Publications by authors named "Xingbin Yin"

49 Publications

Construction of a Multifunctional Nano-Scale Metal-Organic Framework-Based Drug Delivery System for Targeted Cancer Therapy.

Pharmaceutics 2021 Nov 17;13(11). Epub 2021 Nov 17.

School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China.

The antitumor activity of triptolide (TP) has received widespread attention, although its toxicity severely limits its clinical application. Therefore, the design of a targeted drug delivery system (TDDS) has important application prospects in tumor treatment. Metal-organic frameworks (MOFs), with high drug-carrying capacity and good biocompatibility, have aroused widespread interest for drug delivery systems. Herein, folic acid (FA) and 5-carboxylic acid fluorescein (5-FAM) were used to modify Fe-MIL-101 to construct a functionalized nano-platform (5-FAM/FA/[email protected]) for the targeted delivery of the anti-tumor drug triptolide and realize in vivo fluorescence imaging. Compared with Fe-MIL-101, functionalized nanoparticles not only showed better targeted therapy efficiency, but also reduced the systemic toxicity of triptolide. In addition, the modification of 5-FAM facilitated fluorescence imaging of the tumor site and realized the construction of an integrated nano-platform for fluorescence imaging and treatment. Both in vitro and in vivo studies of functionalized nanoparticles have demonstrated excellent fluorescence imaging and synergistic targeting anticancer activity with negligible systemic toxicity. The development of functional nano-platform provides new ideas for the design of MOF-based multifunctional nano-drug delivery system, which can be used for precise treatment of tumor.
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http://dx.doi.org/10.3390/pharmaceutics13111945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619429PMC
November 2021

Catalpol Protects ARPE-19 Cells against Oxidative Stress via Activation of the Keap1/Nrf2/ARE Pathway.

Cells 2021 10 2;10(10). Epub 2021 Oct 2.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.

Oxidative damage to retinal pigment epithelial (RPE) has been identified as one of the major regulatory factors in the pathogenesis of age-related macular degeneration (AMD). Catalpol is an iridoid glucoside compound that has been found to possess potential antioxidant activity. In the present study, we aimed to investigate the protective effect of catalpol on RPE cells under oxidative stress and to elucidate the potential molecular mechanism involved. We found that catalpol significantly attenuated hydrogen peroxide (HO)-induced cytotoxicity, G0/G1 phase cell cycle arrest, and apoptosis in RPE cells. The overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) stimulated by oxidative stress and the corresponding reductions in antioxidant glutathione (GSH) and superoxide dismutase (SOD) levels were largely reversed by catalpol pretreatment. Moreover, catalpol pretreatment markedly activated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its downstream antioxidant enzymes, catalase (CAT), heme oxygenase-1 (HO-1), and NADPH dehydrogenase (NQO1). It also increased the expression levels of cyclin E, Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK2) and decreased the expression levels of Bax, Fas, cleaved PARP, p-p53, and p21 cleaved caspase-3, 8, and 9. The oxidative stress-induced formation of the Keap1/Nrf2 complex in the cytoplasm was significantly blocked by catalpol pretreatment. These results indicate that catalpol protected RPE cells from oxidative stress through a mechanism involving the activation of the Keap1/Nrf2/ARE pathways and the inactivation of oxidative stress-mediated pathways of apoptosis.
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http://dx.doi.org/10.3390/cells10102635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534470PMC
October 2021

Topical Delivery of Levocarnitine to the Cornea and Anterior Eye by Thermosensitive in-situ Gel for Dry Eye Disease.

Drug Des Devel Ther 2021 2;15:2357-2373. Epub 2021 Jun 2.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Purpose: To prepare the levocarnitine thermosensitive in situ gel (LCTG) and evaluate its effect on dry eye disease (DED).

Methods: Draize eye irritation test and other examinations were used to evaluate the eye irritation after multiple administration of LCTG. The Schirmer test, fluorescein sodium staining, HE staining and TUNEL staining were used to detect the tear secretion, corneal injury, histopathological changes of the cornea and lacrimal gland, and the apoptosis rate of cornea epithelial cells after 3 days of the administration. The conjunctival goblet cell density was detected by PAS staining, and the expression levels of matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-9 (MMP-9) of corneal epithelial cells were detected by immunofluorescence staining after 7 days of the administration.

Results: LCTG is non-irritating to rabbit eyes and has good biocompatibility. LCTG administration for 3 days can significantly increase the amount of tear secretion in mice with DED, promote corneal epithelial integrity and central corneal epithelium thickness recovery, and improve the pathological morphology and structure of corneal and lacrimal gland tissues, and reduce the apoptosis rate of the corneal epithelial cells. After 7 days of the administration, the preparation can promote the proliferation of conjunctival goblet cells and down-regulate the cornea expression levels of MMP-3 and MMP-9 in epithelial cells.

Conclusion: The LCTG has a good curative effect on mice with DED, and the overall curative effect is better than that of levocarnitine solution.
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http://dx.doi.org/10.2147/DDDT.S309648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188229PMC
December 2021

Hypericin-mediated photodynamic therapy for the treatment of cancer: a review.

J Pharm Pharmacol 2021 Mar;73(4):425-436

Department of Radiology, Division of Translational Nanobiomaterials and Imaging, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: Hypericin is a polycyclic aromatic naphthodianthrone that occurs naturally. It is also an active ingredient in some species of the genus Hypericum. Emerging evidence suggests that hypericin has attracted great attention as a potential anticancer drug and exhibits remarkable antiproliferative effect upon irradiation on various tumour cells. This paper aims to summarise the anticancer effect and molecular mechanisms modulated by hypericin-medicated photodynamic therapy and its potential role in the cancer treatment.

Key Findings: Hypericin-medicated photodynamic therapy could inhibit the proliferation of various tumour cells including bladder, colon, breast, cervical, glioma, leukaemia, hepatic, melanoma, lymphoma and lung cancers. The effect is primarily mediated by p38 mitogen-activated protein kinase (MAPK), JNK, PI3K, CCAAT-enhancer-binding protein homologous protein (CHOP)/TRIB3/Akt/mTOR, TRAIL/TRAIL-receptor, c-Met and Ephrin-Eph, the mitochondria and extrinsic signalling pathways. Furthermore, hypericin-medicated photodynamic therapy in conjunction with chemotherapeutic agents or targeted therapies is more effective in inhibiting the growth of tumour cells.

