Inhibition of EphA2 by Dasatinib Suppresses Radiation-Induced Intestinal Injury.

Radiation-induced multiorgan dysfunction is thought to result primarily from damage to the endothelial system, leading to a systemic inflammatory response that is mediated by the recruitment of leukocytes. The Eph-ephrin signaling pathway in the vascular system participates in various disease developmental processes, including cancer and inflammation. In this study, we demonstrate that radiation exposure increased intestinal inflammation via endothelial dysfunction, caused by the radiation-induced activation of EphA2, an Eph receptor tyrosine kinase, and its ligand ephrinA1. Barrier dysfunction in endothelial and epithelial cells was aggravated by vascular endothelial-cadherin disruption and leukocyte adhesion in radiation-induced inflammation both in vitro and in vivo. Among all Eph receptors and their ligands, EphA2 and ephrinA1 were required for barrier destabilization and leukocyte adhesion. Knockdown of EphA2 in endothelial cells reduced radiation-induced endothelial dysfunction. Furthermore, pharmacological inhibition of EphA2-ephrinA1 by the tyrosine kinase inhibitor dasatinib attenuated the loss of vascular integrity and leukocyte adhesion in vitro. Mice administered dasatinib exhibited resistance to radiation injury characterized by reduced barrier leakage and decreased leukocyte infiltration into the intestine. Taken together, these data suggest that dasatinib therapy represents a potential approach for the protection of radiation-mediated intestinal damage by targeting the EphA2-ephrinA1 complex.

Topical Treatment of Hair Loss with Formononetin by Modulating Apoptosis.

Formononetin is one of the main components of red clover plants and its role on hair regrowth against hair loss has not been established yet. In the present study, we assessed the potential effects of formononetin on alopecia, along with impaired hair cycles by induction of apoptosis-regression.Depilated C57BL/6 mice were used for monitoring the hair cycles. Formononetin (1 and 100 µM) was topically treated to the dorsal skin for 14 days. Topical formononetin treatment induced miniaturized hair follicles to recover to normal sizes. Tapering hair shaft began to grow newly, emerging from the hair follicles by formononetin. In addition, formononetin inhibited the activation of caspase-8 and decreased the procaspase-9 expression. As a result of formononetin treatment, anti-apoptotic Bcl-2 was up-regulated, whereas pro-apoptotic Bax and p53 were down-regulated, resulting in a decrease of caspase-3 activation. Formononetin showed the obvious inhibition of apoptosis under terminal deoxynucleotidyl transferase dUTP nick end labeling staining thereafter.Taken together, our findings demonstrate that formononetin exerted the hair regrowth effect on hair loss, in which the underlying mechanisms were associated with Fas/Fas L-induced caspase activation, thus inhibiting apoptosis.

Effects of Lonicera japonica Thunb. on Type 2 Diabetes via PPAR-γ Activation in Rats.

Lonicera japonica Thunb. (Caprifoliaceae) is a traditional herbal medicine and has been used to treat diabetic symptoms. Notwithstanding its use, the scientific basis on anti-diabetic properties of L. japonica is not yet established. This study is designed to investigate anti-diabetic effects of L. japonica in type 2 diabetic rats. L. japonica was orally administered at the dose of 100 mg/kg in high-fat diet-fed and low-dose streptozotocin-induced rats. After the treatment of 4 weeks, L. japonica reduced high blood glucose level and homeostatic model assessment of insulin resistance in diabetic rats. In addition, body weight and food intake were restored by the L. japonica treatment. In the histopathologic examination, the amelioration of damaged ß-islet in pancreas was observed in L. japonica-treated diabetic rats. The administration of L. japonica elevated peroxisome proliferator-activated receptor gamma and insulin receptor subunit-1 protein expressions. The results demonstrated that L. japonica had anti-diabetic effects in type 2 diabetic rats via the peroxisome proliferator-activated receptor gamma regulatory action of L. japonica as a potential mechanism.

Schizonepeta tenuifolia inhibits the development of atopic dermatitis in mice.

Historically, Schizonepeta tenuifolia (ST) has been used for the treatment of skin disorders, such as allergic dermatitis, eczema, and inflammatory diseases. In this study, we examined whether ST inhibited 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in BALB/c mice. In histopathological analyses of the epidermis and dermis, skin thickness was significantly increased in DNCB-induced mice as compared with normal group. Treatment with ST inhibited this inflammatory change and markedly suppressed the secretion of immunoglobulin E, tumor necrosis factor α, and interleukin 6 levels in the serum of DNCB-induced mice. In addition, ST treatment significantly restored the upregulation of proinflammatory factors, such as nuclear factor (NF)-κB and mitogen-activated protein kinase expression. Taken together, due to its ability to suppress inflammatory factors and upregulate proinflammatory factors, ST may be useful as a therapeutic treatment for AD. ST extract application decreased both epidermis and dermis thickness in DNCB-induced mice. In serum, ST reduced immunoglobulin E, tumor necrosis factor, and interleukin 6 level. In addition, ST suppressed NF-κB activation as well as the mitogen-activated protein kinase activities.

