RESUMO
While there have been advancements in understanding the direct and indirect impact of riboflavin (B2) on intestinal inflammation, the precise mechanisms are still unknown. This study focuses on evaluating the effects of riboflavin (B2) supplementation on a colitis mouse model induced with 3% dextran sodium sulphate (DSS). We administered three different doses of oral B2 (VB2L, VB2M, and VB2H) and assessed its impact on various physiological and biochemical parameters associated with colitis. Mice given any of the three doses exhibited relative improvement in the symptoms and intestinal damage. This was evidenced by the inhibition of the pro-inflammatory cytokines TNF-α, IL-1ß, and CALP, along with an increase in the anti-inflammatory cytokine IL-10. B2 supplementation also led to a restoration of oxidative homeostasis, as indicated by a decrease in myeloperoxidase (MPO) and malondialdehyde (MDA) levels and an increase in reduced glutathione (GSH) and catalase (CAT) activities. B2 intervention showed positive effects on intestinal barrier function, confirmed by increased expression of tight junction proteins (occludin and ZO-1). B2 was linked to an elevated relative abundance of Actinobacteriota, Desulfobacterota, and Verrucomicrobiota. Notably, Verrucomicrobiota showed a significant increase in the VB2H group, reaching 15.03% relative abundance. Akkermansia exhibited a negative correlation with colitis and might be linked to anti-inflammatory function. Additionally, a remarkable increase in n-butyric acid, i-butyric acid, and i-valeric acid was reported in the VB2H group. The ameliorating role of B2 in gut inflammation can be attributed to immune system modulation as well as alterations in the gut microbiota composition, along with elevated levels of fecal SCFAs.
Assuntos
Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Homeostase , Camundongos Endogâmicos C57BL , Riboflavina , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Sulfato de Dextrana/efeitos adversos , Riboflavina/farmacologia , Homeostase/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismoRESUMO
Iron overload can lead to oxidative stress and intestinal damage and happens frequently during blood transfusions and iron supplementation. However, how iron overload influences intestinal mucosa remains unknown. Here, the aim of current study was to investigate the effects of iron overload on the proliferation and differentiation of intestinal stem cells (ISCs). An iron overload mouse model was established by intraperitoneal injection of 120 mg/kg body weight iron dextran once a fortnight for a duration of 12 weeks, and an iron overload enteroid model was produced by treatment with 3 mM or 10 mM of ferric ammonium citrate for 24 h. We found that iron overload caused damage to intestinal morphology with a 64 % reduction in villus height/crypt depth ratio, and microvilli injury in the duodenum. Iron overload mediated epithelial function by inhibiting the expression of nutrient transporters and enhancing the expression of secretory factors in the duodenum. Meanwhile, iron overload inhibited the proliferation of ISCs and regulated their differentiation into secretory mature cells, such as goblet cells, through inhibiting Notch signaling pathway both in mice and enteroid. Furthermore, iron overload caused oxidative stress and ferroptosis in intestinal epithelial cells. In addition, ferroptosis could also inhibit Notch signaling pathway, and affected the proliferation and differentiation of ISCs. These findings reveal the regulatory role of iron overload on the proliferation and differentiation of ISCs, providing a new insight into the internal mechanism of iron overload affecting intestinal health, and offering important theoretical basis for the scientific application of iron nutrition regulation.
Assuntos
Diferenciação Celular , Ferroptose , Células Caliciformes , Sobrecarga de Ferro , Estresse Oxidativo , Receptores Notch , Transdução de Sinais , Células-Tronco , Animais , Ferroptose/efeitos dos fármacos , Camundongos , Células Caliciformes/metabolismo , Sobrecarga de Ferro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/citologia , Diferenciação Celular/efeitos dos fármacos , Receptores Notch/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , MasculinoRESUMO
Structural and functional changes of the intestinal barrier, as a consequence of a number of (epi)genetic and environmental causes, have a main role in penetrations of pathogens and toxic agents, and lead to the development of inflammation-related pathological conditions, not only at the level of the GI tract but also in other extra-digestive tissues and organs. Anthocyanins (ACNs), a subclass of polyphenols belonging to the flavonoid group, are well known for their health-promoting properties and are widely distributed in the human diet. There is large evidence about the correlation between the human intake of ACN-rich products and a reduction of intestinal inflammation and dysfunction. Our review describes the more recent advances in the knowledge of cellular and molecular mechanisms through which ACNs can modulate the main mechanisms involved in intestinal dysfunction and inflammation, in particular the inhibition of the NF-κB, JNK, MAPK, STAT3, and TLR4 proinflammatory pathways, the upregulation of the Nrf2 transcription factor and the expression of tight junction proteins and mucins.
