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1.
J Ethnopharmacol ; 336: 118715, 2025 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-39179058

RESUMO

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.


Assuntos
Colesterol , Colite Ulcerativa , Sulfato de Dextrana , Medicamentos de Ervas Chinesas , Animais , Medicamentos de Ervas Chinesas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colite Ulcerativa/metabolismo , Camundongos , Masculino , Colesterol/sangue , Células Th17/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Farmacologia em Rede , Citocinas/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos
2.
Carbohydr Polym ; 346: 122582, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39245481

RESUMO

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.


Assuntos
Anti-Inflamatórios , Colite , Sulfato de Dextrana , Frutanos , Alho , Microbioma Gastrointestinal , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Alho/química , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Frutanos/farmacologia , Frutanos/química , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Relação Estrutura-Atividade , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Peso Molecular , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Proc Natl Acad Sci U S A ; 121(37): e2314337121, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39226363

RESUMO

Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer's disease (AD) and various cancers, including colorectal cancer (CRC). We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT). AD-like mice experienced a significantly decreased incidence of CRC tumorigenesis induced by azoxymethane-dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella, were increased in both the AD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella-derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella-derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC.


Assuntos
Doença de Alzheimer , Neoplasias Colorretais , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Animais , Doença de Alzheimer/microbiologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Camundongos , Humanos , Masculino , Inflamação , Disfunção Cognitiva , Feminino , Prevotella , Modelos Animais de Doenças , Lipopolissacarídeos , Carcinogênese , Sulfato de Dextrana
4.
Carbohydr Polym ; 345: 122551, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39227094

RESUMO

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.


Assuntos
Colite , Galectina 3 , Oligossacarídeos , Animais , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Camundongos , Galectina 3/metabolismo , Galectina 3/química , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Caryophyllaceae/química , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Masculino , Humanos
5.
Carbohydr Polym ; 345: 122572, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39227107

RESUMO

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.


Assuntos
Cápsulas , Colite , Polifenóis , Polissacarídeos , Probióticos , Probióticos/administração & dosagem , Probióticos/química , Animais , Polifenóis/química , Polifenóis/farmacologia , Colite/tratamento farmacológico , Colite/induzido quimicamente , Camundongos , Polissacarídeos/química , Polissacarídeos/farmacologia , Alimentos Fortificados , Alginatos/química , Alginatos/farmacologia , Masculino , Pectinas/química , Pectinas/farmacologia , Chá/química , Antioxidantes/química , Antioxidantes/farmacologia , Quitosana/química , Sulfato de Dextrana/química , Composição de Medicamentos/métodos
6.
Cell Mol Life Sci ; 81(1): 397, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261351

RESUMO

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.


Assuntos
Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal , Fator 1 Induzível por Hipóxia , Mucosa Intestinal , Transdução de Sinais , Vitamina B 12 , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Vitamina B 12/farmacologia , Vitamina B 12/metabolismo , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Transdução de Sinais/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , Fator 1 Induzível por Hipóxia/metabolismo , Colite/metabolismo , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colite/tratamento farmacológico , Disbiose/microbiologia , Disbiose/metabolismo , Camundongos Endogâmicos C57BL , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Drosophila/metabolismo
7.
Mediators Inflamm ; 2024: 1484806, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39262415

RESUMO

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.


Assuntos
Colite , Sulfato de Dextrana , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Triptofano , Animais , Sulfato de Dextrana/toxicidade , Colite/induzido quimicamente , Colite/tratamento farmacológico , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Triptofano/análogos & derivados , Triptofano/farmacologia , Inflamação/tratamento farmacológico , Masculino , Apoptose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Humanos , Modelos Animais de Doenças , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
8.
Eur J Med Res ; 29(1): 450, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223620

RESUMO

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.


Assuntos
Colite Ulcerativa , Ferroptose , Ginsenosídeos , MicroRNAs , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Ginsenosídeos/farmacologia , MicroRNAs/genética , Camundongos , Ferroptose/efeitos dos fármacos , Humanos , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Regulação para Cima/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Sulfato de Dextrana/toxicidade , Apoptose/efeitos dos fármacos
9.
J Nanobiotechnology ; 22(1): 538, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39227962

RESUMO

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.


