Oxidative apoptosis and stress are implicated in the pathogenesis of diabetic embryopathy. activation of JNK1/2 signaling caspases 3 and 8 and apoptosis in Sox1+ neural progenitors of the developing neural tube. Our results show that JNK1 and JNK2 are equally involved in diabetic embryopathy and that the oxidative stress-JNK1/2-caspase pathway mediates the proapoptotic signals and the teratogenicity of maternal diabetes. The high rate of birth defects associated with diabetic pregnancy is a significant public health problem that results in major congenital malformations in up to 10% of newborn babies (1). Major malformations in children of pregestational diabetic women are neural tube CHIR-265 defects (NTDs) and cardiovascular defects. CHIR-265 The CHIR-265 recent rise in the number of diabetic women (2) makes this pregnancy complication a continuing issue (3). Because glycemic control in diabetic women is difficult to achieve and maintain (4) malformation rates of offspring in diabetic women even under modern preconception care are approximately six times higher than those in nondiabetic women (3). Therefore therapeutic interventions other than the achievement of euglycemia are needed to avert diabetes-associated adverse pregnancy outcomes. Mechanistic studies provide important insights in the development of accessible convenient and effective prevention strategies for diabetic embryopathy. Experimental data support the conclusion that congenital malformations during maternal hyperglycemia are the result of a disruption in the balance between intracellular reactive oxygen species and endogenous antioxidant capacities (5-10). Thus embryonic malformations under hyperglycemic conditions are the result of CHIR-265 oxidative stress. Oxidative stress induced by hyperglycemia stimulates apoptosis in a variety of cell types (11). Maternal hyperglycemia increases cell apoptosis in the embryo (12-14). Apoptosis is specifically seen in neuroepithelial cells which are particularly susceptible to hyperglycemic damage (14). Hyperglycemia-induced apoptosis involves caspase cascade activation (15) and caspase inhibitors abolish hyperglycemia-induced apoptosis and prevent hyperglycemia-induced malformations (16). Caspases are classified as initiator caspases that trigger apoptosis and effector caspases that execute apoptosis and serve as apoptosis indices. We have identified caspase 8 as the initiator caspase in diabetic embryopathy (17) and have consistently used cleaved caspase 3 as an sign for apoptosis (15). Although multiple research suggest that surplus cell loss of life at least in the central nervous system may contribute to the abnormal development of structures in the embryos of diabetic animals (18 19 it is elusive how oxidative stress induces apoptosis in diabetic embryopathy. c-Jun NH2-terminal kinases (JNK)1/2 mediate oxidative stress-induced apoptosis in a variety of cellular systems. In maternal diabetes JNK1/2 activation in the embryos and yolk sacs correlates with excessive apoptosis and NTDs DKK1 (15 20 21 Antioxidant supplementation blocks hyperglycemia-induced JNK1/2 activation resulting in prevention of diabetic embryopathy (22). This obtaining suggests that maternal hyperglycemia-induced oxidative stress is responsible for JNK1/2 activation and the subsequent activation of apoptotic pathways. We have recently demonstrated that a specific pharmacological JNK1/2 inhibitor decreases hyperglycemia-induced malformations and a JNK1/2 activation inducer mimics the teratogenic effect of hyperglycemia (20). Most striking gene deletion significantly reduces maternal diabetes-induced embryonic malformations (20). These findings suggest that JNK1/2 activation plays a causative role in the induction of diabetic embryopathy. However the precise mechanism underlying JNK1/2 activation-mediated diabetic embryopathy needs to be further investigated. The JNK1/2 pathway specifically responds to stress-induced signals that drive apoptosis. The specific molecular CHIR-265 targets of JNK1/2 include transcription factor AP-1 (mainly c-Jun JunB and activating transcription factor 2 [ATF-2]) forkhead box class o (Foxo) factors (23) and many other nontranscription factors such as Bcl-2 proteins which are.