Assuntos
Antocianinas , Inflamação , Intestinos , Animais , Humanos , Antocianinas/administração & dosagem , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Dieta Baseada em PlantasRESUMO
BACKGROUND: Diarrheal irritable bowel syndrome (IBS-D), characterized primarily by the presence of diarrhea and abdominal pain, is a clinical manifestation resulting from a multitude of causative factors. Furthermore, Sishen Wan (SSW) has demonstrated efficacy in treating IBS-D. Nevertheless, its mechanism of action remains unclear. METHODS: A model of IBS-D was induced by a diet containing 45 % lactose and chronic unpredictable mild stress. Additionally, the impact of SSW was assessed by measuring body weight, visceral sensitivity, defecation parameters, intestinal transport velocity, intestinal neurotransmitter levels, immunohistochemistry, and transmission electron microscopy analysis. Immunofluorescent staining was used to detect the expression of Mucin 2 (MUC2) and Occludin in the colon. Western blotting was used to detect changes in proteins related to tight junction (TJ), autophagy, and endoplasmic reticulum (ER) stress in the colon. Finally, 16S rRNA amplicon sequencing was used to monitor the alteration of gut microbiota after SSW treatment. RESULTS: Our study revealed that SSW administration resulted in reduced visceral sensitivity, improved defecation parameters, decreased intestinal transport velocity, and reduced intestinal permeability in IBS-D mice. Furthermore, SSW promotes the secretion of colonic mucus by enhancing autophagy and inhibiting ER stress. SSW treatment caused remodeling of the gut microbiome by increasing the abundance of Blautia, Muribaculum and Ruminococcus torques group. CONCLUSION: SSW can improve intestinal barrier function by promoting autophagy and inhibiting ER stress, thus exerting a therapeutic effect on IBS-D.
Assuntos
Diarreia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Estresse do Retículo Endoplasmático , Microbioma Gastrointestinal , Mucosa Intestinal , Síndrome do Intestino Irritável , Síndrome do Intestino Irritável/tratamento farmacológico , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Diarreia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Mucosa Intestinal/efeitos dos fármacos , Mucina-2/metabolismo , Colo/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Ocludina/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Camundongos Endogâmicos C57BL , Função da Barreira IntestinalRESUMO
Selenium (Se) is indispensable in alleviating various types of intestinal injuries. Here, we thoroughly investigated the protective effect of Se on the regulation of the epithelial cell-M2 macrophages pathway in deoxynivalenol (DON)-induced intestinal damage. In the present study, Se has positive impacts on gut health by improving gut barrier function and reducing the levels of serum DON in vivo. Furthermore, our study revealed that Se supplementation increased the abundances of GPX4, p-PI3K, and AKT, decreased the levels of 4-HNE and inhibited ferroptosis. Moreover, when mice were treated with DON and Fer-1(ferroptosis inhibitor), ferroptosis was suppressed and PI3K/AKT pathway was activated. These results indicated that GPX4-PI3K/AKT-ferroptosis was a predominant pathway in DON-induced intestinal inflammation. Interestingly, we discovered that both the number of M2 anti-inflammatory macrophages and the levels of CSF-1 decreased while the pro-inflammatory cytokine IL-6 increased in the intestine and MODE-K cells supernatant. Therefore, Se supplementation activated the CSF-1-M2 macrophages axis, resulting in a decrease in IL-6 expression and an enhancement of the intestinal anti-inflammatory capacity. This study provides novel insights into how intestinal epithelial cells regulate the CSF-1-M2 macrophage pathway, which is essential in maintaining intestinal homeostasis confer to environmental hazardous stimuli.
