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Biomedical subjects

Qun Wu

Publications and source records attributed to Qun Wu.

16 recordsLinked to original sources
PubMed2025

Uncovering encrypted antimicrobial peptides in health-associated Lactobacillaceae by large-scale genomics and machine learning.

BACKGROUND: Antimicrobial peptides (AMPs) are well known for their broad-spectrum activity and have shown great promise in addressing the antibiotic-resistant crisis. The Lactobacillaceae family, recognized for its health-promoting effects in humans, represents a valuable source of novel AMPs. However, the global prevalence and distribution of AMPs within Lactobacillaceae remains largely unknown, which limits the efficient discovery and development of novel AMPs. RESULTS: We analyzed all available genomes (10,327 genomes), encompassing 38 genera and 515 species, to investigate the biosynthetic potential (indicated by the number of AMP sequences in the genome) of AMP in the Lactobacillaceae family. We demonstrated Lactobacillaceae species had ubiquitous (69.90%) biosynthetic potential of AMPs. Overall, 9601 AMPs were identified, clustering into 2092 gene cluster families (GCFs), which showed strong interspecies specificity (95.27%), intraspecies heterogeneity (93.31%), and habitat uniqueness (95.83%), that greatly expanded on the AMP sequence landscape. Novelty assessment indicated that 1516 GCFs (72.47%) had no similarity to any known AMPs in existing databases. Machine learning predictions suggested that novel AMPs from Lactobacillaceae possessed strong antimicrobial potential, with 664 GCFs having an additive minimum inhibitory concentration (MIC) below 100&#xa0;&#x3bc;M. We randomly synthesized 16 AMPs (with predicted MIC&#x2009;<&#x2009;100&#xa0;&#x3bc;M) and identified 10 AMPs exhibiting varied-spectrum activity against 11 common pathogens. Finally, we identified one Lactobacillus delbrueckii-originated AMP (delbruin_1) having broad-spectrum (all 11 pathogens) and high antimicrobial activity (average MIC&#x2009;=&#x2009;38.56 &#xb5;M), which proved its potential as a clinically viable antimicrobial agent. CONCLUSIONS: We uncovered the global prevalence of AMPs in Lactobacillaceae and proved that Lactobacillaceae is an untapped and invaluable source of novel AMPs to combat the antibiotic-resistance crisis. Meanwhile, we provided a machine learning-guided framework for AMP discovery, offering a scalable roadmap for identifying novel AMPs not only in Lactobacillaceae but also in other organisms. Video Abstract.

Machine Learning↗
PubMed2006

A deficient TLR2 signaling promotes airway mucin production in Mycoplasma pneumoniae-infected allergic mice.

The original hygiene hypothesis suggests that early childhood respiratory infections preceding allergen exposure may decrease the prevalence of allergic diseases. We have recently demonstrated that Mycoplasma pneumoniae infection preceding allergen exposure reduced allergic responses in mice. However, the molecular mechanisms underlying the protective role of M. pneumoniae in allergic responses, particularly airway mucin production, remain unclear. Wild-type and Toll-like receptor 2 (TLR2)-deficient mice with a respiratory M. pneumoniae infection preceding allergen (ovalbumin) challenge were utilized to determine the regulatory role of TLR2-IFN-gamma signaling pathway in airway mucin expression. Furthermore, air-liquid interface cultures of mouse primary tracheal epithelial cells were performed to examine the effects of IFN-gamma on mucin expression. In wild-type mice, M. pneumoniae infection preceding allergen challenge significantly reduced airway mucins but increased IFN-gamma. In sharp contrast, in TLR2-deficient mice, M. pneumoniae preceding allergen challenge resulted in increased mucin protein without a noticeable change of IFN-gamma. In cultured mouse primary tracheal epithelial cells, IFN-gamma was shown to directly inhibit mucin expression in a dose-dependent manner. Our study demonstrates for the first time that a respiratory M. pneumoniae infection preceding allergen challenge reduces airway epithelial mucin expression in part through TLR2-IFN-gamma signaling pathway. A bacterial infection in asthmatic subjects with weakened TLR2-IFN-gamma signaling may result in an exaggerated airway mucin production.

Allergens↗
PubMed2006

IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection.

