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1.  The Novel Analogue of Hirsutine as an Anti-Hypertension and Vasodilatary Agent Both In Vitro and In Vivo 
PLoS ONE  2015;10(4):e0119477.
In this paper, an analogue of hirsutine (compound 1) has been synthesized and evaluated as an anti-hypertension agent, which exhibits extraordinary effects on the contractile response of thoracic aorta rings from male SD rats in vitro (IC50 = 1.129×10-9±0.5025) and the abilities of reducing the systolic blood pressure (SBP) and heart rate (HR) of SHR in vivo. The mechanism investigation reveals that the vasodilatation induced by compound 1 is mediated by both endothelium-dependent and -independent manners. The relaxation in endothelium-intact aortic rings induced by compound 1 can be inhibited by L-NAME (1×10-6 mol•L-1) and ODQ (1×10-6 mol•L-1). Moreover, compound 1 can also block Ca2+ influx through L-type Ca2+ channels and inhibit intracellular Ca2+ release while no effect on K+ channel has been observed. All these data demonstrated that the NO/cyclic GMP pathway can be involved in endothelium-dependent manner induced by compound 1. Meanwhile the mechanism on the vasodilatation of compound 1 probably also related to blockade of Ca2+ influx through L-type Ca2+ channels and inhibition of intracellular Ca2+ release may have no relationship with K+ channels.
doi:10.1371/journal.pone.0119477
PMCID: PMC4409389  PMID: 25909998
2.  Hydrogen Sulfide Targets EGFR Cys797/Cys798 Residues to Induce Na+/K+-ATPase Endocytosis and Inhibition in Renal Tubular Epithelial Cells and Increase Sodium Excretion in Chronic Salt-Loaded Rats 
Antioxidants & Redox Signaling  2014;21(15):2061-2082.
Abstract
Aims: The role of hydrogen sulfide (H2S) in renal sodium and water homeostasis is unknown. We investigated whether H2S promoted Na+/K+-ATPase endocytosis via the H2S/EGFR/gab1/PI3K/Akt pathway in renal tubular epithelial cells. Results: H2S decreased Na+/K+-ATPase activity and induced its endocytosis in renal tubular epithelial cells, which was abrogated by small interfering RNA (siRNA) knockdown of epidermal growth factor receptor (EGFR) and gab1, a dominant-negative mutant of Akt and PI3K inhibitors. H2S increased EGFR, gab1, PI3K, and Akt phosphorylation in both renal tubular epithelial cells and kidneys of chronic salt-loaded rats. These increases were abrogated by siRNA knockdown of EGFR, but not of c-Src. Radiolabeled H2S exhibited transient, direct binding to EGFR and directly activated EGFR. Some disulfide bonds in EGFR intracellular kinase domain were susceptible to H2S-induced cleavage. Mutations of EGFR Cys797 (human) or Cys798 (rat) residues increased EGFR activity and prevented H2S-induced Na+/K+-ATPase endocytosis. H2S also inhibited sodium hydrogen exchanger-3 (NHE3) activity in renal tubular epithelial cells. H2S treatment increased sodium excretion in chronic and acute salt-loaded rats and decreased blood pressure in chronic salt-loaded rats. Innovation and Conclusion: H2S directly targets some disulfide bonds in EGFR, which activates the EGFR/gab1/PI3K/Akt pathway and subsequent Na+/K+-ATPase endocytosis and inhibition in renal tubular epithelial cells. EGFR Cys797/Cys798 residues are essential for an intrinsic inhibitory mechanism and for H2S actions in renal tubular epithelial cells. Other pathways, including NHE3, may be involved in mediating the renal effects of H2S. Our results reveal a new renal sodium homeostasis mechanism, which may provide for novel treatment approaches for diseases related to renal sodium homeostasis dysfunction. Antioxid. Redox Signal. 21, 2061–2082.
doi:10.1089/ars.2013.5304
PMCID: PMC4215382  PMID: 24684506
3.  VEGFR2 Functions As an H2S-Targeting Receptor Protein Kinase with Its Novel Cys1045–Cys1024 Disulfide Bond Serving As a Specific Molecular Switch for Hydrogen Sulfide Actions in Vascular Endothelial Cells 
Antioxidants & Redox Signaling  2013;19(5):448-464.
