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1.  Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease 
Human Molecular Genetics  2013;22(12):2462-2470.
Huntington's disease (HD) is a fatal neurodegenerative disease characterized by abnormal motor coordination, cognitive decline and psychiatric disorders. This disease is caused by an expanded CAG trinucleotide repeat in the gene encoding the protein huntingtin. Reduced levels of brain-derived neurotrophic factor (BDNF) in the brain, which results from transcriptional inhibition and axonal transport deficits mediated by mutant huntingtin, have been suggested as critical factors underlying selective neurodegeneration in both HD patients and HD mouse models. BDNF activates its high-affinity receptor TrkB and promotes neuronal survival; restoring BDNF signaling is thus of particular therapeutic interest. In the present study, we evaluated the ability of a small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4′-dimethylamino-7,8- dihydroxyflavone (4′-DMA-7,8-DHF) to protect neurons in the well-characterized N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 mg/kg) or 4′-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, ameliorated brain atrophy and extended survival in these N171-82Q HD mice. Moreover, 4′-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. These data highlight consideration of TrkB as a therapeutic target in HD and suggest that small-molecule TrkB agonists that penetrate the brain have high potential to be further tested in clinical trials of HD.
PMCID: PMC3658168  PMID: 23446639
2.  The Association Between Early Menarche and Offspring’s Obesity Risk in Early Childhood was Modified by Gestational Weight Gain 
Obesity (Silver Spring, Md.)  2013;22(1):19-23.
Study effect of maternal gestational weight gain (GWG) on the relationship between maternal menarcheal age (MMA) and child growth and overweight risk and examine socio-demographics characteristics of excessive GWG.
Design and Methods
The relationships between GWG and MMA in 54,184 women and their children’s growth trajectories during first 5 years of life (2000–2005) in south China were tested using longitudinal data analysis with mixed models and logistic regression.
Average MMA was 14.8 (1.3) years; 36.3% of the women had excessive GWG. Excessive GWG interacted with adverse effects of early MMA (if ≤ 13 years), leading to the most rapid growth in offspring and highest risk of overweight at age 4–5 (OR = 5.2 [2.0–13.5]) than others. Women with early menarche, high-education, urban residence, and a routine job were more likely to have excessive GWG than the others.
GWG modify the association between early MMA and offspring’s growth and overweight. Controlling for GWG may reduce the adverse influence of early MMA and its own adverse influence on childhood health.
PMCID: PMC4036118  PMID: 23836480
3.  Sterols and Terpenoids from Viburnum odoratissimum 
A new stigmasterol type natural product, viburodorol A (1), along with eleven known sterols and terpenoids (2–12), were isolated from the aerial parts of Viburnum odoratissimum. The structure of 1 was elucidated on the basis of comprehensive spectroscopic analysis. It’s noteworthy that compound 2, the major constituent of this plant, can significantly stimulate glucose absorption in insulin resistant HepG2 cells without affecting cell viability. Furthermore, this compound can also restore the glucose absorption in DXMS-induced insulin resistant 3T3-L1 cells.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0021-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4050308  PMID: 24955299
Viburnum odoratissimum; Insulin sensitizing activity; 6α-Hydroxy-lup-20(29)-en-3-on-28-oic acid; Viburodorol A
4.  Angular Velocity Affects Trunk Muscle Strength and EMG Activation during Isokinetic Axial Rotation 
BioMed Research International  2014;2014:623191.
Objective. To evaluate trunk muscle strength and EMG activation during isokinetic axial rotation at different angular velocities. Method. Twenty-four healthy young men performed isokinetic axial rotation in right and left directions at 30, 60, and 120 degrees per second angular velocity. Simultaneously, surface EMG was recorded on external oblique (EO), internal oblique (IO), and latissimus dorsi (LD) bilaterally. Results. In each direction, with the increase of angular velocity, peak torque decreased, whereas peak power increased. During isokinetic axial rotation, contralateral EO as well as ipsilateral IO and LD acted as primary agonists, whereas, ipsilateral EO as well as contralateral IO and LD acted as primary antagonistic muscles. For each primary agonist, the root mean square values decreased with the increase of angular velocity. Antagonist coactiviation was observed at each velocity; however, it appears to be higher with the increase of angular velocity. Conclusion. Our results suggest that velocity of rotation has great impact on the axial rotation torque and EMG activity. An inverse relationship of angular velocity was suggested with the axial rotation torque as well as root mean square value of individual trunk muscle. In addition, higher velocity is associated with higher coactivation of antagonist, leading to a decrease in torque with the increase of velocity.
