Publications by authors named "Xiao-Qing Guan"

29 Publications

  • Page 1 of 1

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Bioorg Med Chem 2021 Apr 30;40:116187. Epub 2021 Apr 30.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address:

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R), 4-methylbenzyl (R) and cyclohexyl (R) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC value (0.13 μM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.
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http://dx.doi.org/10.1016/j.bmc.2021.116187DOI Listing
April 2021

Discovery of naturally occurring inhibitors against SARS-CoV-2 3CL from Ginkgo biloba leaves via large-scale screening.

Fitoterapia 2021 Apr 22;152:104909. Epub 2021 Apr 22.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address:

3-Chymotrypsin-like protease (3CL) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CL inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CL inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CL, Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CL inhibition activity (IC = 6.68 μg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CL inhibition activities (IC < 10 μM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CL inhibition activities, with IC values of less than 2 μM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CLvia a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CL inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CL.
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http://dx.doi.org/10.1016/j.fitote.2021.104909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061081PMC
April 2021

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ.

Front Pharmacol 2020 8;11:628314. Epub 2021 Feb 8.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
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http://dx.doi.org/10.3389/fphar.2020.628314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897654PMC
February 2021

Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase.

ChemMedChem 2021 Feb 2. Epub 2021 Feb 2.

College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, P. R. China.

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC =0.30 μM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R ) and hydrophobic interactions of phenyl moiety (R ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.
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http://dx.doi.org/10.1002/cmdc.202000850DOI Listing
February 2021

Extensive genetic diversity and host range of rodent-borne coronaviruses.

Virus Evol 2020 Jul 21;6(2):veaa078. Epub 2020 Nov 21.

Shanghai Public Health Clinical Center & School of Life Science, Fudan University, Shanghai 201052, China.

To better understand the genetic diversity, host associations and evolution of coronaviruses (CoVs) in China we analyzed a total of 696 rodents encompassing 16 different species sampled from Zhejiang and Yunnan provinces. Based on reverse transcriptase PCR-based CoV screening of fecal samples and subsequent sequence analysis of the RNA-dependent RNA polymerase gene, we identified CoVs in diverse rodent species, comprising , , , , , , , , and . CoVs were particularly commonplace in , with a detection rate of 12.44 per cent (24/193). Genetic and phylogenetic analysis revealed the presence of three groups of CoVs carried by a range of rodents that were closely related to the Lucheng Rn rat CoV (LRNV), China Rattus CoV HKU24 (ChRCoV_HKU24), and Longquan Rl rat CoV (LRLV) identified previously. One newly identified -associated virus closely related to LRNV lacked an NS2 gene. This virus had a similar genetic organization to AcCoV-JC34, recently discovered in the same rodent species in Yunnan, suggesting that it represents a new viral subtype. Notably, additional variants of LRNV were identified that contained putative non-structural (NS)2b genes located downstream of the NS2 gene that were likely derived from the host genome. Recombination events were also identified in the open reading frame (ORF) 1a gene of Lijiang-71. In sum, these data reveal the substantial genetic diversity and genomic complexity of rodent-borne CoVs, and extend our knowledge of these major wildlife virus reservoirs.
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http://dx.doi.org/10.1093/ve/veaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665783PMC
July 2020

Discovery of hCES2A inhibitors from Glycyrrhiza inflata via combination of docking-based virtual screening and fluorescence-based inhibition assays.

Food Funct 2021 Jan 8;12(1):162-176. Epub 2020 Dec 8.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. and Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200473, China.

Human carboxylesterase 2 (hCES2A) is a key target to ameliorate the intestinal toxicity triggered by irinotecan that causes severe diarrhea in 50%-80% of patients receiving this anticancer agent. Herbal medicines are frequently used for the prevention and treatment of the intestinal toxicity of irinotecan, but it is very hard to find strong hCES2A inhibitors from herbal medicines in an efficient way. Herein, an integrated strategy via combination of chemical profiling, docking-based virtual screening and fluorescence-based high-throughput inhibitor screening assays was utilized. Following the screening of a total of 73 herbal products, licorice (the dried root of Glycyrrhiza species) was found with the most potent hCES2A inhibition activity. Further investigation revealed that the chalcones and several flavonols in licorice displayed strong hCES2A inhibition activities, while isoliquiritigenin, echinatin, naringenin, gancaonin I and glycycoumarin exhibited moderate inhibition of hCES2A. Inhibition kinetic analysis demonstrated that licochalcone A, licochalcone C, licochalcone D and isolicoflavonol potently inhibited hCES2A-mediated fluorescein diacetate hydrolysis in a reversible and mixed inhibition manner, with K values less than 1.0 μM. Further investigations demonstrated that licochalcone C, the most potent hCES2A inhibitor identified from licorice, dose-dependently inhibited intracellular hCES2A in living HepG2 cells. In summary, this study proposed an integrated strategy to find hCES2A inhibitors from herbal medicines, and our findings suggested that the chalcones and isolicoflavonol in licorice were the key ingredients responsible for hCES2A inhibition, which would be very helpful to develop new herbal remedies or drugs for ameliorating hCES2A-associated drug toxicity.
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http://dx.doi.org/10.1039/d0fo02140gDOI Listing
January 2021

Design, synthesis and biological evaluation of novel chalcone-like compounds as potent and reversible pancreatic lipase inhibitors.

