Dataset Information

?-Naphthoflavone Activation of the Ah Receptor Alleviates Irradiation-Induced Intestinal Injury in Mice.

ABSTRACT: Radiotherapy induced gastrointestinal syndrome results from the acute damage of intestinal stem cells, impaired crypts reconstruction, and subsequent breakdown of the mucosal barrier. The toxicity of ionizing radiation is associated with oxidative stress in the intestinal epithelial cells (IECs). Moreover, the rapid proliferation of IECs is a risk factor for radiation damage. ?-naphthoflavone (BNF) is an agonist of the aryl hydrocarbon receptor (AhR) and possesses potential antioxidative activity. We investigated BNF radioprotection in IECs experiencing ?-ray exposure, contributed to mitigation of radiation enteritis. BNF significantly enhanced cell viability and suppressed cell apoptosis in an AhR activation-dependent manner. The mechanism of BNF reducing the IECs radiosensitivity was associated with cell cycle arrest and suppression of cell proliferation. In contrast, AhR antagonist CH-223191 significantly blocked BNF-induced cell cycle arrest. Cyp1a1 mRNA levels are induced after irradiation in a dose-dependent manner, and CYP1A1 protein expression increased in the irradiated intestinal tract as well. BNF also reduces DNA strand breaks induced by irradiation. These studies demonstrate that BNF pretreatment prolonged median survival time of mice upon exposure to a lethal dose of radiation and alleviated irradiation-induced toxicity within the bowel.

SUBMITTER: Zhou X

PROVIDER: S-EPMC7763649 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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β-Naphthoflavone Activation of the Ah Receptor Alleviates Irradiation-Induced Intestinal Injury in Mice.

Zhou Xiaoliang X Li Deguan D Xu Wenqing W Zhang Heng H Wang Hao H Perdew Gary H GH

Antioxidants (Basel, Switzerland) 20201212 12

Radiotherapy induced gastrointestinal syndrome results from the acute damage of intestinal stem cells, impaired crypts reconstruction, and subsequent breakdown of the mucosal barrier. The toxicity of ionizing radiation is associated with oxidative stress in the intestinal epithelial cells (IECs). Moreover, the rapid proliferation of IECs is a risk factor for radiation damage. β-naphthoflavone (BNF) is an agonist of the aryl hydrocarbon receptor (AhR) and possesses potential antioxidative activit ...[more]

PMID: 33322705

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Project description:Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg-1·d-1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.

Project description:BackgroundIn the current context of reduced and limited antibiotic use, several pathogens and stressors cause intestinal oxidative stress in poultry, which leads to a reduced feed intake, slow or stagnant growth and development, and even death, resulting in huge economic losses to the poultry breeding industry. Oxidative stress in animals is a non-specific injury for which no targeted drug therapy is available; however, the health of poultry can be improved by adding appropriate feed additives. Bacillus pumilus, as a feed additive, promotes growth and development and reduces intestinal oxidative stress damage in poultry. Heat shock protein 70 (HSP70) senses oxidative damage and repairs unfolded and misfolded proteins; its protective effect has been widely investigated. Mitogen-activated protein kinase/protein kinase C (MAPK/PKC) and hypoxia inducible factor-1 alpha (HIF-1α) are also common proteins associated with inflammatory response induced by several stressors, but there is limited research on these proteins in the context of poultry intestinal Salmonella Enteritidis (SE) infections. In the present study, we isolated a novel strain of Bacillus pumilus with excellent performance from the feces of healthy yaks, named TS1. To investigate the effect of TS1 on SE-induced enteritis in broilers, 120 6-day-old white-feathered broilers were randomly divided into four groups (con, TS1, SE, TS1 + SE). TS1 and TS1 + SE group chickens were fed with 1.4 × 107 colony-forming units per mL of TS1 for 15 days and intraperitoneally injected with SE to establish the oxidative stress model. Then, we investigated whether TS1 protects the intestine of SE-treated broiler chickens using inflammatory cytokine gene expression analysis, stress protein quantification, antioxidant quantification, and histopathological analysis.ResultsThe TS1 + SE group showed lower MDA and higher GSH-Px, SOD, and T-AOC than the SE group. TS1 alleviated the effects of SE on intestinal villus length and crypt depth. Our results suggest that SE exposure increased the expression of inflammatory factors (IL-1β, IL-6, TNF-α, IL-4, and MCP-1), p38 MAPK, and PKCβ and decreased the expression of HSP60, HSP70, and HIF-1α, whereas TS1 alleviated these effects.ConclusionsBacillus pumilus TS1 alleviated oxidative stress damage caused by SE and attenuated the inflammatory response in broilers through MAPK/PKC regulation of HSPs/HIF-1α.

Dataset Information

?-Naphthoflavone Activation of the Ah Receptor Alleviates Irradiation-Induced Intestinal Injury in Mice.

Publications

β-Naphthoflavone Activation of the Ah Receptor Alleviates Irradiation-Induced Intestinal Injury in Mice.

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