Publications by authors named "Chenggang Huang"

73 Publications

Increased detection of primary carnitine deficiency through second-tier newborn genetic screening.

Orphanet J Rare Dis 2021 03 23;16(1):149. Epub 2021 Mar 23.

Department of Neonatal Intensive Care Unit, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, 362000, Fujian Province, China.

Background: Newborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay.

Results: An Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%).

Conclusion: Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.
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http://dx.doi.org/10.1186/s13023-021-01785-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988980PMC
March 2021

Identification of the absorbed ingredients and metabolites in rats after an intravenous administration of Tanreqing injection using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

J Sep Sci 2021 Mar 14. Epub 2021 Mar 14.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.

The metabolic profiles of Tanreqing injection, which is a traditional Chinese medicine recommended for complementary administration to treat a novel coronavirus, have remained unclear, which inhibit the understanding of the effective chemical compounds of Tanreqing injection. In this study, a sensitive high-performance liquid chromatography quadrupole time-of-flight mass spectrometry method was used to identify the compounds and metabolites in various biosamples, including plasma, bile, liver, lung, kidney, urine, and feces, following the intravenous administration of Tanreqing injection in rats. A total of 89 compounds were characterized in the biosamples of Tanreqing injection-treated rats including 25 precursor constituents and 64 metabolites. Nine flavonoid compounds, twelve phenolic acids, and four iridoid glycosides were identified in the rats. Their metabolites were mainly produced by glucuronidation, deglucuronidation, glycosylation, deglycosylation, methylation, demethylation, N-heterocyclisation, sulphation, dehydroxylation, decarboxylation, dehydration, hydroxylation, and corresponding recombination reactions. This study was the first to comprehensively investigate the metabolic profile of Tanreqing injection and provides a scientific basis to further elucidate the pharmacodynamic material basis and therapeutic mechanism of Tanreqing injection.
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http://dx.doi.org/10.1002/jssc.202000898DOI Listing
March 2021

Efficacy and Metabolism of the Antimalarial Cycleanine and Improved Antiplasmodial Activity of Semisynthetic Analogues.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

School of Pharmacy and Bioengineering, Keele University, Stoke-on-Trent, United Kingdom

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the antiplasmodial activity of three BBIQ alkaloids (cycleanine [compound 1], isochondodendrine [compound 2], and 2'-norcocsuline [compound 3]) isolated from the Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semisynthetic analogues (compounds 4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant strain were determined using a SYBR green 1 fluorescence assay. The antimalarial activity of cycleanine is then investigated in suppressive, prophylactic, and curative murine malaria models after infection with a chloroquine-sensitive strain. BBIQ alkaloids (compounds 1 to 5) exerted antiplasmodial activities with 50% inhibitory concentration (IC) at low micromolar concentrations and the two semisynthetic cycleanine analogues showed an improved potency and selectivity compared to those of cycleanine. At oral doses of 25 and 50 mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitemia and increased mean survival times significantly compared to those of the control groups. The metabolites and metabolic pathways of cycleanine were also studied using high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastric administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these and results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.
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http://dx.doi.org/10.1128/AAC.01995-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848973PMC
January 2021

Baicalin Inhibits Influenza A Virus Infection Promotion of M1 Macrophage Polarization.

Front Pharmacol 2020 6;11:01298. Epub 2020 Oct 6.

Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.

Background And Aims: The natural compound baicalin (BA) possesses potent antiviral properties against the influenza virus. However, the underlying molecular mechanisms of this antiviral activity and whether macrophages are involved remain unclear. In this study, we, therefore, investigated the effect of BA on macrophages.

Methods: We studied macrophage recruitment, functional phenotypes (M1/M2), and the cellular metabolism flow cytometry, qRT-PCR, immunofluorescence, a cell culture transwell system, and GC-MS-based metabolomics both in H1N1 A virus-infected mice and .

Results: BA treatment drastically reduced macrophage recruitment (CD11b, F4/80) by approximately 90% while maintaining the proportion of M1-polarized macrophages in the bronchoalveolar lavage fluid of infected mice. This BA-stimulated macrophage M1 phenotype shift was further verified in ANA-1 and primary peritoneal macrophages by measuring macrophage M1 polarization signals (CD86, iNOS, TNF-α, ratio, and IL-1β cleavage). Meanwhile, we observed an activation of the IFN pathway (upregulation of and ), an inhibition of influenza virus replication (as measured by the gene), and distinct cellular metabolic responses in BA-treated cells.

Conclusion: BA triggered macrophage M1 polarization, IFN activation, and other cellular reactions, which are beneficial for inhibition of H1N1 A virus infection.
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http://dx.doi.org/10.3389/fphar.2020.01298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574031PMC
October 2020

Determination of the antidiabetic chemical basis of Phellodendri Chinensis Cortex by integrating hepatic disposition in vivo and hepatic gluconeogenese inhibition in vitro.

J Ethnopharmacol 2020 Dec 5;263:113215. Epub 2020 Aug 5.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Ethnopharmacological Relevance: Phellodendri Chinensis Cortex (PCC) has been an herb clinically used to treat diabetes, but the chemical basis of its antidiabetic effects has remained unclear.

