Activated Beta-Catenin Signaling Ameliorates Radiation-Induced Skin Injury by Suppressing Marvel D3 Expression.

Radiation-induced skin injury remains a serious concern for cancer radiotherapy, radiation accidents and occupational exposure, and the damage mainly occurs due to apoptosis and reactive oxygen species (ROS) generation. There is currently no effective treatment for this disorder. The ß-catenin signaling pathway is involved in the repair and regeneration of injured tissues. However, the role of the ß-catenin signaling pathway in radiation-induced skin injury has not been reported. In this study, we demonstrated that the ß-catenin signaling pathway was activated in response to radiation and that its activation by Wnt3a, a ligand-protein involved in the ß-catenin signaling pathway, inhibited apoptosis and the production of ROS in irradiated human keratinocyte HaCaT cells and skin fibroblast WS1 cells. Additionally, Wnt3a promoted cell migration after irradiation. In a mouse model of full-thickness skin wounds combined with total-body irradiation, Wnt3a was shown to facilitate skin wound healing. The results from RNA-Seq revealed that 24 genes were upregulated and 154 were downregulated in Wnt3a-treated irradiated skin cells, and these dysregulated genes were mainly enriched in the tight junction pathway. Among them, Marvel D3 showed the most obvious difference. We further found that the activated ß-catenin signaling pathway stimulated the phosphorylation of JNK by silencing Marvel D3. Treatment of irradiated cells with SP600125, a JNK inhibitor, augmented ROS production and impeded cell migration. Furthermore, treatment with Wnt3a or transfection with Marvel D3-specific siRNAs could reverse the above effects. Taken together, these findings illustrate that activated ß-catenin signaling stimulates the activation of JNK by negatively regulating Marvel D3 to ameliorate radiation-induced skin injury.

Monophosphoryl lipid A alleviated radiation-induced testicular injury through TLR4-dependent exosomes.

Radiation protection on male testis is an important task for ionizing radiation-related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll-like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low-toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage-derived exosomes protein expression. We proved that after MPLA treatment, macrophage-derived exosomes played an important role in testis radiation protection, and specially, G-CSF and MIP-2 in exosomes are the core molecules in this protection effect.

Inhibition of AIM2 inflammasome-mediated pyroptosis by Andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis.

Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.

Mitigation of radiation-induced gastro-intestinal injury by the polyphenolic acetate 7, 8-diacetoxy-4-methylthiocoumarin in mice.

Radiation-induced intestinal injury (RIII) constitutes a crucial clinical element of acute radiation syndrome with life-threatening implications posing challenges in devising effective medical countermeasures. Herein, we report the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to mitigate RIII following total-body irradiation (TBI) in C57BL/6 mice and underlying mechanisms. Administration of DAMTC 24 hours post TBI facilitated structural reconstitution and restoration of functional absorption linked to alleviation of radiation-induced apoptotic death of intestinal crypt progenitor/stem (ICPS) and villus stromal cells through induction of Bcl-2 family-mediated anti-apoptotic signalling. Reduction in TBI-induced DNA damage accumulation coupled with inhibition of cell cycle arrest through stimulation of anti-p53- and anti-p21-dependent synergistic signalling protected ICPS cells from radiation injury. Enhanced proliferation of crypt stem cells, induction of anti-oxidant defence, subjugation of TBI-induced lipid peroxidation and phenotypic polarization of intestinal macrophages to anti-inflammatory M2 class underlie amelioration of RIII. Stimulation of multiple mitigative signalling processes by DAMTC appeared to be associated with enhanced protein acetylation, an important regulator of cellular responses to radiation damage. Our findings establish the mitigative potential of DAMTC against RIII by hyper-acetylation-mediated epigenetic regulation, which triggers axes of anti-apoptotic and pro-survival pathways, enabling proliferation and maintenance of ICPS cells leading to epithelial regeneration.

Radioprotective efficacy of GSH based peptidomimetic complex of manganese against radiation induced damage: DT(GS)2Mn(II).

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn2+ in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)2Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)2Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)2Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ±â€¯0.14) compared to radiation alone group (1.60 ±â€¯0.07) was observed. DT(GS)2Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)2Mn(II) with an average of 1546 ±â€¯61 µm versus 763 ±â€¯154 µm for radiation alone group. The present findings suggested DT(GS)2Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.

Therapeutic Effect of Ecdysterone Combine Paeonol Oral Cavity Direct Administered on Radiation-Induced Oral Mucositis in Rats.

