Proton radiation is known to have detrimental neurological effects, but there is limited scientific understanding of these effects at the cellular and tissue levels. We leveraged our 3D in vitro cortical tissue model alongside 2D cortical cultures to study the effects of proton radiation on neuronal tissue. This platform is based on an established biofabrication method that produces tissue-like constructs seeded with human induced pluripotent stem cell-derived neurons and astrocytes or mouse embryonic cortical neurons and glia. Both 2D and 3D cultures were exposed to 3.0 MeV protons (10 Gy cumulative dose), and additional 2D samples were treated with the known radioprotectant drug amifostine. Biological readouts included DNA damage quantification, cytomorphology assessed by quantitative immunocytochemistry, inflammatory cytokine secretion, and electrophysiology using microelectrode array. We found a significant increase in DNA damage in irradiated 3D samples at 30 min post-proton irradiation, as expected. There was a significant decrease in GFAP and Iba1 expression, no significant changes in cytokine secretion due to proton radiation or amifostine treatment alone, and no significant changes in electrophysiological activity in 2D cultures over time. This work represents a functional analysis of a novel 3D multicellular cortical model and highlights neuronal resilience to acute proton-radiation exposure.

Radiation enteritis is a common complication in patients undergoing abdominal radiotherapy. Current management strategies face significant limitations: clinical agents like amifostine are hindered by systemic side effects and demanding administration; direct supplementation with radioprotective metabolites such as propionate suffers from low bioavailability and transient action; and conventional probiotics lack targeted therapeutic output. To address these challenges, we engineered Escherichia coli Nissle 1917 to function as a living therapeutic that continuously produces and delivers propionate directly in the gut. This propionate-engineered probiotic achieved a production yield of 181.33 ± 4.27 mg/L in vitro. In a mouse model of abdominal irradiation, this engineered bacterium alleviated radiation-induced intestinal damage by continuously releasing propionate and enhancing intestinal epithelial barrier function. Multi-omics analysis revealed that the engineered bacterium could restore intestinal microbiota homeostasis, enhancing the abundance of advantageous bacteria with radioprotective properties (e.g., Dubosiella, Akkermansia). Moreover, it modulated intestinal microbiota metabolism, influencing the metabolism of ascorbic acid, aldoses, and other metabolites. Additionally, it protected the intestinal mucosal barrier from radiation-induced damage, which was associated with the modulation of the SOCS1/JAK2/STAT3 signaling pathway. This study introduces a novel biological therapy to mitigate the side effects of radiotherapy and could open new avenues for preventing and treating radiation-induced intestinal injury.

Embolization is an effective treatment modality for intermediate- and advanced-stage Hepatocellular carcinoma (HCC). Transarterial radioembolization (TARE), which combines radiotherapy with embolization, not only induces tumor necrosis by occluding blood flow with embolic agents but also exerts local radiotherapeutic effects to damage tumor cells, thereby significantly enhancing the therapeutic efficacy of embolization. Current radiolabeled microspheres used for internal irradiation therapy in HCC have limitations, such as suboptimal embolization efficacy, a tendency for non-target embolization, an inability to track embolic agents during and after surgery, and the generation of reactive oxygen species (ROS) during radiotherapy, which can damage normal tissues. To address these issues, visualizable cationic quaternary ammonium salt-based drug-eluting microspheres capable of loading [131]I and the radioprotective agent amifostine were developed. The microspheres exhibit good embolic properties and can be visualized over an extended period using CT and DSA. The microspheres, carrying a positive charge, are capable of loading amifostine via ion exchange. After loading amifostine, these microspheres can not only provide local radiotherapy within the tumor but also continuously release amifostine locally to neutralize ROS in normal liver tissue. This approach not only enhances the utilization of amifostine in vivo but also protects the liver without compromising the efficacy of TARE thereby further improving the precision of radiotherapy.

Oral Mucositis and xerostomia are common debilitating side effects of radiotherapy in head and neck cancer patients, leading to treatment interruptions and negatively impacting quality of life. This review was performed to examine the efficacy and safety of interventions for managing these complications, evaluated in completed Phase III and IV clinical trials registered on ClinicalTrials.gov. A range of pharmacological and non-pharmacological therapies were reviewed, with analysis of intervention types, outcomes, and sample sizes. For oral mucositis, effective pharmacological agents included palifermin, avasopasem manganese, doxepin, morphine mouthwash, and gabapentin, while non-pharmacological options such as low-level laser therapy, honey, and Aloe vera showed additional benefit in reducing severity and improving healing. In managing radiotherapy-induced xerostomia, pilocarpine, amifostine, and cevimeline significantly enhanced salivary function, with adaptive radiotherapy techniques offering protective effects on the salivary glands. Phase IV studies supported the role of benzydamine, MuGard, Biotène, and herbal mouthwashes in symptom relief and patient comfort. Although several interventions demonstrated promising clinical efficacy, the heterogeneity in study design, outcome measures, and follow-up duration limits definitive conclusions. Therefore, customized, evidence-driven approaches informed by existing recommendations and developed data are crucial for enhancing outcomes and reducing the burden of therapy-induced toxicities in head and neck cancer patients.

