Radiation-induced Skin Injury Research Articles

18β-glycyrrhetinic acid alleviates radiation-induced skin injury by activating the Nrf2/HO-1 signaling pathway.

Radiation-induced skin injury is a common side effect of radiotherapy, but there are few therapeutic drugs available for prevention or treatment. In this study, we demonstrate that 18β-Glycyrrhetinic acid (18β-GA), a bioactive component derived from Glycyrrhiza glabra, substantially reduces the accumulation of reactive oxygen species (ROS) and inhibits apoptosis in HaCaTcells after ionizing radiation (IR), thereby mitigating radiation-induced skin injury. Mechanistically, 18β-GA promotes the nuclear import of Nrf2, leading to activation of the Nrf2/HO-1 signaling pathway in response to IR. Importantly, Nrf2 silencing increases cell apoptosis and reverse the protective effect of 18β-GA on radiation-induced skin injury. Furthermore, 18β-GA preserves skin tissue structure after irradiation, inhibits inflammatory cell infiltration, and alleviates radiation dermatitis. In conclusion, our results suggest that 18β-GA reduces intracellular ROS production and apoptosis by activating the Nrf2/HO-1 signaling pathway, leading to amelioration of radiation dermatitis.

Radiation Dermatitis: Radiation-Induced Effects on the Structural and Immunological Barrier Function of the Epidermis.

An important hallmark of radiation dermatitis is the impairment of the mitotic ability of the stem/progenitor cells in the basal cell layers due to radiation-induced DNA damage, leading to suppressed cell renewal in the epidermis. However, this mechanism alone does not adequately explain the complex pathogenesis of radiation-induced skin injury. In this review, we summarize the latest findings on the complex pathogenesis of radiation dermatitis and correlate these with the clinical features of radiation-induced skin reactions. The current studies show that skin exposure to ionizing radiation induces cellular senescence in the epidermal keratinocytes. As part of their epithelial stress response, these senescent keratinocytes secrete pro-inflammatory mediators, thereby triggering skin inflammation. Keratinocyte-derived cytokines and chemokines modulate intercellular communication with the immune cells, activating skin-resident and recruiting skin-infiltrating immune cells within the epidermis and dermis, thereby orchestrating the inflammatory response to radiation-induced tissue damage. The increased expression of specific chemoattractant chemokines leads to increased recruitment of neutrophils into the irradiated skin, where they release cytotoxic granules that are responsible for the exacerbation of an inflammatory state. Moreover, the importance of IL-17-expressing γδ-T cells to the radiation-induced hyperproliferation of keratinocytes was demonstrated, leading to reactive hyperplasia of the epidermis. Radiation-induced, reactive hyperproliferation of the keratinocytes disturbs the fine-tuned keratinization and cornification processes, leading to structural dysfunction of the epidermal barrier. In summary, in response to ionizing radiation, epidermal keratinocytes have important structural and immunoregulatory barrier functions in the skin, coordinating interacting immune responses to eliminate radiation-induced damage and to initiate the healing process.

Product Development within the National Institutes of Health Radiation and Nuclear Countermeasures Program.

The Radiation and Nuclear Countermeasures Program (RNCP) at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) was established to facilitate the development of medical countermeasures (MCMs) and diagnostic approaches for use in a radiation public health emergency. Approvals for MCMs can be very challenging but are made possible under the United States Food and Drug Administration (FDA) Animal Rule, which is designed to enable licensure of drugs or biologics when clinical efficacy studies are unethical or unfeasible. The NIAID portfolio includes grants, contracts, and inter-agency agreements designed to span all aspects of drug development and encompasses basic research through FDA approval. In addition, NIAID manages an active portfolio of biodosimetry approaches to assess injuries and absorbed radiation levels to guide triage and treatment decisions. NIAID, together with grantees, contractors, and other stakeholders with promising products, works to advance candidate MCMs and biodosimetry tools through an established product development pipeline. In addition to managing grants and contracts, NIAID tests promising candidates in our established preclinical animal models, and the NIAID Program Officers work closely with sponsors as product managers to guide them through the process. In addition, a valuable benefit for stakeholders is working with the NIAID Office of Regulatory Affairs, where NIAID coordinates with the FDA to facilitate interactions between sponsors and the agency. Activities funded by NIAID include basic research (e.g., library screens to discover new products, determine early efficacy, and delineate mechanism of action) and the development of small and large animal models of radiation-induced hematopoietic, gastrointestinal, lung, kidney, and skin injury, radiation combined injury, and radionuclide decorporation. NIAID also sponsors Good Laboratory Practice product safety, pharmacokinetic, pharmacodynamic, and toxicology studies, as well as efficacy and dose-ranging studies to optimize product regimens. For later-stage candidates, NIAID funds large-scale manufacturing and formulation development of products. The program also supports Phase 1 human clinical studies to ensure human safety and to bridge pharmacokinetic, pharmacodynamic, and efficacy data from animals to humans. To date, NIAID has supported >900 animal studies and one clinical study, evaluating >500 new/repurposed radiation MCMs and biodosimetric approaches. NIAID sponsorship led to the approval of three of the six drugs for acute radiation syndrome under the FDA Animal Rule, five Investigational New Drug applications, and 18 additional submissions for Investigational Device Exemptions, while advancing 38 projects to the Biomedical Advanced Research and Development Authority for follow-on research and development.