Bioorg Med Chem 2021 01 9;29:115853. Epub 2020 Nov 9.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address:

Pancreatic lipase (PL), a crucial enzyme responsible for hydrolysis of dietary lipids, has been validated as a key therapeutic target to prevent and treat obesity-associated metabolic disorders. Herein, we report the design, synthesis and biological evaluation of a series of chalcone-like compounds as potent and reversible PL inhibitors. Following two rounds of structural modifications at both A and B rings of a chalcone-like skeleton, structure-PL inhibition relationships of the chalcone-like compounds were studied, while the key substituents that would be beneficial for PL inhibition were revealed. Among all tested chalcone-like compounds, compound B13 (a novel chalcone-like compound bearing two long carbon chains) displayed the most potent PL inhibition activity, with an IC value of 0.33 μM. Inhibition kinetic analyses demonstrated that B13 could potently inhibit PL-mediated 4-MUO hydrolysis in a mixed inhibition manner, with the K value of 0.12 μM. Molecular docking simulations suggested that B13 could tightly bind on PL at both the catalytic site and a non-catalytic site that was located on the surface of PL, which was consistent with the mixed inhibition mode of this agent. In addition, B13 displayed excellent stability in artificial gastrointestinal fluids and good metabolic stability in human liver preparations. Collectively, our findings suggested that chalcone-like compounds were good choices for design and development of orally administrated PL inhibitors, while B13 could be served as a promising lead compound to develop novel anti-obesity agents via targeting on PL.
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http://dx.doi.org/10.1016/j.bmc.2020.115853DOI Listing
January 2021

Rapalogues as hCES2A Inhibitors: In Vitro and In Silico Investigations.

Eur J Drug Metab Pharmacokinet 2021 Jan;46(1):129-139

Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, People's Republic of China.

Background And Objective: Rapamycin and its semi-synthetic analogues (rapalogues) are frequently used in combination with other prescribed medications in clinical settings. Although the inhibitory effects of rapalogues on cytochrome P450 enzymes (CYPs) have been well examined, the inhibition potentials of rapalogues on human esterases have not been investigated. Herein, the inhibition potentials and inhibitory mechanisms of six marketed rapalogues on human esterases are investigated.

Methods: The inhibitory effects of six marketed rapalogues (rapamycin, zotarolimus, temsirolimus, everolimus, pimecrolimus and tacrolimus) on three major esterases, including human carboxylesterases 1 (hCES1A), human carboxylesterases 2 (hCES2A) and butyrylcholinesterase (BuChE), were assayed using isozyme-specific substrates. Inhibition kinetic analyses and docking simulations were performed to investigate the inhibitory mechanisms of the rapalogues with strong hCES2A inhibition potency.

Results: Zotarolimus and pimecrolimus displayed strong inhibition of human hCES2A but these agents did not inhibit hCES1A or BuChE. Further investigation demonstrated that zotarolimus could strongly inhibit intracellular hCES2A in living HepG2 cells, with an estimated IC value of 4.09 µM. Inhibition kinetic analyses revealed that zotarolimus inhibited hCES2A-catalyzed fluorescein diacetate hydrolysis in a mixed manner, with the K value of 1.61 µM. Docking simulations showed that zotarolimus could tightly bind on hCES2A at two district ligand-binding sites, consistent with its mixed inhibition mode.

Conclusion: Our findings demonstrate that several marketed rapalogues are potent and specific hCES2A inhibitors, and these agents can serve as leading compounds for the development of more efficacious hCES2A inhibitors to modulate the pharmacokinetic profiles and toxicity of hCES2A-substrate drugs (such as the anticancer agent irinotecan).
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http://dx.doi.org/10.1007/s13318-020-00659-9DOI Listing
January 2021

Discovery of natural alkaloids as potent and selective inhibitors against human carboxylesterase 2.

Bioorg Chem 2020 12 12;105:104367. Epub 2020 Oct 12.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address:

Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC = 0.94 μM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications.
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http://dx.doi.org/10.1016/j.bioorg.2020.104367DOI Listing
December 2020

Design, synthesis and biological evaluation of indanone-chalcone hybrids as potent and selective hCES2A inhibitors.

Eur J Med Chem 2021 Jan 24;209:112856. Epub 2020 Sep 24.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address:

Human carboxylesterase 2 (hCES2A), one of the major serine hydrolases distributed in the small intestine, plays a crucial role in hydrolysis of ester-bearing drugs. Accumulating evidence has indicated that hCES2A inhibitor therapy can modulate the pharmacokinetic and toxicological profiles of some important hCES2A-substrate drugs, such as the anticancer agent CPT-11. Herein, a series of indanone-chalcone hybrids are designed and synthesized to find potent and highly selective hCES2A inhibitors. Inhibition assays demonstrated that most indanone-chalcone hybrids displayed strong to moderate hCES2A inhibition activities. Structure-hCES2A inhibition activity relationship studies showed that introduction of a hydroxyl at the C4' site and introduction of an N-alkyl group at the C6 site were beneficial for hCES2A inhibition. Particularly, B7 (an N-alkylated 1-indanone-chalcone hybrid) exhibited the most potent inhibition on hCES2A and excellent specificity (this agent could not inhibit other human esterases including hCES1A and butyrylcholinesterase). Inhibition kinetic analyses demonstrated that B7 potently inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a calculated K value of 0.068 μM. Furthermore, B7 was capable of inhibiting intracellular hCES2A in living cells and displayed good metabolic stability. Collectively, our findings show that indanone-chalcone hybrids are good choices for the development of hCES2A inhibitors, while B7 is a promising candidate for the development of novel anti-diarrhea agents to ameliorate irinotecan-induced intestinal toxicity.
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http://dx.doi.org/10.1016/j.ejmech.2020.112856DOI Listing
January 2021

Pentacyclic triterpenoid acids in Styrax as potent and highly specific inhibitors against human carboxylesterase 1A.

