CoChat
Sign Up
Cited by 36

The DOI matches its Crossref record.

Hepatotoxicity of Pyrrolizidine Alkaloid Compound Intermedine: Comparison with Other Pyrrolizidine Alkaloids and Its Toxicological Mechanism

Wang, Ziqi, Han, Haolei, Wang, Chen, Zheng, Qinqin, Chen, Hongping, Zhang, Xiangchun, Hou, Ruyan·2021·Toxins
DOI 10.3390/toxins13120849PMC PMC8709407
Open this paper in CoChat — free account

Abstract

Pyrrolizidine alkaloids (PAs) are common secondary plant compounds with hepatotoxicity. The consumption of herbal medicines and herbal teas containing PAs is one of the main causes of hepatic sinusoidal obstruction syndrome (HSOS), a potentially life-threatening condition. The present study aimed to reveal the mechanism underlying the cytotoxicity of intermedine (Im), the main PA in Comfrey. We evaluated the toxicity of the retronecine-type PAs with different structures to cell lines derived from mammalian tissues, including primary mouse hepatocytes, human hepatocytes (HepD), mouse hepatoma-22 (H22) and human hepatocellular carcinoma (HepG2) cells. The cytotoxicity of Im to hepatocyte was evaluated by using cell counting kit-8 assay, colony formation experiment, wound healing assay and dead/live fluorescence imaging. In vitro characterization showed that these PAs were cytotoxic and induced cell apoptosis in a dose-dependent manner. We also demonstrated that Im induced cell apoptosis by generating excessive reactive oxygen species (ROS), changing the mitochondrial membrane potential and releasing cytochrome c (Cyt c) before activating the caspase-3 pathway. Importantly, we directly observed the destruction of the cell mitochondrial structure after Im treatment through transmission electron microscopy (TEM). This study provided the first direct evidence of Im inducing hepatotoxicity through mitochondria-mediated apoptosis. These results supplemented the basic toxicity data of PAs and facilitated the comprehensive and systematic evaluation of the toxicity caused by PA compounds.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/toxins13120849