Summary: During the past few decades, the anticancer properties of photoactivated hypericin have been extensively investigated. Hypericin-medicated photodynamic therapy can modulate a variety of proteins and genes and exhibit a great potential to be used as a therapeutic agent for various types of cancer.
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http://dx.doi.org/10.1093/jpp/rgaa018DOI Listing
March 2021

Tumor Receptor-Mediated In Vivo Modulation of the Morphology, Phototherapeutic Properties, and Pharmacokinetics of Smart Nanomaterials.

ACS Nano 2021 01 17;15(1):468-479. Epub 2020 Dec 17.

Department of Biochemistry & Molecular Medicine, UC Davis NCI-designated Comprehensive Cancer Center, University of California Davis, Sacramento, California 95817, United States.

To be clinically efficacious, nanotherapeutic drugs need to reach disease tissues reliably and cause limited side effects to normal organs and tissues. Here, we report a proof-of-concept study on the development of a smart peptidic nanophototherapeutic agent in line with clinical requirements, which can transform its morphology from nanoparticles to nanofibrils at the tumor sites. This in vivo receptor-mediated transformation process resulted in the formation and prolonged tumor-retention of highly ordered (J-aggregate type of photosensitizer) photosensitive peptide nanofibrillar network with greatly enhanced photothermal and photodynamic properties. This strategy of "multiple daily low-intensity laser radiation after each intravenous injection of significantly low-dose of nanomaterials" demonstrated effective elimination of 4T1 orthotopic syngeneic breast cancer in mice. The technology for nanomaterial modulation based on living cell surface receptors, in this case tumor-associated αβ integrin, has great potential for clinical translation and is expected to improve the therapeutic efficacy against many cancers.
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http://dx.doi.org/10.1021/acsnano.0c05065DOI Listing
January 2021

Phillyrin Mitigates Apoptosis and Oxidative Stress in Hydrogen Peroxide-Treated RPE Cells through Activation of the Nrf2 Signaling Pathway.

Oxid Med Cell Longev 2020 12;2020:2684672. Epub 2020 Oct 12.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Oxidative stress-induced dysfunction or apoptosis in retinal pigment epithelial (RPE) cells is an important cause of dry age-related macular degeneration (AMD). Although phillyrin has been shown to exert significant antioxidant effects, the underlying mechanism of action remains unclear. The purpose of this study was to investigate the protective effect of phillyrin on hydrogen peroxide- (HO) induced oxidative stress damage in RPE cells and the potential mechanism involved. It was found that phillyrin significantly protected RPE cells from HO cytotoxicity. Furthermore, phillyrin alleviated oxidative stress-induced apoptosis via inhibition of endogenous and exogenous apoptotic pathways. Compared with the HO-treated group, the expressions of cleaved caspase-3, cleaved caspase-9, cleaved polymerase (PARP), death receptor Fas, and cleaved caspase-8, as well as Bax/Bcl-2 ratio were decreased in RPE cells after the phillyrin intervention. In addition, phillyrin reversed the oxidative stress-induced reductions in superoxide dismutase (SOD) and glutathione (GSH) levels and annulled the elevations in reactive oxygen species (ROS) and malondialdehyde (MDA), thereby restoring oxidant-antioxidant homeostasis. Phillyrin treatment upregulated the expressions of cyclin E, cyclin-dependent kinase 2 (CDK2), and cyclin A and downregulated the expressions of p21 and p-p53, thereby reversing the G0/G1 cell cycle arrest in HO-treated RPE cells. Pretreatment with phillyrin also increased the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), total Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductases-1 (NQO-1) in RPE cells and inhibited the formation of Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 protein complex. Thus, phillyrin effectively protected RPE cells from oxidative stress through activation of the Nrf2 signaling pathway and inhibition of the mitochondria-dependent apoptosis pathway.
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http://dx.doi.org/10.1155/2020/2684672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576358PMC
May 2021

A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine.

Front Pharmacol 2020 16;11:01067. Epub 2020 Sep 16.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Matrine (MT) is a naturally occurring alkaloid and an bioactive component of Chinese herbs, such as and Radix . Emerging evidence suggests that MT possesses anti-cancer, anti-inflammatory, anti-oxidant, antiviral, antimicrobial, anti-fibrotic, anti-allergic, antinociceptive, hepatoprotective, cardioprotective, and neuroprotective properties. These pharmacological properties form the foundation for its application in the treatment of various diseases, such as multiple types of cancers, hepatitis, skin diseases, allergic asthma, diabetic cardiomyopathy, pain, Alzheimer's disease (AD), Parkinson's disease (PD), and central nervous system (CNS) inflammation. However, an increasing number of published studies indicate that MT has serious adverse effects, the most obvious being liver toxicity and neurotoxicity, which are major factors limiting its clinical use. Pharmacokinetic studies have shown that MT has low oral bioavailability and short half-life . This review summarizes the latest advances in research on the pharmacology, toxicology, and pharmacokinetics of MT, with a focus on its biological properties and mechanism of action. The review provides insight into the future of research on traditional Chinese medicine.
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http://dx.doi.org/10.3389/fphar.2020.01067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526649PMC
September 2020

Inhibitory effects of Paris saponin I, II, Ⅵ and Ⅶ on HUVEC cells through regulation of VEGFR2, PI3K/AKT/mTOR, Src/eNOS, PLCγ/ERK/MERK, and JAK2-STAT3 pathways.

