Publications by authors named "Guang-Bo Ge"

152 Publications

Ethnopharmacology, chemodiversity, and bioactivity of Cephalotaxus medicinal plants.

Chin J Nat Med 2021 May;19(5):321-338

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

Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(21)60032-8DOI Listing
May 2021

Discovery and characterization of flavonoids in vine tea as catechol-O-methyltransferase inhibitors.

Fitoterapia 2021 Apr 28;152:104913. Epub 2021 Apr 28.

School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Vine tea has been used as a traditionally functional herbal tea in China for centuries, which exhibits paramount potential for chronic metabolic diseases. Herein, the inhibitory potential of vine tea toward human catechol-O-methyltransferase (hCOMT) was investigated. A practical bioactivity-guided fractionation combined with chemical profiling strategy was developed to identify the naturally occurring hCOMT inhibitors. Five flavonoids in vine tea displayed moderate to strong inhibition on hCOMT with IC values ranging from 0.96 μM to 42.47 μM, in which myricetin was the critically potent constituent against hCOMT. Inhibition kinetics assays and molecular docking simulations showed that myricetin could bind to the active site of COMT and inhibited COMT-catalyzed 3-BTD methylation in a mixed manner. Collectively, our findings not only suggested that the strong hCOMT inhibition of vine tea has guiding significance in the drug exposure of catechol drugs, but also identified a promising lead compound for developing more efficacious hCOMT inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fitote.2021.104913DOI Listing
April 2021

The comparison analysis of Polyphyllin I and its analogues induced apoptosis of colon and lung cancer cells via mitochondrial dysfunction.

Basic Clin Pharmacol Toxicol 2021 Apr 29. Epub 2021 Apr 29.

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

Polyphyllin I (PPI) and its analogues, including polyphyllin II (PPII), polyphyllin VI (PPVI), and polyphyllin VII (PPVII), are major bioactive compounds isolated from the Chinese herb Chonglou. However, the susceptibilities of PPI and its analogues toward the different cell lines are diversified and the mechanisms are not fully clarified. Thus, the present study aimed to investigate the cytotoxicity of PPI and its analogues on two different cell lines, as well as to explore the underlying mechanisms of these agents via inducing mitochondrial dysfunction. The results showed that PPI and its analogues were cytotoxic agents towards both A549 and HT-29 cells, with IC values ranged from 1.0 to 4.5 μM. Further investigations demonstrated that they decreased the mitochondrial membrane potentials of both A549 and HT-29 cells in a dose-dependent manner. Among all tested compounds, PPVI and PPI induced the most obvious changes in Ca hemostasis in these two cell lines. In addition, they could induce the accumulation of ROS in cells and downregulated the Bcl-2 expression, upregulated the Bax expression, induced the activity of cleaved-caspase-3 in cells. Collectively, our findings clearly demonstrated the cytotoxic differences and mechanisms of PPI and its analogues induced cell apoptosis, and could partially explain the anti-cancer effects of these natural consitituents in Chonglou.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcpt.13596DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fitote.2021.104909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061081PMC
April 2021

Comprehensive profiling and characterization of the absorbed components and metabolites in mice serum and tissues following oral administration of Qing-Fei-Pai-Du decoction by UHPLC-Q-Exactive-Orbitrap HRMS.

Chin J Nat Med 2021 Apr;19(4):305-320

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

Qing-Fei-Pai-Du decoction (QFPDD) is a Chinese medicine compound formula recommended for combating corona virus disease 2019 (COVID-19) by National Health Commission of the People's Republic of China. The latest clinical study showed that early treatment with QFPDD was associated with favorable outcomes for patient recovery, viral shedding, hospital stay, and course of the disease. However, the effective constituents of QFPDD remain unclear. In this study, an UHPLC-Q-Orbitrap HRMS based method was developed to identify the chemical constituents in QFPDD and the absorbed prototypes as well as the metabolites in mice serum and tissues following oral administration of QFPDD. A total of 405 chemicals, including 40 kinds of alkaloids, 162 kinds of flavonoids, 44 kinds of organic acids, 71 kinds of triterpene saponins and 88 kinds of other compounds in the water extract of QFPDD were tentatively identified via comparison with the retention times and MS/MS spectra of the standards or refereed by literature. With the help of the standards and in vitro metabolites, 195 chemical components (including 104 prototypes and 91 metabolites) were identified in mice serum after oral administration of QFPDD. In addition, 165, 177, 112, 120, 44, 53 constituents were identified in the lung, liver, heart, kidney, brain, and spleen of QFPDD-treated mice, respectively. These findings provided key information and guidance for further investigation on the pharmacologically active substances and clinical applications of QFPDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(21)60031-6DOI Listing
April 2021

.

