In response to diffused ionizing radiation damage throughout the body caused by nuclear leaks and inaccurate radiotherapy, radioprotectants with considerable free radical scavenging capacities, along with negligible adverse effects, are highly regarded. Herein, unlike being performed as toxic chemotherapeutic drug candidates, molybdenum-based polyoxometalate nanoclusters (Mo-POM NCs) were developed as a non-toxic potent radioprotectant with impressive free radical scavenging capacities for ionizing radiation protection. In comparison to the clinically used radioprotectant drug amifostine (AM), the as-prepared Mo-POM NCs exhibited effective shielding capacity by virtue of their antioxidant properties resulting from a valence shift of molybdenum ions, alleviating not only ionizing radiation-induced DNA damage but also disruption of the radiation-sensitive hematopoietic system. More encouragingly, without trouble with long-term retention in the body, ultra-small sized Mo-POM NCs prepared by the mimetic Folin-Ciocalteu assay can be removed from the body through the renal-urinary pathway and the hepato-enteral excretory system after completing the mission of radiation protection. This work broadened the biological applications of metal-based POM chemotherapeutic drugs to act as a neozoic radioprotectant.

This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.

The aim of this study was to determine accumulation of heavy metals and metalloids which are widely distributed in the environment and in food chain using wild edible mushrooms belonging to the Boletaceae family mushrooms. In addition, methanol extracts of mushrooms were tested for in vitro protective effect by the cytochalasin-B blocked micronucleus (CBMN) assay using chromosome aberrations in human peripheral lymphocytes as a model. The genotoxic activity of methanol extracts prepared at 4 different concentrations (1, 2, 3 or 6 µg/ml) was examined using amifostine and mitomycin C as positive controls. Extracts of species B. regius and B. edulis exhibited the greatest reduction in the frequency of micronuclei (MN). Extract of B. regius at concentrations of 2 µg/ml showed the highest decrease in number of MN. In comparison, extract of mushroom B. edulis at a concentration of 3 µg/ml displayed less reduction. However, as heavy metals and metalloids are found in mushrooms, another aim was to examine whether these agents affected genotoxicity. Principal component analysis (PCA) identified clustering differences between control and heavy metals and metalloids groups and might explain the influence of heavy element content and genotoxic activity in mushrooms.

Chemotherapy is a main treatment for cancer, and it benefits patients by controlling cancer relapse and metastasis, thereby leading to an increase in the overall survival rate. However, this treatment is associated with mild to severe side effects, one of which is cardiotoxicity. The severity of cardiotoxicity, a leading cause of cardiovascular diseases, depends on the type of cancer therapy employed and the time required for its management. A chemotherapeutic agent is used either alone or in combination with other drugs for cancer treatment. The exact mechanism of chemotherapeutic agent-induced cardiotoxicity remains unclear, although it is likely to be multifactorial and to include oxidative stress, apoptosis, and inflammation. There are many approaches to avoid the untoward effects of chemotherapeutic agents. However, the available options for cardiac protection are minimal, and they include renin-angiotensin system blockers, beta-blockers, herbal drugs, or iron chelators such as dexrazoxane. The present review provides information on the molecular mechanism of chemotherapy-induced myocardial infarction and cardiotoxicity along with scientifically studied synthetic molecules, herbal extracts, and natural products to manage chemotherapy-induced cardiotoxicity.

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.

Alkaline phosphatase (ALP), an important hydrolase involved in dephosphorylation, is a common clinical indicator of many diseases. In the present study, we constructed a novel electrochemical sensor using amifostine as the substrate of ALP and activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) as a signal amplification strategy for sensitive determination of ALP activity. In particular, in the presence of ALP, the phosphate group of amifostine was hydrolyzed to form a sulfhydryl group, which could attach to a gold electrode via a sulfur-gold bond. Then, the initiator α-bromophenylacetic acid (BPAA) was linked to the hydrolysis product of amifostine through an amide bond, resulting in the production of electroactive polymer chains on the gold electrode by the monomer ferrocenylmethyl methacrylate (FMMA) via ARGET ATRP. Under optimal parameters, the electrochemical sensor demonstrated a limit of detection (LOD) of 1.71 mU mL-1 with a linear range of 5-100 mU mL-1. In addition to satisfactory selectivity, the potential application of this approach for ALP activity detection in human serum samples was demonstrated. Due to its efficiency, simplicity of operation, and cost-effectiveness, the proposed electrochemical sensor has great promise as a universal method for ALP assays and inhibitor screening.

