Amifostine ameliorates bleomycin-induced murine pulmonary fibrosis via NAD+/SIRT1/AMPK pathway-mediated effects on mitochondrial function and cellular metabolism.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy. OBJECTIVE: We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis. METHODS: C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-ß1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-ß1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK). RESULTS: Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-ß1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-ß1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment. CONCLUSION: Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.

Imaging the radioprotective effect of amifostine in the developing brain using an apoptosis-reporting transgenic zebrafish.

PURPOSE: Normal tissue radioprotectants alleviate radiation-induced damages and preserve critical organ functions. Investigating their efficacy in vivo remains challenging, especially in enclosed organs like the brain. An animal model that enables direct visualization of radiation-induced apoptosis while possessing the structural complexity of a vertebrate brain facilitates these studies in a precise and effective manner. MATERIALS AND METHODS: We employed a secA5 transgenic zebrafish expressing secreted Annexin V fused with a yellow fluorescent protein to visualize radiation-induced apoptosis in vivo. We developed a semi-automated imaging method for standardized acquisition of apoptosis signals in batches of zebrafish larvae. Using these approaches, we studied the protective effect of amifostine (WR-2721) in the irradiated zebrafish larval brain. RESULTS: Upon 2 Gy total-body 137Cs irradiation, increased apoptosis could be visualized at high resolution in the secA5 brain at 2, 24, and 48 hour post irradiation (hpi). Amifostine treatment (4 mM) during irradiation reduced apoptosis significantly at 24 hpi and preserved Wnt active cells in the larval brain. When the 2 Gy irradiation was delivered in combination with cisplatin treatment (0.1 mM), the radioprotective effect of amifostine was also observed. CONCLUSIONS: Our study reveals the radioprotective effect of amifostine in the developing zebrafish larval brain, and highlights the utility of secA5 transgenic zebrafish as a novel system for investigating normal tissue radioprotectants in vivo.

A 3D In Vitro Cortical Tissue Model Based on Dense Collagen to Study the Effects of Gamma Radiation on Neuronal Function.

Studies on gamma radiation-induced injury have long been focused on hematopoietic, gastrointestinal, and cardiovascular systems, yet little is known about the effects of gamma radiation on the function of human cortical tissue. The challenge in studying radiation-induced cortical injury is, in part, due to a lack of human tissue models and physiologically relevant readouts. Here, a physiologically relevant 3D collagen-based cortical tissue model (CTM) is developed for studying the functional response of human iPSC-derived neurons and astrocytes to a sub-lethal radiation exposure (5 Gy). Cytotoxicity, DNA damage, morphology, and extracellular electrophysiology are quantified. It is reported that 5 Gy exposure significantly increases cytotoxicity, DNA damage, and astrocyte reactivity while significantly decreasing neurite length and neuronal network activity. Additionally, it is found that clinically deployed radioprotectant amifostine ameliorates the DNA damage, cytotoxicity, and astrocyte reactivity. The CTM provides a critical experimental platform to understand cell-level mechanisms by which gamma radiation (GR) affects human cortical tissue and to screen prospective radioprotectant compounds.

Advances of Amifostine in Radiation Protection: Administration and Delivery.

Amifostine (AMF, also known as WR-2721) is the only approved broad-spectrum small-molecule radiation protection agent that can combat hematopoietic damage caused by ionizing radiation and is used as an antitumor adjuvant and cell protector in cancer chemotherapy and radiotherapy. Amifostine is usually injected intravenously before chemotherapy or radiotherapy and has been used in the treatment of head and neck cancer. However, the inconvenient intravenous administration and its toxic side effects such as hypotension have severely limited its further application in clinic. In order to reduce the toxic and side effects, scientists are trying to develop a variety of drug administration methods and are devoted to developing a wide application of amifostine in radiation protection. This paper reviews the research progress of amifostine for radiation protection in recent years, discusses its mechanism of action, clinical application, and other aspects, with focus on summarizing the most widely studied amifostine injection administration and drug delivery systems, and explored the correlation between various administrations and drug efficacies.

Modulatory effect of amifostine (WR-1065) against genotoxicity and oxidative stress induced by methotrexate in human umbilical vein endothelial cells (HUVECs).

Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference in vitro model for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining via flow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 µg/mL) and methotrexate (2.5 µM) in pretreatment culture condition. Methotrexate at 2.5 µM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.

Amifostine attenuates bleomycin-induced pulmonary fibrosis in mice through inhibition of the PI3K/Akt/mTOR signaling pathway.

Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancers in order to reduce the toxicity of chemotherapy drugs, and recent studies have reported that the drug can also reduce lung tissue damage in patients with pulmonary fibrosis, but its mechanism of action is not yet fully understood. In this study, we explored the potential therapeutic effects and molecular mechanisms of AMI on bleomycin (BLM)-induced pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established using BLM. We then assessed histopathological changes, inflammatory factors, oxidative indicators, apoptosis, epithelial-mesenchymal transition, extracellular matrix changes, and levels of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway-related proteins in the BLM-treated mice to determine the effect of AMI treatment on these factors. BLM-treated mice had substantial lung inflammation and abnormal extracellular matrix deposition. Overall, treatment with AMI significantly improved BLM-induced lung injury and pulmonary fibrosis. More specifically, AMI alleviated BLM-induced oxidative stress, inflammation, alveolar cell apoptosis, epithelial-mesenchymal transition, and extracellular matrix deposition by regulating the PI3K/Akt/mTOR signaling pathway. This finding that AMI can alleviate pulmonary fibrosis in a mouse model by inhibiting activation of the PI3K/Akt/mTOR signaling pathway lays a foundation for potential future clinical application of this agent in patients with pulmonary fibrosis.

Radioprotective role of amifostine on osteointegration of titanium implants in the tibia of rats.

BACKGROUND: Titanium is the most widely used metal for bone integration, especially for cancer patients receiving ionizing radiation. This study aimed to investigate the amifostine administration that would reduce the effects of radiation on bone healing and osseointegration in rat models. OBJECTIVES: It is aimed that the application of amifostine in rats receiving radiotherapy treatment will reduce the negative effects of ionizing radiation on the bone. METHODS: Thirty-five adult male Wistar rats were randomly divided into one healthy and four experimental groups. In three consecutive days, two experimental groups of rats (AMF-RT-IMP and RT-IMP) were exposed to radiation (15 Gy/3 fractions of 5 Gy each). Then the titanium implants were inserted into the left tibia. Before the radiotherapy process, a 200 mg/kg dose of amifostine (AMF) was administered to the rats in the AMF-IMP and AMF-RT-IMP groups. Twenty-eight days after the screw implant, all rats were sacrificed, and their blood samples and tibia bones were collected for analysis. RESULTS: The results indicated an accelerated bone formation and a more rapid healing process in the screw implants in the AMF-IMP, AMF-RT-IMP, and AMF-RT groups than in the RT-IMP group. Also, bone-implant contact area measurement and inflammation decreased with amifostine treatment in the implants subjected to irradiation (p < 0.05). CONCLUSIONS: The results obtained in the present study suggested that amifostine prevents the losses of bone minerals, bone integrity, and implant position from ionizing-radiation when given before exposure.

Xerostomia: From Pharmacological Treatments to Traditional Medicine-An Overview on the Possible Clinical Management and Prevention Using Systemic Approaches.

Despite high incidence rates and severe complications, the management of xerostomia lacks clinical guidelines. The aim of this overview was to summarize the clinical experience derived from the last 10 years of treatments and prevention using systemic compounds. Results showed that the cytoprotective drug amifostine, and its antioxidant agents, are the most discussed as preventive agents of xerostomia in head and neck cancer (HNC) patients. In the presence of the disease, the pharmacological treatments have been mainly directed to stimulate secretion of the damaged salivary glands, or to counteract a decreased capacity of the antioxidant system, in view of an increasing of reactive oxygen species (ROS). However, the data demonstrated low ability of the drugs, together with a great number of side effects, which strongly limit their use. Concerning traditional medicine (TM), valid clinical trials are so limited that neither the efficacy nor the absence of interferences to concomitant chemical therapies can be validated. Consequently, the management of xerostomia and its devastating complications remain a very significant void in daily clinical practice.

Oral konjac glucomannan for prevention of ionizing radiation-induced injury by regulating gut microbiota and increasing short chain fatty acids.

