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Hexavalent chromium (Cr(VI)) exposure has been linked with gastrointestinal toxicity, whereas the molecular pathways and key targets remain elusive. Computational toxicology analysis predicted the correlation between protein phosphatase 2A (PP2A) and genes regarding Cr(VI)-induced intestinal injury. Here, we generated a mouse model with intestinal epithelium-specific knock-out of Ppp2r1a (encoding PP2A Aα subunit) to investigate the mechanisms underlying Cr(VI)-induced small intestinal toxicity. Heterozygous mice (HE) and matched wild-type (WT) littermates were administrated with Cr(VI) at 0, 5, 20, 80 mg/L for 28 successive days. Cr(VI) treatment led to crypt hyperplasia, epithelial cell apoptosis, and intestinal barrier dysfunction, accompanied by the decline of goblet cell counts and Occludin expression in WT mice. Notably, these effects were aggravated in HE mice, indicating that PP2A Aα deficiency conferred mice with susceptibility to Cr(VI)-induced intestinal injury. Integrated data analysis and biological experiments revealed Cr(VI) exposure could decrease YAP1 phosphorylation at Ser127 but increase protein expression and activity, together with elevated TAZ protein driving epithelial crypt cells proliferation following damage, suggesting the involvement of Hippo/YAP1 signaling pathway in Cr(VI)-induced intestinal toxicity. Nevertheless, the enhanced phosphorylation of YAP1 in HE mice resulted in proliferation/repair defects in intestinal epithelium, thereby exacerbating Cr(VI)-induced gut barrier dysfunction. Notably, by molecular docking and further studies, we identified Urolithin A, a microbial metabolite, attenuated Cr(VI)-induced disruption of intestinal barrier function, partly by modulating YAP1 expression and activity. Our findings reveal the novel molecular pathways participated in Cr(VI)-caused small intestinal injury and urolithin A could potentially protect against environmental hazards-induced intestinal diseases.
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Microplastics and nanoplastics (MNPs) are becoming an increasingly severe global problem due to their widespread distribution and complex impact on living organisms. Apart from their environmental impact, the effects of MNPs on living organisms have also continued to attract attention. The harmful impact of MNPs has been extensively documented in marine invertebrates and larger marine vertebrates like fish. However, the research on the toxicity of these particles on mammals is still limited, and their possible effects on humans are poorly understood. Considering that MNPs are commonly found in food or food packaging, humans are primarily exposed to them through ingestion. It would be valuable to investigate the potential harmful effects of these particles on gut health. This review focuses on recent research exploring the toxicological impacts of micro- and nanoplastics on the gut, as observed in human cell lines and mammalian models. Available data from various studies indicate that the accumulation of MNPs in mammalian models and human cells may result in adverse consequences, in terms of epithelial toxicity, immune toxicity, and the disruption of the gut microbiota. The paper also discusses the current research limitations and prospects in this field, aiming to provide a scientific basis and reference for further studies on the toxic mechanisms of micro- and nanoplastics.
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BACKGROUND: Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence. METHODS: The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure. RESULTS: The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity. CONCLUSION: Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential.
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Bisphenol A (BPA) and its analogues have prompted rising concerns, especially in terms of human safety, due to its broad use and ubiquity throughout the ecosystem. Numerous studies reported various adverse effects of bisphenols, including developmental disorders, reproductive toxicity, cardiovascular toxicity, and so on. There is increasing evidence that bisphenols can enter the gastrointestinal tract. Consequently, it is important to investigate their effects on the intestine. Several in vivo and in vitro studies have examined the impacts of bisphenols on the intestine. Here, we summarized the literature concerning intestinal toxicity of bisphenols over the past decade and presented compelling evidence of the link between bisphenol exposure and intestinal disorders. Experiment studies revealed that even at low levels, bisphenols could promote intestinal barrier dysregulation, disrupt the composition and diversity of intestinal microbiota as well as induce an immunological response. Moreover, possible underlying mechanisms of these effects were discussed. Because of a lack of empirical data, the potential risk of bisphenol exposure in humans is still unidentified, particularly regarding intestinal disorders. Thus, we propose to conduct additional epidemiological investigations and animal experiments to elucidate the associations between bisphenol exposure and human intestinal health and reveal underlying mechanisms to develop preventative and therapeutic techniques.