PMCID: PMC3996988  PMID: 24804227
5.  Hypercohones D–G, New Polycyclic Polyprenylated Acylphloroglucinol Type Natural Products from Hypericum cohaerens 
Four new polycyclic polyprenylated acylphloroglucinol type metabolites, hypercohones D–G (1–4), along with four known analogues (5–8), were isolated from the aerial parts of Hypericum cohaerens. The structures of these isolates were elucidated by extensive spectroscopic methods. The inhibitory activities of these isolates against five human cancer cell lines in vitro were also tested.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0007-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4004852  PMID: 24859375
Guttiferae; Hypericum cohaerens; Acylphloroglucinol; Hypercohones D–G
6.  Positive effects of porcine IL-2 and IL-4 on virus-specific immune responses induced by the porcine reproductive and respiratory syndrome virus (PRRSV) ORF5 DNA vaccine in swine 
Journal of Veterinary Science  2014;15(1):99-109.
The purpose of this study was to investigate the effects of porcine interleukin (IL)-2 and IL-4 genes on enhancing the immunogenicity of a porcine reproductive and respiratory syndrome virus ORF5 DNA vaccine in piglets. Eukaryotic expression plasmids pcDNA-ORF5, pcDNA-IL-2, and pcDNA-IL-4 were constructed and then expressed in Marc-145 cells. The effects of these genes were detected using an indirect immunofluorescent assay and reverse transcription polymerase chain reaction (RT-PCR). Characteristic fluorescence was observed at different times after pcDNA-ORF5 was expressed in the Marc-145 cells, and PCR products corresponding to ORF5, IL-2, and IL-4 genes were detected at 48 h. Based on these data, healthy piglets were injected intramuscularly with different combinations of the purified plasmids: pcDNA-ORF5 alone, pcDNA-ORF5 + pcDNA-IL-2, pcDNA-ORF5 + pcDNA-IL-4, and pcDNA-ORF5 + pcDNAIL-4 + pcDNA-IL-2. The ensuing humoral immune responses, percentages of CD4+ and CD8+ T lymphocytes, proliferation indices, and interferon-γ expression were analyzed. Results revealed that the piglets co-immunized with pcDNA-ORF5 + pcDNA-IL-4 + pcDNA-IL-2 plasmids developed significantly higher antibody titers and neutralizing antibody levels, had significantly increased levels of specific T lymphocyte proliferation, elevated percentages of CD4+ and CD8+ T lymphocytes, and significantly higher IFN-γ production than the other inoculated pigs (p < 0.05).
PMCID: PMC3973771  PMID: 24136204
IL-2; IL-4; immunogenicity; ORF5 DNA vaccine; porcine reproductive and respiratory syndrome virus
7.  Protection of Spiral Ganglion Neurons from Degeneration Using Small-Molecule TrkB Receptor Agonists 
The Journal of Neuroscience  2013;33(32):13042-13052.
Neurotrophins (NTs) play essential roles in the development and survival of neurons in PNS and CNS. In the cochlea, NTs [e.g., NT-3, brain-derived neurotrophic factor (BDNF)] are required for the survival of spiral ganglion neurons (SGNs). Preservation of SGNs in the cochlea of patients suffering sensorineural deafness caused by loss of hair cells is needed for the optimal performance of the cochlear implant. Directly applying exogenous BDNF into the cochlea prevents secondary degeneration of SGNs when hair cells are lost. However, a common translational barrier for in vivo applications of BDNF is the poor pharmacokinetics, which severely limits the efficacy. Here we report that 7,8-dihydroxyflavone and 7,8,3′-trihydroxyflavone, both small-molecule agonists of tyrosine receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. These compounds increased the phosphorylated TrkB and downstream MAPK and protected the SGNs in a TrkB-dependent manner. Their applications in the bulla of conditional connexin26 null mice offered significant protection for SGN survival. The function of survived SGNs was assessed by measuring evoked action potentials (APs) in vitro and electrically evoked auditory brainstem response (eABR) thresholds in vivo. APs were reliably evoked in cultured single SGNs treated with the compounds. In addition, eABR thresholds measured from the treated cochleae were significantly lower than untreated controls. Our findings suggest that these novel small-molecule TrkB agonists are promising in vivo therapeutic agents for preventing degeneration of SGNs.
