Search PubMed⌕ Search

Biomedical subjects

Dan Zhou

Publications and source records attributed to Dan Zhou.

At least 19 recordsLinked to original sources
PubMed2026

A distinct subclade of AlkB family demethylases in ciliates safeguards the positional fidelity of eukaryotic N6-methyladenine (6mA).

DNA N6-methyladenine (6mA) is a newly recognized transcription-associated epigenetic mark in eukaryotes. While its methylation pathway has been well established, the identity of eukaryotic 6mA demethylase(s) responsible for its removal and dynamic regulation has remained elusive. Here, we identify and characterize DMT3 (TtALKBH5), an AlkB family dioxygenase in Tetrahymena thermophila, as a 6mA demethylase in ciliates and potentially several other unicellular eukaryotes with abundant 6mA and a defined AMT1 methyltransferase (MTase) complex, supported by genetic and molecular evidence. DMT3 acts on both fully and hemimethylated ApT dinucleotides, an activity partially facilitated by a naturally occurring cysteine-to-serine substitution. Genome profiling shows that DMT3 is enriched at transcription start sites (TSSs) of 6mA-enriched genes, complementary to the occupancy pattern of the AMT1 complex, where it selectively removes spurious 6mA deposited by AMT1. Genetic disruption of DMT3-mediated demethylation, either by knockout or catalytic inactivation, leads to aberrant 6mA accumulation at TSS regions, transcriptional dysregulation, altered chromatin accessibility, and impaired initiation of sexual reproduction. Notably, simultaneous removal of DMT3 and AMT1 eliminates these defects, indicating that spurious TSS 6mA underlies transcriptional and developmental impairment.

Adenine↗
PubMed2025

Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese.

Subjective cognitive decline (SCD) is widely regarded as a potential preclinical stage of Alzheimer's disease (AD), yet its genetic basis remains poorly understood. To address this gap, we investigated genetic biomarkers associated with SCD using whole-genome sequencing (WGS) in 10,763 Chinese participants from the Healthy Zhejiang One Million People Cohort (HOPE Cohort). The discovery stage included 9284 samples, with 1479 samples used for validation. Using a two-stage design, we systematically investigated both common and rare variants associated with SCD. In rare variant analyses, we identified and replicated an association between the upstream region of SEPHS2 and SCD. SEPHS2 is involved in selenophosphate synthesis, and a Mendelian randomization analysis reveals that its expression levels in both blood and brain cerebellum are associated with AD. Additionally, we identified CLVS2, which encodes a protein primarily expressed in neuronal cells, as a potential regulator for SCD based on missense rare variants. Multi-omics evidence suggests that both SEPHS2 and CLVS2 may play roles in neurodegenerative diseases. For common variants, we validated 8 known loci related to cognitive decline, 3 of which originated from the only existing SCD genetic study conducted under a migraine background. Overall, our WGS-based study fills the gap in SCD research by providing vital genetic evidence from an East Asian population and offers insights into the pathogenic mechanisms of SCD.

Aged↗
PubMed2007

Synthesis and characterization of a new layered fluoroaluminophosphate (C4H11NOH)3.5[Al4(PO4)5F] x 0.5H3O with extra-large 16-rings.

A new two-dimensional-layered fluoroaluminophosphate (C4H11NOH)3.5[Al4(PO4)5F] x 0.5H3O (denoted as AlPO-CJ20) with an Al/P ratio of 4:5 has been synthesized solvothermally by using 2-amino-2-methyl-1-propanol as the structure-directing agent. Its structure was determined by single-crystal X-ray diffraction analysis and further characterized by solid-state NMR techniques, including 27Al, 19F --> 27Al cross-polarization, and 31P magic angle spinning NMR. The alternation of Al-centered tetrahedra (AlO4 and AlO3F) and PO3(=O) tetrahedra gives rise to a new type of 4.6.16-net sheet. The inorganic sheets are stacked in an ABAB sequence along the [010] direction and further held together through strong H bonds between protonated template molecules and P=O groups in the inorganic layers. Except for Mu-4, AlPO-CJ20 is the second layered aluminophosphate with an Al/P ratio of 4:5, and it contains the largest pore opening of 16-rings in the known layered aluminophosphates. Furthermore, the coordination of Al and P of fluoroaluminophosphates is summarized. Crystal data: (C4H11NOH)3.5[Al4(PO4)5F] x 0.5H3O, monoclinic, C2/c (No. 15), a = 32.678(7) A, b = 12.956(3) A, c = 21.045(4) A, beta = 115.17(3) degrees, V = 8064(3) A3, Z = 8, R1 = 0.0837 [I > 2sigma(I)], and wR2 = 0.2428 (all data).