Food Funct 2020 Oct;11(10):8680-8693

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Human carboxylesterase 1A1 (hCES1A) is a promising target for the treatment of hyperlipidemia and obesity-associated metabolic diseases. To date, the highly specific and efficacious hCES1A inhibitors are rarely reported. This study aims to find potent and highly specific hCES1A inhibitors from herbs, and to investigate their inhibitory mechanisms. Following large-scale screening of herbal products, Styrax was found to have the most potent hCES1A inhibition activity. After that, a practical bioactivity-guided fractionation coupling with a chemical profiling strategy was used to identify the fractions from Styrax with strong hCES1A inhibition activity and the major constituents in these bioactive fractions were characterized by LC-TOF-MS/MS. The results demonstrated that seven pentacyclic triterpenoid acids (PTAs) in two bioactive fractions from Styrax potently inhibit hCES1A, with IC50 values ranging from 41 nM to 478 nM. Among all the identified PTAs, epibetulinic acid showed the most potent inhibition activity and excellent specificity towards hCES1A. Both inhibition kinetic analyses and in silico analysis suggested that epibetulinic acid potently inhibited hCES1A in a mixed inhibition manner. Collectively, our findings demonstrate that some PTAs in Styrax are potent and highly specific inhibitors of hCES1A and these constituents can be used as promising lead compounds for the development of more efficacious hCES1A inhibitors.
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http://dx.doi.org/10.1039/d0fo01732aDOI Listing
October 2020

Herb-drug interaction between Styrax and warfarin: Molecular basis and mechanism.

Phytomedicine 2020 Oct 21;77:153287. Epub 2020 Jul 21.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200473, China. Electronic address:

Background: Styrax, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa. It is unclear whether Styrax or Styrax-related herbal medicines may trigger clinically relevant herb-drug interactions.

Purpose: This study was carried out to investigate the inhibitory effects of Styrax on human cytochrome P450 enzymes (CYPs) and to clarify whether this herb may modulate the pharmacokinetic behavior of the CYP-substrate drug warfarin when co-administered.

Study Design: The inhibitory effects of Styrax on CYPs were assayed in human liver microsomes (HLM), while the pharmacokinetic interactions between Styrax and warfarin were investigated in rats. The bioactive constituents in Styrax with strong CYP3A inhibitory activity were identified and their inhibitory mechanisms were carefully investigated.

Methods: The inhibitory effects of Styrax on human CYPs were assayed in vitro, while the pharmacokinetic interactions between Styrax and warfarin were studied in rats. Fingerprinting analysis of Styrax coupled with LC-TOF-MS/MS profiling and CYP inhibition assays were used to identify the constituents with strong CYP3A inhibitory activity. The inhibitory mechanism of oleanonic acid (the most potent CYP3A inhibitor occurring in Styrax) against CYP3A4 was investigated by a panel of inhibition kinetics analyses and in silico analysis.

Results: In vitro assays demonstrated that Styrax extract strongly inhibited human CYP3A and moderately inhibited six other tested human CYPs, as well as potently inhibited warfarin 10-hydroxylation in liver microsomes from both humans and rats. In vivo assays demonstrated that compared with warfarin given individually in rats, Styrax (100 mg/kg) significantly prolonged the plasma half-life of warfarin by 2.3-fold and increased the AUC of warfarin by 2.7-fold when this herb was co-administrated with warfarin (2 mg/kg) in rats. Two LC fractions were found with strong CYP3A inhibitory activity and the major constituents in these fractions were characterized by LC-TOF-MS/MS. Five pentacyclic triterpenoid acids (including epibetulinic acid, betulinic acid, betulonic acid, oleanonic acid and maslinic acid) present in Styrax were potent CYP3A inhibitors, and oleanonic acid was a competitive inhibitor against CYP3A-mediated testosterone 6β-hydroxylation.

Conclusion: Styrax and the pentacyclic triterpenoid acids occurring in this herb strongly modulate the pharmacokinetic behavior of warfarin via inhibition of CYP3A.
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http://dx.doi.org/10.1016/j.phymed.2020.153287DOI Listing
October 2020

Pancreatic Lipase Inhibitory Cyclohexapeptides from the Marine Sponge-Derived Fungus sp. 151304.

J Nat Prod 2020 07 14;83(7):2287-2293. Epub 2020 Jul 14.

Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.

Three new cyclohexapeptides, petrosamides A-C (-), were isolated from the sponge-derived fungus sp. 151304. Their structures were elucidated by detailed 1D and 2D spectroscopic analyses, and the absolute configurations of the amino acid residues were determined by the advanced Marfey's method. These peptides displayed significant and dose-dependent pancreatic lipase (PL) inhibitory activities, with IC values of 7.6 ± 1.5, 1.8 ± 0.3, and 0.5 ± 0.1 μM, respectively. Further inhibition kinetics analyses showed that compound inhibited PL in a noncompetitive manner, while molecular dynamics simulation revealed that it could bind to PL at the entrance of the catalytic pocket.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00549DOI Listing
July 2020

Bioluminescent Sensor Reveals that Carboxylesterase 1A is a Novel Endoplasmic Reticulum-Derived Serologic Indicator for Hepatocyte Injury.