Senescent fibroblast facilitates re-epithelization and collagen deposition in radiation-induced skin injury through IL-33-mediated macrophage polarization

BackgroundThe need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated.ResultsHere, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization.ConclusionsIn conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner.Graphical

Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis.

This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It reviewed the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-beta (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. Additionally, it discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life.

Local Multiple-site Injections of a Plasmid Encoding Human MnSOD Mitigate Radiation-induced Skin Injury by Inhibiting Ferroptosis.

Most patients who undergo radiotherapy develop radiation skin injury, for which effective treatment is urgently needed. MnSOD defends against reactive oxygen species (ROS) damage and may be valuable for treating radiation-induced injury. Here, we (i) investigated the therapeutic and preventive effects of local multiple-site injections of a plasmid, encoding human MnSOD, on radiation-induced skin injury in rats and (ii) explored the mechanism underlying the protective effects of pMnSOD. The recombinant plasmid (pMnSOD) was constructed with human cytomegalovirus (CMV) promoter and pUC-ori. The protective effects of pMnSOD against 20-Gy X-ray irradiation were evaluated in human keratinocytes (HaCaT cells) by determining cell viability, ROS levels, and ferroptosisrelated gene expression. In therapeutic treatment, rats received local multiple-site injections of pMnSOD on days 12, 19, and 21 after 40-Gy γ-ray irradiation. In preventive treatment, rats received pMnSOD injections on day -3 pre-irradiation and on day 4 post-irradiation. The skin injuries were evaluated based on the injury score and pathological examination, and ferroptosis-related gene expression was determined. In irradiated HaCaT cells, pMnSOD transfection resulted in an increased SOD2 expression, reduced intracellular ROS levels, and increased cell viability. Moreover, GPX4 and SLC7A11 expression was significantly upregulated, and erastin-induced ferroptosis was inhibited in HaCaT cells. In the therapeutic and prevention treatment experiments, pMnSOD administration produced local SOD protein expression and evidently promoted the healing of radiation-induced skin injury. In the therapeutic treatment experiments, the injury score in the high-dose pMnSOD group was significantly lower than in the PBS group on day 33 post-irradiation (1.50 vs. 2.80, P < 0.05). In the prevention treatment experiments, the skin injury scores were much lower in the pMnSOD administration groups than in the PBS group from day 21 to day 34. GPX4, SLC7A11, and Bcl-2 were upregulated in irradiated skin tissues after pMnSOD treatment, while ACSL4 was downregulated. The present study provides evidence that the protective effects of MnSOD in irradiated HaCaT cells may be related to the inhibition of ferroptosis. The multi-site injections of pMnSOD had clear therapeutic and preventive effects on radiation-induced skin injury in rats. pMnSOD may have therapeutic value for the treatment of radiation-induced skin injury.

Vitamin D3 and its Potential to Ameliorate Chemical and Radiation-Induced Skin Injury During Cancer Therapy.

