Displaying publications 161 - 172 of 172 in total

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  1. A targeted approach to genome-wide studies reveals new genetic associations with central corneal thickness
    Benson MD, Khor CC, Gage PJ, Lehmann OJ
    Mol Vis, 2017;23:952-962.
    PMID: 29296075
    Purpose: To evaluate the ability of a targeted genome-wide association study (GWAS) to identify genes associated with central corneal thickness (CCT).

    Methods: A targeted GWAS was used to investigate whether ten candidate genes with known roles in corneal development were associated with CCT in two Singaporean populations. The single nucleotide polymorphisms (SNPs) within a 500 kb interval encompassing each candidate were analyzed, and in light of the resulting data, members of the Wnt pathway were subsequently screened using similar methodology.

    Results: Variants within the 500 kb interval encompassing three candidate genes, DKK1 (rs1896368, p=1.32×10-3), DKK2 (rs17510449, p=7.34×10-4), and FOXO1 (rs7326616, p=1.56×10-4 and rs4943785, p=1.19×10-3), were statistically significantly associated with CCT in the Singapore Indian population. DKK2 was statistically significantly associated with CCT in a separate Singapore Malaysian population (rs10015200, p=2.26×10-3). Analysis of Wnt signaling pathway genes in each population demonstrated that TCF7L2 (rs3814573, p=1.18×10-3), RYK (rs6763231, p=1.12×10-3 and rs4854785, p=1.11×10-3), and FZD8 (rs640827, p=5.17×10-4) were statistically significantly associated with CCT.

    Conclusions: The targeted GWAS identified four genes (DKK1, DKK2, RYK, and FZD8) with novel associations with CCT and confirmed known associations with two genes, FOXO1 and TCF7L2. All six participate in the Wnt pathway, supporting a broader role for Wnt signaling in regulating the thickness of the cornea. In parallel, this study demonstrated that a hypothesis-driven candidate gene approach can identify associations in existing GWAS data sets.

