Abstract:
:A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with APP and Abeta amyloid may contribute to the Alzheimer's amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. However, poor target specificity and consequential clinical safety of current metal-complexing agents have limited their widespread clinical use. To develop the next generation of metal chelators, we have designed and synthesized a new bifunctional molecule-XH1, based on a novel 'pharmacophore conjugation' concept. This lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. It achieved a putative binding geometry with Abeta1-40 peptide by the computational chemistry modeling and reduced Zn(II)-induced Abeta1-40 aggregation in vitro as determined by turbidometry. Moreover, our pilot data indicated that XH1 has no significant neurotoxicity at low micromolar concentrations and acute animal toxicity. XH1 specifically reduced APP protein expression in human SH-SY5Y neuroblastoma cells and attenuated cerebral Abeta amyloid pathology in PS1/APP transgenic mice without inducing apparent toxicity and behavior disturbances. Collectively, these preliminary findings carry implication for XH1 being a BBB-permeable lead compound for AD therapeutics targeting Alzheimer's amyloidogenesis, although further studies are needed.
journal_name
Exp Gerontoljournal_title
Experimental gerontologyauthors
Dedeoglu A,Cormier K,Payton S,Tseitlin KA,Kremsky JN,Lai L,Li X,Moir RD,Tanzi RE,Bush AI,Kowall NW,Rogers JT,Huang Xdoi
10.1016/j.exger.2004.08.016keywords:
subject
Has Abstractpub_date
2004-11-01 00:00:00pages
1641-9issue
11-12eissn
0531-5565issn
1873-6815pii
S0531-5565(04)00279-7journal_volume
39pub_type
杂志文章abstract::Long-lived recombinant inbred lines, some of which have mean and maximum life spans up to 70% longer than wild type, were used in these analyses. Longer life results from a slower exponential rate of increase in mortality. General motor activity decreases with chronological age in all genotypes; this decay in general ...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/0531-5565(88)90031-9
更新日期:1988-01-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2012.04.001
更新日期:2012-06-01 00:00:00
abstract::Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The pre...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2015.04.002
更新日期:2015-06-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2018.11.005
更新日期:2019-03-01 00:00:00
abstract:BACKGROUND:Physical activity and sedentary behavior are modifiable risk factors for non-communicable disease and healthy ageing, however the majority of older adults remain insufficiently active. Digital behavior change interventions (DBCI) have the potential to reach many older adults to promote physical activity and ...
journal_title:Experimental gerontology
pub_type: 杂志文章,meta分析
doi:10.1016/j.exger.2019.02.020
更新日期:2019-06-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/s0531-5565(03)00101-3
更新日期:2003-07-01 00:00:00
abstract::Aging is an independent risk factor for the development of atherosclerosis, a vascular abnormality that plays a significant role in the development of many cardiovascular disorders. Animal experiments have demonstrated that aging predisposes the vasculature to advanced atherosclerotic disease and vessel injury and tha...
journal_title:Experimental gerontology
pub_type: 杂志文章,评审
doi:10.1016/s0531-5565(99)00036-4
更新日期:1999-07-01 00:00:00
abstract::Male life history and resource allocation is not frequently studied in aging and life span research. Here, we verify that males of long-lived fruit-feeding butterfly species have reduced longevity on restricted diets [Beck, J., 2007. The importance of amino acids in the adult diet of male tropical rainforest butterfli...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2009.06.008
更新日期:2009-09-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 评论,杂志文章
doi:10.1016/j.exger.2016.08.008
更新日期:2016-10-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2004.12.002
更新日期:2005-03-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/s0531-5565(99)00021-2
更新日期:1999-06-01 00:00:00
abstract::The effect of 3-(4-pyridyl)-1,2,4-thiotriazolyl 5-mercaptoacetic acid kalium salt (Rumosol) and 3-(4-pyridyl)-1,2,4-thiotriazolyl 5-mercaptoacetic acid morpholinium salt (drug 2) on the concentration of Schiff base in myocardium of adult (10-12 months) and old (22-25 months) Wistar rats during immobilized stress were ...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/s0531-5565(01)00181-4
更新日期:2002-04-01 00:00:00
abstract::Dietary restriction (DR) extends lifespan in a wide range of organisms. DR also reduces daily and lifetime fecundity. The latter may be an evolutionary adaptation to survive periods of food shortage. Reproductive rate is often negatively correlated with lifespan, and a reduced cost of reproduction could be the mechani...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2004.03.018
更新日期:2004-07-01 00:00:00
abstract::It is now widely recognized that in order to optimize bone health in the later years, bone healthy behaviors should begin at a young age and continue throughout life. Prescribed orally to lower lipid levels in adults of all ages, statins have also been shown to stimulate bone formation in vitro by promoting bone morph...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2013.04.007
