Showing papers in "International Journal of Radiation Biology in 2014"
TL;DR: This review discusses CSC-specific mechanisms that confer radiation resistance in breast cancer and glioblastoma multiforme and concludes that both C SCs-intrinsic and C SC-extrinsics factors as well as adaptive responses in CSC caused by irradiation and microenvironmental changes all make contributions toCSC-mediated radioresistance.
Abstract: Purpose: Radiation therapy has made significant contributions to cancer treatment. However, despite continuous improvements, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be attributable to the presence of cancer stem cells (CSC). The purpose of this review is to discuss CSC-specific mechanisms that confer radiation resistance.Conclusions: We focus our discussions on breast cancer and glioblastoma multiforme (GBM) and conclude that both CSC-intrinsic and CSC-extrinsic factors as well as adaptive responses in CSC caused by irradiation and microenvironmental changes all make contributions to CSC-mediated radioresistance. Our discussions emphasize CSC as novel therapeutic targets in order to potentiate radiotherapy efficacy.
215 citations
TL;DR: There is growing evidence that one-electron oxidation reactions of nucleobases whose mechanisms have been characterized in model studies involving aqueous solutions take place in a similar way in cells.
Abstract: Purpose: The aim of this survey is to critically review the available information on one-electron oxidation reactions of nucleobases in cellular DNA with emphasis on damage induced through the transient generation of purine and pyrimidine radical cations. Since the indirect effect of ionizing radiation mediated by hydroxyl radical is predominant in cells, efforts have been made to selectively ionize bases using suitable one-electron oxidants that consist among others of high intensity UVC laser pulses. Thus, the main oxidation product in cellular DNA was found to be 8-oxo-7,8-dihydroguanine as a result of direct bi-photonic ionization of guanine bases and indirect formation of guanine radical cations through hole transfer reactions from other base radical cations. The formation of 8-oxo-7,8-dihydroguanine and other purine and pyrimidine degradation products was rationalized in terms of the initial generation of related radical cations followed by either hydration or deprotonation reactions in agre...
122 citations
TL;DR: There is limited evidence to date that targeting hypoxic regions during conventional therapy is effective, however, improved hypoxia-imaging technologies and image guided individualized hypoxic targeted therapy in conjunction with the development of novel molecular targets may be able to challenge the protective effect on the tumor provided by Hypoxia.
Abstract: Background : Tumor initiation, growth and relapse after therapy are thought to be driven by a population of cells with stem cell characteristics, named cancer stem cells (CSC). The regulation of their radiation resistance and their maintenance is poorly understood. CSC are believed to reside preferentially in special microenvironmental niches located within tumor tissues. The features of these niches are of crucial importance for CSC self-renewal, metastatic potential and therapy resistance. One of the characteristics of solid tumors is occurrence of less oxygenated (hypoxic regions), which are believed to serve as so-called hypoxic niches for CSC. Purpose : The purpose of this review was the critical discussion of the supportive role of hypoxia and hypoxia-related pathways during cancer progression and radiotherapy resistance and the relevance for therapeutic implications in the clinic. Conclusion : It is generally known since decades that hypoxia inside solid tumors impedes chemo- and radiotherapy. However, there is limited evidence to date that targeting hypoxic regions during conventional therapy is eff ective. Nonetheless improved hypoxia-imaging technologies and image guided individualized hypoxia targeted therapy in conjunction with the development of novel molecular targets may be able to challenge the protective eff ect on the tumor provided by hypoxia.
117 citations
TL;DR: The emergence of powerful proteomic and genomic technologies in conjunction with advanced bioinformatic tools allows the simultaneous analysis of thousands of biological molecules that yield the discovery of new tumor signatures, which are sensitive and specific enough for early cancer detection, for monitoring disease progression and for proper treatment selection.
