Jingnan Wang

Circulating endothelial progenitor cell deficiency contributes to impaired arterial elasticity in persons of advancing age.

Reduced arterial elasticity is a hallmark of ageing in healthy humans and appears to occur independently of coexisting disease processes. Endothelial-cell injury and dysfunction may be responsible for this fall in arterial elasticity. We hypothesized that circulating endothelial progenitor cells (EPCs) are involved in endothelial repair and that lack of EPCs contributes to impaired arterial elasticity. A total of 56 healthy male volunteers were divided into young (n=26) and elderly (n=30) groups. Large and small artery elasticity indices were noninvasively assessed using pulse wave analysis. The number of circulating EPCs was measured by using flow cytometry. Cells demonstrating DiI-acLDL and FITC-ulex lectin double-positive fluorescence were identified as EPCs. C1 large artery elasticity and C2 small artery elasticity indices were significantly reduced in the elderly group compared with the young group (11.73±1.45 vs 16.88±1.69 ml/mm Hg × 10, P<0.001; 8.40±1.45 vs 10.58±1.18 ml/mm Hg × 100, P<0.001, respectively). In parallel, the number of circulating EPCs was significantly reduced in the elderly group compared with the young group (0.13±0.02 vs 0.17±0.04%, P<0.05). The number of circulating EPCs correlated with C1 large and C2 small artery elasticity indices (r=0.47, P<0.01; r=0.4, P<0.01). The present findings suggest that the fall in circulating EPCs with subsequently impaired endothelial-cell repair and function contributes to reduced arterial elasticity in humans with ageing. The decrease in circulating EPCs may serve as a surrogate biologic measure of vascular function and human age.

Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET

Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models. Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined. Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1-phase arrest. Cabozantinib inhibited tumor growth in p-MET–positive and p-MET–negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET–positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)–stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model. Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res; 20(11); 2959–70. ©2014 AACR.

Elevated circulating endothelial microparticles and brachial–ankle pulse wave velocity in well-controlled hypertensive patients

Vascular dysfunction in hypertensive condition is characterized by impaired endothelial function and reduced artery elasticity. Circulating endothelial microparticles (EMPs) and brachial–ankle pulse wave velocity (baPWV) are novel evaluation parameters for vascular function. However, their changes in patients with well-controlled blood pressure (BP) have not been fully acquired. To address this issue, circulating EMPs, defined as CD31+/CD42− MPs and baPWV were detected in 30 healthy subjects, 30 uncontrolled hypertensive (UCHT) patients and 23 well-controlled hypertensive (WCHT) patients. UCHT patients displayed elevated baPWV (P<0.01) and circulating EMPs (P<0.01) compared with healthy subjects. In WCHT patients, vascular damage represented by these two parameters constantly existed (P<0.01). Values of circulating EMPs were positively related to baPWV (P<0.01). Multivariate regression defined circulating EMPs as an independent contributor to the increase of baPWV value (P<0.05). Our study indicated that though BP was controlled, impaired endothelial function and arterial elasticity continued. The optimal therapy for patients with hypertension should include not only lowering BP but also improvement of vascular injury in parallel.

Electrospinning polyvinylidene fluoride fibrous membranes containing anti-bacterial drugs used as wound dressing

The aim of this study was to synthesis drug-loaded fibrous membrane scaffolds for potential applications as wound dressing. Polyvinylidene fluoride (PVDF) fibrous membranes were loaded with enrofloxacin (Enro) drugs by using an electrospinning process, and their mechanical strength, drug release profile and anti-bacterial properties were evaluated. Enro drug-loaded PVDF membranes exhibited good elasticity, flexibility and excellent mechanical strength. The electrospinning Enro/PVDF membranes showed a burst drug release in the initial 12h, followed by sustained release for the next 3 days, which was an essential property for antibiotic drugs applied for wound healing. The drug-loaded PVDF fibrous membranes displayed excellent anti-bacterial activity toward Escherichia coli and Staphylococcus aureus. The results suggest that electrospinning PVDF membrane scaffolds loaded with drugs can be used as wound dressing.

