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1.  miR-379 Inhibits Cell Proliferation, Invasion, and Migration of Vascular Smooth Muscle Cells by Targeting Insulin-Like Factor-1 
Yonsei Medical Journal  2016;58(1):234-240.
Purpose
MicroRNAs are small non-coding RNAs that play important roles in vascular smooth muscle cell (VSMC) function. This study investigated the role of miR-379 on proliferation, invasion, and migration of VSMCs and explored underlying mechanisms thereof.
Materials and Methods
MicroRNA, mRNA, and protein levels were determined by quantitative real-time PCR and western blot. The proliferative, invasive, and migratory abilities of VSMCs were measured by CCK-8, invasion, and wound healing assay, respectively. Luciferase reporter assay was used to confirm the target of miR-379.
Results
Platelet-derived growth factor-bb was found to promote cell proliferation and suppress miR-379 expression in VSMCs. Functional assays demonstrated that miR-379 inhibited cell proliferation, cell invasion, and migration. Flow cytometry results further showed that miR-379 induced apoptosis in VSMCs. TargetScan analysis and luciferase report assay confirmed that insulin-like growth factor-1 (IGF-1) 3'UTR is a direct target of miR-379, and mRNA and protein levels of miR-379 and IGF-1 were inversely correlated. Rescue experiments showed that enforced expression of IGF-1 sufficiently overcomes the inhibitory effect of miR-379 on cell proliferation, invasion, and migration in VSMCs.
Conclusion
Our results suggest that miR-379 plays an important role in regulating VSMCs proliferation, invasion, and migration by targeting IGF-1.
doi:10.3349/ymj.2017.58.1.234
PMCID: PMC5122642  PMID: 27873518
Vascular smooth muscle cells; miR-379; cell proliferation; invasion; migration; IGF-1
2.  Wuzi Yanzong pill, a Chinese polyherbal formula, alleviates testicular damage in mice induced by ionizing radiation 
Background
Chinese medicine Wuzi Yanzong pill (WZYZP) was firstly documented in ancient Chinese medical works “She Sheng Zhong Miao Fang” by Shi-Che Zhang in 1550 AD. The traditional herbal formula is widely used in treating nephrasthenia lumbago, prospermia, erectile dysfunction and male sterility. The present study was to explore the effects of WZYZP on ionizing irradiation-induced testicular damage in mice.
Methods
The pelvic region of male mice was exposed to X-rays for inducing testicular damage. The effects of WZYZP on testicular damage were evaluated in terms of testes weight, sperm quantity and motility, testes oxidative status and serum hormone levels. The alterations in testicular structure were examined by hematoxylin-eosin staining. Additionally, changes in proliferating cell nuclear antigen (PCNA) expression of testes were explored by western blot.
Results
Pelvic exposure to x-ray induced reduction in testes weight and sperm quality, along with oxidative stress and abnormal testicular architecture in testes. Oral administration of WZYZP for 3 weeks markedly increased testes weight, sperm quantity and motility, and attenuated testicular architecture damage. Meanwhile, WZYZP treatment significantly reversed the reduction of serum testosterone, and decreased testes malondialdehyde (MDA) and Oxidative stress index (OSI) relative to the radiated mice. Additionally, WZYZP effectively prevented the downregulation of PCNA expression in testes induced by x-ray irradiation.
Conclusion
These findings suggest WZYZP exhibits ameliorating effects against ionizing irradiation-induced testicular damage in mice, which may be related to its antioxidation.
doi:10.1186/s12906-016-1481-6
PMCID: PMC5142375  PMID: 27927244
Wuzi Yanzong pill; Ionizing irradiation; Testicular damage
3.  Spatial signalling mediated by the transforming growth factor-β signalling pathway during tooth formation 
Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth-like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day (E) 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-β signalling pathway might play a role in this process.
doi:10.1038/ijos.2016.45
PMCID: PMC5168420  PMID: 27982023
positional information; transforming growth factor-β signalling pathway; tooth development
4.  The antidepressant-like activity of AC-5216, a ligand for 18KDa translocator protein (TSPO), in an animal model of diabetes mellitus 
Scientific Reports  2016;6:37345.