Abstract: Purpose: Cancer is a multigene disease which arises as a result of mutational and epigenetic changes coupled with activation of complex signaling networks. The use of biomarkers for early cancer detection, staging and individualization of therapy might improve patient care. A few fundamental issues such as tumor heterogeneity, a highly dynamic nature of the intrinsic and extrinsic determinants of radio- and chemoresistance, along with the plasticity and diversity of cancer stem cells (CSC) make biomarker development a challenging task. In this review we outline the preclinical strategies of cancer biomarker discovery including genomic, proteomic, metabolomic and microRNomic profiling, comparative genome hybridization (CGH), single nucleotide polymorphism (SNP) analysis, high throughput screening (HTS) and next generation sequencing (NGS). Other promising approaches such as assessment of circulating tumor cells (CTC), analysis of CSC-specific markers and cell-free circulating tumor DNA (ctDNA) are ...
115 citations
TL;DR: The laboratory has found that Neuropilin-2-induced autophagy is a potent mediator of therapy resistance in different cancer types and further research is needed to understand these in more detail.
Abstract: Purpose: Macroautophagy is a catabolic pathway that degrades cellular components through the lysosomal machinery. Cytoplasmic components are sequestered in double-membrane autophagosomes. They fuse with lysosomes where their cargo is delivered for degradation and recycling. Autophagy acts as a survival mechanism under stress by producing energy and as an intracellular quality management system by clearing damaged organelles like mitochondria and proteins. In this review, the regulation and the role of autophagy in cancer and therapy response are discussed. Furthermore, we will summarize methods for detecting autophagy in vitro and in vivo.Conclusion: During the early and late stages of cancer development, the role of autophagy differs. In the very early stages of carcinogenesis, autophagy has an important function by reducing cancer initiating genetic instability and aberrant protein aggregates as well as promoting anti-cancer immune response. In established malignant tumors autophagy confers resi...
87 citations
TL;DR: The role of the CXCR4/CXCL12 axis in the modulation of CSC properties, the regulation of the tumor microenvironment in response to irradiation, therapy resistance and tumor relapse is summarized.
Abstract: Purpose : Radioresistance of cancer cells remains a fundamental barrier for maximum effi cient radiotherapy. Tumor heterogeneity and the existence of distinct cell subpopulations exhibiting diff erent genotypes and biological behaviors raise diffi culties to eradicate all tumorigenic cells. Recent evidence indicates that a distinct population of tumor cells, called cancer stem cells (CSC), is involved in tumor initiation and recurrence and is a putative cause of tumor radioresistance. There is an urgent need to identify the intrinsic molecular mechanisms regulating the generation and maintenance of resistance to radiotherapy, especially within the CSC subset. The chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer, being involved in chemotaxis, stemness and drug resistance. The interaction of CXCR4 with its ligand, the chemokine C-X-C motif ligand 12 (CXCL12), plays an important role in modulating the tumor microenvironment, angiogenesis and CSC niche. Moreover, the therapeutic inhibition of the CXCR4/CXCL12 signaling pathway is sensitizing the malignant cells to conventional anti-cancer therapy. Content : Within this review we are summarizing the role of the CXCR4/CXCL12 axis in the modulation of CSC properties, the regulation of the tumor microenvironment in response to irradiation, therapy resistance and tumor relapse. Conclusion : In light of recent fi ndings, the inhibition of the CXCR4/CXCL12 signaling pathway is a promising therapeutic option to refi ne radiotherapy.
74 citations
TL;DR: It was demonstrated that iron oxide nanoparticles with the appropriate surface modifications can enter the DU145 cells and it can be used as a cell sensitizer to megavoltage ionizing radiations in radiation therapy.
Abstract: Purpose: To examine the radiosensitizing effects of iron oxide nanoparticles in the presence of 6 MV (megavoltage) X-ray radiation.Materials and methods: Iron oxide nanoparticles with two different modifications – dextran coating (plain) and amino-group dextran coating – were used. The rate of iron oxide penetration was monitored using Prussian blue staining, magnetic resonance imaging and atomic adsorption spectroscopy. The effect of iron oxide on the viability of cells was determined using trypan blue dye exclusion assay followed by evaluating the cytotoxicity effect of amino-group iron oxide nanoparticles and ionizing radiation. Radiation dose enhancement studies were carried out on DU145 human prostate carcinoma cell line with 1 mg/ml amino-group iron oxide nanoparticles and different doses of 6 MV X-ray radiation.Results: The uptake of amino-group coated nanoparticles by DU145 cells was significantly more than the plain nanoparticles. In addition, cell viability was decreased with the increas...