Journal Article↗
PubMed2006

Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor.

The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17-producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T-cell transfer severe combined immunodeficiency (SCID) mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in interferon-gamma (IFN-gamma) production was observed in ex vivo culture of lamina propria cells harvested from animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA-5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis.

Animals↗
PubMed2006

Effect of carbon dioxide on neonatal mouse lung: a genomic approach.

Despite the deleterious effects associated with elevated carbon dioxide (CO(2)) or hypercapnia, it has been hypothesized that CO(2) can protect the lung from injury. However, the effects of chronic hypercapnia on the neonatal lung are unknown. Hence, we investigated the effect of chronic hypercapnia on neonatal mouse lung to identify genes that could potentially contribute to hypercapnia-mediated lung protection. Newborn mouse litters were exposed to 8% CO(2), 12% CO(2), or room air for 2 wk. Lungs were excised and analyzed for morphometric alterations. The alveolar walls of CO(2)-exposed mice appeared thinner than those of controls. Analyses of gene expression differences by microarrays revealed that genes from a variety of functional categories were differentially expressed following hypercapnia treatment, including those encoding growth factors, chemokines, cytokines, and endopeptidases. In particular and of major interest, the expression level of genes encoding surfactant proteins A and D, as well as chloride channel calcium-activated 3, were significantly increased, but the expression of WNT1-inducible signaling pathway protein 2 was significantly decreased. The significant changes in gene expression occurred mostly at 8% CO(2), but only a few at 12% CO(2). Our results lead us to conclude that 1) there are a number of gene families that may contribute to hypercapnia-mediated lung protection; 2) the upregulation of surfactant proteins A and D may play a role as anti-inflammatory or antioxidant agents; and 3) the effects of CO(2) seem to depend on the level to which the lung is exposed.

Animals↗
PubMed2006

Solid-state NMR spectroscopy of anionic framework aluminophosphates: a new method to determine the al/p ratio.

A series of anionic framework aluminophosphates, with different Al/P ratios, have been investigated by various solid-state NMR techniques, including 27Al, 31P magic angle spinning (MAS), 27Al-->31P cross polarization (CP), 27Al{31P} rotational echo double resonance (REDOR), and 31P{27Al} transfer of population double resonance (TRAPDOR). Different Al coordinations (AlO4b, AlO5b, and AlO6b) and P coordinations (PO4b, PO3bOt, PO2bO2t, and PObO3t), where b represents bridging oxygens and t represents terminal oxygens, can be unambiguously determined based on the solid-state NMR spectroscopy. Furthermore, a new method to determine the Al/P ratio of open-framework aluminophosphates has been established, which is useful for the understanding of unknown aluminophosphate structures.

Journal Article↗
PubMed2006

[Resolution of alpha-cyclohexyl mandelic acid enantiomers by enantioselective extraction in separation system containing tartaric esters and beta-cyclodextrin].

AIM: To establish a resolution method for alpha-cyclohexyl mandelic acid enantiomers by enantioselective extraction and to observe the effects of all kinds of tartaric esters, pH, the concentration of D-tartaric esters and beta-cyclodextrin on the enantioselectivity. METHODS: Resolution of alpha-cyclohexyl mandelic acid enantiomers by enantioselective extraction with tartaric esters and beta-cyclodextrin has been studied. RESULTS: The distribution behavior of alpha-cyclohexyl mandelic acid enantiomers in the separation system was studied. The effects of all kinds of tartaric esters, pH, the concentration of D-tartaric esters and beta-cyclodextrin on the enantioselectivity has been examined in the two-phase. CONCLUSION: Results showed that the complex formed by D-iso-butyl-D-tartaric ester with R enantiomer is stabler than that with S enantiomer. With the increase of pH, the partition coefficient and separation factor decreased. The concentration of beta-cyclodextrin and D-tartaric ester had visible effect on the enantioselectivity.

Esters↗
PubMed2006

[Determination of ginsenoside rd in human plasma by LC/MS/MS].

OBJECTIVE: To develop a HPLC/MS/MS method for the determination of ginsenoside Rd in human plasma. METHODS: Plasma samples were pretreated by solid phase extraction (SPE). Ginsenoside Rd (m/z 964.6-->m/z 767.5) and gentiopicrin (m/z 374.1-->195.1) was detected by the positive electrospray ionization (ES+I)-MS method under multiple reaction monitoring (MRM) mode. RESULTS: The calibration curve of ginsenoside Rd in plasma was linear over the range of 3.00-5000.00 ng/ml. The limit of quantitation was 3.00 ng/ml. The relative recovery was 81.01-83.39%. The within-day and between-day RSDs were less than 15%. CONCLUSION This method is accurate, sensitive, and specific. It is suitable for the measurement of plasma ginsenoside Rd concentration.