Cites

Statistics

Figures

Figure 1 Structures of 1,2-unsaturated pyrrolizidine alkaloids (PAs). (A) Typical structures of retronecine-type, heliotridine-type and otonecine-type. (B) Structures of intermedine (Im), intermedine N-oxide (ImNO), lycopsamine (La), lycopsamine N-oxide (LaNO), retrorsine (Re), retrorsine N-oxide (ReNO), senecionine (Sc) and senecionine N-oxide (ScNO).
Figure 1 Structures of 1,2-unsaturated pyrrolizidine alkaloids (PAs). (A) Typical structures of retronecine-type, heliotridine-type and otonecine-type. (B) Structures of intermedine (Im), intermedine N-oxide (ImNO), lycopsamine (La), lycopsamine N-oxide (LaNO), retrorsine (Re), retrorsine N-oxide (ReNO), senecionine (Sc) and senecionine N-oxide (ScNO).CC BY · PubMed Central
Figure 2 Im, ImNO, La, LaNO, Re, ReNO, Sc and ScNO inhibited the growth of primary mouse hepatocytes, human hepatocytes (HepD), mouse hepatoma-22 (H22) and human hepatocellular carcinoma (HepG2) cells. The proliferative ability of primary mouse hepatocytes, HepD cells, H22 cells and HepG2 cells was detected using cell counting kit-8 assays after the cells were treated with Im, ImNO, La, LaNO, Re, ReNO, Sc and ScNO. (A) The viability of four kinds of cells after treated by Im. (B) The viability of four kinds of cells after treated by ImNO. (C) The viability of four kinds of cells after treated by La. (D) The viability of four kinds of cells after treated by LaNO. (E) The viability of four kinds of cells after treated by Re. (F) The viability of four kinds of cells after treated by ReNO. (G) The viability of four kinds of cells after treated by Sc. (H) The viability of four kinds of cells after treated by ScNO. Data represent means ± standard deviation (S.D.) of three independent experiments. *: p < 0.05, **: p < 0.01 and ***: p < 0.001 compared with the control group.
Figure 2 Im, ImNO, La, LaNO, Re, ReNO, Sc and ScNO inhibited the growth of primary mouse hepatocytes, human hepatocytes (HepD), mouse hepatoma-22 (H22) and human hepatocellular carcinoma (HepG2) cells. The proliferative ability of primary mouse hepatocytes, HepD cells, H22 cells and HepG2 cells was detected using cell counting kit-8 assays after the cells were treated with Im, ImNO, La, LaNO, Re, ReNO, Sc and ScNO. (A) The viability of four kinds of cells after treated by Im. (B) The viability of four kinds of cells after treated by ImNO. (C) The viability of four kinds of cells after treated by La. (D) The viability of four kinds of cells after treated by LaNO. (E) The viability of four kinds of cells after treated by Re. (F) The viability of four kinds of cells after treated by ReNO. (G) The viability of four kinds of cells after treated by Sc. (H) The viability of four kinds of cells after treated by ScNO. Data represent means ± standard deviation (S.D.) of three independent experiments. *: p < 0.05, **: p < 0.01 and ***: p < 0.001 compared with the control group.CC BY · PubMed Central
Figure 3 Im inhibited cell colony formation and migration. (A)Typical representative photographs of HepD cells that were subjected to a colony formation assay. HepD cells were exposed to various concentrations of Im (0, 20, 50, 75 and 100 µg/mL) for 24 h, followed by staining with crystal violet. (B) Quantitative statistics of the number of cells corresponding to A. Negative control: 0 µg/mL. (C) Quantitative statistics of the scratch distance of cells corresponding to D. (D) For the wound healing assay, HepD cells were treated with 0, 20, 50, 75 and 100 µg/mL Im. Typical representative photographs of HepD cells migration after treatment with Im for 0 h and 24 h. Data represent means ± S.D. of three independent experiments. ***: p < 0.001 compared with the control. Negative control: the scratch distance of cells at 0 h.