Assuntos
Berberina , Compostos de Bifenilo , Colite Ulcerativa , Lignanas , Nanoestruturas , Animais , Colite Ulcerativa/tratamento farmacológico , Berberina/química , Berberina/farmacologia , Berberina/uso terapêutico , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Camundongos , Compostos de Bifenilo/química , Nanoestruturas/química , Masculino , Sulfato de Dextrana/química , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Disponibilidade Biológica
10.
Virulence ; 15(1): 2399217, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39221673

RESUMO

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.


Assuntos
Adesinas Bacterianas , Colite Ulcerativa , Infecções por Fusobacterium , Fusobacterium nucleatum , Animais , Humanos , Camundongos , Adesinas Bacterianas/metabolismo , Adesinas Bacterianas/genética , Aderência Bacteriana , Caderinas/metabolismo , Colite Ulcerativa/microbiologia , Sulfato de Dextrana , Modelos Animais de Doenças , Infecções por Fusobacterium/microbiologia , Fusobacterium nucleatum/patogenicidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Virulência , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
11.
Int Immunopharmacol ; 141: 112990, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39223062

RESUMO

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.


Assuntos
Colite , Sulfato de Dextrana , Macrófagos , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Piroptose/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/imunologia , Transdução de Sinais/efeitos dos fármacos , Inflamassomos/metabolismo , Citocinas/metabolismo , Masculino , Humanos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
12.
Food Funct ; 15(18): 9541-9551, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39225067

RESUMO

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with limited therapeutic options. Dietary components like blueberries have emerged as potential modulators of inflammation and tissue repair in gastrointestinal diseases. This study investigated endoplasmic reticulum (ER) stress-mediated apoptosis mediated protective effects of blueberries in ameliorating dextran sulfate sodium (DSS)-induced IBD. Firstly, a total of 86 anthocyanin compounds were identified in blueberry extract by LC-MS spectroscopy, including 35 cyanidin, 9 delphinidin, 14 malvidin, 10 peonidin, and 9 petunidin. Then, the animal study showed that blueberry supplementation notably ameliorated DSS-induced IBD symptoms, as evidenced by improved histopathological scores and a reduced disease activity index (DAI) score. Additionally, blueberries attenuated ER stress by inhibiting the colonic PERK/eIF2α/ATF4/CHOP signaling pathway. Furthermore, blueberries inhibited the expression of the pro-apoptotic protein, caspase-3, and decreased colonic apoptosis, as evidenced by TUNEL assay results. However, it did not affect the expression of anti-apoptotic proteins, bcl-2 and bcl-xl. Finally, blueberries enhanced the intestinal barrier by upregulating ZO-1, claudin-1, occludin, and E-cadherin. In conclusion, blueberries demonstrate therapeutic potential against DSS-induced IBD-like symptoms in mice, possibly by regulating ER stress-mediated apoptosis pathways. These findings suggest that blueberries might be an effective dietary intervention for IBD management.


Assuntos
Apoptose , Mirtilos Azuis (Planta) , Colo , Sulfato de Dextrana , Estresse do Retículo Endoplasmático , Doenças Inflamatórias Intestinais , Extratos Vegetais , Animais , Mirtilos Azuis (Planta)/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos , Extratos Vegetais/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Sulfato de Dextrana/efeitos adversos , Masculino , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Humanos
13.
Nutrients ; 16(17)2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39275234

RESUMO

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.


Assuntos
Bacteroides , Colo , Sulfato de Dextrana , Modelos Animais de Doenças , Fezes , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Probióticos , Animais , Probióticos/farmacologia , Humanos , Colo/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Bacteroides/isolamento & purificação , Fezes/microbiologia , Masculino , Colite/microbiologia , Colite/induzido quimicamente , Disbiose/microbiologia , Colite Ulcerativa/microbiologia
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(8): 1467-1475, 2024 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-39276042

RESUMO

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.


