RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Smilax glabra rhizome has a long history been used for clinical purposes in traditional Chinese medicinal for treating various inflammatory conditions. Engeletin1 (ENG) is one of the most abundant bioactive compounds found in Smilax glabra rhizome, with anti-inflammatory, antioxidant, and ulcer-preventing activities. AIM OF THE STUDY: The purpose of this study was to investigate the ability of ENG to alleviate inflammatory symptoms and improve epithelial barrier integrity utilize a 2,4,6-trinitrobenzene sulfonic acid2 (TNBS)-induced murine model in Crohn's disease3 (CD)-like colitis, and to characterize the underlying anti-inflammatory mechanisms of action. MATERIALS AND METHODS: A colitis model was established in BALB/c mice and treated with ENG for 7 days. RAW264.7 macrophages were pre-treated with ENG and lipopolysaccharide4 (LPS) stimulation. The mice's weight and colon length were assessed. qPCR and Western blotting were used to analyze gene expression and TLR4-NFκB pathway. Flow cytometry was used to analyze the polarization states of the macrophages. RESULTS: Treatment with ENG was sufficient to significantly alleviate symptoms of inflammation and colonic epithelial barrier integrity in treated mice. Significant inhibition of TNF-α, IL-1ß, and IL-6 expression was observed following ENG treatment in vivo and in vitro. ENG was also determined to be capable of inhibiting the expression of iNOS and CD86, inhibited M1 macrophage polarization in vitro, as well as the TLR4-NFκB signaling pathway. Molecular docking showed a highly stable binding between ENG and TLR4. CONCLUSION: ENG has been proven to alleviate inflammation and ameliorate the damage of epithelial barrier in CD-like colitis. ENG also suppressed the M1 macrophages polarization and the inhibited inflammatory cytokines. TLR4-NFκB signaling pathway, especially TLR4, may be the target of ENG. These data offer a new insight into the therapeutic mechanisms of ENG.
Asunto(s)
Antiinflamatorios , Colitis , Enfermedad de Crohn , FN-kappa B , Transducción de Señal , Receptor Toll-Like 4 , Ácido Trinitrobencenosulfónico , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Enfermedad de Crohn/tratamiento farmacológico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Flavonoles , Glicósidos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Smilax/química , Receptor Toll-Like 4/metabolismoRESUMEN
The present study identified the protective effects of garlic oligo/poly-saccharides of different chain lengths against dextran sulfate sodium (DSS)-induced colitis in mice and elucidated the structure-function relationships. The results showed that oral intake of garlic oligo/poly-saccharides decreased disease activity index, reduced colon shortening and spleen enlargement, and ameliorated pathological damage in the mouse colon. The dysregulation of colonic pro/anti-inflammatory cytokines was significantly alleviated, accompanied by up-regulated antioxidant enzymes, blocked TLR4-MyD88-NF-κB signaling pathway, enhanced intestinal barrier integrity, and restored SCFA production. Garlic oligo/poly-saccharides also reversed gut microbiota dysbiosis in colitic mice by expanding beneficial bacteria and suppressing the growth of harmful bacteria. High-molecular-weight polysaccharides exhibited stronger alleviating effects on DSS-induced colitic symptoms in mice than low-molecular-weight oligo/poly-saccharides did, probably due to their greater ability to be fermented in the colon. Taken together, this study demonstrated the anti-inflammatory effects of garlic oligo/poly-saccharides and revealed that high-molecular-weight polysaccharide fractions were more effective in alleviating DSS-induced colitis.
Asunto(s)
Antiinflamatorios , Colitis , Sulfato de Dextran , Fructanos , Ajo , Microbioma Gastrointestinal , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Ajo/química , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Fructanos/farmacología , Fructanos/química , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Relación Estructura-Actividad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Peso Molecular , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Even though Stellaria dichotoma L. var. lanceolate (S. dichotoma) is a well-known medicinal plant in the family Caryophyllaceae, its oligosaccharides remain unexplored in terms of their potential as bioactive agents. Here, we isolated a mixture of oligosaccharides from S. dichotoma (Yield: 12 % w/w), that are primarily non-classical raffinose family oligosaccharides (RFOs). Nine major oligosaccharides were purified and identified from the mixture, including sucrose, raffinose, 1-planteose, lychnose, stellariose, along with four new non-classical RFOs. Two of the four new oligosaccharides are linear hexose pentamers with α-galactosyl extensions on their lychnose moieties, and the other two are branched hexose hexamers with α-galactosyl extensions on their stellariose groups. Their interactions with galectin-3 (Gal-3) revealed significant binding, with the terminal galactose providing enhanced affinity for the lectin. Notably, Gal-3 residues Arg144, His158, Asn160, Arg162, Asn174, Trp181, Glu184 and Arg186 coordinate with the lychnose. In vivo studies using the dextran sulfate sodium (DSS) mouse model for colitis demonstrated the ability of these carbohydrates in mitigating ulcerative colitis (UC). Overall, our study has provided structural information and potential applications of S. dichotoma oligosaccharides, also offers new approaches for the development of medicinal oligosaccharides.
