Background and Purpose Despite the rapidly increasing global burden of ischemic stroke, no therapeutic options for neuroprotection against stroke currently exist. Recent studies have shown that autophagy plays a key role in ischemic neuronal death and treatments that target autophagy may represent a novel strategy in neuroprotection. We investigated whether autophagy is regulated by carnosine, an endogenous pleiotropic dipeptide which has robust neuroprotective activity against ischemic brain damage. Methods We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures. Results Autophagic pathways such as reduction of phosphorylated mTOR/p70S6K and the conversion of LC3-I to LC3-II were enhanced in the ischemic brain. However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling. The protective effect of carnosine against autophagy was also confirmed in primary cortical neurons. Conclusion Taken together, our data suggest that the neuroprotective effect of carnosine is at least partially mediated by mitochondrial protection, and attenuation of deleterious autophagic processes. Our findings shed new light on the mechanistic pathways that this exciting neuroprotective agent influences.

The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.

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Background: The blood-brain barrier (BBB) maintains homeostasis of the brain environment by tightly regulating the entry of substances from systemic circulation. A breach in the BBB results in increased permeability to potentially toxic substances and is an important contributor to amplification of ischemic brain damage. The precise molecular pathways that result in impairment of BBB integrity remain to be elucidated. Autophagy is a degradation pathway that clears damaged or unnecessary proteins from cells. However, excessive autophagy can lead to cellular dysfunction and death under pathological conditions. Methods:In this study, we investigated whether autophagy is involved in BBB disruption in ischemia, using in vitro cells and in vivo rat models. We used brain endothelial bEnd.3 cells and oxygen glucose deprivation (OGD) to simulate ischemia in culture, along with a rat ischemic stroke model to evaluate the role of autophagy in BBB disruption during cerebral ischemia.Results: OGD 18 h induced cellular dysfunction, and increased permeability with degradation of occludin and activation of autophagy pathways in brain endothelial cells. Immunostaining revealed that occludin degradation is co-localized with ischemic autophagosomes. OGD-induced occludin degradation and permeability changes were significantly decreased by inhibition of autophagy using 3-methyladenine (3-MA). Enhanced autophagic activity and loss of occludin were also observed in brain capillaries isolated from rats with middle cerebral artery occlusion (MCAO). Intravenous administration of 3-MA inhibited these molecular changes in brain capillaries, and recovered the increased permeability as determined using Evans blue. Conclusions:Our findings provide evidence that autophagy plays an important role in ischemia-induced occludin degradation and loss of BBB integrity.

Key words endothelial progenitor cell; high glucose; autophagy; oxidative stress; diabetes; mitochondria In patients with diabetes mellitus, cardiovascular dysfunction is one of the major complications, accounting for upto 80% of deaths. 1) Not only for the mortality, it is also a main cause for the disability in diabetes, where impaired peripheral circulation results in delayed wound healing and lower limb amputation. 2) Nevertheless, the complete mechanisms of the vascular pathogenesis in diabetic condition remain to be established.The role of endothelial progenitor cells (EPCs) in the vascularization has been identified, 3) suggesting that impaired EPC function may contribute to vascular complications under disease states. Of note, clinical observations demonstrated that the number of circulating EPCs is decreased, and their functions are impaired in diabetes. 4,5) In vivo diabetic animal studies revealed that EPC functions of mobilization, differentiation and tube formation are disrupted, 5,6) implying that EPC dysfunction could be critical for defective diabetic angiogenesis. Although several studies have given explanations including increased oxidative stress and impaired nitric oxide signaling, 7) the mechanisms underlying diabetic EPC dysfunction are still largely unknown.Autophagy, a homeostatic process that involves in organelle recycling and protein degradation, is essential for normal cellular physiology. It is upregulated in response to extra-or intra-cellular signals such as starvation and endoplasmic reticulum (ER) stress, to preserve the balance between biosynthesis and turnover. 8) The importance of autophagy has been highlighted based on the observation that defective autophagy plays a significant role in human pathologies. 9) Nevertheless, autophagy plays a double-sided role in pathological states, and excessive autophagy is linked to cellular dysfunction, preceding cell death. 9) Detrimental intracellular changes such as impaired mitochondrial function, oxidative stress, and accumulation of protein aggregates can result in autophagic cell damage. 9,10) Interestingly, impaired function of vascular cells can also be mediated by autophagy. Autophagy in endothelial cells was induced by methylglyoxal, a metabolite specific to diabetes. 11) Despite the important role of EPCs in angiogenesis and vascular regeneration, studies regarding the autophagic regulation in EPCs are very limited. Wang et al. recently observed that hypoxia induced autophagy in EPCs,12) suggesting the role of autophagy in survival of the transplanted EPCs. To our best knowledge, the autophagic alteration in EPCs under pathological conditions has not been investigated.Here, we demonstrated that pathological stress of high glucose (HG) condition increased the autophagic marker in bonemarrow derived EPCs (BM-EPCs), which is correlated to the functional impairment. Mitochondrial damage and generation of oxidative stress were increased in HG-exposed EPCs. With this study, we believe that an important evidence for the role of autopha...

ObjectiveThe aim of this study was to examine the prevalence of Internet addiction in middle school students and to identify associated psychosocial risk factors and depression.MethodsThis study was part of a larger epidemiological study on childhood psychiatric disorders conducted in Osan, a city of Republic of Korea. We used IAS for internet addiction, K-YSR for subjects' emotional and behavioral problems and K-CDI for depressive symptoms. We used the data of n=1217 completed cases. We put on independent variables, which are sex, age, smoking and alcohol experiences, economic status, age of first Internet use, K-YSR and K-CDI score.ResultsThe subjects consisted of addicted users (2.38%), over users (36.89%) and normal Internet users (60.72%). Attention problems, sex, delinquent problems, K-CDI scores, thought problems, age and aggressive behavior were predictable variables of internet addiction. Age of initial Internet use negatively predicted Internet addiction.ConclusionThis result showed similar to other researches about sociodemographic, emotional or behavioral factors related to internet addiction. Generally, subjects with more severe internet addiction had more emotional or behavioral problems. It means that they already have had various difficulties when we found internet addiction of adolescents. Therefore it is necessary to evaluate whether the subjects have any emotional or behavioral troubles and to intervene to prevent internet addiction.

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