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1.  Acupuncture for Refractory Epilepsy: Role of Thalamus 
Neurostimulation procedures like vagus nerve stimulation (VNS) and deep brain stimulation have been used to treat refractory epilepsy and other neurological disorders. While holding promise, they are invasive interventions with serious complications and adverse effects. Moreover, their efficacies are modest with less seizure free. Acupuncture is a simple, safe, and effective traditional healing modality for a wide range of diseases including pain and epilepsy. Thalamus takes critical role in sensory transmission and is highly involved in epilepsy genesis particularly the absence epilepsy. Considering thalamus serves as a convergent structure for both acupuncture and VNS and the thalamic neuronal activities can be modulated by acupuncture, we propose that acupuncture could be a promising therapy or at least a screening tool to select suitable candidates for those invasive modalities in the management of refractory epilepsy.
PMCID: PMC4273587  PMID: 25548594
2.  Triptolide treatment reduces Alzheimer’s disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD 
Disease Models & Mechanisms  2014;7(12):1385-1395.
The complex pathogenesis of Alzheimer’s disease (AD) involves multiple contributing factors, including amyloid β (Aβ) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the β-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.
PMCID: PMC4257007  PMID: 25481013
Alzheimer’s disease; Amyloid β; 5XFAD mice; BACE1; Inflammation; Triptolide
3.  Effect of angiogenesis inhibitor SU6668 in combination with 5-Fu on liver metastasis from transplantation tumors of human colorectal cancer in nude mice 
This study was to investigate inhibiting effect of angiogenesis inhibitor SU6668 in combination with 5-Fu on liver metastasis from human colon cancer. Results showed that metastasis rates in SU6668+5-Fu group, SU6668 group, 5-Fu group decreased obviously (P<0.01). Compared with 5-Fu group and control group, microvessel density significantly decreased in SU6668+5-Fu group and SU6668 group (P<0.05). Vascular endothelial growth factor and base fibroblast growth factor reduced obviously in SU6668+5-Fu group, SU6668 group and 5-Fu group compared with control group, and there were significant differences among SU6668+5-Fu group, SU6668 group and 5-Fu group (P<0.05). Thus, SU6668 can inhibit liver metastasis from colorectal cancer through anti-angiogenesis, and it would have a synergistic effect in combination with 5-Fu. Therefore, SU6668 combined with 5-Fu could be considered as a safe and effective antitumor strategy.
PMCID: PMC4238521  PMID: 25419401
Neovascularization; pathologic; 5-Fu; colon neoplasm; liver metastasis; mice; inbred BALB C
4.  Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo 
Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In addition, INT2-31increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.
PMCID: PMC4052463  PMID: 23272972
FAK; IGF-1R; pancreatic cancer; protein interactions
5.  The Efficacy of Landscape-Level Conservation in Changbai Mountain Biosphere Reserve, China 
PLoS ONE  2014;9(4):e95081.
Anthropogenic landscape alteration is rather common in many protected areas (PAs), jeopardizing the efficacy of PAs conservation. However, the general consensus is that PAs still remain effective in habitat conservation. To assess the efficacy of landscape-level conservation, we examined landscape alterations in the Changbai Mountain Biosphere Reserve (CMBR), which was established in 1960 as a “flagship” protected area in China. Based on analyses of high-resolution satellite images and data of forest inventory, field survey and interview, we developed two new indexes to assess the efficacy of landscape conservation, i.e. the quality index of protected landscape and the interference index of anthropogenic landscape. From 1993 to 2012, the quality index increased from 74.48 to 75.50, and the interference index decreased from 0.49 to 0.06, suggesting that the overall quality of protected landscape improved and the degree of anthropogenic interference decreased in CMBR. The increase in landscape quality was mainly due to the progressive vegetation recovery of previous cutover land in the windthrow area, the cease of the use of the cultivated land, and the amelioration of spatial pattern of protected landscape. We conclude that the current landscape conservation methods used in CMBR are effective, and the method we developed has the potential to be used to assess the efficacy of landscape-level conservation in nature reserves worldwide.
PMCID: PMC3990618  PMID: 24743693
6.  Enhanced phosphorylation of caveolar PKC-α limits peptide internalization in lung endothelial cells 
Molecular and cellular biochemistry  2011;360(0):309-320.
