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.

Alpha-thiol deoxynucleotide triphosphates (S-dNTPs) as radioprotective agents: A novel approach.

In this study, the ability of a mixture of four different alpha-thiol deoxynucleotide triphosphates (S-dNTPs) each at a concentration of 10µM when incorporated into the genomic DNA of proliferating human HL-60 and Mono-Mac-6 (MM-6) cells in vitro to provide protection from 2, 5, and 10 Gy of gamma radiation was investigated. Incorporation of the four different S-dNTPs into nuclear DNA at 10 µM concentration for five days was validated by agarose gel electrophoretic band shift analysis. S-dNTP-treated genomic DNA reacted with BODIPY-iodoacetamide demonstrated a band shift to higher molecular weight to confirm the presence of sulfur moieties in the resultant phosphorothioate DNA backbones. No overt signs of toxicity or obvious morphologic cellular differentiation were noted in the presence of 10 µM S-dNTPs even after 8 days in culture. Significantly reduced radiation-induced persistent DNA damage measured at 24 and 48 h post-exposure by γ-H2AX histone phosphorylation using FACS analysis in S-dNTP incorporated HL-60 and MM6 cells indicated protection against radiation-induced direct and indirect DNA damage. Statistically significant protection by S-dNTPs was noted at the cellular level by CellEvent™ Caspase-3/7 assay, which assess the extent of apoptotic events, and by trypan blue dye exclusion to assed cell viability. The results appear to support an innocuous antioxidant thiol radioprotective effect built into genomic DNA backbones as the last line of defense against ionizing radiation and free radical-induced DNA damage.

[Research progress of irradiation injuries anti-agents].

Irradiation injuries anti-agents refer to drugs that can inhibit the initial stage of radiation injuries, or reduce the development of radiation injuries and promote the recovery of injuries when used early after irradiation exposure. According to the mechanism of action and the time of intervention, the irradiation injuries anti-agents are divided into four categories: radioprotectors, radiomitigators, radiation therapeutics for external radiation exposure, and anti-agents for internalized radionuclides. In this paper, the research progress of irradiation injuries anti-agents in recent years is reviewed.

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure.

There are currently four radiation medical countermeasures that have been approved by the United States Food and Drug Administration to mitigate hematopoietic acute radiation syndrome, all of which are repurposed radiomitigators. The evaluation of additional candidate drugs that may also be helpful for use during a radiological/nuclear emergency is ongoing. A chlorobenzyl sulfone derivative (organosulfur compound) known as Ex-Rad, or ON01210, is one such candidate medical countermeasure, being a novel, small-molecule kinase inhibitor that has demonstrated efficacy in the murine model. In this study, nonhuman primates exposed to ionizing radiation were subsequently administered Ex-Rad as two treatment schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation) and the proteomic profiles of serum using a global molecular profiling approach were assessed. We observed that administration of Ex-Rad post-irradiation is capable of mitigating radiation-induced perturbations in protein abundance, particularly in restoring protein homeostasis, immune response, and mitigating hematopoietic damage, at least in part after acute exposure. Taken together, restoration of functionally significant pathway perturbations may serve to protect damage to vital organs and provide long-term survival benefits to the afflicted population.

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.

Radioprotective countermeasures for radiation injury (Review).

A series of physiological and pathological changes occur after radiotherapy and accidental exposure to ionizing radiation (IR). These changes cause serious damage to human tissues and can lead to death. Radioprotective countermeasures are radioprotective agents that prevent and reduce IR injury or have therapeutic effects. Based on a good understanding of radiobiology, a number of protective agents have achieved positive results in early clinical trials. The present review grouped known radioprotective agents according to biochemical categories and potential clinical use, and reviewed radiation countermeasures, i.e., radioprotectors, radiation mitigators and radiotherapeutic agents, with an emphasis on their current status and research progress. The aim of the present review is to facilitate the selection and application of suitable radioprotectors for clinicians and researchers, to prevent or reduce IR injury.