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.

Bone marrow (BM) transplantation has been used to treat malignant and nonmalignant BM-related disorders. Although an effective strategy, the procedure is associated with numerous complications, including graft rejection and nonspecific stem cell distribution. Avoidance of immune graft rejection has downsized the quantity of available stem cells, whereas nonspecific distribution necessitates the infusion of increased stem cell doses. A dual-purpose approach is needed to reduce the stem cell dose for transplantation. This used cell encapsulation and BM targeting to increase the quantity of transplanted stem cells reaching the BM. Cells were encapsulated with different biomaterials-chitosan (CS), polyallylamine hydrochloride (PAH), polystyrene sulfonate (PSS), and liposomes-and assessed for interaction with immune system components. The biomaterials were conjugated with vascular cell adhesion molecule 1 (VCAM1), a peptide that binds to BM-specific cell surface molecule, and evaluated for a successful transplantation. Encapsulated cells showed reduced interaction with antibody and cytokine without adverse effects on viability. Constitutive expression of VCAM1 was found to be specific on human bone marrow endothelial cells and was used for targeting by conjugating VCAM1-binding peptide to encapsulated cells. Peptide-conjugated-encapsulated stem cell formulations transplanted in irradiated mice with or without treatment with radioprotectant amifostine showed an increased percentage of cells reaching bone marrow. Post-transplantation survival along with blood count of neutrophils, platelets, and leukocytes was also enhanced for VCAM1-binding peptide-conjugated formulations with 100% survival demonstrated by peptide-conjugated CS/PSS/CS encapsulation formulation in irradiated mice for 4 weeks. Encapsulated cells retained their viability with increased shielding to the immune system, ensuring that graft rejection can be avoided. Transplanted encapsulated stem cells were distributed in a higher percentage to BM when conjugated to VCAM1-binding peptide, which could enable the use of lower stem cell doses. The peptide-conjugated CS/PSS/CS encapsulation system conferred 100% survival in irradiated mice, with increased regeneration demonstrating the ability to treat radiation-exposed victims.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Radiation esophagitis is inflammation of the esophagus due to radiation. Radiation esophagitis is typically an adverse effect that develops in individuals receiving radiation cancer therapy, most commonly for breast, lung, and other lymphomas. Symptoms present two to three weeks after the initial therapy and include throat pain, dysphagia, and the sensation that food is stuck. Amifostine is a medication used as a radiation protector in selected populations at risk of radiation esophagitis. Typically administered via injection 30 minutes before therapy, patient studies have been promising, showing a reduced risk of developing radiation esophagitis. The goal when treating this condition is adequate nutrition intake, and it is advisable for patients to refrain from eating hot or spicy foods that can further irritate the esophageal lining. In severe cases, perforations, ulcerations, dysmotility, and tracheoesophageal fistulas can be seen. Although there is no cure for radiation esophagitis, symptoms regress 2 to 4 weeks after the completion of radiation treatment.[1][2][3]

It is well-known that mushrooms of the genus Lactarius constitute a natural food resource providing health benefits as a nutritient. This genus contains 4 mushrooms identified as L. deliciosus, L. volemus, L. sanguifluus, L. semisanguifluus and L. piperatus which were collected in Serbia. The aim of this study aimed was to identify and characterize the content of phenolic compounds and examine the antioxidant potential of 5 wild edible mushrooms. L. sanguifluus contained the highest content of total phenol compounds (75.25 mg gallic acid equivalents (GAE) per g dry extract weight (GAE/g DE) and exhibited the greatest antioxidant activity through the ability to remove radicals as evidenced by ABTS assay (8.99 mg of trolox equivalents (TE) per g dry extract weight (mg TE/g DE); total reducing power (TRP) assay mg ascorbic acid equivalents per mg of dry extract weight (0.42 mg AAE/g DE) and CUPRAC (14.23 mg TE /g DE). L. deliciosus methanolic extract produced greatest scavenging of the DPPH radical (46%). The methanol mushroom extracts were screened for in vitro antimicrobial activity against a panel of pathogenic bacterial strains using the microdilution method. Of all the extracts tested, L. sanguifluus extract showed the best antibacterial properties. The cytokinesis block micronucleus assay results for the examined mushrooms demonstrated that extracts at a concentration of 3 μg/ml decreased the number of micronuclei (MN) in the range of 19-49% which is significant bearing in mind that radioprotectant amifostine reduced the frequency of MN by only 16.3%. Data thus demonstrate that the 5 wild edible mushrooms of genus Lactarius contain constituents that are beneficial not only as nutrients but also have the potential as antioxidants, antibacterial and antigenotoxic properties.

Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Amifostine is a promising selective radioprotector for normal tissues. However, its oral application in intestinal radioprotection remains challenging. Herein, we use microalga Spirulina platensis as a microcarrier of Amifostine to construct an oral delivery system. The system shows comprehensive drug accumulation and effective radioprotection in the whole small intestine that is significantly superior to free drug and its enteric capsule, preventing the radiation-induced intestine injury and prolonging the survival without influencing the tumor regression. It also shows benefits on the gut microbiota homeostasis and long-term safety. Based on a readily available natural microcarrier, this work presents a convenient oral delivery system to achieve effective radioprotection for the whole small intestine, providing a competitive strategy with great clinical translation potential.

With the progress of nuclear technology including radiotherapy and radiodiagnosis, radiation has been widely used in many fields as a powerful diagnostic and therapeutic tool in the medical area. Unfortunately, acute radiation disease will occur if the human body is accidentally exposed to a large dosage of ionizing radiation. However, clinical radioprotective agents are being challenged by the short half-life and several side effects. In this work, a reactive oxygen species-responsive nanodrug is developed for efficient radioprotection. The nanodrug was prepared by modifying Crocin-I with 4-pentylphenylboronic acid (PBA) and exhibited effective responsiveness and scavenging activity of reactive oxygen species. PBA-Crocin nanodrug displayed good biocompatibility and radioprotection effect compared to Crocin-I in vitro. The survival rate of cells treated with PBA-Crocin (10 μg mL-1) is comparable to that treated with amifostine (12.5 μg mL-1, the only radioprotector approved by the United States Food and Drug Administration clinically) after 6 Gy irradiation. Importantly, PBA-Crocin resulted in markedly prevention of radiation-induced damage in peripheral blood cells and a 1.6-fold longer retention time of Crocin-I in plasma in comparison with Crocin-I. The finding suggests a new design for natural medicine in effective radioprotection.

Radiotherapy can be employed as a therapeutic modality alone in the early stages of cancer and is used together with other treatments such as surgery and chemotherapy in more advanced stages. However, exposure to ionizing radiation in association with radiotherapy affects several organs in the head and neck and can give rise to early and late side effects. Exposure to ionizing radiation used in radiotherapy is known to cause cell damage by leading to oxygen stress through the production of free oxygen radicals (such as superoxide radicals, hydroxyl radical, hydrogen peroxide, and singlet oxygen), depending on the total radiation dosage, the fractionation rate, radiosensitivity, and linear energy transfer. The purpose of the present study was to determine the potential protective role of a powerful and highly selective α2-adrenoreceptor agonist with a broad pharmacological spectrum against salivary gland damage induced by ionizing radiation exposure. Forty Sprague-Dawley rats were divided into five groups-control, ionizing radiation, ionizing radiation + dexmedetomidine (100 µg/kg), ionizing radiation + dexmedetomidine (200 µg/kg), and ionizing radiation + amifostine (200 mg/kg). Following exposure to ionizing radiation, we observed necrosis, fibrosis, and vascular congestions in parotid gland epithelial cells. We also observed increases in malondialdehyde (MDA) and cleaved Caspase-3 levels and a decrease in glutathione (GSH). In groups receiving dexmedetomidine, we observed necrotic epithelial cells, fibrosis and vascular congestion in parotid gland tissue, a decrease in MDA levels, and an increase in GSH. Dexmedetomidine may be a promising antioxidant agent for the prevention of oxidative damage following radiation exposure.