Assuntos
Células Epiteliais , Mucosa Intestinal , Macrófagos , Selênio , Tricotecenos , Animais , Tricotecenos/toxicidade , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Selênio/farmacologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
SCOPE: This study investigates the potential of glutamine to mitigate intestinal mucositis and dysbiosis caused by the chemotherapeutic agent 5-fluorouracil (5-FU). METHODS AND RESULTS: Over twelve days, Institute of Cancer Research (ICR) mice are given low (0.5 mg kg-1) or high (2 mg kg-1) doses of L-Glutamine daily, with 5-FU (50 mg kg-1) administered between days six and nine. Mice receiving only 5-FU exhibited weight loss, diarrhea, abnormal cell growth, and colonic inflammation, correlated with decreased mucin proteins, increased endotoxins, reduced fecal short-chain fatty acids, and altered gut microbiota. Glutamine supplementation counteracted these effects by inhibiting the Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) pathway, modulating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) oxidative stress proteins, and increasing mammalian target of rapamycin (mTOR) levels, thereby enhancing microbial diversity and protecting intestinal mucosa. CONCLUSIONS: These findings underscore glutamine's potential in preventing 5-FU-induced mucositis by modulating gut microbiota and inflammation pathways.
Assuntos
Fluoruracila , Microbioma Gastrointestinal , Glutamina , Mucosa Intestinal , Mucosite , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Fluoruracila/efeitos adversos , Glutamina/farmacologia , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos ICR , Masculino , Receptor 4 Toll-Like/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Antimetabólitos Antineoplásicos/efeitos adversos , Heme Oxigenase-1/metabolismoRESUMO
BACKGROUND: Intestinal barrier dysfunction caused by the disrupted balance of group 3 innate lymphoid cells (ILC3)/group 1 innate lymphoid cells (ILC1) is a significant feature in the pathogenesis of inflammatory bowel disease (IBD). Activation of aryl hydrocarbon receptor (AhR) signaling contributes to the maintenance of ILC3/ILC1 balance. Wogonin, a natural flavonoid from Scutellaria baicalensis Georgi, can repair intestinal mucosal damage of IBD. However, it remains unclear if wogonin can exert a therapeutic effect by activating the AhR pathway to regulate the plasticity of ILC3/ILC1. PURPOSE: In this study, we investigated the immunomodulatory effects of wogonin on IBD and its potential mechanisms in vitro and in vivo. STUDY DESIGN AND METHODS: Chronic colitis was induced by four cycles of 2 % DSS treatment in mice. 20 mg kg-1/day wogonin was administrated by oral gavage and mice were treated intraperitoneally with 10 mg kg-1/2 days CH223191 to block the AhR pathway. Colon tissues were processed for histopathological examination and evaluation of the epithelial barrier function by immunohistochemistry. The activation of the AhR pathway and the plasticity of ILC3/ILC1 were determined by western blot and flow cytometry. Then, we also detected the intestinal microflora and their metabolites by 16 s sequencing and non-targeted Metabolomics analysis. Furthermore, an in vitro culture system consisting of MNK3 cells and NCM460 cells, and a CETSA assay were performed to confirm the molecular mechanism. RESULTS: Wogonin ameliorated histological severity of the colon, decreased the secretion of inflammatory factors, and increased tight junction proteins in colitis mice. These effects are associated with the tendency of conversion from ILC3 to ILC1 prevented by wogonin, which was offset by AhR antagonist CH223191. In addition, wogonin exerted the curative effect by altering gut microbiota to produce metabolites such as Kynurenic acid, and 1H-Indole-3-carboxaldehyde as AhR endogenous ligands. In vitro data further verified that wogonin as an exogenous ligand directly binds to the structural domain of AhR by CETSA. Also, the supernatant of MNK-3 cells stimulated with wogonin enhanced expression of Occludin and Claudin1 in NCM460 cells induced by LPS. CONCLUSION: Cumulatively, our study illustrated that wogonin improved the outcomes of DSS-induced chronic colitis via regulating the plasticity of ILC3/ILC1. Its specific mechanism is to binding to AhR directly, and to activate the AhR pathway indirectly by altering the tryptophan metabolisms of gut microbiota.