We previously reported that the vasoactive peptide 1 (P1, “SSWRRKRKESS”) modulates the tension of pulmonary artery vessels through caveolar endothelial nitric oxide synthase (eNOS) activation in intact lung endothelial cells (ECs). Since PKC-α is a caveolae resident protein and caveolae play a critical role in the peptide internalization process, we determined whether modulation of caveolae and/or caveolar PKC-α phosphorylation regulates internalization of P1 in lung ECs. Cell monolayers were incubated in culture medium containing Rhodamine red-labeled P1 (100 μM) for 0–120 min. Confocal examinations indicate that P1 internalization is time-dependent and reaches a plateau at 60 min. Caveolae disruption by methyl-β-cyclodextrin (CD) and filipin (FIL) inhibited the internalization of P1 in ECs suggesting that P1 internalizes via caveolae. P1-stimulation also enhances phosphorylation of caveolar PKC-α and increases intracellular calcium (Ca2+) release in intact cells suggesting that P1 internalization is regulated by PKC-α in ECs. To confirm the roles of increased phosphorylation of PKC-α and Ca2+ release in internalization of P1, PKC-α modulation by phorbol ester (PMA), PKC-α knockdown, and Ca2+ scavenger BAPTA-AM model systems were used. PMA-stimulated phosphorylation of caveolar PKC-α is associated with significant reduction in P1 internalization. In contrast, PKC-α deficiency and reduced phosphorylation of PKC-α enhanced P1 internalization. P1-mediated increased phosphorylation of PKC-α appears to be associated with increased intracellular calcium (Ca2+) release since the Ca2+ scavenger BAPTA-AM enhanced P1 internalization. These data indicate that caveolar integrity and P1-mediated increased phosphorylation of caveolar PKC-α play crucial roles in the regulation of P1 internalization in lung ECs.
PMCID: PMC3748579  PMID: 21948261
Caveolae; PKC-α phosphorylation; Peptide internalization; Lung endothelium; Calcium release
7.  Circulating Tumor Cells: Application as a Biomarker for Molecular Characterization and Predictor of Survival in an All-Comer Solid Tumor Phase I Clinical Study 
PLoS ONE  2013;8(8):e58557.
Clinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study.
Experimental Design
Blood samples for CTC analysis were obtained from 24 cancer patients in a multi-center all-comer Phase I study of MEDI-575, a novel anti-PDGFRα antibody. Samples were taken at screening and analyzed for enumeration of CTC using the CellSearch® platform and for molecular characterization using a novel quantitative RT-PCR assay.
Fifty-nine percent of the patients showed at least 1 CTC per 7.5 ml of blood at baseline. Progression-free survival (PFS) and overall survival (OS) of patients with 0 CTCs at baseline were longer than PFS and Os for patients with 1-3 and >3 CTCs (8.8 versus 1.4 and 1.3 months PFS, P = 0.02; 9.0 vs 7.4 and 3.5 months OS, P = 0.20, respectively). Patients with 0 CTC showed a greater percentage of stable disease than the other 2 groups with 1-3 and >3 CTCs (57% vs 29% and 0%). The multimarker qRT-PCR method detected CTC in 40% of the patients, and 80% of these patients were positive for pre-selected drug target genes.
CTC enumeration of patients in an all-comer study is feasible and may allow for patient stratification for PFS and Os to evaluate the clinical response of investigational agents. Gene expression profiling of isolated CTC may provide a means for molecular characterization of selected tumor targets.
PMCID: PMC3749129  PMID: 23990866
8.  Laparoscopic Management of Perforated Meckel's Diverticulum in Adults 
Objective: To determine the role of laparoscopy in diagnosis and surgical treatment of perforated Meckel's diverticulum (MD) in adults.
Methods: Between July 2003 and July 2011, fifteen patients were seen with perforated MD. Eleven were male and four were female. The median age was 38 years (range, 21-68). All patients presented with a sudden onset of pain. Among them 9 had a past medical history of bloody stools and /or chronic recurrent abdominal pain. 2 were preoperatively diagnosed with perforated MD confirmly and 4 suspiciously, 9 with perforated acute appendicitis. All 15 patients underwent exploratory laparoscopy.
