RESUMO
BACKGROUND/AIMS: This study aimed to investigate the possible positive effects of arbutin in a trinitrobenzene sulfonic acid (TNBS)- induced experimental colitis model, to compare it with mesalazine, which is used in treating inflammatory bowel disease and to observe the effect of its concomitant use. MATERIALS AND METHODS: Forty Wistar albino species male rats were randomized into 5 groups as control, colitis, colitis+arbutin (Arb), colitis+mesalazine (Mes), and colitis+mesalazine+arbutin (M+A). Proinflammatory cytokines [interleukin (IL)-6, IL-1ß, tumor necrosis factor alpha (TNF-α)] and oxidant/antioxidant parameters [malondialdehyde (MDA), superoxide dismutase inhibition (SOD) inhibition, myeloperoxidase (MPO), and catalase, glutathione peroxidase (GPx)] were processed from the samples. Histopathological evaluation evaluated goblet cell reduction, cellular infiltration, and mucosal loss. RESULTS: When the treatment groups and the TNBS group were compared, statistical significance was achieved in MDA, MPO, SOD inhibition, GPx values, IL-6, IL-1ß and TNF-α levels. Histopathological evaluation revealed a statistically significant decrease in the mucosal loss value in the group where mesalazine and arbutin were used together compared to the TNBS group. CONCLUSION: Our study's results elaborated that using arbutin alone or in combination with mesalazine produced positive effects in colitis-induced rats.
Assuntos
Arbutina , Colite , Modelos Animais de Doenças , Mesalamina , Peroxidase , Ratos Wistar , Ácido Trinitrobenzenossulfônico , Animais , Masculino , Arbutina/farmacologia , Arbutina/uso terapêutico , Ratos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Ácido Trinitrobenzenossulfônico/toxicidade , Mesalamina/farmacologia , Mesalamina/uso terapêutico , Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Citocinas/metabolismo , Malondialdeído/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fator de Necrose Tumoral alfa , Distribuição Aleatória , Glutationa Peroxidase/metabolismo , Interleucina-1beta/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêuticoRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a progressive and debilitating inflammatory disease of the gastrointestinal tract (GIT). Despite recent advances, precise treatment and noninvasive monitoring remain challenging. METHODS: Herein, we developed orally-administered, colitis-targeting and hyaluronic acid (HA)-modified, core-shell curcumin (Cur)- and cerium oxide (CeO2)-loaded nanoprobes (Cur@PC-HA/CeO2 NPs) for computed tomography (CT) imaging-guided treatment and monitoring of IBD in living mice. RESULTS: Following oral administration, high-molecular-weight HA maintains integrity with little absorption in the upper GIT, and then actively accumulates at local colitis sites owing to its colitis-targeting ability, leading to specific CT enhancement lasting for 24 h. The retained NPs are further degraded by hyaluronidase in the colon to release Cur and CeO2, thereby exerting anti-inflammatory and antioxidant effects. Combined with the ability of NPs to regulate intestinal flora, the oral NPs result in substantial relief in symptoms. Following multiple treatments, the gradually decreasing range of the colon with high CT attenuation correlates with the change in the clinical biomarkers, indicating the feasibility of treatment response and remission. CONCLUSION: This study provides a proof-of-concept for the design of a novel theranostic integration strategy for concomitant IBD treatment and the real-time monitoring of treatment responses.
Assuntos
Cério , Curcumina , Ácido Hialurônico , Doenças Inflamatórias Intestinais , Nanopartículas , Nanomedicina Teranóstica , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Camundongos , Cério/química , Curcumina/farmacologia , Curcumina/química , Curcumina/uso terapêutico , Nanomedicina Teranóstica/métodos , Administração Oral , Nanopartículas/química , Ácido Hialurônico/química , Hialuronoglucosaminidase/metabolismo , Tomografia Computadorizada por Raios X , Camundongos Endogâmicos C57BL , Colo/diagnóstico por imagem , Colo/patologia , Colo/metabolismo , Humanos , Colite/tratamento farmacológicoRESUMO
BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.
Assuntos
Antígeno CTLA-4 , Interleucina-23 , Animais , Camundongos , Humanos , Antígeno CTLA-4/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Interleucina-23/metabolismo , Feminino , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Modelos Animais de Doenças , Melanoma/tratamento farmacológico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Masculino , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos RetrospectivosRESUMO
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.