PMCID: PMC3735884  PMID: 23926258
8.  Erlotinib in a patient with vaginal carcinoma and pulmonary metastasis: A case report 
Oncology Letters  2014;7(3):805-806.
Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor. It is widely used in the treatment of advanced non-small cell lung cancer and pancreatic cancer. However, there are currently no reports of the efficacy of erlotinib in patients with metastatic vaginal carcinoma. A 48-year-old female with vaginal carcinoma was diagnosed with lung metastasis four years following surgery. The patient received three cycles of chemotherapy but could not tolerate further treatment due to the side effects. Next, erlotinib was administered, prompting a partial response and disease stabilization for 9 months prior to disease progression. While the main treatments for vaginal carcinoma with distant metastasis are chemotherapy and radiotherapy, this case supplies preliminary evidence that erlotinib may have activity in these patients. Further studies are required to determine the potential of this therapy.
PMCID: PMC3919878  PMID: 24527088
erlotinib; vaginal carcinoma; pulmonary metastasis
9.  Metabolic Regulation by the Mitochondrial Phosphatase PTPMT1 Is Required for Hematopoietic Stem Cell Differentiation 
Cell stem cell  2013;12(1):62-74.
The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ~40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function.
PMCID: PMC3632072  PMID: 23290137
10.  Role of Insulin-Transferrin-Selenium in Auricular Chondrocyte Proliferation and Engineered Cartilage Formation in Vitro 
The goal of this study is to determine the effects of Insulin-Transferrin-Selenium (ITS) on proliferation of auricular chondrocytes and formation of engineered cartilage in vitro. Pig auricular monolayer chondrocytes and chondrocyte pellets were cultured in media containing 1% ITS at different concentrations of fetal bovine serum (FBS, 10%, 6%, 2%, 0%), or 10% FBS alone as a control for four weeks. Parameters including cell proliferation in monolayer, wet weight, collagen type I/II/X (Col I, II, X) and glycosaminoglycan (GAG) expression, GAG content of pellets and gene expression associated with cartilage formation/dedifferentiation (lost cartilage phenotype)/hypertrophy within the chondrocyte pellets were assessed. The results showed that chondrocytes proliferation rates increased when FBS concentrations increased (2%, 6%, 10% FBS) in ITS supplemented groups. In addition, 1% ITS plus 10% FBS significantly promoted cell proliferation than 10% FBS alone. No chondrocytes grew in ITS alone medium. 1% ITS plus 10% FBS enhanced cartilage formation in terms of size, wet weight, cartilage specific matrices, and homogeneity, compared to 10% FBS alone group. Furthermore, ITS prevented engineered cartilage from dedifferentiation (i.e., higher index of Col II/Col I mRNA expression and expression of aggrecan) and hypertrophy (i.e., lower mRNA expression of Col X and MMP13). In conclusion, our results indicated that ITS efficiently enhanced auricular chondrocytes proliferation, retained chondrogenic phenotypes, and promoted engineered cartilage formation when combined with FBS, which is potentially used as key supplementation in auricular chondrocytes and engineered cartilage culture.
PMCID: PMC3907884  PMID: 24451136
insulin-transferrin-selenium; auricular chondrocyte; dedifferentiation; hypertrophy; serum; engineered cartilage
11.  The role of intestinal mucosa injury induced by intra-abdominal hypertension in the development of abdominal compartment syndrome and multiple organ dysfunction syndrome 
Critical Care  2013;17(6):R283.
