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1.  Biological Properties of Acidic Cosmetic Water from Seawater 
This current work was to investigate the biological effects of acidic cosmetic water (ACW) on various biological assays. ACW was isolated from seawater and demonstrated several bio-functions at various concentration ranges. ACW showed a satisfactory effect against Staphylococcus aureus, which reduced 90% of bacterial growth after a 5-second exposure. We used cultured human peripheral blood mononuclear cells (PBMCs) to test the properties of ACW in inflammatory cytokine release, and it did not induce inflammatory cytokine release from un-stimulated, normal PBMCs. However, ACW was able to inhibit bacterial lipopolysaccharide (LPS)-induced inflammatory cytokine TNF-α released from PBMCs, showing an anti-inflammation potential. Furthermore, ACW did not stimulate the rat basophilic leukemia cell (RBL-2H3) related allergy response on de-granulation. Our data presented ACW with a strong anti-oxidative ability in a superoxide anion radical scavenging assay. In mass spectrometry information, magnesium and zinc ions demonstrated bio-functional detections for anti-inflammation as well as other metal ions such as potassium and calcium were observed. ACW also had minor tyrosinase and melanin decreasing activities in human epidermal melanocytes (HEMn-MP) without apparent cytotoxicity. In addition, the cell proliferation assay illustrated anti-growth and anti-migration effects of ACW on human skin melanoma cells (A375.S2) indicating that it exerted the anti-cancer potential against skin cancer. The results obtained from biological assays showed that ACW possessed multiple bioactivities, including anti-microorganism, anti-inflammation, allergy-free, antioxidant, anti-melanin and anticancer properties. To our knowledge, this was the first report presenting these bioactivities on ACW.
PMCID: PMC3382787  PMID: 22754342
acidic cosmetic water (ACW); antioxidant activity; anti-microorganism; anti-inflammation; allergy-free; skin-whitening; anti-melanoma
2.  Evolution of Carbapenem-Resistant Acinetobacter baumannii Revealed through Whole-Genome Sequencing and Comparative Genomic Analysis 
Acinetobacter baumannii is a globally important nosocomial pathogen characterized by an evolving multidrug resistance. A total of 35 representative clinical A. baumannii strains isolated from 13 hospitals in nine cities in China from 1999 to 2011, including 32 carbapenem-resistant and 3 carbapenem-susceptible A. baumannii strains, were selected for whole-genome sequencing and comparative genomic analysis. Phylogenetic analysis revealed that the earliest strain, strain 1999BJAB11, and two strains isolated in Zhejiang Province in 2004 were the founder strains of carbapenem-resistant A. baumannii. Ten types of AbaR resistance islands were identified, and a previously unreported AbaR island, which comprised a two-component response regulator, resistance-related proteins, and RND efflux system proteins, was identified in two strains isolated in Zhejiang in 2004. Multiple transposons or insertion sequences (ISs) existed in each strain, and these gradually tended to diversify with evolution. Some of these IS elements or transposons were the first to be reported, and most of them were mainly found in strains from two provinces. Genome feature analysis illustrated diversified resistance genes, surface polysaccharides, and a restriction-modification system, even in strains that were phylogenetically and epidemiologically very closely related. IS-mediated deletions were identified in the type VI secretion system region, the csuE region, and core lipooligosaccharide (LOS) loci. Recombination occurred in the heme utilization region, and intrinsic resistance genes (blaADC and blaOXA-51-like variants) and three novel blaOXA-51-like variants (blaOXA-424, blaOXA-425, and blaOXA-426) were identified. Our results could improve the understanding of the evolutionary processes that contribute to the emergence of carbapenem-resistant A. baumannii strains and help elucidate the molecular evolutionary mechanism in A. baumannii.
PMCID: PMC4335871  PMID: 25487793
3.  Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland 
Human genetics  2014;134(2):217-230.
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.
PMCID: PMC4347882  PMID: 25472526
4.  Synthesis and Structure–Activity Relationships of Pteridine Dione and Trione Monocarboxylate Transporter 1 Inhibitors 
Journal of Medicinal Chemistry  2014;57(17):7317-7324.
Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these compounds as inhibitors of lactate transport was confirmed using a 14C-lactate transport assay, and their potency against MCT1-expressing human tumor cells was established using MTT assays. The four most potent compounds showed substantial anticancer activity (EC50 37–150 nM) vs MCT1-expressing human Raji lymphoma cells.
