Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells
Abstract
:1. Introduction
2. Results
2.1. Effect of FG Extracton BRL-3A Cells Viability
2.2. HPLC-ESI-MSAnalysis of FG Extract
2.3. Effect of Components on BRL-3A Cells Viability
2.4. Effect of Geniposide and Genipin on Aapoptosis and Cell Cycle
2.5. Effects on Biochemical Indicators, Oxidative Damage Index, and Inflammation
2.6. Molecular Docking
3. Discussion
4. Materials and Methods
4.1. Plant Materials
4.2. Reagents and Chemicals
4.3. Extracts of FG Preparation and HPLC- ESI-MS Analysis
4.4. Cell Culture
4.5. Cell Viability Assay
4.6. Apoptosis and Cell Cycle Detection
4.7. Determination of the Biochemical Indicator, Oxidative Damage Index, and Inflammation Indicator
4.8. Molecular Docking
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Chow, H.C.; So, T.H.; Choi, H.C.W.; Lam, K.O. Literature Review of Traditional Chinese Medicine Herbs-Induced Liver Injury from an Oncological Perspective with RUCAM. Integr. Cancer Ther. 2019, 18, 1534735419869479. [Google Scholar] [CrossRef] [PubMed]
- Efferth, T.; Kaina, B. Toxicities by herbal medicines with emphasis to traditional Chinese medicine. Curr. Drug Metab. 2011, 12, 989–996. [Google Scholar] [CrossRef] [PubMed]
- Zongram, O.; Ruangrungsi, N.; Palanuvej, C.; Rungsihirunrat, K. Standardization of Gardenia jasminoides Fruits and Crocin Content Analysis Using UV/visible Spectrophotometry. Chiang Mai J. Sci. 2017, 44, 1453–1462. [Google Scholar]
- Yokoyama, Y.; Nagino, M. Current scenario for the hepatoprotective effects of Inchinkoto, a traditional herbal medicine, and its clinical application in liver surgery: A review. Hepatol. Res. 2014, 44, 384–394. [Google Scholar] [CrossRef]
- Yu, Y.; Xie, Z.L.; Gao, H.; Ma, W.W.; Dai, Y.; Wang, Y.; Zhong, Y.; Yao, X.S. Bioactive iridoid glucosides from the fruit of Gardenia jasminoides. J. Nat. Prod. 2009, 72, 1459–1464. [Google Scholar] [CrossRef]
- Li, L.; Zou, J.; Xia, Q.; Cui, H.; You, S.; Liu, Y.; Wang, Q. Anti-TMV and Insecticidal Potential of Four Iridoid Glycosides from Gardenia Jasminoides Fruit. Chem. Res. Chin. Univ. 2018, 34, 697–699. [Google Scholar] [CrossRef]
- Ni, Y.; Li, L.; Zhang, W.; Lu, D.; Zang, C.; Zhang, D.; Yu, Y.; Yao, X. Discovery and LC-MS Characterization of New Crocins in Gardeniae Fructus and Their Neuroprotective Potential. J. Agric. Food Chem. 2017, 65, 2936–2946. [Google Scholar] [CrossRef]
- Kim, H.J.; Kim, E.J.; Seo, S.H.; Shin, C.G.; Jin, C.; Lee, Y.S. Vanillic acid glycoside and quinic acid derivatives from Gardeniae Fructus. J. Nat. Prod. 2006, 69, 600–603. [Google Scholar] [CrossRef]
- Chen, P.; Chen, Y.; Wang, Y.; Cai, S.; Deng, L.; Liu, J.; Zhang, H. Comparative Evaluation of Hepatoprotective Activities of Geniposide, Crocins and Crocetin by CCl4-Induced liver Injury in Mice. Biomol. Ther. 2016, 24, 156–162. [Google Scholar] [CrossRef] [Green Version]