Abdominal distension is common in critical illness. There is a growing recognition that intra-abdominal hypertension (IAH) may complicate nonsurgical critical illness as well as after abdominal surgery. However, the pathophysiological basis of the injury to the intestinal mucosal barrier and its influence on the onset of abdominal compartment syndrome (ACS) and multiorgan dysfunction syndrome (MODS) remain unclear. We measured intestinal microcirculatory blood flow (MBF) during periods of raised intra-abdominal pressure (IAP) and examined how this influenced intestinal permeability, systemic endotoxin release, and histopathological changes.
To test different grades of IAH to the injury of intestinal mucosa, 96 New Zealand white rabbits aged 5 to 6 months were exposed to increased IAP under nitrogen pneumoperitoneum of 15 mmHg or 25 mmHg for 2, 4 or 6 hours. MBF was measured using a laser Doppler probe placed against the jejunal mucosa through a small laparotomy. Fluorescein isothiocyanate (FITC)-conjugated dextran was administered by gavage. Intestinal injury and permeability were measured using assays for serum FITC-dextran and endotoxin, respectively, after each increase in IAP. Structural injury to the intestinal mucosa at different levels of IAH was confirmed by light and transmission electron microscopy.
MBF reduced from baseline by 40% when IAP was 15 mmHg for 2 hours. This doubled to 81% when IAP was 25 mmHg for 6 hours. Each indicator of intestinal injury increased significantly, proportionately with IAP elevation and exposure time. Baseline serum FITC-dextran was 9.30 (± SD 6.00) μg/ml, rising to 46.89 (±13.43) μg/ml after 15 mmHg IAP for 4 hours (P <0.01), and 284.59 (± 45.18) μg/ml after 25 mmHg IAP for 6 hours (P <0.01). Endotoxin levels showed the same pattern. After prolonged exposure to increased IAP, microscopy showed erosion and necrosis of jejunal villi, mitochondria swelling and discontinuous intracellular tight junctions.
Intra-abdominal hypertension can significantly reduce MBF in the intestinal mucosa, increase intestinal permeability, result in endotoxemia, and lead to irreversible damage to the mitochondria and necrosis of the gut mucosa. The dysfunction of the intestinal mucosal barrier may be one of the important initial factors responsible for the onset of ACS and MODS.
PMCID: PMC4057115  PMID: 24321230
12.  Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages 
European journal of immunology  2012;43(1):10.1002/eji.201242697.
Bone marrow-derived macrophages (BMMs) treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), differentiate into GM-CSF-induced mouse bone marrow-derived macrophages (GM-BMMs) or M-CSF-induced mouse bone marrow-derived macrophages (M-BMMs), which have an M1 or M2 profile, respectively. GM-BMMs produce large amounts of proinflammatory cytokines and mediate resistance to pathogens, whereas M-BMMs produce anti-inflammatory cytokines that contribute to tissue repair and remodeling. M-BMMs stimulated with lipopolysaccharide (LPS) are in an antiinflammatory state, with an IL-12low IL-10high phenotype. However, the regulation of this process remains unclear. Klf10 belongs to the family of Krüppel-like transcription factors and was initially described as a TGF-β inducible early gene 1. IL-12p40 is upregulated in LPS-stimulated M-BMMs from Klf10-deficient mice, but downregulated during Klf10 overexpression. Klf11, another member of the Krüppel-like factor family, can also repress the production of IL-12p40. Furthermore, Klf10 binds to the CACCC element of the IL-12p40 promoter and inhibits its transcription. We have therefore identified Klf10 as a transcription factor that regulates the expression of IL-12p40 in M-BMMs.
PMCID: PMC3842096  PMID: 23065757
IL-12p40; Inflammatory factor; Klf10; Macrophage; Transcription factor
13.  Gemcitabine and carboplatin demonstrate synergistic cytotoxicity in cervical cancer cells by inhibiting DNA synthesis and increasing cell apoptosis 
OncoTargets and therapy  2013;6:1707-1717.
The present study aims to investigate the subunit expression and enzyme activity of ribonucleotide reductase in cervical cancer patients, and detect the combined effect of the ribonucleotide reductase inhibitor gemcitabine and the chemotherapeutic agent carboplatin on cervical cancer cell lines.