更新日期:2013-08-01 00:00:00
abstract::The purposes of this study were to examine the age-related differences in absolute and normalized torque-time parameters in five distinct groups across the adult lifespan, and the relationship between rapid strength and limb acceleration capacities across the lifespan. One-hundred and thirty-six healthy men were categ...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2019.110819
更新日期:2020-03-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2016.03.021
更新日期:2016-07-01 00:00:00
abstract::Primary human dermal fibroblasts isolated from the medial aspect of the proximal forearm of young and old donors were compared for the expression of interstitial collagenase, 72 kDa type IV collagenase, the tissue inhibitor of metalloproteinase type 1, and pro-alpha 2 (I) collagen mRNA at basal levels and after stimul...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/0531-5565(94)90061-2
更新日期:1994-01-01 00:00:00
abstract::Age-related behavioral declines are common manifestations of aging in animals. Negative geotaxis, an innate escape response during which flies ascend the wall of a cylinder after being tapped to its bottom, is one of the behaviors that senesces in Drosophila. Many laboratories, including ours, have used a variety of n...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2005.02.005
更新日期:2005-05-01 00:00:00
abstract::This study examined the beneficial effects of black rice anthocyanin extract (BRAE), which provides as an excellent source of dietary antioxidants, on the lifespan of fruit flies and the underlying molecular mechanisms. Results showed that supplementation of BRAE extended the lifespan of fruit flies by 20% and retarde...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2019.01.015
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2018.10.016
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abstract::Aging is characterized by the progressive decline in mass and function of the skeletal muscle along with increased susceptibility to inflammation, oxidative stress, and atrophy. In this study, we investigate the effect of intermittent bout and single bout exercise training on inflammatory molecules in young (3 months)...
journal_title:Experimental gerontology
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doi:10.1016/j.exger.2015.11.001
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journal_title:Experimental gerontology
pub_type: 杂志文章,评审
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更新日期:1994-05-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2013.12.012
更新日期:2014-03-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2010.09.012
更新日期:2010-12-01 00:00:00
abstract::A non-enzymatic reaction between ketones or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and to the development and progression of various age-related disorders such as vascular complications of diabetes, Alzheimer's disease, cancer growth and metastas...
journal_title:Experimental gerontology
pub_type: 杂志文章,评审
doi:10.1016/j.exger.2010.11.007
更新日期:2011-04-01 00:00:00
abstract::The loss of bone mineral with aging and subsequent development of osteoporosis is a common problem in elderly women, and as life expectancy increases, in elderly men as well. Space flight also causes bone loss and could be a limiting factor for long duration missions, such as, a Mars expedition or extended occupation ...
journal_title:Experimental gerontology
pub_type: 杂志文章,评审
doi:10.1016/0531-5565(91)90011-a
更新日期:1991-01-01 00:00:00
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journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/0531-5565(86)90039-2
更新日期:1986-01-01 00:00:00
abstract::Permethrin is a synthetic pyrethroid extensively used as anti-woodworm agent and for indoor and outdoor pest control. The main route of human exposure is through fruit, vegetable and milk intake. Low dosage exposure to permethrin during neonatal brain development (from postnatal day 6 to postnatal day 21) leads to dop...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/j.exger.2019.06.002
更新日期:2019-09-01 00:00:00
abstract::To understand the mechanism of aging at the cellular level, cellular senescence has been extensively studied as an experimental model of aging in vitro. Although several hypotheses have been proposed for the mechanism of cellular senescence, none of them could give a comprehensive framework to the mechanism. In this s...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/s0531-5565(98)00008-4
更新日期:1998-08-01 00:00:00
abstract::Age-related changes of immune functions have been extensively investigated in both humans and animal models; nevertheless, the literature on potential alterations of dendritic cells, potent antigen presenting cells responsible for initiating immune responses, with aging is very scarce. We studied the immuno-phenotype ...
journal_title:Experimental gerontology
pub_type: 杂志文章
doi:10.1016/s0531-5565(99)00089-3
更新日期:2000-03-01 00:00:00