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Targeting the core of neurodegeneration:FoxO,mTOR,and SIRT1

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Neural Regeneration Research 2021年第3期16卷 448-455页

作者： kenneth Maiese Cellular and Molecular Signaling New York New YorkNYUSA

The global increase in lifespan noted not only in developed nations,but also in large developing countries parallels an observed increase in a significant number of noncommunicable diseases,most notable neurodegenerative *** disorders present a number of challenges for treatment options that do not resolve disease ***,it is believed by the year 2030,the services required to treat cognitive disorders in the United States alone will exceed$2 trillion *** forkhead transcription factors,silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae),the mechanistic target of rapamycin,and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system *** pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster,sometimes in conjunction with trophic factors,enhanced neuronal survival,reduction in toxic intracellular accumulations,and mitochondrial *** mechanisms among these pathways also exist that can oversee reparative processes in the nervous ***,mammalian forkhead transcription factors,silent mating type information regulation 2 homolog 1,mechanistic target of rapamycin,and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment,warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders.

关键词： Alzheimer's disease apoptosis autophagy erythropoietin forkhead FoxO mechanistic target of rapamycin silent mating type information regulation 2 homolog 1

Diabetes mellitus and glymphatic dysfunction:Roles for oxidative stress,mitochondria,circadian rhythm,artificial intelligence,and imaging

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World Journal of Diabetes 2025年第1期16卷 39-48页

作者： kenneth Maiese National Heart Lungand Blood InstituteNational Institutes of HealthBethesdaMD 20810United States

Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the *** represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately *** cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm *** pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic *** studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.

关键词： Artificial intelligence Circadian rhythm Clock genes Diabetes mellitus magnetic resonance imaging Glymphatic pathway Mitochondria Oxidative stress Programmed cell death Sleep fragmentation

Novel applications of trophic factors,Wnt and WISP for neuronal repair and regeneration in metabolic disease

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Neural Regeneration Research 2015年第4期10卷 518-528页

作者： kenneth Maiese Cellular and Molecular Signaling

Diabetes mellitus affects almost 350 million individuals throughout the globe resulting in sig-niifcant morbidity and mortality. Of further concern is the growing population of individuals that remain undiagnosed but are susceptible to the detrimental outcomes of this disorder. Dia-betes mellitus leads to multiple complications in the central and peripheral nervous systems that include cognitive impairment, retinal disease, neuropsychiatric disease, cerebral ischemia, and peripheral nerve degeneration. Although multiple strategies are being considered, novel target-ing of trophic factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1, and stem cell tissue regeneration are considered to be exciting prospects to overcome the cellular mechanisms that lead to neuronal injury in diabetes mellitus involving oxidative stress, apoptosis, and au-tophagy. Pathways that involve insulin-like growth factor-1, ifbroblast growth factor, epidermal growth factor, and erythropoietin can govern glucose homeostasis and are intimately tied to Wnt signaling that involves Wnt1 and Wnt1 inducible signaling pathway protein 1 （CCN4） to foster control over stem cell proliferation, wound repair, cognitive decline,β-cell proliferation, vascular regeneration, and programmed cell death. Ultimately, cellular metabolism through Wnt signal-ing is driven by primary metabolic pathways of the mechanistic target of rapamycin and AMP activated protein kinase. These pathways offer precise biological control of cellular metabolism, but are exquisitely sensitive to the different components of Wnt signaling. As a result, unexpected clinical outcomes can ensue and therefore demand careful translation of the mechanisms that govern neural repair and regeneration in diabetes mellitus.

关键词： Alzheimer’s disease AMPK apoptosis autophagy central nervous system CCN4 EGF diabetes mellitus erythropoietin EPO FGF IGF-1 mTOR neuron neuropathy oxidative stress psychiatric stem cells WISP1 Wnt

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

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Neural Regeneration Research 2016年第3期11卷 372-385页

作者： kenneth Maiese Cellular and Molecular Signaling Newark NJ USA

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this *** impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic *** mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth *** a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this *** studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

关键词： Akt AMP activated protein kinase(AMPK) apoptosis Alzheimer’s disease autophagy β-cell cancer cardiovascular disease caspase CCN family diabetes mellitus epidermal growth factor erythropoietin fibroblast growth factor forkhead transcription factors Fox O FRAP1 hamartin(tuberous sclerosis 1)/tuberin(tuberous sclerosis 2)(TSC1/TSC2) insulin mechanistic target of rapamycin(mTOR) m TOR Complex 1(m T ORC1) m TOR Complex 2(m TORC2) nicotinamide nicotinamide adenine dinucleotide(NAD+) non-communicable diseases oxidative stress phosphoinositide 3-kinase(PI 3-K) programmed cell death silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1) sirtuin stem cells wingless Wnt Wnt1 inducible signaling pathway protein 1(WISP1)

Quo vadis,plasmonic optical tweezers?