ACS Sens 2020 07 15;5(7):1987-1995. Epub 2020 Jul 15.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Discovery of novel liver injury indicators and development of practical assays to detect target indicator(s) would strongly facilitate the diagnosis of liver disorders. Herein, an alternative biomarker discovery strategy was applied to find suitable endoplasmic reticulum-resident protein(s) as serologic indicator(s) for hepatocyte injury via analysis of the human proteome database among plasma and various organs. Both database searching and preliminary experiments suggested that human carboxylesterase 1A (CES1A), one of the most abundant and hepatic-restricted proteins, could serve as a good serologic indicator for hepatocyte injury. Then, a highly selective and practical bioluminescent sensor was developed for real-time sensing of CES1A in various biological systems including plasma. With the help of this bioluminescent sensor, the release of hepatic CES1A into the extracellular medium or the circulation system could be directly monitored. Further investigations demonstrated that serum activity levels of CES1A were elevated dramatically in mice with liver injury or patients with liver diseases. Collectively, this study provided solid evidence to support that CES1A was a novel serological indicator for hepatocyte injury. Furthermore, the strategy used in this study paved a new way for the rational discovery of practical indicators to monitor the dynamic progression of injury in a given tissue or organ.
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http://dx.doi.org/10.1021/acssensors.0c00384DOI Listing
July 2020

Inhibition of pancreatic lipase by environmental xenoestrogens.

Ecotoxicol Environ Saf 2020 Apr 15;192:110305. Epub 2020 Feb 15.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address:

Environmental xenoestrogens are the most accessible endocrine disrupting chemicals that have been reported with harmful effects on human health. Although the influences of xenoestrogens on the endocrine system have been extensively studied, it remains unclear whether these xenoestrogens can affect the digestive system in mammals. This study aimed to investigate the inhibitory effects and the underlying mechanism of six non-steroidal synthetic estrogens (including hexestrol, diethylstilbestrol, dienestrol, bisphenol A, bisphenol AF and bisphenol Z) on pancreatic lipase (PL), a key digestive enzyme responsible for lipid digestion and absorption in mammals. The results clearly demonstrated that hexestrol, diethylstilbestrol and dienestrol exhibited strong inhibition on PL, with the IC values of less than 1.0 μM. Further investigations elucidated that these three synthetic estrogens functioned as mixed inhibitors of PL, with the K values of less than 1 μM. Moreover, molecular dynamics simulations showed that diethylstilbestrol and its analogues might block the binding of substrate on PL via occupying the portal to the active site of PL and thereby inhibit the hydrolytic activity of this key enzyme. Collectively, these results suggested that diethylstilbestrol and its analogues were potent PL inhibitors, which might play a profound role in lipid absorption and weight gain in mammals.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110305DOI Listing
April 2020

Inhibition of pancreatic lipase by the constituents in St. John's Wort: In vitro and in silico investigations.

Int J Biol Macromol 2020 Feb 27;145:620-633. Epub 2019 Dec 27.

College of Basic Medical Sciences, Dalian Medical University, Dalian, China. Electronic address:

Herbal medicines are frequently used for the prevention and treatment of obesity and obesity-related disorders. Our preliminary screening showed that St. John's Wort (SJW) displayed potent inhibition on pancreatic lipase (PL), a key hydrolase responsible for lipid digestion and absorption in mammals. Herein, the inhibition potentials and inhibitory mechanism of SJW extract and its major constituents on PL were fully investigated by a set of in vitro and in silico studies. The results clearly demonstrated that the naphthodianthrones, biflavones and most of flavonoids in SJW displayed strong to moderate inhibition on PL. Among all tested natural compounds, two naphthodianthrones (hypericin and pseudohypericin) and one biflavone (I3,II8-biapigenin) isolated from SJW exhibited potent PL inhibition activity, with the IC values of <1 μM. Inhibition kinetics analyses showed that hypericin, pseudohypericin and I3,II8-biapigenin inhibited PL via a mixed manner, while molecular dynamics simulations revealed that three newly identified PL inhibitors could bind on PL at both the catalytic cavity and the interface between colipase and the C-terminal domain of PL. Collectively, our findings suggested that part of major constituents in SJW displayed potent PL inhibition activities, which could be used as lead compounds for the development of novel PL inhibitors.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.12.231DOI Listing
February 2020

Biflavones from Ginkgo biloba as inhibitors of human thrombin.

Bioorg Chem 2019 11 16;92:103199. Epub 2019 Aug 16.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, China; Henan Key Laboratory of Digestive Organ Transplantation, China; Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, China; Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou 450001, China. Electronic address:

Ginkgo Biloba leaf extract has been widely used for the prevention and treatment of thrombosis and cardiovascular disease in both eastern and western countries, but the bioactive constituents and the underlying mechanism of anti-thrombosis have not been fully characterized. The purpose of this study was to investigate the inhibitory effects of major constituents in Ginkgo biloba on human thrombin, a key serine protease regulating the blood coagulation cascade and the processes of thrombosis. To this end, a fluorescence-based biochemical assay was used to assay the inhibitory effects of sixteen major constituents from Ginkgo biloba on human thrombin. Among all tested natural compounds, four biflavones (ginkgetin, isoginkgetin, bilobetin and amentoflavone), and five flavonoids (luteolin, apigenin, quercetin, kaempferol and isorhamnetin) were found with thrombin inhibition activity, with the IC values ranging from 8.05 μM to 82.08 μM. Inhibition kinetic analyses demonstrated that four biflavones were mixed inhibitors against thrombin-mediated Z-GGRAMC acetate hydrolysis, with the K values ranging from 4.12 μM to 11.01 μM. Molecular docking method showed that the four biflavones could occupy the active cavity with strong interactions of salt bridges and hydrogen bonds. In addition, mass spectrometry-based lysine labeling reactivity assay suggested that the biflavones could bind on human thrombin at exosite I rather than exosite II. All these findings suggested that the biflavones in Ginkgo biloba were naturally occurring inhibitors of human thrombin, and these compounds could be used as lead compounds for the development of novel thrombin inhibitors with improved efficacy and high safety profiles.
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http://dx.doi.org/10.1016/j.bioorg.2019.103199DOI Listing
November 2019

Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening.