Asunto(s)
Colitis , Galectina 3 , Oligosacáridos , Animales , Oligosacáridos/química , Oligosacáridos/farmacología , Ratones , Galectina 3/metabolismo , Galectina 3/química , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Caryophyllaceae/química , Sulfato de Dextran , Ratones Endogámicos C57BL , Masculino , HumanosRESUMEN
Probiotics and polyphenols have multiple bioactivities, and developing co-encapsulated microcapsules (CM) is a novel strategy to enhance their nutritional diversity. However, the development of CMs is challenged by complicated processing, single types, and unclear in vivo effects and applications. In this study, the co-microencapsulations of polyphenol and probiotic were constructed using pectin, alginate (WGCA@LK), and Fu brick tea polysaccharides (WGCF@LK), respectively, with chitosan-whey isolate proteins by layer-by-layer coacervation reaction, and their protective effects, in vivo effectiveness, and application potential were evaluated. WGCA@LK improved the encapsulation rate of polyphenols (42.41 %), and remained high viability of probiotics after passing through gastric acidic environment (8.79 ± 0.04 log CFU/g) and storage for 4 weeks (4.59 ± 0.06 log CFU/g). WGCF@LK exhibited the highest total antioxidant activity (19.40 ± 0.25 µmol/mL) and its prebiotic activity removed the restriction on probiotic growth. WGCA@LK showed strong in vitro colonic adhesion, but WGCF@LK promoted in vivo retention of probiotics at 48 h. WGCF@LK showed excellent anti-inflammatory effects and alleviated symptoms of acute colitis in mice. These findings provide unique insights into the fortification of probiotic-polyphenol CMs by different polysaccharides and the development of novel health foods with rich functional hierarchies and superior therapeutic effects.
Asunto(s)
Cápsulas , Colitis , Polifenoles , Polisacáridos , Probióticos , Probióticos/administración & dosificación , Probióticos/química , Animales , Polifenoles/química , Polifenoles/farmacología , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Ratones , Polisacáridos/química , Polisacáridos/farmacología , Alimentos Fortificados , Alginatos/química , Alginatos/farmacología , Masculino , Pectinas/química , Pectinas/farmacología , Té/química , Antioxidantes/química , Antioxidantes/farmacología , Quitosano/química , Sulfato de Dextran/química , Composición de Medicamentos/métodosRESUMEN
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
Background: Colitis is a refractory intestinal inflammatory disease significantly affecting the quality of a patient's life and increasing the risk of exacerbation. The primary factors leading to colitis encompass infections, insufficient blood flow, and the buildup of collagen as well as white blood cells. Among various available therapeutics, 5-methoxytryptophan (5-MTP) has emerged as one of the protectants by inhibiting inflammatory damage. Nonetheless, there is no report on the role of 5-MTP in the treatment of colitis. Materials and Methods: To verify the anti-inflammatory effect of 5-MTP in vivo, we first constructed mouse model with dextran sulfate sodium-induced colitis. Furthermore, the macrophage infiltration and release of inflammatory factors through western blot (WB) and hematoxylin-eosin staining analyses were examined. Intestinal epithelial cell tight junction damage and apoptosis were investigated by WB analysis, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Finally, we examined the generation of cellular inflammation and analyzed the influence of 5-MTP on M1 polarization at the cellular level. Results: This study initially confirmed that 5-MTP possessed an excellent therapeutic effect on colitis. 5-MTP inhibits macrophage infiltration and the generation of inflammatory factors. In addition to its effects on immune cells, 5-MTP significantly inhibits intestinal epithelial cell tight junction damage and apoptosis in vivo. Moreover, it inhibits inflammation and M1 polarization response in vitro. Conclusion: 5-MTP counteracts excessive inflammation, thereby preventing intestinal epithelial tight junction damage. In addition, inhibition of apoptosis suggests that 5-MTP may be a potential therapeutic agent for colitis.