Figure 3 Im inhibited cell colony formation and migration. (A)Typical representative photographs of HepD cells that were subjected to a colony formation assay. HepD cells were exposed to various concentrations of Im (0, 20, 50, 75 and 100 µg/mL) for 24 h, followed by staining with crystal violet. (B) Quantitative statistics of the number of cells corresponding to A. Negative control: 0 µg/mL. (C) Quantitative statistics of the scratch distance of cells corresponding to D. (D) For the wound healing assay, HepD cells were treated with 0, 20, 50, 75 and 100 µg/mL Im. Typical representative photographs of HepD cells migration after treatment with Im for 0 h and 24 h. Data represent means ± S.D. of three independent experiments. ***: p < 0.001 compared with the control. Negative control: the scratch distance of cells at 0 h.CC BY · PubMed Central
Figure 4 Im-induced HepD cells apoptosis. (A) The Annexin V/PI fluorescent images of cells treated with Im (0, 20, 50, 75 and 100 µg/mL) for 24 h (the early apoptotic cells are in green color, and the late apoptotic cells are in green and red color). (B) Quantitative statistics of the green fluorescence intensity corresponding to A. (C) Quantitative statistics of the red fluorescence intensity corresponding to A. (D) HepD cells were exposed to various concentrations of Im (0, 20 and 50 µg/mL) for 24 h, followed by flow cytometry-based apoptosis assay. (E) Group data analysis of the percentage of apoptotic cells corresponding to D. Data represent means ± S.D. of three independent experiments. **: p < 0.01 and ***: p < 0.001 compared with the control.
Figure 4 Im-induced HepD cells apoptosis. (A) The Annexin V/PI fluorescent images of cells treated with Im (0, 20, 50, 75 and 100 µg/mL) for 24 h (the early apoptotic cells are in green color, and the late apoptotic cells are in green and red color). (B) Quantitative statistics of the green fluorescence intensity corresponding to A. (C) Quantitative statistics of the red fluorescence intensity corresponding to A. (D) HepD cells were exposed to various concentrations of Im (0, 20 and 50 µg/mL) for 24 h, followed by flow cytometry-based apoptosis assay. (E) Group data analysis of the percentage of apoptotic cells corresponding to D. Data represent means ± S.D. of three independent experiments. **: p < 0.01 and ***: p < 0.001 compared with the control.CC BY · PubMed Central
Figure 5 Im-induced ROS production in HepD cells. (A) The production of intracellular ROS levels was detected with DCFH-DA (ROS-positive cells are in green) and the nucleus was stained with Hoechst 33258 (nucleus are in blue). HepD cells were incubated with 0, 20, 50, 75 and 100 µg/mL Im for 24 h and the intensity of green fluorescence increased significantly as the concentration of Im increased. (B) Quantitative statistics of ROS fluorescence intensity corresponding to A. Data represent means ± S.D. of three independent experiments. ***: p < 0.001 compared with the control.
Figure 5 Im-induced ROS production in HepD cells. (A) The production of intracellular ROS levels was detected with DCFH-DA (ROS-positive cells are in green) and the nucleus was stained with Hoechst 33258 (nucleus are in blue). HepD cells were incubated with 0, 20, 50, 75 and 100 µg/mL Im for 24 h and the intensity of green fluorescence increased significantly as the concentration of Im increased. (B) Quantitative statistics of ROS fluorescence intensity corresponding to A. Data represent means ± S.D. of three independent experiments. ***: p < 0.001 compared with the control.CC BY · PubMed Central
Figure 6 Im-induced mitochondrial damage in HepD cells. (A) HepD cells were treated with 0, 20, 50, 75 and 100 µg/mL Im, representative fluorescence images of HepD cells of mitochondrial membrane potential assay. Green fluorescence increased and red fluorescence decreased; Im induced mitochondrial damage and decreased mitochondrial membrane potential. (B) Quantitative statistics red fluorescence intensity statistics graph corresponding to A. (C) Quantitative statistics green fluorescence intensity statistics graph corresponding to A. (D) HepD cells were treated with 0, 75 µg/mL Im and representative images of transmission electron microscope. Red arrows indicated normal mitochondria and green arrows indicated mitochondrial autophagosome. (E) The percentage of mitochondria numbers in 0, 75 µg/mL Im-treated HepD cells. (F) The percentage of mitochondrial autophagy in 0, 75 µg/mL Im-treated HepD cells. *: p < 0.05, **: p < 0.01 and ***: p < 0.001 compared with the control.
