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Scientific Reports Mar 2018Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the...
Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation-induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury.
Topics: Animals; HSP27 Heat-Shock Proteins; Inflammation; Lung; Male; Mice; Mice, Transgenic; Oxidative Stress; Pneumonia; Radiation Injuries, Experimental; Radiation-Protective Agents; Reactive Oxygen Species
PubMed: 29520071
DOI: 10.1038/s41598-018-22635-9 -
Acta Pharmaceutica Sinica. B Mar 2023Radiation protection drugs are often accompanied by toxicity, even amifostine, which has been the dominant radio-protecting drug for nearly 30 years. Furthermore, there...
Radiation protection drugs are often accompanied by toxicity, even amifostine, which has been the dominant radio-protecting drug for nearly 30 years. Furthermore, there is no therapeutic drug for radiation-induced intestinal injury (RIII). This paper intends to find a safe and effective radio-protecting ingredient from natural sources. The radio-protecting effect of Ecliptae Herba (EHE) was discovered preliminarily by antioxidant experiments and the mouse survival rate after Cs irradiation. EHE components and blood substances were identified through UPLC‒Q-TOF. The correlation network of "natural components in EHE-constituents migrating to blood-targets-pathways" was established to predict the active components and pathways. The binding force between potential active components and targets was studied by molecular docking, and the mechanism was further analyzed by Western blotting, cellular thermal shift assay (CETSA), and ChIP. Additionally, the expression levels of Lgr5, Axin2, Ki67, lysozyme, caspase-3, caspase-8,8-OHdG, and p53 in the small intestine of mice were detected. It was found for the first time that EHE is active in radiation protection and that luteolin is the material basis of this protection. Luteolin is a promising candidate for RⅢ. Luteolin can inhibit the p53 signaling pathway and regulate the BAX/BCL2 ratio in the process of apoptosis. Luteolin could also regulate the expression of multitarget proteins related to the same cell cycle.
PubMed: 36970216
DOI: 10.1016/j.apsb.2022.09.003 -
International Journal of Molecular... Jul 2022DNA 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... (Review)
Review
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.
Topics: Alzheimer Disease; Animals; DNA; DNA Breaks, Double-Stranded; DNA Repair; Hippocampus; Mice; Neurons
PubMed: 35955487
DOI: 10.3390/ijms23158352 -
Frontiers in Physiology 2021The deep space environment contains many risks to astronauts during space missions, such as galactic cosmic rays (GCRs) comprised of naturally occurring heavy ions....
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, Si, He, O, and Fe) 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.
PubMed: 34867479
DOI: 10.3389/fphys.2021.770502 -
Journal of Veterinary Research Dec 2017Radioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves' disease or thyroid nodules. However, information available on the impact...
INTRODUCTION
Radioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves' disease or thyroid nodules. However, information available on the impact of RAI therapy on male gonadal function is scarce. This study aimed to determine any possible damage to testicular tissue and sperm quality caused by RAI therapy, and the radioprotective effect of amifostine against such damage.
MATERIAL AND METHODS
In total, 36 rats were randomly allocated to three groups, including a control group, RAI group (111 MBq Iodine-131), and RAI + amifostine group (111 MBq Iodine-131 and a single dose of 200 mg/kg amifostine). Blood and epididymal sperm samples were taken for hormone analyses and the evaluation of spermatological parameters. The TUNEL assay and haematoxylin-eosin were used to stain testicular tissue samples to detect histological changes and apoptosis.
RESULTS
The groups differed insignificantly for the testicular mass index and spermatozoa concentration. However, spermatozoa motility and percentage of viable spermatozoa were higher in the RAI + amifostine group, compared to the RAI group. Sperm DNA fragmentation and the index of apoptotic germ cells significantly decreased in the amifostine group, in comparison to the radioiodine group. While the testosterone levels showed no significant change, the follicle stimulating hormone (FSH) levels significantly decreased in the RAI + amifostine group.
CONCLUSION
All histopathological parameters and some spermatological parameters showed that RAI therapy caused statistically significant damage of testicular tissue and this damage was reduced by amifostine.
PubMed: 29978117
DOI: 10.1515/jvetres-2017-0064 -
Research Square Sep 2023During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the...
During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.
PubMed: 37790388
DOI: 10.21203/rs.3.rs-3246405/v1 -
Journal of Dental Research Oct 2018Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and...
Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.
Topics: Acinar Cells; Amifostine; Animals; Female; Fluorescent Antibody Technique; Injections; Mercaptoethylamines; Mice; Mice, Inbred C57BL; Radiation Injuries, Experimental; Radiation-Protective Agents; Salivary Glands; Submandibular Gland
PubMed: 29634396
DOI: 10.1177/0022034518767408 -
Bioactive Materials Sep 2024Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even...
Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.
PubMed: 38808157
DOI: 10.1016/j.bioactmat.2024.05.017 -
Cancers Feb 2020Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have... (Review)
Review
Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose-response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.
PubMed: 32059447
DOI: 10.3390/cancers12020427 -
Brazilian Journal of Medical and... 2020Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its...
Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.
Topics: Amifostine; Animals; Antineoplastic Agents; Hyperalgesia; Male; Mice; Oxaliplatin; Peripheral Nervous System Diseases
PubMed: 32965323
DOI: 10.1590/1414-431X202010263