Skin injury and dermatitis are common complications following chemotherapy and radiation administration for cancer treatment. Symptomatic relief of these complications is limited to slow-acting therapies and often results in holding or modifying cancer therapy that may impact patient outcomes. The off-label use of oral high dose vitamin D3 has demonstrated rapid clinical improvement in skin inflammation and swelling in both chemotherapy and radiation-induced injury. Furthermore, vitamin D3 has been shown to downregulate pro-inflammatory pathways and cytokines, including NFkB, and CCL2, as well as CCL20, which are not only involved in tissue injury, but may confer resistance to cancer treatment. In this paper, we discuss 2 patients with acute radiation dermatitis and acute radiation recall dermatitis following chemotherapy who received 50 000 - 100 000 IU of oral high dose vitamin D3 with improvement in their symptoms. These findings may indicate the potential use of vitamin D as a therapeutic intervention and future target for studying skin healing following chemotherapy and/ or radiation-induced cutaneous toxicity.

High-Resolution Ultrasound Imaging for Non-Invasive Characterization of Acute Wound Healing in Radiation Injury on Guinea Pig Skin Tissue

Purpose: High-resolution ultrasound imaging is a non-invasive and objective appraisal. Ultrasound imaging accomplishes the target assessment and follow-up of radiation-induced skin injury.&#x0D; The study aimed to investigate the complete anatomical and structural alternations of acute wound healing in skin tissue radiation injury after cell therapy with high-frequency ultrasound imaging techniques.&#x0D; Materials and Methods: Female guinea pigs (250 g) were divided into 3 groups: (a) controls, consisting of non-treated guinea pigs; (b) radiation-treated; (c) radiation-treated receiving adipose-derived mesenchymal stem cells. Acute radiation-induced skin injury was induced by a single fraction of X-ray irradiation of 60Gy to a 3.0×3.0-cm area with a 1.3-cm bolus on 100-cm SSD in the abdominal skin tissue. Ultrasonic imaging of the depth and quality of healing in the skin tissue was performed by processing ultrasound images at 40-MHz and 75-MHz frequencies.&#x0D; Results: Skin thickness indicated a significant difference between the treatment and control groups on Day 10 after 60 Gy irradiation (P&lt;0.05). The highest skin thickness was observed in the irradiated group, and the lowest skin thickness was found in the stem cell treatment group.&#x0D; Conclusion: Evaluation of skin thickness, wound depth, and scar formation is important for the proper assessment and management of wound healing in stem cell therapy of radiation-induced skin damage. High-resolution ultrasound at 40- and 75-MHz frequencies is a major non-invasive method providing unprecedented insight into determining the characterization of the skin, particularly in the context of wound healing.

Therapeutic Potential of Adipose-Derived Stem Cell-Conditioned Medium and Extracellular Vesicles in an In Vitro Radiation-Induced Skin Injury Model.

Radiotherapy (RT) is one of three major treatments for malignant tumors, and one of its most common side effects is skin and soft tissue injury. However, the treatment of these remains challenging. Several studies have shown that mesenchymal stem cell (MSC) treatment enhances skin wound healing. In this study, we extracted human dermal fibroblasts (HDFs) and adipose-derived stem cells (ADSCs) from patients and generated an in vitro radiation-induced skin injury model with HDFs to verify the effect of conditioned medium derived from adipose-derived stem cells (ADSC-CM) and extracellular vesicles derived from adipose-derived stem cells (ADSC-EVs) on the healing of radiation-induced skin injury. The results showed that collagen synthesis was significantly increased in wounds treated with ADSC-CM or ADSC-EVs compared with the control group, which promoted the expression of collagen-related genes and suppressed the expression of inflammation-related genes. These findings indicated that treatment with ADSC-CM or ADSC-EVs suppressed inflammation and promoted extracellular matrix deposition; treatment with ADSC-EVs also promoted fibroblast proliferation. In conclusion, these results demonstrate the effectiveness of ADSC-CM and ADSC-EVs in the healing of radiation-induced skin injury.

Inhibition of cutaneous heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 channels alleviates UVB-induced skin lesions in mice.