- Cui, Y.Z.; Sun, R.; Wang, Q.J.; Wang, M.Z. Hepatotoxicity induced by intragastrically administrated with Gardenia decoction in mice. Nat. Prod. Res. 2017, 31, 2824–2827. [Google Scholar] [CrossRef]
- Yang, H.J.; Fu, M.H.; Wu, Z.L.; Liang, R.X.; Huang, L.Q.; Fang, J.; Li, G.; Cao, Y. Experimental studies on hepatotoxicity of rats induced by Fructus Gardeniae. Zhongguo Zhong Yao Za Zhi Zhongguo Zhongyao Zazhi China J. Chin. Mater. Med. 2006, 31, 1091–1093. [Google Scholar]
- Wang, Y.; Feng, F. Evaluation of the Hepatotoxicity of the Zhi-Zi-Hou-Po Decoction by Combining UPLC-Q-Exactive-MS-Based Metabolomics and HPLC-MS/MS-Based Geniposide Tissue Distribution. Molecules 2019, 24, 511. [Google Scholar] [CrossRef]
- Tian, J.; Yi, Y.; Zhao, Y.; Li, C.; Zhang, Y.; Wang, L.; Pan, C.; Han, J.; Li, G.; Li, X.; et al. Oral chronic toxicity study of geniposide in rats. J. Ethnopharmacol. 2018, 213, 166–175. [Google Scholar] [CrossRef] [PubMed]
- Khanal, T.; Kim, H.G.; Choi, J.H.; Do, M.T.; Kong, M.J.; Kang, M.J.; Noh, K.; Yeo, H.K.; Ahn, Y.T.; Kang, W.; et al. Biotransformation of geniposide by human intestinal microflora on cytotoxicity against HepG2 cells. Toxicol. Lett. 2012, 209, 246–254. [Google Scholar] [CrossRef] [PubMed]
- Sung, H.W.; Huang, R.N.; Huang, L.L.; Tsai, C.C.; Chiu, C.T. Feasibility study of a natural crosslinking reagent for biological tissue fixation. J. Biomed. Mater. Res. 1998, 42, 560–567. [Google Scholar] [CrossRef]
- Hobbs, C.A.; Koyanagi, M.; Swartz, C.; Davis, J.; Maronpot, R.; Recio, L.; Hayashi, S.M. Genotoxicity evaluation of the naturally-derived food colorant, gardenia blue, and its precursor, genipin. Food Chem. Toxicol. 2018, 118, 695–708. [Google Scholar] [CrossRef] [PubMed]
- Han, Y.; Wen, J.; Zhou, T.; Fan, G. Chemical fingerprinting of Gardenia jasminoides Ellis by HPLC-DAD-ESI-MS combined with chemometrics methods. Food Chem. 2015, 188, 648–657. [Google Scholar] [CrossRef] [PubMed]
- Shi, F.; Pan, H.; Li, Y.; Huang, L.; Wu, Q.; Lu, Y. A sensitive LC-MS/MS method for simultaneous quantification of geniposide and its active metabolite genipin in rat plasma and its application to a pharmacokinetic study. Biomed. Chromatogr. 2018, 32. [Google Scholar] [CrossRef]
- Ding, Y.; Zhang, T.; Tao, J.S.; Zhang, L.Y.; Shi, J.R.; Ji, G. Potential hepatotoxicity of geniposide, the major iridoid glycoside in dried ripe fruits of Gardenia jasminoides (Zhi-zi). Nat. Prod. Res. 2013, 27, 929–933. [Google Scholar] [CrossRef]
- Alavizadeh, S.H.; Hosseinzadeh, H. Bioactivity assessment and toxicity of crocin: A comprehensive review. Food Chem. Toxicol. 2014, 64, 65–80. [Google Scholar] [CrossRef]
- Hsu, J.D.; Chou, F.P.; Lee, M.J.; Chiang, H.C.; Lin, Y.L.; Shiow, S.J.; Wang, C.J. Suppression of the TPA-induced expression of nuclear-protooncogenes in mouse epidermis by crocetin via antioxidant activity. Anticancer Res. 1999, 19, 4221–4227. [Google Scholar] [PubMed]