Diabetes mellitus is a chronic disease that is associated with depression. Also, depression is common in adults with type 2 diabetes mellitus (T2DM). Translocator protein (18kDa) (TSPO) and allopregnanolone play an important role in the depression treatment. However, few studies have evaluated TSPO and allopregnanolone in the treatment of depression in T2DM. AC-5216, a ligand for TSPO, produces anxiolytic- and antidepressant-like effects in animal models. The present study aimed to explore antidepressant-like effects of AC-5216 on diabetic rats. Following the development of diabetic model induced by high fat diet (HFD) feeding and streptozotocin (STZ), AC-5216 (0.3 and 1 mg/kg, i.g.) elicited the antidepressant-like effects in behavioral tests while these activities were blocked by TSPO antagonist PK11195 (3 mg/kg, i.p.). The levels of allopregnanolone in the prefrontal cortex and hippocampus were increased by AC-5216 (0.3 and 1 mg/kg, i.g.), which was antagonized by PK11195 (3 mg/kg, i.p.). The increased plasma glucose (PG) and decreased insulin (INS) in HFD-STZ rats were reversed by AC-5216 (0.3 and 1 mg/kg, i.g.). This study indicates that the antidepressant-like effects of AC-5216 on HFD-STZ rats, suggesting that TSPO may represent a novel therapeutic target for depression in T2DM.
doi:10.1038/srep37345
PMCID: PMC5122851  PMID: 27886206
5.  Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy 
Background
Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models.
Material/Methods
Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots.
Results
Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests.
Conclusions
Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice.
doi:10.12659/MSM.897579
PMCID: PMC5117238  PMID: 27855137
Garcinia Cambogia; Pentylenetetrazole; Receptor, trkB; Receptors, GABA
6.  Systemic abnormalities of psoriatic patients: a retrospective study 
Background
Psoriasis is a chronic immune-mediated inflammatory disease related to the metabolic syndrome, cardiovascular disease, and other comorbidities. However, so far there has been no specific research concerning systemic abnormalities in psoriatic patients.
Objective
A retrospective study was conducted focusing on the detailed systemic abnormalities in psoriatic patients.
Methods
Psoriatic inpatients data was collected from July 2009 to September 2015. The inclusion criteria were first-time hospitalization and without administration of systemic drug therapy or exposure to phototherapy for psoriasis for at least 1 month. Detailed systemic indexes were mainly evaluated.
Results
The abnormality rates of blood routine examination, urine examination, blood biochemical examination and chest X-ray of 43 psoriatic patients were significantly higher than those of 44 non-psoriasis controls, and psoriasis patients significantly had higher absolute values of leukocytes and neutrophils, and significantly lower values of lymphocytes. Compared with psoriasis vulgaris, erythrodermic psoriasis had significantly higher abnormality rates of blood biochemical examination and serum electrolyte analysis. Erythrodermic psoriasis had significantly higher absolute values of blood leukocytes, neutrophils, and lower serum calcium compared with those of psoriasis vulgaris. The neutrophil-to-lymphocyte ratio of controls was significantly lower than that of psoriatic patients, and neutrophil-to-lymphocyte ratio of erythrodermic psoriasis was significantly higher in comparison with psoriasis vulgaris.
Conclusion
This study is the first report in relation to a detailed assessment of systemic abnormalities in psoriatic patients prior to onset of systemic treatment. The systemic condition of psoriatic patients should be observed by clinicians before systemic therapy.
doi:10.2147/CCID.S121302
PMCID: PMC5108494  PMID: 27877062
psoriasis; skin; inflammation; treatment
7.  Crystal structure of vilazodone hydro­chloride methanol monosolvate 
In the title compound, the protonated piperazine ring adopts a chair conformation while the indole ring plane is nearly perpendicular to the benzo­furan ring system.