Figure 6 Im-induced mitochondrial damage in HepD cells. (A) HepD cells were treated with 0, 20, 50, 75 and 100 µg/mL Im, representative fluorescence images of HepD cells of mitochondrial membrane potential assay. Green fluorescence increased and red fluorescence decreased; Im induced mitochondrial damage and decreased mitochondrial membrane potential. (B) Quantitative statistics red fluorescence intensity statistics graph corresponding to A. (C) Quantitative statistics green fluorescence intensity statistics graph corresponding to A. (D) HepD cells were treated with 0, 75 µg/mL Im and representative images of transmission electron microscope. Red arrows indicated normal mitochondria and green arrows indicated mitochondrial autophagosome. (E) The percentage of mitochondria numbers in 0, 75 µg/mL Im-treated HepD cells. (F) The percentage of mitochondrial autophagy in 0, 75 µg/mL Im-treated HepD cells. *: p < 0.05, **: p < 0.01 and ***: p < 0.001 compared with the control.CC BY · PubMed Central
Figure 7 HepD cells were treated with 0, 20 and 50 µg/mL Im. (A) Effects of Im on the expression of apoptosis-related proteins B-cell lymphoma-2 (Bcl-2), Bcl-2-Associated X protein (Bax), PARP, cl-PARP, caspase-3, caspase-9, cleaved caspase-9 and Cytochrome c) in HepD cells. HepD cells were treated with 0, 20 and 50 µg/mL Im for 24 h and the expression levels of Bcl-2, Bax, PARP, cl-PARP, caspase-3, caspase-9, cleaved caspase-9 and Cytochrome c (Cyt c) were examined by western blot analysis. (B) The statistics graph shows the expression of these proteins corresponding to A. Data represent means ± S.D. of three independent experiments. **: p < 0.01 and ***: p < 0.001 compared with cells treated with 0 µg/mL Im.
Figure 7 HepD cells were treated with 0, 20 and 50 µg/mL Im. (A) Effects of Im on the expression of apoptosis-related proteins B-cell lymphoma-2 (Bcl-2), Bcl-2-Associated X protein (Bax), PARP, cl-PARP, caspase-3, caspase-9, cleaved caspase-9 and Cytochrome c) in HepD cells. HepD cells were treated with 0, 20 and 50 µg/mL Im for 24 h and the expression levels of Bcl-2, Bax, PARP, cl-PARP, caspase-3, caspase-9, cleaved caspase-9 and Cytochrome c (Cyt c) were examined by western blot analysis. (B) The statistics graph shows the expression of these proteins corresponding to A. Data represent means ± S.D. of three independent experiments. **: p < 0.01 and ***: p < 0.001 compared with cells treated with 0 µg/mL Im.CC BY · PubMed Central
Figure 8 Cultivation and incubation scheme for HepD cells. HepG2 cells were grown in MEM medium supplemented with 10% (v/v) fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. For HepG2 cell differentiation, a two-step procedure was used to prepare cell proliferation assays by first culturing HepG2 cells in MEM medium for 14 days followed by further culturing in medium with 1.7% DMSO for 14 days and then differentiating HepG2 cells into HepD cells.
Figure 8 Cultivation and incubation scheme for HepD cells. HepG2 cells were grown in MEM medium supplemented with 10% (v/v) fetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin. For HepG2 cell differentiation, a two-step procedure was used to prepare cell proliferation assays by first culturing HepG2 cells in MEM medium for 14 days followed by further culturing in medium with 1.7% DMSO for 14 days and then differentiating HepG2 cells into HepD cells.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