Assuntos
Colite , Flavanonas , Imunidade Inata , Linfócitos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico , Transdução de Sinais , Flavanonas/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Camundongos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Linfócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Masculino , Scutellaria baicalensis/química , Mucosa Intestinal/efeitos dos fármacos , Humanos , Modelos Animais de Doenças , Sulfato de Dextrana , Microbioma Gastrointestinal/efeitos dos fármacos , Colo/efeitos dos fármacosRESUMO
BACKGROUND: Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. PURPOSE: The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. METHODS: The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo. And DHL on reducing inflammatory response and regulating TLR4/NF-κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. RESULTS: DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. CONCLUSION: This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
Assuntos
Irinotecano , Lactonas , Antígeno 96 de Linfócito , Mucosite , Sesquiterpenos , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Camundongos , Lactonas/farmacologia , Humanos , Antígeno 96 de Linfócito/metabolismo , Masculino , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células THP-1 , Antineoplásicos Fitogênicos/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos BALB C , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismoRESUMO
BACKGROUND: The damage of chemotherapy drugs to immune function and intestinal mucosa is a common side effect during chemotherapy. Astragalus polysaccharides (APS) exhibit immunomodulatory properties and are recognized for preserving the integrity of the human intestinal barrier. Nevertheless, their application and mechanisms of action in chemotherapy-induced immune damage and intestinal barrier disruption remain insufficiently explored. PURPOSE: This study delved into investigating how APS mitigates chemotherapy-induced immune dysfunction and intestinal mucosal injury, while also providing deeper insights into the underlying mechanisms. METHODS: In a chemotherapy mice model induced by 5-fluorouracil (5-Fu), the assessment of APS's efficacy encompassed evaluations of immune organ weight, body weight, colon length, and histopathology. The regulation of different immune cells in spleen was detected by flow cytometry. 16S rRNA gene sequencings, ex vivo microbiome assay, fecal microbiota transplantation (FMT), and targeted metabolomics analysis were applied to explore the mechanisms of APS effected on chemotherapy-induced mice. RESULTS: APS ameliorated chemotherapy-induced damage to immune organs and regulated immune cell differentiation disorders, including CD4+T, CD8+T, CD19+B, F4/80+CD11B+ macrophages. APS also alleviated colon shortening and upregulated the expression of intestinal barrier proteins. Furthermore, APS significantly restored structure of gut microbiota following chemotherapy intervention. Ex vivo microbiome assays further demonstrated the capacity of APS to improve 5-Fu-induced microbiota growth inhibition and compositional change. FMT demonstrated that the regulation of gut microbiota by APS could promote the recovery of immune functions and alleviate shortening of the colon length. Remarkably, APS significantly ameliorated the imbalance of linoleic acid (LA) and α-linolenic acid in polyunsaturated fatty acid (PUFA) metabolism. Further in vitro experiments showed that LA could promote splenic lymphocyte proliferation. In addition, both LA and DGLA down-regulated the secretion of NO and partially up-regulated the percentage of F4/80+CD11B+CD206+ cells. CONCLUSION: APS can effectively ameliorate chemotherapy-induced immune damage and intestinal mucosal disruption by regulating the composition of the gut microbiota and further restoring PUFA metabolism. These findings indicate that APS can serve as an adjuvant to improve the side effects such as intestinal and immune damage caused by chemotherapy.
Assuntos
Astrágalo , Ácidos Graxos Insaturados , Fluoruracila , Microbioma Gastrointestinal , Polissacarídeos , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Camundongos , Astrágalo/química , Ácidos Graxos Insaturados/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Transplante de Microbiota Fecal , Colo/efeitos dos fármacosRESUMO
The gut microbiome has major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens1-3, including enterohaemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea and acute renal failure4,5 (haemolytic uremic syndrome). Although gut microorganisms can provide colonization resistance by outcompeting some pathogens or modulating host defence provided by the gut barrier and intestinal immune cells6,7, this phenomenon remains poorly understood. Here, we show that activation of the neurotransmitter receptor dopamine receptor D2 (DRD2) in the intestinal epithelium by gut microbial metabolites produced upon dietary supplementation with the essential amino acid L-tryptophan protects the host against Citrobacter rodentium, a mouse AE pathogen that is widely used as a model for EHEC infection8,9. We further find that DRD2 activation by these tryptophan-derived metabolites decreases expression of a host actin regulatory protein involved in C. rodentium and EHEC attachment to the gut epithelium via formation of actin pedestals. Our results reveal a noncanonical colonization resistance pathway against AE pathogens that features an unconventional role for DRD2 outside the nervous system in controlling actin cytoskeletal organization in the gut epithelium. Our findings may inspire prophylactic and therapeutic approaches targeting DRD2 with dietary or pharmacological interventions to improve gut health and treat gastrointestinal infections, which afflict millions globally.