In the title compound, C26H28N5O2 +·Cl−·CH3OH {systematic name: 4-(2-carbamoyl-1-benzo­furan-5-yl)-1-[4-(5-cyano-1H-indol-3-yl)but­yl]piperazin-1-ium chloride methanol monosolvate}, the protonated piperazine ring adopts a chair conformation. The indole ring plane is nearly perpendicular to the benzo­furan ring system, with a dihedral angle of 85.77 (2)°. In the crystal, the organic cations, Cl− anions and methanol solvent mol­ecules are linked by classical N—H⋯O and N—H⋯Cl hydrogen bonds, and weak C—H⋯O and C—H⋯π inter­actions into a three-dimensional supra­molecular architecture.
doi:10.1107/S2056989016017734
PMCID: PMC5137608  PMID: 27980830
crystal structure; benzo­furan; indole; piperazine; hydrogen bonds
8.  Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity 
Scientific Reports  2016;6:36209.
In this study, we aimed to investigate the protective effects and underlying mechanism of Lycium barbarum polysaccharide (LBP) on high-fat-induced nonalcoholic fatty liver disease (NAFLD). Recently, sirtuin 1 (SIRT1) has been shown to play an important role in the regulation of hepatocellular lipid metabolism. Here, we demonstrated that LBP up-regulates SIRT1 deacetylase activity and protein expression by enhancing the NAD+/NADH ratio. Subsequently, LBP promoted LKB1 deacetylation and AMPK phosphorylation via SIRT1-dependent signalling. We also found that LBP increases acetyl-CoA carboxylase (ACC) phosphorylation and adipose triglyceride lipase (ATGL) protein expression and decreases fatty acid synthase (FAS) by activating the SIRT1/LKB1/AMPK pathway in vitro and in vivo. However, SIRT1 small interfering RNA (siRNA)-mediated knockdown reversed the LBP-mediated effects on ACC, FAS and ATGL. Moreover, LBP elevated carnitine palmitoyltransferase-1 alpha (CPT-1α) expression by suppressing malonyl-CoA accumulation. Taken together, our data indicate that LBP plays a vital role in the regulation of hepatic lipid metabolism and that pharmacological activation of SIRT1 by LBP may be a strategy for the prevention of NAFLD.
doi:10.1038/srep36209
PMCID: PMC5099939  PMID: 27824080
9.  Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy 
Acta Pharmacologica Sinica  2016;37(11):1442-1448.
Aim:
Aspirin resistance has an incidence of 5%–65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A2 receptor (TXA2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2 (Lp-PLA2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.
Methods:
A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB2 ELISA kit.
Results:
Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233–0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080–6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590–42.638).
Conclusion:
A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931–rs7756935) polymorphisms.
doi:10.1038/aps.2016.90
PMCID: PMC5099418  PMID: 27641736
ischemic stroke; aspirin resistance; platelet activity; MDR1; TBXA2R; PLA2G7; PEAR1; genetic polymorphisms
10.  Aqueous Extract of Clerodendranthus spicatus Exerts Protective Effect on UV-Induced Photoaged Mice Skin 
Clerodendranthus spicatus (Thunb.) C.Y.Wu (CS) is commonly used to treat kidney diseases in traditional Chinese medicine for its prominent anti-inflammatory effect and nourishing function to kidneys. In this study, aqueous extract of CS was assessed for its protective effect on UV-induced skin damage of mice. The chemical compositions of CS aqueous extract were determined by HPLC-ESI-MS/MS, in which 10 components were identified. During the experimental period, CS (0.9, 1.8, and 3.6 g/mL) was externally applied to shaved dorsal skins of mice prior to UV irradiation, daily for ten weeks. The results presented that CS (3.6 g/mL) apparently improved photodamaged skin appearance such as erythema, edema, and coarseness. The abnormal epidermal thickening was significantly reduced, and the dermal structures became more complete. The underlying protective mechanisms were associated with improving antioxidant enzymes activities including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), downregulating inflammatory cytokines (IL-1β, IL-6, TNF-α, COX-2, and PGE2) expressions, recovering collagen density, and reducing matrix metalloproteinases productions. Sun protection factor of CS (3.6 g/mL) was 16.21 ± 0.03. Our findings for the first time demonstrated that CS had therapeutic effect on the photoaged skin. The results indicated that CS is a potential agent for photoprotective cosmetics.
