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1.  Using expert decision-making to establish indicators of urban friendliness for walking environments: a multidisciplinary assessment 
Numerous studies have suggested that friendly walking environments positively affect physical activity and health. Creating friendly walking environments in urban areas is a complex and wide-ranging topic, and no study has yet established a set of assessment indicators by drawing on the expertise of various disciplines. This study uses a multiple-criteria decision-making technique to elucidate the environmental factors that affect the friendliness of the walking environment.
We conducted a two-phase expert questionnaire survey. Experts from the government sector, as well as the academic disciplines of urban planning, transportation, architecture, and landscape design, were recruited to establish a set of walking environment indicators; the degrees of importance assigned to these indicators by the experts were subsequently compared. In phase 1, the fuzzy Delphi method was used by 20 experts, whose responses were used to identify four dimensions and 22 indicators. In phase 2, an analytical network process approach was performed by 16 experts to determine the weights of the dimensions and indicators.
The results revealed that all of the experts ranked the four dimensions in the order of safety > facilities > aesthetics > land use mix. Of the 22 indicators, land use–diversity, land use–access, sidewalk width, sidewalk continuity, and cleanliness were considered the most important.
The results provide a reference for the management of walking environments by promoting pedestrian-oriented environments and public health.
Electronic supplementary material
The online version of this article (doi:10.1186/s12942-016-0071-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5111263  PMID: 27846889
Multiple-criteria decision-making; Fuzzy Delphi method (FDM); Analytic network process (ANP); Public health
2.  miR-512-5p Suppresses Tumor Growth by Targeting hTERT in Telomerase Positive Head and Neck Squamous Cell Carcinoma In Vitro and In Vivo 
PLoS ONE  2015;10(8):e0135265.
Telomerase activation has very important implications for head and neck squamous cell carcinoma (HNSCC), but the regulatory mechanisms of telomerase in HNSCC remain unclear. In our present study, we found that miR-512-5P was markedly downregulated in telomerase-positive HNSCC cell lines. Both in vitro and in vivo assays revealed that miR-512-5P mimic attenuated HNSCC cell proliferation, and tumor growth in nude mice, which exerts its tumor suppressor function through elevated apoptosis, inhibition of the telomerase activity, decrease of telomere-binding proteins and shortening of telomere length by human telomerase reverse transcriptase (hTERT) downregulation. Furthermore, the dual-luciferase reporter gene assay results demonstrated that hTERT was a direct target of miR-512-5P. We conclude that the frequently miR-512-5P overexpression can regulate hTERT and function as a tumor suppressor in HNSCC. Therefore, miR-512-5P may serve as a potential therapeutic agent for miR-based HNSCC therapy.
PMCID: PMC4530866  PMID: 26258591
3.  Broadly protective immunity against divergent influenza viruses by oral co-administration of Lactococcus lactis expressing nucleoprotein adjuvanted with cholera toxin B subunit in mice 
Current influenza vaccines need to be annually reformulated to well match the predicated circulating strains. Thus, it is critical for developing a novel universal influenza vaccine that would be able to confer cross-protection against constantly emerging divergent influenza virus strains. Influenza virus A is a genus of the Orthomyxoviridae family of viruses. Influenza virus nucleoprotein (NP) is a structural protein which encapsidates the negative strand viral RNA, and anti-NP antibodies play role in cross-protective immunity. Lactococcus lactis (L. lactis) is an ideal vaccine delivery vehicle via oral administration route. However, L. lactis vectored vaccine exhibits poor immunogenicity without the use of mucosal adjuvant. To enhance the immunogenicity of L. lactis vectored vaccine, cholera toxin B (CTB) subunit, one of mucosal adjuvants, is a safe adjuvant for oral route, when combined with L. lactis vectored vaccine. In this study, we hypothesized that pNZ8008, a L. lactis expression plasmid, encoding NP antigen, would be able to elicit cross-protection with the use of CTB via oral administration route.