68 citations
TL;DR: Results imply that the IR-induced phenotype may be enhanced by alterations in genes associated with senescence, and the expression levels of several genesassociated with cell cycle regulation are remarkably increased in IR-exposed endothelial cells.
Abstract: Purpose: Inhibition of growth in mammalian cells in response to damage or stress is known as cellular senescence. Increasing evidence suggests that double-strand breaks (DSB) commonly mediate cellular senescence. Recently, radiation exposure has been reported to induce premature senescence.Materials and methods: We investigated whether ionizing radiation (IR) at 4 Gy induces cellular senescence with DNA damage response in human umbilical vein endothelial cells (HUVEC). To determine alterations in gene expression on IR exposure, we have developed a DNA microarray analysis system that contains genes known to be involved in replicative senescence.Results: The damage by IR exposure is shown to result in a variety of senescence-like phenotypes such as changes in cell morphology, decrease in cell proliferation, increase in senescence- associated β-galactosidase (SA-β-gal) staining, and suppression of angiogenic activity. Moreover, the expression levels of several genes associated with cell cycle regulat...
55 citations
TL;DR: Molecular analyses indicate that p53-dependent signals might be responsible for the abscopal effect in the model system, via a pro-apoptotic pathway, and suggest that the interplay between delivered dose and p53 status might help to sterilize out-of-field tumour cells.
Abstract: Purpose: This study investigates whether the abscopal effect induced by radiation-therapy (RT) is able to sterilize non-irradiated tumour cells through bystander signals.Material and methods: Wild-type (wt)-p53 or p53-null HCT116 human colon cancer cells were xenografted into both flanks of athymic female nude mice. When tumours reached a volume of 0.2 cm3, irradiation was performed, under strict dose monitoring, with a dedicated mobile accelerator designed for intra-Operative-RT (IORT). A dose of 10 or 20 Gy (IR groups), delivered by a 10 MeV electron beam, was delivered to a tumour established in one side flank, leaving the other non-irradiated (NIR groups). A subset of mice were sacrificed early on to carry out short-term molecular analyses.Results: All directly-irradiated tumours, showed a dose-dependent delayed and reduced regrowth, independent of the p53 status. Importantly, a significant effect on tumour-growth inhibition was also demonstrated in NIR wt-p53 tumours in the 20 Gy-irradiation ...
51 citations
TL;DR: A dedicated analysis pointed to the involvement of insulin-like growth factor binding protein 5 (IGFBP5) signaling in radiation-induced premature senescence in HUVEC cells exposed to chronic low dose rate radiation.
Abstract: Purpose: Ionizing radiation has been recognized to increase the risk of cardiovascular diseases (CVD). However, there is no consensus concerning the dose-risk relationship for low radiation doses and a mechanistic understanding of low dose effects is needed. Material and methods: Previously, human umbilical vein endothelial cells (HUVEC) were exposed to chronic low dose rate radiation (1.4 and 4.1 mGy/h) during one, three and six weeks which resulted in premature senescence in cells exposed to 4.1 mGy/h. To gain more insight into the underlying signaling pathways, we analyzed gene expression changes in these cells using microarray technology. The obtained data were analyzed in a dual approach, combining single gene expression analysis and Gene Set Enrichment Analysis. Results: An early stress response was observed after one week of exposure to 4.1 mGy/h which was replaced by a more inflammation-related expression profile after three weeks and onwards. This early stress response may trigger the radiation-induced premature senescence previously observed in HUVEC irradiated with 4.1 mGy/h. A dedicated analysis pointed to the involvement of insulin-like growth factor binding protein 5 (IGFBP5) signaling in radiation-induced premature senescence. Conclusion: Our findings motivate further research on the shape of the dose-response and the dose rate effect for radiation- induced vascular senescence.