doi:10.1155/2016/9623957
PMCID: PMC5101404  PMID: 27847530
11.  Effect of miRNA-27a and Leptin Polymorphisms on Risk of Recurrent Spontaneous Abortion 
Background
The aim of this study was to investigate the possible associations of miRNA-27a and Leptin polymorphisms with the risk of recurrent spontaneous abortion (RSA).
Material/Methods
Between May 2013 and April 2015 at Shenzhen Longhua New District Central Hospital, we randomly recruited 138 RSA patients as the case group and another 142 normal pregnancy women as the control group. We used denaturing high-performance liquid chromatography (DHPLC) to determine the genotypes and allele frequencies of miRNA-27a rs895819 A/G and Leptin rs7799039 G/A.
Results
The GG genotype and G allele frequencies of miRNA-27a rs895819 A/G were higher in the case group than in the control group, and the AA genotype and A allele frequencies of Leptin rs7799039 G/A were also higher in the case group than in the control group (all P<0.05). MiRNA-27a rs895819 A/G and Leptin rs7799039 G/A polymorphisms increased the risk of RSA (Exp (B)=2.732, 95% CI=1.625~4.596, P=0.000; Exp (B)=4.081, 95% CI=1.817~9.164, P=0.001). GG-AA or AG-AA carriers had a higher risk of RSA. The miRNA-27a expression of AA carriers of miRNA-27a rs895819 was lower than that of AG+GG carriers both in the case and control groups (all P=0.024). The plasma leptin concentration of GG carriers was lower than that of GA+AA carriers in the case group (P=0.026).
Conclusions
The polymorphisms of miRNA-27a rs895819 A/G and Leptin rs7799039 G/A may contribute to an increased risk of RSA.
doi:10.12659/MSM.897147
PMCID: PMC5049305  PMID: 27694792
Chromatography; DNA Copy Number Variations; Polymorphism, Genetic
12.  Mechanical stretch‐induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection 
The Journal of Pathology  2015;236(3):373-383.
Abstract
Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (ER) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to TAAD. Therefore, we studied the role of ER stress in TAAD formation. A lysyl oxidase inhibitor, 3‐aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice, which showed significant SMC loss (α‐SMA level). Excessive apoptosis (TUNEL staining) and ER stress (ATF4 and CHOP), along with inflammation, were present in TAAD samples from both mouse and human. Transcriptional profiling of SMCs after mechanical stress demonstrated the expression of genes for ER stress and inflammation. To explore the causal role of ER stress in initiating degenerative signalling events and TAAD, we treated wild‐type (CHOP +/+) or CHOP −/− mice with BAPN and found that CHOP deficiency protected against TAAD formation and rupture, as well as reduction in α‐SMA level. Both SMC apoptosis and inflammation were significantly reduced in CHOP −/− mice. Moreover, SMCs isolated from CHOP −/− mice were resistant to mechanical stress‐induced apoptosis. Taken together, our results demonstrated that mechanical stress‐induced ER stress promotes SMCs apoptosis, inflammation and degeneration, providing insight into TAAD formation and progression. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
doi:10.1002/path.4534
PMCID: PMC5029755  PMID: 25788370
thoracic aortic aneurysm/dissection; SMCs; apoptosis; ER stress; CHOP
13.  Effects of Propofol General Anesthesia on Olfactory Relearning 
Scientific Reports  2016;6:33538.
