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Articles by H Xu
Total Records ( 9 ) for H Xu
  D Zheng , X Li , H Xu , X Lu , Y Hu and W. Fan
 

Docetaxel (Doc) has extraordinary activities against a variety of solid tumors. However, the clinical efficacy of Doc is limited due to its poor solubility, low selective distribution, fast elimination in vivo, etc. In the present study, Doc was incorporated into the core-shell structure of nanoparticles prepared based on our previous work. The obtained docetaxel-loaded nanoparticles (DOCNP) were characterized with various biophysical methodologies, and its antitumor efficacy against malignant melanoma was evaluated both in vitro and in vivo. Our results indicated that Doc could be incorporated into the nanoparticles with high encapsulation efficiency (>90%). The incorporated Doc can be released from DOCNP in a sustained manner. In vitro cytotoxicity studies indicated that DOCNP could effectively kill B16 cells and show a dose- and time-dependent efficacy. Furthermore, intratumoral administration revealed that DOCNP has significantly higher antitumor effect and lower toxicity to normal cells and tissues than free Doc. These results suggest that DOCNP may be a promising drug delivery system in therapy for malignant melanoma.

  H Jiang , Y Zhu , H Xu , Y Sun and Q. Li
 

Accumulating data suggested that hypoxia inducible factor (HIF)-1 plays an important role in the evolution and propagation of the inflammatory process. To characterize the activation of HIF-1 in rats with chronic obstructive pulmonary disease (COPD) and examine the possible role of nuclear factor (NF)-B in this process, rats were challenged by introtracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke. Pyrrolidine dithiocarbamate (PDTC) was administered via the oral route 1 h before LPS or cigarettes administration. Four weeks later, pulmonary function and histology were tested; bronchoalveolar lavage fluid (BALF) and arterial blood gases were assayed. Activation of pulmonary NF-B was assessed by quantitative PCR, immunoblot analysis, and electrophoretic mobility shift assay, respectively. Results showed that LPS and smog induced the characteristics of COPD seen in human. PDTC alleviated the development of COPD and the levels of cytokines in BALF of PDTC+COPD group were significantly decreased compared with that of COPD group. The activation of pulmonary NF-B was inhibited by PDTC and the accumulation of HIF-1 gene expression in the COPD group was attenuated by PDTC pretreatment. Furthermore, the mRNA levels of HIF-1 target genes heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were parallel to the attenuation of HIF-1 by PDTC. These findings indicated that the activation of HIF-1 pathway via NF-B contributes to the development of COPD, and administration of NF-B inhibitor may attenuate the development of COPD.

  S Yao , S Wang , Y Zhu , L Luo , G Zhu , S Flies , H Xu , W Ruff , M Broadwater , I. H Choi , K Tamada and L. Chen
 

Programmed death one (PD-1) is an inducible molecule belonging to the immunoglobulin superfamily. It is expressed on activated T and B lymphocytes and plays pivotal roles in the negative regulation of adaptive immune responses. We report here an unexpected finding: that PD-1 could also be induced on splenic dendritic cells (DCs) by various inflammatory stimuli. Adoptive transfer of PD-1–deficient DCs demonstrates their superior capacity to wild-type DCs in innate protection of mice against lethal infection by Listeria monocytogenes. Furthermore, PD-1–deficient mice are also more resistant to the infection than wild-type controls, even in the absence of T and B cells, accompanied by elevated production of DC-derived interleukin-12 and tumor necrosis factor-. Our results reveal a novel role of PD-1 in the negative regulation of DC function during innate immune response.