Assuntos
Colite , Colo , Preparações de Ação Retardada , Mesalamina , Micelas , Nitrorredutases , Polímeros , Pró-Fármacos , Animais , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Mesalamina/química , Mesalamina/farmacocinética , Nitrorredutases/metabolismo , Camundongos , Colo/metabolismo , Colo/patologia , Polímeros/química , Colite/tratamento farmacológico , Colite/metabolismo , Preparações de Ação Retardada/química , NADH NADPH Oxirredutases/metabolismo , Camundongos Endogâmicos C57BL , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , MasculinoRESUMO
The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.
Assuntos
Doenças Inflamatórias Intestinais , Receptores Purinérgicos P2 , Tiofenos , Animais , Tiofenos/farmacologia , Tiofenos/síntese química , Tiofenos/química , Tiofenos/uso terapêutico , Humanos , Camundongos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Receptores Purinérgicos P2/metabolismo , Relação Estrutura-Atividade , Antagonistas do Receptor Purinérgico P2/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Masculino , Descoberta de Drogas , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Amidas/uso terapêutico , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Colite/tratamento farmacológicoRESUMO
Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes (BMAL1 and PER2) and tight junctions (OCLN, TJP1, and CLND1), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression (Clnd1 and Clnd4), and clock gene expression (Bmal1 and Per2) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.
Assuntos
Ritmo Circadiano , Colite , Cumarínicos , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Animais , Ritmo Circadiano/efeitos dos fármacos , Feminino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Camundongos , Cumarínicos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genética , Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Sulfato de Dextrana , Regulação da Expressão Gênica/efeitos dos fármacos , Imunoglobulina A/metabolismo , Sirtuína 1RESUMO
Hesperetin (HT) is a type of citrus flavonoid with various pharmacological activities, including anti-tumor, anti-inflammation, antioxidant, and neuroprotective properties. However, the role and mechanism of HT in ulcerative colitis (UC) have been rarely studied. Our study aimed to uncover the beneficial effects of HT and its detailed mechanism in UC. Experimental colitis was induced by 2.5% dextran sodium sulfate (DSS) for seven days. HT ameliorated DSS-induced colitis in mice, showing marked improvement in weight loss, colon length, colonic pathological severity, and the levels of TNFα and IL6 in serum. A combination of informatics, network pharmacology, and molecular docking identified eight key targets and multi-pathways influenced by HT in UC. As a highlight, the experimental validation demonstrated that PTGS2, a marker of ferroptosis, along with other indicators of ferroptosis (such as ACSL4, Gpx4, and lipid peroxidation), were regulated by HT in vivo and in vitro. Additionally, the supplement of HT increased the diversity of gut microbiota, decreased the relative abundance of Proteobacteria and Gammaproteobacteria, and restored beneficial bacteria (Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001). In conclusion, HT is an effective nutritional supplement against experimental colitis by suppressing ferroptosis and modulating gut microbiota.
Assuntos
Sulfato de Dextrana , Modelos Animais de Doenças , Ferroptose , Microbioma Gastrointestinal , Hesperidina , Animais , Hesperidina/farmacologia , Ferroptose/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Masculino , Colite Ulcerativa/tratamento farmacológico , Colite/tratamento farmacológico , Colite/induzido quimicamente , Camundongos Endogâmicos C57BL , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/metabolismo , Simulação de Acoplamento Molecular , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Farmacologia em Rede , Peroxidação de Lipídeos/efeitos dos fármacos , Suplementos Nutricionais , Fosfolipídeo Hidroperóxido Glutationa PeroxidaseRESUMO
CONTEXT: Ulcerative colitis has been clinically treated with Qing Hua Chang Yin (QHCY), a traditional Chinese medicine formula. However, its precise mechanisms in mitigating chronic colitis are largely uncharted. OBJECTIVE: To elucidate the therapeutic efficiency of QHCY on chronic colitis and explore its underlying molecular mechanisms. MATERIALS AND METHODS: A total ion chromatogram fingerprint of QHCY was analysed. Chronic colitis was induced in male C57BL/6 mice using 2% dextran sodium sulphate (DSS) over 49 days. Mice were divided into control, DSS, DSS + QHCY (0.8, 1.6 and 3.2 g/kg/d dose, respectively) and DSS + mesalazine (0.2 g/kg/d) groups (n = 6). Mice were intragastrically administered QHCY or mesalazine for 49 days. The changes of disease activity index (DAI), colon length, colon histomorphology and serum pro-inflammatory factors in mice were observed. RNA sequencing was utilized to identify the differentially expressed transcripts (DETs) in colonic tissues and the associated signalling pathways. The expression of endoplasmic reticulum (ER) stress-related protein and NF-κB signalling pathway-related proteins in colonic tissues was detected by immunohistochemistry staining. RESULTS: Forty-seven compounds were identified in QHCY. Compared with the DSS group, QHCY significantly improved symptoms of chronic colitis like DAI increase, weight loss, colon shortening and histological damage. It notably reduced serum levels of IL-6, IL-1ß and TNF-α. QHCY suppressed the activation of PERK-ATF4-CHOP pathway of ER stress and NF-κB signalling pathways in colonic tissues. DISCUSSION AND CONCLUSIONS: The findings in this study provide novel insights into the potential of QHCY in treating chronic colitis patients.