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Ecosistema , Fenoles , Animales , Humanos , Fenoles/toxicidad , Fenoles/análisis , Compuestos de Bencidrilo/toxicidad , Intestinos/químicaRESUMEN
Deoxynivalenol (DON) is the most common mycotoxin in food and feed, which can cause undesirable effects, including diarrhea, emesis, weight loss, and growth delay in livestock. Intestinal epithelial cells were the main target of DON, which can cause oxidative stress and inflammatory injury. Tanshinone IIA (Tan IIA) is fat-soluble diterpene quinone, which is the most abundant active ingredient in salvia miltiorrhiza plant with antioxidant and anti-inflammatory characteristics. However, it is not clear whether Tan IIA can protect against or inhibit intestinal oxidative stress and inflammatory injury under DON exposure. This study aimed to explore the protective effect of Tan IIA on DON-induced toxicity in porcine jejunum epithelial cells (IPEC-J2). Cells were exposed to 0, 0.5, 1.0, 2.0 µM DON and/or 45 µg/mL TAN â ¡A to detect oxidative stress indicators. inflammatory cytokines, NF-κB expression, NLRP3 inflammasome and pyroptosis-related factors. In this study, DON exposure caused IPEC-J2 cells oxidative stress by elevating ROS and 8-OHdG content, inhibited GSH-Px activity. Furthermore, DON increased pro-inflammatory factor (TNF-α, IL-1ß, IL-18 and IL-6) expression and decreased the anti-inflammatory factor (IL-10) expression, causing inflammatory response via triggering NF-κB pathway. Interestingly, above changes were alleviated after Tan IIA treatment. In addition, Tan IIA relieved DON-induced pyroptosis by suppressing the expression of pyroptosis-related factors (NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18). In general, our data suggested that Tan IIA can ameliorate DON-induced intestinal epithelial cells injury associated with suppressing the pyroptosis signaling pathway. Our findings pointed that Tan IIA could be used as the potential therapeutic drugs on DON-induced enterotoxicity.
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Abietanos , Interleucina-18 , FN-kappa B , Tricotecenos , Porcinos , Animales , FN-kappa B/metabolismo , Interleucina-18/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Línea Celular , Antiinflamatorios/farmacología , Células EpitelialesRESUMEN
Nanopolystyrene (NP) and cadmium (Cd) are ubiquitous contaminants in aquatic systems. The present study aimed to investigate the toxic effects of exposure to ambient concentrations of NP and/or Cd on the intestinal tract of the Chinese mitten crab (Eriocheir sinensis). Exposure to NP and/or Cd induced oxidative stress, as evidenced by a significant increase in lipid peroxide content (LPO), total antioxidant capacity (T-AOC), and peroxidase activity (POD), and significant decreases in superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities in E. sinensis. In addition, exposure to NP and/or Cd imbalanced the homeostasis of the intestinal microbiota, as demonstrated by the significantly increased abundance of Spiroplasma. Transcriptomic and metabolomic analyses were performed to investigate the mechanisms underlying intestinal toxicity. Our results showed that ferroptosis, ABC transporters, phosphotransferase system, apoptosis, and leukocyte transendothelial migration were disturbed after exposure to NP and/or Cd. In particular, Cd exposure affected mucin type O-glycan biosynthesis, purine metabolism, and neuroactive ligand-receptor interaction. Intriguingly, co-exposure to NP and Cd might mitigate intestinal toxicity by decreasing oxidative stress and affecting these pathways. Taken together, our study clearly demonstrates that exposure to NP and/or Cd at environmentally relevant concentrations causes intestinal toxicity in E. sinensis.
