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Benencia F.,Heritage University | Benencia F.,U.S. National Institutes of Health | Harshman S.,Edison Biotechnology Institute | Harshman S.,Ohio University | And 17 more authors.
Endocrinology | Year: 2015

White adipose tissue (WAT) is composed of mature adipocytes and a stromal vascular fraction (SVF), which contains a variety of cells, includingimmunecells that varyamongthe differentWATdepots. Growth hormone (GH) impacts immune function and adiposity in an adipose depot-specific manner. However, its effects onWATimmune cell populations remain unstudied. BovineGHtransgenic (bGH) mice are commonly used to study the in vivo effects of GH. These giant mice have an excess of GH action, impaired glucose metabolism, decreased adiposity, increased lean mass, and a shortened lifespan. Therefore, the purpose of this study was to characterize the WAT depot-specific differences inimmunecell populations in the presence of excessGHin vivo. ThreeWATdepotswere assessed: inguinal (sc), epididymal (EPI), and mesenteric (MES). Subcutaneous and MES bGH WAT depots showed a significantly higher number of total SVF cells, yet only MES bGH WAT had higher leukocyte counts compared with control samples. By means of flow cytometry analysis of the SVF, we detected greater macrophage and regulatory T-cell infiltration in sc and MES bGH WAT depots compared with controls. However, no differences were observed in the EPI WAT depot. RNAsequencing confirmed significant alterations in pathways related to T-cell infiltration and activation in the sc depot with fewer significant changes in the EPI bGH WAT depot. These findings collectively point to a previously unrecognized role for GH in influencing the distribution of WAT immune cell populations in a depot-specific manner. Copyright © 2015 by the Endocrine Society.


Wang L.,Edison Biotechnology Institute | Liu W.,Edison Biotechnology Institute | Liu W.,Ohio University | Parker S.H.,Edison Biotechnology Institute | And 2 more authors.
Life Sciences | Year: 2010

Aims: To investigate the role of nitric oxide synthase (NOS) and intracellular free zinc ion (Zn2+) in regulation of ultraviolet B light (UVB)-induced cell damage and apoptosis. Main methods: Real-time confocal microscopy measurement was used to determine the changes of intracellular free zinc concentration under different conditions. Cell apoptotic death was determined using fluorescein isothiocyanate (FITC) conjugated-annexin V (ANX5)/PI labeling followed by flow cytometry. Western analysis was used to determine cell apoptosis and eNOS uncoupling. Key findings: UVB induced an elevation of Zn2+ within 2min of exposure. The UVB-induced intracellular Zn2+ elevation was dependent on the increase of constitutive nitric oxide synthase (cNOS) activity and production of superoxide. Removal of Zn2+ with a lower concentration (<25μM) of N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, did not induce cell death or prevent cells from UVB-induced apoptosis. However, a higher [TPEN] (>50μM) was cytotoxic to cells, but prevented cells from further UVB-induced apoptosis. The higher [TPEN] also induced cNOS uncoupling. Furthermore, treating the cells with a membrane permeable superoxide dismutase (PEG-SOD) inhibited Zn2+ release and reduced apoptotic cell death after UVB treatment. The results demonstrated a complex and dynamic regulation of UVB-induced cell damage. Significance: Our findings not only advance our understanding of the correlations between cNOS activation and Zn elevation, but also elucidated the role of cNOS in regulation of oxidative stress and apoptosis upon UVB-irradiation. © 2010.


Suzuki K.,Japan National Institute of Infectious Diseases | Suzuki K.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Suzuki K.,MedStar Research Institute | Wu H.,Japan National Institute of Infectious Diseases | And 8 more authors.
Biochemical and Biophysical Research Communications | Year: 2010

Although it is well known that an excess of iodide suppresses thyroid function and blood flow in vivo, the underlying molecular mechanisms are not fully known. The functional effect of iodide occurs at multiple steps, which include inhibition of sodium/iodide symporter (NIS) expression, transient block of organification, and inhibition of hormonal release. The vascular effect likely involves suppression of the vascular endothelial growth factor (VEGF) gene. In this report, we show that excess iodide coordinately suppresses the expression of the NIS and VEGF genes in FRTL-5 thyroid cells. We also demonstrate that the mechanism of iodide suppression of NIS gene expression is transcriptional, which is synergized by the addition of thyroglobulin. Based on the findings of reporter gene assays and electrophoretic gel mobility shift analysis, we also report two novel DNA binding proteins that responded specifically to iodide and modulated NIS promoter activity. The results suggest that excess iodide affects thyroid vascular function in addition to iodide uptake. This study provides additional insights into the mechanism of action of excess iodide on thyroid function. © 2010 Elsevier Inc. All rights reserved.