Assuntos
Fator 4 Ativador da Transcrição , Sulfato de Dextrana , Medicamentos de Ervas Chinesas , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , NF-kappa B , Transdução de Sinais , Fator de Transcrição CHOP , eIF-2 Quinase , Animais , Masculino , Transdução de Sinais/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B/metabolismo , eIF-2 Quinase/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Fator de Transcrição CHOP/metabolismo , Doença Crônica , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/patologia , Modelos Animais de Doenças , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Relação Dose-Resposta a DrogaRESUMO
Neohesperidin dihydrochalcone (NHDC) is a citrus-originated, seminatural sweetener. There is no investigation concerning the effect of NHDC on ulcerative colitis. The purpose of this study was to determine the therapeutic and protective effects of NHDC in Wistar Albino rats. NHDC was given for 7 days after or before colitis induction. The results showed that NHDC significantly reduced the interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels. Catalase levels did not show a significant difference between the groups. NHDC provided a remarkable decrease in the expression levels of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κB). Total antioxidant status (TAS) levels were significantly elevated in NHDC treatment groups, while total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly decreased. NHDC provided remarkable improvement in histological symptoms such as epithelial erosion, edema, mucosal necrosis, inflammatory cell infiltration, and hemorrhage. Also, caspase-3 expression levels were statistically decreased in NHDC treatment groups. The results indicated that NHDC might be a protection or alternative treatment for ulcerative colitis.
Assuntos
Anti-Inflamatórios , Antioxidantes , Apoptose , Chalconas , Hesperidina , NF-kappa B , Ratos Wistar , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Ratos , Antioxidantes/farmacologia , Masculino , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Chalconas/administração & dosagem , Hesperidina/análogos & derivados , Hesperidina/farmacologia , Hesperidina/administração & dosagem , NF-kappa B/genética , NF-kappa B/metabolismo , Humanos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/induzido quimicamente , Malondialdeído/metabolismo , Peroxidase/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interferon gama/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
Rapid drug clearance and off-target effects of therapeutic drugs can induce low bioavailability and systemic side effects and gravely restrict the therapeutic effects of inflammatory bowel diseases (IBDs). Here, we propose an amplifying targeting strategy based on orally administered gallium (Ga)-based liquid metal (LM) nano-agents to efficiently eliminate reactive oxygen and nitrogen species (RONS) and modulate the dysregulated microbiome for remission of IBDs. Taking advantage of the favorable adhesive activity and coordination ability of polyphenol structure, epigallocatechin gallate (EGCG) is applied to encapsulate LM to construct the formulations (LM-EGCG). After adhering to the inflamed tissue, EGCG not only eliminates RONS but also captures the dissociated Ga to form EGCG-Ga complexes for enhancive accumulation. The detained composites protect the intestinal barrier and modulate gut microbiota for restoring the disordered enteral microenvironment, thereby relieving IBDs. Unexpectedly, LM-EGCG markedly decreases the Escherichia_Shigella populations while augmenting the abundance of Akkermansia and Bifidobacterium, resulting in favorable therapeutic effects against the dextran sulfate sodium-induced colitis.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Administração Oral , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Catequina/análogos & derivados , Catequina/química , Catequina/administração & dosagem , Catequina/farmacologia , Gálio/química , Gálio/farmacologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Colite/tratamento farmacológico , Humanos , Espécies Reativas de Nitrogênio/metabolismoRESUMO
The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.