IL-23 induces IL-17 production in activated CD4+ T cells and participates in host defense against many encapsulated bacteria. However, whether the IL-23/IL-17 axis contributes to a Mycoplasma pneumoniae (Mp)-induced lung inflammation (e.g., neutrophils) has not been addressed. Using an acute respiratory Mp infection murine model, we found significantly up-regulated lung IL-23p19 mRNA in the early phase of infection (4h), and alveolar macrophages were an important cell source of Mp-induced IL-23. We further showed that Mp significantly increased IL-17 protein levels in bronchoalveolar lavage (BAL). Lung gene expression of IL-17, IL-17C and IL-17F was also markedly up-regulated by Mp in vivo. IL-17 and IL-17F were found to be derived mainly from lung CD4+ T cells, and were increased upon IL-23 stimulation in vitro. In vivo blocking of IL-23p19 alone or in combination with IL-23/IL-12p40 resulted in a significant reduction of Mp-induced IL-17 protein and IL-17/IL-17F mRNA expression, which was accompanied by a trend toward reduced lung neutrophil recruitment, BAL neutrophil activity, and Mp clearance. However, IL-23 neutralization had no effect on Mp-induced lung IL-17C mRNA expression. These results demonstrate that IL-17/IL-17F production is IL-23-dependent in an acute Mp infection, and contributes to neutrophil recruitment and activity in the lung defense against the infection.

Animals↗
PubMed2006

Gas-phase uranyl-nitrile complex ions.

Electrospray ionization was used to generate doubly charged complex ions composed of the uranyl ion and nitrile ligands. The complexes, with general formula [UO2(RCN)n]2+, n = 0-5 (where R=CH3-, CH3CH2-, or C6H5-), were isolated in an ion-trap mass spectrometer to probe intrinsic reactions with H2O. For these complexes, two general reaction pathways were observed: (a) the direct addition of one or more H2O ligands to the doubly charged complexes and (b) charge-reduction reactions. For the latter, the reactions produced uranyl hydroxide, [UO2OH], complexes via collisions with gas-phase H2O molecules and the elimination of protonated nitrile ligands.

Journal Article↗
PubMed2006

Production of epsilon-poly-L-lysine by newly isolated Kitasatospora sp. PL6-3.

A novel epsilon-poly-L-lysine (epsilon-PL)-producing strain PL6-3 was isolated from soil, and was identified as a strain of Kitasatospora sp. This is the first detailed report of production of epsilon-PL by a strain in the genera of Kitasatospora. By controlling the culture pH at 4.0, the yield of epsilon-PL from PL6-3 reached 13.9 g/L after 120 h of cultivation in fed-batch fermentation. The morphological characteristics of Kitasatospora sp. PL6-3 in culture broth were different from those reported from strains of Streptomycetaceae, as no mycelium pellets were observed during the course of fermentation of PL6-3, which was beneficial to the assimilation of nutrition and secretion of the products. Furthermore, the molecular mass of the purified epsilon-PL from PL6-3 was determined to be 5.01 kDa by SDS-PAGE and 5.05 kDa by gel permeation chromatography, indicating that the epsilon-PL produced by this strain might be composed of 40 lysine residues. Usually, epsilon-PL with more lysine residues showed higher antimicrobial activity; however, it was difficult to obtain epsilon-PL with more than 36 lysine residues in this study. As a result, epsilon-PL from Kitasatospora sp. PL6-3, which contains more lysine residues than that from other strains, is more promising in the field of food preservatives.

Polylysine↗
PubMed2006

Investigation of intramolecular proton migration in a series of model, metal-cationized tripeptides using in situ generation of an isotope label.

In this study we used an isotope label, generated in situ, to investigate intramolecular proton migration or scrambling during formation of [b(2)+17+Li](+) products by collision-induced dissociation (CID) of Li(+)-cationized tripeptides. To generate the isotope label, we used a McLafferty-type rearrangement of N-terminally acetylated, C-terminal peptide tert-butyl esters in which all amide positions were exchanged with deuterium. Using a set of small, model peptides, we show that intramolecular proton scrambling occurs during CID, particularly amongst adjacent sites along a peptide backbone, on the time scales employed for low-energy collisional activation in an ion-trap mass spectrometer.

Cations↗
PubMed2005

Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target.