Area Under Curve↗
PubMed2005

Synthesis, crystal structure, and solid-state NMR spectroscopy of a new open-framework aluminophosphate (NH(4))(2)Al(4)(PO(4))(4)(HPO(4))xH(2)O.

A new three-dimensional open-framework aluminophosphate (NH(4))(2)Al(4)(PO(4))(4)(HPO(4)).H(2)O (denoted AlPO-CJ19) with an Al/P ratio of 4/5 has been synthesized, using pyridine as the solvent and 2-aminopyridine as the structure-directing agent, under solvothermal conditions. The structure was determined by single-crystal X-ray diffraction and further characterized by solid-state NMR techniques. The alternation of the Al-centered polyhedra (including AlO(4), AlO(5), and AlO(6)) and the P-centered tetrahedra (including PO(4) and PO(3)OH) results in an interrupted open-framework structure with an eight-membered ring channel along the [100] direction. This is the first aluminophosphate containing three kinds of Al coordinations (AlO(4), AlO(5), and AlO(6)) with all oxygen vertexes connected to framework P atoms. (27)Al MAS NMR, (31)P MAS NMR, and (1)H --> (31)P CPMAS NMR characterizations show that the solid-state NMR techniques are an effective complement to XRD analysis for structure elucidation. Furthermore, all of the possible coordinations of Al and P in the aluminophosphates with an Al/P ratio of 4/5 are summarized. Crystal data: (NH(4))(2)Al(4)(PO(4))(4)(HPO(4))xH(2)O, monoclinic P2(1) (No. 4), a = 5.0568(3) A, b = 21.6211(18) A, c = 8.1724(4) A, beta = 91.361(4) degrees , V = 893.27(10) A(3), Z = 2, R(1) = 0.0456 (I > 2 sigma(I)), and wR(2) = 0.1051 (all data).

Journal Article↗
PubMed2005

Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia.

Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine changes in gene expression in the CCH or CIH mouse heart. Both CCH and CIH induced substantial alterations in gene expression. In addition, a robust right ventricular hypertrophy and cardiac enlargement was found in CCH- but not in CIH-treated mouse heart. On one hand, upregulation in RNA and protein levels of eukaryotic translation initiation factor-2alpha and -4E (eIF-2alpha and eIF-4E) was found in CCH, whereas eIF-4E was downregulated in 1- and 2-wk CIH, suggesting that eIF-4E is likely to play an important role in the cardiac hypertrophy observed in CCH-treated mice. On the other hand, the specific downregulation of heart development-related genes (e.g., notch gene homolog-1, MAD homolog-4) and the upregulation of proteolysis genes (e.g., calpain-5) in the CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not CIH, and this was correlated with an upregulation of proapoptotic genes and downregulation of anti-apoptotic genes in CCH. In summary, our results indicate that 1) the pattern of gene response to CCH is different from that of CIH in mouse heart, and 2) the identified expression differences in certain gene groups are helpful in dissecting mechanisms responsible for phenotypes observed.

Animals↗
PubMed2005

Annexin 7-immunoreactive microglia in the hippocampus of control and adrenalectomized rats.

Annexin 7 (ANX7), also termed synexin, is a member of the annexin family of calcium-binding proteins. In the present study, we examined the distribution and cellular localization of ANX7-immunoreactivity in the rat hippocampus and its response to adrenalectomy (ADX). ANX7 was co-localized with OX42 in microglia distributed throughout the hippocampus of both control and ADX animals. ANX7-immunoreactivity was not detected in GFAP-positive astrocytes or in hippocampal neurons. At 1-week and 4-weeks following ADX, we observed a population of large, ameboid, ANX7-immunopositive microglia ("reactive microglia") which were largely confined to the granule cell layer of the dentate gyrus throughout its rostrocaudal extent. No reactive microglia were present in the hippocampus of sham-ADX or ADX + corticosterone treated animals. In 4-weeks ADX animals but not 1-week ADX, ANX7-immunostaining was significantly increased in the mossy fiber layer of CA3, due to the presence of many small, dark-staining "activated microglia". Our results show that ANX7 is abundantly expressed in the rat hippocampus by different microglial forms (e.g., ramified, activated and reactive microglia), suggesting an important role for this calcium-binding protein in microglial Ca2+-dependent processes.