Abstract
Aims: The potential receptor for hydrogen sulfide (H2S) remains unknown. Results: H2S could directly activate vascular endothelial growth factor receptor 2 (VEGFR2) and that a small interfering RNA (siRNA)-mediated knockdown of VEGFR2 inhibited H2S-induced migration of human vascular endothelial cells. H2S promoted angiogenesis in Matrigel plug assay in mice and this effect was attenuated by a VEGF receptor inhibitor. Using tandem mass spectrometry (MS), we identified a new disulfide complex located between Cys1045 and Cys1024 within VEGFR2 that was labile to H2S-mediated modification. Kinase activity of the mutant VEGFR2 (C1045A) devoid of the Cys1045–Cys1024 disulfide bond was significantly higher than wild-type VEGFR2. Transfection with vectors expressing VEGFR2 (C1045A) caused a significant increase in cell migration, while the migration-promoting effect of H2S disappeared in the cells transfected with VEGFR2 (C1045A). Therefore, the Cys1045–Cys1024 disulfide bond serves as an intrinsic inhibitory motif and functions as a molecular switch for H2S. The formation of the Cys1045–Cys1024 disulfide bond disrupted the integrity of the active conformation of VEGFR2. Breaking the Cys1045–Cys1024 disulfide bond recovered the active conformation of VEGFR2. This motif was prone to a nucleophilic attack by H2S via an interaction of their frontier molecular orbitals. siRNA-mediated knockdown of cystathionine γ-lyase attenuated migration of vascular endothelial cells induced by VEGF or moderate hypoxia. Innovation and Conclusion: The study provides the first piece of evidence of a molecular switch in H2S-targeting receptor protein kinase in H2S-induced angiogenesis and that may be applicable to additional kinases containing functionally important disulfide bonds in mediating various H2S actions. Antioxid. Redox Signal. 19, 448–464.
doi:10.1089/ars.2012.4565
PMCID: PMC3704125  PMID: 23199280
4.  The role of urotensin II in cardiovascular and renal physiology and diseases 
British Journal of Pharmacology  2006;148(7):884-901.
Urotensin II (U-II) is a cyclic neuropeptide that was first isolated from teleost fish some 35 years ago. Mammalian U-II is a powerful vasoconstrictor with a potency greater than that of endothelin-1.Nevertheless, unlike endothelin-1, which constricts all or nearly all vascular beds, the vasoactive effects of U-II are reported to be dependent both on the species and on the regional vascular bed examined. Typical regional variability occurs in the rat in which vasoconstriction to U-II is most robust in thoracic aorta proximal to the aortic arch and decreases gradually towards the distal peripheral arteries. As small peripheral arteries but not larger arteries such as the aorta play a major role in regulating peripheral resistance and consequent blood pressure as well as workload on the heart, doubts have been raised concerning the importance of this peptide in cardiovascular physiology. Moreover, an interaction between U-II and other endogenous vasoactive molecules may add a level of complexity to the vascular actions of U-II.On the other hand, recent experimental and clinical studies have revealed increased expression of U-II and urotensin receptor (UT receptor) in animals with experimentally induced myocardial infarction, heart failure, and in patients with hypertension, atherosclerosis, and diabetic nephropathy, which suggests a potential role for U-II in both cardiovascular and renal diseases. A series of peptidic and nonpeptidic UT receptor ligands have been shown to be effective in antagonizing the effects of U-II in the cardiorenal system.This article aims to review recent advances in our understanding of the physiology and pathophysiology of U-II with particular references to its role in cardiovascular health and disease.
doi:10.1038/sj.bjp.0706800
PMCID: PMC1751922  PMID: 16783414
Urotensin II; urotensin receptor; vasoactive effects; signalling mechanisms; interaction
5.  Papillary thyroid cancer located in malignant struma ovarii with omentum metastasis: a case report and review of the literature 
Background
The present of malignant transformation in struma ovarii is exceedingly rare. Malignant struma ovarii is usually asymptomatic and infrequently diagnosed preoperatively. Because of its rarity, there is no consensus about diagnosis and management in the literature.