Berberine-induced mobilization of circulating endothelial progenitor cells improves human small artery elasticity

Berberine (BR) has been proved to promote endothelial function. However, the exact mechanisms underlying the effect of BR on endothelial function are not completely clear. It has been demonstrated that endothelial progenitor cells (EPCs) contribute to improvement of endothelial function and C2 small artery elasticity index is a surrogate parameter for the clinical evaluation of endothelial function. We hypothesized that BR-induced mobilization of circulating EPCs is associated with BR-related improvement of endothelial function. To address this assumption, 15 healthy volunteers were recruited and received BR 0.4 g three times per day for 30 days. The number of circulating CD34/KDR double-positive cells as well as C1 large and C2 small artery elasticity indices were evaluated before and after BR therapy. The number of CD34/KDR double-positive EPCs increased significantly after BR treatment (0.030±0.020% vs 0.017±0.010%, P<0.01). After 30-day BR therapy C2 increased significantly (6.21±2.80 ml per mm Hg × 100 vs 4.06±2.67 ml per mm Hg × 100, P<0.01) and C1 remained unchanged (10.79±3.27 ml per mm Hg × 10 vs 10.06±2.08 ml per mm Hg × 10, P>0.05). The increment of CD34/KDR double-positive EPCs was positively correlated with the increment of C2 (r=0.68, P<0.01). We concluded that BR-induced mobilization of circulating EPCs contributes to improvement of small artery elasticity in healthy persons.

Cabozantinib reverses multidrug resistance of human hepatoma HepG2/ adr cells by modulating the function of P-glycoprotein

Cabozantinib, a small‐molecule multitargeted tyrosine kinase inhibitor, has entered into a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). This study assessed the mechanistic effect of cabozantinib on the reversal of P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR).

Surface modified titania nanotubes containing anti-bacterial drugs for controlled delivery nanosystems with high bioactivity

Surface functionalization of nanomaterials has been realized to be vital to fabricate drug delivery nanosystems that offer high drug loading and sustained release with remarkable in vivo biocompatibility and bioavailability. From these systems, nanomaterials such as titania nanotubes (TNTs) can be functionalized and designed as specific drug delivery nanosystems. Here, two kinds of novel drug delivery nanosystems, i.e. Enro-NH2-TNTs and Enro-SH-TNTs, were first prepared by combining the characteristic pH adjusted enrofloxacin (Enro) recrystallized loading process and surface silane coupling agent modified titania nanotubes (NH2-TNTs and SH-TNTs). FTIR analysis exhibited that Enro molecules interacted with surface grafted groups, such as -NH2 or -SH, through an electrostatic effect or a hydrogen effect. The recrystallization and loading of Enro molecules into the two types of modified TNTs was identified using X-ray diffraction patterns (XRD), surface area analysis (BET), and transmission electron microscopy (TEM). In vitro experiments exhibited excellent controlled-release properties and further proved that the Enro drugs had been loaded into TiO2 nanotubes, which were influenced by grafted molecules. In vitro cell viability, hemolysis assays and cell apoptosis experiments showed that surface modification could increase the biocompatibility and lower the cytotoxicity of TNT nanomaterials to cells. These modified drug delivery nanosystems afforded higher drug bioavailability and longer drug effects on in vivo administration to chickens. Surface modification combined with a pH adjusted process has a large potential for fabricating long-acting drug delivery nanosystems, especially with hydrochloride drugs.

Outside-in stepwise functionalization of mesoporous silica nanocarriers for matrix type sustained release of fluoroquinolone drugs

In this study, we propose outside-in stepwise functionalization of MCM-41-type mesoporous silica for use as a high-efficiency matrix drug delivery nanosystem aimed at the insoluble antibacterial agent fluoroquinolone. Thiol (-SH) modification on the surface of the nanocarrier and aminopropyl groups (-NH2) in the channels give the system a framework for sustained drug release for 72 h with drug loading capacity of 58.64% as a result of the completely opposite electrostatic interaction between drug molecules of thiol and amino. Unusually, abundant crystals of drug molecules were observed by transmission electron microscopy (TEM) in channels of the nanocarriers, caused by self-organization under the electrostatic attraction of the grafting groups. The elevated crystallinity of drug molecules loaded in the functional mesoporous MCM-41 nanoparticles was proved also through wide-angle XRD. Analysis of the release profiles highlighted the low cytotoxicity and excellent biocompatibility of the modified nanocarriers in vitro. Compared with single functionalization, the outside-in stepwise process can completely modify the deep inner of the channel and achieve effective internal drug loading of mesoporous materials. We believe that this method is not only of use for framework sustained-release tablets, but also other clinical medicine and chemical engineering.

