Publications by authors named "Changxiao Liu"

152 Publications

Nanoparticle conjugation of ginsenoside Rb3 inhibits myocardial fibrosis by regulating PPARα pathway.

Biomed Pharmacother 2021 May 1;139:111630. Epub 2021 May 1.

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, PR China. Electronic address:

Background: Cardiac fibrosis occurs in ischemic and non-ischemic heart failure, hereditary cardiomyopathy, diabetes and aging. Energy metabolism, which serves a crucial function in the course and treatment of cardiovascular diseases, might have therapeutic benefits for myocardial fibrosis. Ginsenoside Rb3 (G-Rb3) is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases. Therefore, the study investigated the effect of chitosan (CS) @ sodium tripolyphosphate (TPP) nanoparticles conjugation with ginsenoside Rb3 (NpRb3) on myocardial fibrosis and studied its possible mechanisms. The results showed that NpRb3 directly participates in the remodeling of myocardial energy metabolism and the regulation of perixisome proliferation-activated receptor alpha (PPARα), thereby improving the degree of myocardial fibrosis. The study also verifies the protective effect of NpRb3 on energy metabolism and mitochondrial function by targeting the PPARα pathway. Therefore, the prepared nanodrug carrier may be a potential solution for the delivery of G-Rb3, which is a promising platform for oral treatment of myocardial fibrosis.
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http://dx.doi.org/10.1016/j.biopha.2021.111630DOI Listing
May 2021

Compensatory Transition of Bile Acid Metabolism from Fecal Disposition of Secondary Bile Acids to Urinary Excretion of Primary Bile Acids Underlies Rifampicin-Induced Cholestasis in Beagle Dogs.

ACS Pharmacol Transl Sci 2021 Apr 22;4(2):1001-1013. Epub 2021 Mar 22.

Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China.

Drug induced cholestasis (DIC) is complexly associated with dysbiosis of the host-gut microbial cometabolism of bile acids (BAs). Murine animals are not suitable for transitional studies because the murine BA metabolism is quite different from human metabolism. In this work, the rifampicin (RFP) induced cholestasis was established in beagle dogs that have a humanlike BA profile to disclose how RFP affects the host-gut microbial cometabolism of BAs. The daily excretion of BA metabolites in urine and feces was extensively analyzed during cholestasis by quantitative BA profiling along the primary-secondary-tertiary axis. Oral midazolam clearance was also acquired to monitor the RFP-induced enterohepatic CYP3A activities because CYP3A is exclusively responsible for the tertiary oxidation of hydrophobic secondary BAs. RFP treatments caused a compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs, resulting in an infantile BA metabolism pattern recently disclosed in newborns. However, the tertiary BAs consistently constituted limitedly in the daily BA excretion, indicating that the detoxification role of the CYP3A catalyzed tertiary BA metabolism was not as strong as expected in this model. Multiple host-gut microbial factors might have contributed to the transition of the BA metabolism, such as inhibition of BA transporters, induction of liver-kidney interplaying detoxification mechanisms, and elimination of gut bacteria responsible for secondary BA production. Transitional studies involving more cholestatic drugs in preclinical animals with a humanlike BA profile and DIC patients may pave the way for understanding the complex mechanism of DIC in the era of metagenomics.
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http://dx.doi.org/10.1021/acsptsci.1c00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033783PMC
April 2021

Tertiary Oxidation of Deoxycholate Is Predictive of CYP3A Activity in Dogs.

Drug Metab Dispos 2021 May 5;49(5):369-378. Epub 2021 Mar 5.

Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China (W.Z., L.G., X.T., P.Z., Y.H., Q.W., K.L.); Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (X.L., L.Y., K.L.); WestChina-Frontier PharmaTech Co., Ltd., Chengdu, China (L.Y.); School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China (W.J.); and State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.)

Deoxycholic acid (DCA, 3, 12-dihydroxy-5-cholan-24-oic acid) is the major circulating secondary bile acid, which is synthesized by gut flora in the lower gut and selectively oxidized by CYP3A into tertiary metabolites, including 1,3,12-trihydroxy-5-cholan-24-oic acid (DCA-1-ol) and 3,5,12-trihydroxy-5-cholan-24-oic acid (DCA-5-ol) in humans. Since DCA has the similar exogenous nature and disposition mechanisms as xenobiotics, this work aimed to investigate whether the tertiary oxidations of DCA are predictive of in vivo CYP3A activities in beagle dogs. In vitro metabolism of midazolam (MDZ) and DCA in recombinant canine CYP1A1, 1A2, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 enzymes clarified that CYP3A12 was primarily responsible for either the oxidation elimination of MDZ or the regioselective oxidation metabolism of DCA into DCA-1-ol and DCA-5-ol in dog liver microsomes. Six male dogs completed the CYP3A intervention studies including phases of baseline, inhibition (ketoconazole treatments), recovery, and induction (rifampicin treatments). The oral MDZ clearance after a single dose was determined on the last day of the baseline, inhibition, and induction phases, and subjected to correlation analysis with the tertiary oxidation ratios of DCA detected in serum and urine samples. The results confirmed that the predosing serum ratios of DCA oxidation, DCA-5-ol/DCA, and DCA-1-ol/DCA were significantly and positively correlated both intraindividually and interindividually with oral MDZ clearance. It was therefore concluded that the tertiary oxidation of DCA is predictive of CYP3A activity in beagle dogs. Clinical transitional studies following the preclinical evidence are promising to provide novel biomarkers of the enterohepatic CYP3A activities. SIGNIFICANCE STATEMENT: Drug development, clinical pharmacology, and therapeutics are under insistent demands of endogenous CYP3A biomarkers that avoid unnecessary drug exposure and invasive sampling. This work has provided the first proof-of-concept preclinical evidence that the CYP3A catalyzed tertiary oxidation of deoxycholate, the major circulating secondary bile acid synthesized in the lower gut by bacteria, may be developed as novel in vivo biomarkers of the enterohepatic CYP3A activities.
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http://dx.doi.org/10.1124/dmd.121.000385DOI Listing
May 2021

An Integrative Pharmacology-Based Pattern to Uncover the Pharmacological Mechanism of Ginsenoside H Dripping Pills in the Treatment of Depression.

Front Pharmacol 2020 15;11:590457. Epub 2021 Feb 15.

State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.

