Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice

Jiang, Shu-Heng,Li, Jun,Dong, Fang-Yuan,Yang, Jian-Yu,Liu, De-Jun,Yang, Xiao-Mei,Wang, Ya-Hui,Yang, Min-Wei,Fu, Xue-Liang,Zhang, Xiao-Xin,Li, Qing,Pang, Xiu-Feng,Huo, Yan-Miao,Li, Jiao,Zhang, Jun-Feng Elsevier 2017 Gastroenterology Vol.153 No.1

<P><B>Background & Aims</B></P> <P>Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors.</P> <P><B>Methods</B></P> <P>We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras<SUP>G12D/+</SUP>/Trp53<SUP>R172H/+</SUP>/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses.</P> <P><B>Results</B></P> <P>In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B–LYN–p85 complex, which increased PI3K–Akt–mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice.</P> <P><B>Conclusions</B></P> <P>Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.</P>

Evidence for Viscoelastic Effects in Surface Capillary Waves of Molten Polymer Films

Jiang, Zhang,Kim, Hyunjung,Jiao, X.,Lee, H.,Lee, Y.-J.,Byun, Y.,Song, S.,Eom, D.,Li, C.,Rafailovich, M. H.,Lurio, L. B.,Sinha, S. K. American Physical Society 2007 Physical Review Letters Vol.98 No.22

The Effects of Puerarin on CYP2D6 and CYP1A2 Activities In Vivo

Jiao Zheng,Bin Chen,Bing Jiang,Ling Zeng,Zhi-Rong Tang,Lan Fan,Hong-Hao Zhou 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.2

Ge-gen (Radix Puerariae) is used in traditional oriental medicine for various medicinal purposes. The drug is the root of a wild leguminous creeper, Pueraria lobata (Willd) Ohwi. It possesses a high content of avonoid derivatives, the most abundant of which is puerarin. Our goal was to find the effect of puerarin on cytochrome P450 enzymes in vivo. The study was conducted in 18 male volunteers of different genotypes (CYP2D6 *1/*1, *1/*10, *10/*10). Plasma was obtained at 6 h after oral administration and urine was collected from 0 to 8 h after probe drug administration. The logarithm value of metabolic rate decrease from -0.0055 ± 0.1887 to -0.1754 ± 0.2411 implied puerarin inhibited activity of CYP2D6. There was no significant relationship between the inhibition with the CYP2D6 genotypes. The paraxanthin/caffeine ratio in the plasma sample at 6th hour was increased by 30 ± 47% (p = 0.003), implied puerarin induced the activity of CYP1A2. While puerarin used together with the substrates of both enzymes, drug interaction worth the attention and at sometimes precautions are needed.

Crack-tip constraint analysis of two collinear cracks under creep condition

Jiao, Guang-Chen,Wang, Wei-Zhe,Jiang, Pu-Ning Techno-Press 2012 Structural Engineering and Mechanics, An Int'l Jou Vol.43 No.3

The higher-order asymptotic C(t) - $A_2(t)$ approach was employed to investigate the crack-tip stress of two collinear cracks in a power-law creeping material under the plane strain conditions. A comprehensive calculation was made of the single crack, collinear crack model with S/a = 0.4 and 0.8, by using the C(t) - $A_2(t)$ approach, HRR-type field and the finite element analysis; the latter two methods were used to check the constraint significance and the calculation accuracy of the C(t) - $A_2(t)$ approach, respectively. With increasing the creep time, the constraint $A_2$ was exponentially increased in the small-scale creep stage, while no discernible dependency of the constraint $A_2$ on the creep time was found at the extensive creep state. In addition, the creep time and the mechanical loads have no distinct influence on accuracy of the results obtained from the higher-order asymptotic C(t) - $A_2(t)$ approach. In comparison with the HRR-type field, the higher-order asymptotic C(t) - $A_2(t)$ solution matches well with the finite element results for the collinear crack model.