Drug Metab Dispos 2021 Apr 2. Epub 2021 Apr 2.

Shanghai University of Traditional Chinese Medicine, China

Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl (MDP) moiety, is one of the major consitituents in the Chinese herb This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes, as well as to decipher the molecular mechanisms for CYP inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYPs1A, 2C8, 2C9, 2C19 and 3A in human liver microsomes (HLMs) in a reversible way, with IC values varying from 1.06 μM to 3.43 μM. By contrast, MOA time-, concentration- and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with K and values of 207 µM and 0.07 min for CYP2D6, as well as 20.9 µM and 0.03 min for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding -qunione intermediate. Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Methylophiopogonanone A (MOA), an abundant homoisoflavonoid isolated from the Chinese herb , is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding -qunione intermediate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/dmd.120.000325DOI Listing
April 2021

Succinate Mediates Tumorigenic Effects Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas.

Front Endocrinol (Lausanne) 2021 12;12:589451. Epub 2021 Mar 12.

Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D () mutations. mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 () in PPGLs and head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in PPGLs and after knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of -transfected PC12 and ERK pathway signaling compared to control cells. Candidate inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in PPGLs, providing a growth advantage .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.589451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994772PMC
March 2021

A broad-spectrum substrate for the human UDP-glucuronosyltransferases and its use for investigating glucuronidation inhibitors.

Int J Biol Macromol 2021 Jun 16;180:252-261. Epub 2021 Mar 16.

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

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drug/herb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O-glucuronidated by all tested human UGTs, including the typical N-glucuronidating enzymes UGT1A4 and UGT2B10. MOA-O-glucuronidation yielded a single mono-O-glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA-O-glucuronidation activity assay, which was then used for investigating MOA-O-glucuronidation kinetics in recombinant human UGTs. The derived K values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijbiomac.2021.03.073DOI Listing
June 2021

Analytical methodologies for sensing catechol--methyltransferase activity and their applications.

J Pharm Anal 2021 Feb 7;11(1):15-27. Epub 2020 Apr 7.

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

Mammalian catechol--methyltransferases (COMT) are an important class of conjugative enzymes, which play a key role in the metabolism and inactivation of catechol neurotransmitters, catechol estrogens and a wide range of endobiotics and xenobiotics that bear the catechol group. Currently, COMT inhibitors are used in combination with levodopa for the treatment of Parkinson's disease in clinical practice. The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples, as well as for rapid screening and characterization of COMT inhibitors as drug candidates. This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications. Several lists of biochemical assays for measuring COMT activity, including the probe substrates, along with their analytical conditions and kinetic parameters, are presented. Finally, the challenges and future perspectives in the field, such as visualization of COMT activity in vivo and in situ, are highlighted. Collectively, this review article overviews the practical assays for measuring COMT activities in complex biological samples, which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpha.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930641PMC
February 2021

A fluorescence-based microplate assay for high-throughput screening and evaluation of human UGT inhibitors.

Anal Chim Acta 2021 Apr 8;1153:338305. Epub 2021 Feb 8.

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

Human UDP-glucuronosyltransferase enzymes (hUGTs), one of the most important classes of conjugative enzymes, are responsible for the glucuronidation and detoxification of a variety of endogenous substances and xenobiotics. Inhibition of hUGTs may cause undesirable effects or adverse drug-drug interactions (DDI) via modulating the glucuronidation rates of endogenous toxins or the drugs that are primarily conjugated by the inhibited hUGTs. Herein, to screen hUGTs inhibitors in a more efficient way, a novel fluorescence-based microplate assay has been developed by utilizing a fluorogenic substrate. Following screening of series of 4-hydroxy-1,8-naphthalimide derivatives, we found that 4-HN-335 is a particularly good substrate for a panel of hUGTs. Under physiological conditions, 4-HN-335 can be readily O-glucuronidated by ten hUGTs, such reactions generate a single O-glucuronide with a high quantum yield (Ф = 0.79) and bring remarkable changes in fluorescence emission. Subsequently, a fluorescence-based microplate assay is developed to simultaneously measure the inhibitory effects of selected compound(s) on ten hUGTs. The newly developed fluorescence-based microplate assay is time- and cost-saving, easy to manage and can be adapted for 96-well microplate format with the Z-factor of 0.92. We further demonstrate the utility of the fluorescence-based assay for high-throughput screening of two compound libraries, resulting in the identification of several potent UGT inhibitors, including natural products and FDA-approved drugs. Collectively, this study reports a novel fluorescence-based microplate assay for simultaneously sensing the residual activities of ten hUGTs, which strongly facilitates the identification and characterization of UGT inhibitors from drugs or herbal constituents and the investigations on UGT-mediated DDI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aca.2021.338305DOI Listing
April 2021