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Braquiuros , Cadmio , Animales , Cadmio/toxicidad , Antioxidantes/metabolismo , Estrés Oxidativo , Intestinos , Braquiuros/metabolismoRESUMEN
Aï¬atoxin B1 (AFB1), a common mycotoxin, can occur in agricultural products. As a metabolite of AFB1, aï¬atoxin M1 (AFM1) mainly exist in dairy products. These two mycotoxins threaten human health, although it is unclear how they affect the function of the intestinal barrier. In this study, mice were exposed to AFB1 (0.3â¯mg/kg body b.w.) and AFM1(3.0â¯mg/kg b.w.) either individually or in combination for 28 days to explore the main differentially expressed proteins (DEPs) and the associated enriched pathways. These findings were preliminarily verified by the transcriptomic and proteomic analyses in differentiated Caco-2 cells. The results revealed that AFB1 and AFM1 exposure in mice disrupted the function of the intestinal barrier, and the combined toxicity was greater than that of each toxin alone. Further proteomic analysis in mice demonstrated that the mechanisms underlying these differences could be explained as follows: (i) lipid metabolism was enriched by AFB1-induced DEPs. (ii) protein export pathway was stimulated by AFM1-induced DEPs. (iii) cell metabolic ability was inhibited (as evidenced by changes in UDP-GT1, UDP-GT2, and Gatm6), apoptosis was induced (MAP4K3), and epithelial cell integrity was disrupted (Claudin7 and IQGAP2), resulting in more extensive intestinal damage after combined treatment. In conclusion, the hazardous impact of co-exposure to AFB1 and AFM1 from proteomic perspectives was demonstrated in the present study.
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Aflatoxina B1 , Aflatoxina M1 , Proteómica , Aflatoxina M1/toxicidad , Aflatoxina B1/toxicidad , Animales , Ratones , Células CACO-2 , Humanos , Masculino , Intestinos/efectos de los fármacos , Intestinos/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismoRESUMEN
This study aims to explore the correlation between intestinal toxicity and composition changes of Euphorbia ebracteolata before and after Terminalia chebula soup(TCS) processing. Intragastric administration was performed on the whole animal model. By using fecal water content, inflammatory causes, and pathological damage of different parts of the intestinal tract of mice as indexes, the differences in intestinal toxicity of dichloromethane extraction of raw E. ebracteolata(REDE), dichloromethane extraction of TCS, and dichloromethane extraction of E. ebracteolata after simulated TCS processing(STREDE) were compared, so as to investigate the effect of TCS processing on the intestinal toxicity of E. ebracteolata. At the same time, the component databases of E. ebracteolata and T. chebula were constructed, and the composition changes of diterpenoids, tannins, and phenolic acids in the three extracted parts were analyzed by HPLC-TOF-MS. HPLC was used to compare the content of four diterpenoids including ent-11α-hydroxyabicta-8(14), 13(15)-dien-16, 12-olide(HAO), jolkinolide B(JNB), fischeria A(FA), and jolkinolide E(JNE) in the E. ebracteolata before and after processing and the residue of container wall after processing, so as to investigate the effect of TCS processing on the content and structure of the diterpenoids. The results showed that the REDE group could significantly increase the fecal water content and the release levels of TNF-α and IL-1ß from each intestinal segment, and intestinal tissue damage was accompanied by significant infiltration of inflammatory cells. However, compared with the REDE group, the intestinal tissue damage in the STREDE group was alleviated, and the infiltration of inflammatory cells decreased. The intestinal toxicity significantly decreased. Mass spectrometry analysis showed that there was no significant difference in the content of diterpenoids of REDE before and after simulated TCS processing, but a large number of tannins and phenolic acids were added. The results of HPLC showed that the content of four diterpenoids of E. ebracteo-lata decreased to varying degrees after TCS processing, ranging from-0.35% to-19.74%, and the decreased part mainly remained in the container wall, indicating that the structure of toxic diterpenoids of E. ebracteolata was not changed after TCS processing. The antagonistic effect of tannic and phenolic acids in the TCS may be the main reason for the reduced intestinal toxicity of E. ebracteolata after TCS processing. The TCS processing for E. ebracteolata is scientific.