Aim Of This Study: Based on the efficacy of herbal medicine resulting from the cooperative response of the effective compounds in the target organs with sufficient exposure, the in vivo hepatic disposition and in vitro hepatic gluconeogenesis inhibition were integrated to elucidate the chemical basis for the antidiabetic effect of orally administered PCC from a target organ, liver, perspective.

Materials And Methods: With a developed and validated HPLC-MS/MS method, three alkaloids and five metabolites were determined in the portal vein plasma, liver, and systemic plasma of rats orally administered PCC. The inhibition of hepatic gluconeogenesis by the eight compounds was evaluated in primary hepatocytes.

Results: The in vivo results showed that magnoflorine was present at the highest concentration among the target constituents in the plasma, where berberine showed a low concentration. In contrast, berberine showed the highest concentration in the liver, and its five metabolites exhibited substantial hepatic accumulation. This discrepancy was strongly associated with the hepatic disposition of the compounds. The hepatic disposition prevented the transfer of 96.1% of the phellodendrine, 71.1% of the berberine and 47.5% of the magnoflorine from the portal vein plasma to the systemic plasma, which corresponded to their hepatic distribution and hepatic metabolism. In vitro, berberine, M1, M4 and M5 significantly and dose-dependently inhibited hepatic glucose production. By integrating the hepatic exposure and inhibitory activity data, we estimated that berberine contributed the most (74%) to the total glucose production inhibition of the orally administered PCC decoction, followed by M4 (14%), M1 (11%) and M5 (1%).

Conclusion: This study was the first to comprehensively describe the pharmacokinetic profiles and hepatic disposition of alkaloids in PCC, and concluded that berberine and its metabolites contributed the most to the total hepatic gluconeogenesis inhibition by orally administered PCC. These results reveal the chemical basis for the antidiabetic effect of orally administered PCC decoction, providing scientific evidence to support the clinical usage of PCC in diabetes treatment.
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http://dx.doi.org/10.1016/j.jep.2020.113215DOI Listing
December 2020

Identification of a novel homozygous nonsense variant in a Chinese patient with ethylmalonic encephalopathy and a genotype-phenotype spectrum review.

Clin Chim Acta 2020 Oct 30;509:8-17. Epub 2020 May 30.

Medical Genetic Center, Changzhi Maternal and Child Health Care Hospital, 38 Weiyuanmen Road, Changzhi, Shanxi 046000, China. Electronic address:

Ethylmalonic encephalopathy (EE) is a rare and devastating neurodegenerative disease caused by mutations in the ETHE1 gene. It is characterized by early-onset encephalopathy, chronic diarrhea, petechiae, orthostatic acrocyanosis, and high levels of methylsuccinic, lactic, and ethylmalonic acids in body fluids. In this study, we report a patient with EE, who was identified through newborn screening, and the diagnosis was confirmed by targeted next-generation sequencing (NGS). The patient displayed recurrent petechiae, intermittent jaundice, protracted diarrhea, and extensive developmental regression. Genetic testing identified a homozygous nonsense variant, c.295C > T (p. Q99*), in the ETHE1 gene. A review of all known ETHE1 variants observed in other EE patients was conducted. This revealed the current difficulties in EE diagnosis. Besides, it also showed that patients with truncated variants of ETHE1 might exhibit pathological symptoms earlier and present more severe manifestations. Finally, a novel nonsense variant was identified, which supported and expanded our current knowledge of the variant spectrum for ETHE1. This novel variant also deepened our understanding of the genotype-phenotype associations that occur in EE patients.
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http://dx.doi.org/10.1016/j.cca.2020.05.051DOI Listing
October 2020

Correction to: Identifying the active components of Baihe-Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests.

Chin Med 2020;15:32. Epub 2020 Apr 2.

2Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 People's Republic of China.

[This corrects the article DOI: 10.1186/s13020-019-0254-9.].
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http://dx.doi.org/10.1186/s13020-020-00312-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115082PMC
April 2020

Alleviation of Synovial Inflammation of Juanbi-Tang on Collagen-Induced Arthritis and TNF-Tg Mice Model.

Front Pharmacol 2020 14;11:45. Epub 2020 Feb 14.

Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. In this study, we found that a traditional Chinese decoction, Juanbi-Tang (JBT), JBT attenuated the symptoms of collagen-induced arthritis (CIA) mice and in tumor necrosis factor transgenic (TNF-Tg) mice by attenuating the arthritis index and hind paw thickness. According to histopathological staining of ankle sections, JBT significantly decreased the area of inflammation and reduced bone destruction of ankle joints in both these two types of mice. Moreover, decreased tartaric acid phosphatase-positive osteoclasts were observed in the JBT group compared with those found in the control group. We also revealed that JBT suppressed monocytes and T cells as well as the production of CCL2, CCR6, and CXCR3 ligands. We next used high-performance liquid chromatography to investigate the components and pharmacological properties of this classical herbal medicine in traditional Chinese medicine. Based on network pharmacology, we performed computational prediction simulation of the potential targets of JBT, which indicated the NF-kappa B pathway as its target, which was confirmed in vitro. JBT suppressed the production of pro-inflammatory cytokines including interleukin-6 (IL-6) and IL-8, and inhibited the expression of matrix metalloproteinase 1 in fibroblast-like synoviocytes derived from RA patients (MH7A cells). Furthermore, JBT also suppressed the phosphorylation of p38, JNK, and p65 in TNF-α-treated MH7A cells. In summary, this study proved that JBT could inhibit synovial inflammation and bone destruction, possibly by blocking the phosphorylation of NF-kappa B pathway-mediated production of proinflammatory effectors.
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http://dx.doi.org/10.3389/fphar.2020.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033619PMC
February 2020