Assuntos
Colite , Sulfato de Dextrana , Estradiol , Receptor alfa de Estrogênio , Ovariectomia , Animais , Feminino , Receptor alfa de Estrogênio/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/tratamento farmacológico , Camundongos , Estradiol/farmacologia , Estradiol/sangue , Camundongos Endogâmicos C57BL , Estrogênios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Interleucina-17/metabolismo , Colo/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Interleucina-6/metabolismo , Interleucina-1beta/metabolismoRESUMO
Coumarin, a phenolic compound, is a secondary metabolite produced by plants such as Tanga and Lime. Coumarin derivatives were prepared via Pechmann condensation. In this study, we performed in vitro and in vivo experiments to determine the antimicrobial and gut immune-regulatory functions of coumarin derivatives. For the in vitro antimicrobial activity assay, coumarin derivatives C1 and C2 were selected based on their pathogen-killing activity against various pathogenic microbes. We further demonstrated that the selected coumarin derivatives disrupted bacterial cell membranes. Next, we examined the regulatory function of the coumarin derivatives in gut inflammation using an infectious colitis model. In an in vivo infectious colitis model, administration of selected C1 coumarin derivatives reduced pathogen loads, the number of inflammatory immune cells (Th1 cells and Th17 cells), and inflammatory cytokine levels (IL-6 and IL-1b) in the intestinal tissue after pathogen infection. In addition, we found that the administration of C1 coumarin derivatives minimized abnormal gut microbiome shift-driven pathogen infection. Potential pathogenic gut microbes, such as Enterobacteriaceae and Staphylococcaceae, were increased by pathogen infection. However, this pathogenic microbial expansion was minimized and beneficial bacteria, such as Ligilactobacillus and Limosilactobacillus, increased with C1 coumarin derivative treatment. Functional gene enrichment assessment revealed that the relative abundance of genes associated with lipid and nucleotide metabolism was reduced by pathogen infection; however, this phenomenon was not observed in C1 coumarin derivative-treated animals. Collectively, our data suggest that C1 coumarin derivative is effective antibacterial agents that minimize pathogen-induced gut inflammation and abnormal gut microbiome modulation through their antibacterial activity.
Assuntos
Antibacterianos , Colite , Cumarínicos , Modelos Animais de Doenças , Microbioma Gastrointestinal , Cumarínicos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Colite/microbiologia , Colite/tratamento farmacológico , Antibacterianos/farmacologia , Camundongos , Citocinas/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/classificação , Camundongos Endogâmicos C57BL , Inflamação/tratamento farmacológico , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th1/imunologia , Células Th1/efeitos dos fármacos , MasculinoRESUMO
BACKGROUND: Sinomenine hydrochloride (SH) has anti-inflammatory and immunosuppressive effects, and its effectiveness in inflammatory diseases, such as rheumatoid arthritis, has been demonstrated. However, whether SH has a therapeutic effect on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice and its mechanism of action have not been clarified. This study aimed to investigate the therapeutic effects and mechanism of action of SH on UC. METHODS: Twenty-four mice were randomly divided into control, model, SH low-dose (SH-L, 20mg/kg), and SH high-dose (SH-H, 60mg/kg) groups with six mice in each group. Disease activity index (DAI), colonic mucosal damage index, and colonic histopathology scores were calculated. The expression levels of related proteins, genes, and downstream inflammatory factors in the Toll-like receptor 2/NF-κB (TLR2/NF-κB) signaling pathway were quantified. RESULTS: SH inhibited weight loss, decreased DAI and histopathological scores, decreased the expression levels of TLR2, MyD88, P-P65, P65 proteins, and TLR2 genes, and also suppressed the expression of inflammatory factors TNF-α, IL-1 ß, and IL-6 in the peripheral blood of mice. CONCLUSION: The therapeutic effect of SH on DSS-induced UC in mice may be related to the inhibition of the TLR2/NF-κB signaling pathway.
