Publications by authors named "Yanrong Qian"

31 Publications

A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism.

Cancer Metab 2021 Mar 26;9(1):14. Epub 2021 Mar 26.

Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA.

Background: Cancer cells drastically increase the uptake of glucose and glucose metabolism by overexpressing class I glucose transporters (GLUT1-4) to meet their energy and biomass synthesis needs and are very sensitive and vulnerable to glucose deprivation. Although targeting glucose uptake via GLUTs has been an attractive anticancer strategy, the relative anticancer efficacy of multi-GLUT targeting or single GLUT targeting is unclear. Here, we report DRB18, a synthetic small molecule, is a potent anticancer compound whose pan-class I GLUT inhibition is superior to single GLUT targeting.

Methods: Glucose uptake and MTT/resazurin assays were used to measure DRB18's inhibitory activities of glucose transport and cell viability/proliferation in human lung cancer and other cancer cell lines. Four HEK293 cell lines expressing GLUT1-4 individually were used to determine the IC values of DRB18's inhibitory activity of glucose transport. Docking studies were performed to investigate the potential direct interaction of DRB18 with GLUT1-4. Metabolomics analysis was performed to identify metabolite changes in A549 lung cancer cells treated with DRB18. DRB18 was used to treat A549 tumor-bearing nude mice. The GLUT1 gene was knocked out to determine how the KO of the gene affected tumor growth.

Results: DRB18 reduced glucose uptake mediated via each of GLUT1-4 with different ICs, which match with the docking glidescores with a correlation coefficient of 0.858. Metabolomics analysis revealed that DRB18 altered energy-related metabolism in A549 cells by changing the abundance of metabolites in glucose-related pathways in vitro and in vivo. DRB18 eventually led to G1/S phase arrest and increased oxidative stress and necrotic cell death. IP injection of DRB18 in A549 tumor-bearing nude mice at 10 mg/kg body weight thrice a week led to a significant reduction in the tumor volume compared with mock-treated tumors. In contrast, the knockout of the GLUT1 gene did not reduce tumor volume.

Conclusions: DRB18 is a potent pan-class I GLUT inhibitor in vitro and in vivo in cancer cells. Mechanistically, it is likely to bind the outward open conformation of GLUT1-4, reducing tumor growth through inhibiting GLUT1-4-mediated glucose transport and metabolisms. Pan-class I GLUT inhibition is a better strategy than single GLUT targeting for inhibiting tumor growth.
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http://dx.doi.org/10.1186/s40170-021-00248-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004435PMC
March 2021

Natural Compound α-PGG and Its Synthetic Derivative 6Cl-TGQ Alter Insulin Secretion: Evidence for Diminishing Glucose Uptake as a Mechanism.

Diabetes Metab Syndr Obes 2021 24;14:759-772. Epub 2021 Feb 24.

Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of California at Davis (UC Davis) School of Medicine, UC Davis Health Science, Sacramento, CA, 95817, USA.

Purpose: Previously we showed that natural compound α-penta-galloyl-glucose (α-PGG) and its synthetic derivative 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ) act to improve insulin signaling in adipocytes by increasing glucose transport. In this study, we investigated the mechanism of actions of α-PGG and 6Cl-TGQ on insulin secretion.

Methods: Mouse islets and/or INS-1832/13 beta-cells were used to test the effects of our compounds on glucose-stimulated insulin secretion (GSIS), intracellular calcium [Ca] using fura-2AM, glucose transport activity via a radioactive glucose uptake assay, intracellular ATP/ADP, and extracellular acidification (ECAR) and mitochondrial oxygen consumption rates (OCAR) using Seahorse metabolic analysis.

Results: Both compounds reduced GSIS in beta-cells without negatively affecting cell viability. The compounds primarily diminished glucose uptake into islets and beta-cells. Despite insulin-like effects in the peripheral tissues, these compounds do not act through the insulin receptor in islets. Further interrogation of the stimulus-secretion pathway showed that all the key metabolic factors involved in GSIS including ECAR, OCAR, ATP/ADP ratios, and [Ca] of INS-1832/13 cells were diminished after the compound treatment.

Conclusion: The compounds suppress glucose uptake of the beta-cells, which consequently slows down the rates of glycolysis and ATP synthesis, leading to decrease in [Ca] and GSIS. The difference between adipocytes and beta-cells in effects on glucose uptake is of great interest. Further structural and functional modifications could produce new compounds with optimized therapeutic potentials for different target cells. The higher potency of synthetic 6Cl-TGQ in enhancing insulin signaling in adipocytes but lower potency in reducing glucose uptake in beta-cells compared to α-PGG suggests the feasibility of such an approach.
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http://dx.doi.org/10.2147/DMSO.S284295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917315PMC
February 2021

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.
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http://dx.doi.org/10.3390/cancers12123640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761932PMC
December 2020

Differential gene signature in adipose tissue depots of growth hormone transgenic mice.

