Ying-yong Zhao

Name:

Organization: Northwest University

Department: Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, the College of Life Sciences

Title:

Chemicals
References

Intrarenal Metabolomic Investigation of Chronic Kidney Disease and its TGF-β1 Mechanism in Induced-adenine Rats using UPLC Q-TOF/HSMS/MSE

Co-reporter:Xiao-Jie Tan;Rui-Chao Lin;Qibing Mei;Xian-Long Cheng;Feng Wei;Xu Bai

Journal of Proteome Research February 1, 2013 Volume 12(Issue 2) pp:692-703

Publication Date(Web):2017-2-22

DOI:10.1021/pr3007792

Chronic kidney disease (CKD) is becoming a worldwide public health problem. In this study, a kidney metabonomics method based on the ultra performance liquid chromatography/high-sensitivity mass spectrometry with MSE data collection technique was undertaken to explore the excretion pattern of low molecular mass metabolites in rat model of adenine-induced chronic renal failure (CRF). Coupled with blood biochemistry and kidney histopathology results, the significant difference in metabolic profiling between the adenine-induced CRF group and the control group by using pattern recognition analysis indicated that changes in global tissue metabolites were occurred. Some significantly changed metabolites like fatty acids, p-cresol sulfate, and indoxyl sulfate have been identified. The results showed that the most important CRF-related metabolites were polyunsaturated fatty acids, indoxyl sulfate, and p-cresyl sulfate. Indoxyl sulfate and p-cresyl sulfate (uremic toxins) were significantly increased in CRF rats. Indoxyl sulfate and p-cresyl sulfate stimulate progressive tubulointerstitial fibrosis by increasing the expression of transforming growth factor-β1 (TGF-β1). These biochemical changes in tissue metabolites are related to the perturbations of fatty acid metabolism and amino metabolism, which may be helpful to further understand the TGF-β1 mechanisms of tubulointerstitial fibrosis. This work shows that the metabonomics method is a valuable tool for studying the essence of CKD.Keywords: chronic kidney disease; metabolomic; MSE; TGF-β1; ultra performance liquid chromatography;

Role of RAS/Wnt/β-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathy

Co-reporter:Lin Chen, Dan-Qian Chen, Ming Wang, Dan Liu, Hua Chen, Fang Dou, Nosratola D. Vaziri, Ying-Yong Zhao

Chemico-Biological Interactions 2017 Volume 273(Volume 273) pp:

Publication Date(Web):1 August 2017

DOI:10.1016/j.cbi.2017.05.025

•RAS plays a key role in the development and progression of CKD.•Recent studies have demonstrated activation of Wnt/β-catenin pathway by RAS in CKD.•RAS and β-catenin and its target protein were up-regulated in HK-2 cell and podocyte.•RAS/Wnt/β-catenin axis activation resulted in HK-2 cell and podocyte injury.•RAS/Wnt/β-catenin activation was restored by alisol B 23-acetate and pachymic acid B.Renin-angiotensin system (RAS) plays a key role in the development and progression of chronic kidney disease (CKD). Recent studies have demonstrated activation of Wnt/β-catenin pathway by RAS in CKD. However, the underlying mechanisms of RAS and Wnt/β-catenin signaling interaction and their contribution to the pathogenesis of CKD have not been fully elucidated. Present study is designed to investigate the role of RAS/Wnt/β-catenin axis activation in tubulo-interstitial fibrosis and glomerulosclerosis by the cultured HK-2 and podocytes. HK-2 cells and podocytes are treated by angiotensin II (Ang II). Ang II up-regulates expression of various Wnt mRNA and active β-catenin protein in HK-2 cells and podocytes in the time- and dose-dependent manners. In addition, Ang II induces injury, oxidative stress and inflammation and impaired Nrf2 activation in HK-2 cells and podocytes. This was accompanied by up-regulations of RAS components as well as Wnt1, activated β-catenin and its target proteins. RAS/Wnt/β-catenin axis activation results in epithelial-to-mesenchymal transition in HK-2 cells and injuries podocytes. The effect of Ang II is inhibited by losartan and ICG-001, a Wnt/β-catenin inhibitor. We further found that treatment with natural products, ergone, alisol B 23-acetate and pachymic acid B inhibit extracellular matrix accumulation in HK-2 cells and attenuated podocyte injury, in part, by inhibiting Ang II induced RAS/Wnt/β-catenin axis activation. In summary, activation of RAS/Wnt/β-catenin axis results in podocytes and tubular epithelial cell, injury and up-regulations of oxidative, inflammatory and fibrotic pathways. These adverse effects are ameliorated by ergone, alisol B 23-acetate and pachymic acid B. Therefore, these natural products could be considered as novel Wnt/β-catenin signaling inhibitors and anti-fibrotic agents.Download high-res image (159KB)Download full-size image