Paeonone A, a novel nonanortriterpenoid from the roots of Paeonia lactiflora.

Bioorg Chem 2021 May 2;110:104783. Epub 2021 Mar 2.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China. Electronic address:

Paeonone A (1), a unique nonanortriterpenoid, and a new octanortriterpenoid, paeonone B (2), were isolated from the roots of Paeonia lactiflora, together with a known analogue, palbinone (3). Paeonone A (1) is the first example of naturally occurring nonanortriterpenoid with a diketo acid group. Extensive NMR and HRESIMS experiments were applied to identify the structures of 1 and 2, and their absolute configurations were solved by single-crystal X-ray diffraction and ECD data. Biological properties of 1-3 were explored against pancreatic lipase and cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.104783DOI Listing
May 2021

[Construction and application of pharmacophore model of human carboxylesterase 2 inhibitors].

Zhongguo Zhong Yao Za Zhi 2021 Feb;46(3):638-644

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050, China.

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20190603.203DOI Listing
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.628314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897654PMC
February 2021

Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy.

Food Chem Toxicol 2021 Mar 19;149:111998. Epub 2021 Jan 19.

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

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fct.2021.111998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816587PMC
March 2021

[Chemical profiling and tissue distribution study of Jingyin Granules in rats using UHPLC-Q-Exactive Orbitrap HR-MS].

Zhongguo Zhong Yao Za Zhi 2020 Nov;45(22):5537-5554

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

In this study, the chemical profiling of Jingyin Granules and the tissue distribution of nine major constituents in this Chinese medicine were performed after oral administration of Jingyin Granules to rats, by using UHPLC-Q-Exactive Orbitrap HR-MS. An Acquity UPLC BEH C_(18) chromatographic column(2.1 mm×100 mm, 1.7 μm) was used as solid phase, while the mobile phase was methanol and 0.1% formic acid water for gradient elution. The major constituents in this Chinese medicine were quickly and accurately identified, via comparison with the retention times and MS/MS spectra of the standards. A total of 106 chemicals were identified from Jingyin Granules, including 24 kinds of organic acids, 47 kinds of flavonoids, 10 kinds of iridoids, and 21 kinds of saponins and 4 kinds of other compounds. After oral administered Jingyin Granules to rats, 48, 30, 25, 23, 45, 34, 39, 26, 19 prototype compounds were identified in serum, heart, liver, spleen, lung, kidney, brain, fat, and testicles, respectively. Meanwhile, an LC-MS based analytical method was established for simultaneous determination of chlorogenic acid, swertiamarin, caffeic acid, sweroside, liquiritin, prim-O-glucosylcimifugin, arctiin, 5-O-methylvisammioside and arctigenin in biological samples. The tissue distribution(serum, liver and lung) of these nine aim constituents in rats after oral administration of Jingyin Granules were investigated. It was found that these nine constituents could be quickly absorbed into circulation system and then distributed to liver and lung tissues. Except arctigenin, the exposure of other eight aim constituents to serum and lung was peaked at 1 h. At 1 h, the exposure of these components to lung tissue were ranked as follows: swertiamarin [(75 191.0±3 483.21) ng·g~(-1)]>arctiin [(2 716.5±36.06) ng·g~(-1)]>5-O-methylvisammioside [(585.1±0.71) ng·g~(-1)]>arctigenin [(437.45±3.18) ng·g~(-1)]>chlorogenic acid [(308.1±5.66) ng·g~(-1)]>prim-O-glucosylcimifugin [(211.35±2.19) ng·g~(-1)]>sweroside [(184.3±9.05) ng·g~(-1)]>caffeic acid [(175.95±2.05) ng·g~(-1)]>liquiritin [(174.78±153.34) ng·g~(-1)]. In summary, an UHPLC-Q-Exactive Orbitrap HR-MS method has been established for rapid and accurate identification of the constituents in Jingyin Granules, while the tissue distribution of nine major absorpted constituents were investigated in rats following oral administration of Jingyin Granules. These findings provided key information and guidance for further studies on pharmacodynamic substances and clinical applications of Jingyin Granules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200903.201DOI Listing
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0fo02140gDOI Listing
January 2021

Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment.