PMCID: PMC4161152  PMID: 25068893
5.  Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 in prostate cancer 
Scientific Reports  2015;5:12495.
Activation of hypoxia-inducible factor 1α (HIF1α) controls the transcription of genes governing angiogenesis under hypoxic condition during tumorigenesis. Here we show that hypoxia-responsive miR-182 is regulated by HIF1α at transcriptional level. Prolyl hydroxylase domain enzymes (PHD) and factor inhibiting HIF-1 (FIH1), negative regulators of HIF1 signaling, are direct targets of miR-182. Overexpression of miR-182 in prostate cancer cells led to a reduction of PHD2 and FIH1 expression and an increase in HIF1α level either under normoxic or hypoxic condition. Consistently, inhibition of miR-182 could increase PHD2 and FIH1 levels, thereby reducing the hypoxia-induced HIF1α expression. Matrigel plug assay showed that angiogenesis was increased by miR-182 overexpression, and vice versa. miR-182 overexpression in PC-3 prostate cancer xenografts decreased PHD2 and FIH1 expression, elevated HIF1α protein levels, and increased tumor size. Lastly, we revealed that the levels of both miR-182 and HIF1α were elevated, while the expression PHD2 and FIH1 was downregulated in a mouse model of prostate cancer. Together, our results suggest that the interplay between miR-182 and HIF1α could result in a sustained activation of HIF1α pathway, which might facilitate tumor cell adaption to hypoxic stress during prostate tumor progression.
PMCID: PMC4513346  PMID: 26205124
6.  Comparative proteomics analysis provide novel insight into laminitis in Chinese Holstein cows 
BMC Veterinary Research  2015;11:161.
Laminitis is considered as the most important cause of hoof lameness in dairy cows, which causes abundant economic losses in husbandry. Through intense efforts in past decades, the etiology of laminitis is preliminarily considered to be subacute ruminal acidosis; however, the pathogenesis of laminitis needs further research. The differentially expressed proteins (DEP) were detected in plasma of healthy cows and clinical laminitis cows by two-dimensional gel electrophoresis (2-DE) and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Nineteen protein spots were differentially expressed, and 16 kinds of proteins were identified after peptide mass fingerprint search and bioinformatics analysis. Of these, 12 proteins were differentially up-regulated and 4 down-regulated. Overall, these differential proteins were involved in carbohydrate metabolism, lipids metabolism, molecular transport, immune regulation, inflammatory response, oxidative stress and so on.
The DEPs were closely related to the occurrence and development of laminitis and the lipid metabolic disturbance may be a new pathway to cause laminitis in dairy cows. The results provide the theory foundation for further revealing the mechanism of laminitis and screening the early diagnostic proteins and therapeutic target.
PMCID: PMC4511986  PMID: 26202328
Comparative proteomics; 2-DE; Laminitis; Plasma; Dairy cow
7.  Yindanxinnaotong, a Chinese compound medicine, synergistically attenuates atherosclerosis progress 
Scientific Reports  2015;5:12333.
Yindanxinnaotong (YD), a traditional Chinese medicine, has been introduced to clinical medicine for more than a decade, while its pharmacological properties are still not to be well addressed. This report aimed to explore the anti-atherosclerosis properties and underlying mechanisms of YD. We initially performed a computational prediction based on a network pharmacology simulation, which clued YD exerted synergistically anti-atherosclerosis properties by vascular endothelium protection, lipid-lowering, anti-inflammation, and anti-oxidation. These outcomes were then validated in atherosclerosis rats. The experiments provided evidences indicating YD’s contribution in this study included, (1) significantly reduced the severity of atherosclerosis, inhibited reconstruction of the artery wall and regulated the lipid profile; (2) enhanced antioxidant power, strengthened the activity of antioxidant enzymes, and decreased malondialdhyde levels; (3) significantly increased the viability of umbilical vein endothelial cells exposed to oxidative stress due to pretreatment with YD; (4) significantly reduced the level of pro-inflammatory cytokines; (5) significantly down-regulated NF-kB/p65 and up-regulated IkB in the YD-treated groups. Overall, these results demonstrated that YD intervention relieves atherosclerosis through regulating lipids, reducing lipid particle deposition in the endothelial layer of artery, enhancing antioxidant power, and repressing inflammation activity by inhibiting the nuclear factor-kappa B signal pathway.
