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“p,p’-DDE, the major metabolite of dic

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“p,p’-DDE, the major metabolite of dichlorodiphenoxytrichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. However, the mechanism underlying its male reproductive toxicity remains limited. Our previous studies have demonstrated that p,p’-DDE could induce mitochondria-mediated apoptosis of cultured rat Sertoli cells. In the present study, we investigated mitogen-activated protein kinase pathways as well as other mitochondria-related molecules including

BMS-754807 solubility dmso Bax family members and cytochrome c. Results showed that p,p’-DDE could induce oxidative stress-mediated p38 and JNK phosphorylation. In addition, elevated mRNA levels of cytochrome c and ratios of bax/bcl-w and bak/bcl-w were induced by p,p’-DDE treatment, which could be inhibited by Anlotinib datasheet RNA synthesis inhibitor (actinomycin D). p,p’-DDE-induced apoptosis was blocked by NAC (N-acetyl-L-cystein) preincubation and attenuated by pretreatment with p38 inhibitor (SB202190) or actinomycin D, but not with JNK inhibitor (SP600125). All of the findings suggested that oxidative stress-mediated p38 MAPK pathway and the balance between pro- and anti-apoptotic box-gene family might play

critical roles in p,p’-DDE-induced apoptosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Nowadays, drug development requires large-scale studies to show the real clinical benefit for the patients, which means recruiting a sufficient number of patients, even internationally. As global studies enable simultaneous delivery of new drugs and sharing GSK2245840 of safety information around the world, multinational studies now account for around 20% of Japanese clinical studies. Until recently, drug development has been centered in Western countries, but interest in Asian regions has increased. In this environment, one important factor in drug development is ethnicity. Various cancers show regional patterns in their incidence, and some (such as liver cancer and gastric cancer) show high incidences in Asian countries. Ethnic factors including genetic differences, such as the CYP drug-metabolizing enzymes in the liver and gene mutations, may result in different

drug responses in terms of efficacy and safety. Examples of ethnic differences in drug responses were seen with gefitinib, which showed a different efficacy data, and with sunitinib, showing a clearly different toxicity profile between the West and Asia. Therefore, ethnic differences need to be taken into account in the early phase of drug development, and Asian countries need to be involved early in clinical development. Asian collaboration among physicians and networks of specialists is also important, and there is good potential for successful establishment of the infrastructure needed for collaborative clinical trials. Establishment of a so-called third development center in Asian countries that will complement the USA and European centers is highly desired.”

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