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>

Two New Monoterpene Alkaloid Derivatives from the Roots of Incarvillea arguta

Jian Jun Fu,Hui Zi Jin,Jiang Jiang Qin,Qi Zeng,Ying Huang,Wei Dong Zhang 대한약학회 2011 Archives of Pharmacal Research Vol.34 No.2

Two new monoterpene alkaloid derivatives, incargutosines C (1) and D (2), together with a known compound, argutine A (3) have been isolated from the roots of Incarvillea arguta Royle. The structures of 1 and 2 were established on the basis of 1D and 2D NMR spectroscopic analysis, while the absolute configurations of 1 and 2 were determined by a synthetic method. In addition, the cytotoxicity of 3 was evaluated using four tumor cell lines, A549, LOVO, 6TCEM, and MDA-MB-435 (MDA) by the MTT assay.

A New ent-Kaurane type Diterpenoid Glycoside from Inula japonica Thunb

Jiang Jiang Qin,Jia Xian Zhu,Wei Dong Zhang1,2,Yan Zhu,Jian Jun Fu,Xiao Hua Liu,Hui Zi Jin 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.10

A new ent-kaurane type diterpenoid glycoside, 17-O-β-D-glucopyranosyl-16α-ent-kauran-19-oic acid (1), together with 17-hydroxy-16α-ent-kauran-19-oic acid (2), 16α,17-dihydroxyl-ent-kauran-19-oic acid (3), and 16α-hydroxy-17-acetoxy-ent- kauran-19-oic acid (4) were isolated from the aerial parts of Inula japonica Thunb. The structure of 1 was determined mainly by use of 1D and 2D NMR spectroscopic techniques including HSQC, 1H-1H COSY, HMBC, and NOESY. In addition, 4 exhibited significant inhibitory activity on NO production in LPS-stimulated RAW264.7 cells with IC50 value of 14.3 μg/mL.

철학 : 현풍중적 반현

강건준 ( Jian Jun Jiang ) 한국중국학회 1998 國際中國學硏究 Vol.1 No.-

Upregulation and biological function of transmembrane protein 119 in osteosarcoma

Zhen-Huan Jiang,Jun Peng,Hui-Lin Yang,Xing-Li Fu,Jin-Zhi Wang,Lei Liu,Jian-Nong Jiang,Yong-Fei Tan,Zhi-Jun Ge 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-

Osteosarcoma is suggested to be caused by genetic and molecular alterations that disrupt osteoblast differentiation. Recent studies have reported that transmembrane protein 119 (TMEM119) contributes to osteoblast differentiation and bone development. However, the level of TMEM119 expression and its roles in osteosarcoma have not yet been elucidated. In the present study, TMEM119 mRNA and protein expression was found to be up-regulated in osteosarcoma compared with normal bone cyst tissues. The level of TMEM119 protein expression was strongly associated with tumor size, clinical stage, distant metastasis and overall survival time. Moreover, gene set enrichment analysis (GSEA) of the Gene Expression Omnibus (GEO) GSE42352 dataset revealed TMEM119 expression in osteosarcoma tissues to be positively correlated with cell cycle, apoptosis, metastasis and TGF-β signaling. We then knocked down TMEM119 expression in U2OS and MG63 cells using small interfering RNA, which revealed that downregulation of TMEM119 could inhibit the proliferation of osteosarcoma cells by inducing cell cycle arrest in G0/G1 phase and apoptosis. We also found that TMEM119 knockdown significantly inhibited cell migration and invasion, and decreased the expression of TGF-β pathway-related factors (BMP2, BMP7 and TGF-β). TGF-β application rescued the inhibitory effects of TMEM119 knockdown on osteosarcoma cell migration and invasion. Further in vitro experiments with a TGF-β inhibitor (SB431542) or BMP inhibitor (dorsomorphin) suggested that TMEM119 significantly promotes cell migration and invasion, partly through TGF-β/BMP signaling. In conclusion, our data support the notion that TMEM119 contributes to the proliferation, migration and invasion of osteosarcoma cells, and functions as an oncogene in osteosarcoma.

Metastasis associated genomic aberrations in stage II rectal cancer

Hong Zhao,Zhi-Zhou Shi,Rui Jiang,Dong-Bing Zhao,Hai-Tao Zhou,Jian-Wei Liang,Xin-Yu Bi,Jian-Jun Zhao,Zhi-Yu Li,Jian-Guo Zhou,Zhen Huang,Ye-Fan Zhang,Jian Wang,Xin Xu,Yan Cai,Ming-Rong Wang,Yu Zhang 한국유전학회 2016 Genes & Genomics Vol.38 No.11