Int J Biol Macromol 2019 Sep 29;137:261-269. Epub 2019 Jun 29.

Translational Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine & Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200473, China. Electronic address:

Human carboxylesterase 2 (CES2A), one of the most abundant hydrolases distributed in human small intestine and colon, play key roles in the hydrolysis of a wide range of prodrugs and other esters. Recent studies have demonstrated that CES2A inhibitors may ameliorate irinotecan-induced severe diarrhea, but the specific and efficacious inhibitors targeting intracellular CES2A are rarely reported. Herein, a large-scale screening campaign was conducted for discovery of potent and specific CES2A inhibitor(s). Following screening of more than one hundred of natural products, glabridin (a bioactive compound of Glycyrrhiza glabra L.) was found displaying potent inhibition on CES2A and high specificity over CES1A (>500-fold) and other serine hydrolases. Further investigation showed that glabridin was cell permeable and low cytotoxic, as well as capable of inhibiting intracellular CES2A in living cells, with the IC value of 0.52 μM. Molecular dynamics simulations showed that glabridin formed strong and stable interactions with both the catalytic cavity and Z site of CES2A via hydrophobic interactions. In summary, glabridin was a potent and specific inhibitor targeting intracellular CES2A, which could be used as an ideal lead compound to develop more efficacious CES2A inhibitors for modulating the pharmacokinetic behaviors of CES2A-substrate drugs and alleviating irinotecan-induced diarrhea.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.06.235DOI Listing
September 2019

Discovery of a Highly Divergent Coronavirus in the Asian House Shrew from China Illuminates the Origin of the Alphacoronaviruses.

J Virol 2017 Sep 10;91(17). Epub 2017 Aug 10.

State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing, China

Although shrews are one of the largest groups of mammals, little is known about their role in the evolution and transmission of viral pathogens, including coronaviruses (CoVs). We captured 266 Asian house shrews () in Jiangxi and Zhejiang Provinces, China, during 2013 to 2015. CoV RNA was detected in 24 Asian house shrews, with an overall prevalence of 9.02%. Complete viral genome sequences were successfully recovered from the RNA-positive samples. The newly discovered shrew CoV fell into four lineages reflecting their geographic origins, indicative of largely allopatric evolution. Notably, these viruses were most closely related to alphacoronaviruses but sufficiently divergent that they should be considered a novel member of the genus , which we denote Wénchéng shrew virus (WESV). Phylogenetic analysis revealed that WESV was a highly divergent member of the alphacoronaviruses and, more dramatically, that the S gene of WESV fell in a cluster that was genetically distinct from that of known coronaviruses. The divergent position of WESV suggests that coronaviruses have a long association with Asian house shrews. In addition, the genome of WESV contains a distinct NS7 gene that exhibits no sequence similarity to genes of any known viruses. Together, these data suggest that shrews are natural reservoirs for coronaviruses and may have played an important and long-term role in CoV evolution. The subfamily contains several notorious human and animal pathogens, including severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and porcine epidemic diarrhea virus. Because of their genetic diversity and phylogenetic relationships, it has been proposed that the alphacoronaviruses likely have their ultimate ancestry in the viruses residing in bats. Here, we describe a novel alphacoronavirus (Wénchéng shrew virus [WESV]) that was sampled from Asian house shrews in China. Notably, WESV is a highly divergent member of the alphacoronaviruses and possesses an S gene that is genetically distinct from those of all known coronaviruses. In addition, the genome of WESV contains a distinct NS7 gene that exhibits no sequence similarity to those of any known viruses. Together, these data suggest that shrews are important and longstanding hosts for coronaviruses that merit additional research and surveillance.
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http://dx.doi.org/10.1128/JVI.00764-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553162PMC
September 2017

Extensive diversity of coronaviruses in bats from China.

Virology 2017 07 3;507:1-10. Epub 2017 Apr 3.

State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Zoonoses, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing, China. Electronic address:

To help reveal the diversity and evolution of bat coronaviruses we collected 1067 bats from 21 species in China. A total of 73 coronaviruses (32 alphacoronaviruses and 41 betacoronaviruses) were identified in these bats, with an overall prevalence of 6.84%. All newly-identified betacoronaviruses were SARS-related Rhinolophus bat coronaviruses (SARSr-Rh-BatCoV). Importantly, with the exception of the S gene, the genome sequences of the SARSr-Rh-BatCoVs sampled in Guizhou province were closely related to SARS-related human coronavirus. Additionally, the newly-identified alphacoronaviruses exhibited high genetic diversity and some may represent novel species. Our phylogenetic analyses also provided insights into the transmission of these viruses among bat species, revealing a general clustering by geographic location rather than by bat species. Inter-species transmission among bats from the same genus was also commonplace in both the alphacoronaviruses and betacoronaviruses. Overall, these data suggest that high contact rates among specific bat species enable the acquisition and spread of coronaviruses.
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http://dx.doi.org/10.1016/j.virol.2017.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111643PMC
July 2017

A new pre-column derivatization for valienamine and beta-valienamine using o-phthalaldehyde to determine the epimeric purity by HPLC and application of this method to monitor enzymatic catalyzed synthesis of beta-valienamine.

J Asian Nat Prod Res 2017 Apr;19(4):347-357

a State Key Laboratory of Microbial Metabolism, School of Life Science & Biotechnology, and Joint International Research Laboratory of Metabolic & Developmental Sciences , Shanghai Jiao Tong University , Shanghai 200240 , China.