Assuntos
Citrobacter rodentium , Mucosa Intestinal , Receptores de Dopamina D2 , Triptofano , Animais , Feminino , Humanos , Masculino , Camundongos , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Carga Bacteriana/efeitos dos fármacos , Citrobacter rodentium/crescimento & desenvolvimento , Citrobacter rodentium/metabolismo , Citrobacter rodentium/patogenicidade , Suplementos Nutricionais , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/prevenção & controle , Escherichia coli O157/patogenicidade , Escherichia coli O157/fisiologia , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Receptores de Dopamina D2/metabolismo , Triptofano/administração & dosagem , Triptofano/metabolismo , Triptofano/farmacologiaRESUMO
Inflammatory bowel disease, a disease featured by intestinal epithelial barrier destruction and dysfunction, has been a constant threat to animal health. The primary objective of this research was to assess the impact of the extract derived from lotus leaves (LLE) on lipopolysaccharide (LPS) induced damage to the intestines in mice, as well as to investigate the fundamental mechanism involved. The LLE was prepared using ultrasonic extraction in this experiment, and the LLE total flavonoid content was 117.02 ± 10.73 mg/g. The LLE had strong antioxidant activity in vitro, as assessed by 2, 2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) methods. In the vivo experiment, different doses of LLE (50, 100, and 200 mg/kg) were administered for 2 weeks before LPS treatment in mice. The results revealed that LLE alleviates intestinal tissue damage in LPS-induced mice. In the jejunum tissue, LLE significantly upregulated mRNA and protein expression levels of tight junction proteins, such as ZO-1, occludin, and claudin-1, and decreased the contents of the inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. Furthermore, the malondialdehyde and lactate dehydrogenase contents increased by LPS in the liver were significantly reduced after administration of LLE, and the total antioxidant capacity, superoxide dismutase, and reduced glutathione decreased by LPS were remarkably increased by LLE. It was found that LLE could relieve LPS-induced oxidative stress by upregulating mRNA and protein expression of Nrf2 and HO-1 in jejunum tissue. In conclusion, LLE alleviates LPS-induced intestinal damage through regulation of the Nrf2/HO-1 signal pathway to alleviate oxidative stress, reducing inflammatory factors and increasing the expression of tight junction proteins in mice.
Assuntos
Lipopolissacarídeos , Lotus , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Extratos Vegetais , Folhas de Planta , Animais , Estresse Oxidativo/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Camundongos , Folhas de Planta/química , Lotus/química , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Humanos , Intestinos/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/metabolismoRESUMO
Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.
Assuntos
Apoptose , Colo , Compostos Férricos , Alimentos Fortificados , Microbioma Gastrointestinal , Inflamação , Estresse Oxidativo , Animais , Masculino , Camundongos , Ratos , Apoptose/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Compostos Férricos/toxicidade , Alimentos Fortificados/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Glutationa/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: The Caoguo-4 decoction, a classical Mongolian medicine formula, is widely used to treat spleen deficiency diarrhea (SDD) in Mongolian for decades. Previously, the Caoguo-4 decoction volatile oil has been confirmed to be effective in ameliorating symptoms of spleen deficiency diarrhea in an animal model. However, the underlying mechanism of the Caoguo-4 decoction volatile oil is yet to be established. The aim of the current study was to investigate the antidiarrheal effects and mechanism of the Caoguo-4 decoction volatile oil. METHOD: Wistar rats were randomly divided into 5 groups of 10 animals including control, model, positive, Caoguo-4 decoction, and Caoguo-4 decoction volatile oil groups (10 rats in each group). All the rats, besides those in the control group, were induced to develop SDD by a bitter-cold purgation method with Xiaochengqi decoction. The antidiarrheal effect of Caoguo-4 decoction volatile oil was evaluated by pathological section, serum D-xylose and AMS content, plasma MTL content, and gut microbiota analysis via 16S rRNA sequencing. RESULTS: The results showed that the developed SDD rat model (model group) had decreased food intake, increased weight loss, soft stool, and bad hair color. When compared with the control group, serum was significantly reduced serum D-xylose