Radiation-induced oral mucositis represents an influential factor in cancer patients' accepted radiation therapy, especially in head and neck cancer. This research investigates the treatment effect of Ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) and Paeonol (a compound derived from Cortex Moutan) on radiation-induced oral mucositis and possible underlying mechanisms. Concisely, 20 Gy of X-rays (single-dose) irradiated the cranial localization in rats for the modeling of oral mucositis. The therapeutic effects of Ecdysterone-Paeonol oral cavity directly administered on radiation-induced oral mucositis were investigated by weight changes, direct observations, visual scoring methods, ulcer area/total area, and basic recovery days. Assessments of tumor necrosis factor α and interleukin-6 were performed to evaluate the inflammatory cytokines secretion in the damaged areas of tongues harvested post-treatment, and changes in signaling pathways were investigated by Western blotting. System Drug Target (SysDT) methods revealed the targets of Ecdysterone-Paeonol in order to support compound-target network construction. Four representative targets with different functions were chosen. The binding interactions between the compound and receptor were evaluated by molecular docking to investigate the binding affinity of the ligand to their protein targets. Ecdysterone-Paeonol, administered orally, effectively improved radiation-induced oral mucositis in rats, and the therapeutic effect was better than Ecdysterone administered orally on its own. In this study, calculational chemistry revealed that Ecdysterone-Paeonol affected 19 function targets associated with radiation-induced oral mucositis, including apoptosis, proliferation, inflammation, and wound healing. These findings position Ecdysterone-Paeonol as a potential treatment candidate for oral mucositis acting on multiple targets in the clinic.

Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review.

Chemoradiotherapy is important for treating malignancies. However, radiation-induced toxicities develop as chemoradiotherapy-related complications. Various agents reduce or prevent toxicities, but there are no standard treatments. Polaprezinc (PZ), a chelating compound used for gastric ulcers, has antioxidant and free radical scavenging effects. Although few studies have evaluated PZ and radiation-induced normal tissue damage, several clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis and taste alterations during and after radiotherapy. Moreover, preclinical data support the clinical data, indicating good potential of testing PZ in future trials. However, as there are only few well-documented review articles on PZ use in cancer treatment, we conducted this literature review. PZ reduced several radiation-induced toxicities and improved the quality of life.

Sivelestat sodium hydrate reduces radiation-induced lung injury in mice by inhibiting neutrophil elastase.

The aim of this study was to investigate whether sivelestat, a neutrophil elastase (NE) inhibitor, mitigates radiation-induced lung injury in mice. C57BL/6J mice were administered a dose of 20 Gy to the bilateral whole lungs. Sivelestat was administered immediately before and 1 h after irradiation in group RE2, and immediately before and 1, 3 and 6 h after irradiation in group RE4. Group R received irradiation without sivelestat injection. Mice that did not receive sivelestat injection or irradiation were used as controls. NE activity was measured 24 and 48 h after irradiation, and the mice were sacrificed 24 h, 48 h and 15 weeks after irradiation for histopathological examination. In groups RE2 and RE4, NE activity was significantly suppressed until 48 h after irradiation compared to group R. The degree of lung damage in each group was scored during histopathological examination. Results showed that the scores of groups RE2 and RE4 were significantly lower compared to those of group R 15 weeks after irradiation. In conclusion, sivelestat reduced radiation­induced lung injury in the mice by suppressing NE activity and excessive inflammatory reactions.

[Radiation protectors within the radiation safety system for extended duration exploration missions].

Radiation environment in extended duration exploration missions is scrutinized in the context of the probability of the risks of deterministic and stochastic effects of radiation. Though the probability of severe radiation damage due to solar flare is very low, nonetheless it is requisite that the crew must be provided with appropriate, including pharmacological safeguards. The current nomenclature of radiation protectors composes short-term agents against acute radiation damage. Among the others, preparation B-190 is distinguished by particularly high effectiveness and universal action, and good tolerance even when organism is exposed to the extreme factors of space flight Regimen of B-290 therapy alone and with combination with aminothiol preparations have been developed to render treatment following multiple solar events. Effectiveness of radioprotectors can be increased substantially by local shielding of the abdomen and pelvis. The most promising nonspecific stimulators of total resistance of organism are riboxin (inosin) and combined preparation aminotetravit as well as vitamins tocopherol and retinol. Therapy combining B-190 with riboxin and aminotetravit is also under discussion. Cytokine neipogen is also viewed as a candidate agent for early therapy. Concern is raised about possible development of chronic oxidative stress in long-duration exploration missions. Highlighted is the significance of adequate nutrition supplemented with fresh vegetables as a source of the most valuable bioflavonoids. Antioxidants L-selenomethionine and melatonin proved their effectiveness against heavy nuclei of galactic radiation. An open issue is how to make natural antioxidants beneficial to oxidative stress control and attenuation of low-intensity galactic radiation.

