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

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

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