Valienamine and β-valienamine are representative C N aminocyclitols with significant glycosidase inhibition activity that have been developed as important precursors of drugs for diabetes and lysosomal storage diseases, respectively. The quantitative analysis of these chiral compounds is crucial for asymmetric in vitro biosynthetic processes for converting valienone into valienamine epimers using aminotransferase. Here, we developed an efficient and sensitive method for separation and quantitative analysis of chiral valienamine using reversed-phase high-performance liquid chromatography (HPLC) through o-phthalaldehyde (OPA) pre-column derivatization of the analytes. The epimers were derivatized by OPA in borate buffer (pH 9.0) at room temperature for 30 s, separated on an Eclipse XDB-C18 (5 μm, 4.6 × 150 mm) column, eluted with 22% acetonitrile at 30 °C for 18 min, and detected by a fluorescence detector using 445 nm emission and 340 nm excitation wavelengths. The average resolution of the epimers is 3.86, and the concentration linearity is in the range of 0.02-20 μg/ml. The method proved to be effective, sensitive, and reliable with good intra- and inter-day precision and accuracy, and successfully evaluated the enantiopreference and catalytic capability of the potential aminotransferases on an unnatural prochiral substrate, facilitating the design of an asymmetric biosynthetic route for optically pure valienamine and β-valienamine.
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http://dx.doi.org/10.1080/10286020.2017.1292257DOI Listing
April 2017

[Population dynamics of ground carabid beetles and spiders in a wheat field along the wheat-alfalfa interface and their response to alfalfa mowing].

Ying Yong Sheng Tai Xue Bao 2014 Sep;25(9):2677-82

Taking the wheat-alfalfa and wheat-wheat interfaces as model systems, sampling points were set by the method of pitfall trapping in the wheat field at the distances of 3 m, 6 m, 9 m, 12 m, 15 m, 18 m, 21 m, 24 m, and 27 m from the interface. The species composition and abundance of ground carabid beetles and spiders captured in pitfalls were investigated. The results showed that, to some extent there was an edge effect on species diversity and abundance of ground carabid beetles and spiders along the two interfaces. A marked edge effect was observed between 15 m and 18 m along the alfalfa-wheat interface, while no edge effect was found at a distance over 20 m. The edge effect along the wheat-wheat interface was weaker in comparison to the alfalfa-wheat interface. Alfalfa mowing resulted in the migration of a large number of ground carabid beetles and spiders to the adjacent wheat filed. During ten days since mowing, both species and abundance of ground carabid beetles and spiders increased in wheat filed within the distance of 20 m along the alfalfa-wheat interface. The spatial distribution of species diversity of ground beetles and spiders, together with the population abundance of the dominant Chlaenius pallipes and Pardosa astrigera, were depicted, which could directly indicate the migrating process of natural enemy from alfalfa to wheat field.
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September 2014

Five Chinese pediatric patients with leukemias possibly arising from immature natural killer cells: clinical features and courses.

Pediatr Hematol Oncol 2011 Apr 27;28(3):187-93. Epub 2011 Jan 27.

Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Leukemias arising from immature nature killer (NK) cells have been proposed as distinct entities and are rare. Treatment and prognosis of these diseases are controversial, and data on children are limited. According to the literature, one of these distinct leukemias may be myeloid/NK cell precursor acute leukemia (MNKPL), with the blasts being cytochemically myeloperoxidase negative (MPO(-)) and phenotypically CD56(+)CD3(-)CD7(+)CD34(+) and myeloid antigens(+). The other may be myeloid/NK cell acute leukemia (MNKL), in which the blasts were cytochemically MPO(dim) and phenotypically CD56(+)CD16(-)CD3(-)CD33(+)HLA-DR(-). Between 2005 and 2008, 4 MNKPL and 1 MNKL children aged 1.3 to 12.5 years were encountered in the First Affiliated Hospital of Sun Yat-Sen University. In those with MNKPL, remarkable extramedullary involvement usually occurring in adults was not observed; however, myelofibrosis was found in 2 children. The child with MNKL abandoned treatment. Those with MNKPL were treated with a protocol designed for childhood high-risk acute lymphoblastic leukemia (ALL) containing cytarabine, mitoxantrone, etoposide, l-asparaginase, and methotrexate according to the myeloid and lymphoid characteristics of MNKPL. They responded slowly to chemotherapy and were in complete remission (CR) for 26 to 63 months, except 1 who died in CR from pneumonia. They had longer survival and seemed to have a better outcome than those reported previously. In conclusion, childhood leukemias with immature NK cell markers may have different characteristics from their adult counterparts. A protocol including agents used for acute myeloid leukemia combined with those for ALL is seemingly effective for treatment of MNKPL. However, a modified treatment strategy designed more specifically for MNKPL and longer observations are needed.
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http://dx.doi.org/10.3109/08880018.2010.535117DOI Listing
April 2011

Current status of diagnosis and prognosis of infant acute leukemia in China.

Pediatr Blood Cancer 2009 Dec;53(6):973-7

Department of Pediatric, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou 510080, China.

Objective: Treatment and outcome of infant acute leukemia (IAL) in developed countries have been well documented. However, reports summarizing diagnosis and outcome of IAL in developing countries are limited.

Methods: Five hundred ninety seven pediatric patients were diagnosed with acute leukemia in our hospital between January 1997 and June 2008, of which 19 were younger than 12 months. Data from our 19 cases and the Chinese literature were analyzed.

Results: Of the 19 cases, 14 had acute lymphoblastic leukemia (ALL) and 5 had acute myeloid leukemia (AML) based on FAB classification. Immunophenotyping and molecular genetic analysis were performed in only 6 cases. Only 16% (3/19) of the infants received treatment. Two infants with immunophenotypic AML who abandoned treatment achieved spontaneous remission without chemotherapy within 2 and 4 months respectively. Combining our data with those from Chinese literature, less than one third of the infants had immunophenotypic and genetic verification of leukemia and 29% (18/63) of them received treatment.