Using quantitative reverse transcription polymerase chain reaction, Western blotting, and cytidine 5′-diphosphate reduction assays, we tested the expression and activity of ribonucleotide reductase in cervical cancer patients. The antitumor activity of gemcitabine and/or carboplatin treatments to SiHa and CaSki human cervical cancer cell lines were assessed by Cell Counting Kit-8 viability assay, EdU incorporation assay, immunofluorescence assay, flow cytometry assay, and Western blotting methods. Additionally, synergistic efficacy was quantitatively analyzed using a combination index based on the Chou-Talalay method.
The mRNA levels of three ribonucleotide reductase subunits were all upregulated in the cervical cancer tissues compared with normal tissues (P<0.0001). Consistently, the protein expression and enzyme activity of ribonucleotide reductase were also increased in the cervical cancer tissues. Interestingly, gemcitabine inhibited DNA synthesis and carboplatin induced DNA damage. Further, the combined drug regime had a significant synergistic effect on inhibiting cervical cancer cell viability (log10[combination index] <0) via enhanced DNA damage and cell apoptosis.
The expression and activity of ribonucleotide reductase was increased in cervical cancer. Our study demonstrated the synergistic cytotoxicity of gemcitabine and carboplatin, through inhibiting DNA synthesis and increasing cell apoptosis in cervical cancer cell lines. This evidence might provide a rational clue of their combined application to improve cervical cancer treatment.
PMCID: PMC3848983  PMID: 24348048
cervical cancer; ribonucleotide reductase; gemcitabine; carboplatin
14.  Distinct Metabolic Profile of Primary Focal Segmental Glomerulosclerosis Revealed by NMR-Based Metabolomics 
PLoS ONE  2013;8(11):e78531.
Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated.
NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (n = 25), membranous nephropathy (MN, n = 24), minimal change disease (MCD, n = 14) and IgA nephropathy (IgAN, n = 26), and healthy controls (CON, n = 35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests.
FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies.
NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.
PMCID: PMC3823857  PMID: 24244321
15.  Genome Sequence of Border Disease Virus Strain JSLS12-01, Isolated from Sheep in China 
Genome Announcements  2013;1(6):e00502-13.
Border disease virus (BDV) is a recognized virus in the genus Pestivirus and causes border disease (BD) in sheep and goats. Here, a novel BDV strain, JSLS12-01, was identified from sheep in Jiangsu Province, China. The complete coding sequence (CDS) was finished, which provides a better understanding of the molecular evolution of BDV isolates.
PMCID: PMC3820770  PMID: 24201189
16.  Fyn Regulates Adipogenesis by Promoting PIKE-A/STAT5a Interaction 
Molecular and Cellular Biology  2013;33(9):1797-1808.
Fyn is a tyrosine kinase with multiple roles in a variety of cellular processes. Here we report that Fyn is a new kinase involved in adipocyte differentiation. Elevated Fyn protein is detected specifically in the adipocytes of obese mice. Moreover, Fyn expression increases progressively in 3T3-L1 cells during in vitro adipogenesis, which correlates with its kinase activity. Inhibition of Fyn by either genetic or pharmacological manipulation restrains the 3T3-L1 preadipocytes from fully differentiating into mature adipocytes. Mechanistically, Fyn regulates the activity of the adipogenic transcription factor signal transducer and activator of transcription 5a (STAT5a) through enhancing its interaction with the GTPase phosphoinositide 3-kinase enhancer A (PIKE-A). The STAT5a activity is therefore reduced in Fyn- or PIKE-ablated adipose tissues, leading to diminished expression of adipogenic markers and adipocyte differentiation. Our data thus demonstrate a novel functional interaction between Fyn, PIKE-A, and STAT5a in mediating adipogenesis.
PMCID: PMC3624174  PMID: 23438599
17.  MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines 
Cell Research  2013;23(11):1270-1283.
The vagus nerve can control inflammatory response through a 'cholinergic anti-inflammatory pathway', which is mediated by the α7-nicotinic acetylcholine receptor (α7nAChR) on macrophages. However, the intracellular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well understood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cholinergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 (STAT3) to decrease IL-6 production and TNF-α converting enzyme (TACE) to reduce TNF-α release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.