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Medicamentos Herbarios Chinos , Euphorbia , Terminalia , Euphorbia/química , Animales , Terminalia/química , Ratones , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/toxicidad , Masculino , Intestinos/efectos de los fármacos , Intestinos/química , Cromatografía Líquida de Alta Presión , HumanosRESUMEN
Cross-species comparison of drug responses at the organoid level could help to determine the human relevance of findings from animal studies. To this end, we first need to evaluate the in vitro to in vivo translatability of preclinical organoids. Here, we used 5-fluorouracil (5-FU) as an exemplar drug to test whether the in vivo gut response to this cytotoxicant was preserved in murine intestinal organoids. Mice treated with 5-FU at 20 or 50 mg/kg IV (low and high dose, respectively) displayed diarrhea at clinically relevant exposures. 5-FU also induced intestinal lesions, increased epithelial apoptosis, and decreased proliferation in a dose-dependent manner. To enable comparison between the in vitro and in vivo response, top nominal in vitro drug concentrations that caused significant cytotoxicity were chosen (dose range 1-1000 µM). The inferred intracellular concentration in organoids at 1000 µM was within the tissue exposure range related to intestinal toxicity in vivo. 5-FU at ≥ 100 µM decreased ATP levels and increased Caspase-3 activity in intestinal organoids. In keeping with the in vivo findings, 5-FU increased the percentage of Caspase-3-positive cells and reduced Ki67 staining. At the transcriptome level, there was an overlap in the activity of pathways related to 5-FU's mode of action, lipid and cholesterol metabolism and integrin signaling across in vivo gut and organoids. The predicted activity state of upstream regulators was generally well preserved between setups. Collectively, our results suggest that despite their inherent limitations, organoids represent an adequate tool to explore the intestinal response to cytotoxicants.
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Apoptosis , Fluorouracilo , Humanos , Animales , Ratones , Caspasa 3/metabolismo , Fluorouracilo/toxicidad , Diarrea/inducido químicamente , Organoides , Mucosa IntestinalRESUMEN
Intestinal cells are continuously exposed to food constituents while adapting to peristaltic movement and fluid shear stress. Oleic acid (OA) and palmitic acid (PA) are among the most prevalent fatty acids with respect to dietary lipids. Despite the central importance of dietary lipids for a balanced diet, awareness about potential detrimental effects related to excessive consumption is increasing; this includes toxicity, metabolic deregulation, and, particularly for cancer cells, a benefit from the uptake of fatty acids related to promotion of metastasis. Expanding on this, we started elucidating the effects of OA and PA (25-500 µM) on non-transformed human intestinal epithelial cells (HCEC-1CT) in comparison to colon carcinoma cells (HCT116), with regard to the mechanosensory apparatus. Hence, intestinal cells' motility is on the one side essential to ensure adaption to peristaltic movement and barrier function, but also to enable metastatic progression. Incubation with both OA and PA (≥ 25 µM) significantly decreased membrane fluidity of HCT116 cells, whereas the effect on HCEC-1CT was more limited. Application of rhodamine-labelled PA demonstrated that the fatty acid is incorporated into the plasma membrane of HCT116, which could not be observed in the non-tumorigenic cell line. Down-streaming into the intracellular compartment, a pronounced rearrangement of actin cytoskeleton was evident in both cell lines (OA and PA; 25 and 100 µM). This was accompanied by a variation of translocation efficiency of the mechanosensitive co-transcription factor YAP1, albeit with a stronger effect seen for PA and the cancer cells. Untargeted proteomic analysis confirmed that exposure to OA and PA could alter the response capacity of HCT116 cells to fluid shear stress. Taken together, OA and PA were able to functionally modulate the mechanosensory apparatus of intestinal cells, implying a novel role for dietary fatty acids in the regulation of intestinal pathophysiology.
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Mecanotransducción Celular , Ácido Palmítico , Humanos , Ácido Palmítico/toxicidad , Ácido Palmítico/metabolismo , Proteómica , Ácidos Grasos , Ácido Oléico/metabolismoRESUMEN
Intestinal organoid may serve as an alternative model for toxicity testing. However, the linkage between specific morphological alterations in organoids and chemical-induced toxicity has yet to be defined. Here, we generated C57BL/6 mouse intestinal organoids and conducted a morphology-based analysis on chemical-induced toxicity. Alterations in morphology were characterized by large spheroids, hyperplastic organoids, small spheroids, and protrusion-loss organoids, which responded in a concentration-dependent manner to the treatment of four metal(loid)s including cadmium (Cd), lead (Pb), hexavalent chromium (Cr-VI), and inorganic trivalent arsenic (iAs-III). Notably, alterations in organoid morphology characterized by abnormal morphology rate were correlated with specific intestinal toxic effects, including reduction in cell viability and differentiation, induction of apoptosis, dysfunction of mucus production, and damage to epithelial barrier upon repeated administration. The benchmark dose (BMDL10) values of morphological alterations (0.007-0.195 µM) were lower than those of conventional bioassays (0.010-0.907 µM). We also established that the morphologic features of organoids upon Cd, Pb, Cr-VI, or iAs-III treatment were metal specific, and mediated by Wnt, bone morphogenetic protein, apoptosis induction, and Notch signaling pathways, respectively. Collectively, these findings provide novel insights into the relevance of morphological alterations in organoids to specific toxic endpoints and identify specific morphological alterations as potential indicators of enterotoxicity.