Ultraviolet B (UVB) radiation causes skin injury by trigging excessive calcium influx and signaling cascades in the skin keratinocytes. The heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 (TRPV3) channels robustly expressed in the keratinocytes play an important role in skin barrier formation and wound healing. Here, we report that inhibition of cutaneous TRPV3 alleviates UVB radiation-induced skin lesions. In mouse models of ear swelling and dorsal skin injury induced by a single exposure of weak UVB radiation, TRPV3 genes and proteins were upregulated in quantitative real-time PCR and Western blot assays. In accompany with TRPV3 upregulations, the expressions of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were also increased. Knockout of the TRPV3 gene alleviates UVB-induced ear swelling and dorsal skin inflammation. Furthermore, topical applications of two selective TRPV3 inhibitors, osthole and verbascoside, resulted in a dose-dependent attenuation of skin inflammation and lesions. Taken together, our findings demonstrate the causative role of overactive TRPV3 channel function in the development of UVB-induced skin injury. Therefore, topical inhibition of TRPV3 may hold potential therapy or prevention of UVB radiation-induced skin injury.

Effects of Radiation-Induced Skin Injury on Hyaluronan Degradation and Its Underlying Mechanisms.

Radiation-induced skin injury (RISI) is a frequent and severe complication with a complex pathogenesis that often occurs during radiation therapy, nuclear incidents, and nuclear war, for which there is no effective treatment. Hyaluronan (HA) plays an overwhelming role in the skin, and it has been shown that UVB irradiation induces increased HA expression. Nevertheless, to the best of our knowledge, there has been no study regarding the biological correlation between RISI and HA degradation and its underlying mechanisms. Therefore, in our study, we investigated low-molecular-weight HA content using an enzyme-linked immunosorbent assay and changes in the expression of HA-related metabolic enzymes using real-time quantitative polymerase chain reaction and a Western blotting assay. The oxidative stress level of the RISI model was assessed using sodium dismutase, malondialdehyde, and reactive oxygen species assays. We demonstrated that low-molecular-weight HA content was significantly upregulated in skin tissues during the late phase of irradiation exposure in the RISI model and that HA-related metabolic enzymes, oxidative stress levels, the MEK5/ERK5 pathway, and inflammatory factors were consistent with changes in low-molecular-weight HA content. These findings prove that HA degradation is biologically relevant to RISI development and that the HA degradation mechanisms are related to HA-related metabolic enzymes, oxidative stress, and inflammatory factors. The MEK5/ERK5 pathway represents a potential mechanism of HA degradation. In conclusion, we aimed to investigate changes in HA content and preliminarily investigate the HA degradation mechanism in a RISI model under γ-ray irradiation, to consider HA as a new target for RISI and provide ideas for novel drug development.

Cold atmospheric plasma alleviates radiation-induced skin injury by suppressing inflammation and promoting repair.

Currently, there is no effective treatment for chronic skin radiation injury, which burdens patients significantly. Previous studies have shown that cold atmospheric plasma has an apparent therapeutic effect on acute and chronic skin injuries in clinical. However, whether CAP is effective for radiation-induced skin injury has not been reported. We created 35Gy X-ray radiation exposure within 3 * 3cm2 region of the left leg of rats and applied CAP to the wound bed. Wound healing, cell proliferation and apoptosis were examined in vivo or vitro. CAP alleviated radiation-induced skin injury by enhancing proliferation and migration and cellular antioxidant stress and promoting DNA damage repair through regulated nuclear translocation of NRF2. In addition, CAP inhibited the proinflammatory factors' expression of IL-1β, TNF-α and temporarily increased the pro repair factor's expression of IL-6 in irradiated tissues. At the same time, CAP also changed the polarity of macrophages to a repair-promoting phenotype. Our finding suggested that CAP ameliorated radiation-induced skin injury by activating NRF2 and ameliorating the inflammatory response. Our work provided a preliminary theoretical foundation for the clinical administration of CAP in high-dose irradiated skin injury.

Paintable graphene oxide-hybridized soy protein-based biogels for skin radioprotection