To evaluate the pharmacodynamical effects and pharmacological mechanism of Ginsenoside H dripping pills (GH) in chronic unpredictable mild stress (CUMS) model rats. First, the CUMS-induced rat model was established to assess the anti-depressant effects of GH (28, 56, and 112 mg/kg) by the changes of the behavioral indexes (sucrose preference, crossing score, rearing score) and biochemical indexes (serotonin, dopamine, norepinephrine) in Hippocampus. Then, the components of GH were identified by ultra-performance liquid chromatography-iron trap-time of flight-mass spectrometry (UPLC/IT-TOF MS). After network pharmacology analysis, the active ingredients of GH were further screened out based on OB and DL, and the PPI network of putative targets of active ingredients of GH and depression candidate targets was established based on STRING database. The PPI network was analyzed topologically to obtain key targets, so as to predict the potential pharmacological mechanism of GH acting on depression. Finally, some major target proteins involved in the predictive signaling pathway were validated experimentally. The establishment of CUMS depression model was successful and GH has antidepressant effects, and the middle dose of GH (56 mg/kg) showed the best inhibitory effects on rats with depressant-like behavior induced by CUMS. Twenty-eight chemical components of GH were identified by UPLC/IT-TOF MS. Subsequently, 20()-ginsenoside Rh2 was selected as active ingredient and the PPI network of the 43 putative targets of 20()-ginsenoside Rh2 containing in GH and the 230 depression candidate targets, was established based on STRING database, and 47 major targets were extracted. Further network pharmacological analysis indicated that the cAMP signaling pathway may be potential pharmacological mechanism regulated by GH acting on depression. Among the cAMP signaling pathway, the major target proteins, namely, cAMP, PKA, CREB, -CREB, BDNF, were used to verify in the CUMS model rats. The results showed that GH could activate the cAMP-PKA-CREB-BDNF signaling pathway to exert antidepressant effects. An integrative pharmacology-based pattern was used to uncover that GH could increase the contents of DA, NE and 5-HT, activate cAMP-PKA-CREB-BDNF signaling pathway exert antidepressant effects.
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http://dx.doi.org/10.3389/fphar.2020.590457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917282PMC
February 2021

Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism.

Pharm Biol 2021 Dec;59(1):200-208

State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.

Context: Rotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application.

Objective: To clarify the potential mechanism for poor oral bioavailability.

Materials And Methods: The single-dose pharmacokinetics of orally administered RA (10 mg/kg) in Sprague-Dawley rats without or with verapamil (25 or 50 mg/kg) were investigated. Additionally, MDCKII-MDR1 and Caco-2 cell monolayers, five recombinant human cytochrome P450 (rhCYP) enzymes (1A2, 2C8, 2C9, 2D6 and 3A4), and rat liver microsomes were also conducted to investigate its potential mechanism.

Results: Verapamil could significantly affect the plasma concentration of RA. Co-administered verapamil at 25 and 50 mg/kg, the AUC increased from 432 ± 64.2 to 539 ± 53.6 and 836 ± 116 ng × h/mL, respectively, and the oral clearance decreased from 23.6 ± 3.50 to 18.7 ± 1.85 and 12.2 ± 1.85 L/h/kg, respectively. The MDCKII-MDR1 cell assay showed that RA might be a P-gp substrate. The rhCYPs experiments indicated that RA was mainly metabolized by CYP3A4. Additionally, verapamil could increase the absorption of RA by inhibiting the activity of P-gp, and slow down the intrinsic clearance of RA from 48.5 ± 3.18 to 12.0 ± 1.06 µL/min/mg protein.

Discussion And Conclusions: These findings indicated that verapamil could significantly affect the pharmacokinetic profiles of RA in rats. It was demonstrated that P-gp and CYP3A were involved in the transport and metabolism of RA, which might contribute to the low oral bioavailability of RA.
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http://dx.doi.org/10.1080/13880209.2021.1871634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894426PMC
December 2021

Research on Quality Markers of Guizhi Fuling Prescription for Endometriosis Treatment Based on Gray Correlation Analysis Strategy.

Front Pharmacol 2020 12;11:588549. Epub 2021 Jan 12.

State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin, China.

Guizhi Fuling prescription (GFP), a prestigious prescription of traditional Chinese medicine (TCM) recorded in "Jingui Yaolue," was composed of five Chinese medicines, including Moutan Cortex, Paeoniae Radix Alba, Persicae Semen, Poria Cocos, and Cinnamomi Ramulus. It was used for the treatment of endometriosis, primary dysmenorrhea, and blood stasis for centuries. However, its Quality Markers of treating endometriosis have not been clearly elucidated. In this study, a rapid ultraperformance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS/MS) method was established for Quality Markers investigation on GFP, and a total of 50 potentially bioactive constituents including triterpenoids, paeoniflorin and its derivatives, phenolic acids, and other species were identified based on their retention time, fragmentation pattern, and accurately measured mass value. Furthermore, regularity of recipe composition and gray correlation analysis revealed that all of the characteristic peaks contributed to the treatment of endometriosis. The relative correlation degrees were greater than 0.6. Among them, peaks 1 and 10, which were most closely correlated to the endometriosis, were identified as amygdalin and cinnamic acid. Finally, all of the active ingredients were molecularly docked with proteins associated with endometriosis by Schrodinger method. Among them, amygdalin, cinnamic acid, paeonol, gallic acid, and paeoniflorin had the lower binding energies. It was proposed that these constituents could be directed at Quality Markers for GFP. Thus, the integrated approach describing for revealing Quality Markers of GFP could be expected to provide a method for quality evaluation.
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http://dx.doi.org/10.3389/fphar.2020.588549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835882PMC
January 2021

Letter to the editor: Neutralizing antibodies for the treatment of COVID-19.

Acta Pharm Sin B 2021 Jan 16;11(1):304-307. Epub 2020 Nov 16.

State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China.

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http://dx.doi.org/10.1016/j.apsb.2020.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668178PMC
January 2021

A review of the phytochemistry and pharmacology of Kadsura heteroclita, an important plant in Tujia ethnomedicine.

J Ethnopharmacol 2021 Mar 7;268:113567. Epub 2020 Nov 7.

TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Material Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, PR China. Electronic address:

Ethnopharmacological Relevance: Kadsura heteroclita (Roxb.) Craib (traditionally known as "Xue Tong") is an important member of the economically and medicinally important plant family Schisandraceae. "Xue Tong" is an imperative ingredient of the Tujia ethnomedicine, traditionally used for the treatment of rheumatoid arthritis (RA), hepatitis, and muscles and joint spasm. The plant is known to be a rich source of lignans and triterpenoids. These classes of natural products have been known to possess various pharmacological activities.

Aim Of Review: This review was motivated by the importance of K. heteroclita in traditional Chinese medicine (TCM). It aims to compile the available information on its botanical distribution and description, traditional uses, phytochemistry, pharmacological activities, toxicity, and quality control to provide a solid base for further research and development.

Materials And Methods: Relevant literature was collected by several scientific databases including PubMed, CNKI, Scifinder, The Plant List, Google Scholar, Baidu Scholar, Books (Tujia pharmaceutical records, Guangxi Chinese herbal medicine, Hunan pharmaceutical records and Field identification manual of Chinese herbal medicine) and other literature sources (Flora of China, Pharmacopoeia of the People's Republic of China) which helped in collecting maximum data about the studied species.

Results: Traditional uses of K. heteroclita have proven its medicinal importance, providing a rationale for scientific research. Phytochemical studies on the stem of K. heteroclita resulted in the identification of 187 chemical constituents, among which lignans and triterpenoids are the predominant groups. The isolates and crude extracts have been found to exhibit a wide spectrum of in vivo and in vitro pharmacological activities such as anti-RA, anti-inflammatory and analgesic, hepatoprotection, anti-HIV, anti-cancer and anti-HBV. Schisanlactone E (xuetongsu), a triterpenoid, is one of the major components of K. heteroclita exhibiting anti-cancer, neuroprotective and anti-neuroinflammation activities. Interestingly and luckily, this plant has been found to be safe and non-toxic within the therapeutic dose range.

Conclusion: Pharmacological investigations have validated the use of K. heteroclita in traditional Chinese medicine (TCM). Literature review has demonstrated that lignans and triterpenoids are possibly responsible for most of the biological activities exhibited by this plant. To conclude, this plant shows immense potential for the discovery of more potent bioactive secondary metabolites and therefore further phytochemical and biological studies on other parts of K. heteroclita need to be conducted and more compounds need to be tested regarding their biological activities to completely explore its value as a tremendously important medicinal plant species.
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http://dx.doi.org/10.1016/j.jep.2020.113567DOI Listing
March 2021

Pharmacokinetics, tissue distribution and excretion of a novel long-acting human insulin analogue - recombinant insulin LysArg in rats.

Xenobiotica 2021 Mar 16;51(3):307-315. Epub 2020 Nov 16.

Tianjin Institute of Pharmaceutical Research, State Key Laboratory of Drug Delivery Technologies and Pharmacokinetics , Tianjin, China.

As a novel long-acting recombinant human insulin analogue, it is necessary to carry out the preclinical research for insulin LysArg. The purpose of this study was to characterise the pharmacokinetic, tissue distribution and excretion of insulin LysArg and provide a reference for its development. Three methods were used to measure the content of insulin LysArg in biological samples after a single subcutaneous administration in rats, including radioassay, radioassay after precipitation with TCA and separation by HPLC. After Subcutaneous administration of recombinant insulin LysArg 1, 2, 4 U/kg in rats, it showed both C and AUC were positively correlated with the dose. In the meanwhile, after a single subcutaneous administration of recombinant insulin LysArg at 2 U/kg in rats, the amount of radioactivity in most organs was highest at 1.5 h and then decreased gradually, no accumulation was found. The highest level of insulin LysArg was observed in the kidney. Like other macromolecules, insulin LysArg was mainly excreted from urine. The study fully illustrated the pharmacokinetic pattern of insulin LysArg, provided valuable informations to support its further development about safety and toxicology.
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http://dx.doi.org/10.1080/00498254.2020.1847361DOI Listing
March 2021

Shunaoxin pills improve the antihypertensive effect of nifedipine and alleviate its renal lipotoxicity in spontaneous hypertension rats.

Environ Toxicol 2021 Mar 24;36(3):386-395. Epub 2020 Oct 24.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.

Shunaoxin pills (SNX) have been used to treat cerebrovascular diseases in China since 2005. Hypertension is a major risk factor for cerebrovascular disease. This study aimed to explore the synergistic antihypertensive effect of SNX and nifedipine and whether SNX could alleviate nifedipine-induced renal lipotoxicity. During administration, systolic blood pressure was measured weekly. After 5 weeks administration, we examined pathological changes of kidney, renal function, the lipid metabolism index, and adipogenesis genes expression in the kidney tissues, and explored its underlying mechanism. Finally, network pharmacology was used for supplement and verification. As a result, SNX improved the antihypertensive effect of nifedipine and apparently improved nifedipine-induced renal pathological changes, dyslipidemia and the levels of adipogenesis gene expression in kidney tissues. SNX reduced the levels of interleukin-6 and interleukin-1β in renal tissues, down-regulated the production of malondialdehyde, and increased superoxide dismutase activity and the protein expression of heme oxygenase-1 in kidney tissues. Network pharmacology also showed that SNX could improve nifedipine-induced renal lipotoxicity. The combination of SNX and nifedipine had certain benefits in the treatment of hypertension.
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http://dx.doi.org/10.1002/tox.23044DOI Listing
March 2021

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription.

Acta Pharm Sin B 2020 Sep 27;10(9):1646-1657. Epub 2020 Jun 27.

Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.

Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy, while the mechanism was not very clear. Here, the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3, the liver transporters OATP1B1 and OATP1B3, and the intestine transporter OATP2B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation (YHP) comprising (CYH) and (AD), which could relieve pain by restraining the central system. The results show that tetrahydropalmatine (TDE), the major component of CYH, could be transported by OAT3 into kidney, OATP1B1 and OATP1B3 into liver, while imperatorin (IPT) and isoimperatorin (ISP), the two key components of AD, and AD extract showed strong inhibition to OAT1 and OAT3. What's more, AD extract also exerted strongly inhibition to human transporters OATP1B1 and OATP1B3. It was also detected that IPT, ISP, and AD extract significantly downregulated the expression of , , and of liver in mice. The results show that the concentration of TDE in liver and kidney significantly decreased, while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT, ISP, and AD extract. These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney. That is to say, TDE with bitter taste could "flood up" into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD. This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3, OATP1B1, and OATP1B3, but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD. This study may offer a valuable clue to illustrate the mechanism of compatibility theory.
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http://dx.doi.org/10.1016/j.apsb.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564327PMC
September 2020

Protective effects of isorhynchophylline against silicon-dioxide-induced lung injury in mice.

