Effects of Thymoquinone on radiation enteritis in mice.
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ABSTRACT:
SUBMITTER: Hou Q
PROVIDER: S-EPMC6181979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Radiation therapy is a cornerstone of modern management methods for malignancies but is accompanied by diverse side effects. In the present study, we showed that food additives such as polysorbate 80 (P80) exacerbate irradiation-induced gastrointestinal (GI) tract toxicity. A 16S ribosomal RNA high-throughput sequencing analysis indicated that P80 consumption altered the abundance and composition of the gut microbiota, leading to severe radiation-induced GI tract injury. Mice harboring fecal microbes from P80-treated mice were highly susceptible to irradiation, and antibiotics-challenged mice also represented more sensitive to radiation following P80 treatment. Importantly, butyrate, a major metabolite of enteric microbial fermentation of dietary fibers, exhibited beneficial effects against P80 consumption-aggravated intestinal toxicity via the activation of G-protein-coupled receptors (GPCRs) and maintenance of the intestinal bacterial composition in irradiated animals. Moreover, butyrate had broad therapeutic effects on common radiation-induced injury. Collectively, our findings demonstrate that P80 are potential risk factors for cancer patients during radiotherapy and indicate that butyrate might be employed as a therapeutic option to mitigate the complications associated with radiotherapy.
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Project description:Thymoquinone (TQ) is a bioactive component derived from the seeds of Nigella sativa that are commonly as black cumin. Evidences indicate that the medicinal properties of TQ have been recognized for more than 2000 years. TQ has been shown to possess potent chemopreventive properties that include anti-inflammatory and anti-neoplastic activities. Recent studies have unraveled the multiple mechanisms through which TQ exerts its chemopreventive and anticancer activity in different cancer cells in a contextual manner. The present review aims to provide a brief compendium on the molecular mechanisms through which TQ inhibits signaling pathways underlying cancer genesis, progression, and metastasis.
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Project description:Wound healing is a regulated biological event that involves several processes including infiltrating leukocyte subtypes and resident cells. Impaired wound healing is one of the major problems in diabetic patients due to the abnormal physiological changes of tissues and cells in major processes. Thymoquinone, a bioactive compound found in Nigella sativa has been demonstrated to possess antidiabetic, anti-inflammatory, and antioxidant effects. Today, the rapidly progressing nanotechnology sets a new alternative carrier to enhance and favour the speed of healing process. In order to overcome its low bioavailability, TQ is loaded into a colloidal drug carrier known as a nanostructured lipid carrier (NLC). This study aimed to determine the effect of TQ-NLC and TQ on cell proliferation and migration, mode of cell death, and the antioxidant levels in normal and diabetic cell models, 3T3 and 3T3-L1. Cytotoxicity of TQ-NLC and TQ was determined by MTT assay. The IC10 values obtained for 3T3-L1 treated with TQ-NLC and TQ for 24 hours were 4.7?±?3.3 and 5.3?±?0.6??M, respectively. As for 3T3, the IC10 values obtained for TQ-NLC and TQ at 24 hours were 4.3?±?0.17 and 3.9?±?2.05??M, respectively. TQ-NLC was observed to increase the number of 3T3 and 3T3-L1 healthy cells (87-95%) and gradually decrease early apoptotic cells in time- and dose-dependant manner compared with TQ. In the proliferation and migration assay, 3T3-L1 treated with TQ-NLC showed higher proliferation and migration rate (p < 0.05) compared with TQ. TQ-NLC also acted as an antioxidant by reducing the ROS levels in both cells after injury at concentration as low as 3??M. Thus, this study demonstrated that TQ-NLC has better proliferation and migration as well as antioxidant effect compared with TQ especially on 3T3-L1 which confirms its ability as a good antidiabetic and antioxidant agent.
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Project description:Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteria-metabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.