To construct L. lactis vectored vaccine, nucleoprotein (NP) gene of A/California/04/2009(H1N1) was sub-cloned into a L. lactis expression plasmid, pNZ8008. The expression of recombinant L. lactis/pNZ8008-NP was confirmed by Western blot, immunofluorescence assay and flow cytometric analysis. Further, immunogenicity of L. lactis/pNZ8008-NP alone or adjuvanted with cholera toxin B (CTB) subunit was evaluated in a mouse model via oral administration route. Antibodies responses were detected by ELISA. The result indicated that oral administration of L. lactis/pNZ8008-NP adjuvanted with CTB could elicit significant humoral and mucosal immune responses, as well as cellular immune response, compared with L. lactis/pNZ8008-NP alone. To further assess the cross-protective immunity of L. lactis/pNZ8008-NP adjuvanted with CTB, we used L. lactis/pNZ8110-pgsA-HA1 alone or adjuvanted with CTB as controls. Mice that received L. lactis/pNZ8008-NP adjuvanted with CTB were completely protected from homologous H1N1 virus and showed 80% protection against heterologous H3N2 or H5N1 virus, respectively. By contrast, L. lactis/pNZ8110-pgsA-HA1 adjuvanted with CTB also conferred 100% protection against H5N1 virus infection, but indicated no cross-protection against H1N1 or H5N1 virus challenge. As controls, mice vaccinated orally with L. lactis/pNZ8008-NP alone or L. lactis/pNZ8110-pgsA-HA1 alone could not survive.
This study is the first to report the construction of recombinant L. lactis/pNZ8008-NP and investigate its immunogenicity with the use of CTB. Compared with L. lactis/pNZ8110-pgsA-HA1 adjuvanted with CTB, our data support 5 × 1011 CFU of L. lactis/pNZ8008-NP adjuvanted with 1 µg of CTB is a better combination for universal influenza vaccines development that would provide cross-protective immunity against divergent influenza A viruses.
PMCID: PMC4524015  PMID: 26242406
L. lactis/pNZ8008-NP adjuvanted with CTB; Cross-protective immunity; Influenza A viruses
4.  Expression of human protection of telomere 1 correlates with telomere length and radiosensitivity in the human laryngeal cancer Hep-2 cell line 
Oncology Letters  2015;10(2):1149-1154.
The close association between telomere length and radiosensitivity has been established by several studies. There is also a hypothesis that telomere length may be regulated by human protection of telomere 1 (hPOT1) in human carcinoma cells. In the present study, the hPOT1 level between the radioresistant Hep-2R cells and the wild-type were compared, and the results showed that the hPOT1 gene was upregulated in the radioresistant Hep-2R cell lines compared with the wild-type. This suggested that the expression level of hPOT1 correlates with radiosensitivity. Additionally, an hPOT1-directed short hairpin (sh)RNA plasmid was constructed and transferred into the Hep-2R cells, which lead to telomere shortening, an increase in apoptosis and markedly decreased growth of the RNAi-Hep-2R cell line. These results demonstrate that hPOT1-directed shRNAs are associated with telomere length and radiosensitivity, and maybe a potent sensitizer for laryngeal cancer radiotherapy.
PMCID: PMC4509373  PMID: 26622642
telomere; radiosensitivity; hPOT1; telomere dysfunction
5.  Protective immunity against influenza H5N1 virus challenge in chickens by oral administration of recombinant Lactococcus lactis expressing neuraminidase 
Highly pathogenic H5N1 avian influenza viruses pose a debilitating pandemic threat in poultry. Current influenza vaccines predominantly focus on hemagglutinin (HA) which anti-HA antibodies are often neutralizing, and are used routinely to assess vaccine immunogenicity. However, Neuraminidase (NA), the other major glycoprotein on the surface of the influenza virus, has historically served as the target for antiviral drug therapy and is much less studied in the context of humoral immunity. The aim of this study was to evaluate the protective immunity of NA based on Lactococcus lactis (L.lactis) expression system against homologous H5N1 virus challenge in a chicken model.
L.lactis/pNZ2103-NA which NA is derived from A/Vietnam/1203/2004 (H5N1) (VN/1203/04) was constructed based on L.lactis constitutive expression system in this study. Chickens vaccinated orally with 1012 colony-forming unit (CFU) of L.lactis/pNZ2103-NA could elicit significant NA-specific serum IgG and mucosa IgA antibodies, as well as neuraminidase inhibition (NI) titer compared with chickens administered orally with saline or L.lactis/pNZ2103 control. Most importantly, the results revealed that chickens administered orally with L.lactis/pNZ2103-NA were completely protected from a lethal H5N1 virus challenge.