  A Manni , H Xu , S Washington , C Aliaga , T Cooper , J. P Richie , R Bruggeman , B Prokopczyk , A Calcagnotto , N Trushin , D Mauger , M. F Verderame and K. El Bayoumy
 

The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor- (PPAR), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPAR receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea–induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPAR is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA–rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies. Cancer Prev Res; 3(3); 322–30

  S. D Sharma , S. M Meeran , N Katiyar , G. B Tisdale , N Yusuf , H Xu , C. A Elmets and S. K. Katiyar
 

Interleukin (IL)-12 deficiency exacerbates tumorigenesis in ultraviolet (UV) radiation-induced skin. Here, we assessed the effects of IL-12 deficiency on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin. Using this two-stage chemical carcinogenesis protocol, we found that the development of DMBA/TPA-induced skin tumors was diminished in IL-12p40-knockout mice than in their wild-type counterparts. At the termination of the experiment (at 24 weeks), the skin tumor incidence and tumor multiplicity were significantly lower (P < 0.005) in interleukin-12-knockout (IL-12 KO) mice than in their wild-type counterparts, as was the malignant transformation of DMBA/TPA-induced papillomas to carcinomas (P < 0.01). Analysis of samples collected at the termination of the experiments for biomarkers of inflammation by immunohistochemical analysis, western blotting, enzyme-linked immunosorbent assay and real-time polymerase chain reaction revealed significantly lower levels of cyclooxygenase-2 (COX-2), prostaglandin (PG) E2, proliferating cell nuclear antigen, cyclin D1 and the proinflammatory cytokines (tumor necrosis factor-, IL-1β and IL-6) in the DMBA/TPA-treated tumors and tumor-uninvolved skin of IL-12 KO mice than the skin and tumors of DMBA/TPA-treated wild-type mice. Analysis of the skin 6 h after TPA treatment showed that the TPA-induced promotion of skin edema, inflammatory leukocyte infiltration, COX-2 expression and PGE2 production was significantly lower in the skin of the IL-12-KO mice than their wild-type counterparts. These results indicate that DMBA/TPA-induced skin tumor development differs from UVB-induced skin tumor development in that endogenous IL-12 acts to inhibit UVB-induced skin tumor development and malignant progression of the skin tumors to carcinoma. In the case of DMBA/TPA-induced skin tumor development, the endogenous IL-12 modulates the tumor promoter stimulation of inflammatory responses.

  H Xu , G. H Posner , M Stevenson and F. C. Campbell
 

A central paradox of vitamin D biology is that 1,25-(OH)2 D3 exposure inversely relates to colorectal cancer (CRC) risk despite a capacity for activation of both pro- and anti-oncogenic mediators including osteopontin (OPN)/CD44 and E-cadherin, respectively. Most sporadic CRCs arise from adenomatous polyposis coli (APC) gene mutation but understanding of its effects on vitamin D growth control is limited. Here we investigate effects of the ApcMin/+ genotype on 1,25-(OH)2 D3 regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo. In untreated ApcMin/+ versus Apc+/+ intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1,25-(OH)2 D3 or rationally designed analogues (QW or BTW) enhanced OPN but inhibited expression of CD44, the OPN receptor implicated in cell growth. These treatments also enhanced E-cadherin tumour suppressor activity, characterized by inhibition of β-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in ApcMin/+ intestine. All secosteroids suppressed ApcMin/+-driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the ApcMin/+ genotype modulates vitamin D secosteroid actions to promote functional predominance of E-cadherin tumour suppressor activity within antagonistic molecular networks. APC heterozygosity may promote favourable tissue- or tumour-specific conditions for growth control by vitamin D secosteroid treatment.

  C. L Miller , M Oikawa , Y Cai , A. P Wojtovich , D. J Nagel , X Xu , H Xu , V Florio , S. D Rybalkin , J. A Beavo , Y. F Chen , J. D Li , B. C Blaxall , J. i Abe and C. Yan
 

Rationale: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca2+/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca2+/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown.

Objective: Herein, we investigate the role of Ca2+/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo.

Methods and Results: Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Furthermore, PDE1A plays a critical role in phenylephrine-induced reduction of intracellular cGMP- and cGMP-dependent protein kinase (PKG) activity and thereby cardiomyocyte hypertrophy in vitro.

