Publications by authors named "Shuanghui Lu"

6 Publications

  • Page 1 of 1

Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway.

Free Radic Biol Med 2021 08 26;172:459-469. Epub 2021 Jun 26.

Laboratory of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) is increasingly identified in inflammatory bowel disease (IBD) patients with unclear etiology. In the current study we assessed the contribution of colonic inflammation to NAFLD development and the underlying mechanism in a mouse model for IBD. Our results showed that dextran sulfate sodium (DSS)-induced gut colitis directly led to hepatic inflammation, injury and further exacerbated hepatic steatosis caused by high fat diet (HF) feeding. The essential genes assessment, hepatic metabolic analysis and triglyceride-rich very low-density lipoprotein (VLDL-TG) secretion assays revealed a higher β-oxidation of fatty acids (FAs) but impaired VLDL-TG secretion in liver of DSS-treated mice. Disruption of the intestinal barrier by DSS promoted liver inflammation, which strongly suppressed hepatic VLDL-TG secretion and further aggravated HF-induced VLDL-TG secretion impairment through down-regulation of apolipoprotein B (APOB), hence promoting the storage of triglycerides (TG) in the liver. Inflammation induced by mixed proinflammatory cytokines or LPS obviously inhibited the expression of microsomal triglyceride transfer protein (MTP) and APOB expression and subsequently increased TG content via the suppression of HNF4α in mouse primary hepatocytes. In addition, the downregulation of MTP and APOB by proinflammatory cytokines was also rescued through activating Hnf4α by cortisol. Altogether, our results demonstrated that chronic inflammation exacerbated hepatic steatosis by inhibiting the secreting of hepatic VLDL-TG through HNF4α pathway, suggesting that restoring hepatic VLDL-TG secretion may be a novel strategy for treatment of NAFLD in IBD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.06.027DOI Listing
August 2021

Downregulation of glucose-6-phosphatase expression contributes to fluoxetine-induced hepatic steatosis.

J Appl Toxicol 2021 08 12;41(8):1232-1240. Epub 2020 Nov 12.

Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Fluoxetine is a first-line selective serotonin reuptake inhibitor widely applied for the treatment of depression; however, it induces abnormal hepatic lipid metabolism. Considering decreased expression or function of glucose-6-phosphatase (G6Pase), a key enzyme in gluconeogenesis, or the upregulation of fatty acid uptake, causes hepatic lipid accumulation. The aim of this study was to elucidate whether G6Pase regulation and fatty acid uptake alteration contribute to fluoxetine-induced abnormal hepatic lipid metabolism. Our study revealed that 8-week oral administration of fluoxetine dose-dependently increased hepatic triglyceride, causing hepatic steatosis. Concomitantly, the expression of G6Pase in mouse livers and primary mouse hepatocytes (PMHs) was downregulated in a concentration-dependent manner. Furthermore, fluoxetine increased the concentrations of glucose-6-phosphate (G6Pase substrate) and acetyl CoA (the substrate for de novo lipogenesis) in mouse livers. Additionally, fluoxetine also induced lipid accumulation and downregulated G6Pase expression in HepG2 cells. However, the uptake of green fluorescent fatty acid (BODIPY™ FL C16) in PMHs was not changed after fluoxetine treatment, indicating that fluoxetine-induced hepatic steatosis was not associated with fatty acid uptake alteration. In conclusion, fluoxetine downregulated hepatic G6Pase expression, subsequently enhanced the transformation of glucose to lipid, and ultimately resulted in hepatic steatosis, but with no impact on fatty acid uptake.
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http://dx.doi.org/10.1002/jat.4109DOI Listing
August 2021

Determination of intracellular anlotinib, osimertinib, afatinib and gefitinib accumulations in human brain microvascular endothelial cells by liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2021 Jan;35(1):e8955

Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China.

Rationale: Brain metastases are a common complication in patients with non-small-cell lung cancer (NSCLC). Anlotinib hydrochloride is a novel multi-target tyrosine kinase inhibitor (TKI) exhibiting a superior overall response rate for brain metastases from NSCLC. The penetrability of anlotinib and three generations of epidermal growth factor receptor (EGFR) TKIs (osimertinib, afatinib and gefitinib) into brain microvascular endothelial cells (HBMECs) was compared.

Methods: A sensitive quantification method for the four TKIs was developed using liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Anlotinib and the three EGFR TKIs were separated on an ACQUITY BEH C18 column after a direct protein precipitation, and then analyzed using electrospray ionization in positive ion mode. The linearity, accuracy, precision, limit of quantification, specificity and stability were assessed.