J Neuroendocrinol 2020 11 12;32(11):e12893. Epub 2020 Oct 12.

Edison Biotechnology Institute, Athens, OH, USA.

Bovine growth hormone (bGH) transgenic mice mimic the clinical condition of acromegaly, having high circulating growth hormone (GH) levels. These mice are giant, have decreased adipose tissue (AT) mass, impaired glucose metabolism and a shortened lifespan. The detrimental effects of excess GH have been suggested, in part, to be a result of its depot-specific actions on AT. To investigate this relationship, we evaluated gene expression, biological mechanisms, cellular pathways and predicted microRNA (miRNA) in two AT depots (subcutaneous [Subq] and epididymal [Epi]) from bGH and littermate controls using RNA sequencing analysis. Two analyses on the differentially expressed genes (DEG) were performed: (i) comparison of the same AT depot between bGH and wild-type (WT) mice (genotype comparison) and (ii) comparison of Subq and Epi AT depots within the same genotype (depot comparison). For the genotype comparison, we found a higher number of significant DEG in the Subq AT depot of bGH mice compared to WT controls, corroborating previous reports that GH has a greater impact on the Subq depot. Furthermore, most of the DEG in bGH mice were not shared by WT mice, suggesting that excess GH induces the expression of genes not commonly present in AT. Through gene ontology and pathway analysis, the genotype comparison revealed that the DEG of the Subq depot of bGH mice relate to fatty acid oxidation, branched-chain amino acid degradation and the immune system. Additionally, the AT depot comparison showed that the immune cell activation and T-cell response appear up-regulated in the Subq compared to the Epi AT depot. The miRNA prediction also suggested a modulation of T-cell-related biological process in Subq. In summary, the present study provides a unique resource for understanding the specific differences in gene expression that are driven by both excess GH action and AT depot location.
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http://dx.doi.org/10.1111/jne.12893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606825PMC
November 2020

Mouse models of growth hormone insensitivity.

Rev Endocr Metab Disord 2021 Mar 10;22(1):17-29. Epub 2020 Oct 10.

Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, 45701, USA.

Growth hormone (GH) induces pleiotropic effects on growth and metabolism via binding and subsequent activation of the growth hormone receptor (GHR) and its downstream signaling pathways. Growth hormone insensitivity (GHI) describes a group of disorders in which there is resistance to the action of GH and resultant insulin-like growth factor I (IGF-I) deficiency. GHI is commonly due to genetic disorders of the GH receptor causing GH receptor deficiency (e.g. Laron Syndrome (LS)), decreased activation of GHR, or defects in post-receptor signaling molecules. Genetically altered mouse lines have been invaluable to better understand the physiological impact of GHI due to the ability to do invasive and longitudinal measures of metabolism, growth, and health on a whole animal or in individual tissues/cells. In the current review, the phenotype of mouse lines with GHI will be reviewed. Mouse lines to be discussed include: 1) GHR-/- mice with a gene disruption in the GHR that results in no functional GHR throughout life, also referred to as the Laron mouse, 2) mice with temporal loss of GHR (aGHRKO) starting at 6 weeks of age, 3) mice transgenic for a GHR antagonist (GHA mice), 4) mice with GHI in select tissues or cells generated via Cre-lox or related technology, and 5) assorted mice with defects in post-receptor signaling molecules. Collectively, these mouse lines have revealed an intriguing role of GH action in health, disease, and aging.
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http://dx.doi.org/10.1007/s11154-020-09600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979446PMC
March 2021

A signal amplification of p DNA@AgS based photoelectrochemical competitive sensor for the sensitive detection of OTA in microfluidic devices.

Biosens Bioelectron 2020 Nov 8;168:112503. Epub 2020 Aug 8.

Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, PR China. Electronic address:

In this work, a signal amplification competitive-type photoelectrochemical system comprised of bismuth sulfide/bismuth oxyiodide/zinc oxide (BiS/BiOI/ZnO) nano-array as platform and AgS-modified aptamers probe DNA (p DNA@AgS) as competition content for rapid and sensitive detection of OTA in microfluidic devices. The BiOI nano-array was first growth on surfaces of ZnO by a simple electrodeposited method, which provided large specific surface area and high stability to solve distribution of sensing platform and loose of combination of sensing substrate. Then, the BiS could be in-situ growth by self-sacrificial part Bi of BiOI to form heterojunction without destroying the structure of the nano-array. A strong photocurrent intensity was acquired by the BiS/BiOI/ZnO modified onto indium tin oxide (ITO) electrode, due to its good matching cascade band-edge levels could improve efficient separation of photo-generated e/h pairs. After immobilizing with the capture DNA (c DNA) and the sequential hybridization of p DNA@AgS, the photocurrent intensity reduced obviously because part photo-generated electron transformed to AgS rather than BiS/BiOI/ZnO electrode. Subsequently, the photocurrent intensity increased evident when immobilized the target OTA, owing to the OTA could bind the p DNA@AgS to form the specific-complex that were released from the electrode surface. Under optimal conditions, the prepared PEC microfluidic sensor exhibited a linear concentration of OTA from 0.01 pg/mL to 200 ng/mL with a low detection limit of 0.0035 pg/mL (S/N = 3). Furthermore, it achieved high sensitivity, good specificity, and acceptable stability and further provided an efficient method for sensitive detection of other target mycotoxins in practical application.
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http://dx.doi.org/10.1016/j.bios.2020.112503DOI Listing
November 2020

Isosteres of ester derived glucose uptake inhibitors.

Bioorg Med Chem Lett 2020 09 15;30(18):127406. Epub 2020 Jul 15.

Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA. Electronic address:

Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.
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http://dx.doi.org/10.1016/j.bmcl.2020.127406DOI Listing
September 2020

The Effects of 20-kDa Human Placental GH in Male and Female GH-deficient Mice: An Improved Human GH?

Endocrinology 2020 08;161(8)

Edison Biotechnology Institute, Ohio University, Athens, Ohio.

A rare 20K isoform of GH-V (here abbreviated as GHv) was discovered in 1998. To date, only 1 research article has characterized this isoform in vivo, observing that GHv treatment in male high-fat fed rats had several GH-like activities, but unlike GH lacked diabetogenic and lactogenic activities and failed to increase IGF-1 or body length. Therefore, the current study was conducted to further characterize the in vivo activities of GHv in a separate species and in a GH-deficient model (GH-/- mice) and with both sexes represented. GHv-treated GH-/- mice had significant increases to serum IGF-1, femur length, body length, body weight, and lean body mass and reduced body fat mass similar to mice receiving GH treatment. GH treatment increased circulating insulin levels and impaired insulin sensitivity; in contrast, both measures were unchanged in GHv-treated mice. Since GHv lacks prolactin receptor (PRLR) binding activity, we tested the ability of GH and GHv to stimulate the proliferation of human cancer cell lines and found that GHv has a decreased proliferative response in cancers with high PRLR. Our findings demonstrate that GHv can stimulate insulin-like growth factor-1 and subsequent longitudinal body growth in GH-deficient mice similar to GH, but unlike GH, GHv promoted growth without inhibiting insulin action and without promoting the growth of PRLR-positive cancers in vitro. Thus, GHv may represent improvements to current GH therapies especially for individuals at risk for metabolic syndrome or PRLR-positive cancers.
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http://dx.doi.org/10.1210/endocr/bqaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375802PMC
August 2020

Zinc and Molybdenum Co-Doped BiVO Nanoarray for Photoelectrochemical Diethylstilbestrol Analysis Based on the Dual-Competitive System of Manganese Hexacyanoferrate Hydrate Nanocubes.

ACS Appl Mater Interfaces 2020 Apr 25;12(14):16662-16669. Epub 2020 Mar 25.

Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.

This study proposes a competitive photoelectrochemical (PEC) immunosensor for detecting diethylstilbestrol (DES). The PEC sensing platform uses a zinc and molybdenum codoped BiVO nanoarray ((Zn,Mo):BiVO) as the photoactive matrix and manganese hexacyanoferrate hydrate loading silicon dioxide layer composite nanocubes (MHCF@SiO NCs) as the signal quencher. The (Zn,Mo):BiVO nanoarray demonstrated brilliant PEC behavior, by virtue of the local electric field formed by the codoped Zn and Mo. This doping accelerated the electron transfer and improved the photoelectric conversion efficiency in BiVO nanoarray under visible light. Furthermore, the nanoarray structure with its large surface area provided abundant binding sites for the immune response. As the MHCF@SiO NCs-anti-DES competitively bonded with either free DES or bovine serum albumin conjugated DES (BSA-DES), hydrogen peroxide (HO) as electron donor was competitively consumed and meanwhile steric resistance blocked electrons transfer. For the above reasons, the photocurrent signal was reduced. Thus, the standard sample free DES was accurately detected, and the fabricated PEC immunosensor displayed an outstanding photocurrent response from 0.1 pg/mL to 50 ng/mL with a detection limit of 0.05 pg/mL. Simultaneously, the acceptable stability, selectivity, and reproducibility of the designed dual-competitive sensing platform suggest its applicability to small molecule detection.
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http://dx.doi.org/10.1021/acsami.0c04010DOI Listing
April 2020

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma.