Renal Clearable Mo-Based Polyoxometalate Nanoclusters: A Promising Radioprotectant against Ionizing Irradiation.

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.

Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives.

INTRODUCTION: The possibility of exposure to high doses of total- or partial-body ionizing radiation at a high dose rate due to radiological/nuclear accidents or terrorist attacks is increasing. Despite research and development during the last six decades, there is a shortage of nontoxic, safe, and effective radiation medical countermeasures (MCMs) for radiological and nuclear emergencies. To date, the US Food and Drug Administration (US FDA) has approved only four agents for the mitigation of hematopoietic acute radiation syndrome (H-ARS). AREA COVERED: We present the current status of a promising radiation countermeasure, gamma-tocotrienol (GT3; a component of vitamin E) as a radiation MCM that has been investigated in murine and nonhuman primate models of H-ARS. There is significant work with this agent using various omic platforms during the last few years to identify its efficacy biomarkers. EXPERT OPINION: GT3 is a newer type of radioprotector having significant injury-countering potential and is currently under advanced development for H-ARS. As a pre-exposure drug, it requires only single doses, lacks significant toxicity, and has minimal, ambient temperature storage requirements; thus, GT3 appears to be an ideal MCM for military and first responders as well as for storage in the Strategic National Stockpile.

Lung ultrasound protocol decreases radiation in newborn population without side effects: A quality improvement project / La implementación de un protocolo de ecografía pulmonar disminuye la radiación sin efectos secundarios: proyecto de mejora cualitativa

Objective To reduce radiation exposure in newborns admitted due respiratory distress based on the implementation of lung ultrasound (LUS). Design Quality improvement (QI), prospective, before-after, pilot study. Setting Third level neonatal intensive care unit (NICU) level with 25-bed and 1800 deliveries/year. Patients Inclusion criteria were neonates admitted with respiratory distress. Interventions After a theoretical and practical LUS training a new protocol was approved and introduced to the unit were LUS was the first-line image. To study the effect of the intervention we compare two 6-month periods: group 1, with the previous chest X-ray (CXR)-protocol (CXR as the first diagnostic technique) vs. group 2, once LUS-protocol had been implemented. Main variables of interest The main QI measures were the total exposure to radiation. Secondary QI were to evaluate if the LUS protocol modified the clinical evolution as well as the frequency of complications. Results 122 patients were included. The number of CXR was inferior in group 2 (group 1: 2 CXR (IQR 1–3) vs. Group 2: 0 (IQR 0–1), p<0.001), as well as had lower median radiation per baby which received at least one CXR: 56 iGy (IQR 32–90) vs. 30 iGy (IQR 30–32), p<0.001. Respiratory support was similar in both groups, with lower duration of non-invasive mechanical ventilation and oxygen duration the second group (p<0.05). No differences regarding respiratory development complications, length of stay and mortality were found. Conclusions The introduction of LUS protocol in unit decreases the exposure radiation in infants without side effects (AU)

Objetivo Reducir la exposición a la radiación en neonatos ingresados por distrés respiratorio mediante implementación de la ecografía pulmonar (EP). Diseño Estudio piloto, prospectivo, anterior-posterior, mejoría de la calidad. Ámbito Unidad de cuidados intensivos neonatal (UCIN) de tercer nivel con 25 camas y 1800 partos/anuales. Pacientes Criterio de inclusión neonatos con distrés respiratorio. Intervenciones Después de una formación teórico-práctica en EP un nuevo protocolo fue implementado y aprobado siendo la EP la primera técnica de imagen. Para estudiar el efecto de la intervención comparamos dos períodos de 6 meses: grupo 1, con el protocolo de radiografía de tórax (RTX) (RTX primera técnica diagnóstica) vs. grupo 2, una vez implementado el protocolo de EP. Variables de interés La principal variable de interés fue la exposición total a la radiación. Las secundarias fueron la evolución clínica y la frecuencia de complicaciones. Resultados Se incluyeron 122 pacientes. El número de RTX fue inferior en el grupo 2 (grupo 1: 2 RTX [RIQ 1-3] vs. grupo 2: 0 [RIQ 0-1], p<0,001), con una menor dosis de radiación media por cada paciente que recibió al menos una RTX: 56 iGy (RIQ 32-90) vs. 30 iGy (RIQ 30-32), p<0,001. El soporte respiratorio fue similar en ambos grupos, con menor duración de la ventilación no invasiva y oxigenoterapia en el segundo grupo (p< 0,05). No hubo diferencias en el desarrollo de complicaciones respiratorias, días de ingreso o mortalidad. Conclusiones La introducción de un protocolo de EP en una unidad disminuye la exposición a la radiación sin efectos secundarios (AU)