Biomed Pharmacother 2020 Nov 15;131:110750. Epub 2020 Sep 15.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Rhizoma Paris is a popular Chinese medicine in clinics. It contains four main saponins which are its major bioactive compounds. These saponins are Paris saponin I, II, VI and VII (PSI, PSII, PSVI and PSVII, respectively). Up to now, the research using HUVEC cells to evaluate the anti-angiogenic activity of four saponins is blank. The purpose of this study was to evaluate the anti-angiogenic properties (also known as angiotoxicity) of the four saponins in Rhizoma Paris on vascular endothelial cells-HUVEC cells, and to investigate the underlying mechanism, which has not been studied before. In this study, MTT assay, Lactate dehydrogenase (LDH) assay, wound healing experiments, transwell cell invasion assay, tubule formation experiment, DAPI staining, AV-PI double staining, and cell cycle analysis were used to determine the effects of Paris saponins. The results showed that, with increases in concentrations of PSI, PSII, PSVI and PSVII, the viability of HUVEC cells decreased significantly. In addition, four saponins dose-dependent enhanced LDH release and inhibited HUVEC cell migration, invasion, and angiogenesis. In terms of mechanism, PSI significantly inhibited protein expression in multiple signaling pathways. In particular, with the VEGF2 as the target, it activate the downstream PI3K / AKT / mTOR, SRC / eNOS, P38, PLCγ / ERK / MERK and JAK2/STAT3 signaling pathways. In conclusion, PSI, PSII, PSVI and PSVII can inhibit endothelial cell proliferation, migration and invasion, block endothelial cell cycle, induce endothelial cell apoptosis, act on protein expression in several anti-angiogenic signaling pathways, and finally inhibit angiogenesis in vitro. This study provides further data support for the clinical application of Paris saponins as antiangiogenic drugs.
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http://dx.doi.org/10.1016/j.biopha.2020.110750DOI Listing
November 2020

Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways.

Biomed Pharmacother 2020 Nov 14;131:110661. Epub 2020 Sep 14.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100102, China. Electronic address:

Hepatocellular carcinoma (HCC) is one of the most common cancers with the highest morbidity and mortality. It is necessary to develop new anti-liver cancer drugs. Itraconazole is a popular systemic anti-fungal drug with a strong anti-tumor effect. However, so far, it is not clear whether itraconazole has specific anti-tumor effect on liver cancer. The purpose of this study was to investigate itraconazole resistant effect of liver cancer and to explore its potential anti-cancer mechanism. The effect of itraconazole on the proliferation of liver cancer cells was studied with MTT assay. Flow cytometry was used to determine the effect of itraconazole on apoptosis, cell cycle distribution, changes in intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). In addition, after DAPI staining, nuclear morphological changes were observed under the fluorescent microscope, and the release of lactate dehydrogenase (LDH) was measured using the microplate reader. Finally, the expressions of proteins related to the anti-tumor signaling pathway were determined by Western blotting. The results showed that itraconazole significantly inhibited the proliferation of HepG2 and Bel-7405 cells. In addition, the data showed that itraconazole induced apoptosis in HepG2 cells, increased the production of ROS, blocked cell cycle, and decreased MMP. Furthermore, itraconazole inhibited HCC cell growth and promoted apoptosis through the Hh, Wnt/catenin, AKT/mTOR/S6K, ROS and death receptor pathways. Finally, we come to the conclusion that itraconazole exerts anti-liver cancer effect, and has potential for use as a new drug for liver cancer in clinic.
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http://dx.doi.org/10.1016/j.biopha.2020.110661DOI Listing
November 2020

Tangshen formula modulates gut Microbiota and reduces gut-derived toxins in diabetic nephropathy rats.

Biomed Pharmacother 2020 Sep 11;129:110325. Epub 2020 Jun 11.

Beijing Key Lab for Immune-Mediated Inflammatory Diseases, Department of Pharmacology, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, PR China. Electronic address:

Growing evidence shows that diabetic kidney disease (DKD) is linked with intestinal dysbiosis from gut-derived toxins. Tangshen Formula (TSF) is a traditional Chinese herbal medicine that has been used to treat DKD. In this study, streptozotocin injection and uninephrectomy-induced diabetic nephropathy (DN) rat model was established to explore the impact of TSF on gut microbiota composition, gut-derived toxins, and the downstream inflammatory pathway of urotoxins in the kidney. TSF treatment for 12 weeks showed significant attenuation of both renal histologic injuries and urinary excretion of albumin compared with DN rats without treatment. TSF treatment also reconstructed gut dysbiosis and reduced levels of indoxyl sulfate and metabolic endotoxemia/lipopolysaccharide. MCP-1 and TNF-α were decreased by TSF both in the serum and kidney. In addition, we revealed that the inhibitory effect of TSF on renal inflammation was associated with the inhibition of aryl hydrocarbon, a receptor of indoxyl sulfate, and TLR4, thereby inhibiting JNK and NF-κB signaling in the kidney. Spearman correlation analysis found that a cluster of gut bacterial phyla and genera were significantly correlated with renal pathology, renal function, and systemic inflammation. In conclusion, orally administered TSF significantly inhibited diabetic renal injury, and modulated gut microbiota, which decreased levels of lipopolysaccharide and indoxyl sulfate, and attenuated renal inflammation. Our results indicate that TSF may be used as an agent in the prevention of gut dysbiosis and elimination of intestinal toxins in DN individuals.
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http://dx.doi.org/10.1016/j.biopha.2020.110325DOI Listing
September 2020

Study on the potential effective ingredients of Xiaosheng prescription for dry eye disease.

Biomed Pharmacother 2020 Jul 16;127:110051. Epub 2020 May 16.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Xiaosheng prescription (XSP) has been used for dry eye disease (DED) for more than 10 years in Eye Hospital of China Academy of Chinese Medicine Sciences. However, the effective ingredients involved have remained unclear, which was investigated in this study by the correlation of ingredient and therapeutic activity. Human corneal epithelial cells (HCEC) cultured with 110 mM NaCl solution in vitro and C57BL/6 mice injected subcutaneously with scopolamine hydrobromide were used to establish dry eye models, and the therapeutic effect of XSP extract 1 was better than that of XSP extract 2 significantly. Then, UPLC-Q-TOF/MS and data analysis program Progenesis QI and Makerlynx XS were used to analyze the potential effective ingredients of XSP, and 4 compounds were speculated and identified, in which Schisandrin and 1 μM of Schisantherin A could obviously increase the cell survival rate of injured cells on the cell model. It can be indicated that Schisandrin and Schisantherin A are probably the potential effective ingredients in XSP for DED.
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http://dx.doi.org/10.1016/j.biopha.2020.110051DOI Listing
July 2020

Underlying mechanisms of apoptosis in HepG2 cells induced by polyphyllin I through Fas death and mitochondrial pathways.

