RESUMEN

Directly administering medication to inflamed intestinal sites for treating ulcerative colitis (UC), poses significant challenges like retention time, absorption variability, side effects, drug stability, and non-specific delivery. Recent advancements in therapy to treat colitis aim to improve local drug availability that is enema therapy at the site of inflammation, thereby reducing systemic adverse effects. Nevertheless, a key limitation lies in enemas' inability to sustain medication in the colon due to rapid peristaltic movement, diarrhea, and poor local adherence. Therefore, in this work, we have developed site-specific thiolated mucoadhesive anionic nanoliposomes to overcome the limitations of conventional enema therapy. The thiolated delivery system allows prolonged residence of the delivery system at the inflamed site in the colon, confirmed by the adhesion potential of thiolated nanoliposomes using in-vitro and in-vivo models. To further provide therapeutic efficacy thiolated nanoliposomes were loaded with gallic acid (GA), a natural compound known for its antibacterial, antioxidant, and potent anti-inflammatory properties. Consequently, Gallic Acid-loaded Thiolated 2,6 DALP DMPG (GATh@APDL) demonstrates the potential for targeted adhesion to the inflamed colon, facilitated by their small size 100 nm and anionic nature. Therapeutic studies indicate that this formulation offers protective effects by mitigating colonic inflammation, downregulating the expression of NF-κB, HIF-1α, and MMP-9, and demonstrating superior efficacy compared to the free GA enema. The encapsulated GA inhibits the NF-κB expression, leading to enhanced expression of MUC2 protein, thereby promoting mucosal healing in the colon. Furthermore, GATh@APDL effectively reduces neutrophil infiltration and regulates immune cell quantification in colonic lamina propria. Our findings suggest that GATh@APDL holds promise for alleviating UC and addressing the limitations of conventional enema therapy.

Asunto(s)

Colitis Ulcerosa , Liposomas , Compuestos de Sulfhidrilo , Colitis Ulcerosa/tratamiento farmacológico , Liposomas/química , Animales , Compuestos de Sulfhidrilo/química , Humanos , Nanopartículas/química , Ratones , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Masculino , Sistemas de Liberación de Medicamentos

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

ETHNOPHARMACOLOGICAL RELEVANCE: Pogostemonis Herba has long been used in traditional Chinese medicine to treat inflammatory disorders. Patchouli essential oil (PEO) is the primary component of Pogostemonis Herba, and it has been suggested to offer curative potential when applied to treat ulcerative colitis (UC). However, the pharmacological mechanisms of PEO for treating UC remain to be clarified. AIM OF THE STUDY: To elucidate the pharmacological mechanisms of PEO for treating UC. METHODS AND RESULTS: In the present study, transcriptomic and network pharmacology approaches were combined to clarify the mechanisms of PEO for treating UC. Our results reveal that rectal PEO administration in UC model mice significantly alleviated symptoms of UC. In addition, PEO effectively suppressed colonic inflammation and oxidative stress. Mechanistically, PEO can ameliorate UC mice by modulating gut microbiota, inhibiting inflammatory targets (OPTC, PTN, IFIT3, EGFR, and TLR4), and inhibiting the PI3K-AKT pathway. Next, the 11 potential bioactive components that play a role in PEO's anti-UC mechanism were identified, and the therapeutic efficacy of the pogostone (a bioactive component) in UC mice was partially validated. CONCLUSION: This study highlights the mechanisms through which PEO can treat UC, providing a rigorous scientific foundation for future efforts to develop and apply PEO for treating UC.

Asunto(s)

Colitis Ulcerosa , Aceites Volátiles , Animales , Colitis Ulcerosa/tratamiento farmacológico , Aceites Volátiles/farmacología , Ratones , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Pogostemon/química , Estrés Oxidativo/efectos de los fármacos , Farmacología en Red , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología

RESUMEN

Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the gastrointestinal tract. In addition to bowel symptoms, patients may also have oral manifestations. This thesis investigated potential associations between disease activity in the gut, oral health, salivary gland function, and saliva composition. Patients with Crohn's disease had a significantly higher DMFT index, but showed no difference in periodontal diseases compared to a healthy control group. The saliva composition in patients with active bowel disease differed from that in patients with inactive bowel disease, suggesting that saliva analysis could potentially be used in the future to determine the degree and severity of bowel disease. The knowledge of gastroenterologists and dentists regarding oral manifestations of bowel diseases was found to be limited. Gastroenterologists and dentists valued interdisciplinary patient consultation as very useful, but the frequency of consultation was considered insufficient.