Artif Cells Nanomed Biotechnol 2020 Dec;48(1):1125-1134

Baotou Medical College, Baotou, China.

Inhalation of silicon dioxide (SD) results in pulmonary inflammatory responses and fibrosis. Isorhynchophylline (Isorhy) is the main alkaloid in the traditional Chinese herb , which is reported to have anti-inflammatory activities in the nervous system. However, the effects of Isorhy on SD-induced pulmonary inflammation and fibrosis in mice are unknown. Male mice were exposed to a single dose of SD (2.5 mg/kg, intranasal inoculation) to induce pulmonary fibrosis (PF). The mice were woken up and immediately treated with Isorhy (20 mg/kg, intraperitoneal injection) for 14 or 42 days. The effects of Isorhy on inflammatory responses and lung fibrosis induced by SD were then investigated. After the 14-day treatment, there was a significant reduction in inflammatory cell infiltration in the lungs of mice, with reduced recruitment of inflammatory cells to the lungs. The concentration of pro-inflammatory factors in the bronchoalveolar lavage fluid was reduced, which alleviated inflammatory injury in the lung tissue. After the 42-day treatment, Isorhy alleviated inflammation and inhibited the release of fibrogenic factors in mice with PF. Isorhy also significantly reduced collagen deposition in the lung tissues of mice. Isorhy has the ability to reduce inflammatory responses and fibrosis associated with SD-induced acute lung injury.
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http://dx.doi.org/10.1080/21691401.2020.1814315DOI Listing
December 2020

Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin.

Toxicol Appl Pharmacol 2020 11 21;406:115206. Epub 2020 Aug 21.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China. Electronic address:

Paris Saponin II (PSII) has been regarded as an effective and imperative component isolated from Rhizoma Paridis saponins (RPS) and exhibited strong anti-tumor effects on a variety of cancer. Our results revealed that human non-small lung cancer cell lines NCI-H460 and NCI-H520 were exposed to 1 μM of PSII, which inhibited the proliferation of lung cancer cells and activated apoptosis, autophagy and paraptosis. PSII induced paraptosis-associated cell death prior to apoptosis and autophagy. It induced paraptosis based on ER stress through activation of the JNK pathway. Meanwhile, PSII increased the cytotoxicity of cisplatin through paraptosis-associated pathway. All in all, PSII induced paraptosis based on induction of non-apoptotic cell death, which would be a possible approach to suppress the multi-drug resistant to apoptosis.
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http://dx.doi.org/10.1016/j.taap.2020.115206DOI Listing
November 2020

Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

J Pharm Anal 2020 Apr 26;10(2):178-186. Epub 2019 Sep 26.

Shenyang Pharmaceutical University, China.

Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite. In this study, potential synergic mechanism of the herb pair was investigated by utilizing multiple approaches. In silico and in vitro Caco-2 cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein (P-gp), as well as the inhibition effects on P-gp. Additionally, anti-inflammatory activity of aconitine (AC) combined with active ingredients of liquorice, as well as pharmacokinetic patterns of AC after co-administration was investigated. Anti-inflammatory effect of AC (1 mg/kg) in rats was enhanced in combination with bioactive ingredients of liquorice (10 mg/kg). In the meanwhile, the exposure of AC in vivo was altered, in terms of Cmax and AUC. For instance, the Cmax and AUC were increased to 1.9 and 1.3 folds, respectively, when used in combination with liquiritigenin. The in silico study revealed the potential binding mode with outward facing conformation of P-gp. The resulting data obtained from transport of rhodamine-123 (Rh-123) across Caco-2 cell monolayer further indicated that the function of P-gp was inhibited by chemicals in liquorice. The synergic effect was therefore proposed to be attributed to inhibition of P-gp by liquorice since AC has been demonstrated to be the substrate of P-gp. The resuls revealed that potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting function of key efflux transporter P-gp to enhance the exposure of AC in systematic circulation, and further the anti-inflammatory effect, which helps clarify the compatibility rationale of these two herbs.
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http://dx.doi.org/10.1016/j.jpha.2019.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192969PMC
April 2020

Species Differences of Bile Acid Redox Metabolism: Tertiary Oxidation of Deoxycholate is Conserved in Preclinical Animals.

Drug Metab Dispos 2020 06 19;48(6):499-507. Epub 2020 Mar 19.

Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., L.X., K.L.); Metabolomics Shared Resource, University of Hawaii Cancer Center, Honolulu, HI, (M.S., W.J.); State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China (C.L.); and Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu, China (Q.L., X.T., W.W., W.Z., L.G., K.L.)

It was recently disclosed that CYP3A is responsible for the tertiary stereoselective oxidations of deoxycholic acid (DCA), which becomes a continuum mechanism of the host-gut microbial cometabolism of bile acids (BAs) in humans. This work aims to investigate the species differences of BA redox metabolism and clarify whether the tertiary metabolism of DCA is a conserved pathway in preclinical animals. With quantitative determination of the total unconjugated BAs in urine and fecal samples of humans, dogs, rats, and mice, it was confirmed that the tertiary oxidized metabolites of DCA were found in all tested animals, whereas DCA and its oxidized metabolites disappeared in germ-free mice. The in vitro metabolism data of DCA and the other unconjugated BAs in liver microsomes of humans, monkeys, dogs, rats, and mice showed consistencies with the BA-profiling data, confirming that the tertiary oxidation of DCA is a conserved pathway. In liver microsomes of all tested animals, however, the oxidation activities toward DCA were far below the murine-specific 6-oxidation activities toward chenodeoxycholic acid (CDCA), ursodeoxycholic acid, and lithocholic acid (LCA), and 7-oxidation activities toward murideoxycholic acid and hyodeoxycholic acid came from the 6-hydroxylation of LCA. These findings provided further explanations for why murine animals have significantly enhanced downstream metabolism of CDCA compared with humans. In conclusion, the species differences of BA redox metabolism disclosed in this work will be useful for the interspecies extrapolation of BA biology and toxicology in translational researches. SIGNIFICANCE STATEMENT: It is important to understand the species differences of bile acid metabolism when deciphering biological and hepatotoxicology findings from preclinical studies. However, the species differences of tertiary bile acids are poorly understood compared with primary and secondary bile acids. This work confirms that the tertiary oxidation of deoxycholic acid is conserved among preclinical animals and provides deeper understanding of how and why the downstream metabolism of chenodeoxycholic acid dominates that of cholic acid in murine animals compared with humans.
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http://dx.doi.org/10.1124/dmd.120.090464DOI Listing
June 2020

Quality transitivity of Danhong Huayu Koufuye: A study on chemical profiles of medicinal herbs, compound preparation and dosed rat plasma using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

Biomed Chromatogr 2020 May 6;34(5):e4813. Epub 2020 Mar 6.

