PubMed Health⌕ Search

Biomedical subjects

Xiaoyan Sun

Publications and source records attributed to Xiaoyan Sun.

At least 19 recordsLinked to original sources
PubMed2026

A geroprotective probiotic and its functional metabolite counteract inflammaging to extend healthspan.

The gut microbiome profoundly influences host aging, yet the specific microbes and mechanisms governing divergent aging trajectories remain elusive. In this study, we delineated enterotype-specific gut microbial remodeling during aging and developed a microbiome-based aging clock (MicroAge) to track biological aging trajectories. We identified Bifidobacterium pseudocatenulatum (B. pseudocatenulatum) as a candidate geroprotective species consistently depleted during aging across both sexes and multiple Chinese cohorts. In naturally aged mice, oral B. pseudocatenulatum monotherapy rescued intestinal homeostasis, mitigated multiorgan inflammaging, enhanced cognitive-motor performance and extended healthspan. Mechanistically, we characterized 5-aminovaleric acid betaine (5-AVAB) as a key B. pseudocatenulatum-derived metabolite whose levels decline physiologically in aging humans. 5-AVAB supplementation partially recapitulated a broad spectrum of the systemic benefits observed with B. pseudocatenulatum treatment, including improved cognitive and motor function and suppressed multiorgan inflammaging. Our findings identify the B. pseudocatenulatum-5-AVAB axis as a promising target for microbiome-based interventions to promote healthy aging.

Animals↗
PubMed2007

Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly.

BACKGROUND: Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-beta peptide 42 (Abeta42) declines before and soon after the onset of AD, yet the relationship between plasma Abeta42 and depression is unclear. METHODS: We used 515 homebound elders aged 60 and older in a population-based, cross-sectional study to investigate associations between plasma Abeta levels and depression with and without cardiovascular co-morbidities. Depression was evaluated by using the Center for Epidemiological Studies Depression (CES-D) scale. Plasma Abeta40 and Abeta42 were measured. RESULTS: The elderly with depression had lower plasma Abeta42 (median: 15.3 vs. 18.9, p = 0.008) than those without depression. The CES-D score was inversely associated with plasma Abeta42 (p = 0.001) in subjects with no cardiovascular disease (CVD); however, in the presence of CVD, this association did not exist. Low plasma Abeta42 (OR = 0.41, p = 0.007) and the presence of CVD (OR = 1.84, p = 0.005) were independently associated with depression after adjusting for the confounders of age, stroke and apolipoprotein E4. CONCLUSIONS: Depressive symptoms are associated with low plasma Abeta42 independently of CVD. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 is a separate depression subtype that could predict the onset of AD.

Age Factors↗
PubMed2006

p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo.

Aberrant processing of the amyloid precursor protein (APP) and the subsequent accumulation of amyloid beta (Abeta) peptide has been widely established as a central event in Alzheimer's disease (AD) pathogenesis. The sequential cleavage steps required for the generation of Abeta are well outlined; however, there is a relative dearth of knowledge pertaining to signaling pathways and molecular mechanisms that can modulate this process. Here, we demonstrate a novel role for p25/cyclin-dependent kinase 5 (Cdk5) in regulating APP processing, Abeta peptide generation, and intraneuronal Abeta accumulation in inducible p25 transgenic and compound PD-APP transgenic mouse models that demonstrate deregulated Cdk5 activity and a neurodegenerative phenotype. Induction of p25 resulted in enhanced forebrain Abeta levels before any evidence of neuropathology in these mice. Intracellular Abeta accumulated in perinuclear regions and distended axons within the forebrains of these mice. Evidence for modulations in axonal transport or beta-site APP cleaving enzyme 1 protein levels and activity are presented as mechanisms that may account for the Abeta accumulation caused by p25/Cdk5 deregulation. Collectively, these findings delineate a novel pathological mechanism involving aberrant APP processing by p25/Cdk5 and have important implications in AD pathogenesis.

Amyloid beta-Peptides↗
PubMed2006

Resolving the motional modes that code for RNA adaptation.

Using a domain elongation strategy, we decoupled internal motions in RNA from overall rotational diffusion. This allowed us to site-specifically resolve a manifold of motional modes in two regulatory RNAs from HIV-1 with the use of nuclear magnetic resonance spin relaxation methods. Base and sugar librations vary on a picosecond time scale and occur within helical domains that move collectively at diffusion-limited nanosecond time scales. Pivot points are short, functionally important, and highly mobile internal loops. These spontaneous changes in RNA conformation correlate quantitatively with those that follow adaptive recognition of diverse targets. Thus, ligands may stabilize existing RNA conformations rather than inducing new ones.