PMCID: PMC4508829  PMID: 26196108
8.  Charge deformation and orbital hybridization: intrinsic mechanisms on tunable chromaticity of Y3Al5O12:Ce3+ luminescence by doping Gd3+ for warm white LEDs 
Scientific Reports  2015;5:11514.
The deficiency of Y3Al5O12:Ce (YAG:Ce) luminescence in red component can be compensated by doping Gd3+, thus lead to it being widely used for packaging warm white light-emitting diode devices. This article presents a systematic study on the photoluminescence properties, crystal structures and electronic band structures of (Y1−xGdx)3Al5O12: Ce3+ using powerful experimental techniques of thermally stimulated luminescence, X-ray diffraction, X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS) and ultraviolet photoelectron spectra (UPS) of the valence band, assisted with theoretical calculations on the band structure, density of states (DOS), and charge deformation density (CDD). A new interpretation from the viewpoint of compression deformation of electron cloud in a rigid structure by combining orbital hybridization with solid-state energy band theory together is put forward to illustrate the intrinsic mechanisms that cause the emission spectral shift, thermal quenching, and luminescence intensity decrease of YAG: Ce upon substitution of Y3+ by Gd3+, which are out of the explanation of the classic configuration coordinate model. The results indicate that in a rigid structure, the charge deformation provides an efficient way to tune chromaticity, but the band gaps and crystal defects must be controlled by comprehensively accounting for luminescence thermal stability and efficiency.
PMCID: PMC4502399  PMID: 26175141
9.  HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study 
PLoS Medicine  2015;12(7):e1001853.
Research has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI.
Methods and Findings
The first cohort, which included dementia-free adults aged ≥75 y (n = 970) at baseline, was followed for 9 y to detect incident dementia (n = 358) and AD (n = 271) cases. The second cohort (for replication), which included 2,060 dementia-free participants aged ≥60 y at baseline, was followed for 6 y to identify incident dementia (n = 166) and AD (n = 121) cases. A subsample (n = 338) of dementia-free participants from the second cohort underwent MRI. HHEX_23 and IDE_9 were genotyped, and diabetes (here including type 2 diabetes and prediabetes) was assessed. In the first cohort, diabetes led to an adjusted hazard ratio (HR) of 1.73 (95% CI 1.19–2.32) and 1.66 (95% CI 1.06–2.40) for dementia and AD, respectively, among all participants. Compared to people carrying the GG genotype without diabetes, AA genotype carriers with diabetes had an adjusted HR of 5.54 (95% CI 2.40–7.18) and 4.81 (95% CI 1.88–8.50) for dementia and AD, respectively. There was a significant interaction between HHEX_23-AA and diabetes on dementia (HR 4.79, 95% CI 1.63–8.90, p = 0.013) and AD (HR 3.55, 95% CI 1.45–9.91, p = 0.025) compared to the GG genotype without diabetes. In the second cohort, the HRs were 1.68 (95% CI 1.04–2.99) and 1.64 (1.02–2.33) for the diabetes–AD and dementia–AD associations, respectively, and 4.06 (95% CI 1.06–7.58, p = 0.039) and 3.29 (95% CI 1.02–8.33, p = 0.044) for the interactions, respectively. MRI data showed that HHEX_23-AA carriers with diabetes had significant structural brain changes compared to HHEX_23-GG carriers without diabetes. No joint effects of IDE_9 and diabetes on dementia were shown. As a limitation, the sample sizes were small for certain subgroups.
A variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people.
In a longitudinal study, Weili Xu and colleagues explore whether variants in two insulin pathway genes modify the association of type 2 diabetes with dementia and AD.
Editors' Summary
Worldwide, about 44 million people have dementia, a group of degenerative, incurable brain disorders that mainly affect older people. Dementia is characterized by an irreversible decline in memory, communication, and other “cognitive” functions. The most common forms of dementia are Alzheimer disease, which is caused by the development of small clumps of proteins (β-amyloid plaques) around brain cells, and vascular dementia, which is caused by reduced blood flow to parts of the brain. Early symptoms of dementia include increasing forgetfulness and losing track of time. As the condition progresses, affected individuals gradually lose the ability to look after themselves and to communicate, and they may become anxious or aggressive. Eventually, affected individuals may lose control of various physical functions and many become totally dependent on specialist nurses and other professional carers for their day-to-day needs.