The effects of medical linear accelerator X-rays on human peripheral blood lymphocytes in the presence of glucosamine.

Glucosamine is widely prescribed as a dietary supplement used to treat arthritis. In this study, the radioprotective ability of glucosamine was evaluated against radiation-induced genotoxicity and cytotoxicity in human peripheral blood lymphocytes. Blood samples were collected from five healthy male donors and were divided into four groups. Isolated lymphocytes and blood samples were treated with 10 µM of glucosamine for 2 h before exposure to 2 Gy radiation. The radioprotective potential of glucosamine was assessed by micronucleus assay, reactive oxygen species (ROS) level analysis, and flow cytometry. Irradiation significantly increased the micronuclei frequency as compared to the control group. Contrary to that pretreatment with glucosamine before irradiation significantly reduced the frequency of micronuclei. Furthermore, pretreatment with glucosamine significantly prevented the percentage of apoptotic lymphocytes. Also, glucosamine pretreatment significantly reduced the production of ROS in irradiated lymphocytes. This study shows glucosamine to be a potent radioprotector against radiation that induces DNA damage and apoptosis in human lymphocytes. Several additional in vivo and in vitro studies are needed before glucosamine can be considered as a radioprotective candidate in patients undergoing radiation therapy.

CLASSIFICATION OF MEDICAL EQUIPMENT FOR ANTI-RADIATION PROTECTION. / KLASYFIKATsIIa MEDYChNYKh ZASOBIV PROTYRADIATsIINOGO ZAKhYSTU.

Any collection of objects of study needs some arrangement, i. e. classification. The existing numerous classifications of antiradiation agents are built on the basis of their antiradiation effects of an integrated or differentiated nature. The work presents the chronology of the main classifications of chemical compounds that are able to protect against the shortterm and longterm effects of ionizing radiation when they are introduced into the body both before and after exposure. The change of views, trends and paradigms regarding radioprotective compounds is shown. These classifications of antiradiation medicines include radioprotectors, means of stimulating the radioresistance of the body, means of prevention and suppression of the primary reaction to irradiation, means of prevention and treatment of lesions from exposure to incorporated radionuclides, means of treatment of acute bone marrow syndrome, means of treatment of local radiation lesions. It is shown that modern concepts of radiation protection are based on fundamentally different «points of application¼ of groups of radioprotective agents and depend on the stage of radiation damage.

High-throughput screening strategies for space-based radiation countermeasure discovery.

As humanity begins to venture further into space, approaches to better protect astronauts from the hazards found in space need to be developed. One particular hazard of concern is the complex radiation that is ever present in deep space. Currently, it is unlikely enough spacecraft shielding could be launched that would provide adequate protection to astronauts during long-duration missions such as a journey to Mars and back. In an effort to identify other means of protection, prophylactic radioprotective drugs have been proposed as a potential means to reduce the biological damage caused by this radiation. Unfortunately, few radioprotectors have been approved by the FDA for usage and for those that have been developed, they protect normal cells/tissues from acute, high levels of radiation exposure such as that from oncology radiation treatments. To date, essentially no radioprotectors have been developed that specifically counteract the effects of chronic low-dose rate space radiation. This review highlights how high-throughput screening (HTS) methodologies could be implemented to identify such a radioprotective agent. Several potential target, pathway, and phenotypic assays are discussed along with potential challenges towards screening for radioprotectors. Utilizing HTS strategies such as the ones proposed here have the potential to identify new chemical scaffolds that can be developed into efficacious radioprotectors that are specifically designed to protect astronauts during deep space journeys. The overarching goal of this review is to elicit broader interest in applying drug discovery techniques, specifically HTS towards the identification of radiation countermeasures designed to be efficacious towards the biological insults likely to be encountered by astronauts on long duration voyages.