Tianjin Key Laboratory of Quality Markers of Traditional Chinese Medicine, Tianjin Institut e of Pharmaceutical Research, Tianjin, China.

Danhong Huayu Koufuye (DHK), an effective Chinese medicine preparation, is mainly used for the treatment of blurred vision and sudden blindness caused by qi stagnation and blood stasis, as well as the absorption period of central retinal vein occlusion. However, the current quality standard is relatively low, only stipulating the content of protocatechualdehyde. Chemical transitivity is the basis for discovering quality markers and is used in quality process control of Chinese medicines. Herein, the chemical profiles of seven medicinal herbs, DHK and dosed rat plasma were comprehensively analyzed using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. As a result, 134 chemical constituents were identified in seven medicinal herbs, including salvianolic acids, diterpene quinones, phenolic acids, phthalides, cyanogenic glycosides, flavonoids and triterpenoid saponins. Among them, 55 chemical constituents were transferred to DHK along with extraction and preparation, and 26 were further absorbed into blood and metabolized to produce 11 metabolites after oral administration. The transitivity of DHK from medicinal herbs to compound preparation and into blood was analyzed for the first time. This article will be valuable to ascertain the quality markers for quality process control and further pharmacokinetic studies.
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http://dx.doi.org/10.1002/bmc.4813DOI Listing
May 2020

Antihypertensive and renal protective effect of Shunaoxin pill combined with captopril on spontaneous hypertension rats.

Biomed Pharmacother 2020 May 4;125:109977. Epub 2020 Feb 4.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China. Electronic address:

Introduction: According to previous reports, hypertension has become the most common chronic disease in the world. Captopril, an angiotensin-converting enzyme inhibitor, has been widely used for the therapy of arterial hypertension and cardiovascular diseases therapy. Besides, Shunaoxin pill (SNX) as a traditional Chinese prescription showed antihypertensive effect in our previous research.

Objective: This study means to investigate whether SNX combining with captopril could show antihypertensive and renal protective effects on spontaneous hypertension rats (SHRs).

Methods: SHRs were randomly assigned to four treatment groups, including non-treated group, captopril, SNX, and captopril + SNX-treated groups. Their body weight and systolic blood pressure (SBP) were measured weekly. Histopathological examination was analyzed through Masson staining and hematoxylin and eosin staining. Biochemical analyses, ELISA, and western blot were used to analyze their combining mechanism.

Results: In this experiment, this combinatorial therapy significantly reduced aortic wall thickness, increased the content of NO, NOS and eNOS, decreased the content of bradykinin and endothelin 1(ET-1), and regulated the levels of TG, TC and HDLC back to normal, which suggested they could induce vasodilation and lower blood pressure. Meanwhile, histological examination alleviated that captopril + SNX remarkably inhibited renal injury, including tubular disorder, inflammatory cell infiltration and fibrosis. They down-regulated the serum levels of BUN and Cr, protein expression of IL-1β, NF-κB, Bax, Cyt c, caspase 3, 8 and 9 in kidney tissues and significantly increased the levels of Bcl-2 in kidney tissues compared with monotherapy group.

Conclusion: The combinatorial treatment of SNX and captopril lowered blood pressure through adjusting NO/NOS, ET-1 and dyslipidemia profile. Furthermore, this treatment alleviated the kidney damage via reducing the release of inflammatory factors and the expression of apoptotic markers. Therefore, these results provided a rationale for future clinical use of SNX combined with captopril in antihypertensive and protecting renal functions in hypertension.
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http://dx.doi.org/10.1016/j.biopha.2020.109977DOI Listing
May 2020

Induction of developmental toxicity and cardiotoxicity in zebrafish embryos/larvae by acetyl-11-keto-β-boswellic acid (AKBA) through oxidative stress.

Drug Chem Toxicol 2019 Oct 28:1-8. Epub 2019 Oct 28.

Biology Institute, Qilu University of Technology (Shandong Academy of Sciences) , Jinan , People's Republic of China.

Acetyl-11-keto-β-boswellic acid (AKBA), a triterpenoid from , is regarded as an angiogenesis inhibitor. However, its toxicity is unknown. The aim of this study was to examine its developmental toxicity and cardiotoxicity. A developmental toxicity assay in zebrafish embryos/larvae from 4 to 96 hours post-fertilization (hpf) was performed and a cardiotoxicity assay was designed from 48 to 72 hpf. Markers of oxidative stress and related genes were selected to access the possible mechanisms. According to the results, AKBA induced pericardium edema, yolk-sac edema, abnormal melanin, spinal curvature, hatching inhibition and shortened body length. Further, increased SV-BA distance, reduced heart rate, increased pericardium area and decreased blood flow velocity were detected in AKBA treated groups. The inhibition of cardiac progenitor gene expression, such as and , may be related to cardiotoxicity. The activities of antioxidant enzymes were decreased and the content of MDA was increased. In addition, AKBA treatment decreased the expression levels of , , and . These results suggested that AKBA induced developmental toxicity and cardiotoxicity through oxidative stress. As far as we know, this is the first report on the toxicity of AKBA. It reminds us to pay attention to developmental toxicity and cardiotoxicity of AKBA.
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http://dx.doi.org/10.1080/01480545.2019.1663865DOI Listing
October 2019

Terrestrosin D from attenuates bleomycin-induced inflammation and suppresses fibrotic changes in the lungs of mice.

Pharm Biol 2019 Dec;57(1):694-700

Department of Pharmacy, Baotou Medical College , Baotou , China.