Assuntos
Sulfato de Dextrana , Morfinanos , NF-kappa B , Transdução de Sinais , Receptor 2 Toll-Like , Animais , Morfinanos/farmacologia , Morfinanos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Camundongos , Masculino , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Modelos Animais de Doenças , Distribuição Aleatória , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/patologiaRESUMO
Phellinus igniarius is a valuable medicinal and edible mushroom, and its polysaccharides exhibit excellent anti-inflammatory activity. During liquid fermentation to produce P. igniarius mycelia, the fermentation liquid is often discarded, but it contains extracellular polysaccharides. To better utilize these resources, P. igniarius SH-1 was fermented in a 100 L fermenter, and PIPS-2 was isolated and purified from the fermentation broth. The structural characteristics and anti-inflammatory activity of PIPS-2 were determined. PIPS-2 had a molecular weight of 22.855 kDa and was composed of galactose and mannose in a molar ratio of 0.38:0.62. Structural analysis revealed that the main chain of PIPS-2 involved â2)-α-D-Manp-(1 â 3)-ß-D-Galf-(1â, and the side chains involved α-D-Manp-(1 â 6)-α-D-Manp-(1â, α-D-Manp-(1 â 3)-α-D-Manp-(1â, and α-D-Manp-(1. PIPS-2 alleviated the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice, improved the imbalance of inflammatory factors and antioxidant enzymes, and increased short-chain fatty acid contents. Combining the intestinal flora and metabolite results, PIPS-2 was found to regulate the abundance of Firmicutes, Lachnospiraceae_NK4A136_group, Proteobacteria, Bacteroides, and many serum metabolites including hexadecenal, copalic acid, 8-hydroxyeicosatetraenoic acid, artepillin C, and uric acid, thereby ameliorating metabolite related disorders in mice with colitis. In summary, PIPS-2 may improve colitis in mice by regulating the gut microbiota and metabolites.
Assuntos
Basidiomycota , Colite , Sulfato de Dextrana , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Basidiomycota/química , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Masculino , Polissacarídeos/química , Polissacarídeos/farmacologia , Peso Molecular , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacosRESUMO
The polysaccharide glucan was extracted from Gastrodia elata Blume, and its structural characterizations and beneficial effects against acute dextran sulfate sodium (DSS)-induced ulcerative colitis were investigated. The results showed that a polysaccharide GP with a molecular weight of 811.0 kDa was isolated from G. elata Blume. It had a backbone of α-D-1,4-linked glucan with branches of α-d-glucose linked to the C-6 position. GP exhibited protective effects against DSS-induced ulcerative colitis, and reflected in ameliorating weight loss and pathological damages in mice, increasing colon length, inhibiting the expression of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), decreasing the levels of inflammatory related proteins NLRP3 and ASC, and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) level in mouse colon tissues. GP supplementation also reinforced the intestinal barrier by promoting the expression of ZO-1, Occludin, and MUC2 of colon tissues, and positively regulated intestinal microbiota. Thus, GP treatment possessed a significant improvement in ulcerative colitis in mice, and it was expected to be developed as a functional food.
Assuntos
Sulfato de Dextrana , Gastrodia , Glucanos , Animais , Sulfato de Dextrana/efeitos adversos , Glucanos/química , Glucanos/farmacologia , Camundongos , Gastrodia/química , Colite/tratamento farmacológico , Colite/induzido quimicamente , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Citocinas/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Modelos Animais de Doenças , Colo/efeitos dos fármacos , Colo/patologia , Colo/metabolismo , Peso MolecularRESUMO
Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/ß-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.
Assuntos
Colite , Camundongos Knockout , Animais , Colite/genética , Colite/induzido quimicamente , Colite/patologia , Colite/tratamento farmacológico , Colite/metabolismo , Humanos , Camundongos , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Células Caliciformes/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Inibidores de Serinopeptidase do Tipo Kazal/genética , Inibidores de Serinopeptidase do Tipo Kazal/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Masculino , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Feminino , Modelos Animais de Doenças , Biomarcadores/sangue , Biomarcadores/metabolismo , Diferenciação CelularRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear. AIMS OF THE STUDY: The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism. METHODS: We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting. RESULTS: The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis. CONCLUSION: HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC.