Exploring Nitric Oxide (NO)-Releasing Celecoxib Derivatives as Modulators of Radioresponse in Pheochromocytoma Cells.

COX-2 can be considered as a clinically relevant molecular target for adjuvant, in particular radiosensitizing treatments. In this regard, using selective COX-2 inhibitors, e.g., in combination with radiotherapy or endoradiotherapy, represents an interesting treatment option. Based on our own findings that nitric oxide (NO)-releasing and celecoxib-derived COX-2 inhibitors (COXIBs) showed promising radiosensitizing effects in vitro, we herein present the development of a series of eight novel NO-COXIBs differing in the peripheral substitution pattern and their chemical and in vitro characterization. COX-1 and COX-2 inhibition potency was found to be comparable to the lead NO-COXIBs, and NO-releasing properties were demonstrated to be mainly influenced by the substituent in 4-position of the pyrazole (Cl vs. H). Introduction of the N-propionamide at the sulfamoyl residue as a potential prodrug strategy lowered lipophilicity markedly and abolished COX inhibition while NO-releasing properties were not markedly influenced. NO-COXIBs were tested in vitro for a combination with single-dose external X-ray irradiation as well as [177Lu]LuCl3 treatment in HIF2α-positive mouse pheochromocytoma (MPC-HIF2a) tumor spheroids. When applied directly before X-ray irradiation or 177Lu treatment, NO-COXIBs showed radioprotective effects, as did celecoxib, which was used as a control. Radiosensitizing effects were observed when applied shortly after X-ray irradiation. Overall, the NO-COXIBs were found to be more radioprotective compared with celecoxib, which does not warrant further preclinical studies with the NO-COXIBs for the treatment of pheochromocytoma. However, evaluation as radioprotective agents for healthy tissues could be considered for the NO-COXIBs developed here, especially when used directly before irradiation.

Synthesis of novel benzothiophene derivatives as protectors against cranial irradiation-induced neuroinflammation.

Aim: Cranial irradiation results in many deleterious effects to normal tissues, including neuroinflammation. There is a need to explore radioprotective agents that could be safely used to ameliorate these effects. Method: Nine novel benzothiophene derivatives bearing pyrimidinone, pyrazolidinone, triazole and other active moieties were synthesized and evaluated as antioxidants in an in vitro screening experiment. The most potent compounds were then tested as protectors against radiation-induced neuroinflammation and oxidative stress in rat brains following cranial irradiation. Results: The most potent antioxidant compounds were compounds 3-5 and 10 . P-fluro,p- bromo and pyrido benzothiophene derivatives offered good antioxidant and anti-inflammatory effects. Conclusion: Compounds 3-5 may be introduced as nontoxic candidates for adjuvant therapeutic protocols used in head and neck tumor radiotherapeutic management.

Geldanamycin Enhances the Radioprotective Effect of Peroxyredoxin 6 in Irradiated 3T3 Fibroblasts.

The aim of the study was to evaluate the possibility of increasing the radioprotective potential of peroxiredoxin 6 (Prdx6) and its mutant form S32A by their combined use with geldanamycin (GA) for 3T3 fibroblasts irradiated with X-rays at a dose of 6 Gy. The mutant enzyme S32A, which does not have phospholipase activity, exhibits a more pronounced radioprotective activity when combined with GA. The use of this combination of radioprotective drugs completely abolishes the peak of NF-κB activity in irradiated 3T3 cells. Another transcription factor, p53, which is an indicator of the level of cell apoptosis and increases upon irradiation, is also reduced by S32A in combination with GA. The low-molecular-weight protein p21, which is a marker of cell senescence and whose production increases upon irradiation, is also normalized when S32A is used in combination with GA. In addition, the use of this combination of radioprotective drugs significantly reduces the stress response of 3T3 cells to X-ray irradiation.