- Yousefsani, B.S.; Mehri, S.; Pourahmad, J.; Hosseinzadeh, H. Crocin Prevents Sub-Cellular Organelle Damage, Proteolysis and Apoptosis in Rat Hepatocytes: A Justification for Its Hepatoprotection. Iran. J. Pharm. Res. IJPR 2018, 17, 553–562. [Google Scholar] [PubMed]
- Xie, Y.; He, Q.; Chen, H.; Lin, Z.; Xu, Y.; Yang, C. Crocin ameliorates chronic obstructive pulmonary disease-induced depression via PI3K/Akt mediated suppression of inflammation. Eur. J. Pharm. 2019, 862, 172640. [Google Scholar] [CrossRef] [PubMed]
- Diao, S.L.; Sun, J.W.; Ma, B.X.; Li, X.M.; Wang, D. Influence of crocetin on high-cholesterol diet induced atherosclerosis in rats via anti-oxidant activity together with inhibition of inflammatory response and p38 MAPK signaling pathway. Saudi J. Biol. Sci. 2018, 25, 493–499. [Google Scholar] [CrossRef] [PubMed]
- Kang, M.J.; Khanal, T.; Kim, H.G.; Lee, D.H.; Yeo, H.K.; Lee, Y.S.; Ahn, Y.T.; Kim, D.H.; Jeong, H.G.; Jeong, T.C. Role of metabolism by human intestinal microflora in geniposide-induced toxicity in HepG2 cells. Arch. Pharmacal. Res. 2012, 35, 733–738. [Google Scholar] [CrossRef] [PubMed]
- Shan, M.Q.; Wang, T.J.; Jiang, Y.L.; Yu, S.; Yan, H.; Zhang, L.; Wu, Q.N.; Geng, T.; Huang, W.Z.; Wang, Z.Z.; et al. Comparative analysis of sixteen active compounds and antioxidant and anti-influenza properties of Gardenia jasminoides fruits at different times and application to the determination of the appropriate harvest period with hierarchical cluster analysis. J. Ethnopharmacol. 2019, 233, 169–178. [Google Scholar] [CrossRef]
- Yu, M.; Zhao, Y.; Zhang, X. Gardenoside combined with ozone inhibits the expression of P2 × 3 and P2 × 7 purine receptors in rats with sciatic nerve injury. Mol. Med. Rep. 2018, 17, 7980–7986. [Google Scholar] [CrossRef]
- Jiang, P.; Ma, Y.; Gao, Y.; Li, Z.; Lian, S.; Xu, Z.; Jiang, W.; Tian, X.; Huang, C. Comprehensive Evaluation of the Metabolism of Genipin-1-beta-d-gentiobioside in Vitro and in Vivo by Using HPLC-Q-TOF. J. Agric. Food Chem. 2016, 64, 5490–5498. [Google Scholar] [CrossRef]
- Liu, L.L.; Zhu, J.M.; Yu, X.N.; Zhu, H.R.; Shi, X.; Bilegsaikhan, E.; Guo, H.Y.; Wu, J.; Shen, X.Z. UBE2T promotes proliferation via G2/M checkpoint in hepatocellular carcinoma. Cancer Manag. Res. 2019, 11, 8359–8370. [Google Scholar] [CrossRef]
- Park, C.; Cha, H.J.; Choi, E.O.; Lee, H.; Hwang-Bo, H.; Ji, S.Y.; Kim, M.Y.; Kim, S.Y.; Hong, S.H.; Cheong, J.; et al. Isorhamnetin Induces Cell Cycle Arrest and Apoptosis Via Reactive Oxygen Species-Mediated AMP-Activated Protein Kinase Signaling Pathway Activation in Human Bladder Cancer Cells. Cancers 2019, 11, 1494. [Google Scholar] [CrossRef]