Cancers (Basel) 2019 Sep 12;11(9). Epub 2019 Sep 12.

Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH-GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.
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http://dx.doi.org/10.3390/cancers11091352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769493PMC
September 2019

GH Knockout Mice Have Increased Subcutaneous Adipose Tissue With Decreased Fibrosis and Enhanced Insulin Sensitivity.

Endocrinology 2019 07;160(7):1743-1756

Edison Biotechnology Institute, Ohio University, Athens, Ohio.

In 1997, our laboratory used targeted gene disruption of the GH receptor (GHR) to generate GHR knockout (GHR-/-) mice, which have been used in >127 published studies to help elucidate GH's numerous activities. However, because GH replacement studies cannot be performed using this line, a GH knockout mouse line via targeted disruption of the GH gene is needed. Therefore, we created and characterized GH gene-disrupted (GH-/-) mice. GH-/- mice have severely decreased IGF-1 levels, small body size, and altered body composition with increased adiposity. GH-/- mice are extremely insulin sensitive but glucose intolerant, with a dramatic reduction in pancreatic islet size. Importantly, disruption of the GH gene had profound and depot-specific effects on white adipose tissue (WAT). Subcutaneous WAT from male and female GH-/- mice have significantly larger adipocytes and reduced fibrosis, neither of which occurred in perigonadal WAT, suggesting that GH has a more pronounced effect on subcutaneous WAT. Comparisons of GH-/- mice to previously published data on GHR-/- mice show a remarkably similar phenotype. Finally, we demonstrate that GH-/- mice are responsive to GH treatment, as shown by changes to serum IGF-1 levels; body length, weight, and composition; and insulin sensitivity. This study not only provides characterization of the first mouse line with targeted mutation of the GH gene but also indicates that GH gene disruption dramatically influences fibrosis of subcutaneous WAT.
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http://dx.doi.org/10.1210/en.2019-00167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760334PMC
July 2019

A sandwich-type photoelectrochemical immunosensor for NT-pro BNP detection based on F-BiWO/AgS and GO/PDA for signal amplification.

Biosens Bioelectron 2019 Apr 19;131:299-306. Epub 2019 Feb 19.

Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China; State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210023, China.

A sandwich-type photoelectrochemical (PEC) immunosensing platform was designed for detection of amino-terminal pro-B-type natriuretic peptide (NT-pro BNP). Thereinto, flower-like BiWO/AgS nanoparticles (F-BiWO/AgS) were employed as photoelectrochemical matrix, and graphene oxide and polydopamine composite (GO/PDA) were prepared as signal labels. In this proposal, AgS was in-situ growth on the surface of F-BiWO modified with thioglycolic acid (TGA). Specially, a cascade-like band-edge level between F-BiWO and AgS effectively improved the photocurrent conversion efficiency and enhanced the photocurrent response. Then, the conjugated GO/PDA aimed to further amplify signal because PDA as electron donor could sweep the holes and inhibit the recombination of photogenerated electron-hole pairs, while GO owned brilliant conductivity speeding up the electrons transfer. The photocurrent increased with the amount of GO/PDA conjugates which had positive correlation with the NT-pro BNP. Under optimal experimental conditions, the proposed sandwich-type PEC immunosensor presented a desirable linear relationship ranged from 0.1 pg/mL to 100 ng/mL for NT-pro BNP with the detection limit of 0.03 pg/mL (S/N = 3). The prepared PEC immunosensor exhibited high stability and selectivity, which offered an innovative idea for the detection of other biomolecules.
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http://dx.doi.org/10.1016/j.bios.2019.02.029DOI Listing
April 2019

Adipocyte-Specific GH Receptor-Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides.

Endocrinology 2019 01;160(1):68-80

Edison Biotechnology Institute, Ohio University, Athens, Ohio.

Global GH receptor-null or knockout (GHRKO) mice have been extensively studied owing to their unique phenotype (dwarf and obese but remarkably insulin sensitive and long-lived). To better understand the influence of adipose tissue (AT) on the GHRKO phenotype, we previously generated fat-specific GHRKO (FaGHRKO) mice using the adipocyte protein-2 (aP2) promoter driving Cre expression. Unlike global GHRKO mice, FaGHRKO mice are larger than control mice and have an increase in white AT (WAT) mass and adipocyte size as well as an increase in brown AT mass. FaGHRKO mice also have an unexpected increase in IGF-1, decrease in adiponectin, no change in insulin sensitivity or liver triglyceride content, and a decreased lifespan. Extensive analysis of the aP2 promoter/enhancer by multiple laboratories has revealed expression in nonadipose tissues, confounding interpretation of results. In the current study, we used the adiponectin promoter/enhancer to drive Cre expression, which better targets mature adipocytes, and generated a new line of adipocyte-specific GHRKO (AdGHRKO) mice. AdGHRKO mice have an increase in adipocyte size and WAT depot mass in all depots except male perigonadal, a WAT accumulation pattern similar to FaGHRKO mice. Likewise, adiponectin levels and WAT fibrosis are decreased in both tissue-specific mouse lines. However, unlike FaGHRKO mice, AdGHRKO mice have no change in IGF-1 levels, improved glucose homeostasis, and reduced liver triglycerides. Thus, AdGHRKO mice should be valuable for future studies assessing the contribution of adipocyte GHR signaling in long-term health and lifespan.
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http://dx.doi.org/10.1210/en.2018-00850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304108PMC
January 2019