Asunto(s)
Colitis , Sulfato de Dextran , Mucosa Intestinal , Ratones Endogámicos C57BL , Triptófano , Animales , Sulfato de Dextran/toxicidad , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Triptófano/análogos & derivados , Triptófano/farmacología , Inflamación/tratamiento farmacológico , Masculino , Apoptosis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Humanos , Modelos Animales de Enfermedad , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.
Asunto(s)
Apigenina , Neoplasias Colorrectales , Macrófagos , Receptores de Calcitriol , Apigenina/farmacología , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Animales , Ratones , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Modelos Animales de Enfermedad , Colitis/tratamiento farmacológico , Colitis/patología , Colitis/metabolismo , Colitis/inducido químicamente , Progresión de la Enfermedad , Células RAW 264.7 , Ratones Endogámicos C57BLRESUMEN
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.
Asunto(s)
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
BACKGROUND/OBJECTIVES: Dietary fats have been linked to the increasing incidence of chronic diseases, including inflammatory bowel diseases (IBD), namely, Crohn's disease (CD). METHODS: This study investigated the impact of pentadecanoic acid (C15:0), a type of an odd-numbered chain saturated fatty acid, for its potential anti-inflammatory properties in different mouse models of experimental IBD using the SAMP1/YitFc (SAMP) mouse line (14- or 24-week-old), including chronic ileitis and DSS-induced colitis. To quantitively assess the effect of C:15, we tested two dosages of C:15 in selected experiments in comparison to control mice. Intestinal inflammation and intestinal permeability were used as primary outcomes. RESULTS: In ileitis, C:15 supplementation showed an anti-inflammatory effect in SAMP mice (e.g., a reduction in ileitis severity vs. control p < 0.0043), which was reproducible when mice were tested in the DSS model of colitis (e.g., reduced permeability vs. control p < 0.0006). Of relevance, even the short-term C:15 therapy prevented colitis in mice by maintaining body weight, decreasing inflammation, preserving gut integrity, and alleviating colitis signs. CONCLUSIONS: Collectively, the findings from both ileitis and colitis in SAMP mice indicate that C:15 may have therapeutic effects in the treatment of IBD (colitis in the short term). This promising effect has major translational potential for the alleviation of IBD in humans.
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Antiinflamatorios , Suplementos Dietéticos , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Permeabilidad , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/dietoterapia , Ileítis/tratamiento farmacológico , Ileítis/prevención & controlRESUMEN
OBJECTIVE: To investigate the mechanism by which swertiamarin (STM) ameliorates CD-like colitis in mice. METHODS: A Caco-2 cell model of TNF-α-stimulated apoptosis was established and divided into three groups: Con, TNF-α and STM, and the effects of STM on apoptosis and barrier function were assessed by Tunel staining, western blotting, immunofluorescence, and transepithelial electric resistance (TEER). A mouse model of 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) -induced CD-like colitis was established to assess the effects of STM on colitis, intestinal barrier function and epithelial cell apoptosis. The regulatory role of the PI3K/AKT pathway in STM-induced resistance to intestinal epithelial cell apoptosis was investigated in both the cell model and mouse models. RESULTS: TUNEL staining showed that in Caco-2 cells with TNF-α stimulation, STM treatment significantly reduced the percentage of TUNEL-stained cells (P<0.05). STM obviously reduced TNF-α-induced enhancement of cleaved-caspase 3 and Bax expressions (P<0.05), increased Bcl-2 expression (P<0.05), protected intestinal barrier integrity and function by restoring transepithelial electrical resistance (TEER) of the cells, promoted normal localization and expressions of the tight junction proteins (ZO1 and claudin 1) (P<0.05), and inhibited the expression of pro-inflammatory factors (IL-6 and CCL3) (P<0.05) in TNF-α-stimulated Caco-2 cells. In the mouse models, STM significantly alleviated TNBS-induced CD-like colitis and intestinal barrier dysfunction (P<0.05) as shown by improved weight loss, lowered Disease Activity Index (DAI) score and inflammation score, reduction of IL-6 and CCL3 release, and restoration of intestinal barrier permeability, colonic TEER, bacterial translocation, and localization and expressions of the tight junction proteins. Mechanistically, STM inhibited the expressions of p-PI3K and p-AKT in both the cell model and mouse model(P<0.05), and treatment with 740Y-P (a PI3K/AKT pathway activator) significantly attenuated the inhibitory effect of STM on TNF-α-induced apoptosis in Caco-2 cells (P<0.05). CONCLUSION: STM inhibits intestinal epithelial cell apoptosis at least in part by suppressing activation of the PI3K/AKT pathway to ameliorate intestinal barrier dysfunction and colitis in mice.