- Kamel, E.O.; Hassanein, E.H.M.; Ahmed, M.A.; Ali, F.E.M. Perindopril ameliorates hepatic IR injury via regulation of NF-kappaB-p65/TLR-4, JAK1/STAT-3, Nrf-2 and PI3K/Akt/mTOR signaling pathways. Anat. Rec. 2019. [Google Scholar] [CrossRef] [PubMed]
- Abdel-Gaber, S.A.; Geddawy, A.; Moussa, R.A. The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway. Pharmacol. Rep. Pr. 2019, 71, 1044–1049. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.; Zhu, A.; Xiao, S.; Zhang, T.; Wang, L.; Wang, Q.; Han, L. Anthraquinones in the aqueous extract of Cassiae semen cause liver injury in rats through lipid metabolism disorder. Phytomed. Int. J. Phytother. Phytopharm. 2019, 64, 153059. [Google Scholar] [CrossRef] [PubMed]
- Sharma, U.; Pal, D.; Prasad, R. Alkaline phosphatase: An overview. Indian J. Clin. Biochem. IJCB 2014, 29, 269–278. [Google Scholar] [CrossRef] [PubMed]
- Sanjeev, S.; Bidanchi, R.M.; Murthy, M.K.; Gurusubramanian, G.; Roy, V.K. Influence of ferulic acid consumption in ameliorating the cadmium-induced liver and renal oxidative damage in rats. Environ. Sci. Pollut. Res. Int. 2019. [Google Scholar] [CrossRef] [PubMed]
- Franco, R.; Cidlowski, J.A. Glutathione Efflux and Cell Death. Antioxid. Redox Signal. 2012, 17, 1694–1713. [Google Scholar] [CrossRef] [Green Version]
- Chen, D.; Zhang, X.Y.; Sun, J.; Cong, Q.J.; Chen, W.X.; Ahsan, H.M.; Gao, J.; Qian, J.J. Asiatic Acid Protects Dopaminergic Neurons from Neuroinflammation by Suppressing Mitochondrial Ros Production. Biomol. Ther. 2019. [Google Scholar] [CrossRef]
- Zhao, L.; Jiang, Y.; Ni, Y.X.; Zhang, T.Z.; Duan, C.C.; Huang, C.; Zhao, Y.J.; Gao, L.; Li, S.Y. Protective effects of Lactobacillus plantarum C88 on chronic ethanol-induced liver injury in mice. J. Funct. Foods 2017, 35, 97–104. [Google Scholar] [CrossRef]
- Wang, Y.Z.; Li, Y.X.; Xie, J.M.; Zhang, Y.; Wang, J.L.; Sun, X.L.; Zhang, H.P. Protective effects of probiotic Lactobacillus casei Zhang against endotoxin- and D-galactosamine-induced liver injury in rats via anti-oxidative and anti-inflammatory capacities. Int. Immunopharmacol. 2013, 15, 30–37. [Google Scholar] [CrossRef]
- Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. [Google Scholar] [CrossRef]
- Zhang, D.; Tang, J.; Zhang, J.; Zhang, L.; Hu, C.X. Responses of pro- and anti-inflammatory cytokines in zebrafish liver exposed to sublethal doses of Aphanizomenon flosaquae DC-1 aphantoxins. Aquat. Toxicol. 2019, 215, 105269. [Google Scholar] [CrossRef] [PubMed]
- Huang, W.; Wang, Y.; Jiang, X.; Sun, Y.; Zhao, Z.; Li, S. Protective Effect of Flavonoids from Ziziphus jujuba cv. Jinsixiaozao against Acetaminophen-Induced Liver Injury by Inhibiting Oxidative Stress and Inflammation in Mice. Molecules 2017, 22, 1781. [Google Scholar] [CrossRef] [PubMed]