Adrenalectomy↗
PubMed2005

Direct effects of polymyxin B on human dendritic cells maturation. The role of IkappaB-alpha/NF-kappaB and ERK1/2 pathways and adhesion.

Polymyxin B is a lipopolysaccharide binding antibiotic used to inactivate potential lipopolysaccharide contaminations when evaluating the activity of different agents on innate immune cells. We report that polymyxin B is able to induce directly in monocyte-derived human dendritic cells (DCs) several functional and molecular modifications characteristic of DCs undergoing a maturation process. DCs incubated with polymyxin B up-regulate the expression of HLA class I and II, the co-stimulatory CD86 molecule, and show an increase in the fraction of adherent cells at short time, which persist at 48 h of incubation. Adhesion to the plate was required for the polymyxin B-induced DCs maturation. A transient activation of IkappaB-alpha/NF-kappaB and ERK1/2 pathways at short time and a further ERK1/2 activation at long term were also detected. Neither up-regulation of the maturation marker CD83 nor activation of p38 nor induction of cytokines secretion was observed in DCs treated with polymyxin B. We demonstrated that inhibition of IkappaB-alpha/NF-kappaB pathway abolishes polymyxin B effects. ERK1/2 inhibition instead allowed DCs treated with polymyxin B to progress in their maturation process as revealed by the increased up-regulation of the CD83 co-stimulatory molecules, the activation of p38, and the reduced adhesion to culture plates at 48 h of incubation. Our results indicate that polymyxin B induces a partial maturation of human DCs through increased adhesion to a substrate and activation of the IkappaB-alpha/NF-kappaB pathway. The increased ERK1/2 activation observed, even though correlating with the initial phases of the maturation process, actually inhibits the occurrence of full maturation.

Anti-Bacterial Agents↗
PubMed2005

Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice.

Mch1r-deficient (Mch1r(-/-)) mice are hyperphagic, hyperactive, lean, and resistant to diet-induced obesity. To examine whether the MCH1R is involved in regulating activity-based energy expenditure, we investigated voluntary wheel running (WR) activity of wild-type (WT) and Mch1r(-/-) mice basally, in response to diets with different caloric density and with different feeding schedules. We also evaluated WR activity of mice with ablation of the prepro-MCH gene (Pmch(-/-) mice). Dark cycle WR activity of Mch1r(-/-) mice fed low fat (LF) chow was increased significantly relative to WT mice. Transition to moderate high-fat (MHF) diet was associated with an increase in nocturnal WR activity in both genotypes. Both Mch1r(-/-) and WT mice exhibited food anticipatory activity (FAA) before the daily scheduled feeding time, indicating that MCH1R is not required for FAA. Naloxone (3 mg/kg, i.p.) suppressed WR activity of both genotypes, suggesting opioid regulation of locomotor activity. WR increased nocturnal dynorphin mRNA levels in Mch1r(-/-) brain. Importantly, Pmch-deficient mice had significantly enhanced WR activity relative to WT controls. These results suggest that endogenous MCH plays an inhibitory role in regulating locomotor activity. In summary, we demonstrated enhanced WR activities in mice lacking either MCH or its cognate receptor.

Animals↗
PubMed2005

[Polymorphism of HLA-B* 40 gene family in Chinese Han population].

To investigate the allele distribution of HLA-B* 40 gene family in Chinese Han population and to study its influence on the selection of clinical transplantation donor, the HLA-B genetypes of 381 individuals randomly selected from Chinese National Marrow Donor Project were identified by PCR-SSO, and then all the HLA-B* 40 positive samples from the above population and the B* 40 homozygote samples received from another 1 270 registered donors were analyzed by PCR-SBT and PCR-SSP at high resolution. The results showed that the population of 381 registered donors was examined at HLA-B locus by using Hardy-Weinberg equilibrium, the gene frequency of HLA-B* 40 was 0.1692. Four different HLA-B* 40 alleles (B* 4001, B* 4002, B* 4003, B* 4006) were identified, and the serological specificity was B60 and B61 respectively. The relative frequency of each allele was 0.1192 for B* 4001, 0.0154 for B* 4002, 0.0038 for B* 4003, 0.0308 for B* 4006. The distribution of B* 40 homozygote revealed a certain regularity at high-resolution, B* 40XX (B* 4001 group), at low-resolution; B* 4001 at high resolution; B* 40XX (B* 4002 group), at low-resolution; B* 4002 or B* 4006 or heterozygote of both at high-resolution. It is concluded that in Chinese Han population, predominant allele in HLA-B* 40 gene family is B* 4001, the high-resolution typing may be recommended to use for the selection of clinical transplantation donor.