Toxicol Mech Methods 2020 Jul 14;30(6):397-406. Epub 2020 Apr 14.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Polyphyllin I, a steroidal saponin in which possess broad application prospects in cancer prevention and treatment. The purpose of this study was to determine the potential cytotoxicity and mechanism of Polyphyllin I in HepG2 cells. In this study, we used MTT to evaluate cell survival. Cell apoptosis rate, cell cycle distribution, mitochondrial membrane potential and ros levels were measured by flow cytometry, and the expression of apoptosis-related proteins was determined by Western blot analysis. Polyphyllin I significantly reduced cell viability and induced HepG2 cell apoptosis in a dose and time-dependent manner. Compared with the control group, it could induce reactive oxygen species (ROS) generation and depolarization of matrix metalloproteinases in liver cells. Polyphyllin I dose-dependent increased the release of mitochondrial cytochrome c, and levels of Fas, p53, p21, and Bax/Bcl-2 ratios, as well as the activation of cleaved caspase-3, -8, -9, and subsequent cleavage of the poly (ADP-ribose) polymerase (PARP). The G2/M phase cell cycle arrest was induced by increasing the expression of p21 and cyclin E1, and significantly reducing the expression of cyclin A2 and CDK2. Our results suggested that Polyphylin I inhibited cell proliferation and growth by triggering G2/M cell cycle arrest, and induced apoptosis through intracellular and extracellular apoptosis pathways to cause cell death by generating reactive oxygen species.
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http://dx.doi.org/10.1080/15376516.2020.1747125DOI Listing
July 2020

Metal Organic Frameworks as Drug Targeting Delivery Vehicles in the Treatment of Cancer.

Pharmaceutics 2020 Mar 5;12(3). Epub 2020 Mar 5.

School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing 102488, China.

In recent years, metal organic frameworks (MOFs) have been widely developed as vehicles for the effective delivery of drugs to tumor tissues. Due to the high loading capacity and excellent biocompatibility of MOFs, they provide an unprecedented opportunity for the treatment of cancer. However, drugs which are commonly used to treat cancer often cause side effects in normal tissue accumulation. Therefore, the strategy of drug targeting delivery based on MOFs has excellent research significance. Here, we introduce several intelligent targeted drug delivery systems based on MOFs and their characteristics as drug-loading systems, and the challenges of MOFs are discussed. This article covers the following types of MOFs: Isoreticular Metal Organic Frameworks (IRMOFs), Materials of Institute Lavoisier (MILs), Zeolitic Imidazolate Frameworks (ZIFs), University of Oslo (UiOs), and MOFs-based core-shell structures. Generally, MOFs can be reasonably controlled at the nanometer size to effectively achieve passive targeting. In addition, different ligands can be modified on MOFs for active or physicochemical targeting. On the one hand, the targeting strategy can improve the concentration of the drugs at the tumor site to improve the efficacy, on the other hand, it can avoid the release of the drugs in normal tissues to improve safety. Despite the challenges of clinical application of MOFs, MOFs have a number of advantages as a kind of smart delivery vehicle, which offer possibilities for clinical applications.
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http://dx.doi.org/10.3390/pharmaceutics12030232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150757PMC
March 2020

-Induced Liver Injury: Clinical Characteristics, Risk Factors, Material Basis, Action Mechanism and Current Challenges.

Front Pharmacol 2019 13;10:1467. Epub 2019 Dec 13.

Research Institute of Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China.

Thunb. (PM), called in China, is a popular Chinese medicine in clinical practice. Several clinical studies have been conducted to evaluate the traditional therapeutic claims and to study the potential therapeutic activity of PM in dyslipidemia and neurodegenerative diseases, highlighting available clinical evidence. In recent years, reports on clinical adverse reactions of Raw Radix (RPM) and Praeparata (PMP) have been on the increase, especially with respect to liver injury. Most liver injury cases had been assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) in this paper. However, the components of PM responsible for the reported hepatotoxic effects have not yet been identified. Moreover, many of the reports are contradictory, while studies on the mechanism involved in PM-induced liver damage are not comprehensive. This study was aimed at reviewing the status of research on liver injury due to PM, including clinical characteristics, risk factors, material basis research and mechanism of action, with a view to understanding PM-induced hepatotoxicity, and taking reasonable and effective measures to prevent it. In short, quality control is still one of the major safety problems in TCM drug safety concerns. The model of safety monitoring and risk management of PM drugs is not yet developed. Indeed, the characteristics and risk factors associated with PM require both proper understanding and control of the risk by strengthening standardization of clinical applications, basic science research, quality control in manufacturing, active monitoring methodology and enhancement of international communication and cooperation. Measures should also be encouraged and implemented to promote healthy development of the TCM industry.
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http://dx.doi.org/10.3389/fphar.2019.01467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923272PMC
December 2019

A Novel Gel-Forming Solution Based on PEG-DSPE/Solutol HS 15 Mixed Micelles and Gellan Gum for Ophthalmic Delivery of Curcumin.

Molecules 2019 Dec 24;25(1). Epub 2019 Dec 24.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.