DNA double strand breaks (DSBs) have been highly studied in the context of cancers, as DSBs can lead to apoptosis or tumorigenesis. Several pharmaceuticals are widely used to target DSBs during cancer therapy. Amifostine (WR-2721) and etoposide are two commonly used drugs: amifostine reduces DSBs, whereas etoposide increases DSBs. Recently, a novel role for DSBs in immediate early gene expression, learning, and memory has been suggested. Neither amifostine nor etoposide have been assessed for their effects on learning and memory without confounding factors. Moreover, sex-dependent effects of these drugs have not been reported. We administered amifostine or etoposide to 3-4-month-old male and female C57Bl/6J mice before or after training in fear conditioning and assessed learning, memory, and immediate early genes. We observed sex-dependent baseline and drug-induced differences, with females expressing higher cFos and FosB levels than males. These were affected by both amifostine and etoposide. Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory. These data support the hypothesis that DSBs contribute to learning and memory, and that these could play a part in cognitive side effects during common treatment regimens. The sex-dependent effects also highlight an important factor when considering treatment plans.

Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including Wnt5a. Non-canonical Wnt5a signaling has been shown by other groups to improve intestinal crypt regeneration in response to injury. Here we show that HIF2 drives Wnt5a expression in multiple duodenal organoid models. Luciferase reporter assays performed in human cells showed that HIF2 directly activates the WNT5A promoter via a hypoxia response element. We then evaluated crypt regeneration using spheroid formation assays. Duodenal organoids that were pre-treated with recombinant Wnt5a had a higher cryptogenic capacity after irradiation, compared to vehicle-treated organoids. Conversely, we found that Wnt5a knockout decreased the cryptogenic potential of intestinal stem cells following irradiation. Treatment with recombinant Wnt5a prior to irradiation rescued the cryptogenic capacity of Wnt5a knockout organoids, indicating that Wnt5a is necessary and sufficient for duodenal radioprotection. Taken together, our results suggest that HIF2 radioprotects the GI tract by inducing Wnt5a expression.

The deep space environment contains many risks to astronauts during space missions, such as galactic cosmic rays (GCRs) comprised of naturally occurring heavy ions. Heavy ion radiation is increasingly being used in cancer therapy, including novel regimens involving carbon therapy. Previous investigations involving simulated space radiation have indicated a host of detrimental cognitive and behavioral effects. Therefore, there is an increasing need to counteract these deleterious effects of heavy ion radiation. Here, we assessed the ability of amifostine to mitigate cognitive injury induced by simulated GCRs in C57Bl/6J male and female mice. Six-month-old mice received an intraperitoneal injection of saline, 107 mg/kg, or 214 mg/kg of amifostine 1 h prior to exposure to a simplified five-ion radiation (protons, 28Si, 4He, 16O, and 56Fe) at 500 mGy or sham radiation. Mice were behaviorally tested 2-3 months later. Male mice that received saline and radiation exposure failed to show novel object recognition, which was reversed by both doses of amifostine. Conversely, female mice that received saline and radiation exposure displayed intact object recognition, but those that received amifostine prior to radiation did not. Amifostine and radiation also had distinct effects on males and females in the open field, with amifostine affecting distance moved over time in both sexes, and radiation affecting time spent in the center in females only. Whole-brain analysis of cFos immunoreactivity in male mice indicated that amifostine and radiation altered regional connectivity in areas involved in novel object recognition. These data support that amifostine has potential as a countermeasure against cognitive injury following proton and heavy ion irradiation in males.

Arbutin is a simple phenolic glucoside biosynthesised in many plant families. Some of the everyday foods that contain arbutin are species of the genus Origanum, peaches, cereal products, coffee and tea and Arctostaphyllos uva ursi L. leaves. Arbutin possesses various beneficial effects in the organism, and was confirmed effective in the treatment of urinary tract infections as well as in preventing skin hyperpigmentation. It shows antioxidant and anti-inflammatory properties, and antitumor activity. The aim of this study was to explore potential radioprotective properties of arbutin in concentrations of 11.4 μg/mL, 57 μg/mL, 200 μg/mL and 400 μg/mL administered as a pre-treatment for one hour before exposing human leukocytes to ionising radiation at a therapeutic dose of 2 Gy. The alkaline comet assay was used to establish the levels of primary DNA damage, and cytokinesis-block micronucleus (CBMN) cytome assay to determine the level of cytogenetic damage. None of the tested concentrations of single arbutin showed genotoxic and cytotoxic effects. Even at the lowest tested concentration, 11.4 μg/mL, arbutin demonstrated remarkable potential for radioprotection in vitro, observed both at the level of primary DNA damage, and using CBMN cytome assay. The best dose reduction compared with amifostine was observed after pre-treatment with the highest concentration of arbutin, corresponding to 400 μg/mL. Promising results obtained on the leukocyte model speak in favour of extending similar experiments on other cell and animal models.