Integrated thyroid endocrine disrupting effect on zebrafish (Danio rario) larvae via simultaneously repressing type II iodothyronine deiodinase and activating thyroid receptor-mediated signaling following waterborne exposure to trace azocyclotin

Fang Jiao,Kun Qiao,Yao Jiang,Shuying Li,jinhao Zhao,Wenjun Gui 대한환경공학회 2019 대한환경공학회 학술발표논문집 Vol.2019 No.-

Association of CAST Gene Polymorphisms with Carcass and Meat Quality Traits in Chinese Commercial Cattle Herds

Li, Jiao,Zhang, Lu-Pei,Gan, Qian-Fu,Li, Jun-Ya,Gao, Hui-Jiang,Yuan, Zheng-Rong,Gao, Xue,Chen, Jin-Bao,Xu, Shang-Zhong Asian Australasian Association of Animal Productio 2010 Animal Bioscience Vol.23 No.11

Calpastatin (CAST), an endogenous inhibitor of the calpains, plays an important role in post-mortem tenderization of meat. The objectives of this study were to investigate single nucleotide polymorphisms (SNPs) in the bovine CAST gene and association with carcass and meat quality traits. A total of 212 cattle from commercial herds were tested in this study including 2 pure introduced breeds, 4 cross populations, and 3 pure Chinese native breeds. Five SNPs were identified at position 2959 (A/G), 2870 (G/A), 3088 (C/T), 3029 (G/A) and 2857 (C/T) in the CAST gene (GenBank Accession No. AF159246). Allele frequencies of SNP2959 and SNP2870 were 0.701 (A) and 0.462 (A), respectively. A general linear model was used to evaluate the associations between the two markers and 7 traits. The results showed that both SNP2959 and SNP2870 were significantly (p<0.01) associated with the Warner-Bratzler shear force (WBSF), while they had no significant association with the other 6 traits in the whole population. However, in Chinese native pure breeds, only SNP2870 had significant association with WBSF (p<0.05). The simultaneous analysis of two-marker genotype effects indicated animals containing the A/G haplotype (A for SNP2959 and G for SNP2870) tended to have lower shear force than those containing the G/A haplotype, and, especially, animals homozygous for the A/G haplotype had approximately 2 kg lower shear force than those homozygous for the G/A haplotype (p<0.01). These results suggested that both markers may be effective for the marker-assisted selection of meat quality traits in Chinese commercial herds, especially SNP2870 which can be used for Chinese native cattle.

Antitumor and Immunomodulating Activity of Polysaccharides from Enteromorpha intestinalis

Lili Jiao,Liping Zhang,Peng Jiang,Mingjiang Wu 한국생물공학회 2010 Biotechnology and Bioprocess Engineering Vol.15 No.3

Two polysaccharides (WEA and WEB) were isolated from Enteromorpha intestinalis by hot water extraction, anion-exchange, and gel-permeation chromatography. The average molecular weights (Mw) of the two fractions were 72.03 kDa (WEA) and 60.12 kDa (WEB). WEA was composed of Rha, Xyl, Man, and Glc in a molar ratio of 1.39:1.00:0.13:3.23. WEB consisted of Rha, Xyl,Gal, and GlcA (glucuronic acid) in a molar ratio of 7.32:1.00:0.51:1.28. Both polysaccharides could inhibit tumor growth in S180 tumor-bearing mice, and increased the relative spleen and thymus weight. They also increased the expression of tumor necrosis factor-alpha (TNF-α) in serum. WEA and WEB induced lymphocyte proliferation,increased the production of TNF-α in macrophages, and stimulated macrophages to produce nitric oxide dosedependently through the up-regulation of inducible NO synthase activity. However, no direct cytotoxicity against Sarcoma 180 was investigated in vitro. These results indicate that the antitumor effects of these polysaccharides are associated with immunostimulation.