Alleles↗
PubMed2004

Na+/H+ exchanger 1 deficiency alters gene expression in mouse brain.

Na(+)/H(+) exchanger 1 (NHE1) is well known to function as a major regulator of intracellular pH (pH(i)). It is activated by low pH(i) and exchanges extracellular Na(+) for intracellular H(+) to maintain cellular homeostasis. Despite the fact that we now have evidence suggesting other roles for NHE1, there has been no comprehensive study investigating its role as a signaling molecule. Toward this aim, we used in this study NHE1 null mutant mice and cDNA microarrays to investigate the effects of NHE1 on global gene expression in various regions of the brain, e.g., cortex, hippocampus, brain stem-diencephalon, and cerebellum. We found that a total of 35 to 79 genes were up- or downregulated in each brain region, with the majority being downregulated. The effect of NHE1 null mutation on gene expression is region specific, and only 11 genes were changed in all brain regions studied. Further analysis of the cis-regulatory regions of downregulated genes revealed that transcription suppressors, BCL6 and E4BP4, were probable candidates that mediated the inhibitory effect of NHE1 null mutation. One of the genes, MCT-13, was not only downregulated in the NHE1 null mutant brain but also in tissue cultures treated with an NHE1 inhibitor. We conclude that 1) a relatively small number of genes were altered in the NHE1 null mouse brain; 2) the effects of NHE1 null mutation on gene expression are region specific; and 3) several genes implicated in neurodegeneration have altered expression, potentially offering a molecular explanation for the phenotype of the NHE1 null mouse.

Acidosis↗
PubMed2004

Voluntary exercise augments acute effects of CB1-receptor inverse agonist on body weight loss in obese and lean mice.

Cannabinoid CB1 receptor (CB1R) inverse agonists reduce appetite and body weight (BW) gain in various species. Exercise is thought to be a natural reward process and the cannabinoid system is also believed to influence reward. We tested the hypothesis that voluntary exercise would augment the effects of AM251, a CB1R inverse agonist, on food intake (FI) and BW loss in murine genetic models of obesity. ob/ob, agouti yellow (A(y)), and lean C57BL/6J mice were treated via oral gavage with vehicle or AM251 (1, 3, or 10 mg/kg) 1 h before the dark cycle. The suppressive effects of 3 and 10 mg/kg AM251 on overnight FI, BW gain, and water intake (WI) were significant in ob/ob mice. In contrast, in A(y) mice, 10 mg/kg AM251 decreased FI and BW gain while it did not influence WI. Food consumption of ob/ob and A(y) mice, as evidenced by feeding frequency (FF) and feeding duration (FD), was reduced by AM251 for 4-6 h. AM251 at these doses had no impact on the appetitive behavior or BW gain of lean mice. After a 1-week wash-out period, mice were given running wheels in their home cages. With running wheel exercise, lean and obese mice exhibited increased sensitivity to AM251. Low voluntary wheel running activity of ob/ob mice precluded detection of combined effects of AM251 and exercise in this genetic model of obesity. Lean and agouti mice given AM251 combined with exercise lost a greater amount of BW than with AM251 alone. Our data suggest that voluntary exercise can enhance CB1R inverse agonist effects on appetite and BW loss in both lean and agouti obese mice.

Animals↗
PubMed2004

[Study of HLA polymorphism in the 6965 Han bone marrow registry donors].

OBJECTIVE: To analyze human leukocyte antigen (HLA) polymorphism and search for new alleles in Chinese Han population bone marrow registry donors. METHODS: DNA-based HLA genotyping methods were used including PCR-SSP, BST and molecular cloning. RESULTS: A total of 6965 unrelated donors, 4707 from South China origin and 2258 from north, were typed for HLA-A, B, and DRB1 loci. Seventy-two specificities of HLA alleles were identified. The HLA-A25, A34, A74, B41, B42, B53, B73 and B81 that were rarely reported in previously Chinese population studies were identified in this study. Estimation of gene frequency indicated that the blank gene frequency was less than 0.2% for HLA-A, 0.25% for HLA-B and 0.70% for HLA-DRB1 loci. Three novel alleles were identified and officially assigned by the World Health Organization (WHO) Nomenclature Committee as A*0253N, A*1114 and B*5610. CONCLUSION: Large-scale DNA-based HLA genotyping used in bone marrow registry donors is highly accurate and reliable for estimating gene frequency and searching for new alleles. The discrepancy of HLA gene distribution between South and North China Han population showed the necessity of setting the more regions in South and North China to screen the bone marrow registry donors for bone marrow transplant.

Bone Marrow Transplantation↗