Terrestrosin D (TED), from L. (Zygophyllaceae), exhibits anti-tumour and anti-inflammatory activities. However, its effects on bleomycin (BLM)-induced pulmonary inflammation and the subsequent fibrotic changes remain unclear. To examine the anti-inflammatory and anti-fibrotic effects of TED against BLM in murine pulmonary tissues. Male SPF mice received saline (control), TED (10 mg/kg), BLM (2.5 mg/kg), or BLM (2.5 mg/kg) + TED (10 mg/kg) group. BLM was administered as a single intranasal inoculation, and TED was intraperitoneally administered once daily. After 2 and 6 weeks of treatment, cell number and differentiation (Giemsa staining) and TNF-α, IL-6, IL-8, TGF-β1, and PDGF-AB levels (ELISA) were determined in the bronchoalveolar lavage fluid (BALF). Hydroxyproline (Hyp) content in the left pulmonary tissue was also determined (ELISA). The right pulmonary tissue was H&E-stained and assessed for the severity of pulmonary fibrosis using the Ashcroft scoring method. Compared with the BLM group, TED decreased inflammatory cell infiltration; number of macrophages ( < 0.05), neutrophils ( < 0.05), lymphocytes ( < 0.05); percentage of macrophages in the monocyte-macrophage system ( < 0.05), and levels of TNF-α ( < 0.01), IL-6 ( < 0.01), IL-8 ( < 0.05), TGF-β1 ( < 0.05), and PDGF-AB ( < 0.05) in the BALF. TED also reduced Hyp content ( < 0.05) in the pulmonary tissue and attenuated the BLM-induced deterioration in lung histopathology. TED can inhibit BLM-induced inflammation and fibrosis in the lungs of mice, which may be related to reduced inflammatory and fibrotic markers. These results could be further tested in humans through clinical studies.
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http://dx.doi.org/10.1080/13880209.2019.1672754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6807862PMC
December 2019

Diosgenyl Saponin Inducing Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptotic Pathways in Liver Cancer Cells.

J Agric Food Chem 2019 Oct 7;67(41):11428-11435. Epub 2019 Oct 7.

Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology , Tianjin University , Tianjin 300072 , People's Republic of China.

Diosgenin and diosgenyl saponins as the major bioactive compounds isolated from dietary fenugreek seeds, yam roots, etc. possessed strong antitumor effects. To understand their detailed antitumor mechanisms, a fluorophore-appended derivative of diosgenin [Glc/CNHphth-diosgenin (GND)] was synthesized, starting from diosgenin and glucosamine hydrochloride in overall yields of 7-12% over 7-10 steps. Co-localization of GND with organelle-specific stains, transmission electron microscopy, and relative protein analyses demonstrated that GND crossed the plasma membrane through organic anion-transporting polypeptide 1B1 and distributed in the endoplasmic reticulum (ER), lysosome, and mitochondria. In this process, GND induced ER swelling, mitochondrial damage, and autophagosome and upregulating IRE-1α to induce autophagy and apoptosis. Furthermore, autophagy inhibitor chloroquine delayed the appearance of cleaved poly(ADP-ribose) polymerase and inhibited cleaved caspase 8, which indicated that GND induced autophagy to activate caspase-8-dependent apoptosis. These observations suggested that diosgenyl saponin was a potent anticancer agent that elicited ER stress and mitochondria-mediated apoptotic pathways in liver cancer.
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http://dx.doi.org/10.1021/acs.jafc.9b05131DOI Listing
October 2019

metabolism and pharmacokinetics of bentysrepinine (Y101), an investigational new drug for anti-HBV-infected hepatitis: focus on interspecies comparison.

Xenobiotica 2020 Apr 24;50(4):468-478. Epub 2019 Sep 24.

State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.

The objective of this study was to clarify the species differences of pharmacokinetics of Y101 (N-[N-benzoyl-O-(2-dimethylaminoethyl)-l-tyrosyl]-l-phenylalaninol hydrochloride), a derivative of herbal ingredient with anti-HBV hepatitis activity, in rats, dogs, monkeys and humans.The metabolic stability and metabolite identification studies using liver microsomes , plasma protein binding using a rapid equilibrium dialysis , pharmacokinetic studies were carried out to evaluate the interspecies differences. The toxicokinetic study in monkeys was also investigated.The metabolic profiles were similar in monkeys and humans, which were significant different from rats and dogs . plasma protein binding showed no major differences between species with medium to high protein binding rates. After single oral dose to rats, dogs, and monkeys, the absolute oral bioavailability of Y101 was 44.9%, 43.1%, and 19.2%, respectively. There was no accumulation for Y101 toxicokinetics in monkeys after oral administration for 90 d.The metabolic profiles indicated monkey was the very animal model for preclinical safety evaluation of Y101. Our results have demonstrated the favorable pharmacokinetics profile of Y101, which supports the clinical trials in humans.
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http://dx.doi.org/10.1080/00498254.2019.1646946DOI Listing
April 2020

Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS.

J Pharm Biomed Anal 2019 Sep 11;174:479-485. Epub 2019 Jun 11.

Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.

Specific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α-hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC-MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC-MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by K, V and CL. As a result, four CYP2D6 enzymes displayed diverse K or V towards MET and the values of CL showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CL*1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CL*2/*1 = 74.87%) while CYP2D6*39 (CL*39/*1 = 29.65%) and CYP2D6*10 (CL*10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prominent influence of CYP2D6 polymorphisms on the metabolism of MET, which could offer valuable information for personalized administration of MET in clinic.
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http://dx.doi.org/10.1016/j.jpba.2019.06.016DOI Listing
September 2019

Identification of absorbed components and their metabolites in rat plasma after oral administration of Shufeng Jiedu capsule using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Rapid Commun Mass Spectrom 2019 Oct;33(19):1494-1501

Tianjin Key Laboratory of Quality Markers of Traditional Chinese Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.

Rationale: Shufeng Jiedu capsule (SFJDC), a prescription of traditional Chinese medicine, is mainly used for the treatment of acute upper respiratory tract infections. However, the bioactive components remain unclear, which partly limits its quality control and further development. This work aimed to carry out a study of plasma pharmacochemistry to identify the potential bioactive components of SFJDC.