As skin injuries caused by radiotherapy can significantly impede the healing process, it is essential to eliminate the interference of excessive reactive oxygen species (ROS) in the treatment of radiation-induced skin injury (RISI). To address this, we developed a temporally programmed hydrogel designed to enhance RISI repair, which was synthesized through the assembly of Lactobacillus reuteri (L. reuteri) and tannic acid (TA)-loaded hydrogel (Gel/LT). These hydrogels demonstrated satisfactory free radical scavenging capacity in the early stages, achieving an effective clearance rate of 93.3 %, thereby reducing the production of ROS associated with RISI. Furthermore, the L. reuteri encapsulated by metal-polyphenol self-assembly is released at the wound site in response to the wound microenvironment, promoting angiogenesis and tissue regeneration. Both in vitro and in vivo experiments demonstrated that Gel/LT achieved ROS scavenging and tissue repair effects at different stages of RISI. The transcriptome results indicate that these hydrogels facilitate a transition from an immune response to cellular proliferation by reducing oxidative stress and upregulating the expression of anti-inflammatory genes. Additionally, they promote the regeneration of extracellular matrix components, such as collagen, ultimately achieving superior repair efficacy compared to the commercial drug amifostine. This hierarchical therapeutic strategy permits temporal drug delivery at various stages of the repair process, presenting a novel approach for the treatment of RISI.

Ferroptosis offers potent anticancer potential but suffers from nonselective toxicity and immune suppression. Here, we develop amifostine-iron nanoparacrystalline (AFe-NPC), a self-delivering nanomedicine assembled from a clinically approved cytoprotective prodrug and ferric ions, enabling tumor-selective immunogenic ferroptosis. AFe-NPC with good T2-weighted magnetic resonance imaging (MRI) contrast exhibits superior Fenton catalytic activity and potent glutathione depletion, outperforming commercial Fe3O4 nanoparticles for enabling efficient ferroptosis induction under MRI guidance. Notably, alkaline phosphatase (ALP) with high expression in normal cells can convert amifostine in AFe-NPC into WR-1065, which scavenges reactive oxygen species and upregulates Col3a1 and Col12a1 to enhance ALP activity for strengthening cytoprotection. Conversely, low ALP expression in tumor cells cannot realize effective cytoprotection, causing AFe-NPC to induce immunogenic ferroptosis. AFe-NPC-induced ferroptosis can boost CD8[+] T cell-mediated systemic anticancer immunity and synergize with immune checkpoint blockade to eradicate primary and metastatic tumors.

Several antidotes and medical countermeasures were experimented for the protection of one of the notorious chemical warfare agents, the mustard gas, also known as sulphur mustard (SM). Among them, the DRDE series of compounds (amino alkyl-alkyl/aryl sulphides) showed good protection and safety in pre-clinical studies as a prophylactic antidote when administered orally. These compounds showed better protection compared to other experimented molecules, such as amifostine, N-acetylcysteine, melatonin, sodium thiosulphate, and flavonoids. Although many studies have focused on the DRDE-07 molecule, the structurally related DRDE-30 and DRDE-35 have shown better safety and protection. Among them, DRDE-30 showed the best protection for SM and nitrogen mustards, as well as against radiation, and also as a cytoprotectant for anticancer agents. In this review, all the published papers on the DRDE series of compounds are compiled and discussed, with the aim that if any one of these molecules is recommended as an oral prophylactic drug, further development would occur for a more effective, broad-spectrum cytoprotectant.

Background/Objectives: Radiotherapy (RT) induces oxidative stress and structural damage in solid tissues, including the liver. This study aimed to investigate the histological and immunohistochemical effects of dexmedetomidine (DEX) and amifostine on their potential protective and regenerative properties against liver injury induced by radiation therapy. Methods: This study consisted of five randomized groups: control, RT, RT-D100, RT-D200, and RT-A (Amifostine). A total of 100 µg/kg DEX, 200 µg/kg DEX, and 200 µg/kg amifostine were administered before radiotherapy as per the experimental design. After RT, liver specimens were analyzed for histological alterations, including periportal and perisinusoidal fibrosis, vacuolization, and pyknotic nuclei. Furthermore, immunohistochemistry investigations were conducted to evaluate apoptosis, mitosis, oxidative stress, and neural regeneration in non-neuronal liver tissue following radiotherapy and subsequent treatment. Results: The control group's liver tissue exhibited standard histological architecture, whereas the RT group displayed severe cellular degeneration, periportal and perisinusoidal fibrosis, cytoplasmic vacuolization, and an increase in pyknotic nuclei. The apoptotic index was markedly reduced in the RT-D100 and RT-D200 groups relative to the RT group. Furthermore, caspase-3 immunoactivity was negligible in the control group, while a significant increase was observed in the RT group. The administration of amifostine significantly increased GAP-43 levels. Conclusions: DEX mitigates RT-induced hepatic injury chiefly through antioxidant and anti-apoptotic pathways, whereas amifostine promotes hepatic regeneration by modulating GAP-43.