49 citations
TL;DR: Reviewing the results from previous studies aiming at the molecular characterization of circulating tumor cells (CTC) addressed the role of epithelial-mesenchymal-transition (EMT) and stemness features of CTC in their contribution to tumor progression and to summarize potential interference of C TC with the efficacy of radiotherapy.
Abstract: Purpose : To review the results from previous studies aiming at the molecular characterization of circulating tumor cells (CTC), to specifi cally address the role of epithelial-mesenchymal-transition (EMT) and stemness features of CTC in their contribution to tumor progression and to summarize potential interference of CTC with the effi cacy of radiotherapy. Conclusions: Detection of CTC has been reported for most epithelial tumors and has been associated with an increased risk of local and regional recurrence as well as the development of distant metastases. Given a causal relationship between the presence of CTC and tumor progression at the primary or distant sites, several distinct features have to be postulated for these cells: First, a change from an epithelial to a mesenchymal cell-like phenotype which should alleviate the disconnection of individual tumor cells from tight cell-to-cell junctions within the epithelial cell layer and endow single tumor cells with the capacity to migrate into blood vessels; secondly, the presence of stem-cell properties which contribute to the re-establishment of bulk tumor tissue at the primary or metastatic site upon tumor recurrence or distant progression, respectively. Indeed, EMT and stem-cell features were frequently observed in CTC and the phenotype of CTC was established as a stronger predictor of outcome than sole enumeration of CTC in a defi ned volume of blood. The exploitation of CTC above their use as prognostic marker is still a subject of many ongoing investigations as are the identifi cation of suitable therapeutic targets for this small cell subpopulation.
TL;DR: The data demonstrate that the MULTIBIODOSE approach of applying multiparametric tools to radiation emergencies is valid and effective.
Abstract: Purpose: The European Union's Seventh Framework Programme-funded project ‘Multi-disciplinary biodosimetric tools to manage high scale radiological casualties’ (MULTIBIODOSE) has developed a multiparametric approach to radiation biodosimetry, with a particular emphasis on triage of large numbers of potentially exposed individuals following accidental exposures. In November 2012, an emergency exercise took place which tested the capabilities of the MULTIBIODOSE project partners. The exercise described here had a dual purpose: Intercomparison of (i) three biodosimetric assays, and (ii) the capabilities of the seven laboratories, with regards to provision of triage status for suspected radiation exposed individuals.Materials and methods: Three biological dosimetry tools – the dicentric, micronucleus and gamma-H2AX (the phosphorylated form of member X of histone H2A, in response to DNA double-strand breaks) foci assays – were tested, in addition to provision of the triage status results (low exposure: ...
TL;DR: Strategies to ameliorate the cognitive deficits after cranial radiotherapy should likely be adapted to the developmental level of the brain, indicating different mechanisms involved in degeneration and regeneration after injury.
Abstract: Purpose : Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially diff erent responses in the juvenile and the adult brain after irradiation, but this has never been verifi ed in a comparative study. Materials and methods : We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of diff erentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed. Results : The major fi ndings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) diff erently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-infl ammatory response in adult brains. Conclusion : We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive defi cits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
TL;DR: Mature, lineage-restricted progenitors appear to be more responsive to the protective effects of low doses of amifostine than the more primitive, multipotential progenitor subtypes.
Abstract: Purpose: Amifostine is a highly efficacious cytoprotectant when administered in vivo at high doses. However, at elevated doses, drug toxicity manifests for general, non-clinical radioprotective purposes. Various strategies have been developed to avoid toxic side-effects: The simplest is reducing the dose. In terms of protecting hematopoietic tissues, where does this effective, non-toxic minimum dose lie?Material and methods: C3H/HEN mice were administered varying doses of amifostine (25–100 mg/kg) 30 min prior to cobalt-60 irradiation and euthanized between 4–14 days for blood and bone marrow collection and analyses.Results: Under steady-state, amifostine had little effect on bipotential and multi-potential marrow progenitors but marginally suppressed a more primitive, lineage negative progenitor subpopulation. In irradiated animals, prophylactic drug doses greater than 50 mg/kg resulted in significant regeneration of bipotential progenitors, moderate regeneration of multipotential progenitors, bu...