The data obtained in the present study indicate that recombinant L.lactis/pNZ2103-NA in the absence of adjuvant can be considered an effective mucosal vaccine against H5N1 infection in chickens via oral administration. Further, these findings support that recombinant L.lactis/pNZ2103-NA can be used to perform mass vaccination in poultry during A/H5N1 pandemic.
PMCID: PMC4389297  PMID: 25880824
L.lactis/pNZ2103-NA; H5N1 virus; Protective immunity
6.  Expression of various protection of telomeres 1 variants is associated with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells in vitro 
Biomedical Reports  2015;3(3):420-424.
Protection of telomeres 1 (POT1) is a telomere-binding protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Different POT1 mRNA variants were examined and compared with telomere length and radiosensitivity in colon and gastric adenocarcinoma cells. POT1 production and telomere lengths were assessed using 10 human cancer cell lines by quantitative polymerase chain reaction (qPCR). POT1 mRNA levels, which were relatively stable, were significantly correlated with telomere length in gastric cancer cells and colon cancer cells, except for HT29 (P<0.01). POT1 v5 indexes were closely associated with radiosensitivity in colon cancer cells and gastric cancer cells (P<0.05). In conclusion, POT1 may be a good marker for the examination of cell-specific telomere length and radiosensitivity.
PMCID: PMC4467277  PMID: 26137248
protection of telomeres 1 variant; telomere length; radiosensitivity; chromosome protection
7.  Lack of an Association between Angiotensin Receptor Blocker Based Therapy and Increased Risk of Cancer: Evidence from Large Observational Studies 
PLoS ONE  2015;10(3):e0119775.
A previous meta-analysis of randomized controlled studies that were not designed to investigate cancer as a primary outcome suggested that ARB-based therapy is associated with increased risk of cancer; however, results of recent observational studies considering the association have been contradictory. This study sought to evaluate the association between angiotensin receptor blocker (ARB)-based therapy and risk of cancer by conducting a meta-analysis of observational studies.
Relevant articles published before February 2014 were identified by searching PubMed and the Cochrane Library. Pooled relative risks (RRs) were determined using a random effects model and were used to assess the strength of association between use of ARB-based therapy and risk of cancer.
Six retrospective cohort studies involving a total of 3,827,109 participants and four case-control studies involving a total of 193,029 cases were included. The present study found that ARB-based therapy was not significantly associated with an increased risk of cancer (RR = 0.87, 95%CI: [0.75, 1.01]). However, an analysis including only cohort studies suggested a significantly decreased risk of cancer among individuals with any history of ARB use as compared to those with no history of ARB use (RR = 0.80, 95%CI: [0.55, 0.95]); no significant association was found between ARB use and risk of cancer when the case-control studies were separately considered (RR = 1.03, 95%CI: [0.93, 1.13]). Subgroup analyses showed that use of ARB-based therapy was associated with decreased risk of lung cancer (RR = 0.81, 95%CI: [0.69, 0.94]); however, no significant associations were found with the other cancer sites investigated. Furthermore, no association was observed upon adjustment by type of ARB drug. No publication bias was detected.
Overall, ARB-based therapy was not associated with increased risk of cancer. However, its use may be related to decreased incidence of lung cancer; this finding should be considered carefully and confirmed with further studies.
PMCID: PMC4366349  PMID: 25790107
8.  Effects of miR-33a-5P on ABCA1/G1-Mediated Cholesterol Efflux under Inflammatory Stress in THP-1 Macrophages 
PLoS ONE  2014;9(10):e109722.