Results: The four analytes could be efficiently quantified in a single run of 3.8 min. The validation parameters of all analytes satisfy the acceptance criteria of bioanalytical method guidelines. The calibration range was 0.2-200 ng mL for anlotinib and gefitinib, 1-500 ng mL for osimertinib and 1-200 ng mL for afatinib. The penetration of anlotinib across HBMECs was comparable with that of afatinib and gefitinib but less than that of osimertinib.

Conclusions: A sensitive LC/MS/MS method to simultaneously measure anlotinib, osimertinib, afatinib and gefitinib in cell extracts was successfully validated and applied to determine their uptake inside HBMECs, which could pave the way for future research on the role of anlotinib in NSCLC brain metastases.
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http://dx.doi.org/10.1002/rcm.8955DOI Listing
January 2021

Pregnancy Impacts Entecavir Pharmacokinetics but Does Not Alter Its Renal Excretion.

J Pharm Sci 2020 05 4;109(5):1811-1818. Epub 2020 Feb 4.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R. China. Electronic address:

Entecavir (ETV) is a first-line antiviral drug against the hepatitis B virus. This study was designed to investigate whether ETV pharmacokinetics changes during pregnancy and the underlying mechanism. The results showed that ETV exposure in plasma was higher in pregnant rats than in nonpregnant rats, whereas the exposure after delivery was recovered to that in nonpregnant rats. Because 70% of orally dosed ETV is eliminated by kidney, the effects of estradiol (E2) and progesterone (P4), 2 important hormones during pregnancy, on ETV-related renal transporters were investigated. Our results revealed that the activities of the ETV-related renal transporters hOAT1, hOAT3, hMATE1, and hMATE2-K were clearly inhibited by E2 and P4, resulting in reduced ETV accumulation in transporter-transfected cell models. However, the cumulative urinary excretion of ETV in pregnant rats exhibited no significant difference compared to nonpregnant rats, although the endogenous creatinine clearance in pregnant rats was 1.5-fold that of nonpregnant rats. In conclusion, ETV plasma exposure is increased during pregnancy, but ETV renal excretion displays no significant alteration. This may be because, during pregnancy, increased glomerular ETV filtration compensated for the decrease in renal tubular ETV secretion that occurs by E2- and P4-mediated inhibition of related transporters.
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http://dx.doi.org/10.1016/j.xphs.2020.01.027DOI Listing
May 2020

Roles of organic anion transporter 2 and equilibrative nucleoside transporter 1 in hepatic disposition and antiviral activity of entecavir during non-pregnancy and pregnancy.

Br J Pharmacol 2019 09 10;176(17):3236-3249. Epub 2019 Jul 10.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Background And Purpose: Entecavir (ETV), a first-line antiviral drug against hepatitis B virus (HBV), has the possibility to be used to prevent mother-to-child transmission. The aim of present study was to clarify the mechanism of ETV uptake into hepatocytes and evaluate the alteration of ETV's hepatic distribution during pregnancy.

Experimental Approach: The roles of equilibrative nucleotide transporter (ENT) 1 and organic anion transporter (OAT) 2 in ETV accumulation and anti-HBV efficacy were studied in human ENT1 or OAT2 overexpressed cell models and HepG2.2.15 cells, respectively; meanwhile, the liver-to-plasma ETV concentration ratios in non-pregnant and pregnant mice were measured to evaluate the effect of pregnancy on ETV hepatic distribution.

Key Results: ETV was shown to be a substrate of ENT1 and OAT2. An ENT1 inhibitor significantly decreased the efficacy of ETV in HepG2.2.15 cells, while overexpression of OAT2 increased susceptibility of HBV to ETV. The liver-to-plasma ETV concentration ratios in pregnant mice were sharply reduced; whereas, the absolute concentration of ETV in the liver did not obviously alter in pregnancy. Although oestradiol and progesterone showed a concentration-dependent inhibition on ETV accumulation both in hepatic cell lines and in primary human hepatocytes, a physiologically relevant concentration of oestradiol and progesterone did not affect antiviral activity of ETV.

Conclusions And Implications: OAT2 and ENT1 are the main transporters involved in the hepatic uptake and anti-HBV efficacy of ETV. The concentration of ETV in the liver was not obviously altered during pregnancy, which indicates that dosage adjustment in pregnancy is not necessary.
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http://dx.doi.org/10.1111/bph.14756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692639PMC
September 2019

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.
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http://dx.doi.org/10.1128/AAC.00199-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658773PMC
August 2019
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