Case presentation
A 40-year-old female presented for her obstetric examination with an incidental finding of a pelvic mass. Patient was asymptomatic at presentation. A follow-up ultrasound confirmed the presence of a 3-cm mass in the left adnexa. Patient underwent a cytoreductive surgery (hysterectomy, bilateral salpingectomy and oophorectomy, omentectomy, appendectomy, and pelvic lymphadenectomy). Histopathology revealed a malignant struma ovarii with a focus of papillary thyroid carcinoma and the omentum metastasis. The patient with stage FIGO IIIc received 6 cycles of paclitaxel/carboplatin regimen after surgery. The patient subsequently had a thyroid scan that was normal with normal thyroid function. At a follow-up of 12 months, she is alive, in good clinical condition, and disease-free.
Conclusions
Because of the rarity of these tumors and their lack of firm prognostic factors, treatment decisions should be made individually, based on pathologic and clinical parameters.
doi:10.1186/s12957-016-0776-x
PMCID: PMC4721013  PMID: 26791568
Struma ovarii; Papillary thyroid cancer; Metastases
6.  Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress 
Nature Communications  2015;6:10057.
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection.
Nicotinamide mononucleotide adenylyltransferase (NMNAT) acts in the NAD biosynthesis pathway and has neuroprotective activity. Ruan et al. show that the neuroprotective activity of NMNAT is restricted to a splice variant of the enzyme, and that this variant is preferentially spliced in response to stress.
doi:10.1038/ncomms10057
PMCID: PMC4674693  PMID: 26616331
7.  Correlation of coronary plaque characteristics and obstructive stenosis with chronic kidney disease by coronary CT angiography 
Background
Chronic kidney disease (CKD) is an independent risk factor for cardiovascular events. We evaluated the correlation of coronary plaque characteristics and obstructive stenosis with CKD by coronary computed tomographic angiography (CCTA).
Methods
We enrolled 491 subjects who were suspected coronary artery disease (CAD) undergoing CCTA. Estimated glomerular filtration rate (eGFR) was calculated by the modification of diet in renal disease (MDRD) equation. Patients were subdivided into four groups based on their eGFR: normal GFR (n=213, eGFR ≥90 mL/min/1.73 m2), mild renal insufficiency (n=191, eGFR 60-89 mL/min/1.73 m2), moderate renal insufficiency(n=78, eGFR <60 mL/min/1.73 m2, ≥30 mL/min/1.73 m2), and severe renal insufficiency (n=9, eGFR <30 mL/min/1.73 m2, ≥15 mL/min/1.73 m2).
Results
Spearman correlation regression analysis showed that the prevalence of any plaque, calcified plaque (CP), mixed plaque (MP) were positively correlate with CKD (r=0.173, P<0.001; r=0.127, P=0.005; r=0.171, P<0.001), after adjustment for traditional risk factors the prevalence of any plaque and MP were still positively correlate with CKD (r=0.106, P=002; r=0.178, P<0.001). And the prevalence of any stenosis and severe stenosis were positively correlate with CKD (r=0.13, P<0.001; r=0.149, P<0.001), after adjustment for traditional risk factors were still positively correlate with CKD (r=0.134, P=0.003; r=0.174, P<0.001).
Conclusions
CKD is closely related with occurrence of CAD. CKD patients from mild renal insufficiency to severe renal insufficiency are the risk factors for CAD. More serious renal function impairment will indicates higher risk of coronary plaque, MP and obstructive stenosis.
doi:10.3978/j.issn.2223-3652.2015.11.01
PMCID: PMC4666694  PMID: 26676159
Chronic kidney disease (CKD); coronary computed tomographic angiography (CCTA); coronary artery disease (CAD)
8.  Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway 
Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H2S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H2S and NO conjugated donor developed by H2S-releasing moiety (S-propyl-L-cysteine (SPRC)) and NO-releasing moiety (furoxan). ZYZ-803 could time- and dose-dependently relax the sustained contraction induced by PE in rat aortic rings, with potencies of 1.5- to 100-fold greater than that of furoxan and SPRC. Inhibition of the generations of H2S and NO with respective inhibitors abolished the vasorelaxant effect of ZYZ-803. ZYZ-803 increased cGMP level and the activity of vasodilator stimulated phosphoprotein (VASP) in aortic rings, and those effects could be suppressed by the inhibitory generation of H2S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of KATP channel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H2S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases.