Ionizing radiation-induced injury commonly happens in radiotherapy, leading to damages of the hematopoietic and gastrointestinal systems. Radioprotective medications are mainly applied in hospitals, although only injections are available and their gut protection is limited. Here, oral konjac glucomannan (KGM), a natural macromolecule and soluble dietary fiber, was used against ionizing radiation-induced injury. The mice were fed with KGM (0.4 g/kg) for 3 days or injected with a clinical medication amifostine before 6.5 Gy γ-ray whole body irradiation (WBI) or 13 Gy whole abdominal irradiation (WAI). In the WBI experiments, KGM improved blood cell recovery and bone marrow cell proliferation in the femur and spleen, though its effect was weaker than or similar to that of amifostine. In the WBI experiments, the gut protection of KGM was similar to or a little better than that of amifostine, involving regenerated crypts numbers, villus length, and gut permeability. Moreover, KGM remarkably enhanced the survival rates of WBI and WAI mice, consistent with amifostine. KGM, as a prebiotic, enhanced gut microbiota abundance, probiotic numbers, and short chain fatty acid production, maintaining gut homeostasis. Moreover, KGM inhibited the apoptosis of irradiated human intestinal epithelial cells. KGM is a promising natural macromolecule against ionizing radiation-induced injury.

Ginkgo biloba extract attenuates cisplatin-induced renal interstitial fibrosis by inhibiting the activation of renal fibroblasts through down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

BACKGROUND: Activation of renal fibroblasts into myofibroblasts plays an important role in promoting renal interstitial fibrosis (RIF). Ginkgo biloba extract (EGb) can alleviate RIF induced by cisplatin (CDDP). PURPOSE: To elucidate the effect of EGb treatment on cisplatin-induced RIF and reveal its potential mechanism. METHODS: The two main active components in EGb were determined by high-performance liquid chromatography (HPLC) analysis. Rats were induced by CDDP and then treated with EGb, 2ME2 (HIF-1α inhibitor) or amifostine. After HK-2 cells and HIF-1α siRNA HK-2 cells were treated with CDDP, EGb or amifostine, the conditioned medium from each group was cultured with NRK-49F cells. The renal function of rats was detected. The renal damage and fibrosis were evaluated by H&E and Masson trichrome staining. The IL-6 content in the cell medium was detected by ELISA. The expression levels of indicators related to renal fibrosis and signaling pathway were examined by western blotting and qRT-PCR. RESULTS: HPLC analysis showed that the contents of quercetin and kaempferol in EGb were 36.0 µg/ml and 45.7 µg/ml, respectively. In vivo, EGb and 2ME2 alleviated renal damage and fibrosis, as well as significantly decreased the levels of α-SMA, HIF-1α, STAT3 and IL-6 in rat tissues induced by CDDP. In vitro, the levels of HIF-1α, STAT3 and IL-6 were significantly increased in HK-2 cells and HIF-1α siRNA HK-2 cells induced by CDDP. Notably, HIF-1α siRNA significantly decreased the levels of HIF-1α, STAT3 and IL-6 in HK-2 cells, as well as the IL-6 level in medium from HK-2 cells. Additionally, the α-SMA level in NRK-49F cells was significantly increased after being cultured with conditioned medium from HK-2 cells or HIF-1α siRNA HK-2 cells exposed to CDDP. Furthermore, exogenous IL-6 increased the α-SMA level in NRK-49F cells. Importantly, the expression levels of the above-mentioned indicators were significantly decreased after the HK-2 cells and HIF-1α siRNA HK-2 cells were treated with EGb. CONCLUSION: This study revealed that EGb improves CDDP-induced RIF, and the mechanism may be related to its inhibition of the renal fibroblast activation by down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

Amifostine-Loaded Nanocarrier Traverses the Blood-Brain Barrier and Prevents Radiation-Induced Brain Injury.