No references could be resolved yet.

Research works printed but not linked: 62

  1. Xu, 2019, Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism, Liver Res., 3, 176, 10.1016/j.livres.2019.11.004 · DOI
  2. Yang, 2019, Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: Pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes, World J. Gastroenterol., 25, 3753, 10.3748/wjg.v25.i28.3753 · DOI · Paper page
  3. Helmy, 2006, Review article: Updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome, Aliment. Pharmacol. Ther., 23, 11, 10.1111/j.1365-2036.2006.02742.x · DOI
  4. Edgar, 2015, Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease, Chem. Res. Toxicol., 28, 4, 10.1021/tx500403t · DOI
  5. Gunthardt, 2021, Retrospective HRMS Screening and Dedicated Target Analysis Reveal a Wide Exposure to Pyrrolizidine Alkaloids in Small Streams, Environ. Sci. Technol., 55, 1036, 10.1021/acs.est.0c06411 · DOI
  6. Yang, 2020, Absorption difference between hepatotoxic pyrrolizidine alkaloids and their N-oxides—Mechanism and its potential toxic impact, J. Ethnopharmacol., 249, 112421, 10.1016/j.jep.2019.112421 · DOI
  7. Hungerford, 2019, Pyrrolizidine Alkaloids of Blue Heliotrope (Heliotropium amplexicaule) and Their Presence in Australian Honey, J. Agric. Food Chem., 67, 7995, 10.1021/acs.jafc.9b02136 · DOI
  8. Fu, 2004, Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms, Drug Metab. Rev., 36, 1, 10.1081/DMR-120028426 · DOI
  9. Colegate, 2014, Profiling of Dehydropyrrolizidine Alkaloids and their N-Oxides in Herbarium-Preserved Specimens of Amsinckia Species Using HPLC-esi(+)MS, J. Agric. Food Chem., 62, 7382, 10.1021/jf500425v · DOI
  10. Hungerford, N., Carter, S., Anuj, S., Tan, B., Hnatko, D., Martin, C., Sharma, E., Yin, M., Nguyen, T., and Melksham, K. (2019). Analysis of Pyrrolizidine Alkaloids in Queensland Honey: Using Low Temperature Chromatography to Resolve Stereoisomers and Identify Botanical Sources by UHPLC-MS/MS. Toxins, 11. · DOI
  11. Han, 2022, Development, optimization, validation and application of ultra high performance liquid chromatography tandem mass spectrometry for the analysis of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides in teas and weeds, Food Control., 132, 108518, 10.1016/j.foodcont.2021.108518 · DOI
  12. Stegelmeier, B.L., Colegate, S.M., and Brown, A.W. (2016). Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity. Toxins, 8. · DOI
  13. Wang, 2020, Seneciphylline, a main pyrrolizidine alkaloid in Gynura japonica, induces hepatotoxicity in mice and primary hepatocytes via activating mitochondria-mediated apoptosis, J. Appl. Toxicol., 40, 1534, 10.1002/jat.4004 · DOI
  14. Song, 2020, Pulmonary toxicity is a common phenomenon of toxic pyrrolizidine alkaloids, J. Environ. Sci. Health Part C, 38, 124, 10.1080/26896583.2020.1743608 · DOI
  15. Chou, 2003, Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine, Toxicol. Lett., 145, 239, 10.1016/S0378-4274(03)00293-5 · DOI
  16. Liu, 2010, Pyrrolizidine alkaloid isoline-induced oxidative injury in various mouse tissues, Exp. Toxicol. Pathol., 62, 251, 10.1016/j.etp.2009.04.008 · DOI
  17. Yang, 2017, First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans, Arch. Toxicol., 91, 3913, 10.1007/s00204-017-2013-y · DOI
  18. Chen, L.H., Wang, J.C., Guo, Q.L., Qiao, Y., Wang, H.-J., Liao, Y.-H., Sun, D.-A., and Si, J.-Y. (2019). Simultaneous Determination and Risk Assessment of Pyrrolizidine Alkaloids in Artemisia capillaris Thunb. by UPLC-MS/MS Together with Chemometrics. Molecules, 24. · DOI
  19. Kerrie, 2004, Solid-Phase Extraction and LC−MS Analysis of Pyrrolizidine Alkaloids in Honeys, J. Agric. Food Chem., 52, 6664, 10.1021/jf049102p · DOI
  20. Waizenegger, 2018, Structure-dependent induction of apoptosis by hepatotoxic pyrrolizidine alkaloids in the human hepatoma cell line HepaRG: Single versus repeated exposure, Food Chem. Toxicol., 114, 215, 10.1016/j.fct.2018.02.036 · DOI