TL;DR: This study indicates that reactive oxygen species (ROS) is eliminated by biosynthesis of anthocyanin and antioxidant enzymes, and suggests that exposure to ionizing radiation according to increase of exposure time has led to efficient induction of antho- and antioxidant enzyme activities.
Abstract: Purpose: To investigate the mechanisms of adaptation and tolerance to ionizing radiation using chronic radiation in wheat.Materials and methods: We exposed wheat plants to chronic gamma irradiation (50 Gy) for 2, 4, and 6 weeks and measured various biological parameters.Results: Plant height was reduced by exposure to gamma irradiation; this effect increased with increasing exposure time. Photosynthetic pigment levels decreased with increasing exposure time, while anthocyanin levels significantly increased after exposure to gamma rays. The activities of antioxidant enzymes (superoxide dismutase [SOD], ascorbate peroxidase [APX], catalase [CAT], and peroxidase [POD]) and malondialdehyde (MDA) levels increased with increasing duration of exposure to gamma irradiation. Electron spin resonance (ESR) signals were strongly detected in wheat that was gamma-irradiated for two weeks and then gradually decreased with increasing exposure time. The expression of anthocyanin biosynthesis genes (flavanone 3-hyd...
TL;DR: Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis).
Abstract: Purpose: We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system.Method: 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals.Results: PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipri...
TL;DR: The study suggests that the induced cardiac remodelling begins with the reduction of intramyocardial vessels in the left ventricle tissue, leading to the replacement of healthy tissue by fibrous tissue.
Abstract: Purpose: Breast cancer treatments can induce important cardiovascular complications. The aim of this study was to evaluate cardiac alterations after irradiation and chemotherapy in an animal model.Material and methods: Wistar rats were divided into three groups: Control, TC+ IR (received chemotherapy and irradiation) and IR (received only irradiation). After 5 months, echocardiography was performed, the animals were euthanized, and the left ventricle was analyzed using light microscopy techniques and Polymerase Chain Reaction (PCR).Results: Echocardiography showed decreases in ejection fraction and cardiac output, in TC+ IR group. Both TC+ IR and IR showed reduced intramyocardial vessel-to-cardiomyocyte ratio, increased connective tissue, cardiomyocyte hypertrophy, increased numbers of apoptotic nuclei and increased Bax/Bcl2 expression. We also observed increased Transforming growth factor (TGF) beta 1 mRNA expression in both groups, but type 1 Procollagen expression was increased in TC+ IR group ...
TL;DR: It is demonstrated that photodynamic therapy with hypocrellin B remarkably induced apoptosis and inhibited adhesion and migration of cancer cells in vitro.
Abstract: Purpose : In the present study, we investigated eff ects of photodynamic therapy with hypocrellin B on apoptosis, adhesion, and migration of cancer cells in vitro. Materials and methods : Human ovarian cancer HO-8910 cell as a cancer model cell was incubated with hypocrellin B at a concentration of 2.5 m M for 5 h and irradiated by light from a light-emitting diodes (LED) source. Cell apoptosis was analyzed by fl ow cytometry with annexin V/propidium iodide (PI) staining and nuclear staining 6 h after hypocrellin B photoirradiation. Cell adhesion was assessed using the 3-(4, 5-dimthylthiazol-2-yl)-2, 5 diphenyl-tetrazolium bromide (MTT) assay 4 h after photodynamic treatment. Cell migration was measured 48 h after photodynamic treatment. Results : Flow cytometry with annexin V/PI staining showed that early apoptotic and late apoptotic (necrotic) rates following photodynamic therapy with hypocrellin B markedly increased to 16.40% and 24.67%, respectively. Nuclear staining found nuclear condensation and typical apoptotic body in the treated cells. The number of cell migration was signifi cantly decreased to 183 28 after photodynamic therapy with hypocrellin B ( p 0.01). Light irradiation alone and hypocrellin B alone had no signifi cant eff ect on cell migration. The cell adhesion inhibitory rate due to photodynamic action of hypocrellin B was 53.2 1.8%, signifi cantly higher than 2.7 2.1% of light treatment alone and 1.0 0.4% of hypocrellin B treatment alone ( p 0.01). Conclusion : The fi ndings demonstrated that photodynamic therapy with hypocrellin B remarkably induced apoptosis and inhibited adhesion and migration of cancer cells in vitro.
