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European Journal of Medical Research Jan 2024Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions...
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-β1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-β1 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-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 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.
Topics: Humans; Animals; Mice; Bleomycin; Transforming Growth Factor beta1; Amifostine; Sirtuin 1; AMP-Activated Protein Kinases; NAD; Reactive Oxygen Species; Lung; Idiopathic Pulmonary Fibrosis; Fibroblasts; Mitochondria; Pneumonia; Mice, Inbred C57BL
PubMed: 38245795
DOI: 10.1186/s40001-023-01623-4 -
European Journal of Pharmacology Jan 2018As the use of radiation technology for nuclear warfare or for the benefits of mankind (e.g. in radiotherapy or radio-diagnosis) is increasing tremendously, the risk of... (Review)
Review
As the use of radiation technology for nuclear warfare or for the benefits of mankind (e.g. in radiotherapy or radio-diagnosis) is increasing tremendously, the risk of associated side effects is becoming a cause of concern. These effects, ranging from nausea/vomiting to death, may result from accidental or deliberate exposure and begin in seconds. Through this review paper, efforts have been done to critically review different compounds which have been investigated as radioprotectors and radiation mitigators. Radioprotectors are compounds which are administered just before or at the time of irradiation so as to minimize the radiation induced damage to normal tissues. And radiation mitigators are the compounds which can even minimize or ameliorate post irradiaion-toxicity provided they are administered before the onset of toxic symptoms. A variety of agents have been investigated for their preventive and ameliorative potential against radiation induced toxic effects. This review article has focused on various aspects of the promising representative agents belonging to different classes of radioprotectors and mitigators. Many compounds have shown promising results, but till date only amifostine and palifermin are clinically approved by FDA. To fill this void in pharmacological armamentarium, focus should be shifted towards novel approaches.
Topics: Animals; Humans; Radiation Injuries; Radiation-Protective Agents
PubMed: 29221951
DOI: 10.1016/j.ejphar.2017.12.011 -
The Lancet. Child & Adolescent Health Aug 2019The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss... (Review)
Review
The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
Topics: Acetylcysteine; Adolescent; Amifostine; Anti-Inflammatory Agents; Antineoplastic Agents; Chelating Agents; Child; Cisplatin; Cytoprotection; Dexamethasone; Disulfiram; Ditiocarb; Humans; Neoplasms; Ototoxicity; Thiosulfates
PubMed: 31160205
DOI: 10.1016/S2352-4642(19)30115-4 -
Journal of Dental Research Aug 2018Varghese JJ, Schmale IL, Mickelsen D, Hansen ME, Newlands SD, Benoit DSW, Korshunov VA, Ovitt CE. 2018. Localized delivery of amifostine enhances salivary gland...
Varghese JJ, Schmale IL, Mickelsen D, Hansen ME, Newlands SD, Benoit DSW, Korshunov VA, Ovitt CE. 2018. Localized delivery of amifostine enhances salivary gland radioprotection. J Dent Res [epub ahead of print 10 April 2018] in press. (Original DOI: 10.1177/0022034518767408) In the original online article, the third author's name was misspelled as D. Mickelson. This has been corrected to D. Mickelsen online and in print.
PubMed: 29738287
DOI: 10.1177/0022034518774759 -
Molecules (Basel, Switzerland) Mar 2021Large doses of ionizing radiation can damage human tissues. Therefore, there is a need to investigate the radiation effects as well as identify effective and non-toxic...
Large doses of ionizing radiation can damage human tissues. Therefore, there is a need to investigate the radiation effects as well as identify effective and non-toxic radioprotectors. This study evaluated the radioprotective effects of Kelulut honey (KH) from stingless bee ( sp.) on zebrafish () embryos. Viable zebrafish embryos at 24 hpf were dechorionated and divided into four groups, namely untreated and non-irradiated, untreated and irradiated, KH pre-treatment and amifostine pre-treatment. The embryos were first treated with KH (8 mg/mL) or amifostine (4 mM) before irradiation at doses of 11 Gy to 20 Gy using gamma ray source, caesium-137 (Cs). Lethality and abnormality analysis were performed on all of the embryos in the study. Immunohistochemistry assay was also performed using selected proteins, namely γ-H2AX and caspase-3, to investigate DNA damages and incidences of apoptosis. KH was found to reduce coagulation effects at up to 20 Gy in the lethality analysis. The embryos developed combinations of abnormality, namely microphthalmia (M), body curvature and microphthalmia (BM), body curvature with microphthalmia and microcephaly (BMC), microphthalmia and pericardial oedema (MO), pericardial oedema (O), microphthalmia with microcephaly and pericardial oedema (MCO) and all of the abnormalities (AA). There were more abnormalities developed from 24 to 72 h (h) post-irradiation in all groups. At 96 h post-irradiation, KH was identified to reduce body curvature effect in the irradiated embryos (up to 16 Gy). γ-H2AX and caspase-3 intensities in the embryos pre-treated with KH were also found to be lower than the untreated group at gamma irradiation doses of 11 Gy to 20 Gy and 11 Gy to 19 Gy, respectively. KH was proven to increase the survival rate of zebrafish embryos and exhibited protection against organ-specific abnormality. KH was also found to possess cellular protective mechanism by reducing DNA damage and apoptosis proteins expression.