Why Was This Study Done?
Epidemiological studies (investigations that examine patterns of disease in populations) suggest that, among older individuals, having type 2 diabetes (a condition in which resistance to the hormone insulin leads to high blood sugar levels) is associated with a 50% increased risk of developing dementia. Even prediabetes (a blood sugar level that is high but not high enough to meet the criteria for diabetes) is associated with an increased risk of dementia. Prediabetes and diabetes increase the risk of vascular disease, but it is thought that polymorphisms (naturally occurring genetic variations) in the IDE/HHEX region of the human genome may be involved in the association between diabetes and dementia/Alzheimer disease. IDE encodes insulin-degrading enzyme, which clears insulin from cells but also degrades β-amyloid; HHEX encodes a transcription factor that controls IDE expression. In this population-based longitudinal study, the researchers explore whether two single nucleotide polymorphisms in this region—IDE_9 and HHEX_23—impact the association between diabetes and dementia. Population-based longitudinal studies measure the baseline characteristics of individuals in the general population and determine which individuals subsequently develop specific conditions.
What Did the Researchers Do and Find?
For their study, the researchers examined data collected from two cohorts (groups) of dementia-free elderly adults living in Stockholm, Sweden. Blood samples taken from 3,030 participants at baseline were used to determine which individuals had diabetes (type 2 diabetes or prediabetes) and to investigate which HHEX_23 and IDE_9 variants each individual carried (genotyping). The researchers also examined the brain structure of a subsample of the second cohort using magnetic resonance imaging (MRI). All the participants were followed for several years to see which individuals developed dementia/Alzheimer disease. In both cohorts, having diabetes was associated with a 60% increased risk of dementia/Alzheimer disease after adjusting for other characteristics that affect the development of these conditions. Pooled data from both cohorts indicated that, compared to people without diabetes carrying HHEX_23-GG (the human genome contains two copies [alleles] of each gene, and an individual carrying HHEX_23-GG has the nucleotide guanine at a particular position in both HHEX_23 copies), people with diabetes carrying HHEX_23-AA (adenine at that position in both HHEX_23 copies) had a 5-fold higher risk of developing dementia/Alzheimer disease. Other analyses indicated that the HHEX_23-AA genotype interacted with diabetes to substantially increase the risk of dementia/Alzheimer disease. Finally, MRI showed that, at baseline, HHEX_23-AA carriers with diabetes had structural brain changes compared to HHEX_23-GG carriers without diabetes, even though they were all free of dementia at the time.
What Do These Findings Mean?
These and other findings indicate that polymorphisms in HHEX_23, but not IDE_9, are involved in the association between diabetes, dementia, and structural brain changes. Thus, a genetic variant in HHEX_23 may play an important role in the development of Alzheimer disease and other forms of dementia among people with diabetes or prediabetes. These findings may not apply to younger or rural populations, and their accuracy may be affected by the use of a single blood sugar level reading to diagnose diabetes and prediabetes. Moreover, because some of the genotype/diabetes subgroups contained very few people, these findings need to be confirmed in additional studies. Further studies are also needed to understand the role of HHEX_23 in the association between diabetes and dementia. Importantly, however, these findings highlight the need to control diabetes to prevent the development of Alzheimer disease and other forms of dementia, particularly among HHEX_23-AA carriers.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at
The UK National Health Service Choices website provides information (including personal stories and links to additional resources) about dementia, vascular dementia, Alzheimer disease, and diabetes
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of dementia
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia, personal stories about dementia, and information about the association between diabetes and dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer disease associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about dementia, Alzheimer disease, vascular dementia, and diabetes (in English and Spanish)
More information about the Kungsholmen Project and the Swedish National Study on Aging and Care–Kungsholmen, the projects that enrolled the cohorts used by the researchers for this study, is available
PMCID: PMC4501827  PMID: 26173052
10.  Integrative proteomics to understand the transmission mechanism of Barley yellow dwarf virus-GPV by its insect vector Rhopalosiphum padi 
Scientific Reports  2015;5:10971.