PMCID: PMC3817544  PMID: 23979021
micorRNA-124; cholinergic anti-inflammatory action; α7nAChR; macrophages; septic shock; STAT3; TACE
18.  Metabolomic Analysis of Anti-Hypoxia and Anti-anxiety Effects of Fu Fang Jin Jing Oral Liquid 
PLoS ONE  2013;8(10):e78281.
Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL) with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics.
In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin) and oxygen consumption increasing (exhaustive swimming) were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified.
Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect.
FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug diazepam on the hypobaric hypoxia mice. FJJOL might serve as an alternative therapy for the hypoxia and anxiety disorders.
PMCID: PMC3799728  PMID: 24205180
19.  Protein tyrosine phosphatase Shp2 (Ptpn11) plays an important role in maintenance of chromosome stability 
Cancer research  2012;72(20):5296-5306.
Both activating and inactivating mutations in protein tyrosine phosphatase Ptpn11 (encoding Shp2) are associated with tumorigenesis. However, the underlying mechanisms remain unclear. Here we demonstrate that Shp2 plays an important role in mitosis, dysregulation of which results in chromosome instability and cancer predisposition. Depletion of Shp2 compromised the mitotic checkpoint. Shp2-depleted cells exhibited a delay in mitotic entry and an earlier mitotic exit. Moreover, Shp2 deficiency caused defective kinetochore-microtubule attachment, chromosome misalignment, chromosomal congression defects, lagging chromosomes, and chromosome missegregation. Reintroduction of wild-type Shp2, but not a catalytically-deficient mutant, restored the checkpoint function and chromosome alignment at metaphase in Shp2-deficient cells, establishing a requirement for the catalytic activity of Shp2 during mitosis. Further analyses revealed that Shp2 was required for the optimal activation of the mitotic kinases PLK1 and Aurora B and thereby the proper kinetochore localization and phosphorylation of BubR1, a core mitotic checkpoint protein that is also critical for chromosome alignment. Together, our findings demonstrate a previously unrecognized role for Shp2 in the maintenance of chromosome stability and suggest a new mechanism by which dysregulation of Shp2 signaling contributes to malignancy development.
PMCID: PMC3473170  PMID: 22890240
Ptpn11 (Shp2); Phosphatase; Mitosis; Chromosome stability
20.  Optimization of a Small Tropomyosin-related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression 
Journal of medicinal chemistry  2012;55(19):8524-8537.
Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for the agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4′-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses the enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.
PMCID: PMC3491656  PMID: 22984948
TrkB agonist; BDNF; synthetic derivatives; antidepressant; neurogenesis
21.  Direct Interaction between AR and PAK6 in Androgen-Stimulated PAK6 Activation 
PLoS ONE  2013;8(10):e77367.
A p21-activated kinase 6 (PAK6) was previously identified to be an androgen receptor (AR) interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.
PMCID: PMC3795072  PMID: 24130878
22.  Associations between Vaginal Pathogenic Community and Bacterial Vaginosis in Chinese Reproductive-Age Women 
PLoS ONE  2013;8(10):e76589.
Bacterial vaginosis (BV) is one of the most common urogenital infections among women of reproductive age that represents shifts in microbiota from Lactobacillus spp. to diverse anaerobes. The aim of our study was to evalute the diagnostic values of Gardnerella, Atopobium, Eggerthella, Megasphaera typeI, Leptotrichia/Sneathia and Prevotella, defined as a vaginal pathogenic community for BV and their associations with vaginal pH and Nugent scores.
Methods and Findings
We investigated the vaginal pathogenic bacteria and Lactobacillus spp. with species-specific real-time quantitative PCR (qPCR) in 50 BV-positive and 50 BV-negative Chinese women of reproductive age. Relative to BV-negative subjects, a siginificant decline in Lactobacillus and an obvious increase in bacteria in the vaginal pathogenic community were observed in BV-postive subjects (P<0.05). With the exception of Megasphaera typeI, other vaginal pathogenic bacteria were highly predictable for BV with a better sensitivity and specificity. The vaginal pathogenic community was positively associated with vaginal pH and Nugent scores, while Lactobacillus spp., such as L. iners and L. crispatus was negatively associated with them (P<0.05).
