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Articles by X Zhou
Total Records ( 12 ) for X Zhou
  J He , R Xu , X Chen , K Jia , X Zhou and K. Zhu

To reduce the immunogenicity of recombinant staphylokinase, structure-based mutagenesis of Glu80 residue in wild-type staphylokinase (wt-Sak) was rationally designed and carried out by a modified QuikChange site-directed mutagenesis. Sak mutants, including Sak(E80A) and Sak(E80S), were successfully expressed in E. coli DH5 as a soluble cytoplasmic proteins and accounted for more than 40% of the total cellular proteins. The expressed proteins were purified by a three-step chromatographic purification process. SDS–PAGE and HPLC analyses results indicated that the purified proteins were almost completely homogeneous and the purities of Sak mutants exceeded 97%. Analysis of fibrinolytic activity revealed that substitution of E80 residue with serine and alanine resulted in slightly increased specific activities of Sak mutants. Investigation of the immunogenicity of Sak mutants showed that the amount of specific anti-Sak IgG antibodies elicited by Sak(E80A) and Sak(E80S) in BALB/c mice decreased ~35% and 27%, respectively compared with wt-Sak. The abilities of Sak mutants to stimulate proliferation of T cells from BALB/c mice and to bind mouse anti-Sak polyclonal serum were significantly lower than those of wt-Sak. These results suggested that substitution of Glu80 residue by alanine and serine successfully eliminated part of T- and B-cell epitope of Sak molecule. Our findings suggested that simultaneous elimination of T- and B-cell epitopes was a useful method to reduce the immunogenicity of wt-Sak molecule and provided a strategy for engineering safe Sak-based fibrinolytics for the clinical treatment of acute myocardial infarction.

  G Wang , X Zhou , Y Bai , Z Zhang and D. Zhao

Prion diseases are infectious and fatal neurodegenerative disorders. The cellular prion protein (PrPC) converting into misfolded isoform of prion protein (PrPSc) is responsible for prion disease infection. Immune system plays an important role in facilitating the spread of prion infections from the periphery to the central nervous system. Macrophages were considered associated with the transportation and replication of PrPSc. So, understanding the PrPC trafficking in macrophages is important to explore the transport mechanism for PrPSc. Here, we isolated exosomes from the culture medium of Ana-1 macrophage cell line and investigated the PrPC trafficked by exosomes and the interaction of PrPC with Hsp70 in secreted exosomes by western blotting, immunoelectron microscopy, and co-immunoprecipitation. The results showed that the isolated vesicles from the culture medium of macrophages were characterized by exosomes and bore PrPC. And PrPC bound to Hsp70 both in intracellular environment and secreted exosomes. In contrast, PrPC had no interaction with marker proteins of exosomes, Tag101 and Flotillin-1. These results suggested that PrPC present in extracellular space might be externalized through secreted exosomes from macrophages, and Hsp70 may play roles in the process of PrPC released via secreted exosomes.

  W Sun , H Xie , J Ji , X Zhou , D Goltzman and D. Miao

We used mice with targeted deletion of 25-hydroxyvitamin D 1-hydroxylase [1(OH)ase–/–] to investigate the effects of calcium and phosphorus on defects in the reproductive system of 1,25-dihydroxyvitamin D [1,25(OH)2D]-deficient female mice. The 1(OH)ase–/– mice and their wild-type littermates were fed either a normal diet or a rescue diet (high calcium, phosphate, and lactose) starting from weaning until 3 mo of age. We then determined serum calcium and phosphorus levels, assessed gonadotropin and gonadal hormone production, and evaluated folliculogenesis, corpus luteum formation, ovarian angiogenesis, uterus development, and fertility. Results showed that hypocalcemic and hypophosphatemic female 1(OH)ase–/– mice developed infertility accompanied by decreased estrogen and progestogen levels, elevated follicle-stimulating hormone and luteinizing hormone levels, defects in follicular development and corpus luteum formation, uterine hypoplasia, and decreased ovarian expression of angiogenic factors including vascular endothelial growth factor (VEGF), angiopoietin-1 and -2, and Tie-2. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the female 1(OH)ase–/– mice, including the dysfunction in the hypothalamic-pituitary-ovarian axis, and ovarian angiogenesis were reversed. These results indicate that the infertility seen in 1,25(OH)2D-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus.