How general anesthesia interferes with sensory processing to cause amnesia remains unclear. Here, we show that activation of a learning-associated immediate early gene in rat olfactory cortices is uninterrupted by propofol, an intravenous general anesthetic with putative actions on the inhibitory GABAA receptors. Once learned under anesthesia, a novel odor can no longer re-activate the same high-level transcription programming during subsequent conscious relearning. Behavioral tests indicate that the animals’ ability to consciously relearn a pure odorant, first experienced under general anesthesia, is indeed compromised. In contrast, when a mixture of two novel odorants is first experienced under anesthesia and then relearned consciously in pairs with one of the components, the animals show a deficit in relearning only the component but not the mixture. Our results reveal a previously unknown mechanism of unconscious memory due to irreplaceable neuronal commitment under general anesthesia and support the notion that general anesthesia acts at stages beyond cellular coding to disrupt sensory integration for higher-order association.
doi:10.1038/srep33538
PMCID: PMC5024337  PMID: 27628686
14.  Prokaryotic Community Structure Driven by Salinity and Ionic Concentrations in Plateau Lakes of the Tibetan Plateau 
The prokaryotic community composition and diversity and the distribution patterns at various taxonomic levels across gradients of salinity and physiochemical properties in the surface waters of seven plateau lakes in the Qaidam Basin, Tibetan Plateau, were evaluated using Illumina MiSeq sequencing. These lakes included Lakes Keluke (salinity, <1 g/liter), Qing (salinity, 5.5 to 6.6 g/liter), Tuosu (salinity, 24 to 35 g/liter), Dasugan (salinity, 30 to 33 g/liter), Gahai (salinity, 92 to 96 g/liter), Xiaochaidan (salinity, 94 to 99 g/liter), and Gasikule (salinity, 317 to 344 g/liter). The communities were dominated by Bacteria in lakes with salinities of <100 g/liter and by Archaea in Lake Gasikule. The clades At12OctB3 and Salinibacter, previously reported only in hypersaline environments, were found in a hyposaline lake (salinity, 5.5 to 6.6 g/liter) at an abundance of ∼1.0%, indicating their ecological plasticity. Salinity and the concentrations of the chemical ions whose concentrations covary with salinity (Mg2+, K+, Cl−, Na+, SO42−, and Ca2+) were found to be the primary environmental factors that directly or indirectly determined the composition and diversity at the level of individual clades as well as entire prokaryotic communities. The distribution patterns of two phyla, five classes, five orders, five families, and three genera were well predicted by salinity. The variation of the prokaryotic community structure also significantly correlated with the dissolved oxygen concentration, pH, the total nitrogen concentration, and the PO43− concentration. Such correlations varied depending on the taxonomic level, demonstrating the importance of comprehensive correlation analyses at various taxonomic levels in evaluating the effects of environmental variable factors on prokaryotic community structures. Our findings clarify the distribution patterns of the prokaryotic community composition in plateau lakes at the levels of individual clades as well as whole communities along gradients of salinity and ionic concentrations.
doi:10.1128/AEM.03332-15
PMCID: PMC4784034  PMID: 26746713
15.  The POR rs1057868–rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients 
Acta Pharmacologica Sinica  2016;37(9):1251-1258.
Aim:
Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients.
Methods:
A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d).
Results:
Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868–rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868–rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868–rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868–rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers.
Conclusion:
The CYP3A5*3 and POR rs1057868–rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868–rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.
doi:10.1038/aps.2016.77
PMCID: PMC5022105  PMID: 27498776
renal transplantion; tacrolimus; pharmacogenetics; POR; CYP3A5
16.  Anti-inflammatory effect of Yu-Ping-Feng-San via TGF-β1 signaling suppression in rat model of COPD 
Objective(s):
Yu-Ping-Feng-San (YPFS) is a classical traditional Chinese medicine that is widely used for treatment of the diseases in respiratory systems, including chronic obstructive pulmonary disease (COPD) recognized as chronic inflammatory disease. However, the molecular mechanism remains unclear. Here we detected the factors involved in transforming growth factor beta 1 (TGF-β1)/Smad2 signaling pathway and inflammatory cytokines, to clarify whether YPFS could attenuate inflammatory response dependent on TGF-β1/Smad2 signaling in COPD rats or cigarette smoke extract (CSE)-treated human bronchial epithelial (Beas-2B) cells.