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Cadmio , Plomo , Ratones , Animales , Ratones Endogámicos C57BL , Intestinos , Organoides , Mucosa IntestinalRESUMEN
Lead (Pb) contamination has been affecting public health for decades. As a plant-derived medicine, the safety and effectiveness of Emblica officinalis (E. officinalis) fruit extract has been emphasized. The current study focused on mitigating the adverse effects of lead (Pb) exposure in reducing its toxicity worldwide. According to our findings, E. officinalis significantly improved weight loss and colon length shortening (p < 0.05 or p < 0.01). The data of colon histopathology and serum levels of inflammatory cytokines indicated a positive impact to the colonic tissue and inflammatory cell infiltration in a dose-dependent manner. Moreover, we confirmed the expression level improvement of tight junction proteins (TJPs), including ZO-1, Claudin-1, and Occludin. Furthermore, we found that the abundance of some commensal species necessary for maintaining homeostasis and other beneficial function decreased in Pb exposure model, while a remarkable reversion impact was noticed on the intestinal microbiome composition in the treatment group. These findings were consistent with our speculations that E. officinalis could mitigate the adverse effects caused by Pb in alleviating intestinal tissue damage, intestinal barrier disruption, and inflammation. Meanwhile, the variations in gut microbiota might drive the fulfilling current impact. Hence, the present study could provide the theoretical basis for mitigating intestinal toxicity induced by Pb exposure with the help of E. officinalis.
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Microbioma Gastrointestinal , Phyllanthus emblica , Ratones , Animales , Plomo/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. METHODS: Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. RESULTS: 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. CONCLUSION: Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.
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Antioxidantes , Estrés Oxidativo , Ratones , Animales , Masculino , Antioxidantes/metabolismo , Mitocondrias , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mitomicina/metabolismo , Mitomicina/farmacología , Mitomicina/uso terapéutico , ApoptosisRESUMEN
Mycotoxins, which are fungal metabolites, pose a significant global food safety concern by extensively contaminating food and feed, thereby seriously threatening public health and economic development. Many foodborne mycotoxins exhibit potent intestinal toxicity. However, the mechanisms underlying mycotoxin-induced intestinal toxicity are diverse and complex, and effective prevention or treatment methods for this condition have not yet been established in clinical and animal husbandry practices. In recent years, there has been increasing attention to the role of gut microbiota in the occurrence and development of intestinal diseases. Hence, this review aims to provide a comprehensive summary of the intestinal toxicity mechanisms of six common foodborne mycotoxins. It also explores novel toxicity mechanisms through the "key gut microbiota-key metabolites-key targets" axis, utilizing multiomics and precision toxicology studies with a specific focus on gut microbiota. Additionally, we examine the potential beneficial effects of probiotic supplementation on mycotoxin-induced toxicity based on initial gut microbiota-mediated mycotoxicity. This review offers a systematic description of how mycotoxins impact gut microbiota, metabolites, and genes or proteins, providing valuable insights for subsequent toxicity studies of mycotoxins. Furthermore, it lays a theoretical foundation for preventing and treating intestinal toxicity caused by mycotoxins and advancing food safety practices.