Results: 4 patients with broad-base(≧ 2 cm) and 2 patients with narrow-base(<2 cm) whose perforative site was near the base underwent laparoscopically assisted extracorporal bowel segment resection, the other 9 patients with narrow-base(<2 cm) underwent laparoscopically intraabdominal wedge resection of the MD. No intraoperative or postoperative complications occurred. The median hospital stay was 4 days (range, 2-7days). The histopathologic studies showed heterotopic gastric mucosa (HGM) in 10 cases (66.7%). All patients recovered uneventfully.
Conclusion: To patients with sudden abdomen pain mimic acute appendicitis accompanied by a past medical history of bloody stools and/or chronic recurrent abdominal pain, proferated MD should be kept in mind as a differential diagnosis. Laparoscopy is a safe and effective surgical modality for diagnosis of proferated MD and has a therapeutic role that results in an excellent cosmetic result.
PMCID: PMC3348529  PMID: 22577339
Meckel's diverticulum; Perforation; Laparoscopy
9.  Role of the CX3CL1-CX3CR1 axis in chronic inflammatory lung diseases 
Persistent inflammation is often present in patients with lung diseases such as chronic obstructive pulmonary diseases (COPD) and pulmonary hypertension. Circulatory leukocyte migration through the lung vascular endothelium contributes to the structural destruction and remodeling seen in these chronic lung diseases. An inflammatory chemokine CX3CL1/fractalkine is associated with inflammatory lung diseases. Membrane-anchored CX3CL1 serves as an adhesion molecule to capture subsets of mononuclear leukocytes that express the sole receptor, CX3CR1. The extracellular chemokine domain of CX3CL1 can be cleaved/shed by a disintegrin and metalloproteinase domain (ADAM) from stimulus-exposed cells. Soluble CX3CL1 chemoattracts and activates CX3CR1+ leukocytes such as CD8+, CD4+, and γδ T lymphocytes, natural killer cells, dendritic cells, and monocytes/macrophages. CX3CR1+ leukocyte attachment to and migration through the lung vascular endothelium lead to mononuclear cell accumulation in the lung vessel walls and parenchyma. Infiltrated CX3CR1+ immune cells can release mediators to induce injury, stimulate proliferation, and/or chemoattract inflammatory cells. This contributes to structural destruction and remodeling in the development of inflammatory lung diseases. Limited clinical success in treating chronic pulmonary diseases-associated lung functional decline indicates the urgency and significance of understanding upstream signaling that triggers inflammation. This article reviews the advances in the CX3CL1-CX3CR1 axis-mediated modulation of mononuclear leukocyte adhesion and migration in inflammatory lung diseases such as COPD and pulmonary hypertension. Better understanding of the constant flow of circulating leukocytes into the lung vessel wall and parenchyma will help set a stage for the development of novel therapeutic approaches to treat or even cure chronic lung diseases including COPD and pulmonary hypertension.
PMCID: PMC2929949  PMID: 20827321
Chemokine; fractalkine; inflammation; pulmonary; COPD; endothelium; vasculature
10.  A cellular model to mimic exhaled cigarette smokeinduced lung microvascular endothelial cell injury and death 
Tobacco smoke exhaled from smokers is a key component of secondhand smoke, contributing to lung alveolar wall destruction seen in chronic lung diseases. Although mainstream and sidestream tobacco smoke are cyto-toxic to lung cells, it is unclear whether exhaled smoke induces lung cell injury or even death. We sought to establish an in vitro model to examine the effects of exhaled smoke on lung cells. Phosphate-buffered saline-conditioned cigarette smoke (CCS) derived from a blow-by system was used to mimic exhaled tobacco smoke exposure. Exposure of medium to CCS leads to dose-dependent increases in nicotine/cotinine levels. Scanning spectrophotometric analysis of the CCS-exposed medium reveals an absorption peak at 290 nm wavelength. The OD values at 290 nm are correlated with nicotine levels in the exposed medium, indicating that a simple measurement of OD at 290 nm can be used to monitor CCS exposure. Tobacco smoke contacts the microvascular endothelium located at lung alveoli, before it enters the blood stream. Hence, human lung microvascular endothelial cells (hMVEC) were exposed to CCS and assessed for cell injury and death. Exposure of hMVEC to CCS equivalent to burning 12-16 cigarettes leads to increased LDH release from the cells into the medium. This suggests that CCS can induce lung cell injury. CCS at a low level increases cell growth, whereas the high level of CCS decreases cell viability. In addition, CCS exposure induces cell detachment and morphological changes. Our results demonstrate that exposure of buffer-conditioned mainstream cigarette smoke leads to increased nicotine/cotinine levels and cell injury/death, which may contribute to the pathophysiology of passive smoking-associated lung diseases.