LDR-adapted liver-derived cytokines have potential to induce atherosclerosis.

PURPOSE: Atherosclerosis is a lipid-driven chronic inflammatory disease that causes cardiovascular diseases (CVD). The association between radiation and atherosclerosis has already been demonstrated; however, the effects of low-dose radiation (LDR) exposure on atherosclerosis have not been reported. Our study aims to propose that LDR may cause atherosclerosis phenotypes by the upregulation of plasminogen activator inhibitor-1 (PAI-1) and downregulation of androgen receptor (AR), which are cytokines secreted from the liver. METHODS: Low-density lipoprotein (LDL) receptor deficient (Ldlr-/-) mice were irradiated at 50 mGy, 100 mGy, and 1000 mGy. LDR irradiated Ldlr-/- mice serum was analyzed by cytokine array and proteomics with silver staining. Oil Red O staining and BODIPY staining were performed to determine lipid accumulation in Human umbilical vein endothelial cells (HUVECs). Foam cell formation and monocyte recruitment were assessed through co-culture system with HUVECs and THP-1 cells. RESULTS: After irradiation with LDR (100 mGy) the mice showed atherosclerotic phenotypes and through analysis results, we selected regulated cytokines, PAI-1 and AR, and found that these were changed in the liver. LDR-regulated cytokines have the potential to be transported to endothelial cells and induce lipid accumulation, inflammation of monocytes, increased oxidized low-density lipoprotein (oxLDL) and foam cells formation, that were series of phenotypes lead to plaque formation in endothelial cells and induces atherosclerosis. As a further aspect of this study, testosterone undecanoate (TU) was found to pharmacologically inhibit a series of atherosclerotic phenotypes exhibited by LDR. This study suggests a role for PAI-1 and AR in regulating the development of atherosclerosis after LDR exposure. Targeting PAI-1 and AR could serve as an attractive strategy for the management of atherosclerosis following LDR exposure.

The miR-126-5p and miR-212-3p in the extracellular vesicles activate monocytes in the early stage of radiation-induced vascular inflammation implicated in atherosclerosis.

People exposed to radiation in cancer therapy and nuclear accidents are at increased risk of cardiovascular outcomes in long-term survivors. Extracellular vesicles (EVs) are involved in radiation-induced endothelial dysfunction, but their role in the early stage of vascular inflammation after radiation exposure remains to be fully understood. Herein, we demonstrate that endothelial cell-derived EVs containing miRNAs initiate monocyte activation in radiation-induced vascular inflammation. In vitro co-culture and in vivo experimental data showed that endothelial EVs can be sensitively increased by radiation exposure in a dose-dependent manner, and stimulate monocytes releasing monocytic EVs and adhesion to endothelial cells together with an increase in the expression of genes encoding specific ligands for cell-cell interaction. Small RNA sequencing and transfection using mimics and inhibitors explained that miR-126-5p and miR-212-3p enriched in endothelial EVs initiate vascular inflammation by monocyte activation after radiation exposure. Moreover, miR-126-5p could be detected in the circulating endothelial EVs of radiation-induced atherosclerosis model mice, which was found to be tightly correlated with the atherogenic index of plasma. In summary, our study showed that miR-126-5p and miR-212-3p present in the endothelial EVs mediate the inflammatory signals to activate monocytes in radiation-induced vascular injury. A better understanding of the circulating endothelial EVs content can promote their use as diagnostic and prognostic biomarkers for atherosclerosis after radiation exposure.

Chronic radiation exposure aggravates atherosclerosis by stimulating neutrophil infiltration.