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Microbioma Gastrointestinal , Micotoxinas , Animales , Micotoxinas/toxicidad , Micotoxinas/análisis , Alimentos , Contaminación de Alimentos/prevención & control , Contaminación de Alimentos/análisisRESUMEN
Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants as commercial products. PBDEs have been demonstrated to induce hepatic, reproductive, neural, and thyroid toxicity effects. This study aimed to clarify the potential intestinal toxicity effects of decabrominated diphenyl ether (PBDE-209) in vivo and in vitro. First, we investigated the change of PBDE-209 on oxidative stress in the intestine of mice. Subsequently, the potential toxicity mechanism of PBDE-209 in vitro was investigated. Caco-2 cells were treated with different concentrations of PBDE-209 (1, 5, and 25 µmol/L) for 24 and 48 h. We determined the cell viability, reactive oxygen species (ROS) level, multiple cellular parameters, and relative mRNA expressions. The results showed that PBDE-209 significantly injured the colon of mice, increased the intestinal levels of malondialdehyde (MDA), and changed the antioxidant enzyme activities. PBDE-209 inhibited the proliferation and induced cytotoxicity of Caco-2 cells. The change in ROS production and mitochondrial membrane potential (MMP) revealed that PBDE-209 caused oxidative stress in Caco-2 cells. The real-time PCR assays revealed that PBDE-209 inhibited the mRNA expression level of antioxidative defense factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, the FAS and Cytochrome P450 1A1 (CYP1A1) mRNA expression levels were increased in Caco-2 cells. These results suggested that PBDE-209 exerts intestinal toxicity effects in vivo and in vitro and inhibits the antioxidative defense gene expression in Caco-2 cells. This study provides an opportunity to advance the understanding of toxicity by the persistent environmental pollutant PBDE-209 to the intestine.
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Retardadores de Llama , Éteres Difenilos Halogenados , Animales , Células CACO-2 , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Humanos , Intestinos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , ARN Mensajero , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Fluorouracil (5-FU) is a widely used chemotherapeutic agent in various malignant tumors. However, intestinal toxicity is considered the irritant unavoidable adverse effect during the course therapy. The aim of the current study was to screen the effect of a new selective histamine receptor 1 blocker and platelet-activating factor (PAF) blocker on 5-FU induced intestinal toxicity. Five groups (6 rats each) of adult male rats (Wistar) were arranged as follows: (1) control group that was treated with carboxymethylcellulose, (2) a group that received rupatadine (higher dose) only, (3) a group that received 5-FU and (4) and (5) groups that received 5-FU plus lower or higher dose rupatadine, respectively. At end of the experiment, we determined intestinal malondialdehyde (MDA), glutathione reduced (GSH), nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin 1ß, 6, 10 (IL-1ß, IL-6, IL-10), PAF, histamine, myeloperoxidase, cysteine-aspartic acid protease-3 (caspase-3), and nuclear factor kappa B (NF-κB) as well as the histological analysis. 5-FU injection caused marked elevation of MDA, NO, TNF-α, IL-1ß, IL-6, PAF, histamine, myeloperoxidase, caspase-3, and NF-κB expressions. The intoxicated animals showed deficient GSH and IL-10 along with significant loss of villi, disorganized crypts, and inflammatory cell infiltration. Rupatadine pretreatment reduced the previously mentioned parameters, preserved a nearly normal intestinal mucosa picture with replenished GSH and elevated IL-10. In conclusion, rupatadine is a dual histamine receptor 1, and a PAF blocker could reduce 5-FU-induced oxidative damage, inflammation, apoptosis, and ulceration of the intestinal epithelium. Rupatadine may be a valuable modality to decrease 5-FU induced intestinal mucositis.