Arginine↗
PubMed2006

Executive dysfunction in homebound older people with diabetes mellitus.

OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus. DESIGN: Cross-sectional, population-based study. SETTING: Three homecare agency areas in Boston, Massachusetts. PARTICIPANTS: Two hundred ninety-one homebound people aged 60 and older; 40% with diabetes mellitus. MEASUREMENTS: Demographic data; evidence of diabetes mellitus and other diseases; Mini-Mental State Examination and tests of memory and executive function; ADLs. RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean score+/-standard deviation 17.1+/-8.6 vs 20.5+/-9.6, P=.003) and Trails B (median seconds to accomplish the task: 255 vs 201, P=.03). For memory, word retention score was lower in those with diabetes mellitus than without (39.1+/-28.9 vs 48.0+/-29.7, P=.01), but the other memory tests did not show a difference between these two subgroups. More individuals with diabetes mellitus suffered from depressive symptoms than those without (55% vs 42%, P=.03). The ADL scores of those with diabetes mellitus were higher than those without. CONCLUSION: The pattern of cognitive deficits in people with diabetes mellitus suggests frontal-subcortical dysfunction, as seen in microvascular disease of the brain. The impairment in ADLs may be associated with this executive dysfunction, which cerebral microvascular disease in diabetes mellitus may cause.

Activities of Daily Living↗
PubMed2005

Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2.

Gamma-secretase catalyzes the proteolytic processing of a number of integral membrane proteins, including amyloid precursor protein (APP) and Notch. The native gamma-secretase is a heterogeneous population of large membrane protein complexes containing presenilin 1 (PS1) or presenilin 2 (PS2), aph-1a or aph-1b, nicastrin, and pen-2. Here we report the reconstitution of a gamma-secretase complex in Sf9 cells by co-infection with baculoviruses carrying the PS1, nicastrin, pen-2, and aph-1a genes. The reconstituted enzyme processes C99 and the Notch-like substrate N160 and displays the characteristic features of gamma-secretase in terms of sensitivity to a gamma-secretase inhibitor, upregulation of Abeta42 production by a familial Alzheimer's disease (FAD) mutation in the APP gene, and downregulation of Notch processing by PS1 FAD mutations. However, the ratio of Abeta42:Abeta40 production by the reconstituted gamma-secretase is significantly higher than that of the native enzyme from 293 cells. Unlike in mammalian cells where PS1 FAD mutations cause an increase in Abeta42 production, PS1 FAD missense mutations in the reconstitution system alter the cleavage sites in the C99 substrate without changing the Abeta42:Abeta40 ratio. In addition, PS1DeltaE9 is a loss-of-function mutation in both C99 and N160 processing. Reconstitution of gamma-secretase provides a homogeneous system for studying the individual gamma-secretase complexes and their roles in Abeta production, Notch processing and AD pathogenesis. These studies may provide important insight into the development of a new generation of selective gamma-secretase inhibitors with an improved side effect profile.

Alzheimer Disease↗
PubMed2005

Hippocampal spatial memory impairments caused by the familial Alzheimer's disease-linked presenilin 1 M146V mutation.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional inactivation of PS1 in the mouse postnatal forebrain leads to mild deficits in spatial learning and memory, whereas inactivation of both PS1 and PS2 results in severe memory and synaptic plasticity impairments, followed by progressive and substantial neurodegeneration. Here we investigate the effect of a familial Alzheimer's disease-linked PS1 missense mutation using knock-in (KI) mice, in which the wild-type PS1 allele is replaced with the M146V mutant allele. In the Morris water maze task, PS1 KI mice at 3 months of age exhibit reduced quadrant occupancy and platform crossing in the probe trial after 6 days of training, though their performance was normal in the probe trial after 12 days of training. By the age of 9 months, even after 12 days of training, PS1 homozygous KI mice still exhibit reduced platform crossing in the post-training probe trial. ELISA analysis revealed a selective increase in cortical levels of beta-amyloid 42 in PS1 KI mice, whereas production of beta-amyloid 40 was normal. Histological and quantitative real-time RT-PCR analyses showed normal gross hippocampal morphology and unaltered expression of three genes involved in inflammatory responses in PS1 KI mice. These results show hippocampal spatial memory impairments caused by the PS1 M146V mutation and age-related deterioration of the memory impairment, suggesting that PS1 KI mice are a valuable model system for the study of memory loss in AD.

Aging↗
PubMed2004

Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain. Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Abeta40 and Abeta42 peptides is similar in PS1 conditional knock-out and PS cDKO mice. We further examined the gene expression profile by oligonucleotide microarrays in the PS cDKO cerebral cortex and found that a high number of genes are differentially expressed, most notably a group of up-regulated inflammatory genes. Quantitative real-time reverse transcription PCR and Western analyses confirmed the elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S, up-regulation of which has been associated with inflammatory responses in various neurodegenerative processes. Immunohistochemical analysis revealed that the increase in complement component C1q is confined to the hippocampal formation, whereas glial fibrillary acidic protein and cathepsin S are up-regulated throughout the entire neocortex and hippocampus. In addition, strong microglial activation occurs in the hippocampus and the deeper cortical layers of PS cDKO mice. These results indicate that the memory impairment and neurodegeneration in PS cDKO mice are not caused by Abeta accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.

Amyloid beta-Peptides↗
PubMed2004

The toppler mouse: a novel mutant exhibiting loss of Purkinje cells.

We describe the genetic and neurological features of toppler, a spontaneous autosomal mutation that appeared in a colony of FVB/N mice and that manifests as severe ataxia appearing at around 12 days of age, worsening with age. The lifespan of affected mice is 8-12 months, with occasional mice living longer. Both homozygous males and females are fertile, and females are able to nurture litters. Histological examination of brain revealed no striking abnormalities other than the loss of cerebellar Purkinje cells. The toppler mutation was mapped to mouse chromosome 8, and to assess whether it was novel or a recurrence of a previously described chromosome 8 mouse mutant, toppler mice were crossed with the nervous and tottering mouse mutants. These studies demonstrate that toppler is a unique mouse mutation. Purkinje cell abnormalities in toppler mice were obvious around postnatal day (P) 14, i.e., toppler Purkinje cells already exhibited abnormal morphology. Staining for calbindin, a calcium binding protein enriched in Purkinje cells, showed altered dendritic morphology. Between P14 and P30, dramatic Purkinje cell loss occurred, although there were differences in the degree of Purkinje cell loss in each lobule. At P30, the surviving Purkinje cells expressed zebrin II. From P30 through 6 months, many of the remaining Purkinje cells gradually degenerated. Purkinje cell loss was analyzed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL), and Purkinje cells were TUNEL-positive most abundantly at P21. In addition, Bergmann glia were TUNEL positive at P21, and they expressed activated caspase-3 at earlier time points. Interestingly, despite the apparent death of some Bergmann glia, there was up-regulation of glial fibrillary acidic protein, expressed in astrocytes as well as Bergmann glia. Given the changes in both Purkinje cells and glia in toppler cerebellum, this may be a very useful model in which to investigate the developmental interaction of Purkinje cells and Bergmann glia.

Animals↗
PubMed2004

Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications.

We previously reported that antiestrogen-liganded estrogen receptor beta (ERbeta) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Our studies also indicate that upregulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites. We now report on the upregulation of glutathione S-transferases Pi (GST-Pi) and gamma-glutamylcysteine synthetase heavy subunit (GCSh) expression by antiestrogens. Studies indicate the regulation of GST-Pi and GCSh transcriptional activity by ER. While ER regulation is mediated by an electrophile response element (EpRE), we identified mechanistic differences in the involvement of other transcription factors. Regardless of these differences, ER beta-mediated regulation of GST-Pi and GCSh point towards an important role for ER beta in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogen-induced DNA damage upon upregulation of GST-Pi and GCSh expression.

Antioxidants↗
PubMed2004

Effect of burn injury on glucocorticoid receptor binding activity in rat muscle.

Burn injury is associated with increased muscle proteolysis and up-regulated gene expression in the proteolytic pathway. Glucocorticoids (GCs) are the most important mediator of burn injury induced muscle cachexia. However, the understanding of the mechanisms of GCs action in response to burn injury remains elusive. It is well known that GC acts by binding its own receptor. Therefore, in the present study, we examined the influence of burn injury on the hormone binding activity of the glucocorticoid receptor (GR) in skeletal muscle. Burn injury resulted in increased hormone binding activity in extensor digitorum longus (EDL) and soleus muscles. Scatchard plots revealed that the increased GR hormone binding activity reflected increased numbers of hormone binding sites, whereas receptor affinity for GCs was unchanged. Western blot analysis showed that dissociation of GR/heat shock protein 90 heterocomplex or increase in GR protein may account for the effect of burn injury. The GR antagonist RU 38486 blocked the burn injury-induced increase in GR hormone binding activity, implicating a positive regulatory effect of GCs on GR binding activity under the present experimental conditions.

Animals↗
PubMed2003

Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death.

Converging evidence suggests that the accumulation of cerebral amyloid beta-protein (Abeta) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Abeta thus represents a novel therapeutic approach to lowering steady-state Abeta levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Abeta levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.

Amyloid beta-Peptides↗
PubMed2003

Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis.

Uncoupling protein 3 (UCP3) is a member of the mitochondrial transporter superfamily that is expressed primarily in skeletal muscle. UCP3 is upregulated in various conditions characterized by skeletal muscle atrophy, including hyperthyroidism, fasting, denervation, diabetes, cancer, lipopolysaccharide (LPS), and treatment with glucocorticoids (GCs). The influence of sepsis, another condition characterized by muscle cachexia, on UCP3 expression and activity is not known. We examined UCP3 gene and protein expression in skeletal muscles from rats after cecal ligation and puncture and from sham-operated control rats. Sepsis resulted in a two- to threefold increase in both mRNA and protein levels of UCP3 in skeletal muscle. Treatment of rats with the glucocorticoid receptor antagonist RU-38486 prevented the sepsis-induced increase in gene and protein expression of UCP3. The UCP3 mRNA and protein levels were increased 2.4- to 3.6-fold when incubated muscles from normal rats were treated with dexamethasone (DEX) and/or free fatty acids (FFA) ex vivo. In addition, UCP3 mRNA and protein levels were significantly increased in normal rat muscles in vivo with treatment of either DEX or FFA. The results suggest that sepsis upregulates the gene and protein expression of UCP3 in skeletal muscle, which may at least in part be mediated by GCs and FFA.

Animals↗
PubMed2003

Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells.

Evidence from a recent study indicates that glucocorticoids (GCs) mediate skeletal muscle proteolysis during sepsis via the GC receptor (GR) pathway. Attempts to identify the mechanisms regulating GR gene expression in skeletal muscle during sepsis have been hampered by the lack of an appropriate in vitro model system that can mimic in vivo septic conditions. In the present study, we report that GR gene transcription in L6 myocytes in vitro is up-regulated by treatment with sera from septic rats in a manner similar to that measured in septic rats in vivo. Sera from septic rats were collected from animals in which sepsis was induced by caecal ligation and puncture and from control rats that were sham-operated. Finally, by treating L6 myotubes with the GR antagonist RU 38486, thereby preventing sepsis-induced GR transcription, we confirmed that the possible septic effect on the GR was due to increased GCs. L6 myocytes treated with sera from septic rats might therefore be useful as an experimental model for identifying the molecular mechanisms by which the GR regulates muscle cachexia during sepsis. Furthermore, RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated rats, as measured by release of tyrosine and 3-methylhistidine respectively. Our results demonstrate for the first time that sepsis induces GR transcription in skeletal muscle, and supports the hypothesis that the GC-induced proteolysis under sepsis is partially a consequence of GR activation.

Animals↗
PubMed2002

Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells.

Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, DeltaMEKK, JNK3, and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this co-expression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.

Alzheimer Disease↗
PubMed2002

The aspartate-257 of presenilin 1 is indispensable for mouse development and production of beta-amyloid peptides through beta-catenin-independent mechanisms.

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1Deltacat) essential for beta-catenin interaction. We show here that although hPS1Deltacat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and beta-amyloid precursor protein (APP) and the generation of beta-amyloid peptides (Abeta). Further, by measuring the levels of endogenous Abeta(X-40) and Abeta(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Abeta.

Amyloid beta-Peptides↗
PubMed2002

Dantrolene downregulates the gene expression and activity of the ubiquitin-proteasome proteolytic pathway in septic skeletal muscle.

BACKGROUND: In previous studies, dantrolene prevented sepsis-induced muscle proteolysis, but the influence of dantrolene on the expression and activity of the ubiquitin-proteasome proteolytic pathway is not known. In addition, the role of glucocorticoids in the anabolic effect of dantrolene is not well understood. METHODS: Sepsis was induced in rats by cecal ligation and puncture (CLP). Other rats underwent sham-operation. Groups of rats were treated with dantrolene (10 mg/kg) administered 2 h before and 8 h after sham-operation or CLP. Sixteen hours after sham-operation or CLP, mRNA levels for ubiquitin, the ubiquitin ligase E3alpha, and the 20S proteasome subunit C3 were determined by dot-blot analysis. In additional experiments, the effect of dantrolene on protein degradation was tested in L6 myotubes cultured in the absence or presence of dexamethasone. RESULTS: Treatment of rats with dantrolene prevented the sepsis-induced increase in mRNA levels for ubiquitin, the ubiquitin ligase E3alpha, and the 20S proteasome subunit C3. In additional experiments, treatment of cultured myotubes with dantrolene reduced protein degradation in both the absence and the presence of dexamethasone. CONCLUSIONS: The results suggest that dantrolene can prevent sepsis-induced activation of the ubiquitin-proteasome proteolytic pathway in skeletal muscle and that dantrolene reduces muscle protein degradation independent of glucocorticoids.

Animals↗