doi:10.1155/2016/7075682
PMCID: PMC4655279  PMID: 26635911
9.  Clinicopathological Significance of MicroRNA-20b Expression in Hepatocellular Carcinoma and Regulation of HIF-1α and VEGF Effect on Cell Biological Behaviour 
Disease Markers  2015;2015:325176.
miRNA-20b has been shown to be aberrantly expressed in several tumor types. However, the clinical significance of miRNA-20b in the prognosis of patients with hepatocellular carcinoma (HCC) is poorly understood, and the exact role of miRNA-20b in HCC remains unclear. The aim of the present study was to investigate the association of the expression of miR-20b with clinicopathological characteristics and overall survival of HCC patients analyzed by Kaplan-Meier analysis and Cox proportional hazards regression models. Meanwhile, the HIF-1α and VEGF targets of miR-20b have been confirmed. We found not only miR-20b regulation of HIF-1α and VEGF in normal but also regulation of miR-20b in hypoxia. This mechanism would help the tumor cells adapt to the different environments thus promoting the tumor invasion and development. The whole study suggests that miR-20b, HIF-1α, and VEGF serve as a potential therapeutic agent for hepatocellular carcinoma.
doi:10.1155/2015/325176
PMCID: PMC4646993  PMID: 26612965
10.  Dimethyl Cardamonin Exhibits Anti-inflammatory Effects via Interfering with the PI3K-PDK1-PKCα Signaling Pathway 
Biomolecules & Therapeutics  2015;23(6):549-556.
Consumption of herbal tea [flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae)] is associated with health beneficial effects against multiple diseases including diabetes, asthma, and inflammatory bowel disease. Emerging evidences have reported that High mobility group box 1 (HMGB1) is considered as a key “late” proinflammatory factor by its unique secretion pattern in aforementioned diseases. Dimethyl cardamonin (2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone, DMC) is a major ingredient of C. operculatus flower buds. In this study, the anti-inflammatory effects of DMC and its underlying molecular mechanisms were investigated on lipopolysaccharide (LPS)-induced macrophages. DMC notably suppressed the mRNA expressions of TNF-α, IL-1β, IL-6, and HMGB1, and also markedly decreased their productions in a time- and dose-dependent manner. Intriguingly, DMC could notably reduce LPS-stimulated HMGB1 secretion and its nucleo-cytoplasmic translocation. Furthermore, DMC dose-dependently inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), and protein kinase C alpha (PKCα). All these data demonstrated that DMC had anti-inflammatory effects through reducing both early (TNF-α, IL-1β, and IL-6) and late (HMGB1) cytokines expressions via interfering with the PI3K-PDK1-PKCα signaling pathway.
doi:10.4062/biomolther.2015.048
PMCID: PMC4624071  PMID: 26535080
Dimethyl cardamonin; Inflammatory mediators; HMGB1; PI3K; PKCα
11.  Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway 
Cisplatin has been a key chemotherapy drug for treatment of non-small cell lung cancer (NSCLC) for decades. However, the efficacy of Cisplatin is usually reduced by the occurrence of drug-resistance of cancer cells. Fisetin is a flavonol naturally found in many fruits and vegetables, which has been reported to suppress cell proliferation and induce apoptosis in various cancers. In this study, we aimed to investigate whether Fisetin was capable of enhancing cytotoxicity of Cisplatin in Cisplatin-resistant NSCLC cells, and explore the possible signaling pathways involved. Cisplatin-resistant NSCLC cells, A549-CR, was established by repeated subculturing of A549 cells with increasing Cisplatin. Proliferation ability was assessed by MTT analysis and apoptosis was detected by flow cytometry. The results showed that Fisetin effectively increased sensitivity of A549-CR cells to Cisplatin, possibly mediated by inhibiting aberrant activation of MAPK signaling pathways. This increases the possibility of Fisetin as a promising agent for lung cancer therapy.