Radiotherapy for abdominal malignancies is limited by intestinal toxicity and secondary colorectal cancers. Here, we develop an oral, microbiota-responsive nano-amifostine (CS/PEC-AMF NPs) system that achieves site-specific radioprotection in the colorectum without compromising antitumor efficacy. By conjugating amifostine to pectin and encapsulating it with chitosan, the nanoparticles enable pH- and microbiota-triggered release in the large bowel, safeguarding drug bioactivity during gastrointestinal transit. In murine models, CS/PEC-AMF NPs attenuate both acute and chronic radiation-induced bowel injury, restore epithelial integrity, preserve stem cell populations, and promote tight junction repair. Integrated metagenomic and metabolomic analyses reveal that the system normalizes gut microbiota diversity and composition, increases short-chain fatty acid production, and facilitates macrophage polarization towards the anti-inflammatory M2 phenotype. Notably, the formulation synergistically enhances tumor suppression and extends survival in orthotopic colorectal tumor models undergoing radiotherapy and reduces the incidence of secondary colorectal tumors post-irradiation. Mechanistically, transcriptomic analysis demonstrates the suppression of proinflammatory pathways and the promotion of DNA repair programs. This study provides a paradigm for leveraging functional nanomaterials to orchestrate precise, tissue-specific radioprotection and immune modulation, addressing a key challenge in abdominal cancer therapy.

Radiation-induced xerostomia is a frequent and debilitating complication in patients undergoing radiotherapy for head and neck cancer. This study aimed to compare the effectiveness of available treatment modalities in preventing or managing radiation-induced xerostomia and associated complications in head and neck cancer patients. A detailed search of PubMed and Google Scholar was conducted. Only randomised controlled trials (RCTs) involving radiotherapy-treated head and neck cancer patients were included. The interventions that were analysed encompassed pharmacological agents (for example, pilocarpine, and amifostine), antioxidants, herbal formulations, acupuncture, low-level laser therapy (LLLT), and regenerative approaches. Primary outcomes included severity of xerostomia, rates of salivary flow, mucositis, oral pain, dysphagia, and fatigue. Thirty-one randomised clinical trials met the inclusion criteria. Pooled analysis showed no significant reduction in severity of xerostomia at weeks 3, 4, or 6, or 6 months. Stimulated salivary flow did not significantly improve (mean difference (MD): 0.22; p = 0.15), while unstimulated salivary flow showed a significant benefit (MD: 0.13; 95% CI: 0.09 to 0.17; p < 0.00001). A significant reduction in the severity of oral pain was also noted (MD: -2.25; p < 0.0001). No significant differences were found for the incidence or duration of mucositis, dysphagia, or fatigue. Considerable heterogeneity was observed across the studies and no single intervention demonstrated consistent efficacy in managing radiation-induced xerostomia. Some therapies have shown promise in improving unstimulated salivary flow and reducing oral pain; however, the overall evidence remains inconclusive. To address this persistent clinical challenge, future trials should adopt standardised outcome measures, assess combination therapies, and investigate novel regenerative strategies.

The global epidemic of NDM-1-producing gram-negative pathogens has significantly undermined the clinical efficacy of carbapenems, exacerbating the issue of bacterial resistance. Consequently, the development of novel inhibitor that can inhibit NDM-1 has been prompted to address the infections it causes. In this study, we redefined amifostine (AMI), which exhibits a 50 % inhibitory concentration (IC50) of 25.4 ± 0.6 μM and significantly inhibits the hydrolytic activity of NDM-1 in a dose-dependent manner, suggesting its potential as an NDM-1 inhibitor. In vitro, AMI effectively restored the antibacterial activity of Meropenem (MEM) against NDM-1 positive E. coli, resulting in a four-fold decrease in MIC of MEM from 64 μg/mL to 16 μg/mL. The combination of AMI and MEM exhibited significant synergy, as indicated by FICI index of 0.375. In vivo, the synergistic therapeutic effect of AMI and MEM was assessed in mice infected with NDM-1 positive E. coli. Compared to the control group, the combination of AMI and MEM significantly enhanced the survival rate of infected mice and reduced both the bacterial burden and the inflammatory response associated with NDM-1-positive E. coli, also alleviated histopathological damage in these mice. Finally, it was demonstrated that AMI could promote the penetration of bacterial cell membrane into the cell by changing the permeability of bacterial cell membrane. Further molecular dynamics simulations and molecular interaction analysis showed that AMI could form stable hydrogen bonds with key amino acid residues in the active pocket of NDM-1, including Asn220, Gln123 and Glu152, thereby competitively inhibiting the meropenem hydrolysis activity of NDM-1. This study presents a novel framework for the development of NDM-1 inhibitors, offering a new strategy to combat infections caused by drug-resistant bacteria.