The present study is to investigate whether inflammatory cytokines inhibit ABCA1/ABCG1-mediated cholesterol efflux by regulating miR-33a-5P in THP-1 macrophages. We used interleukin-6 and tumor necrosis factor-alpha in the presence or absence of native low density lipoprotein (LDL) to stimulate THP-1 macrophages. THP-1 macrophages were infected by either control lentivirus vectors or lentivirus encoding miR-33a-5P or antisense miR-33a-5P. The effects of inflammatory cytokines, miR-33a-5P and antisense miR-33a-5P on intracellular lipids accumulation and intracellular cholesterol contents were assessed by oil red O staining and quantitative intracellular cholesterol assay. ApoA-I-mediated cholesterol efflux was examined using the fluorescent sterol (BODIPY-cholesterol). The gene and protein expressions of the molecules involved in cholesterol trafficking were examined using quantitative real-time polymerase chain reaction and Western blotting. Inflammatory cytokines or miR-33a-5P increased intracellular lipid accumulation and decreased apoA-I-mediated cholesterol efflux via decreasing the expression of ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. However, antisense miR-33a-5P reversed the effects of inflammatory cytokines on intracellular lipid accumulation, cholesterol efflux, and the expression of miR-33a-5P, ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. This study indicated that inflammatory cytokines inhibited ABCA1/ABCG1-mediated cholesterol efflux by up-regulating miR-33a-5P in THP-1 macrophages.
PMCID: PMC4201478  PMID: 25329888
9.  Pre-B Cell Colony Enhancing Factor (PBEF), a Cytokine with Multiple Physiological Functions 
Cytokine & growth factor reviews  2013;24(5):433-442.
Pre-B cell colony enhancing factor (PBEF) is regarded as a proinflammatory cytokine. Named for its first discovered function as a pre-B cell colony enhancing factor, it has since been found to have many other functions relating to cell metabolism, inflammation, and immune modulation. It has also been found to have intracellular and extracellular forms, with the two overlapping in function. Most of the intracellular functions of PBEF are due to its role as a nicotinamide phosphoribosyltransferase (Nampt). It has been found in human endothelial cells, where it is able to induce angiogenesis through upregulation of VEGF and VEGFR and secretion of MCP-1. In human umbilical endothelial cells, PBEF increases levels of the protease MMP 2/9. PBEF has also been found in a variety of immune cells other than B cells and has been shown to inhibit apoptosis of macrophages. Extracellular PBEF has been shown to increase inflammatory cytokines, such as TNF-α, IL-1β, IL-16, and TGF-β1, and the chemokine receptor CCR3. PBEF also increases the production of IL-6, TNF-α, and IL-1β in CD14+ monocyctes, macrophages, and dendritic cells, enhances the effectiveness of T cells, and is vital to the development of both B and T lymphocytes. The purpose of this review is to summarize the recent advances in PBEF research.
PMCID: PMC3791181  PMID: 23787158
pre-B cell enhancing factor; cytokine; chemikine; monocyte; B lymphocyte; T lymphocyte
10.  Effects of lentiviral infection of mesenchymal stem cells on the expression of octamer transcription factor 4 
Molecular Medicine Reports  2014;10(5):2249-2254.
The present study aimed to investigate the effects of lentiviral infection of human umbilical cord mesenchymal stem cells (hUCMSCs) on the expression of octamer transcription factor 4 (Oct4). hUCMSCs were infected with lentivirus carrying the green fluorescent protein gene (GFP) at different multiplicities of infection (MOI), and the optimal MOI was determined by flow cytometry; the proliferation of non-infected and GFP-carrying lentivirus-infected hUCMSCs was evaluated by the MTT assay; and the expression of the Oct4 gene was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence staining in hUCMSCs cultured in vitro for eight weeks. Positive GFP staining of hUCMSCs was estimated at >75% at 48 h following infection with the GFP-carrying lentivirus (MOI = 20); no effect on hUCMSC proliferation was detected by the MTT assay following the infection; immunofluorescence analysis detected positive Oct4 expression in the cell nuclei at two and eight weeks of culture, while the relative expression of Oct4 assessed by qRT-PCR was 0.9075±0.0124. The GFP gene carried by the lentivirus was successfully expressed in hUCMSCs and had no significant effect on Oct4 expression, which lays a solid foundation for future studies investigating gene functions via the use of exogenous markers.
PMCID: PMC4199401  PMID: 25174942
green fluorescent protein; lentivirus; human umbilical cord mesenchymal stem cells; octamer transcription factor 4
11.  Characterization of Zebrafish Pax1b and Pax9 in Fin Bud Development 
BioMed Research International  2014;2014:309385.