Bioorg Med Chem 2021 01 7;29:115851. Epub 2020 Nov 7.

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

Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (K = 0.21 ± 0.02 μM, IC = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2020.115851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855844PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2020.115853DOI Listing
January 2021

[Proteomics analysis of erythrocyte membrane in rats with high altitude polycythemia before and after intervention with salidroside].

Zhongguo Zhong Yao Za Zhi 2020 Oct;45(19):4719-4724

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

To investigate the effect of salidroside on the proteomics of erythrocyte membrane in high altitude erythrocytosis(HAPC) rats, in order to explore the mechanism of salidroside in improving HAPC based on the proteomics analysis. First, HPAC rat models were established, and 16 rats were randomly divided into HAPC model group and salidroside(100 mg·kg~(-1)) treatment group(8 rats per group). Saline was administered to the HAPC model group, while salidroside treatment group was given 100 mg·kg~(-1) salidroside once a day. After continuous oral administration with salidroside for 40 days(once a day), blood was collected from the femoral artery to obtain total red blood cell membrane proteins. Two-dimensional electrophoresis was used to separate total proteins. The two-dimensional electrophoresis of erythrocyte membrane proteins was analyzed before and after salidroside intervention, and the proteins with significant differences were identified by mass spectrometry. Finally, biological functions were analyzed using bioinformatics. A two-dimensional electrophoresis method was used to establish a protein expression profile with a high resolution and reproducibility of erythrocyte membranes in HAPC rats. Salidroside treatment significantly changed 18 protein spots in the 2-DE map of erythrocyte membranes, of which 13 proteins were up-regulated and 5 proteins were down-regulated. Eight differential proteins were successfully identified by mass spectrometry. Moreover, bioinformatics analysis found that these differential proteins were involved in such biological processes as oxidative stress, redox, and peroxisome pathway, which are mainly associated with peroxisome and MAPK signaling pathways. Therefore, salidroside could significantly change the expressions of erythrocyte membrane proteins in HAPC rats. Eight differential proteins were identified by a proteomic-based approach. The differential proteins were involved in such biological processes as oxidative stress, redox, peroxisome pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200323.402DOI Listing
October 2020

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).
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112856DOI Listing
January 2021

Bioactivity-Guided Discovery of Human Carboxylesterase Inhibitors from the Roots of .

J Nat Prod 2020 10 20;83(10):2940-2949. Epub 2020 Sep 20.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

In a continuing search for potential inhibitors against human carboxylesterases 1A1 and 2A1 (hCES1A1 and hCES2A1), an EtOAc extract of the roots of showed strong hCES inhibition activity. Bioassay-guided fractionation led to the isolation of 26 terpenoids including 12 new ones (-, -, and ). Among these, sesquiterpenoids and , monoterpenoids , , and -, and triterpenoids -, , and - contributed to the hCES2A1 inhibition, in the IC range of 1.9-14.5 μM, while the pentacyclic triterpenoids - were responsible for the potent inhibitory activity against hCES1A1, with IC values less than 5.0 μM. The structures of all the compounds were elucidated using MS and 1D and 2D NMR data, and the absolute configurations of the new compounds were resolved via specific rotation, experimental and calculated ECD spectra, and single-crystal X-ray diffraction analysis. The structure-activity relationship analysis highlighted that the free HO-3 group in the pentacyclic triterpenoids is crucial for their potent inhibitory activity against hCES1A1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.0c00464DOI Listing
October 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0fo01732aDOI Listing
October 2020

[Research progress in application and mechanism of Schisandrae Chinensis Fructus for prevention and treatment of liver diseases].