and AML but increased MTL levels in the model group (p < 0.05). However, after treatment with either the Caoguo-4 decoction (the decoction group) or Smecta (the positive group) or volatile oil from the Caoguo-4 decoction (the volatile oil group), a significant increase in the serum D-xylose levels was observed. Additionally, AML levels significantly increased in the positive and volatile oil groups, and MTL levels significantly decreased in the decoction and volatile oil groups, when compared with the model group (p < 0.05). The pathological changes of the intestinal mucosa showed that the structure of the epithelium in the villi of the small intestine was affected, deformed, and incomplete in the model group when compared with the control group. However, either the decoction group or the volatile oil group recovered the villous morphology. The results of OTU analysis and alpha diversity analysis of intestinal bacteria showed that the intestinal microbiota of the SDD model rats showed an obvious decrease in richness and diversity of intestinal microbiota. But the intervention treatment of decoction and volatile oil could significantly recover the richness and diversity of intestinal microbiota. CONCLUSION: The intestinal microbiota destroyed in SDD modelling could be significantly improved by the Caoguo-4 decoction volatile oils, which provides reference for clinical medication.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Óleos Voláteis/farmacologia , Amilases/metabolismo , Animais , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Cianobactérias/genética , Cianobactérias/isolamento & purificação , Diarreia/tratamento farmacológico , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Fezes/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Óleos Voláteis/uso terapêutico , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Ratos , Ratos Wistar , Baço/patologia , Xilose/sangueRESUMO
ETHNIC PHARMACOLOGICAL RELEVANCE: Plant materials are used as complementary and alternative therapies all over the world for the treatment of various diseases. Ulcerative colitis (UC), a chronic nonspecific inflammatory bowel disease listed as one of the modern refractory diseases by the World Health Organization, has a long course, is challenging to cure, and is prone to cause cancer. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) to UC. AIM OF THIS REVIEW: This review presents an overview of the pathogenesis of UC and reports the therapeutic effect of TCM on UC (including TCM prescriptions, single TCM, and treatments using TCM ingredients) to provide a theoretical basis for the use of TCM in treating UC. METHODS: We performed a collection and collation of relevant scientific articles from different scientific databases regarding TCM and its usefulness in treating UC. In this paper, the therapeutic effect of TCM is summarized and analyzed according to the existing experimental and clinical research. RESULTS: There are positive signs that TCM primarily regulates inflammatory cytokines, intestinal flora, and the immune system, and also protects the intestinal mucosa. Hence, it can play a role in treating UC. CONCLUSION: TCM has a definite curative effect in the treatment of UC. It can alleviate and treat UC in a variety of ways. We should take syndrome differentiation and treatment differentiation as the basis. With the help of modern medicine, TCM's clinical curative effects can be enhanced for the treatment of UC.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa/métodos , Animais , Citocinas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacosRESUMO
OBJECTIVE: Sepsis causes excessive systemic inflammation and leads to multiple organ dysfunction syndrome (MODS). The intestine plays a key role in the occurrence and development of sepsis. Tetrastigma hemsleyanum Diels et Gilg (San ye qing, SYQ), a precious Chinese medicine, has been widely used for centuries due to its high traditional value, such as a remarkable anti-inflammatory effect. However, the role of SYQ in intestinal permeability during the development of sepsis needs to be discovered. METHODS: Mice were intraperitoneally injected with lipopolysaccharide (LPS) to simulate intestinal mucosal barrier function damage in sepsis. Pathological section, inflammatory cytokines, tight junctions, cell apoptosis, and intestinal flora were detected to evaluate the protective effect of SYQ on intestinal mucosal barrier injury in LPS-induced septic mice. RESULTS: The results showed that SYQ treatment obviously attenuated LPS-induced intestinal injury and reduced the production of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6). Besides, SYQ also up-regulated the expressions