Methods: An effective approach based on a combination of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS) and multivariate statistical analysis was applied to comprehensively analyze the absorbed components and their metabolites in rat plasma after oral administration of SFJDC. After UPLC/QTOF-MS detection, the differences between control and dosed plasma samples were distinguished by multivariate statistical analysis, and chromatographic signals of xenobiotic compounds were further extracted to identify structures.

Results: A total of 46 SFJDC-related xenobiotic compounds were identified as potential bioactive components in rat plasma. Among these, 27 absorbed prototype constituents were mainly flavonoids, anthraquinones, stilbenes, iridoids, lignans, naphthalenes, phenylethanoid glycosides and triterpenoid saponins. Especially for hastatoside, verbenalin, forsythoside A, phillyrin and emodin, they were closely related to the anti-inflammatory effect of SFJDC.

Conclusions: The absorbed components and metabolites of SFJDC in rat plasma were analyzed for the first time. This study will be conducive for ascertaining the quality markers of SFJDC for quality control and pharmacological mechanism research at the molecular level.
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http://dx.doi.org/10.1002/rcm.8498DOI Listing
October 2019

The Effect of Compound Danshen Dripping Pills on the Dose and Concentration of Warfarin in Patients with Various Genetic Polymorphisms.

Clin Ther 2019 06 1;41(6):1097-1109. Epub 2019 May 1.

Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China. Electronic address:

Purpose: The combination of warfarin and compound Danshen dripping pill (CDDP) is helpful for patients with both coronary heart disease (CHD) and atrial fibrillation (AF). The main adverse drug reaction of warfarin is bleeding because of its narrow therapeutic index. The safety of a combination therapy with warfarin and CDDP is always a concern. Our previous research showed that the combination of warfarin and CDDP improved the quality of life for patients with both CHD and AF. This study describes the changes in dose and concentration of warfarin necessary and evaluates bleeding risk when warfarin is given concomitantly with CDDP.

Methods: An ultra-performance liquid chromatography-MS/MS method with a chiral column was developed to assay the concentration of S-warfarin and R-warfarin in human plasma simultaneously. The method was applied to compare the concentration of warfarin in patients taking warfarin combined with CDDP and without CDDP. International normalized ratio (INR) values were monitored to evaluate bleeding risk. Paired t tests were then used to compare the dose and the concentration in 2 periods. Moreover, patients with VKORC1, CYP2C9*3, CYP4F2, EPHX1, and PROC gene polymorphisms were evaluated to determine interactions.

Findings: The results indicate that the dose of warfarin had no significant change with or without CDDP. Also, the peak concentrations of S-warfarin and total warfarin were significantly different in CYP4F2 C/C patients, but there was no significant difference identified in other genetic groups. No bleeding occurred in the study.

Implications: The dose of warfarin would be sustainable when combined with CDDP, because CDDP did not affect concentration of warfarin significantly in most patients and the change of INR was not significant.

China Clinical Trial Registry Identifier: ChiCTR-ONRC-13003523.
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http://dx.doi.org/10.1016/j.clinthera.2019.04.006DOI Listing
June 2019

Protective effect of magnolol on oxaliplatin-induced intestinal injury in mice.

Phytother Res 2019 Apr 13;33(4):1161-1172. Epub 2019 Mar 13.

Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.

Oxaliplatin (OXL) is the first line treatment therapy for gastrointestinal (GI) cancers and often combines with other chemotherapy. However, few reports have studied on its GI toxicity. Magnolol (MG), one of the mainly active constituents in Magnolia, has been reported to treat digestive diseases. Therefore, the purpose of this study is to evaluate the intestinal protective effect of MG in OXL treatment group. OXL administration mice showed body weight loss, diarrhea, and intestinal damage characterized by the shortening of villi and destruction of intestinal crypts, as well as the colon length change. MG significantly reduced body weight loss, alleviated diarrhea, reversed histopathological changes, and prevented colon length reduction. Oxidative stress and inflammation were activated after OXL, and these responses were repressed by MG through increasing the activities of superoxide dismutase, glutathione peroxidase, and glutathione, decreasing level of nuclear factor of kappa b and downregulating the following pro-inflammatory cytokines. Although the expression of tight junction protein occludin and numbers of proliferative crypt cells were reduced on ileum and colon after OXL, MG administration promoted these expressions. The fecal gut microbiota composition disturbed by OXL was significantly reversed by MG. Thus, MG could prevent the development and progression of mucositis induced by oxaliplatin through multipathway.
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http://dx.doi.org/10.1002/ptr.6311DOI Listing
April 2019

Effects of liquorice on pharmacokinetics of aconitine in rats.

Xenobiotica 2019 Dec 5;49(12):1485-1493. Epub 2019 Mar 5.

Shenyang Pharmaceutical University , Shenyang , PR China.

Aconite alkaloids are the main bioactive ingredients existing in , for instance aconitine (AC), which exhibit potent analgesic, antirheumatic and other pharmacological effects. In this study, effects of long-term treatment with liquorice on pharmacokinetics of AC in rats were investigated. Pharmacokinetics of AC after oral administration of AC at 1.5 mg/kg either with pre-treatment of liquorice water extracts at 0.433 or 1.299 g/kg (crude drug), respectively, for one week or not were studied. Additionally, LS-180 cells and human primary hepatocytes were utilized to explore the potential effects of bioactive ingredients of liquorice on P-glycoprotein (P-gp) and Cytochromes P450 (CYPs), respectively. The results revealed that exposure of AC after pre-treatment with liquorice was altered remarkably. Area under the concentration-time curve (AUC) decreased from 161 ± 37.8 to 58.8 ± 8.97 and 44.7 ± 8.20 ng/mL*h, respectively. Similarly, C decreased from 26.2 ± 5.19 to 11.8 ± 1.15 and 6.86 ± 0.600 ng/mL, respectively. In addition, expressions of CYPs of human primary hepatocytes were enhanced to various contents after induction. Moreover, accumulation of AC and hypaconitine (HA), not mesaconitine (MA) inside of LS-180 cells were reduced after pre-treatment by comparison with control. In conclusion, the exposure of AC declined after pre-treatment with liquorice extract, which may be highly associated with upregulated expression and/or function of CYPs and P-gp.
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http://dx.doi.org/10.1080/00498254.2019.1579007DOI Listing
December 2019

Potential detoxification effect of active ingredients in liquorice by upregulating efflux transporter.