Metabolomic Signatures of Chronic Kidney Disease of Diverse Etiologies in the Rats and Humans

Co-reporter:Zhi-Hao Zhang, Hua Chen, Nosratola D. Vaziri, Jia-Rong Mao, Li Zhang, Xu Bai, and Ying-Yong Zhao

Journal of Proteome Research 2016 Volume 15(Issue 10) pp:3802-3812

Publication Date(Web):September 16, 2016

DOI:10.1021/acs.jproteome.6b00583

Chronic kidney disease (CKD) has emerged as a major public health problem worldwide. It frequently progresses to end-stage renal disease, which is related to very high cost and mortality. Novel biomarkers can provide insight into the novel mechanism, facilitate early detection, and monitor progression of CKD and its response to therapeutic interventions. To identify potential biomarkers, we applied an UPLC-HDMS together with univariate and multivariate statistical analyses using plasma samples from patients with CKD of diverse etiologies (100 sera in discovery set and 120 sera in validation set) and two different rat models of CKD. Using comprehensive screening and validation workflow, we identified a panel of seven metabolites that were shared by all patients and animals regardless of the underlying cause of CKD. These included ricinoleic acid, stearic acid, cytosine, LPA(16:0), LPA(18:2), 3-methylhistidine, and argininic acid. The combination of these seven biomarkers enabled the discrimination of patients with CKD from healthy subjects with a sensitivity of 83.3% and a specificity of 96.7%. In addition, these biomarkers accurately reflected improvements in renal function in response to the therapeutic interventions. Our results indicated that the identified biomarkers may improve the diagnosis of CKD and provide a novel tool for monitoring of the progression of disease and response to treatment in CKD patients.Keywords: 5/6 nephrectomized rats; adenine-induced CKD rats; biomarker; chronic kidney disease; enalapril; irbesartan; metabolomics; plasma;

Lipidomics Biomarkers of Diet-Induced Hyperlipidemia and Its Treatment with Poria cocos

Co-reporter:Hua Miao, Yu-Hui Zhao, Nosratola D. Vaziri, Dan-Dan Tang, Hua Chen, Han Chen, Mahyar Khazaeli, Mehrdokht Tarbiat-Boldaji, Leili Hatami, and Ying-Yong Zhao

Journal of Agricultural and Food Chemistry 2016 Volume 64(Issue 4) pp:969-979

Publication Date(Web):January 12, 2016

DOI:10.1021/acs.jafc.5b05350

Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3-hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites.

The antihyperlipidemic effect of Fu-Ling-Pi is associated with abnormal fatty acid metabolism as assessed by UPLC-HDMS-based lipidomics

Co-reporter:Hua Miao, Ming-Hua Li, Xu Zhang, Sheng-Jun Yuan, Charlene C. Ho and Ying-Yong Zhao

RSC Advances 2015 vol. 5(Issue 79) pp:64208-64219

Publication Date(Web):23 Jul 2015

DOI:10.1039/C5RA09766E

The surface layer of Poria cocos (SLPC), a traditional Chinese medicine, has been commonly used for diuretic and antihyperlipidemia in Asia. In order to understand its biochemical mechanism of antihyperlipidemia, a lipidomic approach based on ultra-performance liquid chromatography coupled with a quadrupole time-of-flight synapt high-definition mass spectrometry was carried out to characterize the plasma lipid metabolic profile of the antihyperlipidemic effect of SLPC in rats fed with a high fat diet. Lipid metabolites with significant changes were characterized as potential biomarkers associated with the development of hyperlipidemia and antihyperlipidemia of SLPC using partial least-squares-discriminate analysis, heatmap display, correlation coefficient analysis and receiver-operating characteristic curves. The analysis of the biological pathway was performed with metabolomics pathway analysis (MetPA). The lipid metabolic profile of hyperlipidemia rats separated from control rats and SLPC treated rats was closer to the control rats. Six lipid metabolites including the five fatty acyl lipids palmitic acid, dodecanoic acid, L-palmitoylcarnitine, oleoylcarnitine and linoleyl carnitine and one sphingolipid phytosphingosine were considered as biomarkers of diet-induced hyperlipidemia and antihyperlipidemic effect of SLPC. MetPA revealed that the identified lipid biomarkers were responsible for diet-induced hyperlipidemia and antihyperlipidemic effect of SLPC. These biomarkers were associated with fatty acid metabolism, fatty acid biosynthesis, sphingolipid metabolism, fatty acid elongation in mitochondria and unsaturated fatty acids biosynthesis. The findings suggest that a high fat diet led to the perturbation of fatty acid metabolism and sphingolipid metabolism, which may be the pharmacological basis of an antihyperlipidemic effect of SLPC.

Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE

Co-reporter:Ying-Yong Zhao, Ping Lei, Dan-Qian Chen, Ya-Long Feng, Xu Bai

Journal of Pharmaceutical and Biomedical Analysis 2013 Volumes 81–82() pp:202-209

Publication Date(Web):July–August 2013

DOI:10.1016/j.jpba.2013.03.028

•Poria cocos epidermis is usually used for the treatment of CKD.•Intrarenal metabolic profiling of FLP therapeutic CKD rats was developed UPLC-HSMS.•The alterations were associated with fatty acids and uremic toxins metabolism.•Metabonomics is helpful to understanding therapeutic mechanism of FLP.Poria cocos epidermis is one of ancient traditional Chinese medicines (TCMs), which is usually used for the treatment of chronic kidney disease (CKD) for thousands of years in China. A metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry (UPLC Q-TOF/HSMS) and a mass spectrometryElevated Energy (MSE) data collection technique was developed to obtained a systematic view of the development and progression of CKD and biochemistry mechanism of therapeutic effects of P. cocos epidermis (Fu-Ling-Pi, FLP). By partial least squares-discriminate analysis, 19 metabolites were identified as potential biomarkers of CKD. Among the 19 biomarkers, 10 biomarkers including eicosapentaenoic acid, docosahexaenoic acid, lysoPC(20:4), lysoPC(18:2), lysoPC(15:0), lysoPE(20:0/0:0), indoxyl sulfate, hippuric acid, p-cresol sulfate and allantoin were reversed to the control level in FLP-treated groups. The study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as fatty acid metabolism, phospholipid metabolism, purine metabolism and tryptophan metabolism. This work was for the first time to investigate the FLP therapeutic effect based on metabonomics technology, which is a potentially powerful tool to study the TCMs.

Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate

Co-reporter:Xuhua Liang, Yang Sun, Wenyuan Zeng, Lusha Liu, Xuan Ma, Yingyong Zhao, Jun Fan

Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 1) pp:178-185

Publication Date(Web):1 January 2013

DOI:10.1016/j.bmc.2012.10.044

To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology.Viability of FR-positive KB cells after exposure to FRHA or parental RHA or the RHA derivative (compound 2 or compound 4) with increasing concentrations in the presence or absence of 0.01 mM FA (as a competitor) at 37 °C for 48 h.

Pharmacokinetics of 2,3,5,4-tetrahydroxystilbene-2-O--D-glucoside in rat using ultra-performance LC-quadrupole TOF-MS

Co-reporter:Ying-Yong Zhao;Li Zhang;Ya-Long Feng;Dan-Qian Chen;Zhi-Hui Xi;Xiao Du;Xu Bai;Rui-Chao Lin

Journal of Separation Science 2013 Volume 36( Issue 5) pp:863-871

Publication Date(Web):

DOI:10.1002/jssc.201200668

2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG) from Polygoni multiflori has been demonstrated to possess a variety of pharmacological activities, including antioxidant, anti-inflammatory and hepatoprotective activities. Ultra-performance LC-quadrupole TOF-MS with MS Elevated Energy data collection technique and rapid resolution LC with diode array detection and ESI multistage MSⁿ methods were developed for the pharmacokinetics, tissue distribution, metabolism, and excretion studies of THSG in rats following a single intravenous or oral dose. The three metabolites were identified by rapid resolution LC-MSⁿ. The concentrations of the THSG in rat plasma, bile, urine, feces, or tissue samples were determined by ultra-performance LC-MS. The results showed that THSG was rapidly distributed and eliminated from rat plasma. After the intravenous administration, THSG was mainly distributing in the liver, heart, and lung. For the rat, the major distribution tissues after oral administration were heart, kidney, liver, and lung. There was no long-term storage of THSG in rat tissues. Total recoveries of THSG within 24 h were low (0.1% in bile, 0.007% in urine, and 0.063% in feces) and THSG was excreted mainly in the forms of metabolites, which may resulted from biotransformation in the liver.