of tight junctions, including Zonula occludens 1 (ZO-1), Claudin-5, and Occludin along with a decreased in the levels of myosin light chain kinase (MLCK) and myosin light chain (MLC). In addition, SYQ down-regulated the expression of Bax/Bcl2 as well as that of cleaved caspase-3 to prevent the cells from undergoing apoptosis. Further, SYQ restored the diversity of the intestinal flora, increased the abundance of Firmicutes, and decreased the abundance of Bacteroidota. CONCLUSIONS: The study indicated that SYQ exerted its protective effect on intestinal mucosal barrier injury in LPS-induced septic mice by reducing inflammatory response, improving the tight junction protein expression, inhibiting cell apoptosis, and adjusting the intestinal flora structure.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Sepse/tratamento farmacológico , Vitaceae/química , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Interleucina-6/metabolismo , Intestinos/patologia , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Ocludina/metabolismo , Sepse/metabolismo , Proteínas de Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Although the incidence of ulcerative colitis (UC) increases every year, there is still a lack of satisfactory treatment options. Anemone chinensis Bunge (AB), a traditional Chinese herb, is a potent compound that can be prepared as a decoction, and then administered as an enema to relieve UC symptoms. However, the therapeutic effect and mechanisms of aqueous AB on UC are still unknown. AIM OF THE STUDY: This study investigates the potential therapeutic value and mechanism of AB aqueous enema for UC. MATERIALS AND METHODS: First, the practical components in aqueous AB were extracted and identified by UPLC-MS/MS. Second, the potential active targets and target genes related to UC were predicted, mapped, and analyzed by network pharmacology. Then, the effects of AB aqueous enema on UC were assessed using the dextran sulfate sodium (DSS)-induced colitis model with mice. Finally, the level of inflammation, the expression level of proteins associated with the colonic mucosal barrier, and the microbiota associated with the intestinal mucosal were investigated. RESULTS: Fourteen active ingredients in AB were identified. The network pharmacology-based analysis demonstrated that the active ingredients possibly affected ten key targets, such as IL-6, TNF, and PTGS2. They are also related to the tight junction proteins ZO-1, occludin, and claudin-1. Furthermore, mice treated with DSS developed severe mucosal colitis. AB aqueous enema decreased the disease activity index (DAI), significantly inhibited colonic damage, and greatly decreased colon length shortening (p < 0.05). AB also significantly restored tight junction proteins and the associated mucin proteins mucin-2 (MUC2) and mucin-3A (MUC3A). In addition, the diversity of the gut microbiota after administration of DSS was significantly decreased. However, the diversity was entirely restored after AB treatment. Recovery of the abundance of colonic mucosal bacteria, especially Lactobacillus reuteri and Lactobacillus gasseri, occurred at the species level after AB treatment. In vitro, AB can be utilized by the two bacteria, especially under glucose deficiency. CONCLUSIONS: Our study demonstrated that the AB aqueous enema alleviated colitis by restoring intestinal barrier proteins and regulating the gut microbiota.
Assuntos
Anemone/química , Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Enema , Feminino , Inflamação/tratamento farmacológico , Inflamação/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Gloiopeltis furcata is an edible alga that has long been consumed in China. However, the bioactive polysaccharides from G. furcata have been largely unexplored. Here, we show for the first time that a sulfated polysaccharide from G. furcata (SAO) could improve the integrity of the colonic epithelial layer and protect against dextran sulfate sodium-induced intestinal mucosal damage. Mechanistically, SAO attenuated colonic mucosal damage by therapeutically remodeling the interactions between gut microbiota and mucin O-glycans. Specifically, SAO increased the proportions of complex long-chain mucin O-glycans in the epithelial layer with two terminal N-acetylneuraminic acid residues and promoted the growth of probiotic bacteria including Roseburia spp. and Muribaculaceae. Altogether, our study demonstrates a novel application of SAO for the treatment of inflammatory bowel disease-associated mucosal damage and forms the basis to understand the therapeutic effects of natural polysaccharides from the perspective of symbiotic interactions between host mucin O-glycome and gut microbiome.