Our data implied that the prevalance of vaginal pathogenic bacteria as well as the depletion of Lactobacillus was highly accurate for BV diagnosis. Vaginal microbiota shifts, especially the overgrowth of the vaginal pathogenic community, showed well diagnostic values in predicting BV. Postive correlations between those vaginal pathogenic bacteria and vaginal pH, Nugent score indicated the vaginal pathogenic community rather than a single vaginal microorganism, was participated in the onset of BV directly.
PMCID: PMC3790675  PMID: 24124575
23.  Effect of 7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, on Emotional Learning 
The American journal of psychiatry  2010;168(2):163-172.
Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intra-peritoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.
The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure.
Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress.
These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology.
PMCID: PMC3770732  PMID: 21123312
24.  Cell Surface-Specific N-Glycan Profiling in Breast Cancer 
PLoS ONE  2013;8(8):e72704.
Aberrant changes in specific glycans have been shown to be associated with immunosurveillance, tumorigenesis, tumor progression and metastasis. In this study, the N-glycan profiling of membrane proteins from human breast cancer cell lines and tissues was detected using modified DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). The N-glycan profiles of membrane proteins were analyzed from 7 breast cancer cell lines and MCF 10A, as well as from 100 pairs of breast cancer and corresponding adjacent tissues. The results showed that, compared with the matched adjacent normal tissue samples, two biantennary N-glycans (NA2 and NA2FB) were significantly decreased (p <0.0001) in the breast cancer tissue samples, while the triantennary glycan (NA3FB) and a high-mannose glycan (M8) were dramatically increased (p = 0.001 and p <0.0001, respectively). Moreover, the alterations in these specific N-glycans occurred through the oncogenesis and progression of breast cancer. These results suggested that the modified method based on DSA-FACE is a high-throughput detection technology that is suited for analyzing cell surface N-glycans. These cell surface-specific N-glycans may be helpful in recognizing the mechanisms of tumor cell immunologic escape and could be potential targets for new breast cancer drugs.
PMCID: PMC3751845  PMID: 24009699
25.  Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo 
Repair of large bone defects is a major challenge, requiring sustained stimulation to continually promote bone formation locally. Bone morphogenetic protein 2 (BMP-2) plays an important role in bone development. In an attempt to overcome this difficulty of bone repair, we created a delivery system to slowly release human BMP-2 cDNA plasmid locally, efficiently transfecting local target cells and secreting functional human BMP-2 protein. For transfection, we used polyethylenimine (PEI) to create pBMP-2/PEI nanoparticles, and to ensure slow release we used poly(lactic-co-glycolic acid) (PLGA) to create microsphere encapsulated pBMP-2/PEI nanoparticles, PLGA@pBMP-2/PEI. We demonstrated that pBMP-2/PEI nanoparticles could slowly release from the PLGA@pBMP-2/PEI microspheres for a long period of time. The 3–15 μm diameter of the PLGA@pBMP-2/PEI further supported this slow release ability of the PLGA@pBMP-2/PEI. In vitro transfection assays demonstrated that pBMP-2/PEI released from PLGA@pBMP-2/PEI could efficiently transfect MC3T3-E1 cells, causing MC3T3-E1 cells to secrete human BMP-2 protein, increase calcium deposition and gene expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), SP7 and I type collagen (COLL I), and finally induce MC3T3-E1 cell differentiation. Importantly, in vivo data from micro-computed tomography (micro-CT) and histological staining demonstrated that the human BMP-2 released from PLGA@pBMP-2/PEI had a long-term effect locally and efficiently promoted bone formation in the bone defect area compared to control animals. All our data suggest that our PLGA-nanoparticle delivery system efficiently and functionally delivers the human BMP-2 cDNA and has potential clinical application in the future after further modification.
PMCID: PMC3748902  PMID: 23990717
gene therapy; bone regeneration; biodegradable polymer; human BMP-2

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