Asunto(s)
Apoptosis , Colitis , Células Epiteliales , Ácido Trinitrobencenosulfónico , Factor de Necrosis Tumoral alfa , Animales , Ratones , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Células CACO-2 , Factor de Necrosis Tumoral alfa/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Modelos Animales de Enfermedad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Glucósidos Iridoides/farmacología , Transducción de Señal/efectos de los fármacos , Caspasa 3/metabolismoRESUMEN
Inflammatory bowel disease (IBD) is a chronic non-specific intestinal inflammatory disease that affects millions of people worldwide, and current treatment methods have certain limitations. This study aimed to explore the therapeutic potential and mechanism of action of lemairamin (Wgx-50) in inflammatory bowel disease (IBD). We used dextran sulfate sodium (DSS)-treated zebrafish as an inflammatory bowel disease model, and observed the effect of Wgx-50 on DSS-induced colitis inflammation. The results of the study showed that Wgx-50 could reduce the expression of pro-inflammatory cytokines induced by DSS and inhibit the recruitment of neutrophils to the site of intestinal injury. Further experiments revealed that Wgx-50 exerted its anti-inflammatory effect by regulating the activation of the Akt pathway. These research findings indicate that Wgx-50 possesses anti-inflammatory activity.
Asunto(s)
Antiinflamatorios , Colitis , Sulfato de Dextran , Modelos Animales de Enfermedad , Pez Cebra , Animales , Sulfato de Dextran/efectos adversos , Antiinflamatorios/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/patología , Citocinas/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Transducción de Señal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/inducido químicamente , Inflamación/metabolismoRESUMEN
Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.
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Colitis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Células Th17 , Ácido Trinitrobencenosulfónico , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Humanos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inmunología , Masculino , Ratas , Ratones , Células Th17/inmunología , Células Th17/efectos de los fármacos , Ratas Sprague-Dawley , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inhibidores , Acetamidas/uso terapéutico , Acetamidas/farmacología , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Colon/efectos de los fármacos , Colon/patología , Colon/inmunología , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: The number of inflammatory bowel diseases cases has increased throughout the years. Since, the current therapeutic methods have their adverse effects, this is leading to the development of alternative therapy derived from natural products. MATERIALS AND METHODS: In the present study, our objective was to explore the potential of Citrus aurantifolia peel extract (CAPE) on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) induced colitis in mice. Twenty-eight male Balb/c mice were divided into four groups: (1) normal group, (2) TNBS group, (3) 125 mg/kg CAPE group and (4) 250 mg/kg CAPE group. Colitis was induced through rectal administration of TNBS. The anti-inflammatory effects of CAPE against colitis were assessed by body weight, DAI score, colonic length, weight-to-length ratio, haematology profile and histopathological examinations. RESULTS: Our results showed that CAPE maintained the body weight of mice, repressed the increase of DAI score, maintained mice colonic length and weight, improved blood profile and suppressed the excessive production of TNF-α, IL-6 and IL-1ß. Furthermore, CAPE improved the histopathological score of colitis mice. CONCLUSION: All the findings of this study suggested that Citrus aurantifolia peel extract may be a potential natural agent for protecting mice against TNBS-induced colitis.
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Citrus , Colitis , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Extractos Vegetales , Ácido Trinitrobencenosulfónico , Animales , Extractos Vegetales/farmacología , Masculino , Citrus/química , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , RatonesRESUMEN
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.