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Eur J Endocrinol 2018 May 19;178(5):R155-R181. Epub 2018 Feb 19.

Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.

Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 70 years. Work on the GH receptor (R)-knockout (GHRKO) mice and results of studies on GH-resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.
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http://dx.doi.org/10.1530/EJE-18-0018DOI Listing
May 2018

Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase.

Oncotarget 2017 Oct 23;8(50):87860-87877. Epub 2017 Sep 23.

Department of Biological Sciences, Ohio University, Athens, Ohio 45701, USA.

Cancer cells are able to uptake extracellular ATP (eATP) via macropinocytosis to elevate intracellular ATP (iATP) levels, enhancing their survival in drug treatment. However, the involved drug resistance mechanisms are unknown. Here we investigated the roles of eATP as either an energy or a phosphorylating molecule in general drug resistance mediated by ATP internalization and iATP elevation. We report that eATP increased iATP levels and promoted drug resistance to various tyrosine kinase inhibitors (TKIs) and chemo-drugs in human cancer cell lines of five cancer types. In A549 lung cancer cells, the resistance was downregulated by macropinocytosis inhibition or siRNA knockdown of PAK1, an essential macropinocytosis enzyme. The elevated iATP upregulated the efflux activity of ABC transporters in A549 and SK-Hep-1 cells as well as phosphorylation of PDGFRα and proteins in the PDGFR-mediated Akt-mTOR and Raf-MEK signaling pathways in A549 cells. Similar phosphorylation upregulations were found in A549 tumors. These results demonstrate that eATP induces different types of drug resistance by eATP internalization and iATP elevation, implicating the ATP-rich tumor microenvironment in cancer drug resistance, expanding our understanding of the roles of eATP in the Warburg effect and offering new anticancer drug resistance targets.
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http://dx.doi.org/10.18632/oncotarget.21231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675678PMC
October 2017

Growth Hormone and the Epithelial-to-Mesenchymal Transition.

J Clin Endocrinol Metab 2017 10;102(10):3662-3673

Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701.

Context: Previous studies have implicated growth hormone (GH) in the progression of several cancers, including breast, colorectal, and pancreatic. A mechanism by which GH may play this role in cancer is through the induction of the epithelial-to-mesenchymal transition (EMT). During the EMT process, epithelial cells lose their defining phenotypes, causing loss of cellular adhesion and increased cell migration. This review aims to carefully summarize the previous two decades of research that points to GH as an initiator of EMT, in both cancerous and noncancerous tissues.

Evidence Acquisition: Sources were collected using PubMed and Google Scholar search engines by using specific GH- and/or EMT-related terms. Identified manuscripts were selected for further analysis based on presentation of GH-induced molecular markers of the EMT process in vivo or in vitro.

Evidence Synthesis: Cellular mechanisms involved in GH-induced EMT are the focus of this review, both in cancerous and noncancerous epithelial cells.

Conclusions: Our findings suggest that a myriad of molecular mechanisms are induced by GH that cause EMT and may point to potential therapeutic use of GH antagonists or any downregulator of GH action in EMT-related disease.
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http://dx.doi.org/10.1210/jc.2017-01000DOI Listing
October 2017

Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP In Vitro and In Vivo Using Multiple Endocytic Mechanisms.

Mol Cancer Res 2016 11 30;14(11):1087-1096. Epub 2016 Aug 30.

The Edison Biotechnology Institute, Ohio University, Athens, Ohio.