Barley yellow dwarf virus-GPV (BYDV-GPV) is transmitted by Rhopalosiphum padi and Schizaphis graminum in a persistent nonpropagative manner. To improve our understanding of its transmission mechanism by aphid vectors, we used two approaches, isobaric tags for relative and absolute quantitation (iTRAQ) and yeast two-hybrid (YTH) system, to identify proteins in R. padi that may interact with or direct the spread of BYDV-GPV along the circulative transmission pathway. Thirty-three differential aphid proteins in viruliferous and nonviruliferous insects were identified using iTRAQ coupled to 2DLC-MS/MS. With the yeast two-hybrid system, 25 prey proteins were identified as interacting with the readthrough protein (RTP) and eight with the coat protein (CP), which are encoded by BYDV-GPV. Among the aphid proteins identified, most were involved in primary energy metabolism, synaptic vesicle cycle, the proteasome pathway and the cell cytoskeleton organization pathway. In a systematic comparison of the two methods, we found that the information generated by the two methods was complementary. Taken together, our findings provide useful information on the interactions between BYDV-GPV and its vector R. padi to further our understanding of the mechanisms regulating circulative transmission in aphid vectors.
PMCID: PMC4498328  PMID: 26161807
11.  Melanoma tumor growth is accelerated in a mouse model of sickle cell disease 
The effect of sickle cell disease (SCD) on tumor growth is unknown. Sickled red blood cells may form aggregates within the microvasculature of hypoxic tumors and reduce blood flow leading to impairment of tumor growth. However, there is a paucity of data related to tumor growth in SCD.
To investigate the effect of SCD on tumor growth in a melanoma model, we generated SCD and control mice using bone marrow transplantation and inoculated the chest wall with B16-F10 melanoma cells. Tumor growth was monitored and angiogenesis was studied in vivo and in vitro.
From day 1 to 21, tumor growth rate was nearly identical between SCD and WT mice, however from day 22 to day 29 tumor growth was accelerated in SCD mice compared to WT mice. Disparity in tumor size was confirmed at autopsy with an approximate 2-fold increase in tumor weights from SCD mice. Tumors from SCD mice showed increased vascularity and elevated levels of heme oxygenase-1 (HO-1). HO-1 inhibition with zinc protoporphyrin (ZnPP) blocked the angiogenic and tumor growth response to SCD in vivo and the response to hemin in vitro.
Growth of melanoma tumors is potentiated in a mouse model of SCD. Therapies targeting angiogenesis or HO-1 may be useful in SCD patients with malignant tumors.
PMCID: PMC4496890  PMID: 26161296
Sickle cell disease; Melanoma; Angiogenesis; Heme oxygenase-1
12.  Selective Roles of E2Fs for ErbB2- and Myc-mediated Mammary Tumorigenesis 
Oncogene  2013;34(1):119-128.
Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 over-expression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay on tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-over-expression. Furthermore, Southern blot analysis of final tumors derived from conditionally deleted E2f3−/loxP mammary glands revealed that there is a selection against E2f3−/− cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.
PMCID: PMC4032808  PMID: 24276244
Myc; ErbB2; E2F; mammary tumorigenesis; oncogene
13.  Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in non-obese diabetic (NOD) mice 
Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D), and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of non-obese diabetic (NOD) mice. 4-week-old female NOD/ShiLtJ mice were fed with a control diet (CON, 10% energy from fat) or a high fat diet (HFD, 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test and, then, ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 as well as mature forms of interleukin (IL) -1β and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor (TNF)α level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 were heightened in offspring ileum (P < 0.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might pre-dispose them to the development of T1D and other gut permeability associated diseases.
PMCID: PMC4050341  PMID: 24775094
Maternal obesity; intestine; inflammation; oxidative stress; permeability; tight junction proteins; NOD; offspring
14.  Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear 
Neuropsychopharmacology  2014;39(8):1933-1945.
Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the β-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the β-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another β-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.