PubMed | Edison Biotechnology Institute, Ohio University, Medical University of Lódz, Polish Academy of Sciences and University of Illinois at Springfield
Type: Journal Article | Journal: The journals of gerontology. Series A, Biological sciences and medical sciences | Year: 2014

Apoptosis is a process that affects life span and health. Mice with liver-specific disruption of the growth hormone receptor (GHR) gene (ie, Ghr gene) liver-specific growth hormone receptor knockout [LiGHRKO] mice), as opposed to mice with global deletion of the Ghr gene (GHRKO; Ghr-/-), are characterized by severe hepatic steatosis and lack of improved insulin sensitivity. We have previously shown that levels of proapoptotic factors are decreased in long-lived and insulin-sensitive GHRKO mice. In the current study, expression of specific apoptosis-related genes was assessed in brains, kidneys, and livers of male and female LiGHRKO and wild-type mice using real-time PCR. In the brain, expression of Caspase 3, Caspase 9, Smac/DIABLO, and p53 was decreased in females compared with males. Renal expression of Caspase 3 and Noxa also decreased in female mice. In the liver, no differences were seen between males and females. Also, no significant genotype effects were detected in the examined organs. Lack of significant genotype effect in kidneys contrasts with previous observations in GHRKO mice. Apparently, global GHR deletion induces beneficial changes in apoptotic factors, whereas liver-specific GHR disruption does not. Furthermore, sexual dimorphism may play an important role in regulating apoptosis during liver-specific suppression of the somatotrophic signaling.


Chen X.,Ohio University | Qian Y.,Ohio University | Wu S.,Ohio University | Wu S.,Edison Biotechnology Institute
Free Radical Biology and Medicine | Year: 2015

Metabolic reprogramming and altered bioenergetics have emerged as hallmarks of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless of the oxygen supply, a phenomenon called the Warburg effect, is a major focuses of the research. Warburg speculated that cancer cells, due to defective mitochondrial oxidative phosphorylation (OXPHOS), switch to glycolysis for ATP synthesis, even in the presence of oxygen. Studies in the recent decade indicated that while glycolysis is indeed drastically upregulated in almost all cancer cells, mitochondrial respiration continues to operate normally at rates proportional to oxygen supply. There is no OXPHOS-to-glycolysis switch but rather upregulation of glycolysis. Furthermore, upregulated glycolysis appears to be for synthesis of biomass and reducing equivalents in addition to ATP production. The new finding that a significant amount of glycolytic intermediates is diverted to the pentose phosphate pathway (PPP) for production of NADPH has profound implications in how cancer cells use the Warburg effect to cope with reactive oxygen species (ROS) generation and oxidative stress, opening the door for anticancer interventions taking advantage of this. Recent findings in the Warburg effect and its relationship with ROS and oxidative stress controls will be reviewed. Cancer treatment strategies based on these new findings will be presented and discussed.


Sustarsic E.G.,Edison Biotechnology Institute | Sustarsic E.G.,Ohio University | Junnila R.K.,Edison Biotechnology Institute | Kopchick J.J.,Edison Biotechnology Institute | Kopchick J.J.,Ohio University
Biochemical and Biophysical Research Communications | Year: 2013

Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute's NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on this data, GH could be a new therapeutic target in melanoma. © 2013 Elsevier Inc. All rights reserved.


PubMed | Chongqing University and Edison Biotechnology Institute
Type: | Journal: Molecular carcinogenesis | Year: 2016

UV induces CIRP expression and subsequent Stat3 activation, but the biological function and mechanism of CIRP and Stat3 in mediating UVB-induced skin carcinogenesis have not been fully elucidated. In this study, we demonstrate that CIRP is elevated in all tested melanoma and non-melanoma skin cancer cell lines; and the expression of CIRP is upregulated in keratinocytes after being irradiated with relatively low dose (<5mJ/cm


Yang T.,Edison Biotechnology Institute | Householder L.A.,Edison Biotechnology Institute | Lubbers E.R.,Edison Biotechnology Institute | List E.O.,Edison Biotechnology Institute | And 5 more authors.
Endocrinology | Year: 2015

Reduced GH levels have been associated with improved glucose metabolism and increased longevity despite obesity in multiple mouse lines. However, one mouse line, the GH receptor antagonist (GHA) transgenic mouse, defies this trend because it has reduced GH action and increased adiposity, but glucose metabolism and life span are similar to controls. Slight differences in glucose metabolism and adiposity profiles can become exaggerated on a high-fat (HF) diet. Thus, in this study, male and female GHA and wild-type (WT) mice in a C57BL/6 background were placed on HF and low-fat (LF) diets for 11 weeks, starting at 10 weeks of age, to assess how GHA mice respond to additional metabolic stress of HF feeding. On a HF diet, all mice showed significant weight gain, although GHA gained weight more dramatically than WT mice, with males gaining more than females. Most of this weight gain was due to an increase in fat mass with WT mice increasing primarily in the white adipose tissue perigonadal depots, whereas GHA mice gained in both the sc and perigonadal white adipose tissue regions. Notably, GHA mice were somewhat protected from detrimental glucose metabolism changes on a HF diet because they had only modest increases in serum glucose levels, remained glucose tolerant, and did not develop hyperinsulinemia. Sex differences were observed in many measures with males reacting more dramatically to both a reduction inGHaction andHFdiet. In conclusion, our findingsshowthatGHAmice, which are already obese, are susceptible to further adipose tissue expansion with HF feeding while remaining resilient to alterations in glucose homeostasis.. Copyright © 2015 by the Endocrine Society.


Tong L.,Edison Biotechnology Institute | Wu S.,Edison Biotechnology Institute
Journal of Biological Chemistry | Year: 2014

Background: Early activation of NF-κB upon UVB irradiation is through a noncanonical eIF2-dependent IκB reduction pathway.Results: Inhibition of constitutive nitric-oxide synthase inhibited UVB-induced NF-κB activation.Conclusion: Constitutive nitric-oxide synthase is required for NF-κB activation.Significance: Learning the regulation of NF-κB upon UVB irradiation is critical for understanding the initiation and development of UVB-induced tumorigenesis. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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