Topics: Amifostine; Animals; Apoptosis; Bees; DNA Damage; Gamma Rays; Histones; Honey; Radiation Injuries, Experimental; Radiation-Protective Agents; Zebrafish; Zebrafish Proteins
PubMed: 33809054
DOI: 10.3390/molecules26061557 -
Anti-cancer Agents in Medicinal... 2022Ionising radiation has been an important modality in cancer treatment and its value is immense when surgical intervention is risky or might debilitate/adversely affect... (Review)
Review
UNLABELLED
Ionising radiation has been an important modality in cancer treatment and its value is immense when surgical intervention is risky or might debilitate/adversely affect the patient. However, the beneficial effect of radiation modality is negated by the damage to the adjacent healthy tissue in the field of radiation. Under these situations, the use of radioprotective compounds that can selectively protect normal tissues against radiation injury is considered very useful. However, research spanning over half a century has shown that there are no ideal radioprotectors available. The United States Food and Drug Administration (FDA or USFDA) approved amifostine, or WR-2721 (Walter Reed-2721) [chemically S-2-(3-aminopropyl-amino) ethyl phosphorothioic acid] is toxic at their optimal concentrations. This has necessitated the need for agents that are safe and easily acceptable to humans.
BACKGROUND
Dietary agents with beneficial effects like free radical scavenging, antioxidant and immunomodulatory effects are being recognized as useful and have been investigated for their radioprotective properties. Studies in these lines have shown that the fruits of Aegle marmelos (stone apple or bael), Emblica officinalis or Phyllanthus emblica (Indian gooseberry/amla), Eugenia jambolana or Syzygium jambolana (black plum/jamun), Mangifera indica (mango) and Grewia asiatica (phalsa or falsa) that are originally reported to be indigenous to India have been investigated for their usefulness as radioprotective agents.
OBJECTIVE
The objective of this review is to summarize the beneficial effects of the Indian indigenous fruits, stone apple, mango, Indian gooseberry, black plum, and phalsa, in mitigating radiation-induced side effects, emphasize the underlying mechanism of action for the beneficial effects and address aspects that merit detail investigations for these fruits to move towards clinical application in the near future.
METHODS
The authors data-mined Google Scholar, PubMed, Embase, and the Cochrane Library for publications in the field from 1981 up to July 2020. The focus was on the radioprotection and the mechanism responsible for the beneficial effects, and accordingly, the articles were collated and analyzed.
RESULTS
This article emphasizes the usefulness of stone apple, mango, Indian gooseberry, black plum, and phalsa as radioprotective agents. From a mechanistic view, reports are suggestive that the beneficial effects are mediated by triggering free radical scavenging, antioxidant, anti-mutagenic and anti-inflammatory effects.
CONCLUSION
For the first time, this review addresses the beneficial effects of mango, Indian gooseberry, black plum, stone apple and phalsa as radioprotective agents. The authors suggest that future studies should be directed at understanding the selective radioprotective effects with tumor-bearing laboratory animals to understand their usefulness as radioprotective drug/s during radiotherapy and as a food supplement to protect people from getting exposed to low doses of radiation in occupational settings. Phase I clinical trial studies are also required to ascertain the optimal dose and the schedule to be followed with the standardized extract of these fruits. The most important aspect is that these fruits, being a part of the diet, have been consumed since the beginning of mankind, are non-toxic, possess diverse medicinal properties, have easy acceptability, all of which will help take research forward and be of benefit to patients, occupational workers, agro-based sectors and pharma industries.