Ultra performance liquid chromatography coupled with electrospray and atmospheric pressure chemical ionization (ESCi)-quadrupole time-of-flight mass spectrometry with novel mass spectrometryElevated Energy (MSE) data collection technique: Determination and pharmacokinetics, tissue distribution and biliary excretion study of ergone in rat

Co-reporter:Ying-Yong Zhao;Xian-Long Cheng;Feng Wei;Xu Bai;Rui-Chao Lin

Journal of Separation Science 2012 Volume 35( Issue 13) pp:1619-1626

Publication Date(Web):

DOI:10.1002/jssc.201200131

Ergosta-4,6,8(14),22-tetraen-3-one (ergone) has been proved to have novel antitumor effects on HepG2 cells. The aim of this study was to investigate the pharmacokinetics, tissue distribution, and biliary excretion of ergone in rats following a single oral administration (5, 10, and 20 mg/kg). The levels of ergone in plasma, tissues, and bile were measured by ultra performance liquid chromatography coupled with electrospray and atmospheric pressure chemical ionization (ESCi)-quadrupole time-of-flight mass spectrometry with novel mass spectrometry^{Elevated Energy} (MS^E) data collection technique method. The results show ergone was distributed and eliminated from rat plasma and in non-linear pharmacokinetics from a dose range of 5–20 mg/kg. The ergone was found to distribute widely in the internal organs, with tissue concentrations in order of lungs, spleen, liver, intestine, kidneys, heart, stomach, parorchis, teasticles, and brain. At 12 h after dosing, the tissue concentrations in the organs were markedly decreased. The lungs, spleen, and liver were the dominant organs with high tissue concentrations that might be the primary sites for metabolism and elimination of ergone. Total recoveries of ergone within 24 h in bile were 34.14%.

Solvent effect on the absorption and fluorescence of ergone: Determination of ground and excited state dipole moments

Co-reporter:Lusha Liu, Yang Sun, Song Wei, Xiaoyun Hu, Yingyong Zhao, Jun Fan

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2012 Volume 86() pp:120-123

Publication Date(Web):February 2012

DOI:10.1016/j.saa.2011.10.016

The effect of solvents on the absorption and emission spectra of ergone has been studied in various solvents at 298 K. The bathochromic shift was observed in absorption and fluorescence spectra with the increase of solvents polarity, which implied that transition involved was π → π*. And the normalized transition energy value ETN showed some scattering when plotted versus Δν. The ground state and excited state dipole moments were calculated by quantum-mechanical second-order perturbation method as a function of the dielectric constant (ɛ) and refractive index (n). The result was found to be 1.435 D and 2.520 D in ground state and excited state respectively. And also, the density functional calculations were used to obtain the ground state and excited state dipole moments for it has proven to be suitable for calculating electronic excitation energy. And the result is consistent with the experimental.Graphical abstractHighlights► Ergosta-4,6,8(14),22-tetraen-3-one was synthesized by ourselves. ► The property of ergone was studied by absorption and emission spectra in various solvents at 298 K. ► Time Dependent Density Functional Theory (TDDFT) was used to validate our results and the conclusion was consistent with experimental.

Pharmacokinetics of ergosterol in rats using rapid resolution liquid chromatography–atmospheric pressure chemical ionization multi-stage tandem mass spectrometry and rapid resolution liquid chromatography/tandem mass spectrometry

Co-reporter:Ying-Yong Zhao, Xian-Long Cheng, Rui Liu, Charlene C. Ho, Feng Wei, Sui-Hong Yan, Rui-Chao Lin, Yongmin Zhang, Wen-Ji Sun

Journal of Chromatography B 2011 Volume 879(Issue 21) pp:1945-1953

Publication Date(Web):1 July 2011

DOI:10.1016/j.jchromb.2011.05.025

Rapid resolution liquid chromatography/tandem multi-stage mass spectrometry (RRLC–MSn) and rapid resolution liquid chromatography/tandem mass spectrometry (RRLC/MS/MS) methods were developed for the identification and quantification of ergosterol and its metabolites from rat plasma, urine and faeces. Two metabolites (ERG1 and ERG2) were identified by RRLC/MSn. The concentrations of the ergosterol were determined by RRLC/MS/MS. The separation was performed on an Agilent Zorbax SB-C18 with the mobile phase consisting of methanol and water (containing 0.1% formic acid). The detection was carried out by means of atmospheric pressure chemical ionization mass spectrometry in positive ion mode with multiple reaction monitoring (MRM). Linear calibration curves were obtained in the concentration range of 7–2000, 6–2000 and 8–7500 ng/mL for plasma, urine and faecal homogenate, respectively. The intra- and inter-day precision values (RSD) were below 10%. The method was applied to the pharmacokinetic properties and elimination pathway of ergosterol in rats.