Systematic investigation on the chemical basis of anti-NAFLD Qushi Huayu Fang. Part 1: A study of metabolic profiles in vivo and in vitro by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

Biomed Chromatogr 2020 May 20;34(5):e4805. Epub 2020 Feb 20.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Qushi Huayu Fang (QHF) is a clinic-empirical prescription for treating non-alcoholic fatty liver disease (NAFLD) in China, which is composed of five herbs. However, the bioactive constituents responsible for the efficacy of QHF remain unclear. Thus, a high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method was established and adopted to identify the constituents of QHF, and profile its metabolism in vivo and in vitro. Among the 66 constituents in QHF, only 14 compounds of six structural types were absorbed, and 34 metabolites were generated through eight metabolic pathways. A total of 20 metabolites were first reported, including four organic acids, one iridoid, two flavones, five naphthols, three anthraquinones, and five stilbenes. Glucuronidation and sulfation were the main metabolic pathways, and the intestinal metabolism played an important role in the biotransformation of QHF. Many compounds, especially those detected in the liver, the target organ of QHF, were reported to display the anti-NAFLD activity. This is the first study to explore the constituents of QHF and its metabolism in vivo and in vitro, thus realizing the first step to clarify the chemical basis of QHF qualitatively, and laying the foundation for further research on the anti-NAFLD mechanism of QHF.
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http://dx.doi.org/10.1002/bmc.4805DOI Listing
May 2020

Newborn Screening for Spinal Muscular Atrophy in China Using DNA Mass Spectrometry.

Front Genet 2019 17;10:1255. Epub 2019 Dec 17.

Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality. Early detection of SMA through newborn screening (NBS) is essential to selecting pre-symptomatic treatment and ensuring optimal outcome, as well as, prompting the urgent need for effective screening methods. This study aimed to determine the feasibility of applying an Agena iPLEX SMA assay in NBS for SMA in China. We developed an Agena iPLEX SMA assay based on the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and evaluated the performance of this assay through assessment of 167 previously-genotyped samples. Then we conducted a pilot study to apply this assay for SMA NBS. The and copy number of screen-positive patients were determined by multiplex ligation-dependent probe amplification analysis. The sensitivity and specificity of the Agena iPLEX SMA assay were both 100%. Three patients with homozygous deletion were successfully identified and conformed by multiplex ligation-dependent probe amplification analysis. Two patients had two copies, which was correlated with severe SMA type I phenotype; both of them exhibited neurogenic lesion and with decreased muscle power. Another patient with four copies, whose genotype correlated with milder SMA type III or IV phenotype, had normal growth and development without clinical symptoms. The Agena iPLEX SMA assay is an effective and reliable approach for population-based SMA NBS. The first large-scale pilot study using this assay in the Mainland of China showed that large-scale implementation of population-based NBS for SMA is feasible.
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http://dx.doi.org/10.3389/fgene.2019.01255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928056PMC
December 2019

Newborn screening and diagnosis of inborn errors of metabolism: A 5-year study in an eastern Chinese population.

Clin Chim Acta 2020 Mar 29;502:133-138. Epub 2019 Dec 29.

Center of Neonatal Disease Screening, Maternal and Child Health Care Hospital, 12 Gongxiao Road, Jining, Shandong Province, China. Electronic address:

Inborn errors of metabolism (IEMs) can cause intellectual disability or even death in children. To evaluate the disease spectrum and genetic characteristics of IEMs in Jining City of Shandong Province in East China, we used tandem mass spectrometry (MS/MS) technology for IEMs screening combined with genetic analysis. Newborns were screened from July 14, 2014, to December 31, 2018. Amino acid and carnitine contents were detected by MS/MS. According to the results for normal newborns, the reference range of our laboratory was established with the percentile method. The suspected positive newborns were further diagnosed using next-generation sequencing. A total of 514,234 newborns were screened, and 265 were diagnosed with IEMs, with a detection rate of 1:1941. Of the 265 patients, 130 (49.06%) had organic acid disorders, 83 (31.32%) had amino acid disorders, 34 (12.83%) had fatty acid oxidation disorders, and 18 (6.79%) had urea circulatory disorders. PAHD and MMA were the two most common disorders. IEMs-associated genes were identified in 233 patients. Our data indicated that IEMs are never uncommon in Jining, and the disease spectrum and genetic background were clearly elucidated, contributing to the treatment and prenatal genetic counseling of these disorders in the region.
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http://dx.doi.org/10.1016/j.cca.2019.12.022DOI Listing
March 2020

Combining newborn metabolic and genetic screening for neonatal intrahepatic cholestasis caused by citrin deficiency.

J Inherit Metab Dis 2020 05 29;43(3):467-477. Epub 2019 Dec 29.

Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

To evaluate the feasibility of incorporating genetic screening for neonatal intrahepatic cholestasis, caused by citrin deficiency (NICCD), into the current newborn screening (NBS) program. We designed a high-throughput iPLEX genotyping assay to detect 28 SLC25A13 mutations in the Chinese population. From March 2018 to June 2018, 237 630 newborns were screened by tandem mass spectrometry at six hospitals. Newborns with citrulline levels between cutoff and cutoff values of the upper limit were recruited for genetic screening using the newly developed assay. The sensitivity and specificity of the iPLEX genotyping assay both reached 100% in clinical practice. Overall, 29 364 (12.4%) newborns received further genetic screening. Five patients with conclusive genotypes were successfully identified. The most common SLC25A13 mutation was c.851_854del, with an allele frequency of 60%. In total, 658 individuals with one mutant allele were identified as carriers. Eighteen different mutations were observed, yielding a carrier rate of 1/45. Notably, Quanzhou in southern China had a carrier rate of up to 1/28, whereas Jining in northern China had a carrier rate higher than that of other southern and border cities. The high throughput iPLEX genotyping assay is an effective and reliable approach for NICCD genotyping. The combined genetic screening could identify an additional subgroup of patients with NICCD, undetectable by conventional NBS. Therefore, this study demonstrates the viability of incorporating genetic screening for NICCD into the current NBS program.
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http://dx.doi.org/10.1002/jimd.12206DOI Listing
May 2020

Identifying the active components of Baihe-Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests.

Chin Med 2019 24;14:37. Epub 2019 Sep 24.

2Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, 201203 People's Republic of China.

Background: Modern pharmacological studies have demonstrated that Baihe-Zhimu decoction (BZD) has antidepressant effects. However, the complex composition and lack of clear evaluation standards for BZD make it less likely to be understood and accepted than evidence-based active natural compounds.

Methods: In this study, an effective method for the identification of antidepressant components was demonstrated and applied to BZD. The first step was to evaluate the efficacy of BZD by the forced swimming test (FST) and the tail suspension test (TST), followed by successive quantitative analyses of the absorbed constituents at different stages, such as before hepatic disposition, liver distribution, after hepatic disposition and brain distribution after the oral administration of BZD. Finally, the compounds detected in the brain were confirmed by activity testing.

Results: Our investigation observed that timosaponin BII and timosaponin BIII were accurately determined in the brain after oral administration of BZD, and they were further confirmed to reduce the immobility time in the FST and TST. As described above, timosaponin BII and timosaponin BIII were used to scientifically and reasonably explain the effective chemical basis of the effect of BZD on depression.

Conclusions: This research affords an effective method to discover lead molecules for antidepressants from traditional Chinese medicine.
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http://dx.doi.org/10.1186/s13020-019-0254-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757420PMC
September 2019

A comprehensive study of pomegranate flowers polyphenols and metabolites in rat biological samples by high-performance liquid chromatography quadrupole time-of-flight mass spectrometry.

J Chromatogr A 2019 Oct 22;1604:460472. Epub 2019 Aug 22.

University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:

Pomegranate flowers is an ancient medicine that has commonly been used to treat various diseases such as diabetes. However, no reports are available on the metabolic profile of pomegranate flowers in vivo. In the present study, with the aid of HPLC-Q-TOF-MS, 67 compounds were identified in pomegranate flowers extract, including 18 ellagitannins, 14 gallic acid and galloyl derivatives, five anthocyanins and 18 flavonoids. Seven compounds were firstly identified. In vivo, 22 absorbed compounds and 35 metabolites were identified in rat biosamples (urine, feces, plasma and tissues) after orally administered with pomegranate flowers extract. This result showed that not all compounds abundant in pomegranate flowers extract could be absorbed well in plasma and tissues. This finding also suggested a potential correlation between study on metabolic profile of these compounds in vivo and study on strategy of screening bioactivity of the isolates with in vitro cell systems evaluation. Notably, mono-glucuronide conjugated metabolite of ellagitannin compound (corilagin) was firstly identified. In addition, this is first report to identify phase II conjugate metabolites of ellagitannins in vivo after oral administration of ellagitannins-rich extracts (or foods). Thus, characterizing its multiple constitution, absorption and metabolic fate of these compounds in vivo is helpful to better analyze the active components in pomegranate flowers.
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http://dx.doi.org/10.1016/j.chroma.2019.460472DOI Listing
October 2019

Determining the protective effects of Yin-Chen-Hao Tang against acute liver injury induced by carbon tetrachloride using 16S rRNA gene sequencing and LC/MS-based metabolomics.

J Pharm Biomed Anal 2019 Sep 21;174:567-577. Epub 2019 Jun 21.

Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, 201203, PR China. Electronic address:

Yin-Chen-Hao Tang (YCHT), consisting of Artemisia annua L., Gardenia jasminoides Ellis, and Rheum Palmatum L., has been used to relieve liver diseases in China for thousands of years. Several protective mechanisms of YCHT on liver injury have been investigated based on metabolomics, but the effects of YCHT on the alterations in the gut microbiota are still unclear. In this study, an integrated approach based on 16S rRNA gene sequencing combined with high-performance liquid chromatography-mass spectrometry (HPLC-MS) metabolic profiling was performed to assess the effects of YCHT on liver injury induced by carbon tetrachloride (CCl) through the regulation of the relative abundances of gut microbiota and their relationships with biomarker candidates. A total of twelve significantly altered bacterial genera and nine metabolites were identified, which returned to normal levels after YCHT treatment. The relative abundances of the identified microbiota, including significantly elevated amounts of p_Firmicutes, c_Clostridia, o_Clostridiales, f_Ruminococcaceae, g_[Eubacterium]_coprostanoligenes_group, s_uncultured_bacterium_f_Lachnospiraceae and remarkedly increased amounts of p_Bacteroidetes, c_Bacteroidia, o_Bacteroidales, f_Bacteroidaceae, g_Bacteroides and s_uncultured_bacterium_g_Bacteroides, were found in model rats compared with controls. Potential biomarkers, including lower levels of LysoPC (16:1(9Z)/0:0), LysoPC (20:3(5Z,8Z,11Z)), LysoPC (17:0), LysoPC (20:1(11Z)) and 3-hydroxybutyric acid and higher amounts of ornithine, L-kynurenine, hippuric acid and taurocholic acid are involved in several custom metabolic pathways, such as arginine and proline metabolism, tryptophan metabolism, glycerophospholipid metabolism and primary bile acid biosynthesis. Interestingly, there was a strong correlation between the perturbed gut microbiota in genera c_Clostridia and o_Clostridiales and the altered plasma metabolite 3-hydroxybutyric acid. This finding means that the hepatoprotective effects of YCHT may be due to the regulation of the production of the functional metabolite 3-hydroxybutyric acid through changes in the proportions of c_Clostridia and o_Clostridiales. These results showed that the hepatoprotective effects of YCHT not only focused on custom metabolic pathways but also depended on the changes in the gut microbiota in liver injury. These findings suggest that the 16S rRNA gene sequencing and LC-MS based metabolomics approach can be applied to comprehensively evaluate the effects of traditional Chinese medicines (TCMs).
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http://dx.doi.org/10.1016/j.jpba.2019.06.028DOI Listing
September 2019

Metabonomics Study on the Hepatoprotective Effect of Leaf Saponins Using UPLC/Q-TOF-MS Analysis.

Am J Chin Med 2019 23;47(3):559-575. Epub 2019 Apr 23.

* Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai Zhangjiang Hitech Park, Shanghai 201203, P. R. China.

Alcohol liver disease is a major public health problem associated with lifestyle. Our recent study demonstrated that the roots of saponins (PNS) exert hepatoprotective effects against alcohol consumption. Considering that the leaves of saponins (LPNS) have similar chemical ingredients with PNS, increased attention should be given to the hepatoprotective effects of LPNS. In this study, a metabonomic approach based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was developed to evaluate the hepatoprotective effect of LPNS on alcoholic fatty liver and elucidate the interaction mechanisms. Results showed that the ethanol-induced metabolic perturbations were restored after treatment with LPNS. Furthermore, 12 potential biomarkers (11 upregulated and 1 downregulated) were identified by V-plot and orthogonal partial least square discriminant analysis. Changes in the levels of these metabolites indicated that glycerophospholipid and fatty acid metabolism were disturbed in alcoholic fatty liver mouse. Our findings demonstrated that the UHPLC-QTOF/MS-based metabonomic method may provide a useful means for exploring biomarkers involved in alcoholic fatty liver and elucidating the therapeutic effects of LPNS. This work also showed that the metabonomic approach is a powerful and promising tool for the evaluation of the efficacy of traditional Chinese medicine and elucidation of related mechanisms.
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http://dx.doi.org/10.1142/S0192415X19500290DOI Listing
October 2019

Exploration of the hepatoprotective chemical base of an orally administered herbal formulation (YCHT) in normal and CCl-intoxicated liver injury rats. Part 1: Metabolic profiles from the liver-centric perspective.

J Ethnopharmacol 2019 Jun 20;237:81-91. Epub 2019 Mar 20.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Ethnopharmacological Relevance: Yin-Chen-Hao Tang (YCHT), derived from "Treatise on Febrile Diseases" in ancient China, has been a very popular hepatoprotective three-herb formula in China and Japan, although its chemical base remains unclear.

Aim Of This Study: As the first step in revealing the hepatoprotective chemical base of YCHT, we aimed to clarify the absorbed ingredients and associated metabolic pathways for orally dosed YCHT in both normal and liver injury rats from a liver-centric perspective.

Materials And Methods: With the aid of 10 reference compounds, the absorbed ingredients and generated metabolites were systematically characterized by high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF) in the portal vein plasma (the plasma before hepatic disposition) - liver - systemic plasma (the plasma after hepatic disposition), following oral administration of YCHT in normal and CCl-induced liver injury rats.

Results: A total of 38 compounds with six chemical structures, consisting of 10 prototypes and 28 metabolites generated through 9 biotransformations, were absolutely or tentatively identified, and 25 compounds were first reported on YCHT treatments. Among them, 8 compounds were absolutely confirmed by comparing with standard substances, and some had published hepatoprotective activities. Compared with the 35, 15, and 29 compounds identified in the portal vein plasma, liver, and systemic plasma of normal rats, respectively, the corresponding numbers of characterized compounds were 37, 13 and 29 in the liver injury rats.

Conclusions: Sulfation and glucuronidation were the predominant biotransformations, and intestinal metabolism, prior to hepatic metabolism, occurred for most compounds. CCl-induced liver injury caused only slight changes in the metabolic profiles of rats orally administered YCHT. These results provided the precondition for further quantitative analysis and pharmacodynamic screening of compounds in YCHT.
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http://dx.doi.org/10.1016/j.jep.2019.03.044DOI Listing
June 2019

Exploration of the hepatoprotective chemical base of an orally administered herbal formulation (YCHT) in normal and CCl-intoxicated liver injury rats. Part 2: Hepatic disposition in vivo and hepatoprotective activity in vitro.