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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 C57BLRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a disease involving the enteric canal which is characterised by chronisch inflammatory reaction. Coptisine (COP), the distinctive component of Coptis chinensis Franch., is famous for its anti-inflammation, antioxidation, anti-bacteria, and anti-cancer. Earlier researches certified that COP is a prospective remedy for colitis, but the mechanism of colitis and the therapeutical target of COP are deficiently elucidated. AIM OF THIS STUDY: In this follow-up study, we adopted dextran sulfate sodium (DSS)-elicited UC model to further elucidate the possible mechanism of COP on UC in mice. MATERIALS AND METHODS: COP and the positive drug sulfasalazine (SASP) were administered by oral gavage in DSS-induced colitis mouse model. Oxidative stress, inflammatory cytokines, intestinal barrier permeability, protein expression of the TXNIP/NLRP3 inflammasome pathway and intestinal microbiome structure were assessed. RESULTS: Among this investigation, our team discovered that COP could mitigate DSS-elicited UC in murines, with prominent amelioration in weight loss, disease activity index, intestinal permeability (serum diamine oxidase and D-lactate), contracted colonal length and histologic alterations. Furthermore, COP greatly lowered the generation of pro-inflammatory factors, malondialdehyde (MDA) activity and reactive oxygen species (ROS) level, while increased superoxide dismutase (SOD) activity in colonal tissues. Additionally, COP downmodulated the proteic expressions of thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, IL-1ß and IL-18. Enteric microbiome sequencing displayed that DSS and COP tremendously influenced the constitution and diversity of enteric microbes in DSS-elicited UC murines. Besides, COP elevated the abundance of probiotic bacteria Bacteroidota, Akkermansia_muciniphila and Bacteroides_acidifaciens, lowered the proportions of potential pathogenic bacteria, such as Lachnospiraceae, Acetatifactor_muris, Clostridium_XlVa, Alistipes and Oscillibacter, and reduced the ratio of Bacillota/Bacteroidota, which vastly helped to reverse the enteric microbiome to a balanceable condition. Alterations in these bacteria were strongly correlated with the colitis relative index. CONCLUSION: The mechanism of COP against UC is connected with the suppression of TXNIP/NLRP3 inflammasome signalling pathway and the adjustment of the enteric microbiome profiles. The proofs offer new understandings upon the anti-UC function of COP, which might be a prospective candidate against UC.
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Berberina , Proteínas Portadoras , Colitis Ulcerosa , Sulfato de Dextran , Microbioma Gastrointestinal , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Berberina/farmacología , Berberina/análogos & derivados , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Proteínas Portadoras/metabolismo , Ratones , Masculino , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Antiinflamatorios/farmacología , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Tiorredoxinas/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismoRESUMEN
Proanthocyanidins (PA) have been proven to have an anti-inflammation effect in multiple models by regulating oxidative stress. ß-glucan (BG) could alleviate colitis from the perspectives of intestinal permeability and gut microbiota. In the present study, the synergistic anti-inflammatory function of PA and BG was explored from multiple aspects including immune response, intestinal barrier, gut microbiota, and differential metabolites. The results showed that the supplementation of PA and BG improved the colitis symptoms including atrophy of the colon, body weight loss, and organ index increase. Additionally, inflammatory cytokine levels and oxidative stress status were significantly regulated with the intake of PA and BG. Moreover, PA and BG intervention improved intestinal permeability and promoted the expression of barrier proteins. The microbiome and metabolic profile of cecal contents showed that PA and BG supplementation increased the abundance of anti-inflammatory bacteria and decreased the abundance of pro-inflammatory bacteria. Furthermore, some beneficial metabolites involved in amino acid metabolism, carbohydrate metabolism, and biosynthesis of other secondary metabolite pathways were increased. Overall, these findings have demonstrated the regulation of the inflammatory response and remodel of metabolite profiles by PA and BG complexes, indicating that it may serve as a new strategy for inflammatory bowel disease treatment in the future.