Conclusion: Family financial difficulties and physicians' lack of confidence in treatment outcome in IAL contributed to a high treatment abandonment rate and poor outcome. Public health insurance as well as physician education on current IAL treatment strategies may decrease treatment abandonment in China.
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http://dx.doi.org/10.1002/pbc.22145DOI Listing
December 2009

Improved outcome for Chinese children with acute promyelocytic leukemia: a comparison of two protocols.

Pediatr Blood Cancer 2009 Sep;53(3):325-8

Department of Pediatric, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou, China.

Objective: Acute promyelocytic leukemia (APL) is now highly curable, except in many developing countries. Introduction of current treatment strategies may improve the outcome for children with APL in these countries.

Methods: The diagnosis was based on the FAB classification and detection of PML-RAR alpha rearrangement. From December 1999 to September 2004, 16 eligible children were treated with an intensive in-house protocol including high-dose AraC and anthracycline. Subsequently, 14 cases were treated with a less intensive protocol modified from the PETHEMA LPA99.

Results: The 3.5 years event-free survival (EFS) was 37.5% (95% CI, 13.8-61.2%) for patients treated on initial protocol. The treatment failures were: six patients abandoned treatment (37.5%), two who died of intracranial hemorrhage at diagnosis (6.3%) and sepsis in remission (6.3%) respectively, and two who relapsed (12.5%). Those treated on modified PETHEMA had a 3.5 years EFS of 79.6% (95% CI, 52.9-106.3%). Treatment failures included: one who died of intracranial hemorrhage at diagnosis (7.1%) and one who relapsed (7.1%). The patients on modified PETHEMA had a significantly higher EFS (P = 0.012), lower frequency of sepsis during treatment (7.7% vs. 77.8%; P = 0.0015), and lower hospitalization cost (median US$ 4,700 vs. US$ 20,000; P < 0.0001) than those on in-house protocol.

Conclusion: Treatment with the less intensive protocol based on the PETHEMA LPA99 study of childhood APL successfully reduced chemotherapy toxicity and lowered hospitalization costs without increasing relapses. This led to decreases in treatment-related morbidity and the treatment abandonment rate, thus improving overall outcome.
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http://dx.doi.org/10.1002/pbc.22042DOI Listing
September 2009

High-risk childhood acute lymphoblastic leukemia in China: factors influencing the treatment and outcome.

Pediatr Blood Cancer 2009 Feb;52(2):191-5

Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou, China.

Objective: Acute lymphoblastic leukemia (ALL) with high-risk features has an inferior outcome. Factors influencing the treatment and outcome of pediatric ALL with high-risk features in developing countries have not been well studied.

Methods: High-risk features were defined as: age <1 year or >10 years, white blood cell (WBC) > 50 x 10(9)/L, CNS or testicular involvement at diagnosis, T-ALL, BCR-ABL/MLL-AF4, poor prednisone response, slow early response to induction chemotherapy which was defined as M3 status (>25% blasts) on day 15 bone marrow with age >6 years or presenting WBC > 20 x 10(9)/L at diagnosis and/or non-remission (NR) after 33 days of induction therapy.

Results: Ninety-one children were analyzed. The total rate of treatment abandonment was 24.2% and treatment-related mortality was 3.3% (3/91). The event-free survival (EFS) was 52.3% (95% CI, 41.5-63.1%) at 4 years and 49.9% (95% CI, 38.9-60.9%) at 8 years, respectively. When the cases who abandoned treatment were excluded, the EFS of the remainder was 68.3% (95% CI, 56.5-80.1%) at 4 years and 65.2% (95% CI, 52.5-77.9%) at 8 years, respectively. NR on day 33 or BCR-ABL remained as an independent unfavorable prognostic factor in the Cox model even if more intense chemotherapy was administrated.

Conclusion: A decreased treatment-related death frequency was associated with an improved outcome of leukemia. This emphasizes the importance of improving supportive care in developing countries for children with high-risk ALL who receive very intensive chemotherapy. Treatment abandonment remains a prominent reason for treatment failure in China.
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http://dx.doi.org/10.1002/pbc.21810DOI Listing
February 2009

Maintenance therapy with dose-adjusted 6-mercaptopurine in idiopathic pulmonary hemosiderosis.

Pediatr Pulmonol 2008 Nov;43(11):1067-1071

Department of Pediatric, The First Affiliated Hospital of Sun Yat-Sen University, Zhongshan Er Lu, Guangzhou 510080, China.

There are challenges for diagnosis and treatment of idiopathic pulmonary hemosiderosis (IPH). This clinical trial was to review the diagnosis and evaluate the efficacy of maintenance therapy with dose-adjusted 6-mercaptopurine (6MP) in IPH children. Fifteen children were enrolled. Prednisone was administered at 2 mg/kg/day for 4 weeks in acute phase of the disease followed by taper. 6MP was also started at 60 mg/m(2)/day simultaneously and continued for 3 years in outpatient. The delay in diagnosis of IPH is common and probably due to a lack of classical triad of IPH in most children. All the patients exhibited response to the initial treatment. Only one of eight patients with relative leukopenia on 6MP maintenance recurred while 5 of 7 others recurred (P < 0.05) during median 4.5-year follow-up. Of the latter five patients who recurred, 4 remained recurrence-free after adjusting the dose of 6MP upwards to keep relative leucopenia. It suggests that children with IPH could achieve steroid-free long term remission on 6MP maintenance therapy, and relative leukopenia on 6MP might be a simple maker of predicting clinical response in most IPH children.
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http://dx.doi.org/10.1002/ppul.20894DOI Listing
November 2008

The comparison of outcome and cost of three protocols for childhood non-high risk acute lymphoblastic leukemia in China.