Asunto(s)

Salud Bucal , Humanos , Saliva/química , Saliva/metabolismo , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedad de Crohn/complicaciones , Enfermedades de la Boca/etiología , Enfermedades Periodontales/etiología , Colitis Ulcerosa/complicaciones , Glándulas Salivales

Asunto(s)

Alopecia , Colitis Ulcerosa , Compuestos Heterocíclicos con 3 Anillos , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/complicaciones , Alopecia/tratamiento farmacológico , Alopecia/etiología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Adulto

RESUMEN

PURPOSE: This study aimed to assess the efficacy and safety of berberine(BBR) plus 5-aminosalicylic acid (5-ASA) for treating ulcerative colitis (UC). METHODS: A comprehensive search was conducted in electronic databases, including Medline/PubMed, Sinomed, Embase, CNKI, Wanfang, and VIP, through January 2024 to identify all randomized controlled trials (RCTs) that administered BBR conjunction in standard therapy(5-ASA) for to support the treatment of UC. The data were synthesized using a meta-analysis approach with RevMan 5.4.1. The primary endpoint was the clinical efficacy rate. In contrast, the secondary endpoints included the Baron score, disease activity index (DAI) score, symptom relief latency, inflammatory markers, immunological indicators, and adverse events. RESULTS: In this analysis, 10 RCTs comprising 952 patients with UC were examined. BBR considerably improved the clinical efficacy rate (RR = 1.22, 95% CI [1.15, 1.30], P < 0.00001), attenuated the Baron score (SMD = -1.72, 95% CI [-2.30, -1.13], P < 0.00001) and reduced the DAI score (SMD = -2.93, 95% CI [-4.42, -1.43], P < 0.00001). Additionally, it ameliorated clinical symptoms (SMD = -2.74, 95% CI [-3.45, 2.02], P < 0.00001), diminished inflammatory responses (SMD = -1.59, 95% CI [-2.14, 1.04], P < 0.00001), and modulated immune reactions (SMD = 1.06,95% CI [0.24,1.87], P <0.00001). Nonetheless, the impact of BBR on reducing adverse reactions was not statistically significant (RR = 0.75, 95% CI [0.42, 1.33], P > 0.05). CONCLUSION: BBR demonstrates substantial efficacy in treating UC without causing severe adverse reactions and may serve as a viable complementary therapy. However, its clinical application warrants confirmation by additional high-quality, low-bias RCTs.

Asunto(s)

Berberina , Colitis Ulcerosa , Mesalamina , Colitis Ulcerosa/tratamiento farmacológico , Humanos , Berberina/uso terapéutico , Berberina/administración & dosificación , Berberina/efectos adversos , Mesalamina/uso terapéutico , Mesalamina/efectos adversos , Mesalamina/administración & dosificación , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Quimioterapia Combinada , Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos

RESUMEN

BACKGROUND: Mesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms. METHODS: This prospective, self-controlled clinical study was conducted at Henan Provincial People's Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation. RESULTS: Forty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1ß, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy. CONCLUSION: UMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines. TRIAL REGISTRATION: The study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.

Asunto(s)

Colitis Ulcerosa , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Cordón Umbilical , Humanos , Colitis Ulcerosa/terapia , Colitis Ulcerosa/patología , Femenino , Masculino , Adulto , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Cordón Umbilical/citología , Persona de Mediana Edad , Estudios Prospectivos , Citocinas/metabolismo , Citocinas/sangre , Resultado del Tratamiento

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

OBJECTIVE: Ulcerative colitis and Crohn's disease are chronic inflammatory diseases and represent the two most important types of inflammatory bowel diseases (IBD), while spondyloarthritis (SpA) comprises a heterogeneous group of systemic inflammatory chronic rheumatic diseases, including peripheral SpA and axial SpA. Joint manifestations are the most commonly observed extraintestinal manifestations, and they can precede or not the diagnosis of IBD. Notably, in women, misdiagnoses of IBD as irritable bowel syndrome and SpA as fibromyalgia are common, leading to delayed diagnoses, increased disease burden, and poorer prognoses. This narrative review emphasizes the critical role of diagnostic tools in facilitating early referrals of IBD patients with suspected SpA and vice versa to rheumatologists and gastroenterologists, respectively. Special attention is given to the multidisciplinary approach for more effective management of these conditions, particularly in female patients. METHODS: In this narrative review, we critically evaluated the literature on this topic, focusing on papers written in English that address female issues in IBD and SpA. RESULTS: IBD and SpA are chronic inflammatory disorders often occurring in the same patients. Female patients are often misdiagnosed, and this delay in diagnosis is associated with a higher disease burden and a poorer prognosis. CONCLUSIONS: A multidisciplinary approach is needed to enable early referral between gastroenterologists and rheumatologists, as this means a better prognosis for patients with a reduction in the economic and social burden associated with IBD and SpA.