Topics: Animals; Antineoplastic Agents; Fruit; Humans; India; Neoplasms; Radiation, Ionizing; Radiation-Protective Agents
PubMed: 34229590
DOI: 10.2174/1871520621666210706124315 -
Supportive Care in Cancer : Official... Jan 2021Taste and smell disturbances in patients affected by cancer are very common, but often under-recognized symptoms. If not addressed properly, they may impact nutritional... (Review)
Review
PURPOSE
Taste and smell disturbances in patients affected by cancer are very common, but often under-recognized symptoms. If not addressed properly, they may impact nutritional status, food enjoyment, and quality of life. Treatment tools available for clinicians to manage chemosensory alterations are limited and are often based on personal clinical experiences. The aim of this study was to assess current oncological and palliative care literature through a scoping review, in order to identify available treatments for taste and smell alterations in cancer patients.
METHODS
Medline, Embase, CINAHL, ProQuest Dissertations and Theses, and Google Scholar were searched from inception until January 2020, with subject headings relevant to the domains of chemosensory alterations, palliative, and cancer care. A total of 10,718 English and French language publications were reviewed, yielding 43 articles on the researched topic.
RESULTS
The heterogeneity of selected articles led to difficulties in interpretation and analysis of the available evidence. Included publications differed in study design, population sample, anticancer treatments, and measures of assessment for taste and smell disturbances. A broad variety of treatment options were described including zinc and polaprezinc, radio-protectors, vitamins and supplements, anti-xerostomia agents, active swallowing exercises, nutritional interventions, delta-9-tetrahydrocannabinol, and photobiomodulation.
CONCLUSION
This scoping review identifies the current state of knowledge regarding chemosensory alterations within supportive cancer care. Despite not reaching firm conclusions, this article offers therapeutic venues to further explore in larger and more methodologically sound studies.
Topics: Adult; Amifostine; Carnosine; Dronabinol; Humans; Neoplasms; Nutritional Status; Olfaction Disorders; Organometallic Compounds; Palliative Care; Quality of Life; Selenium; Smell; Taste; Taste Disorders; Zinc Compounds
PubMed: 32734392
DOI: 10.1007/s00520-020-05609-4 -
International Journal of Radiation... Aug 2019Radioprotectors can enhance the efficacy of cancer radiotherapy, but their clinical use remains uncommon. The present study aimed to assess the radioprotective...
Radioprotectors can enhance the efficacy of cancer radiotherapy, but their clinical use remains uncommon. The present study aimed to assess the radioprotective potential of mistletoe extract (commercial name: Abnoba Viscum), a well-known complementary cancer medicine, in zebrafish larvae. Wild-type AB zebrafish embryos at 4 h-post-fertilization were exposed to 5 Gy 9-MeV electron beam irradiation after being treated for 1 h with 4 mMl/L amifostine or 0.2 mg/ml Abnoba Viscum A, F, M, or Q. Primary endpoints were abnormality-free survival and abnormality-free rates among survivors at 5 days-post-fertilization. The crude abnormality-free survival rates were 33.7%, 49.0%, 38.8%, 43.9%, 38.1%, and 52.6%, whereas abnormality-free rates among survivors were 36.4%, 49.6%, 37.8%, 45.6%, 52.0%, and 62.8% for the control (with no pharmacologic treatment), amifostine, Abnoba Viscum A, F, M, and Q groups, respectively. Abnormality-free survival rates in the amifostine and Abnoba Viscum Q groups were significantly different from those in the control ( = .040 and .012, respectively), with an odds ratio (OR) of 1.90 [95% confidence interval (CI): 1.03-3.51] and 2.20 (95% CI: 1.19-4.08), respectively. Abnormality-free rates among survivors in the amifostine and Abnoba Viscum M and Q groups were significantly different from those in the control group ( = .048, .042, and <.001, respectively), with an OR of 1.79 (95% CI: 1.00-3.20), 1.82 (95% CI: 1.02-3.26), and 2.98 (1.67-5.33), respectively. Abnoba Viscum Q has at least a similar radioprotective effect to that of amifostine. Mistletoe extracts have been clinically applied for a long time and their effectiveness and feasibility have been verified. Abnoba Viscum Q might be a new candidate radioprotectant to enhance cancer radiotherapy efficacy.
Topics: Amifostine; Animals; Embryo, Nonmammalian; Mistletoe; Plant Extracts; Radiation-Protective Agents; Zebrafish
PubMed: 30836032
DOI: 10.1080/09553002.2019.1590661 -
Biomedicines Oct 2020The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and... (Review)
Review
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
PubMed: 33142986
DOI: 10.3390/biomedicines8110461 -
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