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TL;DR: It could be concluded that purslane extract and fish oil may have therapeutic potential to improve hepatic and renal functions as well as oxidative stress in irradiated rats.
Abstract: Purpose: To evaluate the impact of oral administration of purslane (Portulaca oleracea) extract or fish oil and their co-treatments in the modulation of radiation-induced damage.Material and methods: Purslane (P) (400 mg/kg body weight) or fish oil (Fo) (60 mg/kg body weight) was administrated to male albino rats via gastric intubation for 15 days after whole body exposure to a single dose of 6 Gy gamma rays. The animals were sacrificed after the elapse of 15 days.Results: The results revealed that irradiation induced a significant elevation of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), and atherogenic index: TC/high density lipoprotein cholesterol (HDL-c) in addition to aspartate and alanine transaminase (AST, ALT), alkaline phophatase (ALP), bilirubin, as well as urea, creatinine and uric acid. Moreover, liver, kidney and heart malondialdehyde (MDA) was significantly elevated, whereas nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT) and ...
TL;DR: In this article, the authors characterized mechanisms underlying ionizing radiation (IR)-induced UPR signaling pathways in human umbilical vein endothelial cells (HUVEC) irradiated with 15 Gy IR and showed that IR selectively activated the eIF2α/ATF4 branch of the UPR signalling pathway, with no alterations in the IRE1 and ATF6 branches in HUVEC and HCAEC.
Abstract: Purpose: Perturbations in protein folding induce endoplasmic reticulum (ER) stress, which elicits coordinated response, namely the unfolded protein response (UPR), to cope with the accumulation of misfolded proteins in ER. In this study, we characterized mechanisms underlying ionizing radiation (IR)-induced UPR signaling pathways.Materials and methods: We analyzed alterations in UPR signaling pathways in human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) irradiated with 15 Gy IR.Results: IR selectively activated the eIF2α/ATF4 branch of the UPR signaling pathway, with no alterations in the IRE1 and ATF6 branches in HUVEC and HCAEC. Phosphorylation of PERK was enhanced in response to IR, and the IR-induced activation of the eIF2α/ATF4 signaling pathway was completely inhibited by PERK knockdown with siRNA. Surprisingly, chemical chaperones, which inhibit the formation of misfolded proteins and sequential protein aggregates to reduce ER stress, failed ...
TL;DR: It may be concluded that low level EMF at 2.45 GHz MWR increases the DNA damage in both brain tissues and plasma of the rats whereas it increases protein oxidation only in plasma.
Abstract: Purpose: To investigate the oxidative damage and protective effect of garlic on rats exposed to low level of electromagnetic fields (EMF) at 2.45 GHz Microwave radiation (MWR). Methods: Thirty-six Wistar rats were divided into three groups. Group I was the control group and not exposed to EMF. Group II and III were exposed to low level EMF (3.68 0.36 V/m) at 2.45 GHz MWR for 1 hour/day for 30 consecutive days. Daily 500 mg/kg garlic was given to Group III during the study period. At the end of the study, thiobarbituric acid reactive substances (TBARS), advanced oxidation protein products (AOPP) and 8-hydroxydeoxyguanosine (8-OHdG) levels were investigated in brain tissue and blood samples. Results: Exposure to low level of EMF increased 8-OHdG level in both plasma and brain tissue whereas it increased AOPP level only in plasma. Garlic prevented the increase of 8-OHdG level in brain tissue and plasma AOPP levels. Conclusions: It may be concluded that low level EMF at 2.45 GHz MWR increases the DNA damage in both brain tissues and plasma of the rats whereas it increases protein oxidation only in plasma. It may also be argued that the use of garlic decreases these effects.