Both Pax1 and Pax9 belong to the important paired box gene family (PAX), which mainly participates in animal development and sclerotome differentiation. To date, the precise molecular mechanism and related signaling pathway of Pax1 remain unclear. In our study, microinjection of morpholino- (MO-) modified antisense oligonucleotides against pax1b induced pectoral fin bud defects. Furthermore, we demonstrate that the phenotypes caused by the knockdown of Pax1b in zebrafish could not be phenocopied by pax9 MO and could not be rescued by either Pax1a or Pax9 overexpression. We further find that Pax1b affects the expression of col2a1, Uncx4.1, Noggin3, and aggrecan, confirming the role of Pax1b in chondrocyte differentiation and bone maturation. Moreover, we identify an interaction between PAX1 and FOXO1 and find that the interaction was enhanced under hypoxia stress. Together, this evidence for cell death caused by pax1b knockdown provides new insight into the role of the Pax protein family in cell fate determination and tissue specification.
PMCID: PMC4147360  PMID: 25197636
12.  β-Defensin 2 Ameliorates Lung Injury Caused by Pseudomonas Infection and Regulates Proinflammatory and Anti-Inflammatory Cytokines in Rat 
An important member of the defensin family, β-defensin 2, is believed to play an important role in defense against foreign pathogens. In the present study, we constructed lentiviral vectors to express and knockdown β-defensin 2 in rat lungs. The results showed that the infection of β-defensin 2 overexpression lentivirus and β-defensin 2 shRNA effectively increased and suppressed the expression of β-defensin 2 in rat lung, respectively. The overexpression of β-defensin 2 mediated by the lentiviral vector protected lung from infection of Pseudomonas aeruginosa, but shRNA targeting β-defensin 2 aggregated the damage of lung. In addition, we also found that β-defensin 2 overexpression increased basal expression of anti-inflammatory cytokine such as IL-4, IL-10 and IL-13 and decreased levels of proinflammatory cytokines which include IL-1α, IL-1β, IL-5, IL-6, IL-8, IL-18, and TNF-α. Moreover, in the process of cytokine regulation, NF-κB pathway may be involved. Taken together, these data suggest that β-defensin 2 has protective effects against infection of Pseudomonas aeruginosa in rat and plays a role in inflammatory regulation by adjusting cytokine levels.
PMCID: PMC4159799  PMID: 25079443
β-defensin 2; lentiviral vector; shRNA; infection; cytokines; NF-κB
13.  Telomere-Binding Protein TPP1 Modulates Telomere Homeostasis and Confers Radioresistance to Human Colorectal Cancer Cells 
PLoS ONE  2013;8(11):e81034.
Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear.
Principal Findings
In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telomere length in human colorectal cancer cell lines. Moreover, TPP1 overexpression showed lengthened telomere length and a significant decrease of radiosensitivity to X-rays. TPP1 mediated radioresistance was correlated with a decreased apoptosis rate after IR exposure. Furthermore, TPP1 overexpression showed prolonged G2/M arrest mediated by ATM/ATR-Chk1 signal pathway after IR exposure. Moreover, TPP1 overexpression accelerated the repair kinetics of total DNA damage and telomere dysfunction induced by ionizing radiation.
We demonstrated that elevated expressions of TPP1 in human colorectal cancer cells could protect telomere from DNA damage and confer radioresistance. These results suggested that TPP1 may be a potential target in the radiotherapy of colorectal cancer.
PMCID: PMC3834294  PMID: 24260532
14.  Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation 
PLoS ONE  2013;8(10):e75650.
Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation.
PMCID: PMC3797718  PMID: 24146768
15.  Inhibition of UBE2D3 Expression Attenuates Radiosensitivity of MCF-7 Human Breast Cancer Cells by Increasing hTERT Expression and Activity 
PLoS ONE  2013;8(5):e64660.