PMCID: PMC4656781  PMID: 26692948
Cisplatin; fisetin; resistance; NSCLC A549 cells; MAPK signaling pathway
12.  Efficiency of muscle strength training on motor function in patients with coronary artery disease: a meta-analysis 
Background: Existing literature has shown that patients with coronary artery disease (CAD) can benefit greatly from the strength training; therefore, the strength training should play a more important role in cardiac rehabilitation. However, the medical community may still have conservation to apply the strength training owing to no comprehensive study so far to compare the effectiveness of the strength training to the other trainings, such as aerobic training. Objective: To evaluate the effect of strength training on motor function in patients with CAD. Methods: Published articles from the earliest date available to July 2015 were identified using electronic searches. Two reviewers selected independently relevant randomized controlled trials (RCTs) investigating exercise program with strength training versus control interventions (exercise without strength training, including aerobic training and no exercise group) for the treatment of CAD patients. We examined effects of exercise with strength training versus control interventions on peak oxygen uptake (VO2peak), duration of exercise test and muscle strength. Two reviewers extracted data independently. Results: Twenty seven trials that represented 1151 participants passed the selection criteria and were evaluated for the effects of strength training in CAD patients. For improving VO2peak [SMD (95%CI) = 0.58 (0.11, 1.06)] and muscle strength [upper limb, SMD (95% CI) =0.44 (0.34, 0.55); lower limb, SMD (95% CI) =0.33 (0.16, 0.50)], exercise program with strength training were significantly more effective than one without it. But there is no significantly difference on duration of exercise test [SMD (95%CI) = 0.17 (-0.04, 0.39)] in strength training group than in control group. Conclusions: We conclude strength training is effective in improving muscle strength and VO2peak, in CAD patients, when compared to patients with control group. Furthermore, our evaluations suggest that strength training does not compromise clinical trial completion or safety.
PMCID: PMC4694245  PMID: 26770345
Coronary artery disease; muscle strength training; motor function; randomized controlled trials; meta-analysis
13.  Experiencing Physical Pain Leads to More Sympathetic Moral Judgments 
PLoS ONE  2015;10(10):e0140580.
Previous studies have shown that observing another’s pain can evoke other-oriented emotions, which instigate empathic concern for another’s needs. It is not clear whether experiencing first-hand physical pain may also evoke other-oriented emotion and thus influence people’s moral judgment. Based on the embodied simulation literature and neuroimaging evidence, the present research tested the idea that participants who experienced physical pain would be more sympathetic in their moral judgments. Study 1 showed that ice-induced physical pain facilitated higher self-assessments of empathy, which motivated participants to be more sympathetic in their moral judgments. Study 2 confirmed findings in study 1 and also showed that State Perspective Taking subscale of the State Empathy Scale mediated the effects of physical pain on moral judgment. These results provide support for embodied view of morality and for the view that pain can serve a positive psychosocial function.
doi:10.1371/journal.pone.0140580
PMCID: PMC4605675  PMID: 26465603
14.  Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels 
PLoS ONE  2015;10(10):e0139417.
Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = —0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans.
doi:10.1371/journal.pone.0139417
PMCID: PMC4595343  PMID: 26439934
15.  Proteomics and bioinformatics analysis of mouse hypothalamic neurogenesis with or without EPHX2 gene deletion 
The aim of this study was to identify differently expressed proteins in the presence and absence of EPHX2 gene in mouse hypothalamus using proteomics profiling and bioinformatics analysis. This study was performed on 3 wild type (WT) and 3 EPHX2 gene global knockout (KO) mice (EPHX2 -/-). Using the nano- electrospray ionization (ESI)-LC-MS/MS detector, we identified 31 over-expressed proteins in WT mouse hypothalamus compared to the KO counterparts. Gene Ontology (GO) annotation in terms of the protein-protein interaction network indicated that cellular metabolic process, protein metabolic process, signaling transduction and protein post-translation biological processes involved in EPHX2 -/- regulatory network. In addition, signaling pathway enrichment analysis also highlighted chronic neurodegenerative diseases and some other signaling pathways, such as TGF-beta signaling pathway, T cell receptor signaling pathway, ErbB signaling pathway, Neurotrophin signaling pathway and MAPK signaling pathway, were strongly coupled with EPHX2 gene knockout. Further studies into the molecular functions of EPHX2 gene in hypothalamus will help to provide new perspective in neurogenesis.