- Aggarwal, B.B. Signalling pathways of the TNF superfamily: A double-edged sword. Nat. Rev. Immunol. 2003, 3, 745–756. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Y.; Li, S.; Hu, R.; Cheng, F.; Zhang, L. GFI-1 Protects Against Lipopolysaccharide-Induced Inflammatory Responses and Apoptosis by Inhibition of the NF-kappaB/TNF-alpha Pathway in H9c2 Cells. Inflammation 2019. [Google Scholar] [CrossRef] [PubMed]
- Weiler, J.; Dittmar, T. Minocycline impairs TNF-alpha-induced cell fusion of M13SV1-Cre cells with MDA-MB-435-pFDR1 cells by suppressing NF-kappaB transcriptional activity and its induction of target-gene expression of fusion-relevant factors. Cell Commun. Signal. Ccs 2019, 17, 71. [Google Scholar] [CrossRef] [PubMed]
- Dyari, H.R.E.; Rawling, T.; Chen, Y.; Sudarmana, W.; Bourget, K.; Dwyer, J.M.; Allison, S.E.; Murray, M. A novel synthetic analogue of omega-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells. Faseb J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2017, 31, 5246–5257. [Google Scholar] [CrossRef]
- Jiang, Y.; Yu, M.; Hu, X.; Han, L.; Yang, K.; Ba, H.; Zhang, Z.; Yin, B.; Yang, X.P.; Li, Z.; et al. STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1. Cell Death Differ. 2017, 24, 660–671. [Google Scholar] [CrossRef] [Green Version]
- Gao, X.C.; Lv, J.W.; Li, C.N.; Zhang, N.X.; Tian, L.L.; Han, X.Y.; Zhang, H.; Sun, J.M. Screening of the Active Component Promoting Leydig Cell Proliferation from Lepidium meyenii Using HPLC-ESI-MS/MS Coupled with Multivariate Statistical Analysis. Molecules 2019, 24, 2101. [Google Scholar] [CrossRef]
- Zhang, H.Y.; Liu, H.; Yang, M.; Wei, S.F. Antithrombotic activities of aqueous extract from Gardenia jasminoides and its main constituent. Pharm Biol. 2012, 51, 221–226. [Google Scholar] [CrossRef]
- Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999, 17, 57–61. [Google Scholar]
- Patil, M.; Noonikara-Poyil, A.; Joshi, S.D.; Patil, S.A.; Patil, S.A.; Bugarin, A. New Urea Derivatives as Potential Antimicrobial Agents: Synthesis, Biological Evaluation, and Molecular Docking Studies. Antibiotics 2019, 8, 178. [Google Scholar] [CrossRef] [PubMed]
- Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Modeling 2011, 51, 2778–2786. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Not available. |
No. | Retention Time (min) | λmax(nm) | Observed m/z | Fragment Ion | Component Name |
---|---|---|---|---|---|
1 | 5.23 | 238 | 414.8 [M + Na]+ | 216.2, 234.3, 252.3 | Shanzhiside |
2 | 5.78 | 238 | 397.0 [M + Na]+ | 202.0, 216.2, 234.2 | Geniposidic acid |
3 | 6.66 | 238 | 426.9 [M + Na]+ | 232.2, 246.3, 264.3 | Gardenoside |
4 | 13.20 | 238 | 573.0 [M + Na]+ | 304.4, 364.5 | Genipin-1-gentiobioside |
5 | 13.32 | 320 | 376.7 [M + Na]+ | 184.3, 215.3 | Chlorogenic acid |
6 | 16.63 | 238 | 410.7 [M + Na]+ | 230.2 | Geniposide |
7 | 31.28 | 440 | 999.7 [M + Na]+ | 346.5, 582.8, 674.8 | Crocin-1 |
8 | 34.09 | 440 | 837.5 [M + Na]+ | 346.5, 512.7, 674.8 | Crocin-2 |