Modulatory effect of curcumin on survival of irradiated human intestinal microvascular endothelial cells: role of Akt/mTOR and NF-{kappa}B.

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.

Pathophysiology of radiation-induced growth hormone deficiency: efficacy and safety of GH replacement.

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced. Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80-90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.

Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis.

GOAL OF WORK: The aim of the study was to investigate the incidence of herpes simplex virus-1 (HSV-1) infection in mucositis during head and neck cancer radiotherapy. PATIENTS AND METHODS: Sixty patients with malignant head and neck tumor, eligible to receive radiotherapy, who were referred to the Dental Oncology Unit, entered the study. Sixteen patients (26.6%) received concomitant chemotherapy. Mucositis was recorded weekly. Smears taken from the ulcers of mucositis grade 2, or 3, or 4 were stained with Papanicolaou and alkaline phosphatase/antialkaline phosphatase immunocytochemical method to identify HSV-1. MAIN RESULTS: Forty-eight of all 60 patients developed ulcerative mucositis. Smear was available from 29 of 48 patients with ulcerations. HSV-1 infection was identified in 14 of 29 smears available (48.2%). Mucositis healed or was reduced after 1 week of antiviral treatment in 11 of those 14 HSV-1-positive patients; 3 patients responded to 1 g/day of valacyclovir, 7-2 g/day, and 1 patient responded to i.v. acyclovir. Ulcerations recurred after quitting antivirals. Three patients did not respond to 1 g/day of valacyclovir. No HSV-1-negative patient responded to acyclovir (P = 0.000). CONCLUSION: HSV-1 was isolated from 14 of 29 available smears taken from 48 patients with ulcerative mucositis. The incidence of HSV-1 infection during radiotherapy was estimated as being 14 of all 48 patients at risk (29.1%). Healing or reduction in the grade of mucositis after antivirals in HSV-1 positive patients, combined with the negative response to antivirals in HSV-1 negative patients, denoted that HSV-1 infection was a component of ulcerative radiation mucositis in those HSV-1-positive patients.

Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review.

PURPOSE: Events of the recent past have focused attention on the possibility of radiological (nuclear) terrorism and on the implications of such terrorist threats for radiation accident preparedness. This review discusses recent advances in the knowledge about how radiation injuries from such events might be treated pharmacologically, and the practical barriers to clinical utilization of these approaches. CONCLUSIONS: A wide range of pharmacological approaches are being developed in the laboratory that could greatly expand the ability to treat acute and chronic radiation injuries. However, there are currently a variety of practical and legal barriers that would prevent the actual clinical use of most of the approaches. There are also the potential weaknesses in most of the current programmes for dealing with the consequences of radiation accidents or nuclear terrorism, including the absence of widespread radiation biodosimetry capabilities and the resulting inability to triage. If a major radiation accident or terrorist event occurs, the lack of biodosimetry and treatment capabilities will be compounded by widespread public fear of 'radiation'.

Clinical evaluation of human placental extract (placentrex) in radiation-induced oral mucositis.

To evaluate human placental extract in the treatment of radiation mucositis involving the oral/oropharyngeal region, a prospective randomized study was carried out in 120 patients with squamous cell carcinoma of the head and neck from August 1997 to March 1999. The study was conducted in patients receiving radical external radiation therapy, planned for = > 60 Gy/30 F/6 weeks, who developed grade 2 radiation mucositis (patchy mucositis) during radiation treatment. The patients were randomized in two groups of 60 patients each to receive either placentrex treatment (placentrex group) or conventional treatment (control group). Placentrex treatment was given as Inj Placentrex 2 ml by deep intramuscular injection 5 days a week for 15 injections. Conventional treatment given in the control group was disprin gargles and betamethasone oral drops. A subjective decrease in pain was observed in 48/60 (80%) of patients in the placentrex group compared with 22/60 (36.7%) in the control group. The progression to grade 3 radiation mucositis was 24/60 (40%) in the placentrex group compared with 52/60 (86.7%) in the control group. The subjective improvement in difficulty in swallowing was seen in 56/60 (93%) of patients in the placentrex group compared with 9/60 (15%) of patients in the control group. Only one patient in the placentrex group compared with three in the control group required interruption of radiation therapy because of severe radiation reactions. Human placental extract appears to be effective in the management of radiation-induced oral/oropharyngeal mucositis and especially in controlling subjective symptoms.