Asunto(s)

Enfermedades Inflamatorias del Intestino , Espondiloartritis , Humanos , Femenino , Espondiloartritis/diagnóstico , Espondiloartritis/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/complicaciones , Pronóstico , Diagnóstico Tardío , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/terapia , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/terapia , Errores Diagnósticos , Diagnóstico Diferencial , Factores Sexuales , Derivación y Consulta , Fibromialgia/diagnóstico , Síndrome del Colon Irritable/diagnóstico

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

Objective: To evaluate the causal relationship between lipids and ulcerative colitis (UC) through Mendelian Randomization (MR), and to further investigate the involvement of immune cells in mediating this process. Methods: Utilizing summary statistics from genome-wide association studies (GWAS) of individuals with European ancestry, we analyzed the causal link between 179 lipid types and UC (2,569 UC cases and 453,779 controls) through Two-sample Mendelian randomization (2SMR) and Bayesian-weighted MR (BWMR). Based on this, a mediation screening of 731 immune cell phenotypes was conducted to identify exposure and mediator factors. Lastly, the role and proportion of immune cells in mediating the causal effects of lipids on UC were assessed via reverse MR (RMR) and two-step MR. Results: The results of MR showed that there was a causal relationship between the six genetically predicted lipid types and UC (P <0.05), and the four immune cell phenotypes were identified as mediators of the association between lipids and UC. Notably, Phosphatidylcholine (PC) (16:0_0:0) served as the exposure factor, and myeloid cells CD11b on CD33+ HLA DR+ CD14dim acted as the mediator. Mediation analysis showed that CD11b on CD33+ HLA DR+ CD14dim had a mediation effect of -0.0205 between PC (16:0_0:0) and UC, with the mediation effect ratio at 15.38%. Conclusion: Our findings elucidate the causal effect of lipids on UC and identify the significant mediating role of myeloid cells CD11b on CD33+ HLA DR+ CD14dim in regulating UC through PC (16:0_0:0), offering new pathways and strategies for UC clinical treatment.

Asunto(s)

Colitis Ulcerosa , Estudio de Asociación del Genoma Completo , Lípidos , Análisis de la Aleatorización Mendeliana , Células Mieloides , Humanos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/genética , Células Mieloides/inmunología , Células Mieloides/metabolismo , Teorema de Bayes , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple

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

The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals.

Asunto(s)

Berberina , Compuestos de Bifenilo , Colitis Ulcerosa , Lignanos , Nanoestructuras , Animales , Colitis Ulcerosa/tratamiento farmacológico , Berberina/química , Berberina/farmacología , Berberina/uso terapéutico , Lignanos/química , Lignanos/farmacología , Lignanos/uso terapéutico , Ratones , Compuestos de Bifenilo/química , Nanoestructuras/química , Masculino , Sulfato de Dextran/química , Colon/efectos de los fármacos , Colon/patología , Modelos Animales de Enfermedad , Distribución Tisular , Ratones Endogámicos C57BL , Microbioma Gastrointestinal/efectos de los fármacos , Disponibilidad Biológica

RESUMEN

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 Tratamiento

RESUMEN

Fusobacterium nucleatum (F. nucleatum), an anaerobic resident of the oral cavity, is increasingly recognized as a contributing factor to ulcerative colitis (UC). The adhesive properties of F. nucleatum are mediated by its key virulence protein, FadA adhesin. However, further investigations are needed to understand the pathogenic mechanisms of this oral pathogen in UC. The present study aimed to explore the role of the FadA adhesin in the colonization and invasion of oral F. nucleatum in dextran sulphate sodium (DSS)-induced colitis mice via molecular techniques. In this study, we found that oral inoculation of F. nucleatum strain carrying the FadA adhesin further exacerbated DSS-induced colitis, leading to elevated alveolar bone loss, disease severity, and mortality. Additionally, CDH1 gene knockout mice treated with DSS presented increases in body weight and alveolar bone density, as well as a reduction in disease severity. Furthermore, FadA adhesin adhered to its mucosal receptor E-cadherin, leading to the phosphorylation of ß-catenin and the degradation of IκBα, the activation of the NF-κB signalling pathway and the upregulation of downstream cytokines. In conclusion, this research revealed that oral inoculation with F. nucleatum facilitates experimental colitis via the secretion of the virulence adhesin FadA. Targeting the oral pathogen F. nucleatum and its virulence factor FadA may represent a promising therapeutic approach for a portion of UC patients.