Radiation-induced skin injury (RISI) represents a prevalent issue following radiotherapy. The main factors influencing RISI wound recovery include ROS and NLRP3 inflammasome activation as well as wound infection, amongst others. Herein, a biomaterial for the healing of radio-induced injury was designed using multiple strategies. A gallic acid (GA)-assisted isolation process was first applied to prepare gallic acid-grafted soy protein (SPI-GA) from spherical soy protein. The SPI-GA was then modified with simultaneously-grafted phenol and thiol cohorts (SH) (SPI-GA-SH). Due to the antibacterial properties of graphene oxide (GO), SPI-SH-GA@PGO biogels was finally self-assembled into an adhesive biogel in a binary solvent system (dopamine-glycerol/water). Characterization for adhesive and paintable SPI-based biogels indicated that the material was successfully synthesized. Cytological studies further highlighted the antibacterial properties of SPI-SH-GA@PGO, its non-toxicity to HaCaT cultures as well as its ability to promote vascularization and cell migrative while inhibiting apoptotic. Genomics assessment also demonstrated that the material could effectively improve the abnormal expression of skin cultures induced by radiation. Finally, a murine model suggested that SPI-SH-GA@PGO could reduce ROS and NLRP3 expression while promoting wound recovery. This work pioneered SPI-based biogel deployment as material for RISI recovery.

Autophagy gene Atg7 regulates the development of radiation-induced skin injury and fibrosis of skin.

Radiation-induced skin injury, which may progress to fibrosis, is a severe side effect of radiotherapy in patients with cancer. However, currently, there is a lack of preventive or curative treatments for this injury. Meanwhile, the mechanisms underlying this injury remain poorly understood. Here, we elucidated whether autophagy is essential for the development of radiation-induced skin injury and the potential molecular pathways and mechanisms involved. We used the myofibroblast-specific Atg7 knockout (namely, conditional Atg7 knockout) mice irradiated with a single electron beam irradiation dose of 30Gy. Vaseline-based 0.2% rapamycin ointment was topically applied once daily from the day of irradiation for 30days. On day 30 post irradiation, skin tissues were harvested for further analysis. In vitro, human foreskin fibroblast cells were treated with rapamycin (100nM) for 24h and pretreated with 3-MA (5mM) for 12h. Macroscopic skin manifestations, histological changes, and fibrosis markers at the mRNA and protein expression levels were measured. Post irradiation, the myofibroblast-specific autophagy-deficient (Atg7Flox/Flox Cre+ ) mice had increased fibrosis marker (COL1A1, CTGF, TGF-β1, and α-SMA) levels in the irradiated area and had more severe macroscopic skin manifestations than the control group (Atg7Flox/Flox Cre- ) mice. Treatment with an autophagy agonist rapamycin attenuated macroscopic skin injury scores and skin fibrosis marker levels with decreased epidermal thickness and dermal collagen deposition in Atg7Flox/Flox Cre+ mice compared with the vehicle control. Moreover, in vitro experiment results were consistent with the in vivo results. Together with studies at the molecular level, we found that these changes involved the Akt/mTOR pathway. In addition, this phenomenon might also relate to Nrf2-autophagy signaling pathway under oxidative stress conditions. In conclusion, Atg7 and autophagy-related mechanisms confer radioprotection, and reactivation of the autophagy process can be a novel therapeutic strategy to reduce and prevent the occurrence of radiodermatitis, particularly skin fibrosis, in patients with cancer.

Autologous i-PRF promotes healing of radiation-induced skin injury.

Skin, as an exposed tissue, often suffers damage after exposure to radiotherapy and accidental events, which may lead to the formation of chronic refractory wounds. However, effective treatment options are usually limited for severe radiation-induced skin injury (RSI). Platelet-rich plasma (PRP) has been identified to promote wound healing, but whether a new generation of blood-derived biomaterial, injectable platelet-rich fibrin (i-PRF), is effective in repairing RSI remains unclear. In this study, blood was drawn from humans and Sprague-Dawley rats to prepare PRP and i-PRF, and the regenerative functions of PRP and i-PRF were investigated by exposing the dorsal skin of SD rats to local radiation (45 Gy) and exposing HDF-α cells and human umbilical vein endothelial cells (HUVECs) cells to X-rays (10 Gy). The healing effect of i-PRF on RSI was analysed by tube formation assay, cell migration and apoptosis assays, ROS assay, wound healing assay, histological characterisation and immunostaining. The results showed that exposure to high doses of radiation reduced cell viability, increased ROS levels and induced cell apoptosis, thereby causing dorsal trauma of rats. However, both PRP and i-PRF could resisted RSI, and they were capable of reducing inflammation and promoting angiogenesis and vascular regeneration. i-PRF has a higher concentration of platelets and platelet-derived growth factors, which has a more convenient preparation method and better repair effect and possesses a good application prospect for the repair of RSI.

