Radiomitigative Effects of Approved Hematopoietic Drugs on Mice Exposed to Lethal Total-body Irradiation

In cases of radiological accidents, especially for victims exposed to high-dose total-body irradiation (TBI), the administration of appropriate approved hematopoietic drugs is the most rapid medical treatment for preventing severe acute radiation syndrome, which is associated with a high mortality rate. However, at present, there are few suitable pharmaceutical drugs available in Japan, aside from granulocyte colony-stimulating factor (G-CSF). Depending on the situation surrounding the accident, various drug treatment options and the development of effective drug therapies may be required. In the present study, we assessed various combinations of seven commercially available drugs-G-CSF, erythropoietin (EPO), romiplostim (RP), ancer (AN), cepharanthine (CE), leucon (LC) and leukoprol (LP)-in mice exposed to a lethal dose of 7 or 8 Gy of X-ray irradiation. Each drug was administered as a single or mixed intraperitoneal injection once or twice daily for three consecutive days. The single administration of the approved hematopoietic drugs CE, LC, or LP twice a day for 3 days significantly improved the 30-day survival rate of lethal TBI mice (p < 0.05; 75%, 100%, or 100%, respectively) compared with the untreated TBI mice, accompanied by a gradual increase in the body weight. Furthermore, the combined administration of RP, EPO and G-CSF or single administration of RP alone gradually increased the body weight of mice exposed to lethal TBI, with 30-day survival rates of 75% or 100%, respectively (p < 0.05). This study suggested that some new domestically approved hematopoietic drugs may have radiomitigative potential for mice exposed to lethal TBI, and the 12-h interval administration of LC or LP for 3 days to 7-Gy-TBI mice and 12-h interval administration of RP alone for 3 days to 8-Gy-TBI mice were the most suitable medications with respect to the 30-day survival rate. As long as the threat of nuclear disaster exists, diverse efforts in thefield of radiation emergency medicine, including the development of effective drug therapies, will be necessary

Expression of γ-H2AX, 53BP1 and Micronuclei as Genome Damage Biomarker of Population in Keang and Salumati Village, Mamuju West Sulawesi Province

The residents living in high background radiation area have risk to be exposed by ionizing radiation that also potentially cause their DNA damage. The aim of this study was to determine the expression of γ-H2AX, 53BP1 foci and micronuclei in the residentswho live in high background radiation area of Salumati village, Mamuju, West Sulawesi, Indonesia. Twenty one blood samples which consist of 11 from the study area and 10 from control were assessed for their expression of γ-H2AX and 53BPI foci by using specific antibodies and observed under fluorescence microscope whereas micronuclei was detected after being cultured and giemsa stainedaccording to standard procedures. Results showed that both γ-H2AX and 53BP1foci from high background area was lower than that of control area (0.37±0.24vs 0.19±0.11 (p=0.03) for γ-H2AX and 0.61±0.30vs 0.31±0.12 for 53BP1 (p=0.01)). The mean of micronuclei frequency in exposed area was 0.02 (0,01-0,03) while in control area was 0.02 (0.003-0.02). There was statistical significant in corellation between both γ-H2AX, 53BP1 foci with micronuclei index in exposed area (p=0.02, p=0,04 respectively).In conclusion,there was a positive correlation between γ-H2AX and 53BP1 foci to micronuclei and this might be a clue of the occurrence of genome repairing mechanism caused by natural radiation at low dose chronical exposure in thestudied area

Assessment of Individual Radiosensitivity in Inhabitants of Takandeang Village - A High Background Radiation Area in Indonesia

People living in high background radiation area (HBRA) possibly developed the radioadaptive response (RAR) phenomena. Mamuju area in West Sulawesi Indonesia also known as the HBRA in Indonesia due to high natural uranium contents. It is possible that RAR was developed in Mamuju inhabitants. To prove this hypothesis, here in this study evaluation of the individual radiosensitivity in Takandeang Village, Mamuju inhabitants using G2 micronucleus (MN) assay was conducted. Association between blood groups and TP53 Arg72Pro polymorphism with individual radiosensitivity also evaluated in this study. Using G2 MN assay we assessed the individual radiosensitivity of Takandeang Village inhabitants and control samples. For each sample, three parameters were calculated. The spontaneous (baseline) MN number, MN number after 0.5 Gy in vitro irradiation and radiation induced MN were calculated to predict the individual radiosensitivity. The radiation induced MN was defined by subtracting the spontaneous MN number from the MN number after irradiation. The mean and SD of the number of micronucleus induced by radiation found in control group (CG) was set as the cut-off value to determine the individual radiosensitivity in all samples. The radiation induced MN higher than the mean CG + 1SD CS was scored as 1, indicating a milder radiosensitive phenotype, whereas a result higher than the mean CG + 2SD CG was scored as 2, and indicated a more severe radiosensitive phenotype. When the individual value was lower than the mean CG + 1SD CG, a score of 0 was attributed to the tested subject. Results showed that four individuals in Takandeang Village inhabitants were having a milder radiosensitive phenotype, whilst the other was categorized as normal radiosensitive. The similar finding also found in control samples. Our study failed to find a correlation between radiosensitivity and blood group also the TP53 Arg72Pro polymorphism. Overall our study revealed the possibility of RAR phenomena in Takandeang Village inhabitants. Further investigation using a different point of radiation dose value and larger sample number should be performed to validate this study results.       

Inhibition of HIF-1α by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo

In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1α observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 μM TAS106. To study the function of HIF-1α protein in apoptosis of hypoxic cells, we employed an HIF-1α reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1α gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg−1) suppressed HIF-1α expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1α expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours

DNA methylation status of REIC/Dkk-3 gene in human malignancies

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies. We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed. The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group. REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies

RNA interference approaches for treatment of HIV-1 infection

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery

Influence of breastfeeding on maternal blood pressure at one month postpartum

Satoko Ebina,1 Ikuo Kashiwakura21Department of Disability and Health, 2Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki, JapanBackground: The benefits of breastfeeding for improved health and developmental outcomes in mothers and their infants have been widely recognized. The purpose of the present study was to assess whether feeding modes influence maternal blood pressure at one month postpartum.Methods: The pregnancy charts of 407 women who delivered at a birthing center in rural Japan between August 1998 and September 2007 were analyzed. The criteria for inclusion were low-risk, full-term pregnancy (duration, 37–42 weeks) resulting in spontaneous vaginal deliveries, intrapartum hemorrhage < 500 mL, and a healthy infant (Apgar score ≥ 8 at one minute).Results: The subjects were classified into three groups based on feeding modes. The proportion of each mode was 28.3% in the breastfeeding group, 56.5% in the mixed-feeding group, and 15.2% in the formula-feeding group. The systolic blood pressure (SBP) in mothers at one month postpartum for each feeding mode was 118.4 ± 8.7 mmHg in the breastfeeding group, 120.6 ± 9.3 mmHg in the mixed-feeding group, and 122.0 ± 9.9 mmHg in the formula-feeding group. SBP at one month postpartum in the breastfeeding group was significantly lower than that in the other groups. No significant differences were observed in diastolic blood pressure in the three groups at one month postpartum.Conclusion: Breastfeeding resulted in lower SBP in mothers at one month postpartum compared with those using other feeding modes, thus indicating an effect of breastfeeding on maternal blood pressure.Keywords: breastfeeding, blood pressure, feeding mode, postpartu