Assuntos
Aminoácidos , Neoplasias Associadas a Colite , Sulfato de Dextrana , Medicamentos de Ervas Chinesas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Masculino , Neoplasias Associadas a Colite/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos , Azoximetano/toxicidade , Modelos Animais de Doenças , Homeostase/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Camundongos Endogâmicos C57BL , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Apoptose/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proliferação de Células/efeitos dos fármacosRESUMO
Excessive apoptosis of intestinal epithelial cells leads to intestinal barrier dysfunction, which is not only one of the pathological features of inflammatory bowel disease (IBD) but also a therapeutic target. A natural plant extract, Ginkgetin (GK), has been reported to have anti-apoptotic activity, but its role in IBD is unknown. This study aimed to explore whether GK has anti-colitis effects and related mechanisms. An experimental colitis model induced by dextran sulfate sodium (DSS) was established, and GK was found to relieve colitis in DSS-induced mice as evidenced by improvements in weight loss, colon shortening, Disease Activity Index (DAI), macroscopic and tissue scores, and proinflammatory mediators. In addition, in DSS mice and TNF-α-induced colonic organoids, GK protected the intestinal barrier and inhibited intestinal epithelial cell apoptosis, by improving permeability and inhibiting the number of apoptotic cells and the expression of key apoptotic regulators (cleaved caspase 3, Bax and Bcl-2). The underlying mechanism of GK's protective effect was explored by bioinformatics, rescue experiments and molecular docking, and it was found that GK might directly target and activate EGFR, thereby interfering with PI3K/AKT signaling to inhibit apoptosis of intestinal epithelial cells in vivo and in vitro. In conclusion, GK inhibited intestinal epithelial apoptosis in mice with experimental colitis, at least in part, by activating EGFR and interfering with PI3K/AKT activation, explaining the underlying mechanism for ameliorating colitis, which may provide new options for the treatment of IBD.
Assuntos
Apoptose , Biflavonoides , Colite , Sulfato de Dextrana , Células Epiteliais , Receptores ErbB , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Receptores ErbB/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Sulfato de Dextrana/toxicidade , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Masculino , HumanosRESUMO
BACKGROUND: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.
Assuntos
Proteínas Quinases Dependentes de GMP Cíclico , GMP Cíclico , Medicamentos de Ervas Chinesas , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Transdução de Sinais , Animais , Medicamentos de Ervas Chinesas/farmacologia , GMP Cíclico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Humanos , Modelos Animais de Doenças , Guanilil Ciclase Solúvel/metabolismo , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Função da Barreira IntestinalRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Based on the core pathogenesis of hepatosplenic disorder and qi transformation disorder in ulcerative colitis, Tong-Xie-Yao-Fang (TXYF) is a classical traditional Chinese medicine commonly used to treat ulcerative colitis. Our study revealed that it has the potential to prevent colitis-associated colorectal cancer, which embodies the academic concept in traditional Chinese medicine of treating the disease before it develops. AIM OF THE STUDY: This study was aimed at evaluating the therapeutic role of TXYF in treating colitis-associated colorectal cancer and exploring its possible underlying mechanisms. MATERIALS AND METHODS: A colitis-associated colorectal cancer model was established in mice using azoxymethane and dextran sulfate sodium salt to examine the therapeutic effect of TXYF. The mouse body weights were observed. Hematoxylin-eosin staining was used to evaluate mouse colon histopathology. Colon cancer cells and colon epithelial cells were used to explore the potential molecular mechanisms. The proliferation and apoptosis of cells were detected by CCK8 and cell colony assays, flow cytometry and western blotting. The epithelial-mesenchymal transition (EMT) and mitophagy markers were examined by immunohistochemistry, western blotting, quantitative real-time PCR and immunofluorescence staining. RESULTS: TXYF inhibited the tumorigenesis of mice with colitis-associated colorectal cancer and the growth of inflammatory colon cells. TXYF induced mitophagy in colon cancer cells through the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway to reverse EMT, which was consistent with the results in mice with colitis-associated colorectal cancer. CONCLUSIONS: The results of the present study demonstrated that TXYF effectively inhibited the progression of colitis-associated colorectal cancer through the PINK1/Parkin pathway, which provides new evidence for prevention strategies for this disease.