PMCID: PMC4059903  PMID: 24553734
15.  Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins 
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a master transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes. While knockout of Nrf2 exaggerates cardiac pathological remodeling and dysfunction in diverse pathological settings, pharmacological activation of Nrf2 protects against cardiomyocyte injury and cardiac dysfunction. In contrast, there is also a concern that the chronic activation of Nrf2 secondary to oxidative stress is a contributing mechanism for the reductive stress-mediated heart failure. However, a direct link between cardiac specific activation of Nrf2 and cardiac protection or dysfunction in vivo remains to be established. Therefore, we investigated the effect of cardiomyocyte-specific transgenic activation of Nrf2 (Nrf2ctg) on cardiac pathological remodeling and dysfunction. We found that the cardiomyocyte-specific activation of Nrf2 suppressed myocardial oxidative stress as well as cardiac apoptosis, fibrosis, hypertrophy, and dysfunction in a setting of sustained pressure overload induced by transverse aortic arch constriction (TAC) in mice. Notably, the constitutive activation of Nrf2 increased the steady level of autophagosomes while decreasing the ubiquitinated protein aggregates in the heart after TAC. Nrf2 gene gain- and loss-of-function approaches revealed that Nrf2 enhances autophagosome formation and autophagic flux in cardiomyocytes. Unexpectedly, while Nrf2 minimally regulated apoptosis, it suppressed significantly the proteotoxic necrosis in cardiomyocytes. In addition, Nrf2 attenuated the proteocytotoxicity presumably via enhancing autophagy-mediated clearance of ubiquitinated protein aggregates in cardiomyocytes. Taken together, we demonstrated for the first time that cardiac specific activation of Nrf2 suppresses cardiac maladaptive remodeling and dysfunction most likely by enhancing autophagic clearance of toxic protein aggregates in the heart.
PMCID: PMC4418517  PMID: 24747945
Nrf2; Cardiac dysfunction; Autophagy; Proteinopathy; Necrosis; Oxidative stress
16.  Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis 
Severe acute pancreatitis (SAP) is normally related to multiorgan dysfunction and local complications. Studies have found that local pancreatic renin-angiotensin system (RAS) was significantly upregulated in drug-induced SAP. The present study aimed to investigate the effects of angiotensin II receptors inhibitor valsartan on dual role of RAS in SAP in a rat model and to elucidate the underlying mechanisms. 3.8% sodium taurocholate (1 ml/kg) was injected to the pancreatic capsule in order for pancreatitis induction. Rats in the sham group were injected with normal saline in identical locations. We also investigated the regulation of experimentally induced SAP on local RAS expression in the pancreas through determination of the activities of serum amylase, lipase and myeloperoxidase, histological and biochemical analysis, radioimmunoassay, fluorescence quantitative PCR and Western blot analysis. The results indicated that valsartan could effectively suppress the local RAS to protect against experimental acute pancreatitis through inhibition of microcirculation disturbances and inflammation. The results suggest that pancreatic RAS plays a critical role in the regulation of pancreatic functions and demonstrates application potential as AT1 receptor antagonists. Moreover, other RAS inhibitors could be a new therapeutic target in acute pancreatitis.
PMCID: PMC4499641  PMID: 26170733
ICAM-1; MDA; P-selectin; Renin-angiotensin System; Severe acute pancreatitis
17.  Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy 
British Journal of Pharmacology  2014;171(13):3146-3157.
Recent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose-lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre-activation of AMPK-dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).
Male Sprague-Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3-methyladenine, and were injected with a single dose of metformin (10 mg kg−1, i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later.
A single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3-methyladenine.
These results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well-known hypoglycaemic drug, may have a practical clinical use for stroke prevention.
PMCID: PMC4080970  PMID: 24611741
metformin; autophagy; stroke; preconditioning; AMPK; neuroprotection
18.  Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma*  
Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.