Bio-Inspired Antioxidant Heparin-Mimetic Peptide Hydrogel for Radiation-Induced Skin Injury Repair.

Radiotherapy is one of the most important means of cancer treatment, however, radiation can also cause adverse reactions and even serious injuries to the skin. Radiation-induced excess reactive oxygen species (ROS) production and inflammatory infiltration make skin wounds difficult to heal compared to normal skin injuries. Herein, an antioxidant heparin-mimetic peptide hydrogel (K16, KYKYEYEYAGEGDSS-4Sa) is designed for radiation-induced skin injury (RISI) repair. First, the K16 peptide can self-assemble into a hydrogel with a 3D mesh-like porous nanofiber structure, which can provide certain physical support for skin repair like extracellular matrix (ECM). Then, K16 hydrogel not only scavenges ROS and prevents radiation damage to cellular DNA, but also promotes cell proliferation, migration, and angiogenesis. Meanwhile, 4-sulfobenzoic acid (4Sa) modified at the N-terminal end of the K16 peptide can adsorb inflammatory cytokines, thus acting to eliminate inflammation at the wound site. In vivo experiments showed that K16 hydrogel can inhibit early wound degradation, reduce inflammatory infiltration, and promote angiogenesis and collagen deposition, thus promoting wound healing. Therefore, the K16 hydrogel designed in this study has good potential for application in the field of radiation-induced skin injury repair.

The Therapeutic Application of Stem Cells and Their Derived Exosomes in the Treatment of Radiation-Induced Skin Injury.

Radiation-induced skin injury (RISI) is a serious concern for nuclear accidents and cancer radiotherapy, which seriously affects the quality of life of patients. This injury differs from traditional wounds due to impaired healing and the propensity to recurrence and is divided into acute and chronic phases on the basis of the injury time. Unfortunately, there are few effective therapies for preventing or mitigating this injury. Over the last few decades, various studies have focused on the effects of stem cell-based therapies to address the tissue repair and regeneration of irradiated skin. These stem cells modulate inflammation and instigate tissue repair by differentiating into specific kinds of cells or releasing paracrine factors. Stem cell-based therapies, including bone marrow-derived stem cells (BMSCs), adipose-derived stem cells (ADSCs) and stromal vascular fraction (SVF), have been reported to facilitate wound healing after radiation exposure. Moreover, stem cell-derived exosomes have recently been suggested as an effective and cell-free approach to support skin regeneration, circumventing the concerns respecting direct application of stem cells. Based on the literature on stem cell-based therapies for radiation-induced skin injury, we summarize the characteristics of different stem cells and describe their latest animal and clinical applications, as well as potential mechanisms. The promise of stem-cell based therapies against radiation-induced skin injury contribute to our response to nuclear events and smooth progress of cancer radiotherapy.

Integrative multi-omic analysis of radiation-induced skin injury reveals the alteration of fatty acid metabolism in early response of ionizing radiation

BackgroundRadiation-induced skin injury is a serious concern during radiotherapy and accidental exposure to radiation. ObjectiveThis study aims to investigate the molecular events in early response to ionizing radiation of skin tissues and underlying mechanism. MethodsMice and rats were irradiated with an electron beam. Skin tissues were used for liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, mRNA-Seq and single-cell RNA sequencing (scRNA-Seq). Human keratinocytes (HaCaT) and skin fibroblasts (WS1) were used for functional studies. ResultsThe integrated analysis of metabolomics and transcriptomics showed that 6 key fatty acid-associated metabolites, 9 key fatty acid-associated genes and multiple fatty acid-associated pathways were most obviously enriched and increased in the irradiated skins. Among them, acyl-CoA dehydrogenase very long chain (ACADVL) was investigated in greater detail due to its most obvious expression difference and significance in fatty acid metabolism. ScRNA-Seq of rat skin from irradiated individuals revealed that ACADVL was expressed in all subpopulations of skin tissues, with variations at different timepoints after radiation. Immunohistochemistry confirmed an increased ACADVL expression in the epidermis from human sample and various animal models, including monkeys, rats and mice. The knockdown of ACADVL increased the radiosensitivity of human keratinocytes and human skin fibroblasts. Silencing of ACADVL facilitated the expression of apoptosis and pyroptosis-related proteins following ionizing radiation. ConclusionThis study illustrated that cutaneous fatty acid metabolism was altered in the early response of ionizing radiation, and fatty acid metabolism-associated ACADVL is involved in radiation-induced cell death.