Radiation-induced brain injury (RIBI) is a severe, irreversible, or even life-threatening cerebral complication of radiotherapy in patients with head and neck tumors, and there is no satisfying prevention and effective treatment available for these patients. Amifostine (AMF) is a well-known free radical scavenger with demonstrated effectiveness in preventing radiation-induced toxicity. However, the limited permeability of AMF across the blood-brain barrier (BBB) when administered intravenously reduces the effectiveness of AMF in preventing RIBI. Herein, we construct a nanoparticle (NP) platform for BBB delivery of AMF. AMF is conjugated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)]-hydroxy succinamide [DSPE-PEG-NHS, PEG M 2000], and the product is DSPE-PEG-AMF. Then, the nanoparticles (DAPP NPs) were formed by self-assembly of poly(lactic-co-glycolic acid) (PLGA), DSPE-PEG-AMF, and polysorbate 80 (PS 80). PEG shields the nanoparticles from blood clearance by the reticuloendothelial system and lengthens the drug circulation time. PS 80 is used to encapsulate nanoparticles for medication delivery to the brain. The results of our study showed that DAPP NPs were able to effectively penetrate the blood-brain barrier (BBB) in healthy C57BL/6 mice. Furthermore, in a well-established mouse model of X-knife-induced brain injury, treatment with DAPP NPs (corresponding to 250 mg/kg AMF) was found to significantly reduce the volume of brain necrosis compared to mice treated with AMF (250 mg/kg). Importantly, the use of DAPP NPs was also shown to significantly mitigate the effects of radiation-induced neuronal damage and glial activation. This work presents a convenient brain-targeted AMF delivery system to achieve effective radioprotection for the brain, providing a promising strategy with tremendous clinical translation potential.

Molecular Influence of the ATM Protein in the Treatment of Human Cells with Different Radioprotective Drugs: Comparisons between Antioxidative and Pro-Episkevic Strategies.

The radiation protection strategy with chemical agents has long been based on an antioxidative approach consisting in reducing the number of radical oxygen and nitrogen species responsible for the formation of the radiation-induced (RI) DNA damage, notably the DNA double-strand breaks (DSB), whose subset participates in the RI lethal effect as unrepairable damage. Conversely, a DSB repair-stimulating strategy that may be called the "pro-episkevic" approach (from the ancient Greek episkeve, meaning repair) can be proposed. The pro-episkevic approach directly derives from a mechanistic model based on the RI nucleoshuttling of the ATM protein (RIANS) and contributes to increase the number of DSB managed by NHEJ, the most predominant DSB repair and signaling pathway in mammalians. Here, three radioresistant and three radiosensitive human fibroblast cell lines were pretreated with antioxidative agents (N-acetylcysteine or amifostine) or to two pro-episkevic agents (zoledronate or pravastatin or both (ZOPRA)) before X-ray irradiation. The fate of the RI DSB was analyzed by using γH2AX and pATM immunofluorescence. While amifostine pretreatment appeared to be the most efficient antioxidative process, ZOPRA shows the most powerful radiation protection, suggesting that the pro-episkevic strategy may be an alternative to the antioxidative one. Additional investigations are needed to develop some new drugs that may elicit both antioxidative and pro-episkevic properties and to quantify the radiation protection action of both types of drugs applied concomitantly.

Effects of amifostine against blunt chest trauma-induced cardiac injury in rats.

BACKGROUND: This study aimed to examine whether two different doses of dexamethasone (DXM), which is a corticosteroid, and amifostine (AMI), which reduces cumulative tissue toxicity induced by cisplatin in advanced-stage cancer patients, have ameliorative effects on pathologic changes associated with cardiac contusion (CC) induced in rats. METHODS: Forty-two Wistar albino rats were equally divided into six groups (n=7): C, CC, CC+AMI 400, CC+AMI 200, CC+AMI+DXM, and CC+DXM. Tomography images and electrocardiographic analyzes were performed, mean arterial pressure was measured from the carotid artery, and blood and tissue samples were obtained for histopathological and biochemical analyses after trauma-induced CC. RESULTS: While the total oxidant status and disulfide parameters in the cardiac tissue and serum were significantly higher (p<0.05), the total antioxidant status, total thiol, and native thiol parameters were significantly lower (p<0.01) in rats with trauma-induced CC. The most frequently observed finding in the electrocardiography analyze was ST elevation. CONCLUSION: According to evaluation based on histological, biochemical, and electrocardiographic examinations, we believe that only 400 mg/kg dose of AMI or DXM can be effective in the treatment of myocardial contusion in rats. Evaluation based on histological findings.

Repurposing of Various Current Medicines as Radioprotective Agents.