Genomic aberrations of rectal carcinoma, especially DNA copy number changes associated with metastasis were largely unclear. We aim to identify the metastasis associated biomarkers in stage II rectal cancer. Formalin-fixed, paraffin-embedded primary tumor tissues of stage II rectal carcinoma were analyzed by array-based comparative genomic hybridization, and genomic aberrations were identified by Genomic Workbench and SAM software. Copy number changes and mRNA expressions were validated by Real-time PCR in an independent rectal cancer samples. The results showed that the most frequent gains in stage II rectal cancer were at 1q21.2-q23.1, 3p21.31, 11q12.2-q23.3, 12q24.11-q24.31, 12q13.11-q14.1 and losses in 18q11.2-q23, 17q21.33-q22, 13q31.1-q31.3, 21q21.1-q21.3, 8p23.3-p23.1 and 4q22.1-q23. Twenty-two amplifications and five homozygous deletions were also identified. We further found that S100A1 (1q21.3-q23.1), MCM7 (7q22.1) and JUND (19p13.11) were amplified and overexpressed in stage II rectal cancer. Interestingly, the genomic aberrations affected 14 signaling pathways including VEGF signaling pathway and fatty acid metabolism. Most importantly, loss of 13q31.1-q34 and gain of 1q44 were associated with distant metastasis. Our results indicated that these metastasis associated genomic changes may be useful to reveal the pathogenesis of rectal cancer metastasis and identify candidate biomarkers.

Experimental study of TiO2 hollow microspheres removal on elemental mercury in simulated flue gas

Jiang Wu,Xian Li,Jian-Xing Ren,Xuemei Qi,Ping He,Bu Ni,Chong Zhang,Chengzhen Hu,Jun Zhou 한국공업화학회 2015 Journal of Industrial and Engineering Chemistry Vol.32 No.-

TiO2 hollow sphere was synthesized by hydrothermal method using trifluoroacetic acid (TFA) andTi(SO4)2 as raw materials, and it was applied to photocatalytic oxidization of elemental mercury (Hg0) inthe simulated flue gas. The prepared samples were well characterized by X-ray diffraction (XRD),scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectronspectroscopy (XPS), UV–vis diffuse reflectance spectra (UV-vis DRS) and nitrogen adsorption/desorption. The results showed that only anatase phase TiO2 hollow sphere was obtained. The average diameter ofTiO2 hollow spheres was about 800 nm and the shell thickness was about 200–400 nm. When M, themolar ratio of TFA to Ti(SO4)2, was higher than a certain value, the photocatalytic activity of preparedTiO2 hollow spheres began to reduce. When M = 2, addition TFA content was the best quantity, which gotthe best TiO2 hollow spheres and provided the most appropriate F decomposed from TFA during thesample preparation, which was helpful to its photocatalytic ability. In the experimental temperaturerange, the photocatalytic oxidation efficiency decreased with the increasing of reaction temperature, andthe intensity of UV irradiation had an important effect on the photocatalytic reaction. When UVirradiation intensity was 303.45 mW cm 2 and reaction temperature was 55 8C, TiO2 hollow spheresample prepared at M = 2 had the highest photocatalytic ability and the mercury removal efficiencyreached up to 82.75%.

A Human Case of Lumbosacral Canal Sparganosis in China

Jian-Feng Fan,Sheng Huang,Jing Li,Ren-Jun Peng,He Huang,Xi-Ping Ding,Li-Ping Jiang,Jian Xi 대한기생충학열대의학회 2021 The Korean Journal of Parasitology Vol.59 No.6

Experimental research for the protective effect of Naoxingtong-containing serum on rat cerebral microvascular endothelial cells

Jun, Zhou,Jianyou, Guo,Jian, Guo,Lanfang, Li,Canghai, Li,Nan, Jiang,Shuying, Guo,Hairu, Huo,JiangTingliang, JiangTingliang Kyung Hee Oriental Medicine Research Center 2005 Oriental pharmacy and experimental medicine Vol.5 No.2

The protective effect of Naoxingtong (NXT) on rat cerebral microvascular endothelial cell (rCMEC) was investigated. rCMEC was injured in vitro by incubating for 4 hours at 100% NO in a hypoxia chamber. After treated with NXT-containing serum, the cellular viability rate (90.3%) was significantly elevated when compared with that of control group and the inhibitive rate of lactic dehydrogenase activity (9.2%) was far lower than the control group with dose-dependent effect. The results indicate that NXT can increase viability of rCMEC, and protect cell membrane from injury during hypoxia.

Organization process of the hierarchical structures in microbially synthesized polyhydroxyalkanoates

Jun Xu,Bao-Hua Guo,Qiong Wu,Jin-Chun Chen,Guo-Qiang Chen,Jian-Jun Zhou,Yong Jiang,Lin Li 한국물리학회 2007 Current Applied Physics Vol.7 No.s1

cess of the high-order structures in biomaterials. Real-time Fourier transform infrared spectroscopy and optical microscopy demon-strated that helical segments formed along with the spherulite growth. Atomic force microscopy revealed the details of growth,twisting and branching of lamellar crystals. Cooperative packing of these twisting lamellae led to regular banded spherulites observedunder polarized light microscopy. Real-time observation on the crystallization process provided richer information than the characterization of the final structures; consequently, it provides deeper insight into the organization mechanism of the hierarchical structures.