The small molecule AUTEN-99 (autophagy enhancer-99) prevents the progression of neurodegenerative symptoms

Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation. Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson's and Huntington's diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging

Multiple Hits in Acute Pancreatitis: Components of Metabolic Syndrome Synergize Each Other's Deteriorating Effects

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A Multicenter, International Cohort Analysis of 1435 Cases to Support Clinical Trial Design in Acute Pancreatitis

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Decreased VEGF Level Is Associated with Elevated Ferritin Concentration in Bronchoalveolar Lavage Fluid of Children with Interstitial Lung Diseases

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Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients

The role of platelets in the development of atherosclerosis and obesityrelatedprothrombotic state is still under investigation. In this cross-sectionalcohort study, we measured the levels of different platelet activationmarkers and evaluated their relationship with carotid intimamediathickness (IMT) along with other atherosclerotic risk factors inobese patients with or without atherosclerotic co-morbidities. We enrolled154 obese patients, including 98 with either hypertension, type 2diabetes mellitus or dyslipidaemia, 56 without these co-morbiditiesand 62 age- and sex-matched healthy controls. Platelet P-selectin expressionand the number of platelet-derived microparticles (PMPs)were measured by flow cytometry; soluble P-selectin levels were analysedby ELISA and Thr715Pro P-selectin polymorphism was determinedby PCR-RFLP. Carotid IMT was examined by ultrasonography. The levelsof platelet activation parameters were significantly elevated in allobese subjects with increased carotid IMT compared to healthy con-trols. There was no effect of Thr715Pro genotype on soluble P-selectinlevels in obese individuals contrary to normal subjects. Significant andpositive association was revealed between carotid IMT and plateletP-selectin (p<0.0001), soluble P-selectin (p=0.039) and PMP(p=0.0001) levels. After adjusting for multiple variables, independentassociation was found between soluble P-selectin and fibrinogen(p=0.007), PMP levels and body mass index (p<0.0001) as well as plateletP-selectin and carotid IMT (p=0.012) plus plasminogen activatorinhibitor-1 (p=0.009). In conclusion, P-selectin and PMP levels showedpositive associations with abnormal carotid IMT and other risk factorsin obesity suggesting a critical role of enhanced platelet reactivity inatherosclerotic wall alteration

AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects.

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases