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Xiaoping Yang

Publications and source records attributed to Xiaoping Yang.

At least 19 recordsLinked to original sources
PubMed2025

Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis.

Cockayne Syndrome (CS) is a premature aging disorder caused by mutations in the CSA and CSB genes involved in DNA metabolism and other cellular processes. CS patients display many features including premature aging, neurodegeneration, and kidney abnormalities. Nicotinamide dinucleotide (NAD+) deprivation has been observed in CS patient-derived cells. NAD+ has essential roles in regulating cellular health, stress responses, and renal homeostasis. While kidney dysfunction is a common feature in CS patients, its molecular pathogenesis is not understood. Here, we report that severe kidney pathology is present in CS A and B mice. We find that the NAD+ biosynthetic pathways are impaired in kidneys from these mice. Using human renal tubular epithelial cells, we show that CSA/B downregulation causes persistent activation of the ATF3 transcription factor on the quinolinate phosphoribosyl transferase gene locus, a rate-limiting enzyme in de novo NAD+ biosynthesis in the kidney, causing impaired transcription and deficient NAD+ homeostasis.

Animals↗
PubMed2006

Designed boronate ligands for glucose-selective holographic sensors.

In this study, 2-acrylamidophenylboronate (2-APB) was synthesised and its ability to bind with glucose was investigated both in solution and when integrated into a holographic sensor. Multiple forms of 2-APB, resulting from the neighbouring effect of the amido group with the boronic acid through an intramolecular B--O-coordinated interaction, were shown to exist in solution by using multinuclear NMR spectrometry. It was found that 2-APB predominantly adopts a zwitterionic tetrahedral form at physiological pH values. The complex formation of 2-APB with glucose and lactate was investigated in DMSO; 2-APB favours binding with glucose rather than lactate and generates a five-membered-ring complex. Furthermore, a 2-APB-based holographic sensor displayed a significant response to glucose with little interference from lactate, and with no dependence on pH in the physiological pH range. These features suggest that the new ligand 2-APB is a potential candidate for the development of glucose-selective sensors.

Amides↗
PubMed2006

Heterobimetallic Zn(II)-Ln(III) phenylene-bridged schiff base complexes, computational studies, and evidence for singlet energy transfer as the main pathway in the sensitization of near-infrared Nd3+ luminescence.

A series of 3d-4f heterobimetallic phenylene-bridged Schiff base complexes of the general formula [Zn(mu-L1)Ln(NO3)3(S)n] [Ln = La (1), Nd (2), Gd (3), Er (4), Yb (5); S = H(2)O, EtOH; n = 1, 2; H2L1 = N,N'-bis(3-methoxysalicylidene)phenylene-1,2-diamine] and [Zn(mu-L2)Ln(NO3)3(H2O)n] [Ln = La (6), Nd (7), Gd (8), Er (9), Yb (10); n = 1, 2; H(2)L(2) = N,N'-bis(3-methoxy-5-p-tolylsalicylidene)phenylene-1,2-diamine] were synthesized and characterized. Complexes 1, 2, 4, and 7 were structurally characterized by X-ray crystallography. At room temperature in CH(3)CN, both neodymium(III) (2 and 7) and ytterbium(III) (5 and 10) complexes also exhibited, in addition to the ligand-centered emission in the UV-vis region, their lanthanide(III) ion emission in the near-infrared (NIR) region. The photophysical properties of the zinc(II) phenylene-bridged complexes (ZnL1 and ZnL2) were measured and compared with those of the corresponding zinc(II) ethylene-bridged complexes (ZnL3 and ZnL4). Our results revealed that, at 77 K, both ligand-centered triplet (3LC) and singlet (1LC) states existed for the ethylene-bridged complexes (ZnL3 and ZnL4), whereas only the (1)LC state was detected for the phenylene-bridged complexes (ZnL1 and ZnL2). NIR sensitization studies of [Zn(mu-L')Nd(NO3)3(H2O)n] (L' = L1-L4) complexes further showed that Nd3+ sensitization took place via the 3LC and 1LC states when the spacer between the imine groups of the Schiff base ligand was an ethylene and a phenylene unit, respectively. Ab initio calculations show that the observed differences can be attributed to the difference in the molecular vibrational properties and electron densities of the electronic states between the ethylene- and phenylene-bridged complexes.

Journal Article↗
PubMed2006

Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells.

Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [(3)H]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation.

Acetaldehyde↗
PubMed2006

Holographic lactate sensor.

Measurement of blood l-lactate is used to assess and monitor exercise performance in sports medicine. This report describes the initial development of a holographic sensor, which employs a synthetic receptor, to enable the selective and continuous real-time measurement of l-lactate for eventual in vivo application. Three boronic acid-based receptors have been synthesized, integrated into thin acrylamide hydrogel films, and then subsequently transformed into holographic sensors. Changes in the replay wavelength of the sensors were used to characterize the swelling behavior of the matrix as a function of l-lactate concentration. It was found that the incorporation of 3-acrylamidophenyl boronic acid into an acrylamide hydrogel produced the largest response toward l-lactate. The effects of hydrogel composition, fluctuating l-lactate concentrations, and the response of potential interfering agents to the sensor have been investigated.

Acrylamide↗
PubMed2006

Multinuclear luminescent Schiff-base Zn-Nd sandwich complexes.

Multinuclear 3d-4f complexes with sandwichlike molecular structures are formed with the Schiff-base ligand bis(3-methoxysalicylidene)ethylene-1,2-phenylenediamine(H(2)L). The stoichiometry and structures are dependent on the Zn:Nd ratio and counteranions present. They are trinuclear [Nd(ZnL)2(NO3)2(H2O)2].NO3.EtOH.H2O (1), [Nd(ZnL)2Cl2(H2O)3].Cl.2MeOH.5H2O (2), and tetranuclear [Nd2(ZnL)2Cl6(MeOH)2].MeOH (3). Dinuclear complex [NdZnL(NO3)3MeCN].MeCN (4) was also characterized. Near-infrared (NIR) lanthanide luminescence is observed in these complexes.

Crystallography, X-Ray↗
PubMed2006

DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

Chromosome 17 is unusual among the human chromosomes in many respects. It is the largest human autosome with orthology to only a single mouse chromosome, mapping entirely to the distal half of mouse chromosome 11. Chromosome 17 is rich in protein-coding genes, having the second highest gene density in the genome. It is also enriched in segmental duplications, ranking third in density among the autosomes. Here we report a finished sequence for human chromosome 17, as well as a structural comparison with the finished sequence for mouse chromosome 11, the first finished mouse chromosome. Comparison of the orthologous regions reveals striking differences. In contrast to the typical pattern seen in mammalian evolution, the human sequence has undergone extensive intrachromosomal rearrangement, whereas the mouse sequence has been remarkably stable. Moreover, although the human sequence has a high density of segmental duplication, the mouse sequence has a very low density. Notably, these segmental duplications correspond closely to the sites of structural rearrangement, demonstrating a link between duplication and rearrangement. Examination of the main classes of duplicated segments provides insight into the dynamics underlying expansion of chromosome-specific, low-copy repeats in the human genome.

Animals↗
PubMed2006

Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress.

Senescence is accompanied by oxidative stress and cardiac dysfunction, although the link between the two remains unclear. This study examined the role of antioxidant metallothionein on cardiomyocyte function, superoxide generation, the oxidative stress biomarker aconitase activity, cytochrome c release, and expression of oxidative stress-related proteins, such as the GTPase RhoA and NADPH oxidase protein p47phox in young (5-6 mo) and aged (26-28 mo) FVB wild-type (WT) and cardiac-specific metallothionein transgenic mice. Metallothionein mice showed a longer life span (by approximately 4 mo) than FVB mice evaluated by the Kaplan-Meier survival curve. Compared with young cardiomyocytes, aged myocytes displayed prolonged TR(90), reduced tolerance to high stimulus frequency, and slowed intracellular Ca2+ decay, all of which were nullified by metallothionein. Aging increased superoxide generation, active RhoA abundance, cytochrome c release, and p47phox expression and suppressed aconitase activity without affecting protein nitrotyrosine formation in the hearts. These aging-induced changes in oxidative stress and related protein biomarkers were attenuated by metallothionein. Aged metallothionein mouse myocytes were more resistant to the superoxide donor pyrogallol-induced superoxide generation and apoptosis. In addition, aging-associated prolongation in TR90 was blunted by the Rho kinase inhibitor Y-27632. Collectively, our data demonstrated that metallothionein may alleviate aging-induced cardiac contractile defects and oxidative stress, which may contribute to prolonged life span in metallothionein transgenic mice.

Aconitate Hydratase↗
PubMed2006

Analysis of the DNA sequence and duplication history of human chromosome 15.

Here we present a finished sequence of human chromosome 15, together with a high-quality gene catalogue. As chromosome 15 is one of seven human chromosomes with a high rate of segmental duplication, we have carried out a detailed analysis of the duplication structure of the chromosome. Segmental duplications in chromosome 15 are largely clustered in two regions, on proximal and distal 15q; the proximal region is notable because recombination among the segmental duplications can result in deletions causing Prader-Willi and Angelman syndromes. Sequence analysis shows that the proximal and distal regions of 15q share extensive ancient similarity. Using a simple approach, we have been able to reconstruct many of the events by which the current duplication structure arose. We find that most of the intrachromosomal duplications seem to share a common ancestry. Finally, we demonstrate that some remaining gaps in the genome sequence are probably due to structural polymorphisms between haplotypes; this may explain a significant fraction of the gaps remaining in the human genome.

Animals↗
PubMed2006

A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen.

To enable arrayed or pooled loss-of-function screens in a wide range of mammalian cell types, including primary and nondividing cells, we are developing lentiviral short hairpin RNA (shRNA) libraries targeting the human and murine genomes. The libraries currently contain 104,000 vectors, targeting each of 22,000 human and mouse genes with multiple sequence-verified constructs. To test the utility of the library for arrayed screens, we developed a screen based on high-content imaging to identify genes required for mitotic progression in human cancer cells and applied it to an arrayed set of 5,000 unique shRNA-expressing lentiviruses that target 1,028 human genes. The screen identified several known and approximately 100 candidate regulators of mitotic progression and proliferation; the availability of multiple shRNAs targeting the same gene facilitated functional validation of putative hits. This work provides a widely applicable resource for loss-of-function screens, as well as a roadmap for its application to biological discovery.

Animals↗
PubMed2006

Human chromosome 11 DNA sequence and analysis including novel gene identification.

Chromosome 11, although average in size, is one of the most gene- and disease-rich chromosomes in the human genome. Initial gene annotation indicates an average gene density of 11.6 genes per megabase, including 1,524 protein-coding genes, some of which were identified using novel methods, and 765 pseudogenes. One-quarter of the protein-coding genes shows overlap with other genes. Of the 856 olfactory receptor genes in the human genome, more than 40% are located in 28 single- and multi-gene clusters along this chromosome. Out of the 171 disorders currently attributed to the chromosome, 86 remain for which the underlying molecular basis is not yet known, including several mendelian traits, cancer and susceptibility loci. The high-quality data presented here--nearly 134.5 million base pairs representing 99.8% coverage of the euchromatic sequence--provide scientists with a solid foundation for understanding the genetic basis of these disorders and other biological phenomena.

Chromosomes, Human, Pair 11↗
PubMed2006

Insulin-sensitizing and cholesterol-lowering effects of chromium (D-Phenylalanine)3.

Low-molecular weight organic chromium complexes are thought to play a key role in carbohydrate and lipid metabolism and therefore have been gaining popularity as nutritional supplement for patients with diabetes and concomitant lipid disorders. The aim of the present study was to evaluate the effects of a novel synthetic chromium (d-phenylalanine)(3) complex on insulin-sensitivity, plasma lipid-profile and oxidant stress in a mouse model of type II diabetes. Plasma glucose levels following intraperitoneal insulin-challenge (1U/kg) to obese ob/ob(+/+) mice treated with Cr(d-Phe)(3) (150 microg/kg/day for 6 weeks) were significantly lower compared to vehicle-control (control: 175.8+/-43.2mg/dL versus Cr(d-Phe)(3) 115.3+/-18.0mg/dL, p<0.01, n=12). Total serum cholesterol to high-density lipoprotein ratio was significantly reduced following Cr(d-Phe)(3)-treatment (control: 2.19+/-0.08 versus Cr(d-Phe)(3) 1.63+/-0.05; p<0.05). Hepatic oxidant stress, assessed as malondialdehyde equivalents and protein-carbonyl content were significantly attenuated following Cr(d-Phe)(3) treatment. The complex also inhibited lipid-peroxidation in vitro, in a concentration dependent manner. Taken together, these data suggest that Cr(d-Phe)(3) may be of potential value in the therapy or prophylaxis of insulin-resistance and dyslipidemia associated with obesity.

Animals↗
PubMed2006

DNA sequence and analysis of human chromosome 8.

The International Human Genome Sequencing Consortium (IHGSC) recently completed a sequence of the human genome. As part of this project, we have focused on chromosome 8. Although some chromosomes exhibit extreme characteristics in terms of length, gene content, repeat content and fraction segmentally duplicated, chromosome 8 is distinctly typical in character, being very close to the genome median in each of these aspects. This work describes a finished sequence and gene catalogue for the chromosome, which represents just over 5% of the euchromatic human genome. A unique feature of the chromosome is a vast region of approximately 15 megabases on distal 8p that appears to have a strikingly high mutation rate, which has accelerated in the hominids relative to other sequenced mammals. This fast-evolving region contains a number of genes related to innate immunity and the nervous system, including loci that appear to be under positive selection--these include the major defensin (DEF) gene cluster and MCPH1, a gene that may have contributed to the evolution of expanded brain size in the great apes. The data from chromosome 8 should allow a better understanding of both normal and disease biology and genome evolution.