Intratumoral extracellular ATP concentrations are 1000 times higher than those in normal tissues of the same cell origin. However, whether or not cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP. The internalized ATP was found to substantially increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells. Here, using a nonhydrolyzable fluorescent ATP (NHF-ATP), radioactive and regular ATP, coupled with high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy and ATP assays, cultured human NSCLC A549 and H1299 cells as well as A549 tumor xenografts were found to internalize extracellular ATP at concentrations within the reported intratumoral extracellular ATP concentration range. In addition to macropinocytosis, both clathrin- and caveolae-mediated endocytosis significantly contribute to the ATP internalization, which led to an approximately 30% (within 45 minutes) or more than 50% (within 4 hours) increase in intracellular ATP levels after ATP incubation. This increase could not be accounted for by either purinergic receptor signaling or increased intracellular ATP synthesis rates in the ATP-treated cancer cells. These new findings significantly deepen our understanding of the Warburg effect by shedding light on how cancer cells in tumors, which are heterogeneous for oxygen and nutrition supplies, take up extracellular ATP and use the internalized ATP to perform multiple previously unrecognized functions of biological importance. They strongly suggest the existence of ATP sharing among cancer and stromal cells in tumors and simultaneously identify multiple new anticancer targets.

Implications: Extracellular ATP is taken up by human lung cancer cells and tumors via macropinocytosis and other endocytic processes to supplement their extra energy needs for cancer growth, survival, and drug resistance, thus providing novel targets for future cancer therapy. Mol Cancer Res; 14(11); 1087-96. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0118DOI Listing
November 2016

Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

Endocrinology 2016 05 1;157(5):1929-41. Epub 2016 Apr 1.

Edison Biotechnology Institute (A.J., X.L., D.S., C.M.B., S.D.-O., Y.Q., E.O.L., D.E.B., J.J.K.), Departments of Biomedical Sciences (A.J., D.E.B., J.J.K.) and Specialty Medicine (E.O.L.), Heritage College of Osteopathic Medicine, Department of Biological Sciences (S.D.-O., J.J.K.), School of Applied Health Sciences and Wellness (X.L., C.M.B., D.E.B.), College of Health Sciences and Professions, Department of Social and Public Health (D.S.), Ohio University, Athens, Ohio 45701; and Program in Molecular Medicine (J.K.K.), University of Massachusetts Medical School, Worcester, Massachusetts 01605.

GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.
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http://dx.doi.org/10.1210/en.2015-1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870885PMC
May 2016

Computed tomography manifestation of acute exacerbation of chronic obstructive pulmonary disease: A pilot study.

Exp Ther Med 2016 Feb 11;11(2):519-529. Epub 2015 Dec 11.

Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an acute event characterized by the worsening of a patient's respiratory symptoms. To the best of our knowledge, few studies have investigated the computed tomography (CT) manifestation of AECOPD. Thus, the aim of the present study was to examine the CT manifestations during AECOPD. In total, 40 patients with AECOPD admitted to the emergency department were enrolled. CT images obtained at the time of exacerbation and at the 3-month follow-up were paired. Clinical characteristics and routine blood test results were also recorded. Airway dimensions and attenuation per patient were quantified from the 3rd to the 6th generation of four bronchi by Airway Inspector Slicer 2.8. The emphysema extent was also quantified and lung infiltration was detected, classified and measured. The CT images showed an increased wall area percentage (WA%) and increased mean and peak wall attenuation during the AECOPD; however, the extent of emphysema did not change significantly. In total, 60% of AECOPD patients presented with lung infiltration, compared with those at the follow-up CT scanning. The presence and extent of segmental distribution consolidation was correlated with the neutrophil percentage (N%), with a statistically significant difference observed. The total volume of lung parenchymal infiltration was correlated with the white blood cell (WBC) count and N%; however, no significant correlations were detected between the presence or extent of acinar shadow, air space consolidation with lobular distribution, ground-glass attenuation with lobular distribution, thickening of the interlobular septa and signs of infection (including the number of main symptoms, body temperature, WBC count and N%). The WA%, mean wall attenuation and peak wall attenuation increased during AECOPD, but the emphysema extent was unchanged. Lung infiltration existed frequently; however, only consolidation with segmental distribution appeared to be associated with bacterial infection.
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http://dx.doi.org/10.3892/etm.2015.2930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734063PMC
February 2016

A predictive model for the development of chronic obstructive pulmonary disease.

Biomed Rep 2015 Nov 5;3(6):853-863. Epub 2015 Aug 5.

Department of Pulmonary Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.