  N Bhatnagar , X Li , Y Chen , X Zhou , S. H Garrett and B. Guo

Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor–induced apoptosis in colon cancers. Here, we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer-preventive agent, 3,3'-diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34cdc2-cyclin B1–mediated survivin Thr34 phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate–induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APCmin/+ mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.

  J. C Lopshire , X Zhou , C Dusa , T Ueyama , J Rosenberger , N Courtney , M Ujhelyi , T Mullen , M Das and D. P. Zipes

Background— Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model.

Methods and Results— In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65±5% at baseline, 17±3% at the end of stage 1, and 47±7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61±4% at baseline, 18±3% at the end of stage 1, and 34±4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64±5% at baseline, 19±5% at the end of stage 1, and 28±3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (P<0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27±17 and 27%, respectively; P<0.03) and MED (58±42 and 33%; P<0.05) versus CTRL (88±52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52±5%) and SCS+MEDS (46±4%) groups compared with the MEDS (38±2%) and CTRL (31±4%) groups.

Conclusion— SCS significantly improved cardiac contractile function and decreased ventricular arrhythmias in canine heart failure.

  F Dong , M Khalil , M Kiedrowski , C O'Connor , E Petrovic , X Zhou and M. S. Penn

Rationale: Hypoxia inducible factor (HIF)-1 is a transcription factor stabilized by hypoxia. It regulates cytokines involved in the inflammatory response after ischemia and affects white blood cell (WBCs) function. The effect of HIF-1 on WBC function and inflammation following myocardial infarction (MI) is unknown.

Objective: We assessed peritoneal and myocardial inflammation in the setting of low WBC HIF-1 expression through bone marrow transplantation of hematopoietic stem cells transfected with scramble or HIF-1 small interfering (si)RNA.

Methods and Results: Rosa hematopoietic stem cells (lin, cKit+) were transfected with a green fluorescent protein (GFP) reporter lentivirus encoding a siRNA to HIF-1 or scramble. Irradiated 6- to 8-week-old C57/BL6J mice received 50 000 GFP+ HIF-1 or scramble siRNA-transfected hematopoietic stem cells. Peritonitis or myocardial infarction via left anterior descending coronary artery ligation was induced 6 weeks after bone marrow transplantation. In the peritonitis model, HIF-1 siRNA group exhibited a significant decrease in neutrophil and monocyte entry to the peritoneum compared to scramble mice. Similarly neutrophil infiltration into the infarct zone was decreased in the HIF-1 siRNA group. No difference of myocardial infarct size was observed between groups. Interestingly, the ejection fraction were similar in both groups at baseline and 3 days post-MI but increased significantly in the HIF-1 siRNA group compared to control beginning 7 days after MI. Gene array studies demonstrated that downregulation of WBC HIF-1 was associated with decreased WBC CCR1, -2, and -4 expression. Chemotaxis assay results confirmed that decreased monocyte migration induced by downregulation of HIF-1 was partially reversed by overexpression of CCR2.

Conclusions: Downregulation of leukocyte HIF-1 expression resulted in decreased recruitment of WBC to the sites of inflammation and improvement in cardiac function following MI. Downregulation of HIF-1 suppressed WBC cytokine receptors CCR1, -2, and -4, which are necessary for WBC mobilization and recruitment to inflammatory cytokines following MI. The effects of downregulation of leukocyte HIF-1 on WBC migration are attributable, at least in part, to the decreased CCR2 expression. These results demonstrate that WBC infiltration into the newly injured myocardium plays a significant role in left ventricular remodeling, but not infarct size.