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.

Phytochemicals: A potential next generation agent for radioprotection.

BACKGROUND: Radiation hazards are accountable for extensive damage in the biological system and acts as a public health burden. Owing to the rapid increasing in radiation technology, both Ionizing radiation (IR) from natural and man made source poses detrimental outcome to public health. IR releases free radicals which induces oxidative stress and deleterious biological damage by modulating radiation induced signalling intermediates. The efficacy of existing therapeutic approach and treatment strategy are limited owing to their toxicity and associated side effects. Indian system of traditional medicine is enriched with prospective phytochemicals with potential radioprotection ability. PURPOSE: The present review elucidated and summarized the potential role of plant derived novel chemical compound with prospective radioprotective potential. METHOD: So far as the traditional system of Indian medicine is concerned, plant kingdom is enriched with potential bioactive molecules with diverse pharmacological activities. We reviewed several compounds mostly secondary metabolites from plant origin using various search engines. RESULTS: Both compounds from land plants and marine source exhibited antioxidant antiinflammatory, free radical scavenging ability. These compounds have tremendous potential in fine-tuning of several signalling intermediates, which are actively participated in the progression and development of a pathological condition associated with radiation stress. CONCLUSION: Development and explore of an operational radioprotective agent from originated from plant source that can be used as a novel molecular tool to eliminate the widespread damage caused by space exploration, ionizing radiation, nuclear war and radiotherapy has been significantly appreciated. Through extensive literature search we highlighted several compounds from both land plant and marine origin can be implemented for a better therapeutic potential against radiation induced injury. Furthermore, extensive clinical trials must be carried out in near future for better therapeutic modality and clinical efficacy.

Protection of the hematopoietic system against radiation-induced damage: drugs, mechanisms, and developments.

Sometimes, people can be exposed to moderate or high doses of radiation accidentally or through the environment. Radiation can cause great harm to several systems within organisms, especially the hematopoietic system. Several types of drugs protect the hematopoietic system against radiation damage in different ways. They can be classified as "synthetic drugs" and "natural compounds." Their cellular mechanisms to protect organisms from radiation damage include free radical-scavenging, anti-oxidation, reducing genotoxicity and apoptosis, and alleviating suppression of the bone marrow. These topics have been reviewed to provide new ideas for the development and research of drugs alleviating radiation-induced damage to the hematopoietic system.

Molecular mechanisms of Marine-Derived Natural Compounds as photoprotective strategies.

Excessive exposure of the skin to ultraviolet radiation (UVR) causes oxidative stress, inflammation, immunosuppression, apoptosis, and changes in the extracellular matrix, which lead to the development of photoaging and photodamage of skin. At the molecular level, these pathological changes are mainly caused by the activation of related protein kinases and downstream transcription pathways, the increase of matrix metalloproteinase, the formation of reactive oxygen species, and the combined action of cytokines and inflammatory mediators. At present, the photostability, toxicity, and damage to marine ecosystems of most sun protection products in the market have affected their efficacy and safety. Another way is to use natural products produced by various marine species. Marine organisms have evolved a variety of molecular strategies to protect themselves from the harmful effects of ultraviolet radiation, and their unique chemicals have attracted more and more attention in the research of photoprotection and photoaging resistance. This article provides an extensive description of the recent literature on the potential of Marine-Derived Natural Compounds (MDNCs) as photoprotective and photoprotective agents. It reviews the positive effects of MDNCs in counteracting UV-induced oxidative stress, inflammation, DNA damage, apoptosis, immunosuppression, and extracellular matrix degradation. Some MDNCs have the potential to develop feasible solutions for related phenomena, such as photoaging and photodamage caused by UVR.