PMCID: PMC4680398  PMID: 26722453
EPHX2; hypothalamic neurogenesis; proteomics profiling; protein network
16.  Effects of paternal cadmium exposure on the sperm quality of male rats and the neurobehavioral system of their offspring 
Cadmium (Cd) is a testicular toxicant and an endocrine disruptor in humans and rodents. The aim of the present study was to investigate the effects of paternal Cd exposure on the sperm quality of male rats and the neurobehavioral system of their offspring. A total of 12 male rats were randomized into a control and Cd-treated group (n=6 per group), and 12 female rats were administered distilled water and randomly divided into two groups (n=6 per group). Subsequently, sperm motility, viability, malformation rate of male rats and the neuromotor maturation, antioxidant ability, Cd accumulation in different organs of their offspring were measured. Compared with the control rats, the sperm motility rate and vitality were significantly reduced (P<0.01) and the sperm malformation rate was significantly increased (P<0.01) in the male rats following Cd treatment. Regarding the nervous system development of the offspring, the cliff-avoidance reflex, surface-righting reflex and negative geotaxis results exhibited significant differences between the Cd exposure and control groups (P<0.05). The Cd content in the liver and heart of the offspring of the Cd exposure rats was higher than that in the control rats (P<0.05), and the liver content peaked on postnatal day 21. Furthermore, Cd exposure affected the antioxidant activity of the offspring, which was shown by glutathione, malondialdehyde and superoxide dismutase assays. Collectively, the results indicate that Cd exposure affects the sperm quality of male rats and the neurobehavioral system of their offspring.
doi:10.3892/etm.2015.2777
PMCID: PMC4665723  PMID: 26668641
reproduction; offspring; neurobehavioral system; sperm quality; cadmium exposure
17.  A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer 
Oncotarget  2015;6(28):25046-25060.
A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121–1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03–1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.
PMCID: PMC4694814  PMID: 26208480
night shift work; colorectal cancer; meta-analysis; epidemiology; risk factor
18.  The effect of radish sourced 4-(Methylthio)-3-butenyl isothiocyanate on ameliorating the severity of high fat diet inducted nonalcoholic fatty liver disease in rats 
The aim of this study is to develop a high fat diet and over nutrition induced nonalcoholic fatty liver disease(NAFLD) in rat, and to investigate the effect of 4-(Methylthio)-3-butenyl isothiocyanate (MTBITC) on ameliorating the NAFLD. Twenty Sprague-Dawley (SD) rats were equally divided into 4 groups (C, M, E1 & E2). Control group (C) were treated with standard restricted diet; Model group (M) were given high fat liquid diet ad libitum; Experimental group (E1 & E2) were treated with high fat liquid diet ad libitum and MTBITC by gavage. The experiment last 9 weeks, and serum chemistry and liver histology were assessed. The rats of M group showed severe lipid deposition and peroxidation in liver. When compared with group C, group M also showed significantly higher serum concentration of low-density lipoprotein, tumor necrosis factor-α and glucose. Histopathologic sections demonstrated lipid accumulation and macrovascular steatosis with ballooning degeneration in the livers of M. Group E2 presented significantly better conditions when assessed based on the parameters of NAFLD. The data suggested that MTBITC might significantly attenuate fat liquid diet induced NAFLD.
PMCID: PMC4658983  PMID: 26629094
Nonalcoholic fatty liver disease; Chinese white radish; 4-(Methylthio)-3-butenyl isothiocyanate; phytochemical; antioxidative stress
20.  MicroRNA-195-5p, a new regulator of Fra-1, suppresses the migration and invasion of prostate cancer cells 
Background
An increasing number of studies have demonstrated that deregulation of microRNAs (miRNAs) was a common event in tumor tissues and miRNAs would be treated as ideal tumor biomarkers or therapeutic targets. miR-195-5p (termed as miR-195 for briefly in the following part) was suggested to function as a tumor suppressor in cancer development and progression. However, the roles of miR-195 in human prostate cancer are still elusive. Thus, this study was performed to investigate the biological functions and its molecular mechanisms of miR-195 in human prostate cancer cell lines, discussing whether it has a potential to be a therapeutic way of prostate cancer.
Methods
Two human prostate cancer cell lines were analyzed for the expression of miR-195 by quantitative real-time reverse transcription–polymerase chain reaction (RT–PCR). A gain-of-function study of miR-195 was conducted by transfecting mimics into DU145 and PC3 cells and cell motility and invasion ability were evaluated by wound healing assay and transwell assay. Tissue microarray, and immunohistochemistry with antibodies against Fra-1 was performed using the peroxidase and DAB methods. The target gene of miR-195 was determined by luciferase assay, quantitative RT–PCR and western blot. The regulation of motility by miR-195 was analyzed by western blot.