Materials and Methods:
The COPD rat model was established by exposure to cigarette smoke and intratracheal instillation of lipopolysaccharide, YPFS was administered to the animals. The efficacy of YPFS was evaluated by comparing the severity of pulmonary pathological damage, pro-inflammation cytokines, collagen related genes and the activation of TGF-β1/Smad2 signaling pathway. Furthermore, CSE-treated cells were employed to confirm whether the effect of YPFS was dependent on the TGF-β1/Smad2 signaling via knockdown Smad2 (Si-RNA), or pretreatment with the inhibitor of TGF-β1.
Results:
Administration of YPFS effectively alleviated injury of lung, suppressed releasing of pro-inflammatory cytokines and collagen deposition in COPD animals (P<0.05), whereas exogenous TGF-β1 promoted releasing of IL-1β, IL-6, TNFα (P<0.05). Administration YPFS reduced inflammatory response significantly, also down-regulated TGF-β1/Smad2 signaling in vivo and in vitro. Unexpectedly, knockdown Smad2 or inhibition of TGF-β1 abolished anti-inflammatory effect of YPFS in CSE-treated cells.
Conclusion:
YPFS accomplished anti-inflammatory effects mainly by suppressing phosphorylation of Smad2, TGF-β1/Smad2 signaling pathway was required for YPFS-mediated anti-inflammation in COPD rats or CSE-treated Beas-2B cells.
PMCID: PMC5080430  PMID: 27803787
COPD; Pro-inflammatory; Cytokine; TGF-β1/Smad2; YPFS
17.  Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation 
Autophagy  2015;11(10):1745-1759.
Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/α-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.
doi:10.1080/15548627.2015.1082020
PMCID: PMC4824603  PMID: 26292069
autophagy; CDK5; melatonin; MPTP; SNCA; TH
18.  Assessing postural stability via the correlation patterns of vertical ground reaction force components 
Background
Many methods have been proposed to assess the stability of human postural balance by using a force plate. While most of these approaches characterize postural stability by extracting features from the trajectory of the center of pressure (COP), this work develops stability measures derived from components of the ground reaction force (GRF).
Methods
In comparison with previous GRF-based approaches that extract stability features from the GRF resultant force, this study proposes three feature sets derived from the correlation patterns among the vertical GRF (VGRF) components. The first and second feature sets quantitatively assess the strength and changing speed of the correlation patterns, respectively. The third feature set is used to quantify the stabilizing effect of the GRF coordination patterns on the COP.
Results
In addition to experimentally demonstrating the reliability of the proposed features, the efficacy of the proposed features has also been tested by using them to classify two age groups (18–24 and 65–73 years) in quiet standing. The experimental results show that the proposed features are considerably more sensitive to aging than one of the most effective conventional COP features and two recently proposed COM features.
Conclusions
By extracting information from the correlation patterns of the VGRF components, this study proposes three sets of features to assess human postural stability during quiet standing. As demonstrated by the experimental results, the proposed features are not only robust to inter-trial variability but also more accurate than the tested COP and COM features in classifying the older and younger age groups. An additional advantage of the proposed approach is that it reduces the force sensing requirement from 3D to 1D, substantially reducing the cost of the force plate measurement system.
doi:10.1186/s12938-016-0212-z
PMCID: PMC4969977  PMID: 27485525
Ground reaction force; Postural balance; Quiet standing; Force plate
19.  iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation 
Stem Cells and Development  2015;24(15):1793-1804.
Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×106 iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (>100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4+ and CD8+ T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-β was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell–cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.
doi:10.1089/scd.2014.0488
PMCID: PMC4507355  PMID: 25867817
20.  Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke 
Acta Pharmacologica Sinica  2016;37(7):882-888.
Aim:
There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke.
Methods:
A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4*1G (rs2242480), CYP2C19*2 (rs4244285) and P2RY12 (rs2046934) were genotyped.
