title: New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity.
abstract: Aristolochic acids (AA) are nephrotoxic agents found in Aristolochia species whose consumption leads to the onset of a progressive tubulointerstitial fibrosis. This AA-nephropathy was first reported during the Belgian outbreak of the 1990's in which more than a hundred patients consumed slimming pills containing an Aristolochia species and Magnolia officinalis. The patients developed an end-stage kidney disease requiring dialysis or transplantation. Magnolol and honokiol are bioactive compounds from M. officinalis known for their potent antioxidant activity. As they can alleviate oxidative stress, we investigated their respective effects on AA-mediated tubulotoxicity using HK-2 cells. Magnolol and honokiol were able to reduce the oxidative stress associated with AA-treatment. Cytotoxicity alleviation was further investigated and overall cell viability measurements unexpectedly revealed that both compounds worsened the survival of AA-treated cells. Flow cytometry analyses of annexin V/PI stained cells indicated that the lignans efficiently prevented AA-induced apoptosis; but favored necrosis. Microscopy observations highlighted extensive vacuolization; other types of cell death, including autophagy, paraptosis or accelerated senescence were excluded. Ki-67 index and cell cycle analysis indicated that both magnolol and honokiol inhibited proliferation by blocking the cell cycle at the G1 phase; they also prevented the AA-induced G2/M arrest.
authors.affiliation: Laboratory of Experimental Nephrology, Université Libre de Bruxelles (ULB), Brussels, Belgium; Laboratory of Pharmacognosy, Bromatology and Human Nutrition, Université Libre de Bruxelles (ULB), Brussels, Belgium. Electronic address: valerian.bunel@outlook.com.
authors.forename: Valérian
authors.initials: V
authors.lastname: Bunel
authors.affiliation: Laboratory of Experimental Nephrology, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.affiliation: Laboratory of Pharmacognosy, Bromatology and Human Nutrition, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stévigny
authors.affiliation: Laboratory of Experimental Nephrology, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Nortier
authors.affiliation: Laboratory of Pharmacognosy, Bromatology and Human Nutrition, Université Libre de Bruxelles (ULB), Brussels, Belgium; Laboratory of Therapeutic Chemistry and Pharmacognosy, Université de Mons (UMONS), Mons, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Duez
mesh_terms: D034341:Aristolochic Acids / Q000737:chemistry / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D016166:Free Radical Scavengers; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects*; D017705:Lignans / Q000737:chemistry / Q000633:toxicity*; D015394:Molecular Structure; D018384:Oxidative Stress; D010851:Picrates; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D034341:Aristolochic Acids; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D017705:Lignans; D010851:Picrates; C005498:magnolol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C000228:aristolochic acid I; C004931:1,1-diphenyl-2-picrylhydrazyl
keywords: Aristolochic acids; Cell cycle; Cell death; Honokiol; Magnolol; Nephrotoxicity