Endogenous leptin promotes autophagy in EBSS-induced PFCs

Deling Jiao,Zhen Yang,Lulu Wang,Binyue Hu,Jing Wang,Anyong Xu,Wenmin Cheng,Baoyu Jia,Yubo Qing,Hong-Ye Zhao,Hong-Jiang Wei 한국통합생물학회 2019 Animal cells and systems Vol.23 No.5

Leptin is an important adipokine and plays a vital role in animals. However, the role of leptin in the autophagic response of pig fibroblast cells (PFCs) has not been fully elucidated. In this study, we investigated the relationship between leptin and autophagy as well as underlying molecular basis. We found that PFCs treated with EBSS could secrete leptin, and the leptin concentration in the supernatant of leptin transgenic PFCs was higher than that of WT PFCs. We found an increase in LC3-II protein level and a decrease in p62 protein level in treated leptin transgenic PFCs compared with treated WT PFCs. Meanwhile, we observed an increase of autophagosomes by transmission electron microscopy and an enhancement of the accumulation of LC3 puncta in the cytoplasm of treated leptin transgenic PFCs, and these effects were further augmented by Baf A1 treatment. Furthermore, we detected the expression levels of 7 autophagy signaling pathway genes and 17 autophagy-related (ATG) genes by q-PCR. We found that between the two types of EBSS-treated cells 3 genes expression pattern were significantly different among the 7 autophagy signaling pathway genes and 8 genes expression pattern were significantly differernt among the ATG genes. These results indicated that leptin may promote autophagy and involving the downregulation of FOXO1 and LMNA genes via an unknown pathway which causes the upregulation of the 4 genes and the downregulation of 4 genes.

Facile Fabrication and Characterization of Ytterbium Oxide Hollow Spheres using Carbon Spheres as Template

Xueliang Jiang,Lu Yu,Chu Yao,Feng You,Jiao Zhang 성균관대학교(자연과학캠퍼스) 성균나노과학기술원 2016 NANO Vol.11 No.6

Uniform rare-earth ytterbium oxide (Yb2O3) hollow microspheres have been successfully prepared via a urea-based homogenous precipitation method using carbon spheres as template, followed by a heat treatment. The main synthesis process was carried out in aqueous conditions without any organic solvents, surfactants or etching agents. X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetry, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, Brunauer–Emmett–Teller surface area measurement were employed to characterize the samples. The results show that the final products can be indexed to cubic Yb2O3 phase with high purity. The as-obtained Yb2O3 microspheres with spherical shape and hollow structure are uniform in size and distribution of about 450 nm and wall thickness of approximately 15 nm.

Improved performance of polyamide nanofiltration membranes by incorporating reduced glutathione during interfacial polymerization

Zhiwei Jiao,Linjie Zhou,Mengyuan Wu,Kang Gao,Yanlei Su,Zhongyi Jiang 한국화학공학회 2018 Korean Journal of Chemical Engineering Vol.35 No.12

Inspired by the specific amino acid sequence Asn-Pro-Ala (NPA) of water channel aquaporins (AQPs), we fabricated polyamide (PA) nanofiltration (NF) membranes by introducing reduced glutathione (GSH) in interfacial polymerization (IP) method. Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectrometry (XPS), scanning electron microscope (SEM), atomic force microscopy (AFM), zeta potential and static water contact angle measurement were employed to characterize the chemical composition, morphology, electronegativity and hydrophilicity of the NF membranes. The water flux of GSH/PIP-TMC NF membrane reached 32.00 L m2 h1 at 0.2MPa, which was approximately twice than that of pristine PIP-TMC NF membrane when the ratio of GHS to piperazidine (PIP) was 40% during IP process. More water channels were built as GSH was embedded into PA layer. The fabricated NF membranes also took on potent rejection for dyes and Na2SO4. This study presents a simple and facile method to simulate water channels-based biological materials which may find potential application in water treatment.