Necroptosis inhibition counteracts neurodegeneration,memory decline,and key hallmarks of aging,promoting brain rejuvenation

Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.     

Effect of neural crest ablation on development of the heart and arch arteries in the chick

Mesenchymal derivatives of the neural crest contribute to the connective tissues and blood vessels of the pharyngeal arches, and participate in the septation of the outflow tract of the heart. The present study was designed to determine the nature and timing of alterations in the development of the heart and arch arteries subsequent to diminished neural crest contributions. The neural crest contributing to the three caudalmost pharyngeal arches was ablated bilaterally in chick embryos and compared with sham or unoperated controls. Heart development was studied by scanning electron microscopy. Arch artery development was studied microscopically after intravascular injection of India ink and clearing of the specimen. Neural crest ablation caused morphological changes in most hearts. Hearts in experimental animals commonly were elongate and were subject to inappropriate development of ventricular and atrial areas. A surgical effect delayed the disappearance of arch arteries one and two, and removal of neural crest produced an additional delay. Neural crest ablation caused failure of arch arteries three, four (right), and six to develop to the proper size in some animals. Survival of those whose sixth arch arteries achieved the proper size caused group measurements to reach normal values again by stage 32. Closure of arch arteries in some animals and maintenance in others produced greater variability in experimental animals than in controls. It is significant that heart morphology was altered before septation of the outflow tract normally occurs. This indicates at the least that another factor, such as altered blood flow, contributes to the abnormal development. Altered flow may result from changes in pharyngeal arch mesenchyme and arch artery endothelium.     

Release of acetylcholinesterase (AChE) from β-amyloid plaques assemblies improves the spatial memory impairments in APP-transgenic mice

The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid-β-peptide (Aβ). Amyloid deposits contain “chaperone molecules” which play critical roles in amyloid formation and toxicity. In the present work, we test an analog of hyperforin (IDN 5706) which releases the AChE from both the Aβ fibrils and the AChE-Aβ burdens in transgenic mice. Hyperforin is an acylphloroglucinol compound isolated from Hypericum perforatum (St. John's Wort), which is able to prevent the Aβ-induced spatial memory impairments and Aβ neurotoxicity. Altogether this gathered evidence indicates the important role of AChE in the neurotoxicity of Aβ plaques and finding new compounds which decrease the AChE-Aβ interaction may be a putative therapeutic agent to fight the disease.     

Genetic diversity and biological activity of Curcuma longa ecotypes from Rapa Nui using molecular markers

Curcuma Longa (CL) has been used for hundreds of years by native people from Rapa Nui for the treatment of different illness. Despite this plant was introduced from Polynesia or India, there is still scarce information about its origin. The objective of this study was to analyze the genetic variation of three CL ecotypes based on molecular phylogenetic and genotypification using internal transcribed spacer 2 (ITS2) and simple sequence repeats (SSR). Antioxidant and anti-inflammatory properties of rhizomes and leaves extracts of three CL plants were analyzed by spectrophotometric methods and cyclooxygenase 2 (COX-2) inhibition assay. Complementarily, we predicted the potential binding mode and binding energy of curcuminoids and nonsteroidals anti-inflammatory drugs (NSAIDs) into COX-2 via molecular docking. The ITS2 sequence shows two major clusters (I and II), group I consisted of Curcuma haritha and group II consisted of different species of Curcuma and Rapa Nui samples (MR-1, MR-2 and RK-2). Results of SSR markers show that genotype MR-2 was similar to MR-1 and RK-2 with 70.8 and 42.9% similarity, whereas genotype was similar to RK-2, MR-1 and MR-2 with 63.9, 43.2 and 42.9% similarity, respectively. MR-1 have better antioxidant and autoinflammatory activity than rest of CL samples due to its high concentration of polyphenols (33.68 mg/g) and curcumin (29.69 mg/g). Furthermore, docking results show that three curcuminoids of CL and selective NAIDs, as celecoxib, etodolac and meloxicam, share the same binding pocket into COX-2. However, three curcuminoids have a lower ΔG_binding than other COX-2 selective NAIDs as etodolac and meloxicam, except for Coxib family as valdecoxib, celecoxib and rofecoxib. Our findings suggest MR-1, MR-2 and MK-2 from Germplasm Bank (Mataveri Otai of CONAF) are closely related to Curcuma amada and Curcuma montana even though they have genetic variability.     

METABOLISM OF TISSUE CULTURES : III. A METHOD FOR MEASURING THE PERMEABILITY OF TISSUE CELLS TO SOLUTES

By using radioactive isotopes in tissue cultures, the rate of permeation of substances into cells can be measured independently of concurrent metabolic reactions of these substances. Techniques of obtaining and analyzing data are described. Examples are given using radioactive potassium and phosphorus. Using cultures of chick embryo muscle, turnover time for cell potassium is 6 hours, and for cell inorganic phosphate is 7 hours in the examples cited. Permeability rates, based on estimates of the cell surface involved and expressed as millimoles per cm.² per hour, are of the order of magnitude of 10^–6 for potassium and of 10^–7 for phosphate.