Hainan Zhao

Grape seed pro-anthocyanidins ameliorates radiation-induced lung injury.

Radiation‐induced lung injury (RILI) is a potentially fatal and dose‐limiting complication of thoracic radiotherapy. This study was to investigate the protective effects of grape seed pro‐anthocyanidins (GSPs), an efficient antioxidant and anti‐carcinogenic agent, on RILI. In our study, it was demonstrated that acute and late RILI was ameliorated after GSPs treatment possibly through suppressing TGF‐β1/Smad3/Snail signalling pathway and modulating the levels of cytokines (interferon‐γ, IL‐4 and IL‐13) derived from Th1/Th2 cells. In addition, a sustained high level of PGE2 was also maintained by GSPs treatment to limited fibroblast functions. As shown by electron spin resonance spectrometry, GSPs could scavenge hydroxyl radical (•OH) in a dose‐dependent manner, which might account for the mitigation of lipid peroxidation and consequent apoptosis of lung cells. In vitro, GSPs radiosensitized lung cancer cell A549 while mitigating radiation injury on normal alveolar epithelial cell RLE‐6TN. In conclusion, the results showed that GSPs protects mice from RILI through scavenging free radicals and modulating RILI‐associated cytokines, suggesting GSPs as a novel protective agent in RILI.

Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury.

Background/Aims: As a major complication after thoracic radiotherapy, radiation-induced lung injury (RILI) has great impact on long term quality of life and could result in fatal respiratory insufficiency The present study was aimed to evaluate the effects of Myrtol standardized on RILI, and to investigate the underlying mechanism. Methods: A mouse model of radiation-induced lung injury was generated by using thoracic irradiation with a single dose of 16Gy. Mice were orally administrated with Myrtol (25 mg/kg/day) for 4 weeks after irradiation, while prednisone (5 mg/kg/day) was used as a positive control. After then, the body weight and lung coefficient were calculated. The severity of fibrosis was evaluated by observing pulmonary sections after radiation and collagen content in lung tissues was calculated following the hydroxyproline (HYP) assay. Pathological changes were observed in all the groups by using HE staining and Masson staining. The serum levels of TGF-β1, TNF-α, IL-1β, IL-6, and PGE2 were also measured with an ELISA assay. Western blot assay was used to measure the impact of Myrtol on AKT and its downstream signaling pathway, including MMP-2 and MMP-9. The levels of Vimentin and α-SMA were evaluated with an immunofluorescence assay. Results: Treatment with Myrtol standardized, but not prednisone, reduced lung coefficient and collagen deposition in lung tissues, while attenuated histological damages induced by irradiation. Myrtol standardized also reduced the production of MDA, while increased the level of SOD. It was also observed that Myrtol standardized inhibited TGF-β1 and a series of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, PGE2. While in prednisone group, even though the early pneumonitis was ameliorated, the collagen disposition remained unchanged in latter times. Immunofluorescence analysis also revealed elevation of vimentin and α-SMA in the alveoli after a single dose of 16Gy. Conclusion: The present results suggest Myrtol standardized as an effective agent for attenuating the lung injury induced by irradiation.

Glibenclamide, a diabetic drug, prevents acute radiation-induced liver injury of mice via up-regulating intracellular ROS and subsequently activating Akt–NF-κB pathway

Background Acute radiation-induced liver injury is a limitation for hepatoma radiotherapy. Come so far the clinical treatments are insufficient. The effective, specific, low toxicity and novel drugs are in powerful need. Glibenclamide is a common hypoglycemic. Some studies have revealed its relation with intracellular reactive oxygen species, the crucial mediator to radiation injury. This study is aimed to investigate if glibenclamide could act on the acute radiation-induced liver injury. Results Glibenclamide mitigated acute radiation-induced liver injury of mice, indicating as regression of hepatocellular edema, reduction of hepatic sinusoid, decline in serum ALP level and reduction of hepatocellular apoptosis. Pretreatment of glibenclamide reduced the radiosensitivity of NCTC-1469 cells. In mechanism, glibenclamide elevated cells membrane potential to up-regulate intracellular reactive oxygen species. The increased reactive oxygen species subsequently activated Akt–NF-κB pathway to promote survival of irradiated cells. Methods BALB/C male mice were intraperitoneal injected with glibenclamide 1 hour before hepatic irradiation. At designed time points the livers were taken to make histological study and bloods were collected to measure serum transaminase. With/without glibenclamide pretreatment the irradiated NCTC-1469 cells were tested apoptosis, viability and proliferation. By western blotting the involved molecules were detected. Conclusions Glibenclamide, prevents acute radiation-induced liver injury of mice via up-regulating intracellular reactive oxygen species and subsequently activating Akt–NF-κB pathway.

Polydatin alleviated radiation-induced lung injury through activation of Sirt3 and inhibition of epithelial–mesenchymal transition

Radiation‐induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. It is characterized with two main features including early radiation pneumonitis and fibrosis in later phase. This study was to investigate the potential radioprotective effects of polydatin (PD), which was shown to exert anti‐inflammation and anti‐oxidative capacities in other diseases. In this study, we demonstrated that PD‐mitigated acute inflammation and late fibrosis caused by irradiation. PD treatment inhibited TGF‐β1‐Smad3 signalling pathway and epithelial–mesenchymal transition. Moreover, radiation‐induced imbalance of Th1/Th2 was also alleviated by PD treatment. Besides its free radical scavenging capacity, PD induced a huge increase of Sirt3 in culture cells and lung tissues. The level of Nrf2 and PGC1α in lung tissues was also elevated. In conclusion, our data showed that PD attenuated radiation‐induced lung injury through inhibiting epithelial–mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.