Phytomedicine 2019 Mar 29;56:175-182. Epub 2018 Oct 29.

Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province, China. Electronic address:

Background: As one of most widely used herbal medicine, liquorice exhibits diverse pharmacological activities, for instance, analgesic, antitussive, antiarrhythmic, anti-inflammatory, and immune regulation. Additionally, detoxification effects were observed in combination of liquorice with other herbal drugs. The mechanism of detoxification of liquorice has been extensively investigated through material basis and interference with CYPs though, investigations of its effect on transporters were very limited, according to the literature.

Purpose: The objective of this study was attempt to investigate the effect of active ingredients existing in liquorice on the efflux transporters as to clarify the potential mechanism of detoxification of liquorice.

Methods: Multiple analytical approaches have been explored, including flow cytometry, fluorescent detection, RT-PCR, Western blot to measure the function, activity as well as mRNA/protein expression of efflux transporters on LS-180 cell model after treatments with active compounds of liquorice. Additionally, Caco-2 cell model was utilized to further investigate the potential impact of those ingredients on efflux transporter.

Results: The resulting data indicated that those active ingredients, including flavonoids (liquiritin, liquiritigenin, isoliquiritin, isoliquiritigenin and licochalcone A) and pentacyclic triterpene saponin (glycyrrhetinic acid) were able to upregulate the expression of efflux transporters, for example P-gp, BCRP and MRP2. The gene expressions were approximately over 2.5 folds by comparison with that of control, and up to 13 folds and 16 folds for BCRP by isoliquiritin and isoliquiritigenin, and further confirmed by Western blot. The functional assay also supported up-regulation of efflux transporter by those ingredients. Flow cytometry study showed that the level of rhodamine123 as probe substrate in LS-180 cells decreased to approximately 50% after treatment with active ingredients of liquorice, compared with that of control. The fluorescent assay confirmed that change of rhodamine 123 was correlated with the concentrations of active ingredients given. The efflux transport of rhodamine 123 was enhanced in Caco-2 cell models as well.

Conclusion: The study clarified potential detoxification mechanism of liquorice by up-regulating efflux transporter as to reduce absorption of xenobiotics across small intestinal membrane, which provided a new insight into pharmacological function of liquorice.
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http://dx.doi.org/10.1016/j.phymed.2018.10.033DOI Listing
March 2019

The effect of polymorphism of uric acid transporters on uric acid transport.

J Nephrol 2019 Apr 31;32(2):177-187. Epub 2018 Oct 31.

Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.

The abnormal metabolism of uric acid results in many disease such as chronic kidney disease, hyperuricemia, nephrolithiasis, gout, hypertension, vascular disease and so on. Serum uric acid levels are maintained by the balance between production and elimination. There are many factors that maintain the balance of serum uric acid. One of them is transporters which are responsible for the debouchment of uric acid within blood. The transport and excretion of uric acid is a complicated procedure which is related with various transporters such as OAT1, OAT3, OAT4, URAT1, GLUT9, BCRP, MRP4, NPT1, NTP4, and so on. In recent years, a large number of genome-wide association studies have shown that the single nucleotide polymorphisms of uric acid transporters were closely related to serum uric acid level. What's more, some mutations on these gene locus may also break the balance of serum uric acid. Here, the polymorphisms of uric acid transporters closely related with the serum uric acid balance were reviewed and discussed because of their important significance in clinical therapy for a precision medicine. The mechanism of metabolic diseases with gene variation may provide new strategy for the design and development of innovative drug to treat diseases with uric acid metabolic disturbance.
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http://dx.doi.org/10.1007/s40620-018-0546-7DOI Listing
April 2019

A strategy for the discovery and validation of toxicity quality marker of Chinese medicine based on network toxicology.

Phytomedicine 2019 Feb 2;54:365-370. Epub 2018 Feb 2.

The State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, 308 Anshan west Road, Tianjin 300193, China.

Background: Considering that the quality control indicators in Chinese medicine (CM) are disconnected from safety and effectiveness, Prof. Chang-xiao Liu et al. has proposed a concept regarding the quality marker (Q-marker) of CM to promote the healthy development of the CM industry and improve the CM quality control method.

Purpose: In this study, we proposed a strategy to discover and verify the toxicity Q-marker of CM based on network toxicology.

Methods: First, traditional biochemical pathology indicators and sensitive biomarkers were used to predict the toxicity of CM. Next, the chemical composition of toxic CMs and their metabolites were rapidly identified by multidimensional detection techniques. Subsequently, the interaction network between "toxicity - toxic chemical composition - toxic target - effect pathway" was built through network toxicology, and the potential toxicity Q-marker of CM was initially screened. Finally, the chemical properties of toxicity Q-markers were verified by traceability and testability.

Results: Based on the predicted results of network toxicology, the toxic compounds of CM were preliminarily identified, and the toxic mechanism was comprehensively interpreted. In the context of definite biological properties and chemical properties, the toxicity Q-marker was finally confirmed.

Conclusion: This extensive review provides a study method for the toxicity Q-marker of CM, which helps to systemically and thoroughly reveal the internal toxicity mechanism of CM. The in-depth study of the toxicity Q-marker provides the material basis and technical support for the safety evaluation of CM.
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http://dx.doi.org/10.1016/j.phymed.2018.01.018DOI Listing
February 2019

FGF Family: From Drug Development to Clinical Application.

Int J Mol Sci 2018 Jun 26;19(7). Epub 2018 Jun 26.

School of Pharmacy, Wenzhou Medical University, Chashan University Park, Wenzhou 325035, China.

Fibroblast growth factor (FGF) belongs to a large family of growth factors. FGFs use paracrine or endocrine signaling to mediate a myriad of biological and pathophysiological process, including angiogenesis, wound healing, embryonic development, and metabolism regulation. FGF drugs for the treatment of burn and ulcer wounds are now available. The recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in maintaining homeostasis of bile acid, glucose, and phosphate further extended the activity profile of this family. Here, the applications of recombinant FGFs for the treatment of wounds, diabetes, hypophosphatemia, the development of FGF receptor inhibitors as anti-neoplastic drugs, and the achievements of basic research and applications of FGFs in China are reviewed.
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http://dx.doi.org/10.3390/ijms19071875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073187PMC
June 2018