Abstract
Patulin, a mycotoxin, is known to have cytotoxic effects, but few studies have focused on the involvement of the endoplasmic reticulum (ER) stress response in patulin toxicity and the natural compounds that attenuate it in HepG2 cells. This study tested the ability of patulin to induce ER stress, and that of four thiols and three thioethers to attenuate patulin-induced ER stress in HepG2 cells. Patulin dose-dependently inhibited cell proliferation (IC50, 8.43 μM). Additionally, patulin was found to increase the expression levels of ER stress-related genes and/or protein markers, including BiP, CHOP, and spliced XBP1, in HepG2 cells compared to the vehicle control, indicating its potential in ER stress induction. Patulin-induced cytotoxicity in HepG2 cells was reduced by naturally occurring thiol compounds (glutathione, L-acetyl-L-cysteine, cysteine, and captopril), but not by thioether compounds (sulforaphane, sulforaphene, and S-allyl-L-cysteine). Patulin-thiol co-treatment decreased CHOP expression and BiP and CHOP levels in HepG2 cells but did not alter BiP expression. Spliced XBP1 expression was decreased by patulin-thiol co-treatment. Thus, patulin induced ER stress in HepG2 cells and thiols, but not in thioethers, attenuated patulin-induced ER stress.
Highlights
Patulin (4-hydroxy-4H-furo(3,2-c)pyran-2(6H)-one) is a heat-stable polyketide lactone mycotoxin (Figure 1) [1]
Patulin inhibited the metabolic activity of HepG2 cells in a dose-dependent manner and induced endoplasmic reticulum (ER) stress
Among the seven tested sulfur-containing compounds, thiols (GSH, NAC, Cys, and CAP) markedly reduced patulin-induced cytotoxicity, whereas thioethers (SulA, sulforaphane E (SulE), and SAC) had no effect. This reduction by thiols may have been related to the decrease in the mRNA and protein expression levels of the molecules associated with ER stress caused by the patulin treatment
Summary
Patulin (4-hydroxy-4H-furo(3,2-c)pyran-2(6H)-one) is a heat-stable polyketide lactone mycotoxin (Figure 1) [1]. A US Department of Agriculture survey showed that children consume more apple products during their first year of life (6.4 g/kg body weight/day) than adults do in a year (1 g/kg body weight/day) [3] This places young children at an increased risk of patulin toxicity. The oxidative damage induced by patulin is deleterious to cells, and exposure to this mycotoxin may pose a risk to humans [22]. Patulin increased the BiP mRNA and protein levels in HepG2 cells compared (aaFtnitctcdgrooouepnnatrrhccetoeeee3tndneAvttiwrren,aaChittltiii)ehcoo.vlnneve,selcsBhooidifnPci1tlderm0ocnaRloonaNntdttAirnc2oo5calnrnμ(ecFdaMeisngpe.utrHrcroaoeottmeiw3oiAnnpes,valCereoev)rf.,dea1lstt0oadati5hnd0odnsμe2oM5tiniμpncMacertlue.laslHistneorewccaooetnmevcdepernwa, trairetatdhtaivtoo5en0h,thiBμcoilMPseecmpionaRntcNtureolAlillns. The co-treatment with four thiols at 50 μM attenuated the expression levels of the ER stress-related biomarkers that were increased by patulin exposure. Blot analysis, respectively, showed that the expression of ER stress-related biomarkers (BiP, CHOP, and spliced XBP1) was increased by patulin treatment. In a5dE,dF)i.tiIonna,didnitciroena, sinecdrelaesvedellsevoeflsuonfduingdeigsteestdedXXBBPP11 wiitthhPPstsItIwwereroebsoebrvsedrvaeftderacfot-er co-treatment wtreiathtmpenattwuliithnpaantudlinGaSnHd G, SCHy,sC,yNs, NAACC, ,aanddCCAAP.PF.roFmrotmhesethfiensdeinfigsn,dwiencgosn,clwudeedconcluded that tthhaiot lt-hcioonl-ctaonintaiinngincgocmomppoouunnddss ddeeccrreeaasseeddoor rpparatiratlilaylliynhinibhitiebditpeadtupliant-uinldinu-cienddEuRced ER stress in HstreepssGin HceelplGs. cells
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