  21. Suparmi, 2020, Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach, Arch. Toxicol., 94, 3281, 10.1007/s00204-020-02798-z · DOI
  22. Nakai, 2019, Pyruvate dehydrogenase activation precedes the down-regulation of fatty acid oxidation in monocrotaline-induced myocardial toxicity in mice, Hear. Vessel., 34, 545, 10.1007/s00380-018-1293-3 · DOI
  23. Dalefield, 2016, A 28-day oral toxicity study of echimidine and lasiocarpine in Wistar rats, Regul. Toxicol. Pharmacol., 81, 146, 10.1016/j.yrtph.2016.08.006 · DOI
  24. Ruan, 2014, Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis, Chem. Res. Toxicol., 27, 1030, 10.1021/tx500071q · DOI
  25. Gao, 2020, Structure-dependent hepato-cytotoxic potencies of selected pyrrolizidine alkaloids in primary rat hepatocyte culture, Food Chem. Toxicol., 135, 110923, 10.1016/j.fct.2019.110923 · DOI
  26. Rutz, 2020, Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells, Arch. Toxicol., 94, 4159, 10.1007/s00204-020-02895-z · DOI
  27. Geburek, 2020, In vitro biotransformation of pyrrolizidine alkaloids in different species: Part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids, Arch. Toxicol., 94, 3759, 10.1007/s00204-020-02853-9 · DOI
  28. Ruan, 2015, Blood Pyrrole-Protein Adducts—A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans, J. Environ. Sci. Health Part C, 33, 404, 10.1080/10590501.2015.1096882 · DOI
  29. Zheng, 2021, Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells, Oxid. Med. Cell. Longev., 2021, 1, 10.1155/2021/8822304 · DOI
  30. Xiong, 2020, Protein cross-linking in primary cultured mouse hepatocytes by dehydropyrrolizidine alkaloids: Structure–toxicity relationship, Toxicon, 186, 4, 10.1016/j.toxicon.2020.07.015 · DOI
  31. Lu, 2018, The role of formation of pyrrole–ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity, Arch. Toxicol., 92, 3403, 10.1007/s00204-018-2309-6 · DOI
  32. Waizenegger, J., Glück, J., Henricsson, M., Luckert, C., Braeuning, A., and Hessel-Pras, S. (2021). Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG. Foods, 10. · DOI
  33. Brown, 2016, The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus), J. Appl. Toxicol., 36, 716, 10.1002/jat.3205 · DOI
  34. Colegate, 2015, Pro-toxic dehydropyrrolizidine alkaloids in the traditional Andean herbal medicine “asmachilca”, J. Ethnopharmacol., 172, 179, 10.1016/j.jep.2015.06.012 · DOI
  35. Colegate, 2018, Potentially toxic pyrrolizidine alkaloids in Eupatorium perfoliatum and three related species. Implications for herbal use as boneset, Phytochem. Anal., 29, 613, 10.1002/pca.2775 · DOI
  36. Izcara, S., Casado, N., Morante-Zarcero, S., and Sierra, I. (2020). A Miniaturized QuEChERS Method Combined with Ultrahigh Liquid Chromatography Coupled to Tandem Mass Spectrometry for the Analysis of Pyrrolizidine Alkaloids in Oregano Samples. Foods, 9. · DOI
  37. Mei, 2010, Metabolism, Genotoxicity, and Carcinogenicity of Comfrey, J. Toxicol. Environ. Health Part B, 13, 509, 10.1080/10937404.2010.509013 · DOI
  38. European Food Safety Authority (2016). Dietary exposure assessment to pyrrolizidine alkaloids in the European population. EFSA J., 14, e04572. · DOI
  39. Huybrechts, 2015, Pyrrolizidine alkaloids in food and feed on the Belgian market, Food Addit. Contam. Part A, 32, 1939, 10.1080/19440049.2015.1086821 · DOI
  40. Liu, 2021, MicroRNA-26a inhibits cell proliferation and invasion by targeting FAM98A in breast cancer, Oncol. Lett., 21, 367, 10.3892/ol.2021.12628 · DOI
  41. Gluck, J., Waizenegger, J., Braeuning, A., and Hessel-Pras, S. (2020). Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner. Int. J. Mol. Sci., 22. · DOI
  42. Allemang, 2018, Relative potency of fifteen pyrrolizidine alkaloids to induce DNA damage as measured by micronucleus induction in HepaRG human liver cells, Food Chem Toxicol., 121, 72, 10.1016/j.fct.2018.08.003 · DOI