Radioprotective Effect of Grape Seed Proanthocyanidins In Vitro and In Vivo

We have demonstrated that grape seed proanthocyanidins (GSPs) could effectively scavenge hydroxyl radical (•OH) in a dose-dependent manner. Since most of the ionizing radiation- (IR-) induced injuries were caused by •OH, this study was to investigate whether GSPs would mitigate IR-induced injuries in vitro and in vivo. We demonstrated that GSPs could significantly reduce IR-induced DNA strand breaks (DSBs) and apoptosis of human lymphocyte AHH-1 cells. This study also showed that GSPs could protect white blood cells (WBC) from IR-induced injuries, speed up the weight of mice back, and decrease plasma malondialdehyde (MDA), thus improving the survival rates of mice after ionizing radiation. It is suggested that GSPs have a potential as an effective and safe radioprotective agent.

CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis

Pulmonary fibrosis is a serious adverse effect of radiotherapy for thoracic tumor, which is believed to be a process that is tightly regulated by the phenotype of the developing Th response after radiation. Here, we will investigate whether CpG-oligodeoxynucleotides (ODN) prevent radiation-induced pulmonary fibrosis by shifting the imbalance of Th1 and Th2 response and summarizes the possible mechanism. In this study, female C57BL/6 mice were chosen to preform pulmonary fibrosis model, the whole-thorax of mice was exposed to a single radiation dose of 15 Gy. When irradiated mice were administrated with CpG-ODN, forming of pulmonary fibrosis was significantly prevented. Th2-related cytokines (IL-4 and IL-13) expression decreased, Th1 related-cytokine (IFN-γ and IL-12) expression increased. Alveolar macrophage accumulation was reduced in irradiated tissue. Profibrotic cytokine TGF-β1 expression stayed at lower level. In TGF-β1-Smad-dependent pathways, TGF-β1, TβR and phosphor-Smad 2/3 were down regulated, and Smad 7 was up regulated. These suggested that CpG-ODN prevented pulmonary fibrosis after radiation. The mechanism might be associated with reduction of alveolar macrophages accumulation and profibrogenic cytokines secretion TGF-β1 through stimulating the combination of Th1-promoting and Th2-limiting responses after radiation, and finally inhibited the fibrosis-related downstream TGF-β1-Smad-dependent pathway.

The mechanism for the radioprotective effects of zymosan-A in mice

It proved that Zymosan‐A protected the haematopoietic system from radiation‐induced damage via Toll‐Like Receptor2 in our previous study. In this study, we investigated the potential mechanism for the radioprotective effects of Zymosan‐A. The mice were treated with Zymosan‐A (50 mg/kg, dissolved in NS) via peritoneal injection 24 and 2 hours before ionizing radiation. Apoptosis of bone marrow cells and the levels of IL‐6, IL‐12, G‐CSF and GM‐CSF were evaluated by flow cytometry assay. DNA damage was determined by γ‐H2AX foci assay. In addition, RNA sequencing was performed to identify differentially expressed genes (DEGs). Zymosan‐A protected bone marrow cells from radiation‐induced apoptosis, up‐regulated IL‐6, IL‐12, G‐CSF and GM‐CSF in bone marrow cells. Zymosan‐A also protected cells from radiation‐induced DNA damage. Moreover, RNA sequencing analysis revealed that Zymosan‐A induced 131 DEGs involved in the regulation of immune system process and inflammatory response. The DEGs were mainly clustered in 18 KEGG pathways which were also associated with immune system processes. Zymosan‐A protected bone marrow cells from radiation‐induced apoptosis and up‐regulated IL‐6, IL‐12, G‐CSF and GM‐CSF. Moreover, Zymosan‐A might also exhibit radioprotective effects through regulating immune system process and inflammatory response. These results provided new knowledge regarding the radioprotective effect of Zymosan‐A.

Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice

Molecular hydrogen (H2) has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR). All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM) observation, forced swim test (FST), the open field test (OFT), the chromosome aberration (CA), the peripheral blood cells parameters analysis, the sperm abnormality (SA), the lymphocyte transformation test (LTT), and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR.

Radioprotective effects of roxadustat (FG-4592) in haematopoietic system

Ionizing radiation often causes severe injuries to radiosensitive tissues, especially haematopoietic system. Novel radioprotective drugs with low toxicity and high effectiveness are required. Prolyl hydroxylases domain (PHD) inhibitors have been reported to protect against radiation‐induced gastrointestinal toxicity. In this study, we demonstrated the protective effects of a PHD inhibitor, roxadustat (FG‐4592), against radiation‐induced haematopoietic injuries in vitro and in vivo.

Polymyxin B Attenuates LPS-Induced Death but Aggravates Radiation-Induced Death via TLR4-Myd88-IL-6 Pathway

Background/Aims: Polymyxin B (PMB) is a cyclic cationic polypeptide antibiotic widely used to counteract the effects of endotoxin contamination, both in vitro and in vivo. Lipopolysaccharide (LPS) is an endotoxin that acts as a radiation protection factor. In this study, we focus on the role of PMB in LPS-induced and radiation-induced mortality in mice. Methods: Mice received total-body radiation or were pretreated by LPS or PMB, and the survival of mice was recorded. Elisa were used to detect the cytokines levels. Results: PMB decreased LPS-induced, but increased radiation-induced mortality in mice. Moreover, PMB could block the LPS-induced radioprotective effect. The ELISA and gene knock-out experiments indicated that PMB reduces TNF-α level to block LPS-induced mortality in mice, and inhibits IL-6, G-CSF and IL-10 to increase radiation-induced mortality via the TLR4-Myd88-IL-6 pathway. Conclusions: Our study revealed a role of PMB in LPS-induced endotoxemia and radiation exposure. We infer that the TLR4-Myd88-IL-6 pathway may play a crucial role in the process.