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Project description:BackgroundPatients with familial adenomatous polyposis (FAP) are at increased risk for the development of colorectal cancer. Surgery and chemoprevention are the most effective means to prevent cancer development. Thymoquinone (TQ) is considered the main compound of the volatile Nigella sativa seed oil and has been reported to possess anticarcinogenic properties. In this study we evaluated the chemopreventive properties of TQ in a mouse model of FAP.MethodsAPCMin mice were fed with chow containing 37.5 mg/kg or 375 mg/kg TQ for 12 weeks. H&E stained intestine tissue sections were assessed for tumor number, localization, size, and grade. Immunohistochemistry for ?-catenin, c-myc, Ki-67 and TUNEL-staining was performed to investigate TQ's effect on major colorectal cancer pathways. TQ's impact on GSK-3? and ?-catenin were studied in RKO cells.Results375 mg/kg but not 37.5 mg/kg TQ decreased the number of large polyps in the small intestine of APCMin mice. TQ induced apoptosis in the neoplastic tissue but not in the normal mucosa. Furthermore, upon TQ treatment, ?-catenin was retained at the membrane and c-myc decreased in the nucleus, which was associated with a reduced cell proliferation in the villi. In vitro, TQ activated GSK-3?, which induced membranous localization of ?-catenin and reduced nuclear c-myc expression.ConclusionsIn summary, TQ interferes with polyp progression in ApcMin mice through induction of tumor-cell specific apoptosis and by modulating Wnt signaling through activation of GSK-3?. Nigella sativa oil (or TQ) might be useful as nutritional supplement to complement surgery and chemoprevention in FAP.
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Project description:Radiotherapy is an important method for cancer treatment but it has serious side-effects at high doses. One of the greatest challenges in radiotherapy is that radiation affects both healthy tissue and cancer tissues. For abdominal or pelvic lesions, the bowel is the most easily injured by irradiation. Radiation may cause radiation enteritis, intestinal inflammatory infiltration, or intestinal perforation. Coenzyme NADH involves in energy metabolism and transportation of nucleic acid, proteins and carbohydrates. In our study, NADH was used to protect the intestinal wall from irradiation injury in IEC-6 normal intestinal epithelial cells. By flow cytometry, we found that NADH can inhibit the cell death and the producing of reactive oxygen species (ROS). The immunofluorescence assay showed that cell autophagy was increased in the NADH group. Western blot data indicated that NADH promoted the microtubule associated protein 1A/1B-light chain 3(LC3)-I to LC3II and the expression of IL-1? and TNF? decreased in a dose dependent manner. Interestingly, a specific PI3K/AKT inhibitor (3MA) decreased the expression of inflammatory factors. In the animal experiment, after 12 Gy radiation, there were less TNF? and more LC3II in the RT+NADH group than that of RT group. Compared with the mock, there was no significant damage in the NADH group. Thus, our study provides the evidence that NADH may protect against radiation enteritis by suppressing inflammation and enhancing autophagy through PI3K/AKT pathway in normal intestinal cells.
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Project description:Thymoquinone (TQ) is the main bioactive constituent present in black seed oil (Nigella sativa); it has shown anti-inflammatory and anti-neoplastic effects in various cancer cell types. The aim of the present study was to investigate the effects of TQ on head and neck squamous cell carcinoma (HNSCC) cell lines, on its own and in combination with radiation and cisplatin, respectively. The SCC25 and CAL27 HNSCC cell lines were treated with TQ alone and in combination with cisplatin or radiation, respectively. Proliferation assays and clonogenic assays were performed. Apoptosis was detected by flow cytometry. TQ exhibited dose-dependent cytotoxicity via apoptosis in the investigated cell lines. In combination with cisplatin, TQ resulted in no significant increase in cytotoxicity. Combined with radiation, TQ significantly reduced clonogenic survival compared with each treatment method alone. TQ is a promising agent in the treatment of head and neck cancer due to its anti-proliferative and radiosensitizing properties. However, the combination of TQ with cisplatin showed no therapeutic benefit in vitro.