Zhongguo Zhong Yao Za Zhi 2020 Aug;45(16):3759-3769

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

Schisandra is the mature fruit of Schisandra chinensis(known as "north Schisandra") or S. shenanthera(known as "south Schisandra"). S. chinensis contains a variety of lignans, volatile oils, polysaccharides, organic acids and other chemical constituents; among them, lignans are recognized as the characteristic active components. Clinical studies have found that Schisandra and Schisandra-related products have a better effect in the prevention and treatment of viral hepatitis, drug-induced liver injury, liver cirrhosis, liver failure and other liver diseases. Modern pharmacological studies have demonstrated that Schisandra has a variety of pharmacological activities, such as anti-inflammation, antioxidation, anticancer, regulation of nuclear receptor, antivirus, regulation of cytochrome P450 enzyme, inhibition of liver cell apoptosis and promotion of liver regeneration. This paper reviews the studies about the applications and mechanism of Schisandra in the prevention and treatment of liver diseases, in the expectation of providing guidance for the development of hepatoprotective drugs from Schisandra and the clinical applications of Schisandra-related products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200513.601DOI Listing
August 2020

[Investigation of modulating effect of Qingfei Paidu Decoction on host metabolism and gut microbiome in rats].

Zhongguo Zhong Yao Za Zhi 2020 Aug;45(15):3726-3739

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

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200609.201DOI Listing
August 2020

Accurate and sensitive detection of Catechol-O-methyltransferase activity by liquid chromatography with fluorescence detection.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Nov 16;1157:122333. Epub 2020 Aug 16.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.

Catechol-O-methyltransferase (COMT) is a major drug metabolizing enzyme in humans. COMT expression is directedly associated with various mental diseases and cancers due to its essential role in catalyzing metabolic inactivation of endogenous catecholamines and catechol estrogens. However, a practical method to precisely measure COMT activities in biological samples is lacking. In the current study, we established a liquid chromatography-fluorescence detection (LC-FD) method based on fluorometric detection of the methylated product of 3-BTD, a fluorescent probe for COMT, to sensitively quantify COMT activities in human erythrocytes and cell homogenates. Assay validation of the established LC-FD based method was conducted for selectivity and sensitivity, range of linearity, precision and accuracy, recovery, biological matrices effect and stability. The limit of quantification for 3-BTMD (the methylated product of 3-BTD by COMT) of this method was 0.0083 nM, which is nearly 10-fold lower than that for previously published methods. The method was precise with intra- and inter-day relative standard deviation (RSD) lower than 5%. In addition, this method showed an excellent anti-interference ability with no effects of the endogenous substances on the fluorometric detection of 3-BTMD. The practical use of this method was established by its successful application for the measurement of COMT activities in individual human erythrocytes (n = 13), and in cell homogenates generated from four different human cell lines. Our results suggest that this method will be of great value in accurately determining the native activity of COMT in biological samples, which is beneficial for a complete understand of the role of COMT both in physiological and pathological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2020.122333DOI Listing
November 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.0c00549DOI Listing
July 2020

An ultra-sensitive and easy-to-use assay for sensing human UGT1A1 activities in biological systems.

J Pharm Anal 2020 Jun 23;10(3):263-270. Epub 2020 May 23.

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

The human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most essential conjugative enzymes, is responsible for the metabolism and detoxification of bilirubin and other endogenous substances, as well as many different xenobiotic compounds. Deciphering UGT1A1 relevance to human diseases and characterizing the effects of small molecules on the activities of UGT1A1 requires reliable tools for probing the function of this key enzyme in complex biological matrices. Herein, an easy-to-use assay for highly-selective and sensitive monitoring of UGT1A1 activities in various biological matrices, using liquid chromatography with fluorescence detection (LC-FD), has been developed and validated. The newly developed LC-FD based assay has been confirmed in terms of sensitivity, specificity, precision, quantitative linear range and stability. One of its main advantages is lowering the limits of detection and quantification by about 100-fold in comparison to the previous assay that used the same probe substrate, enabling reliable quantification of lower amounts of active enzyme than any other method. The precision test demonstrated that both intra- and inter-day variations for this assay were less than 5.5%. Furthermore, the newly developed assay has also been successfully used to screen and characterize the regulatory effects of small molecules on the expression level of UGT1A1 in living cells. Overall, an easy-to-use LC-FD based assay has been developed for ultra-sensitive UGT1A1 activities measurements in various biological systems, providing an inexpensive and practical approach for exploring the role of UGT1A1 in human diseases, interactions with xenobiotics, and characterization modulatory effects of small molecules on this conjugative enzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpha.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322753PMC
June 2020