Assuntos
Antibacterianos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucinas/farmacologia , Polissacarídeos/farmacologia , Alga Marinha/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bactérias/efeitos dos fármacos , Configuração de Carboidratos , Sulfato de Dextrana , Testes de Sensibilidade Microbiana , Mucinas/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificaçãoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), that is associated with a significantly increased risk of colon cancer. As a classic traditional Chinese medicine, Ganluyin (GLY) has a long history as an anti-inflammatory medication, but its impacts on UC has not been established. AIM OF THE STUDY: This study aims to evaluate the protective effect and mechanism of GLY on a pathway involving enteric-origin lipopolysaccharide (LPS), toll-like receptor (TLR)4, and NF-κB in mice with dextran sulfate sodium (DSS)-induced UC. MATERIALS AND METHODS: After three weeks of intragastric administration of GLY, a UC model was induced in mice by administration of 4% DSS in drinking water for one week. The disease activity index (DAI) was measured, and histological staining was used to detect histopathological changes of colon. LPS content of the serum was measured by ELISA, and the expression of tight junction proteins and proteins related to TLR4/NF-κB pathway in colon were analyzed by immunohistochemistry or Western Blotting. The intestinal flora was analyzed by 16S rRNA sequencing. RESULTS: GLY improved the histological pathological changes of DSS-induced UC, as assessed by DAI, colonic mucosal damage, inflammatory cell infiltration, and goblet cell and mucus reduction. GLY also protected the intestinal mucosal barrier by increasing the expression of the tight junction proteins, occludin, claudin-1, and ZO-1 and by reducing the serum LPS content and decreasing the expression of TLR4, MyD88, NF-κB, IL-6, IL-1ß, and TNF-α proteins in colon. Analyses of the intestinal flora showed that GLY restored the homeostasis of the intestinal flora through increases in the abundance of Firmicutes and decreases in the abundance of Proteobacteria and Bacteroidetes, which is associated with the production of LPS. CONCLUSION: GLY might exert an anti-UC effect by improving the colonic mucosal barrier and inhibiting the enteric-origin LPS/TLR4/NF-κB inflammatory pathway, and restoring the homeostasis of the intestinal flora in UC mice. These discoveries lay a strong foundation for GLY as a UC treatment.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sulfato de Dextrana , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra sphenanthera Rehder & E.H. Wilson (S. sphenanthera) is a botanical medicine included in the 2020 edition of the ChP that has a variety of medicinal activities, including hepatoprotective, anticancer, antioxidant and anti-inflammatory properties. Wuzhi capsule (WZ) is a proprietary Chinese medicine made from an ethanolic extract of S. sphenanthera that is commonly used to treat drug-induced liver injury. However, there are no research reports exploring the effects of WZ on the prevention of mycophenolate mofetil (MMF)-induced intestinal injury and its underlying mechanisms. AIM OF THE STUDY: This experiment aimed to evaluate the ameliorative effect of WZ on MMF-induced intestinal injury in mice and its underlying mechanisms. MATERIALS AND METHODS: A mouse model of MMF-induced intestinal injury was established and treated with WZ during the 21-day experimental period. The pathological characteristics of the mouse ileum were observed. Tight junction (TJ) protein changes were observed after immunofluorescence staining and transmission electron microscopy, and ROS levels were measured by using DHE fluorescent dye and the TUNEL assay for apoptosis. The expression of p65, p-p65, IκBα, p-IκBα, the TJ proteins occludin and ZO-1 and the apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 and caspase-3 were analysed by Western blot. Levels of DAO, ET, TNF-α, IL-1ß, IL-6, IFN-γ, MDA and SOD were analysed by using kits. RESULTS: MMF activated the NF-κB signaling pathway to cause intestinal inflammation, increased intestinal permeability, changed the expression of TJ protein in the intestinal epithelium, and increased oxidative stress and apoptosis levels. WZ significantly downregulated the expression of p-p65 and p-IκBα to relieve the inflammatory response, reduced intestinal permeability, maintained intestinal TJ protein expression, and reduced intestinal oxidative stress and apoptosis. CONCLUSION: Our research suggested that MMF can cause intestinal injury; by contrast, WZ may exert anti-inflammatory, antioxidant and apoptosis-reducing effects to alleviate MMF-induced intestinal injury.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Ácido Micofenólico/toxicidade , Animais , Animais não Endogâmicos , Apoptose/efeitos dos fármacos , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Enteropatias/induzido quimicamente , Enteropatias/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the ApcMin /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of ApcMin /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcMmin /+ mice.