Asunto(s)

Adhesinas Bacterianas , Colitis Ulcerosa , Infecciones por Fusobacterium , Fusobacterium nucleatum , Animales , Humanos , Ratones , Adhesinas Bacterianas/metabolismo , Adhesinas Bacterianas/genética , Adhesión Bacteriana , Cadherinas/metabolismo , Colitis Ulcerosa/microbiología , Sulfato de Dextran , Modelos Animales de Enfermedad , Infecciones por Fusobacterium/microbiología , Fusobacterium nucleatum/patogenicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Virulencia , Factores de Virulencia/genética , Factores de Virulencia/metabolismo

RESUMEN

Previous studies have indicated a critical role of intestinal bacteria in the pathogenesis of ulcerative colitis (UC). B. salyersiae is a commensal species from the human gut microbiota. However, what effect it has on UC development has not been investigated. In the present study, we explored this issue and demonstrated for the first time that oral administration of B. salyersiae CSP6, a bacterium previously isolated from the fecal sample of a healthy individual, protected against dextran sulfate sodium (DSS)-induced colitis in C57BL/6J mice. In particular, B. salyersiae CSP6 improved mucosal damage and attenuated gut dysbiosis in the colon of DSS-fed mice. Specifically, B. salyersiae CSP6 decreased the population of pathogenic Escherichia-Shigella spp. and increased the abundance of probiotic Dubosiella spp. and Bifidobacterium pseudolongum. Additionally, by reshaping the colonic microbiota, B. salyersiae CSP6 remarkably increased the fecal concentrations of equol, 8-deoxylactucin, and tiglic acid, three beneficial metabolites that have been well documented to exert strong anti-inflammatory effects. Altogether, our study provides novel evidence that B. salyersiae is a candidate probiotic species with potential anti-colitis properties in the human colon, which has applications for the development of next-generation probiotics.

Asunto(s)

Bacteroides , Colon , Sulfato de Dextran , Modelos Animales de Enfermedad , Heces , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Probióticos , Animales , Probióticos/farmacología , Humanos , Colon/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Bacteroides/aislamiento & purificación , Heces/microbiología , Masculino , Colitis/microbiología , Colitis/inducido químicamente , Disbiosis/microbiología , Colitis Ulcerosa/microbiología

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

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.

Asunto(s)

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/microbiología

RESUMEN

Inflammatory Bowel Diseases (IBD), which encompass ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation and tissue damage of the gastrointestinal tract. This study aimed to uncover novel disease-gene signatures, dysregulated pathways, and the immune cell infiltration landscape of inflamed tissues. Eight publicly available transcriptomic datasets, including inflamed and non-inflamed tissues from CD and UC patients were analyzed. Common differentially expressed genes (DEGs) were identified through meta-analysis, revealing 180 DEGs. DEGs were implicated in leukocyte transendothelial migration, PI3K-Akt, chemokine, NOD-like receptors, TNF signaling pathways, and pathways in cancer. Protein-protein interaction network and cluster analysis identified 14 central IBD players, which were validated using eight external datasets. Disease module construction using the NeDRex platform identified nine out of 14 disease-associated genes (CYBB, RAC2, GNAI2, ITGA4, CYBA, NCF4, CPT1A, NCF2, and PCK1). Immune infiltration profile assessment revealed a significantly higher degree of infiltration of neutrophils, activated dendritic cells, plasma cells, mast cells (resting/activated), B cells (memory/naïve), regulatory T cells, and M0 and M1 macrophages in inflamed IBD tissue. Collectively, this study identified the immune infiltration profile and nine disease-associated genes as potential modulators of IBD pathogenesis, offering insights into disease molecular mechanisms, and highlighting potential disease modulators and immune cell dynamics.

Asunto(s)

Biología Computacional , Mapas de Interacción de Proteínas , Humanos , Biología Computacional/métodos , Mapas de Interacción de Proteínas/genética , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Transcriptoma , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Perfilación de la Expresión Génica , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Redes Reguladoras de Genes , Neutrófilos/inmunología , Neutrófilos/metabolismo , Transducción de Señal/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , NADPH Oxidasas