  43. Xie, 2007, Autophagosome formation: Core machinery and adaptations, Nat. Cell Biol., 9, 1102, 10.1038/ncb1007-1102 · DOI
  44. Klionsky, 2007, Autophagy: From phenomenology to molecular understanding in less than a decade, Nat. Rev. Mol. Cell Biol., 8, 931, 10.1038/nrm2245 · DOI
  45. Lu, 2013, Regulation and function of mitophagy in development and cancer, Autophagy, 9, 1720, 10.4161/auto.26550 · DOI
  46. Mathew, 2011, Autophagy in tumorigenesis and energy metabolism: Friend by day, foe by night, Curr. Opin. Genet. Dev., 21, 113, 10.1016/j.gde.2010.12.008 · DOI
  47. Yu, 2006, Autophagic programmed cell death by selective catalase degradation, Proc. Natl. Acad. Sci. USA, 103, 4952, 10.1073/pnas.0511288103 · DOI
  48. Gump, 2011, Autophagy and Apoptosis: What is the connection?, Trends Cell Biol., 21, 387, 10.1016/j.tcb.2011.03.007 · DOI
  49. Kolrep, 2018, In vitro biotransformation of pyrrolizidine alkaloids in different species. Part I: Microsomal degradation, Arch. Toxicol., 92, 1089, 10.1007/s00204-017-2114-7 · DOI
  50. Pan, 1993, Strain differences in the response of Fischer 344 and Sprague-Dawley rats to monocrotaline induced pulmonary vascular disease, Toxicol., 79, 21, 10.1016/0300-483X(93)90203-5 · DOI
  51. Ji, 2010, Pyrrolizidine alkaloid clivorine induced oxidative injury on primary cultured rat hepatocytes, Hum. Exp. Toxicol., 29, 303, 10.1177/0960327110361757 · DOI
  52. Godin, 2006, Species Differences in the in Vitro Metabolism of Deltamethrin and Esfenvalerate: Differential Oxidative and Hydrolytic Metabolism by Humans and Rats, Drug Metab. Dispos., 34, 1764, 10.1124/dmd.106.010058 · DOI
  53. Zhang, 2018, The Precise Diagnosis of Cancer Invasion/Metastasis via 2D Laser Ablation Mass Mapping of Metalloproteinase in Primary Cancer Tissue, ACS Nano, 12, 11139, 10.1021/acsnano.8b05584 · DOI
  54. Zhang, P., Yan, Y., Wang, J., Dong, X., Zhang, G., Zeng, Y., and Liu, Z. (2020). An Anti-Cancer Peptide LVTX-8 Inhibits the Proliferation and Migration of Lung Tumor Cells by Regulating Causal Genes’ Expression in p53-Related Pathways. Toxins, 12. · DOI
  55. Yang, 2016, Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity, Chem. Interact., 243, 119, 10.1016/j.cbi.2015.09.011 · DOI
  56. Begriche, 2011, Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver, J. Hepatol., 54, 773, 10.1016/j.jhep.2010.11.006 · DOI
  57. Liu, J., Liu, Q., Han, J., Feng, J., Guo, T., Li, Z., Min, F., Jin, R., and Peng, X. (2021). N-Acetylcysteine Inhibits Patulin-Induced Apoptosis by Affecting ROS-Mediated Oxidative Damage Pathway. Toxins, 13. · DOI
  58. Onishi, 2021, Mitochondrial clearance: Mechanisms and roles in cellular fitness, FEBS Lett., 595, 1239, 10.1002/1873-3468.14060 · DOI
  59. Taylor, 2008, Apoptosis: Controlled demolition at the cellular level, Nat. Rev. Mol. Cell Biol., 9, 231, 10.1038/nrm2312 · DOI
  60. Lee, S.M., Kim, N.H., Jeong, E.J., and Rho, J.R. (2020). Cytotoxic 4-Hydroxyprorocentrolide and Prorocentrolide C from Cultured Dinoflagellate Prorocentrum lima Induce Human Cancer Cell Death through Apoptosis and Cell Cycle Arrest. Toxins, 12. · DOI
  61. Seglen, 1976, Chapter 4 Preparation of Isolated Rat Liver Cells, Methods Cell Biol., 13, 29, 10.1016/S0091-679X(08)61797-5 · DOI
  62. Yan, 2016, The inducing differentiation effect of two dimethyl sulfoxide (DMSO) on human hepatocellular carcinoma HepG2 cells in vitro, Mod. Oncol., 24, 2525

Cited by

Sorted by citations

Metadata

Authors
Wang, Z., Han, H., Wang, C., Zheng, Q., Chen, H., Zhang, X., & Hou, R.
Venue
Toxins
Publisher
MDPI AG
Published
2021-11-28
Volume
13
Issue
12
Pages
849
ISSN
2072-6651
DOI
10.3390/toxins13120849
PMC
PMC8709407
Cited by
36
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review