PMCID: PMC4506953  PMID: 26160720
Cluster of differentiation 69 (CD69); Eosinophil; Interleukin-5 (IL-5); Asthma
19.  Diagnosis and treatment of allergic diseases in Zhejiang Province: a cross-sectional survey* #  
Background: The specialty of allergy developed quickly in western countries because of the rapid increase of allergic diseases, whereas it developed relatively slowly in China. The prevalence of allergen sensitization and allergic diseases in Zhejiang Province of China is high and improving the medical services for these diseases is critically needed. Objective: To investigate the working status of the diagnosis and treatment of allergic diseases, including doctor resources, diagnostic methods, and allergen-specific immunotherapy in patients of Zhejiang Province, and to provide instructions for the strategic development of subspecialties of allergic diseases. Methods: First we defined the doctors who treat allergic diseases, and designed a comprehensive questionnaire to collect personal and hospital information for these doctors. The questionnaires were distributed to hospitals with different ranks and from different areas in the province. The general condition of doctor’s resources, carryout of diagnostic methods, and allergen-specific immunotherapy were described and variations in the different specialties, hospitals, and areas were further analyzed. Results: Doctors in their thirties with bachelor’s degrees were the mainstream for diagnosing and treating allergic diseases. The main specialties of the doctor resources were the specialties of Ear, Nose and Throat (ENT), Respirology, Pediatrics, and Dermatology. The Pediatrics specialty had a more reasonable infrastructure of doctor resources with more young doctors working in this subspecialty. The development of allergy subspecialty varied within hospitals at different levels or from different areas. The carryout of the skin prick test (SPT), serum specific IgE (ssIgE), and subcutaneous immunotherapy (SCIT) was best performed in provincial hospitals, while sublingual immunotherapy (SLIT) was prescribed most commonly in municipal hospitals. The performance of SPT and ssIgE in Hangzhou, Jiaxing, and Wenzhou areas was much better than that in other places. The performance of SCIT and SLIT was best in Wenzhou. Conclusions: Our survey revealed a very initial and unbalanced development for the allergy subspecialty in Zhejiang Province. Doctor resources for allergic diseases were mainly from the specialties of ENT, Respirology, and Pediatrics, and the performance of diagnosis and treatment was mainly focused on provincial and municipal hospitals. Continuous education of allergies could be extended to primary healthcare centers and more efforts should be directed to those areas with poor medical resources.
PMCID: PMC4506955  PMID: 26160722
Allergy; Diagnosis; Treatment; Allergen-specific immunotherapy
20.  Simulation Analysis on Photoelectric Conversion Characteristics of Silicon Nanowire Array Photoelectrodes 
Semiconductor nanowire photoelectrochemical cells have attracted extensive attention in the light-conversion field owing to the low-cost preparation, excellent optical absorption, and short distance of carrier collection. Although there are numbers of experimental investigations to improve the device performance, the understanding of the detailed process of photoelectric conversion needs to be further improved. In this work, a thorough optoelectronic simulation is employed to figure out how the nanowire diameter, doping concentration, and illumination wavelength affect the photoelectric conversion characteristics of the silicon nanowire array photoelectrodes. We find that two balances should be carefully weighted between optical absorption and photogenerated-carrier collection, along with between short-circuit photocurrent density and open-circuit voltage. For the small-diameter nanowire array photoelectrodes, the overall absorption is higher than that of the larger-diameter ones with the most contribution from the nanowires. However, the substrate shows increasing absorption with increasing illumination wavelength. Higher doping density leads to a larger open-circuit voltage; while lower doping density can guarantee a relatively higher short-circuit photocurrent. To obtain high-light-conversion-efficiency photoelectrodes, the doping density should be carefully chosen with considerations of illumination wavelength and surface recombination. Suppressing the surface recombination velocity can effectively enhance the short-circuit photocurrent (open-circuit voltage) for the lightly (heavily) doped nanowire array photoelectrodes. Our systematical results provide a theoretical guidance for the photoelectrochemical devices based on semiconductor nanostructures.
PMCID: PMC4485660  PMID: 26123274
Si nanowire; Photoelectrode; Simulation; Conversion efficiency
21.  Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells 
Leukemia  2013;27(11):2177-2186.
The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 4 lysine 3 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in NF-kB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrated that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-kB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals play a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
PMCID: PMC4476310  PMID: 23538751
myelodysplastic syndromes; H3K4me3; CHIP-Seq; JMJD3; innate immunity
22.  The MicroRNA-217 Functions as a Potential Tumor Suppressor in Gastric Cancer by Targeting GPC5 
PLoS ONE  2015;10(6):e0125474.
