Dihydropyridine derivatives modulate heat shock responses and have a neuroprotective effect in a transgenic mouse model of Alzheimer’s disease

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells and by maintaining proteins in an active state. Alzheimer’s disease (AD) is thought to be caused by β- amyloid peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD

Environmental factors shaping the distribution of common wintering waterbirds in a lake ecosystem with developed shoreline

In this study, we tested whether the spatial distribution of waterbirds is influenced by shoreline urbanization or other habitat characteristics. We conducted monthly censuses along shoreline sections of a continental lake (Lake Balaton, Hungary) to assess the abundance of 11 common species that use this lake as a feeding and staging area during migration and winter. We estimated the degree of urbanization of the same shoreline sections and also measured other habitat characteristics (water depth, extent of reed cover, biomass of zebra mussels, distances to waste dumps and to other wetlands). We applied linear models and model averaging to identify habitat variables with high relative importance for predicting bird distributions. Bird abundance and urbanization were strongly related only in one species. Other habitat variables exhibited stronger relationships with bird distribution: (1) diving ducks and coots preferred shoreline sections with high zebra mussel biomass, (2) gulls preferred sites close to waste dumps, and (3) the abundances of several species were higher on shoreline sections close to other wetlands. Our findings suggest that the distribution of waterbirds on Lake Balaton is largely independent of shoreline urbanization and influenced by food availability and connectivity between wetlands

Low dose cranial irradiation-induced cerebrovascular damage is reversible in mice

BACKGROUND: High-dose radiation-induced blood-brain barrier breakdown contributes to acute radiation toxicity syndrome and delayed brain injury, but there are few data on the effects of low dose cranial irradiation. Our goal was to measure blood-brain barrier changes after low (0.1 Gy), moderate (2 Gy) and high (10 Gy) dose irradiation under in vivo and in vitro conditions. METHODOLOGY: Cranial irradiation was performed on 10-day-old and 10-week-old mice. Blood-brain barrier permeability for Evans blue, body weight and number of peripheral mononuclear and circulating endothelial progenitor cells were evaluated 1, 4 and 26 weeks postirradiation. Barrier properties of primary mouse brain endothelial cells co-cultured with glial cells were determined by measurement of resistance and permeability for marker molecules and staining for interendothelial junctions. Endothelial senescence was determined by senescence associated β-galactosidase staining. PRINCIPLE FINDINGS: Extravasation of Evans blue increased in cerebrum and cerebellum in adult mice 1 week and in infant mice 4 weeks postirradiation at all treatment doses. Head irradiation with 10 Gy decreased body weight. The number of circulating endothelial progenitor cells in blood was decreased 1 day after irradiation with 0.1 and 2 Gy. Increase in the permeability of cultured brain endothelial monolayers for fluorescein and albumin was time- and radiation dose dependent and accompanied by changes in junctional immunostaining for claudin-5, ZO-1 and β-catenin. The number of cultured brain endothelial and glial cells decreased from third day of postirradiation and senescence in endothelial cells increased at 2 and 10 Gy. CONCLUSION: Not only high but low and moderate doses of cranial irradiation increase permeability of cerebral vessels in mice, but this effect is reversible by 6 months. In-vitro experiments suggest that irradiation changes junctional morphology, decreases cell number and causes senescence in brain endothelial cells

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

Hepatic mitochondrial and ER stress induced by defective PPARalpha signaling in the pathogenesis of hepatic steatosis.

Emerging evidence demonstrates a close interplay between disturbances in mitochondrial function and ER homeostasis in the development of the metabolic syndrome. The present investigation sought to advance our understanding of the communication between mitochondrial dysfunction and ER stress in the onset of hepatic steatosis in male rodents with defective peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling. Genetic depletion of PPARalpha or perturbation of PPARalpha signaling by high-fructose diet compromised the functional activity of metabolic enzymes involved in mitochondrial fatty acid beta-oxidation and induced hepatic mitochondrial stress in rats and mice. Inhibition of PPARalpha activity further enhanced the expression of apolipoprotein B (apoB) mRNA and protein, which was associated with reduced mRNA expression of the sarco/endoplasmic reticulum calcium ATPase (SERCA), the induction of hepatic ER stress, and hepatic steatosis. Restoration of PPARalpha activity recovered the metabolic function of the mitochondria and ER, alleviated systemic hypertriglyceridemia, and improved hepatic steatosis. These findings unveil novel roles for PPARalpha in mediating stress signals between hepatic subcellular stress-responding machinery and in the onset of hepatic steatosis under conditions of metabolic stress

ALTERED GENE EXPRESSION AND FUNCTIONAL ACTIVITY OF OPIOID RECEPTORS IN THE CEREBELLUM OF CB 1 CANNABINOID RECEPTOR KNOCKOUT MICE AFTER ACUTE TREATMENTS WITH CANNABINOIDS

Numerous studies have shown functional links between the cannabinoid and opioid systems. The goal of this study was to evaluate whether acute treatments by endogenous cannabinoid agonist, selective CB 1 or CB 2 receptor antagonists modulate the expression of μ - (MOR) and δ - (DOR) opioid receptor mRNA levels and functional activity in the cerebellum of transgenic mice deficient in the CB 1 type of cannabis receptors. We examined the effect of noladin ether (endogenous cannabinoid agonist) pretreatment on MOR and DOR mRNA expression by using reverse transcription and real-time polimerase chain reac- tion (PCR) and the ability of subsequent application of the opioid agonists to activate G-proteins, as mea- sured by [ 35 S]GTP γ S binding, in wild-type (CB 1 +/+ ) and CB 1 cannabinoid receptor deficient (CB 1 ñ/ñ , ëknockoutí, K.O.) mice. The acute administration of noladin ether markedly reduced MOR-mediated G- protein activation and caused a significant increase in the level of MOR mRNAs in the cerebella of wild- type, but not in the CB 1 ñ/ñ mice. No significant differences were observed in DOR functional activity and mRNA expression in wild-type animals. In CB 1 ñ/ñ mice the expression of DOR mRNA increased after noladin ether treatment, but no changes were found in DOR functional activity. In addition, Rimonabant (selective central cannabinoid CB 1 receptor antagonist) and SR144528 (selective peripheral cannabinoid CB 2 receptor antagonist) caused significant potentiation in MOR functional activity in the wild-type ani- mals, whereas DOR mediated G-protein activation was increased in the CB 1 ñ/ñ mice. In contrast, Rimonabant and SR144528 decreased the MOR and DOR mRNA expressions in both CB 1 +/+ and CB 1 ñ/ñ mice. Taken together, these results indicate that acute treatment with cannabinoids causes alterations in MOR and DOR mRNA expression and functional activity in the cerebella of wild-type and CB 1 knock- out mice indicating indirect interactions between these two signaling systems

New Imperfect Random Source with Applications to Coin-Flipping

We introduce a new imperfect random source that realistically generalizes the SV-source of Santha and Vazirani [SV86] and the bit-fixing source of Lichtenstein, Linial and Saks [LLS89]. Our source is expected to generate a known sequence of (possibly dependent) random variables (for example, a stream of unbiased random bits). However, the realizations/observations of these variables could be imperfect in the following two ways: (1) inevitably, each of the observations could be slightly biased (due to noise, small measurements errors, imperfections of the source, etc.), which is characterized by the "statistical noise" parameter 2 [0; 1 2 ], and (2) few of the observations could be completely incorrect (due to very poor measurement, improper setup, unlikely but certain internal correlations, etc.), which is characterized by the "number of errors" parameter b 0. While the SV-source considered only scenario (1), and the bit-fixing source --- only scenario (2), we believe that..