Results:
The CR rate in this population was 36%. The CYP2C19*2 variant was a risk factor for CR (*2/*2+wt/*2 vs wt/wt, OR: 2.366, 95% CI: 1.180–4.741, P=0.014), whereas the CYP3A4*1G variant had a protective effect on CR (*1/*1 vs *1G/*1G+*1/*1G, OR: 2.360, 95% CI: 1.247–4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286–0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs TT, OR: 0.407, 95% CI: 0.191–0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022).
Conclusion:
The individuals with both the CYP2C19*2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4*1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.
doi:10.1038/aps.2016.41
PMCID: PMC4933760  PMID: 27133299
clopidogrel resistance; ischemic stroke; genotype analysis; SNPs; CYP3A4*1G; NR1I2; CYP2C19*2; P2RY12; pharmacogenomics
21.  Nickel-Refining Fumes Induced DNA Damage and Apoptosis of NIH/3T3 Cells via Oxidative Stress 
Although there have been numerous studies examining the toxicity and carcinogenicity of nickel compounds in humans and animals, its molecular mechanisms of action are not fully elucidated. In our research, NIH/3T3 cells were exposed to nickel-refining fumes at the concentrations of 0, 6.25, 12.50, 25, 50 and 100 μg/mL for 24 h. Cell viability, cell apoptosis, reactive oxygen species (ROS) level, lactate dehydrogenase (LDH) assay, the level of glutathione (GSH), activities of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) level were detected. The exposure of NIH/3T3 cells to nickel-refining fumes significantly reduced cell viability and induced cell apoptotic death in a dose-dependent manner. Nickel-refining fumes significantly increased ROS levels and induced DNA damage. Nickel-refining fumes may induce the changes in the state of ROS, which may eventually initiate oxidative stress, DNA damage and apoptosis of NIH/3T3 cells.
doi:10.3390/ijerph13070629
PMCID: PMC4962170  PMID: 27347984
nickel-refining fumes; NIH/3T3cell; DNA damage; apoptosis; oxidative stress
22.  The Clinical Significance of Glycoprotein Phospholipase D Levels in Distinguishing Early Stage Latent Autoimmune Diabetes in Adults and Type 2 Diabetes 
PLoS ONE  2016;11(6):e0156959.
Autoantibodies have been widely used as markers of latent autoimmune diabetes in adults (LADA); however, the specificity and sensitivity of autoantibodies as markers of LADA are weak compared with those found in type 1 diabetes (T1DM). In this study, we aimed to identify other plasma proteins as potential candidates that can be used effectively to determine early stage LADA and type 2 diabetes (T2DM) to facilitate early diagnosis and treatment. These issues were addressed by studying new-onset ‘classic’ T1DM (n = 156), LADA (n = 174), T2DM (n = 195) and healthy cohorts (n = 166). Plasma samples were obtained from the four cohorts. We employed isobaric tag for relative and absolute quantitation (iTRAQ) together with liquid chromatography tandem mass spectrometry (LC-MS) to identify plasma proteins with significant changes in LADA. The changes were validated by Western blot and ELISA analyses. Among the four cohorts, 311 unique proteins were identified in three iTRAQ runs, with 157 present across the three data sets. Among them, 49/311 (16.0%) proteins had significant changes in LADA compared with normal controls, including glycoprotein phospholipase D (GPLD1), which was upregulated in LADA. Western blot and ELISA analyses showed that GPLD1 levels were higher in both LADA and T1DM cohorts than in both T2DM and healthy cohorts, while there were no significant differences in the plasma concentrations of GPLD1 between the LADA and T1DM cohorts. GPLD1 is implicated as a potential candidate plasma protein for determining early stage LADA and T2DM.
doi:10.1371/journal.pone.0156959
PMCID: PMC4925120  PMID: 27351175
23.  Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque 
Oncotarget  2016;7(24):35562-35576.