Curcumin (Cur) is a naturally hydrophobic polyphenol with potential pharmacological properties. However, the poor aqueous solubility and low bioavailability of curcumin limits its ocular administration. Thus, the aim of this study was to prepare a mixed micelle in situ gelling system of curcumin (Cur-MM-ISG) for ophthalmic drug delivery. The curcumin mixed micelles (Cur-MMs) were prepared via the solvent evaporation method, after which they were incorporated into gellan gum gels. Characterization tests showed that Cur-MMs were small in size and spherical in shape, with a low critical micelle concentration. Compared with free curcumin, Cur-MMs improved the solubility and stability of curcumin significantly. The ex vivo penetration study revealed that Cur-MMs could penetrate the rabbit cornea more efficiently than the free curcumin. After dispersing the micelles in the gellan gum solution at a ratio of 1:1 (/), a transparent Cur-MM-ISG with the characteristics of a pseudoplastic fluid was formed. No obvious irritations were observed in the rabbit eyes after ocular instillation of Cur-MM-ISG. Moreover, Cur-MM-ISG showed a longer retention time on the corneal surface when compared to Cur-MMs using the fluorescein sodium labeling method. These findings indicate that biocompatible Cur-MM-ISG has great potential in ophthalmic drug therapy.
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http://dx.doi.org/10.3390/molecules25010081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983186PMC
December 2019

Matrine Exerts Hepatotoxic Effects via the ROS-Dependent Mitochondrial Apoptosis Pathway and Inhibition of Nrf2-Mediated Antioxidant Response.

Oxid Med Cell Longev 2019 14;2019:1045345. Epub 2019 Oct 14.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Matrine, an alkaloid isolated from , possesses a wide range of pharmacological properties. However, the use of matrine in clinical practice is limited due to its toxic effects. The present study investigated the roles of mitochondria and reactive oxygen species (ROS) in matrine-induced liver injury. Our results showed that treatment of HL-7702 cells with matrine led to significant and concentration- and time-dependent reductions in their viability, as well as significant and concentration-dependent increases in the number of apoptotic cells and supernatant lactate dehydrogenase (LDH) activity. The treatment led to significant increases in the population of cells in S phase and significant reduction of cell proportion in G0/G1 and G2/M phases. It also significantly and concentration-dependently increased the levels of ROS and malondialdehyde (MDA) but significantly and concentration-dependently reduced superoxide dismutase (SOD) activity, level of reduced glutathione (GSH), and mitochondrial membrane potential (MMP). Matrine treatment significantly and concentration-dependently upregulated the expressions of Bax, p53, p-p53, p21, cyclin E, Fas, cleaved caspase-3, caspase-8, and caspase-9 proteins and downregulated the expressions of Bcl-2, cyclin-dependent kinase 2 (CDK2), and cyclin A. It also significantly promoted the cleavage of poly(ADP-ribose)polymerase (PARP), upregulated Kelch-like ECH-associated protein 1 (Keap1) expression, and downregulated the expressions of cellular total and nuclear Nrf2. Matrine significantly inhibited the expressions of downstream oxidoreductases (Heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductases 1 (NQO-1)) and enhanced the formation of Keap1/Nrf2 protein complex. These results show that the hepatotoxic effect of matrine is exerted via inhibition of Nrf2 pathway, activation of ROS-mediated mitochondrial apoptosis pathway, and cell cycle arrest at S phase. Pretreatment with N-acetyl cysteine (NAC) partially reversed matrine-induced hepatotoxicity.
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http://dx.doi.org/10.1155/2019/1045345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815593PMC
May 2020

Aloe-emodin: A review of its pharmacology, toxicity, and pharmacokinetics.

Phytother Res 2020 Feb 3;34(2):270-281. Epub 2019 Nov 3.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Aloe-emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe-emodin exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe-emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe-emodin has a poor intestinal absorption, short elimination half-life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe-emodin reported to date with an emphasis on its biological properties and mechanisms of action.
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http://dx.doi.org/10.1002/ptr.6532DOI Listing
February 2020

Investigation of Metal-Organic Framework-5 (MOF-5) as an Antitumor Drug Oridonin Sustained Release Carrier.

Molecules 2019 Sep 16;24(18). Epub 2019 Sep 16.

School of Chinese materia medica, Beijing University of Chinese Medicine, Beijing 102488, China.

Oridonin (ORI) is a natural active ingredient with strong anticancer activity. But its clinical use is restricted due to its poor water solubility, short half-life, and low bioavailability. The aim of this study is to utilize the metal organic framework material MOF-5 to load ORI in order to improve its release characteristics and bioavailability. Herein, MOF-5 was synthesized by the solvothermal method and direct addition method, and characterized by Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TG), Brunauer-Emmett-Teller (BET), and Dynamic Light Scattering (DLS), respectively. MOF-5 prepared by the optimal synthesis method was selected for drug-loading and in vitro release experiments. HepG2 cells were model cells. MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V/PI assay were used to detect the biological safety of blank carriers and the anticancer activity of drug-loaded materials. The results showed that nano-MOF-5 prepared by the direct addition method had complete structure, uniform size and good biocompatibility, and was suitable as an ORI carrier. The drug loading of [email protected] was 52.86% ± 0.59%. The sustained release effect was reliable, and the cumulative release rate was about 87% in 60 h. [email protected] had significant cytotoxicity (IC50:22.99 μg/mL) and apoptosis effect on HepG2 cells. [email protected] is hopeful to become a new anticancer sustained release preparation. MOF-5 has significant potential as a drug carrier material.
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http://dx.doi.org/10.3390/molecules24183369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767262PMC
September 2019

Hepatocellular Toxicity of Paris Saponins I, II, VI and VII on Two Kinds of Hepatocytes-HL-7702 and HepaRG Cells, and the Underlying Mechanisms.