  C Zhang , C Wang , X Chen , C Yang , K Li , J Wang , J Dai , Z Hu , X Zhou , L Chen , Y Zhang , Y Li , H Qiu , J Xing , Z Liang , B Ren , K Zen and C. Y. Zhang

Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker.


Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe–based stem–loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls.


The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls.


This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC.

  X Miro , X Zhou , S Boretius , T Michaelis , C Kubisch , G Alvarez Bolado and P. Gruss
  Xavier Miro, Xunlei Zhou, Susann Boretius, Thomas Michaelis, Christian Kubisch, Gonzalo Alvarez-Bolado, and Peter Gruss

Polycomb proteins are epigenetic regulators of gene expression. Human central nervous system (CNS) malformations are congenital defects of the brain and spinal cord. One example of a human CNS malformation is Chiari malformation (CM), which presents as abnormal brainstem growth and cerebellar herniation, sometimes accompanied by spina bifida and cortical defects; it can occur in families. Clinically, CM ranges from an asymptomatic condition to one with incapacitating or lethal symptoms, including neural tube defects and hydrocephalus. However, no genes that are causally involved in any manifestation of CM or similar malformations have been identified. Here, we show that a pathway that involves Zac1 (also known as Plagl1 or Lot1) and controls neuronal proliferation is altered in mice that are heterozygous for the polycomb gene Suz12, resulting in a phenotype that overlaps with some clinical manifestations of the CM spectrum. Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem, accompanied by...

  A Takakura , L Contrino , X Zhou , J. V Bonventre , Y Sun , B. D Humphreys and J. Zhou

The ‘two-hit’ model is a widely accepted genetic mechanism for progressive cyst formation in autosomal dominant polycystic kidney disease. We have previously shown that adult inactivation of Pkd1 using the Mx1Cre+ allele causes a late onset of focal cystic disease. An explanation for the delayed appearance of cysts is the requirement for an additional independent factor, or ‘third hit’. Here we show that renal injury leads to massive cystic disease in the same mouse line. Cysts are labeled with a collecting duct/tubule marker, Lectin Dolichos biflorus Agglutinin, which correlates with the site of Cre-mediated recombination in the collecting system. 5-Bromo-2'-deoxyuridine labeling reveals that cyst-lining epithelial cells are comprised of regenerated cells in response to renal injury. These data demonstrate, for the first time, a role for polycystin-1 in kidney injury and repair and indicate that renal injury constitutes a ‘third hit’ resulting in rapid cyst formation in adulthood.

  Y Hao , L Li , W Li , X Zhou and J. Lu

Bacterial virulence could be altered by the antimicrobial agents of the host. Our aim was to identify the damage and survival of Streptococcus sanguinis induced by lysozymes in vitro and to analyse the potential of oral microorganisms to shirk host defences, which cause infective endocarditis. S. sanguinis ATCC 10556 received lysozyme at concentrations of 12.5, 25, 50 and 100 µg/ml. Cells were examined by electron microscopy. The survival was assessed by colony counting and construction of a growth curve. Challenged by lysozymes, cells mainly exhibited cell wall damage, which seemed to increase with increasing lysozyme concentration and longer incubation period in the presence of ions. Cells with little as well as apparent lesion were observed under the same treatment set, and anomalous stick and huge rotund bodies were occasionally observed. After the removal of the lysozyme, some damaged cells could be reverted to its original form with brain heart infusion (BHI), and their growth curve was similar to the control cells. After further incubation in BHI containing lysozyme, S. sanguinis cell damage stopped progressing, and their growth curve was also similar to the control cells. The results suggested that the S. sanguinis lesions caused by the lysozyme in the oral cavity may be nonhomogeneous and that some damaged cells could self-repair and survive. It also indicated that S. sanguinis with damaged cell walls may survive and be transmitted in the bloodstream.

  X Huang , X Bai , Y Cao , J Wu , M Huang , D Tang , S Tao , T Zhu , Y Liu , Y Yang , X Zhou , Y Zhao , M Wu , J Wei , D Wang , G Xu , S Wang , D Ma and J. Zhou

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

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