Previous studies demonstrated that aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which eliminates ALDH2 activity down to 1%-6%, is a susceptibility gene for coronary disease. Here we investigated the underlying mechanisms based on our prior clinical and experimental studies. Male apoE−/− mice were transfected with GFP, ALDH2-overexpression and ALDH2-RNAi lentivirus respectively (n=20 each) after constrictive collars were placed around the right common carotid arteries. Consequently, ALDH2 gene silencing led to an increased en face plaque area, more unstable plaque with heavier accumulation of lipids, more macrophages, less smooth muscle cells and collagen, which were associated with aggravated inflammation. However, ALDH2 overexpression displayed opposing effects. We also found that ALDH2 activity decreased in atherosclerotic plaques of human and aged apoE−/− mice. Moreover, in vitro experiments with human umbilical vein endothelial cells further illustrated that, inhibition of ALDH2 activity resulted in elevating inflammatory molecules, an increase of nuclear translocation of NF-κB, and enhanced phosphorylation of NF-κB p65, AP-1 c-Jun, Jun-N terminal kinase and p38 MAPK, while ALDH2 activation could trigger contrary effects. These findings suggested that ALDH2 can influence plaque development and vulnerability, and inflammation via MAPK, NF-κB and AP-1 signaling pathways.
doi:10.18632/oncotarget.9384
PMCID: PMC5094945  PMID: 27191745
ALDH2; polymorphism; atherosclerotic plaque vulnerability; inflammation; MAPK signaling pathway; Pathology Section
24.  B7-H3 protein expression in a murine model of osteosarcoma 
Oncology Letters  2016;12(1):383-386.
Osteosarcoma is an aggressive type of bone tumor that commonly occurs in pediatric age groups. The complete molecular mechanisms behind osteosarcoma formation and progression require elucidation. B7-H3 is a protein of the B7 family that acts as a co-stimulatory molecule with a significant role in adaptive immune responses. The link between B7-H3 expression and its role in different types of cancer remains unclear. B7-H3 protein exhibits different functional roles in in vivo and in vitro conditions that remain controversial. In the present study, a murine model of osteosarcoma was successfully established using a modified protocol so as to easily obtain a low grade and metastatic form of osteosarcoma tissue without complication. Histological data showed that a less organized and highly proliferative mass of cells was observed in the osteosarcoma tissue. A higher expression level of B7-H3 protein was also observed at each advanced stage of osteosarcoma, which indicated the contributory role of the protein in the development of the primary and metastatic forms of osteosarcoma. Immunohistochemistry was performed, which showed that the overexpression of B7-H3 protein in the metastatic form of osteosarcoma may be associated with its migration and invasion.
doi:10.3892/ol.2016.4675
PMCID: PMC4906827  PMID: 27347155
osteosarcoma; B7-H3 protein; K7M2 cells; BALB/c strain
25.  Dietary, circulating beta-carotene and risk of all-cause mortality: a meta-analysis from prospective studies 
Scientific Reports  2016;6:26983.
Observational studies evaluating the relation between dietary or circulating level of beta-carotene and risk of total mortality yielded inconsistent results. We conducted a comprehensive search on publications of PubMed and EMBASE up to 31 March 2016. Random effect models were used to combine the results. Potential publication bias was assessed using Egger’s and Begg’s test. Seven studies that evaluated dietary beta-carotene intake in relation to overall mortality, indicated that a higher intake of beta-carotene was related to a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.83, 95%CI: 0.78–0.88) with no evidence of heterogeneity between studies (I2 = 1.0%, P = 0.416). A random-effect analysis comprising seven studies showed high beta-carotene level in serum or plasma was associated with a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.69, 95%CI: 0.59–0.80) with low heterogeneity (I2 = 37.1%, P = 0.145). No evidence of publication bias was detected by Begg’s and Egger’s regression tests. In conclusion, dietary or circulating beta-carotene was inversely associated with risk of all-cause mortality. More studies should be conducted to clarify the dose-response relationship between beta-carotene and all-cause mortality.
doi:10.1038/srep26983
PMCID: PMC4886629  PMID: 27243945

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