J Ethnopharmacol 2019 May 22;236:161-172. Epub 2019 Feb 22.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai Ke Road Zhangjiang, Pudong, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Ethnopharmacological Relevance: Yin-Chen-Hao Tang (YCHT) has been a very popular, hepatoprotective three-herb formula with an unclear chemical base.

Aim Of This Study: To reveal the hepatoprotective chemical base of oral-dosed YCHT, we bridged the hepatic disposition of six compounds in vivo and their hepatoprotection in vitro.

Materials And Methods: In vivo, following the oral administration of YCHT in normal and CCl-induced liver injury rats, the determinations of chlorogenic acid, 4-hydroxyacetophenone, geniposide, genipin, rhein and emodin were conducted in the portal vein plasma, the liver, and the systemic plasma. In vitro, the hepatoprotective activities of these compounds were determined in the CCl-induced HepG2 cells.

Results: Consistent with the highest content in YCHT, geniposide had the highest exposure in vivo. Inconsistent with the negligible content, rhein, 4-hydroxyacetophenone, emodin and genipin showed substantial hepatic accumulations. In contrast, chlorogenic acid, an ingredient that has a high content in YCHT, elicited no hepatic exposure. In normal rats, the hepatic disposition prevented the compounds entering into the systemic plasma from the portal vein plasma by 44.9-100%, except for rhein. CCl-induced liver injury caused a decreased hepatic exposure of 4-hydroxyacetophenone, rhein and emodin by 50%. In vitro, all six compounds exerted the hepatoprotection by increasing cell viability, decreasing hepatic marker enzymes and inhibiting lipid peroxidation at varying levels.

Conclusion: Geniposide, rhein, emodin, 4-hydroxyacetophenone and genipin directly resisted liver injury in oral-dosed YCHT, while chlorogenic acid likely played an indirect role. This study proved that YCHT exerted hepatoprotection through multiple components and multiple actions. However, close attention should be paid to the possible side effects and oral dosage of YCHT in clinics.
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http://dx.doi.org/10.1016/j.jep.2019.02.022DOI Listing
May 2019

Evaluation of the chemical consistency of Yin-Chen-Hao-Tang prepared by combined and separated decoction methods using high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry coupled with multivariate statistical analysis.

J Sep Sci 2019 May 8;42(9):1664-1675. Epub 2019 Mar 8.

Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Material Medica, Pudong, Shanghai, P. R. China.

In this study, Yin-Chen-Hao-Tang prepared by two decoction methods, namely, combined decoction (modern decoction method) and separated decoction (traditional decoction method), was analyzed by high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The acquired datasets containing sample codes, t -m/z pairs and ion intensities were processed with multivariate statistical analyses, such as principal component analysis and an orthogonal partial least squared discriminant analysis model, to globally compare the chemical differences between the different decoction samples. Then, the chemical differences between the combined and separated decoctions were screened out by S-plots generated from the orthogonal partial least squared discriminant analysis model and compared with chemical information from an established in-house library. The six components that contributed the most to the chemical differences were identified as chlorogenic acid, caffeic acid, geniposide, genipin, scopoletin, and 3,5-dicaffeoylquinic acid. The concentrations of genipin and caffeic acid from the separated decoction were higher than those from the combined decoction, indicating that the separated decoction may present a stronger hepatoprotective effect. However, the results still require further investigation through pharmacological and clinical studies. Our findings not only establish a strategy to evaluate chemical consistency of Yin-Chen-Hao-Tang but also provide the scientific basis for using traditional separated decoction method.
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http://dx.doi.org/10.1002/jssc.201800961DOI Listing
May 2019

Enhanced Anti-diabetic Effect of Berberine Combined With Timosaponin B2 in Goto-Kakizaki Rats, Associated With Increased Variety and Exposure of Effective Substances Through Intestinal Absorption.

Front Pharmacol 2019 24;10:19. Epub 2019 Jan 24.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Inspired by the traditionally clinical application of herb pair - to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms. The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1-M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively. After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1-M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41-114% for BBR, 141-230% for TB-2, and 12-282% for M1-M5. , the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism. Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair.
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http://dx.doi.org/10.3389/fphar.2019.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353801PMC
January 2019

Metabolic profiling analysis of corilagin in vivo and in vitro using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry.

J Pharm Biomed Anal 2019 Feb 10;165:251-260. Epub 2018 Dec 10.