Cells 2019 07 9;8(7). Epub 2019 Jul 9.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100102, China.

is a popularly-used Chinese medicine in clinics, based on the pharmacodynamic properties of its saponin components. The four main saponins in are designated saponins I, II, VI, and VII. At present, much attention is focused on the anticancer effect of which is manifested in its cytotoxicity to various cancer cells. The purpose of this study was to investigate the hepatocellular toxicities of the four saponins in and the relative intensities of their cytotoxic effects. It was found that the four saponins were cytotoxic to two types of hepatocytes-HL-7702 and HepaRG cells. The cytotoxicities of the four saponins to the two cell models were compared. One of the most cytotoxic saponins was saponin I (PSI). This was used to determine the mechanism of hepatocellular toxicity. Results from MTT assays demonstrated that the four saponins induced apoptosis of the two hepatocyte models in a dose-dependent and time-dependent manner. In addition, fluorescent 4',6-diamidino-2-phenylindole (DAPI) staining was used to observe the morphological changes of HepaRG cells after saponin administration. Further, as the concentration increased, PSI-induced lactate dehydrogenase (LDH) release from HepaRG cells increased gradually. In addition, PSI enhanced the levels of reactive oxygen species (ROS) and blocked the S and G2 phases of the cell cycle in HepaRG cells. A western blot indicated that PSI upregulated the protein expression levels of p53, p21, and Fas. Furthermore, the PSI-induced changes in the p53 protein increased the Bax/bcl-2 ratio, resulting in enhancement of the release of mitochondrial cytochrome c, activation of caspases-3, -8, and -9, poly-ADP ribose polymerase (PARP), and ultimately apoptosis. Increased Fas protein activated caspase-8, which led to the activation of caspase-3 and its downstream PARP protein, resulting in cell apoptosis. These results indicate that PSI induced apoptosis in HepaRG cells through activation of ROS and death receptor pathways. The results obtained in this study suggest that the hepatocellular toxicity of saponins in should be considered during the clinical application of this drug. In addition, they provide a reference for future anti-cancer studies on .
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http://dx.doi.org/10.3390/cells8070690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678998PMC
July 2019

In Vitro Toxicity Study of a Porous Iron(III) Metal‒Organic Framework.

Molecules 2019 Mar 28;24(7). Epub 2019 Mar 28.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.

A MIL series metal‒organic framework (MOF), MIL-100(Fe), was successfully synthesized at the nanoscale and fully characterized by TEM, TGA, XRD, FTIR, DLS, and BET. A toxicological assessment was performed using two different cell lines: human normal liver cells (HL-7702) and hepatocellular carcinoma (HepG2). In vitro cytotoxicity of MIL-100(Fe) was evaluated by the MTT assay, LDH releasing rate assay, DAPI staining, and annexin V/PI double staining assay. The safe dose of MIL-100(Fe) was 80 μg/mL. It exhibited good biocompatibility, low cytotoxicity, and high cell survival rate (HL-7702 cells' viability >85.97%, HepG2 cells' viability >91.20%). Therefore, MIL-100(Fe) has a potential application as a drug carrier.
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http://dx.doi.org/10.3390/molecules24071211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480057PMC
March 2019

Zirconium-Porphyrin PCN-222: pH-responsive Controlled Anticancer Drug Oridonin.

Evid Based Complement Alternat Med 2018 4;2018:3249023. Epub 2018 Dec 4.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Drug delivery carriers with a high drug loading capacity and biocompatibility, especially for controlled drug release, are urgently needed due to the side effects and frequent dose in the traditional therapeutic method. Guided by nanomaterials, we have successfully synthesized zirconium-based metal-organic frameworks, Zr-TCPP (TCPP: tetrakis (4-carboxyphenyl) porphyrin), namely, PCN-222, which is synthesized by solvothermal method. And it has been designed as a drug delivery system (DDS) with a high drug loading of 38.77 wt%. In our work, PCN-222 has achieved pH-sensitive drug release and showed comprehensive SEM, TEM, PXRD, DSC, FTIR, and N adsorption-desorption. The low cytotoxicity and good biocompatibility of PCN-222 were certificated by the in vitro results from an MTT assay, DAPI staining, and Annexin V/PI double-staining even cultivated L02 cells and HepG2 cells for 48h. Furthermore, Oridonin, a commonly used cancer chemotherapy drug, is adsorbed into PCN-222 via the solvent diffusion technique. Based on an analysis of the Oridonin release profile, results suggest that it can last for more than 7 days in vitro. And cumulative release rate of Ori at the 7 d was about 86.29% and 63.23% in PBS (pH 5.5 and pH 7.2, respectively) at 37°C. HepG2 cells were chosen to research the cytotoxicity of [email protected] and free Oridonin. The results demonstrated that the [email protected] nanocarrier shows higher cytotoxicity in HepG2 cells compared to Oridonin.
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http://dx.doi.org/10.1155/2018/3249023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304552PMC
December 2018

Preformulation study and initial determination of biological Properties of isopropylidene shikimic acid.

Pak J Pharm Sci 2018 Nov;31(6):2329-2332

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.

Isopropylidene shikimic acid (ISA), a new drug derviatived from Shikimic Acid, had been proved to be effective in the cerebral protection after cerebral ischemia and reperfusion. But there was little research on the physical pharmacy and biopharmaceutical properties about the drug. In order to provide some useful data for the pharmaceutical development of ISA, the solubility, stability and Oil/Water partition coefficient (LogP) were determined by the classic preformulation study method, and the transmembrane performance of ISA was studied by Franz -diffusion cell method in vitro. The results showed that ISA was water-soluble with a solubility 32.52mg/ml, which could be improved to 44.32 mg/ml by 1% (w/v) sodium dodecylsulfate; the LogP was -0.63; ISA was less stable in water but it was stable when pH greater than 6.0 and unstable when pH less than 6.0; the accumulated permeation rates at 1h were about 50% and more than 80% at 6h. Data obtained by the study indicated that the medium selection and pH control were important for liquid preparation of ISA, and avoiding dissolution and absorption in stomach was critical for the oral solid dosage forms. Mucosal drug delivery systems would be considered, according to the certain hydrophilic-lipophilic characters and good transmembrane capability.
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November 2018

Apoptosis in HepaRG and HL-7702 cells inducted by polyphyllin II through caspases activation and cell-cycle arrest.

J Cell Physiol 2019 05 26;234(5):7078-7089. Epub 2018 Oct 26.