BACKGROUND: The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in radiotherapy for cancer treatment. These radiations can cause damage to the cell membrane, lipids, proteins, and DNA and generate free radicals. Evidence reports stated that radiotherapy accounts for 17-19% of secondary malignancies, labelling this treatment option a double-edged sword. OBJECTIVE: Radioprotective molecules are used for mitigating radiotherapy's side effects. These agents show free radical scavenging, antioxidant, collagen synthesis inhibition, protease inhibition, immune stimulation, increased cytokine production, electron transfer, and toxicity reduction properties. The most frequently used amifostine has an array of cancer applications, showing multitarget action as nephroprotective to cisplatin and reducing the chances of xerostomia. Many other agents, such as metformin, edaravone, mercaptopropionylglycine, in specific diseases, such as diabetes, cerebral infarction, cystinuria, have shown radioprotective action. This article will discuss potentially repurposed radioprotectors that can be used in the clinical setting, along with a brief discussion on specific synthetic agents like amifostine and PrC-210. METHODS: Rigorous literature search using various electronic databases, such as PubMed, ScienceDirect, Scopus, EMBASE, Bentham Science, Cochrane Library, etc., was made. Peer-review research and review papers were selected, studied, reviewed, and analysed. CONCLUSION: Safety and risk-free treatment can be guaranteed with the repurposed agents. Agents like metformin, captopril, nifedipine, simvastatin, and various others have shown potent radioprotective action in various studies. This review compiled repurposed synthetic radioprotective agents.

Radioprotective effect of mistletoe extract on intestinal toxicity: in vivo study using adult zebrafish.

PURPOSE: The intestine is a dose-limiting organ in the treatment of intra-abdominal cancer. We previously reported that the extract of mistletoe parasites on Quercus had a more potent radioprotective effect than amifostine in reducing the developmental toxicities of zebrafish embryos. In this study, radioprotection against intestinal toxicity was investigated in adult zebrafish. METHODS: Wild-type adult AB zebrafish were exposed to 45-50 Gy of photon beam irradiation and/or treated with mistletoe extract orally 1 h before. The main endpoints of the study were survival and degree of deformation of the intestinal villi. RESULTS: The median follow-up period was 10 d post-irradiation (range: 7-11 d). A total of 105 zebrafish were used, including 42 in the radiation alone, 42 in the radiation and mistletoe arms, and 21 control subjects (mistletoe alone, mock-irradiated arm). The rate of both significant deformity and death was 53% in the radiation-alone arm, whereas the corresponding rate was 30% in the radiation and mistletoe arms. Significant deformity-free survival rates at 10 d post-irradiation in the radiation alone, and radiation and mistletoe arms were 44.7% (95% confidence interval [CI]:20-54.3) and 68.4% (95% CI:53.8-86.8), respectively (p=.046). The radiation and mistletoe arms showed decreased expression of two of three inflammatory genes (IL-1ß and IL-6) compared to the radiation alone group (p<.05). CONCLUSION: The radioprotective effect against intestinal toxicity was successfully shown in an adult zebrafish model. This result suggests the possibility of clinical use of mistletoe extract for the treatment of abdominal cancers.

The protective effects of red ginseng and amifostine against renal damage caused by ionizing radiation.

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.

Could Amifostine Prevent Experimental Radiotherapy-Induced Acute Pericarditis?

BACKGROUND: Amifostine is a powerful antioxidant that is one of the documented three chemo-radio prototectants recommended for clinical use. There is no data exploring amifostine in prevention of acute pericardial damage. We aimed to investigate whether amifostine has protective effect against acute pericardial injury due to radiotherapy in an experimental rat model. METHODS: Twenty-four rats were divided into four groups: control group, radiotherapy-only group, amifostine-only group, radiotherapy+amifostine group. In groups receiving radiotherapy, hearts were irradiated with a Co 60 teletherapy device at a distance of 80 cm and 20 Gy at a depth of 2 cm. Thirty minutes before interventions, 200 mg/kg amifostine or same volume 0.9% NaCl were administered intraperitoneally. Subjects were sacrificed 24 hours after the procedure. Pericardial histopathological changes were investigated by light microscopy. RESULTS: There was focal inflammation of >= 50% in all rats exposed-to-radiotherapy. All groups receiving radiotherapy revealed a significant increase in pericardial inflammation compared to the groups that did not receive irradiation (p<0.05). There was no difference between the radiotherapy-only group and amifostine+radiotherapy group for pericardial inflammatory response (p>0.05). CONCLUSION: Acute pericarditis was detected in all rats receiving radiotherapy. There was no positive effect of amifostine administration before radiotherapy on acute pericardial inflammation.