9 | 54.72 | 440 | 350.9 [M + Na]+ | 249.5, 289.5, 306.5 | Crocetin |
Analyte | Regression Equation (Liner Model) | Linear Range(µg/mL) | R2 | Content (mg/g) |
---|---|---|---|---|
Shanzhiside | y = 14.21x + 18.97 | 3.8–190 | 0.9992 | 2.12 ± 0.11 |
Geniposidic acid | y = 12.96x + 48.43 | 4.4–220 | 0.9994 | 4.84 ± 0.15 |
Gardenoside | y = 8.60x + 17.56 | 3–150 | 0.9993 | 4.04 ± 0.02 |
Genipin-1-gentiobioside | y = 7.28x − 26.28 | 11.8–590 | 0.9999 | 8.41 ± 0.50 |
Chlorogenic acid | y = 33.06x − 32.16 | 2.4–120 | 0.9992 | 1.14 ± 0.49 |
Geniposide | y = 11.30x + 51.55 | 16.2–810 | 0.9999 | 46.6 ± 1.14 |
Crocin-1 | y = 18.24x + 15.99 | 10–500 | 0.9997 | 13.9 ± 1.47 |
Crocin-2 | y = 15.24x + 62.03 | 8–400 | 0.9996 | 3.1 ± 0.48 |
Crocetin | y = 15.07x + 54.47 | 7.8–390 | 0.9993 | 0.81 ± 0.15 |
Samples | 10 µg/mL | 50 µg/mL | 100 µg/mL | 150 µg/mL | 200 µg/mL | 500 µg/mL |
---|---|---|---|---|---|---|
Shanzhiside | 89.14 ± 8.02 ** | 79.73 ± 4.72 ** | 75.69 ± 5.23 ** | 76.53 ± 4.37 ** | 76.66 ± 4.22 ** | 63.60 ± 3.58 ** |
Geniposidic acid | 109.71 ± 10.65 ** | 99.70 ± 1.63 | 85.03 ± 10.05 ** | 96.79 ± 2.64 | 91.77 ± 4.40 * | 92.28 ± 2.62 * |
Gardenoside | 97.59 ± 3.60 | 95.29 ± 3.36 * | 89.02 ± 1.74 ** | 93.67 ± 0.95 ** | 85.91 ± 3.38 ** | 77.39 ± 5.49 ** |
genipin-1-Gentiobioside | 93.22 ± 9.63 | 92.93 ± 13.15 * | 76.43 ± 9.79 ** | 89.81 ± 8.74 * | 82.46 ± 10.18 ** | 64.62 ± 8.51 ** |
Chlorogenic acid | 95.21 ± 3.30 * | 86.84 ± 4.91 ** | 94.10 ± 0.86 * | 89.53 ± 3.67 * | 100.50 ± 0.45 | 98.21 ± 2.03 |
Geniposide | 98.88 ± 2.39 | 81.38 ± 2.27 ** | 72.78 ± 3.09 ** | 67.93 ± 1.51 ** | 57.81 ± 1.62 ** | 43.15 ± 0.97 ** |
Crocin-1 | 85.29 ± 8.46 ** | 105.57 ± 4.05 | 110.25 ± 4.87 ** | 126.32 ± 9.93 ** | 142.79 ± 6.81 ** | 186.74 ± 4.57 ** |
Crocin-2 | 117.25 ± 7.61 * | 126.52 ± 15.73 ** | 144.66 ± 7.48 ** | 141.21 ± 8.66 ** | 161.16 ± 17.77 ** | 191.43 ± 10.33 ** |
Crocetin | 153.53 ± 19.22 ** | 153.18 ± 19.95 ** | 163.79 ± 18.09 ** | 196.94 ± 29.78 ** | 235.18 ± 35.72 ** | 327.49 ± 26.22 ** |
Genipin | 86.16 ± 1.73 ** | 77.80 ± 7.22 ** | 53.76 ± 2.25 ** | 42.99 ± 5.14 ** | 41.76 ± 1.48 ** | 38.98 ± 2.61 ** |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Li, C.; Lan, M.; Lv, J.; Zhang, Y.; Gao, X.; Gao, X.; Dong, L.; Luo, G.; Zhang, H.; Sun, J. Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells. Molecules 2019, 24, 3920. https://doi.org/10.3390/molecules24213920
Li C, Lan M, Lv J, Zhang Y, Gao X, Gao X, Dong L, Luo G, Zhang H, Sun J. Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells. Molecules. 2019; 24(21):3920. https://doi.org/10.3390/molecules24213920
Chicago/Turabian StyleLi, Chunnan, Meng Lan, Jingwei Lv, Ye Zhang, Xiaochen Gao, Xu Gao, Lihua Dong, Guangming Luo, Hui Zhang, and Jiaming Sun. 2019. "Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells" Molecules 24, no. 21: 3920. https://doi.org/10.3390/molecules24213920