Abeta peptide is the major proteinateous component of the amyloid plaques found in the brains of Alzheimer's disease (AD) patients and is regarded by many as the culprit of the disorder. It is well documented that brain lipids are intricately involved in Abeta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin. Here we demonstrate leptin's ability to modify Abeta levels in vitro and in vivo. Similar to methyl-beta-cyclodextrin, leptin reduces beta-secretase activity in neuronal cells possibly by altering the lipid composition of membrane lipid rafts. This phenotype contrasts treatments with cholesterol and etomoxir, an inhibitor of carnitine-palmitoyl transferase-1. Conversely, inhibitors of acetyl CoA carboxylase and fatty acid synthase mimicked leptin's action. Leptin was also able to increase apoE-dependent Abeta uptake in vitro. Thus, leptin can modulate bidirectional Abeta kinesis, reducing its levels extracellularly. Most strikingly, chronic administration of leptin to AD-transgenic animals reduced the brain Abeta load, underlying its therapeutic potential.
The purpose of the current study was to determine if, and to what extent, sex differences in performance fatigability after a sustained, bilateral leg extension, anchored to a moderate rating of perceived exertion (RPE), could be attributed to muscle size, muscular strength, or pain pressure threshold (PPT) in young, healthy adults. Thirty adults (men: n = 15, women: n = 15) volunteered to complete a sustained leg extension task anchored to RPE = 5 (10-point OMNI scale) as well as pretest and posttest maximal voluntary isometric contraction (MVIC) trials. The fatigue-induced decline in MVIC force was defined as performance fatigability. We used muscle cross-sectional area (mCSA) to quantify muscle size and a dolorimeter to assess PPT. The sustained task induced fatigue such that both men and women exhibited significant ( p < 0.05) decreases in MVIC force from pretest to posttest ( M = 113.3, SD =24.2 kg vs. M = 98.3, SD = 23.1 kg and M = 73.1, SD =14.5 kg vs. M = 64.1, SD = 16.2 kg, respectively), with no significant sex differences in performance fatigability (grand M = 12.6, SD =10.6%). Men, however, exhibited significantly ( p < 0.05) longer time to task failure (TTF) than women ( M = 166.1, SD =83.0 seconds vs. M = 94.6, SD =41.7) as well as greater PPT ( M = 5.9, SD = 2.2 kg vs. M = 3.4, SD =1.1 kg). The only significant predictor of performance fatigability was PPT. In conclusion, differences in PPT, at least in part, mediate variations in TTF during self-paced exercise anchored to a specific RPE and resulting in performance fatigability.
Human adaptation to extreme environments has been explored for over a century to understand human psychology, integrated physiology, comparative pathologies, and exploratory potential. It has been demonstrated that these environments can provide multiple external stimuli and stressors, which are sufficient to disrupt internal homeostasis and induce adaptation processes. Multiday hyperbaric and/or saturated (HBS) environments represent the most understudied of environmental extremes due to inherent experimental, analytical, technical, temporal, and safety limitations. National Aeronautic Space Agency (NASA) Extreme Environment Mission Operation (NEEMO) is a space-flight analog mission conducted within Florida International University’s Aquarius Undersea Research Laboratory (AURL), the only existing operational and habitable undersea saturated environment. To investigate human objective and subjective adaptations to multiday HBS, we evaluated aquanauts living at saturation for 9–10 days via NASA NEEMO 22 and 23, across psychologic, cardiac, respiratory, autonomic, thermic, hemodynamic, sleep, and body composition parameters. We found that aquanauts exposed to saturation over 9–10 days experienced intrapersonal physical and mental burden, sustained good mood and work satisfaction, decreased heart and respiratory rates, increased parasympathetic and reduced sympathetic modulation, lower cerebral blood flow velocity, intact cerebral autoregulation and maintenance of baroreflex functionality, as well as losses in systemic bodyweight and adipose tissue. Together, these findings illustrate novel insights into human adaptation across multiple body systems in response to multiday hyperbaric saturation.
Background Tumors can be viewed as populations of cells which may succumb to eradication principles observed in nature. For example, population reduction or eradication occurs when populations are exposed to simultaneous press and pulse pressures. Press disturbances are pressures which produce chronic stress in populations, while pulse disturbances produce acute stress. We recently proposed a novel Press‐Pulse therapeutic strategy for the metabolic management of cancer that is based on these principles ( https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-017-0178-2). We hypothesize that specific press‐pulse protocols will be effective in managing even aggressive cancers, while allowing for the use of low dose and low‐ or non‐toxic metabolic‐targeted therapies. Methods In this project, we are testing the press disturbances of the ketogenic diet and ketone supplementation, and the pulse disturbances of 2‐deoxyglucose (glycolytic inhibitor), sodium phenylbutyrate (glutamine targeting agent), hyperbaric oxygen therapy, and pharmacological ascorbic acid, in the MMTV‐PyMT mouse model of breast cancer. Preliminary Results To date, we have tested the proposed metabolic treatments as monotherapies and combination therapies. Tumor growth rate and survival time were largely unaltered by the treatments tested. Ketogenic diet and sodium phenylbutyrate were the only treatments to affect survival time as a monotherapy. Ketogenic diet treated mice lived 8.7% longer than standard diet fed mice (p<0.05). Sodium phenylbutyrate treated mice had a decrease in survival of 8.1% from the standard diet fed mice (p<.05). Data analyses pending for the effects of combination therapies. Conclusions We are not yet able to determine if Press‐Pulse targeting is effective in this model system as we have only tested and analyzed monotherapies. Ketogenic diet therapy appears to elicit a minor therapeutic effect as a stand‐alone, but the other metabolic‐targeted treatments utilized were not effective as monotherapies. Studies to test combinations of these therapies have been completed, and the analyses of the data is ongoing. Support or Funding Information Donner Foundation, Florida High Tech Corridor
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.