The screening of a person at risk for chronic obstructive pulmonary disease (COPD) and timely treatment may provide opportunities to delay the progressive destruction of lung function. Therefore, a model to predict the disease is required. We hypothesized that demographic and clinical information in combination with genetic markers would aid in the prediction of COPD development, prior to its onset. The aim of the present study was to create a predictive model for COPD development. Demographic, clinical presentation and genetic polymorphisms were recorded in COPD patients and control subjects. Nighty-six single-nucleotide polymorphisms of 46 genes were selected for genotyping in the case-control study. A predictive model was produced using logistic regression with a stepwise model-building approach and was validated. A total of 331 patients and 351 control subjects were included. The logistic regression identified the following predictors: Gender, respiratory infection in early life, low birth weight, smoking history and genotype polymorphisms (rs2070600, rs10947233, rs1800629, rs2241712 and rs1205). The model was established using the following formula: COPD = 1/[1 + exp (-2.4933-1.2197 gender + 1.1842 respiratory infection in early life + 2.4350 low birth weight + 1.8524 smoking - 1.1978 rs2070600 + 2.0270 rs10947233 + 1.1913 rs10947233 + 0.6468 rs1800629 + 0.5272 rs2241712 + 0.4024 rs1205)] (when the value is >0.5). The Hosmer-Lemeshow test showed no significant deviations between the observed and predicted events. Validation of the model in 50 patients showed a modest sensitivity and specificity. Therefore, a predictive model based on demographic, clinical and genetic information may identify COPD prior to its onset.
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http://dx.doi.org/10.3892/br.2015.503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660625PMC
November 2015

Salicylketoximes That Target Glucose Transporter 1 Restrict Energy Supply to Lung Cancer Cells.

ChemMedChem 2015 Nov 1;10(11):1892-900. Epub 2015 Sep 1.

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126, Pisa, Italy.

The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a notable antiproliferative effect. In contrast to their 5-aryl-substituted regioisomers, the newly synthesized compounds reported herein do not display significant binding to the estrogen receptors. The inhibition of glucose uptake in cancer cells by these compounds was further observed by fluorescence microscopy imaging using a fluorescent analogue of glucose. Therefore, blocking the ability of tumor cells to take up glucose by means of these small molecules, or by further optimized derivatives, may be a successful approach in the development of novel anticancer drugs.
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http://dx.doi.org/10.1002/cmdc.201500320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743644PMC
November 2015

The Warburg effect: evolving interpretations of an established concept.

Free Radic Biol Med 2015 Feb 30;79:253-63. Epub 2014 Sep 30.

Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA; Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356994PMC
February 2015

Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells.

Cancer Lett 2014 Sep 26;351(2):242-51. Epub 2014 Jun 26.

Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Department of Biological Sciences, Ohio University, Athens, OH 45701, USA; Department of Biomedical Sciences, Ohio University, Athens, OH 45701, USA; Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA; The Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA. Electronic address:

ATP plays central roles in cancer metabolism and the Warburg effect. Intratumoral ATP concentrations are up to 10(4) times higher than those of interstitial ATP in normal tissues. However, extracellular ATP is not known to enter cancer cells. Here we report that human A549 lung cancer cells internalized extracellular ATP by macropinocytosis as demonstrated by colocalization of a nonhydrolyzable fluorescent ATP and a macropinocytosis tracer high-molecular-weight dextran, as well as by a macropinocytosis inhibitor study. Extracellular ATP also induced increase of intracellular ATP levels, without involving transcription and translation at significant levels, and cancer cells' resistance to ATP-competitor anticancer drugs, likely through the mechanism of ATP internalization. These findings, described for the first time, have profound implications in ATP-sharing among cancer cells in tumors and highlight a novel anticancer target.
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http://dx.doi.org/10.1016/j.canlet.2014.06.008DOI Listing
September 2014

Biological and biomedical functions of Penta-O-galloyl-D-glucose and its derivatives.

J Nat Med 2014 Jul 15;68(3):465-72. Epub 2014 Feb 15.

Department of Biological Sciences, Ohio University, Athens, OH, USA.

Penta-O-galloyl-D-glucose (PGG) is a simple hydrolysable tannin in plants. PGG exists in two anomeric forms, α-PGG and β-PGG. While β-PGG can be found in a wide variety of plants, α-PGG is rather rare in nature. Numerous studies with β-PGG revealed a wide variety of biological activities, such as anti-microbial and anti-cancer functions. Until recently, studies with α-PGG were limited by the lack of its availability. Since the development of an efficient chemical synthesis of the compound, several investigations have revealed its anti-diabetic, anti-cancer, and anti-platelet-coagulation functions. Based on structure-activity-relationship (SAR) studies with α-PGG, a variety of α-PGG-related novel compounds were synthesized and some of them have been shown to possess promising therapeutic activities. In this review, the authors will survey and evaluate the biological functions of PGG with a focus on α-PGG and its derivatives.
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http://dx.doi.org/10.1007/s11418-014-0823-2DOI Listing
July 2014

Constituents of an extract of Cryptocarya rubra housed in a repository with cytotoxic and glucose transport inhibitory effects.

J Nat Prod 2014 Mar 17;77(3):550-6. Epub 2013 Dec 17.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.