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Proteasas de Ácido Aspártico , Peroxidasa , Animales , Masculino , Ratas , Apoptosis , Proteasas de Ácido Aspártico/metabolismo , Proteasas de Ácido Aspártico/farmacología , Carboximetilcelulosa de Sodio/metabolismo , Carboximetilcelulosa de Sodio/farmacología , Caspasa 3/metabolismo , Cisteína , Fluorouracilo/efectos adversos , Fluorouracilo/toxicidad , Glutatión/metabolismo , Histamina/metabolismo , Histamina/farmacología , Inflamación/inducido químicamente , Inflamación/prevención & control , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6 , Mucosa Intestinal/metabolismo , Irritantes , Malondialdehído/metabolismo , FN-kappa B , Óxido Nítrico/metabolismo , Permeabilidad , Peroxidasa/metabolismo , Peroxidasa/farmacología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: The increased use of indomethacin (IND) is associated with gastrointestinal injury. This research aims to investigate the effects of a beta-blocker, carvedilol (CAR) on a rat model of IND-induced acute intestinal damage and clarify the probable underlying protective mechanisms. MATERIALS AND METHODS: Twenty-four male Wistar rats were divided into four groups. Control group: given vehicles; CAR-treated group: given 10 mg/kg/day CAR PO daily by gastric gavage for 10 consecutive days; IND-treated group: given a single Sc dose of 10 mg/kg IND at the end of the ninth day of the experiment; combined CAR/IND-treated group: given both IND and CAR. RESULTS: In the rats that received IND, severe intestinal histopathological changes together with oxidative and nitrosative intestinal stress were present biochemically and immunohistochemically. Obvious inflammatory and tissue damage were represented by the significant intestinal increases in TNF-α, COX-2, and caspase-3 together with the elevated expression of VCAM-1 adhesion molecules. Intestinal gene expression of NF-kB and COX-2 was also increased. Pretreatment with CAR significantly reversed the IND-induced intestinal toxic manifestations. CONCLUSION: CAR has beneficial intestinal protective effects. Its ameliorative action is conferred through its antioxidant, antinitrosative, anti-inflammatory, and antiapoptotic properties.
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FN-kappa B , Factor de Necrosis Tumoral alfa , Animales , Carvedilol/farmacología , Ciclooxigenasa 2/metabolismo , Indometacina/farmacología , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Social hierarchy governs the physiological and biochemical behaviors of animals. Intestinal radiation injuries are common complications connected with radiotherapy. However, it remains unclear whether social hierarchy impacts the development of radiation-induced intestinal toxicity. Dominant mice exhibited more serious intestinal toxicity following total abdominal irradiation compared with their subordinate counterparts, as judged by higher inflammatory status and lower epithelial integrity. Radiation-elicited changes in gut microbiota varied between dominant and subordinate mice, being more overt in mice of higher status. Deletion of gut microbes by using an antibiotic cocktail or restructuring of the gut microecology of dominant mice by using fecal microbiome from their subordinate companions erased the difference in radiogenic intestinal injuries. Lactobacillus murinus and Akkermansia muciniphila were both found to be potential probiotics for use against radiation toxicity in mouse models without social hierarchy. However, only Akkermansia muciniphila showed stable colonization in the digestive tracts of dominant mice, and significantly mitigated their intestinal radiation injuries. Our findings demonstrate that social hierarchy impacts the development of radiation-induced intestinal injuries, in a manner dependent on gut microbiota. The results also suggest that the gut microhabitats of hosts determine the colonization and efficacy of foreign probiotics. Thus, screening suitable microbial preparations based on the gut microecology of patients might be necessary in clinical application.
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Microbioma Gastrointestinal , Probióticos , Traumatismos por Radiación , Ratones , Animales , Microbioma Gastrointestinal/fisiología , Jerarquia Social , Probióticos/farmacología , Verrucomicrobia/fisiología , Ratones Endogámicos C57BLRESUMEN
Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo.Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Espectrometría de Masas en Tándem , Animales , Antivirales/toxicidad , Cromatografía Líquida de Alta Presión , Ratones , Microsomas Hepáticos , PodofilotoxinaRESUMEN
Methotrexate (MTX) is a widely used therapeutic agent for the treatment of cancer and autoimmune diseases. However, its efficacy is often limited by adverse effects, such as intestinal toxicity. Although treatment with leucovorin (LV) is the most common method to reduce the toxic effects of MTX, it may also compromise the therapeutic effects of MTX. The gut microbiome has been reported to be associated with the intestinal toxicity of MTX. In this study, the intestinal damage of MTX was ameliorated by treatment with LV. Moreover, the population, diversity, and principal components of the gut microbiota in MTX-treated mice were restored by treatment with LV. The only element of the gut microbiota that was significantly changed after treatment with LV was Bifidobacterium, and supplementation with Bifidobacterium longum ameliorated MTX-induced intestinal damage. In conclusion, our results suggest that the balance and the composition of gut microbiota have an important role in the LV-mediated protection against MTX-induced intestinal toxicity. This work provides foundation of data in support of a new potential mechanism for the prevention of MTX-induced intestinal toxicity.