PMCID: PMC2929948  PMID: 20827320
Cellular model; secondhand smoke; chronic lung diseases; lung microvascular endothelial cells; passive smoking-associated lung diseases
11.  A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides 
Nicotinic acetylcholine receptors (nAChRs) containing α7 subunits are thought to assemble as homomers. α7-nAChR function has been implicated in learning and memory, and alterations of α7-nAChR have been found in patients with Alzheimer’s disease (AD). Here we report findings consistent with a novel, naturally-occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, α7 subunits are co-expressed, co-localize and co-assemble with β2 subunit(s). Compared to homomeric α7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric α7β2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the β2 subunit-containing nAChR-selective antagonist, dihydro-β-erythroidine (DHβE). Interestingly, presumed, heteromeric α7β2-nAChRs are highly sensitive to functional inhibition by pathologically-relevant concentrations of oligomeric, but not monomeric or fibrillar forms of amyloid β1-42 (Aβ1-42). Slow whole-cell current kinetics, sensitivity to DHβE, and specific antagonism by oligomeric Aβ1-42 also are characteristic of heteromeric α7β2-nAChRs, but not of homomeric α7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to Aβ when elicited from MS/DB neurons derived from nAChR β2 subunit knockout mice rather than from wild-type mice. The presence of novel, functional, heteromeric α7β2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric Aβ1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.
PMCID: PMC2857410  PMID: 19176801
nicotinic receptor; basal forebrain; cholinergic neurons; patch clamp; amyloid beta; Alzheimer’s disease
12.  Development of Potential Pharmacodynamic and Diagnostic Markers for Anti-IFN-α Monoclonal Antibody Trials in Systemic Lupus Erythematosus 
To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.
PMCID: PMC2950308  PMID: 20948567
13.  Hypoxic upregulation of preproendothelin-1 gene expression is associated with protein tyrosine kinase-PI3K signaling in cultured lung vascular endothelial cells 
Hypoxia-increased endothelin-1 (ET-1) expression contributes to vasoconstriction and vessel wall thickening, often seen in the progression of pulmonary hypertension. We sought to investigate whether hypoxic modulation of preproET-1 transcription is associated with protein tyrosine kinase and phosphatidylinositol-3-kinase (PI3K). ET-1 is predominantly produced in and secreted from the vascular endothelium. Cultured human pulmonary artery endothelial cells (PAEC) in basic medium EBM-2 were exposed to hypoxia (1% oxygen, 5% CO2, 37°C) or normoxia (room air containing 5% CO2) for 0–48 hr. RNA was extracted from the treated cells and subjected to quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Hypoxia increases the relative levels of steady-state preproET-1 mRNA. The results of actinomycin D chase studies suggest that hypoxia-increased levels of preproET-1 mRNA are unlikely to be caused by increased RNA stability. A modified nuclear run-on method coupled with the sensitive qRT-PCR technique was used to assess preproET-1 gene transcription. The synthesis rate of preproET-1 mRNA in the cells exposed to hypoxia is higher than that in normoxic cells. The inhibitors of protein tyrosine kinases and PI3K, genistein and PI3Kγ inhibitor II, were used to elucidate the role of protein tyrosine kinase and PI3K in hypoxic modulation of preproET-1 expression. Pre-incubation of human PAEC with genistein or PI3Kγ inhibitor II abolishes hypoxia-increased levels of preproET-1 mRNA. Our observations support the notion that hypoxia increases the level of preproET-1 mRNA through upregulation of RNA synthesis, which is associated with protein tyrosine kinase- and PI3K-mediated signal transduction pathways. This implies that therapeutic interventions targeting protein tyrosine kinases and/or PI3K might be used to treat hypoxic pulmonary hypertension.
PMCID: PMC2680048  PMID: 19436835
Preproendothelin-1 gene (PreproET-1); protein tyrosine kinase (PI3K); lung vascular endothelial cells; hypoxia; signal transduction

Results 1-13 (13)