Assuntos
Colite Ulcerativa , Sulfato de Dextrana , Modelos Animais de Doenças , Isoquinolinas , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , NF-kappa B , Transdução de Sinais , Animais , Colite Ulcerativa/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Masculino , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Colo/metabolismo , Colo/patologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Ocludina/metabolismo , Malondialdeído/metabolismo , Interleucina-1beta/metabolismo , Benzofenantridinas
15.
Food Res Int ; 195: 114950, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39277228

RESUMO

Rosa roxburghii Tratt (RRT), a traditional Chinese plant known as the 'King of Vitamin C (VitC; ascorbic acid, AsA)', contains a wealth of nutrients and functional components, including polysaccharides, organic acids, flavonoids, triterpenes, and high superoxide dismutase (SOD) activity. The various functional components of RRT suggest that it may theoretically have a stronger potential for alleviating colitis compared to VitC. This study aims to verify whether RRT has a stronger ability to alleviate colitis than equimolar doses of VitC and to explore the mechanisms underlying this improvement. Results showed that RRT significantly mitigated body weight loss, intestinal damage, elevated inflammation levels, and compromised barriers in mice induced by Dextran sulfate sodium (DSS). Additionally, RRT enhanced the diversity and composition of intestinal microbiota in these DSS-induced mice. Colon RNA sequencing analysis revealed that compared to VitC, RRT further downregulated multiple immune-related signaling pathways, particularly the B cell receptor (BCR) pathway, which is centered around genes like Btk and its downstream PI3K-AKT, NF-κB, and MAPK signaling pathways. Correlation analysis between microbiota and genes demonstrated a significant relationship between the taxa improved by RRT and the key genes in the BCR and its downstream signaling pathways. Overall, RRT exhibited superior capabilities in alleviating DSS-induced colitis compared to VitC by decreasing intestinal inflammation and modulating BCR and its downstream signaling pathways, potentially regulated by the improved intestinal microbiota.


Assuntos
Ácido Ascórbico , Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Rosa , Transdução de Sinais , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Rosa/química , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Masculino , Colo/metabolismo , Colo/microbiologia , Colo/efeitos dos fármacos , Modelos Animais de Doenças
16.
Appl Microbiol Biotechnol ; 108(1): 463, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39269473

RESUMO

The fecal microbiome is identical to the gut microbial communities and provides an easy access to the gut microbiome. Therefore, fecal microbial transplantation (FMT) strategies have been used to alter dysbiotic gut microbiomes with healthy fecal microbiota, successfully alleviating various metabolic disorders, such as obesity, type 2 diabetes, and inflammatory bowel disease (IBD). However, the success of FMT treatment is donor-dependent and variations in gut microbes cannot be avoided. This problem may be overcome by using a cultured fecal microbiome. In this study, a human fecal microbiome was cultured using five different media; growth in brain heart infusion (BHI) media resulted in the highest microbial community cell count. The microbiome (16S rRNA) data demonstrated that the cultured microbial communities were similar to that of the original fecal sample. Therefore, the BHI-cultured fecal microbiome was selected for cultured FMT (cFMT). Furthermore, a dextran sodium sulfate (DSS)-induced mice-IBD model was used to confirm the impact of cFMT. Results showed that cFMT effectively alleviated IBD-associated symptoms, including improved gut permeability, restoration of the inflamed gut epithelium, decreased expression of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1, IL-6, IL-12, and IL-17), and increased expression of anti-inflammatory cytokines (IL-4 and IL-10). Thus, study's findings suggest that cFMT can be a potential alternative to nFMT. KEY POINTS: • In vitro fecal microbial communities were grown in a batch culture using five different media. • Fecal microbial transplantation was performed on DSS-treated mice using cultured and normal fecal microbes. • Cultured fecal microbes effectively alleviated IBD-associated symptoms.


Assuntos
Citocinas , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Fezes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , RNA Ribossômico 16S , Transplante de Microbiota Fecal/métodos , Animais , Fezes/microbiologia , Camundongos , Humanos , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/microbiologia , Citocinas/metabolismo , RNA Ribossômico 16S/genética , Camundongos Endogâmicos C57BL , Sulfato de Dextrana , Masculino , Meios de Cultura/química , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação
17.
Int J Mol Sci ; 25(17)2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39273457

RESUMO

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.


Assuntos
Anti-Inflamatórios , Colite , Sulfato de Dextrana , Modelos Animais de Doenças , Peixe-Zebra , Animais , Sulfato de Dextrana/efeitos adversos , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo
18.
Molecules ; 29(17)2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39274878

RESUMO

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.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , NF-kappa B , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Modelos Animais de Doenças , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Sulfato de Dextrana
19.
NPJ Biofilms Microbiomes ; 10(1): 84, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266529