Gastric cancer (GC) is one of the most common malignancies worldwide. Emerging evidence has shown that aberrant expression of microRNAs (miRNAs) plays important roles in cancer progression. However, little is known about the potential role of miR-217 in GC. In this study, we investigated the role of miR-217 on GC cell proliferation and invasion. The expression of miR-217 was down-regulated in GC cells and human GC tissues. Enforced expression of miR-217 inhibited GC cells proliferation and invasion. Moreover, Glypican-5 (GPC5), a new ocncogene, was identified as the potential target of miR-217. In addition, overexpression of miR-217 impaired GPC5-induced promotion of proliferation and invasion in GC cells. In conclusion, these findings revealed that miR-217 functioned as a tumor suppressor and inhibited the proliferation and invasion of GC cells by targeting GPC5, which might consequently serve as a therapeutic target for GC patients.
PMCID: PMC4476558  PMID: 26098560
23.  Effect of H. pylori Infection on Cytokine Profiles and Oxidative Balance in Subjects with Chronic Alcohol Ingestion 
PLoS ONE  2015;10(6):e0129352.
Different amounts of ingested alcohol can have distinct effects on the human body. However, there is limited research on chronic alcohol consumption with Helicobacter pylori infection. We sought to investigate the relationship between the cytokine profile, oxidative balance and H. pylori infection in subjects with chronic alcohol consumption. A total of 142 subjects were divided into three groups: 59 subjects with chronic alcohol ingestion and H. pylori infection (group A); 53 subjects with chronic alcohol ingestion without H. pylori infection (group B); and 30 control subjects (group C). The serum levels of CagA, interleukin (IL)-10, E-selectin, TNF-α, malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured by enzyme-linked immunosorbent assay (ELISA). We found that the ages and serum H. pylori CagA levels among the three groups, as well as both the mean drinking age and the mean daily alcohol consumption between groups A and B, were matched and comparable. Comparing the BMIs among the three groups, the BMI differences were found to be statistically significant (F=3.921, P<0.05). Compared with group C, the BMIs in groups A and B were significantly higher (P<0.001 and P<0.01, respectively); however, the BMI differences between group A and group B were not statistically significant (P>0.05). Additionally, no differences in the serum CagA levels were found in comparisons among the groups (all P>0.05). The serum IL-10 and E-selectin levels in group A were significantly lower than those in group B (serum IL-10: P<0.05; E-selectin: P<0.05). The serum IL-10 in group A was significantly higher than that in group C (P<0.01); the serum E-selectin levels in group A did not significantly differ compared with those in group C (P>0.05). Furthermore, the serum IL-10 and E-selectin levels in group B were significantly higher than those in group C (serum IL-10: P<0.001; E-selectin: P<0.05); however, the serum TNF-α levels did not differ among groups (all P>0.05). Although the serum levels of MDA and SOD in groups A and B were slightly lower than those in group C, there were no significant differences among groups (all P>0.05). In conclusion, we believe that H. pylori infection might cause a significant inhibition of certain cytokine profiles in subjects with chronic alcohol ingestion. Moreover, chronically ingested alcohol may exert an adjusted inflammatory effect, but there was no association between H. pylori infection, chronic alcohol consumption and oxidative balance.
PMCID: PMC4472927  PMID: 26087062
24.  Control of Protein Activity and Cell Fate Specification via Light-Mediated Nuclear Translocation 
PLoS ONE  2015;10(6):e0128443.
Light-activatable proteins allow precise spatial and temporal control of biological processes in living cells and animals. Several approaches have been developed for controlling protein localization with light, including the conditional inhibition of a nuclear localization signal (NLS) with the Light Oxygen Voltage (AsLOV2) domain of phototropin 1 from Avena sativa. In the dark, the switch adopts a closed conformation that sterically blocks the NLS motif. Upon activation with blue light the C-terminus of the protein unfolds, freeing the NLS to direct the protein to the nucleus. A previous study showed that this approach can be used to control the localization and activity of proteins in mammalian tissue culture cells. Here, we extend this result by characterizing the binding properties of a LOV/NLS switch and demonstrating that it can be used to control gene transcription in yeast. Additionally, we show that the switch, referred to as LANS (light-activated nuclear shuttle), functions in the C. elegans embryo and allows for control of nuclear localization in individual cells. By inserting LANS into the C. elegans lin-1 locus using Cas9-triggered homologous recombination, we demonstrated control of cell fate via light-dependent manipulation of a native transcription factor. We conclude that LANS can be a valuable experimental method for spatial and temporal control of nuclear localization in vivo.
PMCID: PMC4471001  PMID: 26083500

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