An efficient nonviral gene-delivery vector based on hyperbranched cationic glycogen derivatives.

Background The purpose of this study was to synthesize and evaluate hyperbranched cationic glycogen derivatives as an efficient nonviral gene-delivery vector. Methods A series of hyperbranched cationic glycogen derivatives conjugated with 3-(dimethylamino)-1-propylamine (DMAPA-Glyp) and 1-(2-aminoethyl) piperazine (AEPZ-Glyp) residues were synthesized and characterized by Fourier-transform infrared and hydrogen-1 nuclear magnetic resonance spectroscopy. Their buffer capacity was assessed by acid–base titration in aqueous NaCl solution. Plasmid deoxyribonucleic acid (pDNA) condensation ability and protection against DNase I degradation of the glycogen derivatives were assessed using agarose gel electrophoresis. The zeta potentials and particle sizes of the glycogen derivative/pDNA complexes were measured, and the images of the complexes were observed using atomic force microscopy. Blood compatibility and cytotoxicity were evaluated by hemolysis assay and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, respectively. pDNA transfection efficiency mediated by the cationic glycogen derivatives was evaluated by flow cytometry and fluorescence microscopy in the 293T (human embryonic kidney) and the CNE2 (human nasopharyngeal carcinoma) cell lines. In vivo delivery of pDNA in model animals (Sprague Dawley rats) was evaluated to identify the safety and transfection efficiency. Results The hyperbranched cationic glycogen derivatives conjugated with DMAPA and AEPZ residues were synthesized. They exhibited better blood compatibility and lower cytotoxicity when compared to branched polyethyleneimine (bPEI). They were able to bind and condense pDNA to form the complexes of 100–250 nm in size. The transfection efficiency of the DMAPA-Glyp/pDNA complexes was higher than those of the AEPZ-Glyp/pDNA complexes in both the 293T and CNE2 cells, and almost equal to those of bPEI. Furthermore, pDNA could be more safely delivered to the blood vessels in brain tissue of Sprague Dawley rats by the DMAPA-Glyp derivatives, and then expressed as green fluorescence protein, compared with the control group. Conclusion The hyperbranched cationic glycogen derivatives, especially the DMAPA-Glyp derivatives, showed high gene-transfection efficiency, good blood compatibility, and low cyto toxicity when transfected in vitro and in vivo, which are novel potential nonviral gene vectors.

Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma

BackgroundTivantinib has been described as a highly selective inhibitor of MET and is currently in a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). However, the mechanism of tivantinib anti-tumor effect has been questioned by recent studies.ResultsWe show that tivantinib indiscriminately inhibited MET dependent and independent HCC cells proliferation. In contrast, other MET inhibitors, JNJ-38877605 and PHA-665752, just specifically inhibited the growth of MET dependent HCC cells. Tivantinib neither inhibit constitutive MET phosphorylation nor HGF-induced MET phosphorylation in HCC cells. In the microtubule polymerization analysis, tivantinib affected microtubule dynamics by a mechanism as a microtubule depolymerizer. Interesting, unlike other microtubule-targeting agents, paclitaxel and vincristine, tivantinib showed similar anti-proliferative activity in parental and multidrug-resistant cells. Further studies demonstrated that tivantinib induced a G2/M arrest and promoted apoptosis by both intrinsic and extrinsic pathway. The in vivo efficacy evaluation showed that tivantinib exhibited a good anti-tumor growth activity with anti-proliferative and pro-apoptotic effects.ConclusionsThe potent anti-tumor activity of tivantinib in HCC was achieved by targeting microtubule. Tivantinib treatment for patients with HCC should not be selected based on MET status.