. Meanwhile, multivariate MR suggested that the risk effects of Omega-3 FA and DHA for UC and CD were mainly affected by Saturated FA and Monounsaturated fatty acid (MUFA). Furthermore, although there was the causal association between Ratio of MUFA to total FA as well as Ratio of Polyunsaturated fatty acid (PUFA) to MUFA and CD, sensitivity analysis prompted that the findings were not robust. None of the above results had a reverse causal effect. Conclusion: This MR investigation provided evidence of causality between diverse FA and IBD. These findings offered new insights into the treatment and prevention of IBD.

Asunto(s)

Ácidos Grasos , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino , Humanos , Ácidos Grasos/metabolismo , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Predisposición Genética a la Enfermedad , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/etiología , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Ácidos Docosahexaenoicos

RESUMEN

Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.

Asunto(s)

Colitis , Colon , Preparaciones de Acción Retardada , Mesalamina , Micelas , Nitrorreductasas , Polímeros , Profármacos , Animales , Profármacos/química , Profármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorreductasas/metabolismo , Ratones , Colon/metabolismo , Colon/patología , Polímeros/química , Colitis/tratamiento farmacológico , Colitis/metabolismo , Preparaciones de Acción Retardada/química , NADH NADPH Oxidorreductasas/metabolismo , Ratones Endogámicos C57BL , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Masculino

RESUMEN

The utility of spatial omics in leveraging cellular interactions in normal and diseased states for precision medicine is hampered by a lack of strategies for matching disease states with spatial heterogeneity-guided cellular annotations. Here we use a spatial context-dependent approach that matches spatial pattern detection to cell annotation. Using this approach in existing datasets from ulcerative colitis patient colonic biopsies, we identified architectural complexities and associated difficult-to-detect rare cell types in ulcerative colitis germinal-center B cell follicles. Our approach deepens our understanding of health and disease pathogenesis, illustrates a strategy for automating nested architecture detection for highly multiplexed spatial biology data, and informs precision diagnosis and therapeutic strategies.

Asunto(s)

Colitis Ulcerosa , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/genética , Humanos , Colon/patología , Colon/metabolismo , Biopsia

RESUMEN

Background: Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods: The GSE75214, GSE48959, and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results: A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion: SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic.

Asunto(s)

Colitis Ulcerosa , Redes Reguladoras de Genes , MicroARNs , Estrés Oxidativo , ARN Endógeno Competitivo , ARN Largo no Codificante , ARN Mensajero , Animales , Humanos , Ratones , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inducido químicamente , Biología Computacional , Bases de Datos Genéticas , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Estrés Oxidativo/genética , Estrés Oxidativo/efectos de los fármacos , ARN Endógeno Competitivo/genética , ARN Endógeno Competitivo/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo

RESUMEN

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease involving the mucosa and submucosa of the rectum and colon. Lindera aggregate (Sims) Kosterm is a traditional Chinese herb used for thousands of years in the treatment of gastrointestinal diseases. Previously, we have demonstrated that the extracts of Lindera aggregate have good anti-UC effects, but their pharmacodynamic active components have not been fully clarified. Therefore, we explored the therapeutic effect of Linderanine C (LDC), a characteristic component of Lindera aggregata, on UC and its mechanism in this study. Firstly, we found that LDC could significantly reduce the disease activity index of UC and improve shortened colon and pathological changes in vivo. Colon tissue transcriptomics suggested that the anti-UC effect of LDC might be related to its anti-inflammatory activity. Cellular experiments revealed that LDC could inhibit the expression of the M1 cell marker CD86 in RAW264.7 cells, reduce the production of inflammatory mediators such as IL-6 and TNF-α, and have good anti-inflammatory activity in vitro. Cellular transcriptomics reveal the potential involvement of the MAPK signaling pathway in the anti-inflammatory effect of LDC. The co-culture assay confirmed that LDC could significantly reduce inflammation-mediated intestinal epithelial cell injury. In conclusion, LDC was able to inhibit macrophage M1 polarization and reduce inflammatory mediator production by inhibiting the MAPK signaling pathway, effectively improving UC.

Asunto(s)

Antiinflamatorios , Colitis Ulcerosa , Sistema de Señalización de MAP Quinasas , Macrófagos , Animales , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Ratones , Células RAW 264.7 , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Antiinflamatorios/farmacología , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Ratones Endogámicos C57BL , Humanos , Polaridad Celular/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Modelos Animales de Enfermedad

RESUMEN

Currently, there is no known cause for ulcerative colitis (UC), an inflammatory bowel disease that is difficult to treat. This assay aimed to investigate the protective effects and mechanisms of Dendrobium officinale polysaccharide (DOP) in mice with acute UC induced by dextran sulphate sodium (DSS). We found that DOP could improve weight loss, decrease the disease activity index (DAI), and regulate the release of interleukin 2 (IL-2), IL-4, IL-6, and IL-10 in DSS-induced acute UC mice. Additionally, DOP preserved the integrity of the intestinal barrier in UC mice by increasing goblet cell density and maintaining tight junctions. DOP significantly enhanced total antioxidant capacity (T-AOC), and reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) levels in the bloodstream. In terms of serum biochemistry, DOP markedly elevated levels of bilirubin (BIL), alkaline phosphatase (ALP), total bile acid (TBA), creatinine (Crea), and creative kinase isoenzyme (CKMB). Furthermore, DOP increased the relative abundance of Lactobacillales. DOP also improved intestinal health and stimulated the synthesis of potent anti-inflammatory and antiviral substances by regulating the metabolism of purines, prostaglandins, and leukotrienes. Therefore, DOP can be considered a functional dietary supplement for the treatment of UC, as it improves the condition of DSS-induced UC mice.

Asunto(s)

Colitis Ulcerosa , Dendrobium , Sulfato de Dextran , Metaboloma , Polisacáridos , Animales , Dendrobium/química , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Polisacáridos/farmacología , Polisacáridos/química , Sulfato de Dextran/efectos adversos , Ratones , Metaboloma/efectos de los fármacos , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Citocinas/metabolismo , Antioxidantes/farmacología , Modelos Animales de Enfermedad