BACKGROUND: Radiation exposure is known to increase the risk of chronic inflammatory diseases, such as atherosclerosis, by modulating inflammation. METHODS: To investigate the infiltration of leukocytes in radiation-aggravated atherosclerosis, we examined low-density lipoprotein receptor-deficient (Ldlr-/-) mice and C57BL/6j mice after exposure to 0.5 or 1 Gy radiation over 16 weeks. RESULTS: We found that radiation exposure induced atherosclerosis development in Ldlr-/- mice, as demonstrated by increased lipid-laden plaque size, reactive oxygen species levels, and levels of the pro-inflammatory cytokines, IL-1ß and TNF-α, in the aortas and spleens. Total plasma cholesterol, triglyceride, and LDL cholesterol levels were also increased by radiation exposure, along with cardiovascular risk. We also showed dose-dependent increases in neutrophils and monocytes that coincided with a reduction in lymphocytes in the spleens of Ldlr-/- mice. The correlation between the infiltration of leukocytes and cytokine production was also confirmed in the hearts and spleens of these mice. CONCLUSIONS: We concluded that chronic radiation exposure increased the production of pro-inflammatory mediators, which was associated with the migration of neutrophils and inflammatory monocytes into sites of atherosclerosis. Thus, our data suggest that the accumulation of neutrophils and inflammatory monocytes, together with the reduction of lymphocytes, contribute to aggravated atherosclerosis in Ldlr-/- mice under prolonged exposure to radiation.

The Current Safety Regulation for Radiation Emergency Medicine in Korea.

Radiation emergency medicine (REM) systems are operated around the world to provide specialized care for injured individuals who require immediate medical attention in accidents. This manuscript describes the current status of REM safety regulation in Korea and summarizes an assessment of the effects of this regulation. Responding to the requests of people for stronger safety regulations related to radiation exposure, a unique REM safety regulation for nuclear licensees, which is enforceable by laws, has been established and implemented. It is not found in other countries. It can provide a good example in practice for sustainable REM management including document reviews on medical response procedures and inspections of equipment and facilities. REM preparedness of nuclear or radiologic facilities has been improved with systematic implementation of processes contained in the regulation. In particular, the medical care system of licensees has become firmly coordinated in the REM network at the national level, which has enhanced their abilities by providing adequate medical personnel and facilities. This legal regulation service has contributed to preparing the actual medical emergency response for unexpected accidents and should ultimately secure the occupational safety for workers in radiation facilities.

Assessment of an Emergency Medicine System for Radiation Accidents in Korea: A State Survey of the Workers Involved the Medical Response to Radiation Accidents.

Radiation emergency medicine systems are operated around the world to provide special care for the injured that require immediate medical attention in accidents. The objective of this survey was to evaluate people's perception of those who design the emergency medical plan for radiation accidents and those who supervise it in Korea. A questionnaire survey was conducted on the people involved in a regulatory system for medical response in a radiation emergency. Of 150 survey recipients, 133 (88.7%) completed the survey, including 92 workers and 41 inspectors. The respondents expressed the view that the national emergency medical plan is prepared above the average level using a Likert-style scale of 1 to 5 (mean = 3.55, SD = 0.74). Interestingly, using the Mann-Whitney U test, it could be shown that inspectors evaluated the emergency medical system for radiation accidents more strictly in all of the questions than the licensee workers, especially on radiation medical emergency preparedness (p = 0.004) and the governmental regulatory policy for radiation safety (p = 0.007). For a more efficient system of radiation emergency medicine, licensee workers prioritized the workforce, whereas inspectors favored laws and regulations for safety. The survey results show different perspectives between inspectors and licensee workers, which stem from the actual properties of each occupational role in the regulatory system for radiation medical emergency. These data could be utilized for communication and interaction with relevant people to improve the medical response preparedness against radiation accidents.

Expansion of monocytic myeloid-derived suppressor cells ameliorated intestinal inflammatory response by radiation through SOCS3 expression.

Radiation-induced colitis is a common clinical problem after radiation therapy and accidental radiation exposure. Myeloid-derived suppressor cells (MDSCs) have immunosuppressive functions that use a variety of mechanisms to alter both the innate and the adaptive immune systems. Here, we demonstrated that radiation exposure in mice promoted the expansion of splenic and intestinal MDSCs and caused intestinal inflammation due to the increased secretion of cytokines. Depletion of monocytic MDSCs using anti-Ly6C exacerbated radiation-induced colitis and altered the expression of inflammatory cytokine IL10. Adoptive transfers of 0.5 Gy-derived MDSCs ameliorated this radiation-induced colitis through the production IL10 and activation of both STAT3 and SOCS3 signaling. Intestinal-inflammation recovery using 0.5 Gy-induced MDSCs was assessed using histological grading of colitis, colon length, body weight, and survival rate. Using in vitro co-cultures, we found that 0.5 Gy-induced MDSCs had higher expression levels of IL10 and SOCS3 compared with 5 Gy-induced MDSCs. In addition, IL10 expression was not enhanced in SOCS3-depleted cells, even in the presence of 0.5 Gy-induced monocytic MDSCs. Collectively, the results indicate that 0.5 Gy-induced MDSCs play an important immunoregulatory role in this radiation-induced colitis mouse model by releasing anti-inflammatory cytokines and suggest that IL10-overexpressing mMDSCs may be potential immune-therapy targets for treating colitis.