Haptoglobin is an early indicator of survival after radiation-induced severe injury and bone marrow transplantation in mice.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the main treatment for acute radiation sickness, especially after fatal radiation. The determination of HSCT for radiation patients is mainly based on radiation dose, hemogram and bone marrow injury severity. This study aims to explore a better biomarker of acute radiation injury from the perspective of systemic immune response. METHODS: C57BL/6J female mice were exposed to total body irradiation (TBI) and partial body irradiation (PBI). Changes in haptoglobin (Hp) level in plasma were shown at different doses and time points after the exposure and treatment with amifostine or bone marrow transplantation. Student's t-test/two tailed test were used in two groups. To decide the Hp levels as a predictor of the radiation dose in TBI and PBI, multiple linear regression analysis were performed. The ability of biomarkers to identify two groups of different samples was determined by the receiver operating characteristic (ROC) curve. The results were expressed as mean ± standard deviation (SD). Significance was set at P value < 0.05, and P value < 0.01 was set as highly significant. Survival distribution was determined by log-rank test. RESULTS: In this study, we found that Hp was elevated dose-dependently in plasma in the early post-irradiation period and decreased on the second day, which can be used as a molecular indicator for early dose assessment. Moreover, we detected the second increase of Hp on the 3rd and 5th days after the lethal irradiation at 10 Gy, which was eliminated by amifostine, a radiation protection drug, while protected mice from death. Most importantly, bone marrow transplantation (BMT) on the 3rd and 5th day after 10 Gy radiation improved the 30-days survival rate, and effectively accelerated the regression of secondary increased Hp level. CONCLUSIONS: Our study suggests that Hp can be used not only as an early molecule marker of radiation injury, but also as an important indicator of bone marrow transplantation therapy for radiation injury, bringing new scientific discoveries in the diagnosis and treatment of acute radiation injury from the perspective of systemic immunity.

Prevention of salivary gland dysfunction in patients treated with radioiodine for differentiated thyroid cancer: A systematic review of randomized controlled trials.

Introduction: Salivary gland dysfunction (e.g., sialadenitis and xerostomia) is the most common complication of radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC). Several methods have been used to reduce/prevent this adverse effect. We aimed to systematically review the effectiveness of non-pharmacological and pharmacological interventions in preventing RAI-induced salivary gland dysfunction in patients with DTC. Methods: A systematic review was conducted, according to PRISMA guidelines. The protocol was registered (PROSPERO: CRD42022295229). PubMed, Embase, Scopus, and the Cochrane Library electronic databases were searched from inception to November 2021. Inclusion criteria were randomized controlled trials of DTC patients who were older than 18 years and underwent RAI after thyroidectomy in which at least one studied group received an intervention to prevent salivary gland dysfunction. Results: Twelve studies (a total of 667 participants) were included. Among DTC patients who were treated with RAI, nonpharmacological treatment such as parotid gland massage and aromatherapy ameliorated salivary gland dysfunction. Antioxidants such as vitamin E and selenium demonstrated radioprotective effects on the salivary gland, while other antioxidants did not show radioprotective benefits. Vitamin C showed no significant effects on preventing salivary gland dysfunction. Amifostine had inconsistent outcomes among studies. Among cholinergic agonists, pilocarpine did not demonstrate the radioprotective effect on parotid glands, while bethanechol lowered salivary gland dysfunction. However, the negative results from pilocarpine may be explained by the strong sialorrheic effect of the Cincinnati regimen in both study arms. Conclusion: Among non-pharmacological and pharmacological methods, parotid gland massage, aromatherapy, vitamin E, selenium, amifostine, and bethanechol may have benefits in minimizing RAI-induced salivary gland dysfunction in patients with DTC. The results are limited by a small number of patients and should be confirmed in future larger randomized controlled trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=295229, PROSPERO, identifier CRD42022295229.

A novel electrochemical platform for assay of alkaline phosphatase based on amifostine and ATRP signal amplification.

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.