In this study, differential gene expression between normal human mammary epithelial cells and their malignant counterparts (eight well established breast cancer cell lines) was studied using Incyte GeneAlbum 1-6, which contains 65,873 cDNA clones representing 33,515 individual genes. 3,152 cDNAs showed a > or =3.0-fold expression level change in at least one of the human breast cancer cell lines as compared with normal human mammary epithelial cells. Integration of breast tumor gene expression data with the genes in the tumor suppressor p53 signaling pathway yielded 128 genes whose expression is altered in breast tumor cell lines and in response to p53 expression. A hierarchical cluster analysis of the 128 genes revealed that a significant portion of genes demonstrate an opposing expression pattern, i.e. p53-activated genes are down-regulated in the breast tumor lines, whereas p53-repressed genes are up-regulated. Most of these genes are involved in cell cycle regulation and/or apoptosis, consistent with the tumor suppressor function of p53. Follow-up studies on one gene, RAI3, suggested that p53 interacts with the promoter of RAI3 and repressed its expression at the onset of apoptosis. The expression of RAI3 is elevated in most tumor cell lines expressing mutant p53, whereas RAI3 mRNA is relatively repressed in the tumor cell lines expressing wild-type p53. Furthermore, ectopic expression of RAI3 in 293 cells promotes anchorage-independent growth and small interfering RNA-mediated depletion of RAI3 in AsPc-1 pancreatic tumor cells induces cell morphological change. Taken together, these data suggest a role for RAI3 in tumor growth and demonstrate the predictive power of integrative genomics.

Agar↗
PubMed2005

[Clinical applications of devitalized autogenous calvarial bone flaps fixed with titanium clamps (CranioFix) for cranioplasty].

OBJECTIVE: To evaluate reimplantation of devitalized autogenous calvarial bone flaps and the fixation of titanium clamps (CranioFix) for cranioplasty. METHODS: From March 2000 to December 2003, 21 patients underwent (1) delayed reimplantation of preserved autogenous bone flaps, which were removed during the initial operations for increased intracranial pressure and stored in a freezer and autoclaved before use, or (2) immediate reimplantation of tumor invaded bone flaps that were devitalized by boiling. All of these flaps were fixed with titanium clamps (CranioFix). Resorption of the bone flaps was monitored by skull roentgenograms and computed tomography (CT). The clinical and aesthetic results were evaluated. RESULTS: During the follow-up period of 6 to 30 months, no complications were found. There was slight resorption of the bone flaps in all cases, but the edge of the bone flaps was within the range of the titanium clamps according to skull roentgenograms and CT. Clinical and aesthetic results were highly satisfactory. CONCLUSIONS: It is simple and practical using devitalized autogenous calvarial bone flaps for cranioplasty. The firmness decreasing of the reimplanted bone flap due to resorption can be prevented greatly by titanium clamps (CranioFix).

Adolescent↗
PubMed2004

Locomotion induced by non-contingent intracranial electrical stimulation: Dopamine dependence and general characteristics.

Intracranial self-stimulation (ICSS) is induced by delivery of electrical stimulation contingent upon a response such as bar pressing. This procedure has been widely used to investigate the brain reward system. Recent investigations, however, have noted that non-contingent electrical stimulation, also called experimenter applied stimulation (EAS), produces a unique set of locomotion behaviors that appear to be related to ICSS, and that these behaviors resemble locomotion similar to those elicited by dopamine enhancing drugs. However, little is known about the general characteristics of EAS-induced locomotion. While ICSS appears to be robust, long lasting, and highly rewarding in that the rat will invest vast amounts of time or energy to obtain the electrical stimulation, these parameters have not been explored for EAS. Moreover, the dopamine dependence of EAS-evoked locomotion is also not firmly established. Thus, the present study investigated dopamine dependence and general characteristics of the EAS-induced locomotion to determine its similarity to ICSS. Results suggested that motor and limbic systems were strongly activated by non-contingent EAS, and that the resulting locomotion was dopamine dependent, robust, continued across long time horizons, and was greater than that evoked by contingent electrical stimulation.

Animals↗
PubMed2004

PEG10 activation by co-stimulation of CXCR5 and CCR7 essentially contributes to resistance to apoptosis in CD19+CD34+ B cells from patients with B cell lineage acute and chronic lymphocytic leukemia.

We investigated CD19+CD34+ and CD19+CD34- B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-alpha-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevated level of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-alpha-mediated apoptosis. We suggested that normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration, resistance to apoptosis, and inappropriate proliferation.

Adult↗
PubMed2003

Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression.