Beijing Research Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. Polyphyllin II is one of the most significant saponins in Rhizoma Paridis and it has toxic effects on kinds of cancer cells. However, our results in this study proved that the polyphyllin II has hepatotoxicity in vitro through caspases activation and cell-cycle arrest. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide results indicated polyphyllin II inhibited proliferation, induced apoptosis in HepaRG cells and HL-7702 cells and showed a concentration and time-dependent. Then, we selected the innovative cell model-HepaRG cells to explore the mechanism of hepatotoxicity. Our data showed the reactive oxygen species (ROS) increased and the mitochondrial membrane potential decreased in HepaRG cells after administration of polyphyllin II. Besides, with the increase of concentration, the release of lactate dehydrogenase increased and the S phase of the cell cycle was arrested. Nevertheless, when pretreatment with antioxidant N-acetylcysteine, apoptotic cells decreased significantly, inhibited the production of ROS and improved the decrease of membrane potential in HepaRG cells. Moreover, polyphyllin II treatment increased levels of Fas, Bax, cytochrome c, activated caspase-3, -8, -9, cleaved poly(ADP-ribose) polymerase and decreased Bcl-2 expression levels. Finally, we identified two signal pathways of apoptosis induced by polyphyllin II including the death receptor pathway and the mitochondria pathway. This study confirmed the hepatotoxicity of the polyphyllin II in vitro, which has never been discovered and gave a wake-up call for the clinical application of Rhizoma Paridis.
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http://dx.doi.org/10.1002/jcp.27462DOI Listing
May 2019

Biocompatible Fe-Based Micropore Metal-Organic Frameworks as Sustained-Release Anticancer Drug Carriers.

Molecules 2018 Sep 28;23(10). Epub 2018 Sep 28.

School of Chinese Material Medical, Beijing University of Chinese Medicine, Beijing 102488, China.

Sustained-release preparation is a hot spot in antitumor drug research, where the first task is to select suitable drug carriers. Research has revealed that carboxylic acid iron metal⁻organic frameworks (MOFs), constructed from iron (Fe) ions and terephthalic acid, are nontoxic and biocompatible. Due to the breathing effect, the skeleton of this mesoporous material is flexible and can reversibly adapt its pore size through drug adsorption. Therefore, we chose one kind of Fe-MOF, MIL-53(Fe), as a carrier for the anticancer drug oridonin (Ori). In this work, we report the design and synthesis of MIL-53(Fe) and explore its ability as a transport vehicle to deliver Ori. MIL-53(Fe) is characterized by scanning electron microscopy and X-ray powder diffraction. A loading capacity of 56.25 wt % was measured by high performance liquid chromatography. This carrier was safe and nontoxic (cell viability > 95.27%), depending on the results of 3-(4,5-dimethylthiazol-2-yl)--2,5-diphenyltetrazolium bromide assays, lactate dehydrogenase assays, and Annexin V-fluoresce isothiocyanate/propidium iodide double-staining assays. After loading the drug, the structure of the MIL-53(Fe) was not destroyed, and Ori was amorphous in MIL-53(Fe). Based on an analysis of the Ori release profile, results suggest that it lasts for more than seven days in vitro. The cumulative release rate of Ori at the seventh day was about 82.23% and 91.75% in phosphate buffer saline solution at 37 °C under pH 7.2 and pH 5.5, respectively. HepG2 cells were chosen to study the cytotoxicity of [email protected](Fe), and the results show that the anticancer ratio of [email protected](Fe) system reaches 90.62%. Thus, MIL-53 can be used as a carrier for anticancer drugs and [email protected](Fe) is a promising sustained-release drug delivery system for the cancer therapy.
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http://dx.doi.org/10.3390/molecules23102490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222375PMC
September 2018

Emodin induces apoptosis in human hepatocellular carcinoma HepaRG cells via the mitochondrial caspase‑dependent pathway.

Oncol Rep 2018 Oct 2;40(4):1985-1993. Epub 2018 Aug 2.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, P.R. China.

Emodin‑induced hepatotoxicity in vivo and in vitro has been gaining increasing attention. However, the exact molecular pathways underlying these effects remain poorly clarified. The aim of the present study was to evaluate the cytotoxic effect of emodin on HepaRG cells and to define the underlying mechanism. The results demonstrated that emodin evidently inhibited HepaRG cell growth in a dose‑ and time‑dependent manner by blocking cell cycle progression in the S and G2/M phase and by inducing apoptosis. Emodin treatment also resulted in generation of reactive oxygen species (ROS), which abrogated mitochondrial membrane potential (MMP). The above effects were all suppressed by antioxidants, such as N‑acetylcysteine (NAC). Further studies by western blot analysis howed that emodin upregulated p53, p21, Bax, cyclin E, cleaved caspase‑3, 8 and 9, and cleaved poly(ADP‑ribose)polymerase (PARP). However, the protein expression of Bcl‑2, cyclin A and CDK2 was downregulated. Taken together, our results suggest that emodin induces apoptosis via the mitochondrial apoptosis pathway through cell cycle arrest and ROS generation in HepaRG cells.
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http://dx.doi.org/10.3892/or.2018.6620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111625PMC
October 2018

Triptolide Induces Apoptosis Through Fas Death and Mitochondrial Pathways in HepaRG Cell Line.

Front Pharmacol 2018 26;9:813. Epub 2018 Jul 26.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Triptolide isolated from the traditional Chinese herb Hook F., possesses anti-tumor, anti-fertility, and anti-inflammatory properties. Triptolide-induced hepatotoxicity has continued to engage the attention of researchers. However, not much is yet known about the cytotoxicity of triptolide, and the precise mechanisms involved. In the present study, we investigated the cytotoxicity of triptolide and its underlying mechanisms, using the model (HepaRG cell). The results demonstrated that triptolide significantly reduced cell viability and induced apoptosis in HepaRG cells in a dose- and time-dependent manner. Triptolide treatment also provoked reactive oxygen species (ROS) generation and depolarization of mitochondrial membrane potential (MMP). Moreover, triptolide dose-dependently increased the protein expression levels of Fas, Bax, p53, p21, cyclin E, cleaved caspase-3, 8, and 9; and subsequent cleavage of poly (ADP-ribose) polymerase (PARP). However, the protein expression of Bcl-2, cyclin A, and CDK 2 were significantly decreased. These results suggest that triptolide inhibits cell proliferation and induces apoptosis via the Fas death pathway and the mitochondrial pathway.
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http://dx.doi.org/10.3389/fphar.2018.00813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070613PMC
July 2018

Molecular Mechanisms of Apoptosis in HepaRG Cell Line Induced by Polyphyllin VI via the Fas Death Pathway and Mitochondrial-Dependent Pathway.