The known functions of telomerase in tumor cells include replenishing telomeric DNA and maintaining cell immortality. We have previously shown the existence of a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Here we set out to elucidate the molecular mechanisms underlying regulation by telomerase of radiosensitivity in MCF-7 cells. Toward this aim, yeast two-hybrid (Y2H) screening of a human laryngeal squamous cell carcinoma radioresistant (Hep2R) cDNA library was first performed to search for potential hTERT interacting proteins. We identified ubiquitin-conjugating enzyme E2D3 (UBE2D3) as a principle hTERT-interacting protein and validated this association biochemically. ShRNA-mediated inhibition of UBE2D3 expression attenuated MCF-7 radiosensitivity, and induced the accumulation of hTERT and cyclin D1 in these cells. Moreover, down-regulation of UBE2D3 increased hTERT activity and cell proliferation, accelerating G1 to S phase transition in MCF-7 cells. Collectively these findings suggest that UBE2D3 participates in the process of hTERT-mediated radiosensitivity in human breast cancer MCF-7 cells by regulating hTERT and cyclin D1.
PMCID: PMC3669415  PMID: 23741361
16.  Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production 
Age  2010;33(3):261-274.
The purpose of this study was to determine changes in klotho, endothelin (ET) receptors, and superoxide production in kidneys of aged rats and whether these changes are exacerbated in aged rats with cognitive impairment. Twenty aged rats (male, 27 months) were divided into an Old Impaired group (n = 9) and an Old Intact group (n = 11) according to a cognitive function test. A group of 12-month-old rats (n = 10) was used as a Young Intact group. Serum creatinine was increased significantly in the Old Impaired group, suggesting impaired renal function. Aged rats showed glomerulosclerosis and tubulointerstitialfibrosis. These pathological changes were markedly aggravated in the old cognitively impaired than in the old cognitively intact animals. Notably, aged rats demonstrated a significant decrease in klotho protein expression in renal cortex and medulla. Protein expression of IL-6, Nox2, ETa receptors and superoxide production were increased whereas mitochondrial SOD (MnSOD) and ETb receptors expression were decreased in kidneys of the aged rats. Interestingly, these changes were more pronounced in the old impaired than in the old intact rats. In conclusion, the aging-related kidney damage was exacerbated in aged rats with cognitive impairment. Klotho, ETB, and MnSOD were downregulated but ETa, IL-6, Nox2, and superoxide production were upregulated in the aging-related kidney damage. These changes were more pronounced in rats with cognitive impairment.
PMCID: PMC3168600  PMID: 20830528
Aging; Klotho; Glomerusclerosis; ET receptor; Superoxide; Interleukin-6
17.  Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella Typhimurium strain 
Scientific Reports  2012;2:436.
Using bacteria as therapeutic agents against solid tumors is emerging as an area of great potential in the treatment of cancer. Obligate and facultative anaerobic bacteria have been shown to infiltrate the hypoxic regions of solid tumors, thereby reducing their growth rate or causing regression. However, a major challenge for bacterial therapy of cancer with facultative anaerobes is avoiding damage to normal tissues. Consequently the virulence of bacteria must be adequately attenuated for therapeutic use. By placing an essential gene under a hypoxia conditioned promoter, Salmonella Typhimurium strain SL7207 was engineered to survive only in anaerobic conditions (strain YB1) without otherwise affecting its functions. In breast tumor bearing nude mice, YB1 grew within the tumor, retarding its growth, while being rapidly eliminated from normal tissues. YB1 provides a safe bacterial vector for anti-tumor therapies without compromising the other functions or tumor fitness of the bacterium as attenuation methods normally do.
PMCID: PMC3365283  PMID: 22666539
18.  The miR-17-92 cluster regulates FOG-2 expression and inhibits proliferation of mouse embryonic cardiomyocytes 
MicroRNAs (miRNAs) have gradually been recognized as regulators of embryonic development; however, relatively few miRNAs have been identified that regulate cardiac development. A series of recent papers have established an essential role for the miRNA-17-92 (miR-17-92) cluster of miRNAs in the development of the heart. Previous research has shown that the Friend of Gata-2 (FOG-2) is critical for cardiac development. To investigate the possibility that the miR-17-92 cluster regulates FOG-2 expression and inhibits proliferation in mouse embryonic cardiomyocytes we initially used bioinformatics to analyze 3′ untranslated regions (3′UTR) of FOG-2 to predict the potential of miR-17-92 to target it. We used luciferase assays to demonstrate that miR-17-5p and miR-20a of miR-17-92 interact with the predicted target sites in the 3′UTR of FOG-2. Furthermore, RT-PCR and Western blot were used to demonstrate the post-transcriptional regulation of FOG-2 by miR-17-92 in embryonic cardiomyocytes from E12.5-day pregnant C57BL/6J mice. Finally, EdU cell assays together with the FOG-2 rescue strategy were employed to evaluate the effect of proliferation on embryonic cardiomyocytes. We first found that the miR-17-5p and miR-20a of miR-17-92 directly target the 3′UTR of FOG-2 and post-transcriptionally repress the expression of FOG-2. Moreover, our findings demonstrated that over-expression of miR-17-92 may inhibit cell proliferation via post-transcriptional repression of FOG-2 in embryonic cardiomyocytes. These results indicate that the miR-17-92 cluster regulates the expression of FOG-2 protein and suggest that the miR-17-92 cluster might play an important role in heart development.