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Project description:Germicidal lamps that emit primarily 254 nm ultraviolet radiation (UV) are routinely utilized for surface sterilization but cannot be used for human skin because they cause genotoxicity. As an alternative, 222-nm UVC has been reported to exert sterilizing ability comparable to that of 254-nm UVC without producing cyclobutane pyrimidine dimers (CPDs), the major DNA lesions caused by UV. However, there has been no clear evidence for safety in chronic exposure to skin, particularly with respect to carcinogenesis. We therefore investigated the long-term effects of 222-nm UVC on skin using a highly photocarcinogenic phenotype mice that lack xeroderma pigmentosum complementation group A (Xpa-) gene, which is involved in repairing of CPDs. CPDs formation was recognized only uppermost layer of epidermis even with high dose of 222-nm UVC exposure. No tumors were observed in Xpa-knockout mice and wild-type mice by repetitive irradiation with 222-nm UVC, using a protocol which had shown to produce tumor in Xpa-knockout mice irradiated with broad-band UVB. Furthermore, erythema and ear swelling were not observed in both genotype mice following 222-nm UVC exposure. Our data suggest that 222-nm UVC lamps can be safely used for sterilizing human skin as far as the perspective of skin cancer development.
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Project description:Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. The Nrf2/HO-1 pathway is a critical endogenous antioxidant stress pathway, but its precise role in radiation-induced enteritis remains to be clarified. Polysaccharides extracted from Rheum tanguticum (RTP) can protect the intestinal cells from radiation-induced damage, but the underlying mechanism is unknown. SD rats and IEC-6 cells were exposed to 12 or 10 Gy X-ray radiation. Rat survival, and histopathological and immunohistochemical profiles were analyzed at different time points. Indicators of oxidative stress and inflammatory response were also assessed. Cell viability, apoptosis and Nrf2/HO-1 expression were evaluated at multiple time points. Significant changes were observed in the physiological and biochemical indexes of rats after radiation, accompanied by significant oxidative stress response. The mRNA and protein expression of Nrf2 peaked at 12 h after irradiation, and HO-1 expression peaked at 48 h after irradiation. RTP administration reduced radiation-induced intestinal damage, upregulated Nrf2/HO-1, improved physiological indexes, significantly decreased apoptosis and inflammatory factors, and upregulated HO-1, particularly at 48 h after irradiation. In conclusion, Nrf2 is activated in the early stage of radiation-induced intestinal injury and plays a protective role. RTP significantly ameliorates radiation-induced intestinal injury via the regulation of Nrf2 and its downstream protein HO-1.
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Project description:Radiation enteritis (RE) is the most common complication of radiotherapy for pelvic irradiation receivers. Herein we investigated the alterations in gut microbial profiles and their association with enteritis in patients undergoing pelvic radiotherapy. Faecal samples were collected from 18 cervical cancer patients during radiotherapy. Microbiota profiles were characterized based on 16S rRNA sequencing using the Illumina HiSeq platform. Epithelial inflammatory response was evaluated using bacterial-epithelial co-cultures. Dysbiosis was observed among patients with RE, which was characterized by significantly reduced α-diversity but increased β-diversity, relative higher abundance of Proteobacteria and Gammaproteobacteria and lower abundance of Bacteroides. Coprococcus was clearly enriched prior to radiotherapy in patients who later developed RE. Metastat analysis further revealed unique grade-related microbial features, such as more abundant Virgibacillus and Alcanivorax in patients with mild enteritis. Additionally, using bacterial-epithelial co-cultures, RE patient-derived microbiota induced epithelial inflammation and barrier dysfunction, enhanced TNF-α and IL-1β expression compared with control microbiota. Taken together, we define the overall picture of gut microbiota in patients with RE. Our results suggest that dysbiosis of gut microbiota may contribute to development and progression of RE. Gut microbiota can offer a set of biomarkers for prediction, disease activity evaluation and treatment selection in RE.
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