Toxins (Basel) 2018 05 15;10(5). Epub 2018 May 15.

Beijing Research Institute of Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing 100102, China.

Polyphyllin VI, which is an active saponin, is mainly isolated from traditional medicinal plant , which causes liver damage in rats. In the present study, we aimed to explore the potential cytotoxicity of polyphyllin VI on the growth of HepaRG cells and to determine the molecular mechanism. The results revealed that polyphyllin VI changed cell morphology and induced apoptosis in HepaRG cells. Flow cytometric assay displayed that polyphyllin VI promoted the generation of reactive oxygen species (ROS), depolarized the mitochondrial membrane potential (MMP), and induced S phase cell cycle arrest by decreasing the expression of cyclin A2 and CDK2, while significantly increasing the expression of p21 protein. Polyphyllin VI induced the release of cytochrome c from the mitochondria to the cytosol and activated Fas, caspase-3, -8, -9, and PARP proteins. Pretreatment with NAC and Z-VAD-FMK (ROS scavenger and caspase inhibitor, respectively) on HepaRG cells increased the percentage of viable cells, which indicated that polyphyllin VI induced cell apoptosis through mitochondrial pathway by the generation of ROS and Fas death-dependent pathway. All of the effects are in dose- and time-dependent manners. Taken together, these findings emphasize the necessity of risk assessment to polyphyllin VI and offer an insight into polyphyllin VI-induced apoptosis of HepaRG cells.
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http://dx.doi.org/10.3390/toxins10050201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983257PMC
May 2018

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway.

Int J Mol Sci 2018 Apr 2;19(4). Epub 2018 Apr 2.

Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Rhein, a naturally occurring active anthraquinone found abundantly in various medicinal and nutritional herbs, possesses a wide spectrum of pharmacological effects. Furthermore, previous studies have reported that rhein could induce hepatotoxicity in rats. However, its cytotoxicity and potential molecular mechanisms remain unclear. Therefore, the present study aimed to investigate the cytotoxicity of rhein on HepaRG cells and the underlying mechanisms of its cytotoxicity. Our results demonstrate, by 3-(4,5-dimethyl thiazol-2-yl-)-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-fluoresce isothiocyanate (FITC)/propidium iodide (PI) double-staining assays, that rhein significantly inhibited cell viability and induced apoptosis in HepaRG cells. Moreover, rhein treatmnt resulted in the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and S phase cell cycle arrest. The results of Western blotting showed that rhein treatment resulted in a significant increase in the protein levels of Fas, p53, p21, Bax, cleaved caspases-3, -8, -9, and poly(ADP-ribose)polymerase (PARP). The protein expression of Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK 2) was decreased. In conclusion, these results suggest that rhein treatment could inhibit cell viability of HepaRG cells and induce cell death through cell cycle arrest in the S phase and activation of Fas- and mitochondrial-mediated pathways of apoptosis. These findings emphasize the need to assess the risk of exposure for humans to rhein.
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http://dx.doi.org/10.3390/ijms19041060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979559PMC
April 2018

Heterophyllin B Ameliorates Lipopolysaccharide-Induced Inflammation and Oxidative Stress in RAW 264.7 Macrophages by Suppressing the PI3K/Akt Pathways.

Molecules 2018 Mar 21;23(4). Epub 2018 Mar 21.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.

Heterophyllin B (HB), an active cyclic peptide, is a compound existing in the ethyl acetate extract of (Miq.) Pax and exhibited the activity of inhibiting the production of NO and cytokines, such as IL-1β and IL-6, in LPS-stimulated RAW 264.7 macrophages. In addition, HB suppressed the production of ROS and the apoptosis induced by LPS in RAW 264.7 macrophages. The underlying mechanism was investigated in the LPS-induced RAW 264.7 cells. The results showed that HB decreased the level of IL-1β and IL-6 expression by qRT-PCR analysis. HB up-regulated the relative ratio of p-AKT/AKT and p-PI3K/PI3K as indicated by western blot analysis. In summary, HB inhibited the LPS-induced inflammation and apoptosis through the PI3K/Akt signaling pathways and represented a potential therapeutic target for treatment of inflammatory diseases.
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http://dx.doi.org/10.3390/molecules23040717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017815PMC
March 2018

Application of iTRAQ-Based Quantitative Proteomics Approach to Identify Deregulated Proteins Associated with Liver Toxicity Induced by Polygonum Multiflorum in Rats.

Cell Physiol Biochem 2017 24;43(5):2102-2116. Epub 2017 Oct 24.

School of Chinese material medica, Beijing University of Chinese Medicine, Beijing, China.

Background/aims: Clinical reports on adverse reactions that result from Polygonum multiflorum (PM) and its preparations, especially regarding liver injury, have recently received widespread attention. This study aimed to investigate the mechanism of hepatotoxicity induced by different PM extracts through iTRAQ quantitative proteomics.

Methods: The different PM extracts were orally administrated for 90 days to rats, and the hepatotoxicity effect was evaluated through measurement of biochemical indexes, oxidative damage indexes and hematoxylin-eosin (HE) staining. Then, the hepatotoxicity mechanism was investigated by iTRAQ quantitative proteomics.

Results: The results of biochemical and histopathological analyses showed that liver injury occurred in all groups of rats given by various PM extracts, which proved all of the PM extracts could induce hepatotoxicity. The hepatotoxicity mechanism may differ between the total extract group and the other groups through the results of biochemical indicators. The iTRAQ proteomics study showed that hepatotoxicity resulting from PM was mainly related to the abnormal activity of mitochondrion function-related oxidative phosphorylation pathways.

Conclusion: This iTRAQ proteomics study revealed that the hepatotoxicity induced by PM is primarily related to the oxidative phosphorylation pathways. NADH dehydrogenase family proteins and Slc16a2 could be potential biomarkers of hepatotoxicity resulting from PM.
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http://dx.doi.org/10.1159/000484229DOI Listing
January 2018
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