Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3

Kim, Jin Mo; Yoo, Hyera; Kim, Jee Youn; Oh, Sang Ho; Kang, Ji-Won; Yoo, Byung Rok; Han, Song Yi; Kim, Cha Soon; Choi, Won Hoon; Lee, Eun Jung; Byeon, Hyeong Ju; Lee, Won Jai; Lee, Yun Sil; Cho, Jaeho

doi:10.1159/000491964

Cited by 25 publications

(22 citation statements)

References 47 publications

(60 reference statements)

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“…In our investigation, the Masson's staining allowed us to detect the two types of collagen fibers in the control group (type I collagen fibers in blue; type III collagen fibers in red [35,36]). However, in the irradiated calvaria skin, it was possible to determine a significant change in the pattern of the color of collagen fibers by Masson staining not previously well explored.…”

Section: Discussionmentioning

confidence: 87%

Initial damage produced by a single 15-Gy x-ray irradiation to the rat calvaria skin

et al. 2020

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Background: Calvaria skin has a reduced thickness, and its initial damage produced by irradiation was scarcely reported. We aimed to identify the initial effects of x-ray irradiation in the rat calvaria skin. Methods: After approval by the Animal Ethical Committee, calvaria skin sections of five Wistar rats per time point were evaluated on days 4, 9, 14, and 25 following a single 15-Gy x-ray irradiation of the head. The control group was composed of five rats and evaluated on day 4. Sections were assessed using hematoxylin-eosin and Masson's trichrome staining for morphology, inflammation, and fibrosis. Fibrosis was also evaluated by the collagen maturation index from Picrosirius red staining and by cell proliferation using the immunohistochemistry, after 5bromo-2-deoxyuridine intraperitoneal injection. Results: In irradiated rats, we observed a reduction in epithelial cell proliferation (p = 0.004) and in matrix metalloproteinase-9 expression (p < 0.001), an increase in the maturation index, and with a predominance in the type I collagen fibers, on days 9 and 14 (1.19 and 1.17, respectively). A progressive disorganization in the morphology of the collagen fibers at all time points and changes in morphology of the sebaceous gland cells and hair follicle were present until day 14. Conclusions: The initial damage produced by a single 15-Gy x-ray irradiation to the rat calvaria skin was a change in the normal morphology of collagen fibers to an amorphous aspect, a temporary absence of the sebaceous gland and hair follicles, and without a visible inflammatory process, cell proliferation, or fibrosis process in the dermis.

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Section: Discussionmentioning

confidence: 87%

Initial damage produced by a single 15-Gy x-ray irradiation to the rat calvaria skin

et al. 2020

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“…Metformin as another kind of type 2 diabetes drug approved by FDA, our previous study has shown that it alleviates HSCs aging by inhibiting NOX4-mediated oxidative stress, thus improving long-term HSCs injury induced by IR in mice [13]. In addition, metformin improves ARS symptoms such as pulmonary fibrosis and skin collagen deposition [37,38]. Therefore, we speculate that sitagliptin may also have therapeutic effects on IR-induced tissue damage.…”

Section: Discussionmentioning

confidence: 91%

Sitagliptin Mitigates Total Body Irradiation-Induced Hematopoietic Injury in Mice

Wang

Dong

et al. 2020

Oxidative Medicine and Cellular Longevity

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Sitagliptin, an inhibitor of the dipeptidyl peptidase IV (DPP4), has been implicated in the regulation of type 2 diabetes. However, the role and mechanism of sitagliptin administration in total body irradiation (TBI)- induced hematopoietic cells injury are unclear. In this study, we demonstrated that sitagliptin had therapeutic effects on hematopoietic damage, which protected mice from 7.5 Gy TBI-induced death, increased the numbers and colony formation ability of hematopoietic cells. These therapeutic effects might be attributed to the inhibition of NOX4-mediated oxidative stress in hematopoietic cells, and the alleviation of inflammation was also helpful. Therefore, sitagliptin has potential as an effective radiotherapeutic agent for ameliorating TBI-induced hematopoietic injury.

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“…In addition, metformin can attenuate chronic production of ROS and alleviates fibrosis, through modulation of pro-oxidant genes such as NOX4 [37]. Metformin has shown ability to attenuate radiation-induced toxicity via neutralization of free radicals, stimulation of antioxidant defense enzymes as well as stimulation of DNA repair enzymes [38,39]. It has also shown ability to trigger DNA damage responses (DDR), leading to protection of cells against toxic agents including ionizing radiation [40].…”

Section: Discussionmentioning

confidence: 99%

Mitigation of Radiation-Induced Lung Pneumonitis and Fibrosis Using Metformin and Melatonin: A Histopathological Study

et al. 2019

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Background and objectives: Pneumonitis and fibrosis are the most common consequences of lung exposure to a high dose of ionizing radiation during an accidental radiological or nuclear event, and may lead to death, after some months to years. So far, some anti-inflammatory and antioxidant agents have been used for mitigation of lung injury. In the present study, we aimed to detect possible mitigatory effects of melatonin and metformin on radiation-induced pneumonitis and lung fibrosis. Materials and methods: 40 male mice were divided into 4 groups (10 mice in each). For control group, mice did not receive radiation or drugs. In group 2, mice were irradiated to chest area with 18 Gy gamma rays. In groups 3 and 4, mice were first irradiated similar to group 2. After 24 h, treatment with melatonin as well as metformin began. Mice were sacrificed after 100 days for determination of mitigation of lung pneumonitis and fibrosis by melatonin or metformin. Results: Results showed that both melatonin and metformin are able to mitigate pneumonitis and fibrosis markers such as infiltration of inflammatory cells, edema, vascular and alveolar thickening, as well as collagen deposition. Conclusion: Melatonin and metformin may have some interesting properties for mitigation of radiation pneumonitis and fibrosis after an accidental radiation event.

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Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3

Cited by 25 publications

References 47 publications

Initial damage produced by a single 15-Gy x-ray irradiation to the rat calvaria skin

Initial damage produced by a single 15-Gy x-ray irradiation to the rat calvaria skin

Sitagliptin Mitigates Total Body Irradiation-Induced Hematopoietic Injury in Mice

Mitigation of Radiation-Induced Lung Pneumonitis and Fibrosis Using Metformin and Melatonin: A Histopathological Study

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