University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:

Corilagin is an Ellagitannin with favorable pharmacological activities. But there was no report regarding the metabolism of corilagin in vitro or in vivo. In this study, the metabolic profile of corilagin in rats as well as in rat intestinal bacteria and liver microsomes incubation system in vitro were investigated comprehensively for the first time. Consequently, with the aid of sensitive HPLC-Q-TOF-MS/MS, corilagin and its twenty-four metabolites (fourteen phase II conjugate metabolites of corilagin, three hydrolyzed metabolites EA, GA, M3 and their seven derived metabolites) were absolutely or tentatively identified in rat biological samples (urine, feces, plasma and tissues) after oral administration of corilagin. In vitro, the three hydrolyzed metabolites were identified in rat intestinal microflora and liver microsomes. These results demonstrated that corilagin itself not only could underwent extensive phase II metabolism in rats, but also could underwent hydrolysis reaction in rats as well as in rat intestinal bacteria and liver microsomes in vitro. This study is first report to identify phase II conjugate metabolites (except mono-methylate conjugated metabolites) of pure Ellagitannin and distribution of these metabolites in vivo. In addition, clear, detailed metabolic pathways of corilagin were shown to involve hydrolysis, methylation, glycosylation, reduction, glucuronidation and sulfation.
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http://dx.doi.org/10.1016/j.jpba.2018.12.013DOI Listing
February 2019

Absorption, Metabolism, and Pharmacokinetics Profiles of Norathyriol, an Aglycone of Mangiferin, in Rats by HPLC-MS/MS.

J Agric Food Chem 2018 Nov 8;66(46):12227-12235. Epub 2018 Nov 8.

Shanghai Institute of Material Medica , Chinese Academy of Sciences , Shanghai 201203 , China.

Norathyriol, an aglycone of mangiferin, is a bioactive tetrahydroxyxanthone present in mangosteen and many medicinal plants. However, the biological fate of norathyriol in vivo remains unclear. In this study, the absorption and metabolism of norathyriol in rats were evaluated through HPLC-MS/MS. Results showed that norathyriol was well absorbed, as indicated by its absolute bioavailability of 30.4%. Besides, a total of 21 metabolites of norathyriol were identified in rats, including methylated, glucuronidated, sulfated and glycosylated conjugates, which suggested norathyriol underwent extensive phase II metabolism. Among those metabolites, 15 metabolites were also identified in hepatocytes incubated with norathyriol, indicating the presence of hepatic metabolism. Furthermore, glucuronide and sulfate conjugates, rather than their parent compound, were found to be the main forms existing in vivo after administration of norathyriol, as implicated by the great increase of exposure of norathyriol determined after hydrolysis with β-glucuronidase and sulfatase. The information obtained from this study contributes to better understanding of the pharmacological mechanism of norathyriol.
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http://dx.doi.org/10.1021/acs.jafc.8b03763DOI Listing
November 2018

Simultaneous determination of eight bioactive compounds by LC-MS/MS and its application to the pharmacokinetics, liver first-pass effect, liver and brain distribution of orally administrated Gouteng-Baitouweng (GB) in rats.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 May 9;1084:122-131. Epub 2018 Mar 9.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Only focusing on the circulating levels is insufficient for the comprehensive understanding of the physiological disposition of herbal medicine in vivo. Therefore, we conducted the comprehensive investigation on the in vivo dynamic process of orally administrated Gouteng-Baitouweng (GB), a classical herb pair with anti-Parkinson potentials. Serving as the technical base, a sensitive and selective liquid chromatography-tandem mass spectrometry method was established and validated in the plasma, liver and brain, for simultaneous determination of five alkaloids (rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine and geissoschizine methyl ether) and three saponins (anemoside B4, anemoside A3 and 23-hydroxybetulinic acid). Following liquid-liquid extraction, favorable chromatographic behaviors of eight analytes were obtained on Waters Xbrigde C18 column within 13 min. This method elicited good linearity for the analytes at the concentration range of 0.3-1000 or 1.8-6000 ng/mL with favorable precision, accuracy and stability. Following oral administration of GB (25 g/kg) in rats, this method was applied to the quantitative analysis in the portal vein plasma, liver, systemic plasma, and brain. Consequently, anemoside B4 was of the highest exposure, followed by 23-hydroxybetulinic acid, anemoside A3, rhynchophylline and isocorynoxeine in vivo. Notably, three saponins were all observed with certain exposure in the brain, along with rhynchophylline at low levels. Besides, five alkaloids and 23-hydroxybetulinic acid underwent serious liver first-pass effect. Hence, the pharmacokinetics, liver first-pass effect, liver and brain distribution of ingredients in GB were clarified, which laid a solid foundation for interpreting its efficacy and safety.
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http://dx.doi.org/10.1016/j.jchromb.2018.03.013DOI Listing
May 2018

Absorption, liver first-pass effect, pharmacokinetics and tissue distribution of calycosin-7-O-ß-d-glucopyranoside (C7G) and its major active metabolite, calycosin, following oral administration of C7G in rats by LC-MS/MS.

J Pharm Biomed Anal 2018 Jan 24;148:350-354. Epub 2017 Oct 24.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Previously, we discovered calycosin, an extensively distributed metabolite of Calycosin-7-O-ß-d-glucopyranoside (C7G), elicited stronger anti-virus activity than C7G. However, the pharmacokinetics and tissue distribution of C7G and calycosin remained obscure on C7G treatments. In this study, a liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of C7G and calycosin, and it was applied to the pharmacokinetics and tissue distribution of C7G and calycosin following oral administration of C7G at 120mg/kg in rats. Consequently, the exposure of C7G and calycosin was both similarly low in the systemic plasma, but the levels of calycosin were 53.5 folds higher than that of C7G in the portal vein plasma, corresponding to the liver extraction ratio (ER) of C7G and calycosin at 0.3% and 98.5% respectively. Therefore, our results revealed that liver first-pass effect played the predominant role in the poor circulating levels of calycosin on C7G treatments, whereas the intestinal first-pass effect was predominant for those of C7G. In contrast to no observation of C7G, the calycosin levels were 212.1, 30.5 and 4.7 folds higher in the liver, kidney and heart than its circulating levels, respectively. The high tissue distribution of calycosin provided new hints and evidences to the pharmacological mechanisms of C7G and Astragali Radix.
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http://dx.doi.org/10.1016/j.jpba.2017.10.027DOI Listing
January 2018

A sensitive HPLC-MS/MS method for the simultaneous determination of anemoside B4, anemoside A3 and 23-hydroxybetulinic acid: Application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins.