Pediatr Blood Cancer 2008 Aug;51(2):204-9

Department of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Objective: To compare the outcome and treatment cost of three protocols for childhood non-high risk acute lymphoblastic leukemia (ALL), and evaluate the feasibility of less intensive treatment protocol for low income families.

Methods: Two hundred forty-three children were newly diagnosed ALL in a university hospital from May 1999 to August 2006. Three protocols were offered to the patients: China-98 protocol, or modified ALLIC BFM2002 protocol, or an in-house Reduced Intensity Protocol (or also known as Economic Protocol).

Results: Among 243 patients, 19 abandoned treatment, 3 transferred to other hospitals, 48 were high-risk and were treated with the high risk protocol, and 4 had mature B-ALL. A total of 169 cases were enrolled on non-high risk protocols: 46 treated on China-98 protocol, 73 on modified ALLIC BFM2002 and 50 from low income families on Economic Protocol. The event-free survival (EFS) at 4 years was 80.4% (95%CI, 68.8-92.2%), 83.5% (95%CI, 73.5-93.5%), and 72.8% (95%CI, 59.3-86.3%) for China-98 protocol, modified ALLIC BFM2002, and Economic Protocol respectively. The hospitalization costs (range and median) were significantly different between protocols: US$ 8,700-25,500 (12,500), US$ 6,900-16,400 (9,900), US$ 3,100-6,800 (4,300) for China-98 protocol, modified ALLIC BFM2002, and Economic Protocol respectively.

Conclusion: This report from China has systematically reviewed the outcome and costs of protocols for ALL having different dose intensity. The reduced intensity protocol appears to achieve reasonable EFS (72.8% at 4 years) for non-high risk ALL at a much lower cost. This is especially important for low income families in developing countries.
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http://dx.doi.org/10.1002/pbc.21598DOI Listing
August 2008

[Study on mesenchymal stem cells entering the brain through the blood-brain barrier].

Zhonghua Er Ke Za Zhi 2004 Dec;42(12):920-3

Department of Neonatology, Children's Hospital, Chongqing University of Medical Sciences, Chongqing 400014, China.

Objective: Neonatal hypoxic-ischemic encephalopathy (HIE) harms the lives and health of newborn infants and children severely. The prognosis is not satisfied, especially of the severe HIE. Mesenchymal stem cells (MSCs) can secrete a series of growth factors and neurotrophic factors. As well they have the potential ability to differentiate to the neural cells in vitro and in vivo. Therefore MSCs transplantation has been employed as a source of progenitor cells for cell therapy in patients with HIE in order to promote recovery of brain function and reduce the sequelae. Studies have shown that MSCs could enter the cerebral parenchyma and differentiate to neural cells through systemic infusion, but most of the researches applied adult stroke animal models. This study used neonatal HIE models to test the hypothesis that MSCs could enter the brain of newborn Wistar rats through the blood-brain barrier (BBB) by intraperitoneal infusion followed by observing the characteristics of the distribution and differentiation of MSCs in brain tissues, and exploring the effects of hypoxic-ischemic brain damage to the penetration and differentiation of MSCs.

Methods: Isolation and purification of MSCs were established from the whole bone marrow of juvenile Wistar rats by removing the nonadherent cells in primary and passage cultures. For cellular identification, MSCs of three to five passages were continuously pre-labeled with 5-bromo-2-deoxyuridine (BrdU) for 72 hours before transplantation. Animal models of HIE were built in 7-day-postnatal Wistar rats according to the method described by Rice. Two hours after hypoxia-ischemia, rats in HIE group (n = 8) were intraperitoneally infused with MSCs (4 x 10(6), 0.5 ml). In control group (n = 8), 7-day-postnatal normal Wistar rats were intraperitoneally infused with the same amount of MSCs. All rats were sacrificed and their cerebra were sectioned by cryomicrotome 14 days after transplantation. Immunohistochemical staining with chromogen diaminobenzidine (DAB) was used to detect and measure the cells derived from MSCs, and study the characteristics of distribution. To determine the differentiation of the BrdU positive cells entering the brains, immunofluorescence double labeling for BrdU and neural cells specific antigens was performed.

Results: MSCs were distributed throughout the cerebra in both groups at the 14th day after transplantation. The number of MSCs detected was 2415 +/- 226 in the control group, and 3626 +/- 461 in HIE group, respectively (t = 6.68, P < 0.05). More BrdU reactive cells were observed in the right ischemic hemisphere (1904 +/- 267) than in the contralateral hemisphere (1723 +/- 204), (t = 4.47, P < 0.05). No significant difference was found while comparing both cerebral hemispheres of the control group (t = 0.31, P > 0.05). In the HIE group, MSCs distributed more extensively, and some focal aggregations of MSCs were noticed. A few MSCs expressed Nestin-protein marker of neural progenitor cells, and almost none of the MSCs which expressed proteins characteristic of neuron (e.g. NSE) and astrocyte (e.g. GFAP) was detected at the 14th day after transplantation.

Conclusion: 1. MSCs could enter the cerebral parenchyma through BBB and migrate throughout the brain by intraperitoneal infusion. 2. More MSCs injected intraperitoneally were localized and directed to the sites of hypoxic-ischemic brain damage. 3. Transplanted MSCs could not differentiate to neuron and astrocyte without other interventions during 14 days after transplantation.
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December 2004