RESUMO

The role of mast cells (MCs) in ulcerative colitis (UC) development is controversial. FcεRI, the IgE high-affinity receptor, is known to activate MCs. However, its role in UC remains unclear. In our study, Anti-FcεRI showed highly diagnostic value for UC. FcεRIα knockout in mice ameliorated DSS-induced colitis in a gut microbiota-dependent manner. Increased Lactobacillus abundance in FcεRIα deficient mice showed strongly correlation with the remission of colitis. RNA sequencing indicated activation of the NLRP6 inflammasome pathway in FcεRIα knockout mice. Additionally, Lactobacillus plantarum supplementation protected against inflammatory injury and goblet cell loss, with activation of the NLRP6 inflammasome during colitis. Notably, this effect was absent when the strain is unable to produce lactic acid. In summary, colitis was mitigated in FcεRIα deficient mice, which may be attributed to the increased abundance of Lactobacillus. These findings contribute to a better understanding of the relationship between allergic reactions, microbiota, and colitis.


Assuntos
Sulfato de Dextrana , Microbioma Gastrointestinal , Receptores de IgE , Animais , Camundongos , Colite/prevenção & controle , Colite/microbiologia , Colite/induzido quimicamente , Colite Ulcerativa/microbiologia , Modelos Animais de Doenças , Inflamassomos/metabolismo , Lactobacillus , Lactobacillus plantarum/genética , Lactobacillus plantarum/fisiologia , Mastócitos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Probióticos , Receptores de IgE/genética
20.
BMC Cancer ; 24(1): 1141, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267014

RESUMO

BACKGROUND: Curcumin has been reported to have activity for prevention and therapy of CRC, yet its underlying mechanisms remain largely unknown. Recently, emerging evidence suggests that the gut microbiota and its metabolites contribute to the causation and progression of Colorectal cancer (CRC). In this study, we aimed to investigate if curcumin affects the tumorigenesis of CRC by modulating gut microbiota and its metabolites. METHODS: Forty male C57BL/6JGpt mice were randomly divided into four groups: negative control (NC), curcumin control, CRC model, and curcumin treatment (CRC-Cur) groups. CRC mouse model was induced by using azoxymethane (AOM) and dextran sodium sulfate (DSS), and the mice in CRC model and curcumin treatment groups received oral PBS or curcumin (150 mg/kg/day), respectively. Additionally, fecal samples were collected. 16 S rRNA sequencing and Liquid Chromatography Mass Spectrometry (LC-MS)-based untargeted metabolomics were used to observe the changes of intestinal flora and intestinal metabolites. RESULTS: Curcumin treatment restored colon length and structural morphology, and significantly inhibited tumor formation in AOM/DSS-induced CRC model mice. The 16S rRNA sequencing analysis indicated that the diversity and richness of core and total species of intestinal microflora in the CRC group were significantly lower than those in the NC group, which were substantially restored in the curcumin treatment group. Curcumin reduced harmful bacteria, including Ileibacterium, Monoglobus and Desulfovibrio, which were elevated in CRC model mice. Moreover, curcumin increased the abundance of Clostridia_UCG-014, Bifidobacterium and Lactobacillus, which were decreased in CRC model mice. In addition, 13 different metabolites were identified. Compared to the NC group, ethosuximide, xanthosine, and 17-beta-estradiol 3-sulfate-17-(beta-D-glucuronide) were elevated in the CRC model group, whereas curcumin treatment significantly reduced their levels. Conversely, glutamylleucine, gamma-Glutamylleucine, liquiritin, ubenimex, 5'-deoxy-5'-fluorouridine, 7,8-Dihydropteroic acid, neobyakangelicol, libenzapril, xenognosin A, and 7,4'-dihydroxy-8-methylflavan were decreased in the CRC group but notably upregulated by curcumin. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis revealed enrichment in seven pathways, including folate biosynthesis (P < 0.05). CONCLUSIONS: The gut microecological balance was disrupted in AOM/DSS-induced CRC mice, accompanied by metabolite dysbiosis. Curcumin restored the equilibrium of the microbiota and regulated metabolites, highly indicating that curcumin may alleviate the development of AOM/DSS induced colorectal cancer in mice by regulating intestinal flora homeostasis and intestinal metabolites.


Assuntos
Neoplasias Colorretais , Curcumina , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Curcumina/farmacologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/induzido quimicamente , Camundongos , Masculino , Modelos Animais de Doenças , Azoximetano/toxicidade , Carcinogênese/efeitos dos fármacos , Sulfato de Dextrana/toxicidade , RNA Ribossômico 16S/genética , Metabolômica/métodos , Humanos
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