TL;DR: Generic (element-independent) absorption rates from the respiratory and alimentary tracts to blood and systemic biokinetic models are proposed, which include some element-specific parameter values to reflect regular changes with ionic radius in certain aspects of the behavior of the lanthanoids.
Abstract: Purpose: This paper reviews data related to the behavior of the lanthanoid elements (lanthanum through lutetium, atomic numbers 57–71) in the human body and proposes biokinetic models for internall...
TL;DR: Existing epidemiological data on the physicochemical properties of uranium and associated health outcomes are inconclusive and further studies among certain groups of uranium-processing workers (uranium-enrichment and fuel-fabrication workers) could contribute to the knowledge of the health effects of uranium with respect to its physic biochemical properties.
Abstract: Purpose: Physicochemical properties of uranium, including isotopic composition and solubility, are determinants of its toxicity. We reviewed epidemiological studies in civilian and military workers known to be exposed to uranium with different physicochemical properties to investigate its long-term effects, such as cancerous and circulatory diseases.Materials and methods: We systematically searched the Pubmed and the Scopus databases to identify studies of uranium- processing workers (published between 1980 and 2013) and veterans of the wars in the Persian Gulf and the Balkans (published between 1991 and 2013) in which defined outcomes, such as lung, lymphohematopoietic, kidney cancers, and circulatory diseases were examined. Results from these studies in terms of risk of each health outcome (mortality or incidence) and analyses of dose-response relationship were examined to present the impact of uranium physicochemical properties on the observed results.Results: Twenty-seven articles were reviewe...
TL;DR: The oxidation of liver enzymes may underlie some radiation-induced alterations in hepatic function, and radiation exposure increased carbonylation of specific liver proteins including carbonic anhydrase 1, α-enolase, and regucalcin.
Abstract: Purpose: Protein oxidation in response to radiation results in DNA damage, endoplasmic reticulum stress/unfolded protein response, cell cycle arrest, cell death and senescence. The liver, a relatively radiosensitive organ, undergoes measurable alterations in metabolic functions following irradiation. Accordingly, we investigated radiation-induced changes in liver metabolism and alterations in protein oxidation.Materials and methods: C57BL/6 mice were sham irradiated or exposed to 8.5 Gy 60Co (0.6 Gy/min) total body irradiation. Metabolites and metabolic enzymes in the blood and liver tissue were analyzed. Two-dimensional gel electrophoresis and OxyBlot™ were used to detect carbonylated proteins that were then identified by peptide mass fingerprinting.Results: Analysis of serum metabolites revealed elevated glucose, bilirubin, lactate dehydrogenase (LDH), high-density lipoprotein, and aspartate aminotransferase within 24–72 h post irradiation. Liver tissue LDH and alkaline phosphatase activities we...
TL;DR: Methods that could be used to study protein profiling of CSC and to identify novel CSC-specific biomarkers and therapeutic targets are discussed.
Abstract: Purpose: New understanding of cancer stem cell (CSC) biology continues to emerge due to development of novel methods in genomics and proteomics. Analysis of nucleic acids (RNA, DNA) is widely used to elucidate molecular perturbations in malignant tumors and carcinoma cells, however genome data do not reflect the functional activities of encoded proteins. Therefore proteome-based methods could enhance knowledge about deregulation of pathways as a result of altered expression and activities of proteins in CSC.Methods and results: A sufficient number of CSC for proteomic analyses can be obtained in a variety of ways: Fluorescence (FACS) and magnetic (MACS) activated cell sorting, laser cell capture microdissection, and three-dimensional spheroid/organoid cell culture. These methods to enrich and isolate CSC can be performed either with or without staining using antibodies against currently known CSC-specific cell surface molecules, such as clusters of differentiation 44, 24, 133 (CD44, CD24, CD133), ...
TL;DR: There is large variability in the strategies used to generate and validate isogenic models of radioresistance and further characterization of these models is required.
Abstract: Purpose: The comparison of cell lines with differing radiosensitivities and their molecular response to radiation exposure has been used in a number of human cancer models to study the molecular response to radiation. This review proposes to analyze and compare the protocols used by investigators for the development and validation of these isogenic models of radioresistance.Conclusion: There is large variability in the strategies used to generate and validate isogenic models of radioresistance. Further characterization of these models is required.