Conclusions: These results elucidate a novel role for Ca2+/CaM-stimulated PDE1, particularly PDE1A, in regulating pathological cardiomyocyte hypertrophy via a cGMP/PKG-dependent mechanism, thereby demonstrating Ca2+ and cGMP signaling cross-talk during cardiac hypertrophy.

  H Xu , B Zhang , J Li , H Chen , J Tooley and F. K. Ghishan
 

Sodium/hydrogen exchangers (NHEs) play a major role in Na+ absorption, cell volume regulation, and intracellular pH regulation. Of the nine identified mammalian NHEs, three (NHE2, NHE3, and NHE8) are localized on the apical membrane of epithelial cells in the small intestine and the kidney. Although the regulation of NHE2 and NHE3 expression has been extensively studied in the past decade, little is known about the regulation of NHE8 gene expression under physiological conditions. The current studies were performed to explore the role of epidermal growth factor (EGF) on NHE8 expression during intestinal maturation. Brush-border membrane vesicles (BBMV) were isolated from intestinal epithelia, and Western blot analysis was performed to determine NHE8 protein expression of sucking male rats treated with EGF. Real-time PCR was used to quantitate NHE8 mRNA expression in rats and Caco-2 cells. Human NHE8 promoter activity was characterized through transfection of Caco-2 cells. Gel mobility shift assays (GMSAs) were used to identify the promoter sequences and the transcriptional factors involved in EGF-mediated regulation. Our results showed that intestinal NHE8 mRNA expression was decreased in EGF-treated rats and Caco-2 cells, and NHE8 protein abundance was also decreased in EGF-treated rats. The activity of the human NHE8 gene promoter transfected in Caco-2 cells was also reduced by EGF treatment. This could be explained by reduced binding of transcription factor Sp3 on the NHE8 basal promoter region in the presence of EGF. Pretreatment with MEK1/2 inhibitor UO-126 could prevent EGF-mediated inhibition of NHE8 gene expression. In conclusion, this study showed that EGF inhibits NHE8 gene expression through reducing its basal transcription, suggesting an important role of EGF in regulating NHE expression during intestinal maturation.

  J Eldstrom , H Xu , D Werry , C Kang , M. E Loewen , A Degenhardt , S Sanatani , G. F Tibbits , C Sanders and D. Fedida
 

Long QT interval syndrome (LQTS) type 1 (LQT1) has been reported to arise from mutations in the S3 domain of KCNQ1, but none of the seven S3 mutations in the literature have been characterized with respect to trafficking or biophysical deficiencies. Surface channel expression was studied using a proteinase K assay for KCNQ1 D202H/N, I204F/M, V205M, S209F, and V215M coexpressed with KCNE1 in mammalian cells. In each case, the majority of synthesized channel was found at the surface, but mutant IKs current density at +100 mV was reduced significantly for S209F, which showed ~75% reduction over wild type (WT). All mutants except S209F showed positively shifted V1/2’s of activation and slowed channel activation compared with WT (V1/2 = +17.7 ± 2.4 mV and activation of 729 ms at +20 mV; n = 18). Deactivation was also accelerated in all mutants versus WT (126 ± 8 ms at –50 mV; n = 27), and these changes led to marked loss of repolarizing currents during action potential clamps at 2 and 4 Hz, except again S209F. KCNQ1 models localize these naturally occurring S3 mutants to the surface of the helices facing the other voltage sensor transmembrane domains and highlight inter-residue interactions involved in activation gating. V207M, currently classified as a polymorphism and facing lipid in the model, was indistinguishable from WT IKs. We conclude that S3 mutants of KCNQ1 cause LQTS predominantly through biophysical effects on the gating of IKs, but some mutants also show protein stability/trafficking defects, which explains why the kinetic gain-of-function mutation S209F causes LQT1.

 
 
 
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