HPRT1 Most Suitable Reference Gene for Accurate Normalization of mRNA Expression in Canine Dermal Tissues with Radiation Therapy.

Reference genes are crucial in molecular biological studies as an internal control for gene re-search as they exhibit consistent expression patterns across many tissue types. In canines, radiation therapy is the most important therapeutic tool to cure various diseases like cancer. However, when using radiation for therapeutic strategy, radiation exposure to healthy tissues leads to some possible side effects such as acute radiation-induced skin injury and alters gene expression. Therefore, the analysis of a change in reference gene expression during the skin recovery process after radiation therapy is essential in healthy canine tissue. In the present study, we analyzed eight reference genes (ACTB, GAPDH, YWHAZ, GUSB, HPRT1, RPL4, RPS5, and TBP) in canine dermal tissues at 0, 1, 2, 3, 4, 5, 7, and 9 weeks of radiation exposure that affected the skin condition of canines. The stability of reference genes is determined by evaluating radiation therapy's effect on healthy canine dermal tissue. Epidermal marker, Keratin 10 expression varies each week after irradiation, and HPRT1 is found to be the most suitable for normalization of mRNA expression in radiation-exposed canine dermal tissues. Changes in the gene expression level were evaluated by using a reliable tool such as quantitative real-time polymerase chain reaction (qRT-PCR). In order to achieve a valid qRT-PCR result, the most stable reference genes used for normalization after the radiation exposure process are important. Therefore, the current study was designed to evaluate the most stable reference gene for the post-irradiation canine tissues. After radiation exposure, the alternation of reference gene expression was estimated by three algorithms (geNorm, Normfinder, and Bestkeeper). The RG validation programs (GeNorm and NormFinder) suggested that HPRT1, RPL4, and TBP were suitable for normalization in qRT-PCR. Furthermore, three algorithms suggested that HPRT1 was the most stable reference gene for normalization with qRT-PCR results, regardless of before and after radiation exposure. Whereas GAPDH was found to be the most unstable reference gene. In addition, the use of stable or unstable reference genes for the normalization of Keratin 10 expression showed statistical differences. Therefore, we observed that, to obtain accurate and suitable PCR results of the canine tissues with and without radiation exposure, the HPRT1 reference gene is recommended for normalization with its high stability. Additionally, the use of RGs such as HPRT1, RPL4, and TBP for normalization in qRT-PCR experiments is recommended for post-radiation canine tissues to generate more accurate and reliable data. These results will provide fundamental information regarding internal controls for gene expression studies and can be used for the analysis of gene patterns in regenerative medicine.

Bioinspired and Inflammation-Modulatory Glycopeptide Hydrogels for Radiation-Induced Chronic Skin Injury Repair.

Clinical wound management of radiation-induced skin injury (RSI) remains a great challenge due to acute injuries induced by excessive reactive oxygen species (ROS), and the concomitant repetitive inflammatory microenvironment caused by an imbalance in macrophage homeostasis. Herein, a cutaneous extracellular matrix (ECM)-inspired glycopeptide hydrogel (GK@TAgel ) is rationally designed for accelerating wound healing through modulating the chronic inflammation in RSI. The glycopeptide hydrogel not only replicates ECM-like glycoprotein components and nanofibrous architecture, but also displays effective ROS scavenging and radioprotective capability that can reduce the acute injuries after exposure to irradiation. Importantly, the mannose receptor (MR) in GK@TAgel exhibits high affinity and bioactivity to drive the M2 macrophage polarization, thereby overcoming the persistent inflammatory microenvironment in chronic RSI. The repair of RSI in mice demonstrates that GK@TAgel significantly reduces the hyperplasia of epithelial, promotes appendage regeneration and angiogenesis, and decreased the proinflammatory cytokine expression, which is superior to the treatment of commercial radioprotective drug amifostine. Collectively, the ECM-mimetic hydrogel dressing can protect the tissue from irradiation and heal the chronic wound in RSI, holding great potential in clinical wound management and tissue regeneration.