    Matched MeSH terms: Mice, Inbred C57BL
  2. Fulltext Fucoidan Extracts Ameliorate Acute Colitis
    Lean QY, Eri RD, Fitton JH, Patel RP, Gueven N
    PLoS One, 2015;10(6):e0128453.
    PMID: 26083103 DOI: 10.1371/journal.pone.0128453
    Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent a novel nutraceutical option for the management of IBD.
    Matched MeSH terms: Mice, Inbred C57BL
  3. Fulltext Mesenchymal stem cell-based HSP70 promoter-driven VEGFA induction by resveratrol alleviates elastase-induced emphysema in a mouse model
    Chen YB, Lan YW, Chen LG, Huang TT, Choo KB, Cheng WT, et al.
    Cell Stress Chaperones, 2015 Nov;20(6):979-89.
    PMID: 26243699 DOI: 10.1007/s12192-015-0627-7
    Chronic obstructive pulmonary disease (COPD) is a sustained blockage of the airways due to lung inflammation occurring with chronic bronchitis and/or emphysema. Progression of emphysema may be slowed by vascular endothelial growth factor A (VEGFA), which reduces apoptotic tissue depletion. Previously, authors of the present report demonstrated that cis-resveratrol (c-RSV)-induced heat-shock protein 70 (HSP70) promoter-regulated VEGFA expression promoted neovascularization of genetically modified mesenchymal stem cells (HSP-VEGFA-MSC) in a mouse model of ischemic disease. Here, this same stem cell line was evaluated for its protective capacity to alleviate elastase-induced pulmonary emphysema in mice. Results of this study showed that c-RSV-treatment of HSP-VEGFA-MSC exhibited synergy between HSP70 transcription activity and induced expression of anti-oxidant-related genes when challenged by cigarette smoke extracts. Eight weeks after jugular vein injection of HSP-VEGFA-MSC into mice with elastase-induced pulmonary emphysema followed by c-RSV treatment to induce transgene expression, significant improvement was observed in respiratory functions. Expression of VEGFA, endogenous nuclear factor erythroid 2-related factor (Nrf 2), and manganese superoxide dismutase (MnSOD) was significantly increased in the lung tissues of the c-RSV-treated mice. Histopathologic examination of treated mice revealed gradual but significant abatement of emphysema and restoration of airspace volume. In conclusion, the present investigation demonstrates that c-RSV-regulated VEGFA expression in HSP-VEGFA-MSC significantly improved the therapeutic effects on the treatment of COPD in the mouse, possibly avoiding side effects associated with constitutive VEGFA expression.
    Matched MeSH terms: Mice, Inbred C57BL
  4. Fulltext Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses
    Lean QY, Eri RD, Randall-Demllo S, Sohal SS, Stewart N, Peterson GM, et al.
    PLoS One, 2015;10(7):e0134259.
    PMID: 26218284 DOI: 10.1371/journal.pone.0134259
    Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.
    Matched MeSH terms: Mice, Inbred C57BL
  5. Fulltext Boldine improves endothelial function in diabetic db/db mice through inhibition of angiotensin II-mediated BMP4-oxidative stress cascade
    Lau YS, Tian XY, Mustafa MR, Murugan D, Liu J, Zhang Y, et al.
    Br J Pharmacol, 2013 Nov;170(6):1190-8.
    PMID: 23992296 DOI: 10.1111/bph.12350
    Boldine is a potent natural antioxidant present in the leaves and bark of the Chilean boldo tree. Here we assessed the protective effects of boldine on endothelium in a range of models of diabetes, ex vivo and in vitro.
    Matched MeSH terms: Mice, Inbred C57BL
  6. Early-life citalopram-induced impairments in sexual behavior and the role of androgen receptor
    Soga T, Wong DW, Putteeraj M, Song KP, Parhar IS
    Neuroscience, 2012 Dec 6;225:172-84.
    PMID: 22960312 DOI: 10.1016/j.neuroscience.2012.08.061
    Postnatal treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to affect brain development and the regulation of reproduction in rodent models. The normal masculinization process in the brain requires a transient decrease in serotonin (5-HT) levels in the brain during the second postnatal week. Strict regulation of androgen receptor (AR) and gonadotropin-releasing hormone (GnRH) expression is important to control male reproductive activity. Therefore, this study was designed to examine the effects of a potent SSRI (citalopram) on male sexual behavior and expression levels of AR and GnRH in adult male mice receiving either vehicle or citalopram (10mg/kg) daily during postnatal days 8-21. The citalopram-treated male mice showed altered sexual behavior, specifically a significant reduction in the number of intromissions preceding ejaculation compared with the vehicle-treated mice. The citalopram-treated male mice displayed elevated anxiety-like behavior in an open field test and lower locomotor activity in their home cage during the subjective night. Although there was no change in GnRH and AR mRNA levels in the preoptic area (POA), quantified by real-time polymerase chain reaction, immunostained AR cell numbers in the medial POA were decreased in the citalopram-treated male mice. These results suggest that the early-life inhibition of 5-HT transporters alters the regulation of AR expression in the medial POA, likely causing decreased sexual behavior and altered home cage activity in the subjective night.
    Matched MeSH terms: Mice, Inbred C57BL
  7. Fulltext Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
    Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, et al.
    Stem Cell Res Ther, 2015;6:97.
    PMID: 25986930 DOI: 10.1186/s13287-015-0081-6
    Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs.
    Matched MeSH terms: Mice, Inbred C57BL
  8. Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARδ signaling pathway
    Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, et al.
    Biochem Pharmacol, 2016 09 15;116:51-62.
    PMID: 27449753 DOI: 10.1016/j.bcp.2016.07.013
    Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by paeonol treatment. These beneficial effects of paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
    Matched MeSH terms: Mice, Inbred C57BL
  9. Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119
    Arifin SA, Paternoster S, Carlessi R, Casari I, Ekberg JH, Maffucci T, et al.
    Biochim Biophys Acta Mol Cell Biol Lipids, 2018 09;1863(9):1132-1141.
    PMID: 29883799 DOI: 10.1016/j.bbalip.2018.06.007
    The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119-/- mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119-/- mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55-/- mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable.
    Matched MeSH terms: Mice, Inbred C57BL
  10. Fulltext Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation
    Sakihama H, Lee GR, Chin BY, Csizmadia E, Gallo D, Qi Y, et al.
    Arterioscler Thromb Vasc Biol, 2021 Jun;41(6):1915-1927.
    PMID: 33853347 DOI: 10.1161/ATVBAHA.120.315558
    [Figure: see text].
    Matched MeSH terms: Mice, Inbred C57BL
  11. Fulltext Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation
    Shawish HB, Wong WY, Wong YL, Loh SW, Looi CY, Hassandarvish P, et al.
    PLoS One, 2014;9(6):e100933.
    PMID: 24977407 DOI: 10.1371/journal.pone.0100933
    BACKGROUND: The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity.

    METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.

    CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.

    Matched MeSH terms: Mice, Inbred C57BL
  12. Counterpoint. Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine
    Bhattachary-Chatterjee M, Nath Baral R, Chatterjee SK, Das R, Zeytin H, Chakraborty M, et al.
    Cancer Immunol Immunother, 2000 Jun;49(3):133-41.
    PMID: 10881692
    Anti-idiotype (Id) vaccine therapy has been tested and shown to be effective, in several animal models, for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections. The administration of anti-Id antibodies as surrogate tumor-associated antigens (TAA) also represents another potential application of the concept of the Id network. Limited experience in human trials using anti-Id to stimulate immunity against tumors has shown promising results. In this "counter-point" article, we discuss our own findings showing the potential of anti-Id antibody vaccines to be novel therapeutic approaches to various human cancers and also discuss where anti-Id vaccines may perform better than traditional multiple-epitope antigen vaccines.
    Matched MeSH terms: Mice, Inbred C57BL
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