PMCID: PMC3854259  PMID: 22267003
MicroRNAs; miR-17-92; FOG-2; Proliferation
19.  Evaluation of Oral Immunization with Recombinant Avian Influenza Virus HA1 Displayed on the Lactococcus lactis Surface and Combined with the Mucosal Adjuvant Cholera Toxin Subunit B ▿ 
The development of safe and efficient avian influenza vaccines for human and animal uses is essential for preventing virulent outbreaks and pandemics worldwide. In this study, we constructed a recombinant (pgsA-HA1 gene fusion) Lactococcus lactis strain that expresses and displays the avian influenza virus HA1 antigens on its surface. The vectors were administered by oral delivery with or without the addition of cholera toxin subunit B (CTB). The resulting immune responses were analyzed, and the mice were eventually challenged with lethal doses of H5N1 viruses. Significant titers of hemagglutinin (HA)-specific serum IgG and fecal IgA were detected in the group that also received CTB. Cellular immunities were also shown in both cell proliferation and gamma interferon (IFN-γ) enzyme-linked immunospot (ELISpot) assays. Most importantly, the mice that received the L. lactis pgsA-HA1 strain combined with CTB were completely protected from lethal challenge of the H5N1 virus. These findings support the further development of L. lactis-based avian influenza virus vaccines for human and animal uses.
PMCID: PMC3147322  PMID: 21632890
20.  MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN 
BMC Cancer  2010;10:367.
MicroRNAs (miRNAs) can function as either oncogenes or tumor suppressor genes via regulation of cell proliferation and/or apoptosis. MiR-221 and miR-222 were discovered to induce cell growth and cell cycle progression via direct targeting of p27 and p57 in various human malignancies. However, the roles of miR-221 and miR-222 have not been reported in human gastric cancer. In this study, we examined the impact of miR-221 and miR-222 on human gastric cancer cells, and identified target genes for miR-221 and miR-222 that might mediate their biology.
The human gastric cancer cell line SGC7901 was transfected with AS-miR-221/222 or transduced with pMSCV-miR-221/222 to knockdown or restore expression of miR-221 and miR-222, respectively. The effects of miR-221 and miR-222 were then assessed by cell viability, cell cycle analysis, apoptosis, transwell, and clonogenic assay. Potential target genes were identified by Western blot and luciferase reporter assay.
Upregulation of miR-221 and miR-222 induced the malignant phenotype of SGC7901 cells, whereas knockdown of miR-221 and miR-222 reversed this phenotype via induction of PTEN expression. In addition, knockdonwn of miR-221 and miR-222 inhibited cell growth and invasion and increased the radiosensitivity of SGC7901 cells. Notably, the seed sequence of miR-221 and miR-222 matched the 3'UTR of PTEN, and introducing a PTEN cDNA without the 3'UTR into SGC7901 cells abrogated the miR-221 and miR-222-induced malignant phenotype. PTEN-3'UTR luciferase reporter assay confirmed PTEN as a direct target of miR-221 and miR-222.
These results demonstrate that miR-221 and miR-222 regulate radiosensitivity, and cell growth and invasion of SGC7901 cells, possibly via direct modulation of PTEN expression. Our study suggests that inhibition of miR-221 and miR-222 might form a novel therapeutic strategy for human gastric cancer.
PMCID: PMC2914702  PMID: 20618998

Results 1-20 (20)