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Light(Science & Applications) 2019年第1期8卷 878-883页

作者： kenneth B.Crozier School of Physics and Department of Electrical and Electronic EngineeringThe University of MelbourneMelbourneVictoria 3010Australia

Conventional optical tweezers based on traditional optical microscopes are subject to the diffraction limit,making the precise trapping and manipulation of very small particles *** optical tweezers can surpass this constraint,but many potential applications would benefit from further enhanced performance and/or expanded *** this Perspective,we discuss trends in plasmonic tweezers and describe important opportunities presented by its interdisciplinary combination with other techniques in *** furthermore highlight several open questions concerning fundamentals that are likely to be important for many potential applications.

关键词： optical furthermore precise

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Texas Helimak

Plasma Science and Technology 2008年第3期10卷 284-289页

作者： kenneth W.GENTLE Fusion Research Center University of Texas at Austin Texas USA

Helimak is an experimental approximation to the ideal cylindrical slab, a onedimensional magnetized plasma with magnetic curvature and shear. The Texas Helimak realizes this approximation to a large degree; the finite size of the device can be neglected for many phenomena. Specifically, the drift-wave turbulence characteristic of a slab is observed with scale lengths small compared with the device size. The device and the general features of its behavior are described here. The device is capable of studying drift-wave turbulence, scrape-off layer （SOL） turbulence, and the stabilization of turbulence by imposing velocity shear.

关键词： plasma turbulence drift waves particle transport turbulence suppression

Tribological Performance of Coated Surfaces

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材料热处理学报 2004年第5期25卷 20-27页

作者： kenneth Holmberg Anssi Laukkanen VTT Technical Research Centre of Finland Espoo FinlandVTT Technical Research Centre of Finland Espoo Finland

The fundamentals of coating tribology is presented in a generalised holistic approach to friction and wear mechanisms of coated surfaces in dry sliding contacts. It is based on a classification of the tribological contact process into macromechanical, micromechanical, tribochemical contact mechanisms and material transfer. The tribological contact process is dominated by the macromechanical mechanisms, which have been systematically analysed by using four main parameters: the coating-to-substrate hardness relationship, the film thickness, the surface roughness and the debris in the contact. In this paper special attention is given to the microlevel mechanisms, and in particular new techniques for modelling the elastic, plastic and brittle behaviour of the surface by finite element (FEM) computer simulations. The contact condition with a sphere sliding over a plate coated with a very thin hard coating is analysed. A three dimensional FEM model has been developed for calculating the first principal stress distribution in the scratch tester contact of a diamond spherical tip moving with increased load on a 2 thick titanium nitride (TiN) coated steel surface. The model is comprehensive in that sense that it considers elastic, plastic and fracture behaviour of the contact surfaces. By identifying from a scratch experiment the location of the first crack and using this as input data can the fracture toughness of the coating be determined.

关键词：硬敷层 FEM 应力模拟断口摩擦性能贴合表面

Driving neural regeneration through the mammalian target of rapamycin

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Neural Regeneration Research 2014年第15期9卷 1413-1417页

作者： kenneth Maiese Cellular and Molecular Signaling Newark NJUSA

Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer＇s disease, and Parkinson＇s disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin （mTOR）. mTOR is a component of the protein complexes roTOR Complex 1 （mTORC1） and mTOR Complex 2 （mTORC2） that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence, roTOR through its relationship with phosphoinositide 3-kinas e （PI 3-K） and protein kinase B （Akt） and multiple downstream signaling pathways such as p70 ribosomal $6 kinase （p70S6K） and proline rich Akt substrate 40 kDa （PRAS40） promotes neuro- nal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and [3-amyl old toxicity may offer new strategies for disorders such as stroke and Alzheimer＇s disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clini- cal efficacy and eliminate any clinical toxic side effects.

关键词： Alzheimer's disease apoptosis autophagy mTOR necroptosis rapamycin stem cells stroke

Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock

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Neural Regeneration Research 2019年第5期14卷 773-774页

作者： kenneth Maiese Cellular and Molecular Signaling

A significant global impact from dementia:According to the World Health Organization(Dua et al.,2017),the current numbers for the prevalence and treatment costs for dementia worldwide are *** 50 million individuals suffer from *** is now considered to be the 7^th leading cause of ***,at least five percent of the world’s elderly population,equal to approximately 47 million individuals,have ***,at least sixty percent reside in low and middle income *** seventy-five percent of these new cases are to occur in these *** number of new cases each year throughout the globe is increasing at approximately 10 million per *** the year 2030,82 million people are expected to have dementia and by the year 2050,152 million are expected to have the disease.

关键词： Impacting dementia cognitive loss innovative strategies