A new alkylated chalcone (1), a new 1,16-hexadecanediol diester (2), and eight known compounds were isolated from a dichloromethane-soluble repository extract of the leaves and twigs of Cryptocarya rubra collected in Hawaii. The structures of the new compounds were determined by interpretation of their spectroscopic data, and the absolute configurations of the two known cryptocaryanone-type flavonoid dimers, (+)-bicaryanone A (3) and (+)-chalcocaryanone C (4), were ascertained by analysis of their electronic circular dichroism and NOESY NMR spectra. All compounds isolated were evaluated against HT-29 human colon cancer cells, and, of these, (+)-cryptocaryone (5) was found to be potently cytotoxic toward this cancer cell line, with an IC50 value of 0.32 μM. This compound also exhibited glucose transport inhibitory activity when tested in a glucose uptake assay.
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http://dx.doi.org/10.1021/np400809wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047178PMC
March 2014

Oxime-based inhibitors of glucose transporter 1 displaying antiproliferative effects in cancer cells.

Bioorg Med Chem Lett 2013 Dec 28;23(24):6923-7. Epub 2013 Sep 28.

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.

An analysis of the main pharmacophoric features present in the still limited number of inhibitors of glucose transporter GLUT1 led to the identification of new oxime-based inhibitors, which proved to be able to efficiently hinder glucose uptake and cell growth in H1299 lung cancer cells. The most important interactions of a representative inhibitor were indicated by a novel computational model of GLUT1, which was purposely developed to explain these results and to provide useful indications for the design and the development of new and more efficient GLUT1 inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.037DOI Listing
December 2013

Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes.

J Mol Endocrinol 2013 17;51(1):15-26. Epub 2013 May 17.

Department of Biological Science, Ohio University, Athens, Ohio, USA.

Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocin-induced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than α-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.
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http://dx.doi.org/10.1530/JME-12-0171DOI Listing
January 2014

Association of genetic polymorphisms with chronic obstructive pulmonary disease in the Chinese Han population: a case-control study.

BMC Med Genomics 2012 Dec 26;5:64. Epub 2012 Dec 26.

Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025, Shanghai, China.

Background: Chronic obstructive pulmonary disease (COPD) is influenced by both environmental and genetic factors. Few gene studies of the Chinese population have focused on COPD. We investigated candidate genes associated with susceptibility to COPD in the Chinese Han population.

Methods: A total of 331 COPD patients and 213 control subjects were recruited for this study. Nighty-seven single-nucleotide polymorphisms (SNPs) of 46 genes were selected for genotyping. Genotypes were determined using multiplex polymerase chain reaction (PCR).

Results: Significant differences between patients and healthy controls were observed in the allele frequencies of seven SNPs: rs1205 C, rs2353397 C, rs20541 T, rs2070600 G, rs10947233 G, rs1800629 G, and rs2241712 A. After Bonferroni correction, rs2353397 C was most strongly associated with susceptibility to COPD. Haplotype analysis showed that the frequencies of the GC, GT haplotypes of rs2241718 (TGF-β1 gene), and rs6957 (CDC97 gene) were significantly higher in the control group than in the COPD case group (p=1.88×10-9); the frequencies of the TT haplotype of rs1205 and rs2808630 (CRP gene) were significantly higher in the control group (p=0.0377).

Conclusion: Our study suggests some genetic variants associated with the susceptibility of COPD in the Chinese Han population.
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http://dx.doi.org/10.1186/1755-8794-5-64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582579PMC
December 2012

A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo.

Mol Cancer Ther 2012 Aug 11;11(8):1672-82. Epub 2012 Jun 11.

Department of Biological Science, Ohio University, Athens, OH, USA.

The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.
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http://dx.doi.org/10.1158/1535-7163.MCT-12-0131DOI Listing
August 2012

Angiotensin-(1-7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways.

Oncol Rep 2012 Mar 15;27(3):783-90. Epub 2011 Nov 15.

Department of Respiration, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, PR China.

The local renin-angiotensin system (RAS) is one of the crucial components in the tumor microenvironment. Recent evidence suggests that the local RAS plays an important role in tumor metabolism, survival, angiogenesis and invasion processes. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide of the RAS with vasodilator and anti-proliferative properties. Previous studies have demonstrated that Ang-(1-7) inhibits both the growth of human lung cancer cells in vitro and tumor angiogenesis in vivo through activation of the MAS receptor. This study investigated the anti-metastatic effect of Ang-(1-7) in A549 human lung adenocarcinoma cells in vitro. We found that Ang-(1-7) reduced the cell migratory and invasive abilities by reducing the expression and activity of MMP-2 and MMP-9. Furthermore, we demonstrated that the anti-migration and anti-invasion effect of Ang-(1-7) was mediated through inactivation of the PI3K/Akt, P38 and JNK signal pathways. Our results suggest that Ang-(1-7) may have therapeutic potential against advanced lung carcinoma as a new agent.
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http://dx.doi.org/10.3892/or.2011.1554DOI Listing
March 2012