Results
miR-195 was frequently down-regulated in both prostate cancer cell lines, DU145 and PC3. Overexpression of miR-195 significantly repressed the capability of migration and invasion of prostate cancer cells. In addition, we identified Fra-1, a cell motility regulator, as a novel target of miR-195. Fra-1 was up-regulated in prostate cancer tissues. We also observed that inhibition of miR-195 or restoration of Fra-1 in miR-195-over-expressed prostate cancer cells partially reversed the suppressive effects of miR-195. Furthermore, we demonstrated miR-195 could inhibit prostate cancer cell motility by regulated the expression of c-Met, MMP1, MMP9.
Conclusions
miR-195 can repress the migration and invasion of prostate cancer cells via regulating Fra-1. Our results indicate that miR-195 could be a tumor suppressor and may have a potential to be a diagnostics or therapeutic target in prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0650-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0650-6
PMCID: PMC4558968  PMID: 26337460
miR-195; Fra-1; Prostate cancer; Migration; Invasion
21.  NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells 
Oncotarget  2015;6(25):21443-21451.
The nucleophosmin (NPM1) activates cancer development and progression in many malignant tumors. However, the regulatory role and underlying mechanisms of NPM1 in pancreatic cancer are unknown. In this study, we showed that NPM1 was up-regulated in PDAC, which indicated a poor prognosis. We also identified NPM1could stimulate aerobic glycolysis and repress fructose-1, 6-bisphosphatase 1 (FBP1) in pancreatic cancer cells. Restoring FBP1 expression partially reversed the tumor-promoting effects of NPM1, while the loss of FBP1 in PDAC tissues was indicative of a poorer prognosis. In sum, NPM1 promotes aerobic glycolysis and tumor progression in patients with pancreatic cancer by inhibiting FBP1.
PMCID: PMC4673277  PMID: 26068981
pancreatic ductal adenocarcinoma; NPM1; FBP1; warburg effect
22.  Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis 
Background/aims: Primary biliary cirrhosis (PBC), an autoimmune disease of the liver, is marked by slow progressive destruction of bile ducts. These patients with PBC often undergo orthotopic liver transplantation (OLT). Ischemic bile duct lesion (IBDL) is a major source of morbidity and even mortality after OLT. Cirrhosis of the liver has a higher tolerance to ischemia than a normal liver, but the mechanism remains unknown. Angiogenesis and proliferation of bile duct often responses in bile duct ischemia, which may enhance ischemic tolerance in patients with cirrhosis. Methodology: To test the hypothesis, a rat model with cirrhosis was established. Biochemical indexes of ischemic severity were measured including total bilirubin (TBIL) and direct bilirubin (DBIL). Immunohistochemical assay was performed for Ki67 (a biomarker for the proliferation of bile duct) and CD34 (a biomarker of angiogenesis). Results: The levels were lower for TBIL and DBIL in the bile duct from rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). The levels were higher for Ki67 and CD34 from a rat model with cirrhosis than that from a normal rat after ischemic surgery (P < 0.05). Conclusions: The results suggest that a liver with cirrhosis has a better ischemic tolerance than a normal liver. Angiogenesis and proliferation of bile duct enhances ischemic tolerance in rats with cirrhosis. More research on the pathogenesis of IBDLs is needed for developing more specific preventive or therapeutic strategies.
PMCID: PMC4612805  PMID: 26550120
Angiogenesis; bile duct; cirrhosis; ischemia; proliferation
23.  Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts 
Diabetes  2014;63(8):2676-2689.
Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.
doi:10.2337/db13-1763
PMCID: PMC4113065  PMID: 24677713
24.  The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs 
Aging Cell  2015;14(4):644-658.
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
doi:10.1111/acel.12344
PMCID: PMC4531078  PMID: 25754370
dasatinib; dependence receptors; ephrins; p21; PI3K delta; plasminogen-activated inhibitor; quercetin
25.  SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice 
SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.
doi:10.3390/ijms160818544
PMCID: PMC4581259  PMID: 26262618
SCM-198; amyloid-β; Alzheimer’s disease; Morris water maze; novel object recognition; cAMP-responsive element-binding protein; brain-derived neurotrophic factor; tropomyosin-related kinase B

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