Biomed Chromatogr 2018 Mar 22;32(3). Epub 2017 Nov 22.

Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai, China.

Pulsatilla chinensis saponins, the major active components in the herb, have drawn great attention as potential hepatitis B virus infection and hepatoma treatments. Here, a sensitive and accurate HPLC-MS/MS method was established for simultaneous determination of three saponins - anemoside B4, anemoside A3 and 23-hydroxybetulinic acid - in rat plasma and liver, and fully validated. The method was successfully applied to a pharmacokinetics and liver distribution study of P. chinensis saponins. Consequently, 23-hydroxybetulinic acid, with an extremely low content in the P. chinensis saponins, exhibited the highest exposure in the liver and in sites before and after hepatic disposition, namely, in the portal vein plasma and systemic plasma, followed by anemoside B4, which showed the highest content in the herb, whereas anemoside A3 displayed quite limited exposure. The hepatic first-pass effects were 71% for 23-hydroxybetulinic acid, 27% for anemoside B4 and 37% for anemoside A3, corresponding to their different extents of liver distribution. To our knowledge, this is the first investigation on the liver first-pass effect and distribution of P. chinensis saponins to date. These results also provide valuable information for the understanding of the pharmacological effect of P. chinensis saponins on liver diseases.
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http://dx.doi.org/10.1002/bmc.4124DOI Listing
March 2018

Material basis studies of anti-Influenza A active ingredients in Tanreqing Injection.

Biomed Chromatogr 2018 Feb 10;32(2). Epub 2017 Oct 10.

Shanghai Institutes of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Tanreqing Injection (TRQ) has been used primarily in treating infections of the upper respiratory tract and serious influenza in China, as a classical compound herbal recipe. TRQ had been demonstrated to have effects of clearing heat, eliminating phlegm, detoxification, reducing inflammation and alleviating cough. The survival rate, histopathology of lungs and viral titers in mice were evaluated in this study to verify the curative effect of TRQ. However, there is not enough information about the components. In the present study, a high-performance and practical LC/QTOF/MS method was developed for characterization and identification of the natural ingredients in TRQ. A total of 60 compounds, including 10 amino acids, 10 iridoid glucosides, 14 flavonoids, 13 other phenolic compounds, 10 steroid acids and three other compounds, were characterized and identified. We also confirmed the material basis of anti-Influenza A active ingredients in TRQ. Therefore, we have developed an accurate analytical method. LC/QTOF/MS could be applied for identification the complex components in traditional Chinese medicine.
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http://dx.doi.org/10.1002/bmc.4097DOI Listing
February 2018

Pharmacokinetics of mangiferin and its metabolite-norathyriol, Part 2: Influence of UGT, CYP450, P-gp, and enterobacteria and the potential interaction in Rhizoma Anemarrhenae decoction with timosaponin B2 as the major contributor.

Biofactors 2016 Sep 6;42(5):545-555. Epub 2016 May 6.

Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.

The poor bioavailability of mangiferin (MGF) is a major obstacle on its further development. Aimed to illustrate the underlying mechanism and improve its poor exposure, the compared PK profiles of MGF and norathyriol (NTR) after different MGF preparation were performed: pure MGF, the Rhizoma Anemarrhenae (Zhi-mu) decoction, MGF, and timosaponin B2 (TB-2) combination. Furthermore, the potential contributing factors, including uridine diphosphoglucuronosyltransferase (UGT), cytochrome P450 (CYP450), P-gp, and enterobacterial were investigated by comparing the PK profiles with and without the corresponding inhibitors or in different rat models. After taking MGF, CYP450 and UGT inhibition could decrease MGF and NTR exposure; P-gp inhibition slightly enhanced (48%) MGF exposure, whereas more apparent for the improved NTR exposure (302%); enterobacterial inhibition almost completely stopped the NTR production, but no such effect was observed for MGF. Compared with the limited improvement by the abovementioned inhibition, the MGF and NTR exposure could significantly increase by 11.5- and 5.9-fold in the Zhi-mu decoction compared with the MGF treatment, probably contributed to TB-2 as an absorption enhancer because the MGF and TB-2 combination produced a similar level of improvement on the PK paremeters of MGF and NTR to the herb treatment. Likewise, most of the effects by UGT, CYP450, P-gp, and enterobacteria followed a similar variation tendency between them. Therefore, the poor bioavailability of MGF possibly mainly attributed to its poor membrane permeability, but not transporters or metabolic enzymes, and the compatibility of MGF and TB-2 could probably expand the prospective application of MGF by improving its bioavailability. © 2016 BioFactors, 42(5):545-555, 2016.
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http://dx.doi.org/10.1002/biof.1290DOI Listing
September 2016