TL;DR: The findings suggest that hNSC transplantation promotes the long-term recovery of the irradiated brain, where intrahippocampal stem cell grafting helps to preserve cognitive function.
Abstract: Purpose: Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition.Materials and methods: Athymic nude rats were cranially irradiated (10 Gy) and subjected to intrahippocampal transplantation surgery 2 days later. Human embryonic stem cells (hESC) or human neural stem cells (hNSC) were transplanted, and animals were subjected to cognitive testing on a novel place recognition task 8 months later.Results: Grafting of hNSC was found to provide long lasting cognitive benefits over an 8-month post-irradiation interval. At this protracted time, hNSC grafting improved behavioral performance on a novel place recognition task ...
TL;DR: The percentage of comets formed can be used to assess DNA damage in sonochemotherapy against chemoresistant cells when adjusting the threshold, reflecting the temporal shift in DNA damage.
Abstract: Purpose: To explore methodological modifications in the detection of DNA damage in sonochemotherapy for cisplatin-resistant human ovarian cancer cells using the comet assays.Materials and methods: Chemoresistant cells COC1/DDP were subjected to sonochemotherapy and DNA damage detected with the alkaline and neutral comet assays.Results: In the alkaline assay, the percentage of comets formed was less than that of dead cells, and most values for the percentage of comets formed were < 5% when using the default value to identify comets, showing an underestimation. These values were corrected when adjusting the threshold to the 95th percentile in control cells. In the neutral assay, this modification was not needed. Tail length (TL), tail moment (TM) and Olive tail moment (OTM) dramatically varied between comets. The 75th percentiles of TL, TM and OTM in the alkaline assay, and 90th percentiles in the neutral assay, correlated with the percentage of comets formed, thereby reflecting the temporal shift i...
TL;DR: An accelerated hematopoietic subsyndrome (AH-ARS) is observed at radiation doses between those producing H-ARS and GI-ARS, characterized by early onset of SIRS and FN, and greater lung damage, compared to H-ars.
Abstract: Purpose: To characterize acute radiation syndrome (ARS) sequelae at doses intermediate between the bone marrow (H-ARS) and full gastrointestinal (GI-ARS) syndrome.Methods: Male minipigs, approximat...
TL;DR: The alterations in the functioning of the mitochondrial ETC cause increase of superoxide radicals generation rate in all samples, formation of cellular hypoxia, and intensification of the oxide-initiated metabolic changes; and electron paramagnetic resonance methods could be used to track the qualitative and quantitative changes in the mitochondria ETC caused by the UHF EMR.
Abstract: Purpose : To study the eff ects of electromagnetic radiation (EMR) of ultra high frequency (UHF) in the doses equivalent to the maximal permitted energy load for the staff s of the radar stations on the biochemical processes that occur in the cell organelles. Materials and methods : Liver, cardiac and aorta tissues from the male rats exposed to non-thermal UHF EMR in pulsed and continuous modes were studied during 28 days after the irradiation by the electron paramagnetic resonance (EPR) methods including a spin trapping of superoxide radicals. Results : The qualitative and quantitative disturbances in electron transport chain (ETC) of mitochondria are registered. A formation of the iron-nitrosyl complexes of nitric oxide (NO) radicals with the iron-sulphide (FeS) proteins, the decreased activity of FeS-protein N2 of NADH-ubiquinone oxidoreductase complex and fl avo - ubisemiquinone growth combined with the increased rates of superoxide production are obtained. Conclusions : (i) Abnormalities in the mitochondrial ETC of liver and aorta cells are more pronounced for animals radiated in a pulsed mode; (ii) the alterations in the functioning of the mitochondrial ETC cause increase of superoxide radicals generation rate in all samples, formation of cellular hypoxia, and intensifi cation of the oxide-initiated metabolic changes; and (iii) electron paramagnetic resonance methods could be used to track the qualitative and quantitative changes in the mitochondrial ETC caused by the UHF EMR.