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Colitis , Sulfato de Dextran , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Proantocianidinas , beta-Glucanos , Animales , beta-Glucanos/administración & dosificación , beta-Glucanos/farmacología , Sulfato de Dextran/efectos adversos , Ratones , Proantocianidinas/administración & dosificación , Proantocianidinas/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/inmunología , Masculino , Humanos , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Antiinflamatorios/administración & dosificación , Sinergismo Farmacológico , Modelos Animales de Enfermedad , Colon/metabolismo , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Ulcerative colitis (UC), a chronic idiopathic inflammatory bowel disease (IBD), presents with limited current drug treatment options. Consequently, the search for safe and effective drug for UC prevention and treatment is imperative. Our prior studies have demonstrated that the phenolic compound p-Hydroxybenzaldehyde (HD) from Nostoc commune, effectively mitigates intestinal inflammation. However, the mechanisms underlying HD's anti-inflammatory effects remain unclear. PURPOSE: This study delved into the pharmacodynamics of HD and its underlying anti-inflammation mechanisms. METHODS: For in vivo experiments, dextran sodium sulfate (DSS)-induced colitis mouse model was established. In vitro inflammation model was established using lipopolysaccharide (LPS)-induced RAW264.7 and bone marrow-derived macrophages (BMDMs). The protective effect of HD against colitis was determined by monitoring clinical symptoms and histological morphology in mice. The levels of inflammatory factors and oxidative stress markers were subsequently analyzed with enzyme-linked immunosorbent assay (ELISA) and biochemical kits. Furthermore, western blotting (WB), immunofluorescence (IF), luciferase reporter gene, drug affinity reaction target stability (DARTS) assay, molecular docking, and molecular dynamics (MD) simulation were used to determine the potential target and molecular mechanism of HD. RESULTS: Our findings indicate that HD significantly alleviated the clinical symptoms and histological morphology of colitis in mice, and curtailed the production of pro-inflammatory cytokines, including TNF-α, IL-6, IFN-γ, COX-2, and iNOS. Furthermore, HD stimulated the production of SOD, CAT, and GSH-px, enhanced total antioxidant capacity (T-AOC), and reduced MDA levels. Mechanically, HD augmented the expression of Nrf2, HO-1, and NQO-1, while concurrently downregulating the phosphorylation of p65, IκBα, c-Jun, and c-Fos. ML385 and siNrf2 largely attenuated the protective effect of HD in enteritis mice and RAW 264.7 cells, as well as the promotion of HO-1 expression levels. ZnPP-mediated HO-1 knockdown reversed HD-induced inhibition of colonic inflammation. Luciferase reporter assay and IF assay confirmed the transcriptional activation of Nrf2 by HD. DARTS analysis, molecular docking, and MD results showed high binding strength, interaction efficiency and remarkable stability between Nrf2 and HD. CONCLUSION: These outcomes extend our previous research results that HD can combat oxidative stress through the Nrf2/HO-1/NQO-1/NF-κB/AP-1 pathways, effectively alleviating colitis, and propose new targets for HD to protect against intestinal barrier damage.
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Benzaldehídos , Sulfato de Dextran , Factor 2 Relacionado con NF-E2 , FN-kappa B , Estrés Oxidativo , Factor de Transcripción AP-1 , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Benzaldehídos/farmacología , Estrés Oxidativo/efectos de los fármacos , FN-kappa B/metabolismo , Células RAW 264.7 , Factor de Transcripción AP-1/metabolismo , Masculino , Antiinflamatorios/farmacología , Ratones Endogámicos C57BL , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Modelos Animales de Enfermedad , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Transducción de Señal/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Lipopolisacáridos , Hemo Oxigenasa (Desciclizante)/metabolismo , Proteínas de la Membrana/metabolismoRESUMEN
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.
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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 , MasculinoRESUMEN
Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.
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Lesión Renal Aguda , Antioxidantes , Catequina , Nanopartículas , Catequina/análogos & derivados , Catequina/química , Catequina/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacología , Ratones , Nanopartículas/química , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Colitis/tratamiento farmacológico , Colitis/patología , Inflamación/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Mesalamina/química , Mesalamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Masculino , Portadores de Fármacos/química , HumanosRESUMEN
Fat and sugar overconsumption is the cause of increasing worldwide incidence of gastrointestinal tract in inflammatory conditions. The intestinal pre-inflammatory alterations are partially reversible, simultaneously inhibiting the predisposition to colitis. Searching for an effective pharmacotherapy for treating inflammatory conditions in the intestine is essential. This study aimed to investigate the effect of cannabigerol (CBG) on the inflammation state in the colon tissue of rats subjected to high-caloric diet. The experiment was conducted on male Wistar rats subjected to a standard or a high-fat high-sucrose diets for six weeks. For the last 14 days, half of rats from both groups received intragastrically cannabigerol solution (30â¯mg/kg of body mass). The ratio of n-6/n-3 PUFA, the activity of n-6 and n-3 PUFA, and arachidonic acid (AA) content in selected lipid fractions were determined by gas-liquid chromatography. Immunoblotting examined the expression of proteins involved in inflammation development. ELISA kits measured the content of arachidonic acid derivatives. CBG treatment reduced the n-6/n-3 PUFA ratio in TAG fraction and increased the n-3 PUFA pathway activity in almost all lipid fractions. Cannabigerol supplementation decreased AA concentration in PL and TAG. CBG also caused diminishments in the expression of cPLA2, COX-1, COX-2, and 12/15-LOX, which was indirectly correlated with a decreased LTB4 level and an increased LXA4 level. We concluded that cannabigerol has a protective influence on the development of inflammation in the colon tissue under lipid and sugar overload condition, thereby favoring cancer initiation and progression.