The temporal gene expression profile during the entire process of apoptosis and cell cycle progression in response to p53 in human ovarian cancer cells was explored with cDNA microarrays representing 33 615 individual human genes. A total of 1501 genes (4.4%) were found to respond to p53 (approximately 80% of these were repressed by p53) using 2.5-fold change as a cutoff. It was anticipated that most of p53 responsive genes resulted from the secondary effect of p53 expression at late stage of apoptosis. To delineate potential p53 direct and indirect target genes during the process of apoptosis and cell cycle progression, microarray data were combined with global p53 DNA-binding site analysis. Here we showed that 361 out of 1501 p53 responsive genes contained p53 consensus DNA-binding sequence(s) in their regulatory region, approximately 80% of which were repressed by p53. This is the first time that a large number of p53-repressed genes have been identified to contain p53 consensus DNA-binding sequence(s) in their regulatory region. Hierarchical cluster analysis of these genes revealed distinct temporal expression patterns of transcriptional activation and repression by p53. More genes were activated at early time points, while more repressed genes were found after the onset of apoptosis. A small-scale quantitative chromatin immunoprecipitation analysis indicated that in vivo p53-DNA interaction was detected in eight out of 10 genes, most of which were repressed by p53 at the early onset of apoptosis, suggesting that a portion of p53 target genes in the human genome could be negatively regulated by p53 via sequence-specific DNA binding. The approaches and genes described here should aid the understanding of global gene regulatory network of p53.

Adenoviridae↗
PubMed2002

Transcriptional regulation during p21WAF1/CIP1-induced apoptosis in human ovarian cancer cells.

In this study we used adenovirus vector-mediated transduction of either the p53 gene (rAd-p53) or the p21(WAF1/CIP1) gene (rAd-p21) to mimic both p53-dependent and -independent up-regulation of p21(WAF1/CIP1) within a human ovarian cancer cell line, 2774, and the derivative cell lines, 2774qw1 and 2774qw2. We observed that rAd-p53 can induce apoptosis in both 2774 and 2774qw1 cells but not in 2774qw2 cells. Surprisingly, overexpression of p21(WAF1/CIP1) also triggered apoptosis within these two cell lines. Quantitative reverse transcription-PCR analysis revealed that the differential expression of BAX, BCL2, and caspase 3 genes, specific in rAd-p53-induced apoptotic cells, was not altered in rAd-p21-induced apoptotic cells, suggesting p21(WAF1/CIP1)-induced apoptosis through a pathway distinguishable from p53-induced apoptosis. Expression analysis of 2774qw1 cells infected with rAd-p21 on 60,000 cDNA microarrays identified 159 genes in response to p21(WAF1/CIP1) expression in at least one time point with 2.5-fold change as a cutoff. Integration of the data with the parallel microarray experiments with rAd-p53 infection allowed us to extract 66 genes downstream of both p53 and p21(WAF1/CIP1) and 93 genes in response to p21(WAF1/CIP1) expression in a p53-independent pathway. The genes in the former set may play a dual role in both p53-dependent and p53-independent pathways, and the genes in the latter set gave a mechanistic molecular explanation for p53-independent p21(WAF1/CIP1)-induced apoptosis. Furthermore, promoter sequence analysis suggested that transcription factor E2F family is partially responsible for the differential expression of genes following p21(WAF1/CIP1). This study has profound significance toward understanding the role of p21(WAF1/CIP1) in p53-independent apoptosis.

Adenoviridae↗
PubMed2002

Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study.

Receptor-mediated feedback control plays an important role in dopamine (DA) neurotransmission. Recent evidence suggests that release and uptake, key mechanisms determining brain extracellular levels of the neurotransmitter, are governed by presynaptic autoreceptors. The goal of this study was to investigate whether autoreceptors regulate both mechanisms concurrently. Extracellular DA in the caudate-putamen and nucleus accumbens, evoked by electrical stimulation of the medial forebrain bundle, was monitored in the anesthetized rat by real-time voltammetry. Effects of the D2 antagonist haloperidol (0.5 mg/kg, i.p.) on evoked DA levels were measured to evaluate autoreceptor control mechanisms. Two strategies were used to resolve individual contributions of release and uptake to the robust increases in DA signals observed after acute haloperidol challenge in naive animals: pretreatment with 3beta-(p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), an irreversible inhibitor of the DA transporter, and kinetic analysis of extracellular DA dynamics. RTI-76 effectively removed the uptake component from recorded signals. In RTI-76-pretreated rats, haloperidol induced only modest increases in DA elicited by low frequencies and had little or no effect at high frequencies. These results suggest that D2 antagonism alters uptake at all frequencies but only release at low frequencies. Kinetic analysis similarly demonstrated that haloperidol decreased V(max) for DA uptake and increased DA release at low (10-30 Hz) but not high (40-60 Hz) stimulus frequencies. We conclude that presynaptic DA autoreceptors concurrently downregulate release and upregulate uptake, and that the mechanisms are also independently controlled during neurotransmission.

Animals↗
PubMed2002

Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway.

Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.

Adenoviridae↗