Animals↗
PubMed2006

Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme.

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt) and intracellular Ca(2+) fluorescence. Diabetes significantly depressed PS, +/-dL/dt, prolonged TPS, TR(90) and intracellular Ca(2+) clearing, elevated resting intracellular Ca(2+), reduced caffeine-induced sarcoplasmic reticulum Ca(2+) release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na(+)-Ca(2+) exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch.

Animals↗
PubMed2006

Construction and characterization of an HCV-derived multi-epitope peptide antigen containing B-cell HVR1 mimotopes and T-cell conserved epitopes.

Hepatitis C (HCV) genome is highly variable, particularly in the hypervariable region 1 (HVR1) of its E2 envelope gene. The variability of HCV genome has been a major obstacle for developing HCV vaccines. Due to B-cell HVR1 mimotopes mimicking the antigenicity of natural HVR1 epitopes and some T-cell epitopes from the consensus sequence of HCV genes conserving among the different HCV genotypes, we synthesized an minigene of HCV-derived multi-epitope peptide antigen (CMEP), which contains 9 B-cell HVR1 mimotopes in E2, 2 conserved CTL epitopes in C, 1 conserved CTL epitope in NS3 and 1 conserved Th epitope in NS3. This minigene was cloned into a GST expression vector to generate a fusion protein GST-CMEP. The immunogenic properties of CEMP were characterized by HCV infected patients' sera, and found that the reactivity frequency reached 75%. The cross reactivity of anti-CEMP antibody with different natural HVR1 variants was up to 90%. Meanwhile, we constructed an HCV DNA vaccine candidate, plasmid pVAX1.0-st-CMEP carrying the recombinant gene (st) of a secretion signal peptide and PADRE universal Th cell epitope sequence in front of the CMEP minigene. Immunization of rabbits with pVAX1.0-st-CMEP resulted in the production of antibody, which was of the same cross reactivity as the fusion protein GST-CMEP. Our findings indicate that the HCV-derived multi-epitope peptide antigen in some degree possessed the characteristics of neutralizing HCV epitopes, and would be of the value as a candidate for the development of HCV vaccines.

Amino Acid Sequence↗
PubMed2006

Cytotoxic diterpenoids from the soft coral Sarcophyton crassocaule.

Five new cembrane diterpenoids, sarcrassins A-E (1-5) along with a known compound, emblide (6), have been isolated from the soft coral Sarcophyton crassocaule collected from the Bay of Sanya, Hainan Island, China. The structures of 1-5 were determined by spectroscopic methods including 1D and 2D NMR techniques. Their relative configurations were determined by NMR data and NOESY experiments. Compounds 2, 4, and 6 exhibited significant cytotoxic activities against KB cell lines with IC50 values of 5.0, 4.0, and 5.0 microg/mL, respectively, while compounds 1 and 5 showed moderate cytotoxicity toward KB cell lines with IC50 values of 19.0 and 13.0 microg/mL, respectively.

Animals↗
PubMed2006

Metallothionein antagonizes aging-induced cardiac contractile dysfunction: role of PTP1B, insulin receptor tyrosine phosphorylation and Akt.

Aging is often accompanied by reduced insulin sensitivity and cardiac dysfunction. However, the causal relationship between the two remains poorly understood. This study was designed to determine the impact of cardiac-specific overexpression of antioxidant metallothionein (MT) on aging-associated cardiac dysfunction and impaired insulin signaling. Contractile and intracellular Ca(2+) properties were evaluated in left ventricular myocytes including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), fura-2 fluorescence intensity change (DeltaFFI) and intracellular Ca(2+) decay rate. Expression of insulin receptor, protein-tyrosine phosphatase 1B (PTP1B), phosphorylation of insulin receptor (Tyr1146) and Akt were evaluated by Western blot analysis. Aged wild-type FVB and MT transgenic mice (26-28 months old) displayed glucose intolerance and hyperinsulinemia. Cardiomyocytes from aged FVB mice exhibited prolonged TR(90) and intracellular Ca(2+) decay associated with normal PS, +/- dL/dt, TPS and DeltaFFI compared with those from young (2-3 months old) mice. Western blot analysis revealed reduced Akt expression and insulin (5 mU g(-1))-stimulated Akt phosphorylation, elevated PTP1B expression and diminished basal insulin receptor tyrosine phosphorylation associated with comparable insulin receptor expression in aged FVB mouse hearts. All of these aging-related defects in cardiac contractile function and insulin signaling (although not hyperinsulinemia and glucose intolerance) were significantly attenuated or ablated by MT transgene. These data indicate that enhanced antioxidant defense is beneficial for aging-induced cardiac contractile dysfunction and alteration in insulin signaling.

Aging↗