Our earlier studies have demonstrated that the cigarette smoke in the form of cigarette smoke condensate(CSC)causes growth arrest of a mouse spermatocyte cell line[GC-2spd(ts)]through activation of the AHR–NRF2 pathw...Our earlier studies have demonstrated that the cigarette smoke in the form of cigarette smoke condensate(CSC)causes growth arrest of a mouse spermatocyte cell line[GC-2spd(ts)]through activation of the AHR–NRF2 pathway.The present study demonstrates the CSC-activated p38 and ERK MAPK signaling in GC-2spd(ts)via arylhydrocarbon receptor(AHR).Pharmacological inhibition by using AHR-antagonist,or p38 MAPK and ERK(MEK1)inhibitors significantly abrogates CSC-induced growth arrest by AHR and MAPK inactivation.QRT-PCR,western blot,and immunofluorescence of Ahr-target of Nrf2,and stress-inducible growth suppressive Atf3 and E2f4 following treatments indicate a crosstalk among these pathways.Regulation of Atf3 by Nrf2 and Ahr through RNA interference suggests the existence of a cross-regulatory loop between the targets.CSC induction of E2f4 via Atf3 and its regulation by pharmacological inhibitors reveal a possible regulatory mechanism of growth inhibitory CSC.SiRNA silencing of Ahr,Nrf2,Atf3,and E2f4 genes and downregulation of cyclins by CSC corroborate the growth inhibitory effect of cigarette smoke.Thus,the data obtained suggest that the CSC-mediated MAPKs and AHR–NRF2 crosstalks lay the molecular basis for the growth arrest and cell death of spermatocytes.展开更多
Atopic dermatitis(AD)and psoriasis are common chronic and relapsing inflammatory skin diseases mainly mediated by T cells.Type 2 and 17 inflammations are essential in the pathogenesis of AD and psoriasis,respectively....Atopic dermatitis(AD)and psoriasis are common chronic and relapsing inflammatory skin diseases mainly mediated by T cells.Type 2 and 17 inflammations are essential in the pathogenesis of AD and psoriasis,respectively.Clinical evidence suggests that benvitimod,a natural metabolite produced by bacterial symbionts,plays a therapeutic role in the development and progression of both AD and psoriasis.Mechanistically,the two most potent interactions with benvitimod are observed in the aryl hydrocarbon receptor(AhR)and nuclear factor-erythroid 2-related factor-2(Nrf2)pathways.However,it remains largely unknown how is the local interplay among benvitimod,AhR,and Nrf2,and how the epithelial microenvironment contributes to the complex inflammatory context that results in the treatment of AD and psoriasis.In the present study,the modulatory effects of benvitimod on treating AD and psoriasis.展开更多
基金This material is based upon work supported by the Department of Veterans Affairs,Veterans Health Administration,Biomedical Laboratory Research and Development Award#I01BX007080.
文摘Our earlier studies have demonstrated that the cigarette smoke in the form of cigarette smoke condensate(CSC)causes growth arrest of a mouse spermatocyte cell line[GC-2spd(ts)]through activation of the AHR–NRF2 pathway.The present study demonstrates the CSC-activated p38 and ERK MAPK signaling in GC-2spd(ts)via arylhydrocarbon receptor(AHR).Pharmacological inhibition by using AHR-antagonist,or p38 MAPK and ERK(MEK1)inhibitors significantly abrogates CSC-induced growth arrest by AHR and MAPK inactivation.QRT-PCR,western blot,and immunofluorescence of Ahr-target of Nrf2,and stress-inducible growth suppressive Atf3 and E2f4 following treatments indicate a crosstalk among these pathways.Regulation of Atf3 by Nrf2 and Ahr through RNA interference suggests the existence of a cross-regulatory loop between the targets.CSC induction of E2f4 via Atf3 and its regulation by pharmacological inhibitors reveal a possible regulatory mechanism of growth inhibitory CSC.SiRNA silencing of Ahr,Nrf2,Atf3,and E2f4 genes and downregulation of cyclins by CSC corroborate the growth inhibitory effect of cigarette smoke.Thus,the data obtained suggest that the CSC-mediated MAPKs and AHR–NRF2 crosstalks lay the molecular basis for the growth arrest and cell death of spermatocytes.
文摘Atopic dermatitis(AD)and psoriasis are common chronic and relapsing inflammatory skin diseases mainly mediated by T cells.Type 2 and 17 inflammations are essential in the pathogenesis of AD and psoriasis,respectively.Clinical evidence suggests that benvitimod,a natural metabolite produced by bacterial symbionts,plays a therapeutic role in the development and progression of both AD and psoriasis.Mechanistically,the two most potent interactions with benvitimod are observed in the aryl hydrocarbon receptor(AhR)and nuclear factor-erythroid 2-related factor-2(Nrf2)pathways.However,it remains largely unknown how is the local interplay among benvitimod,AhR,and Nrf2,and how the epithelial microenvironment contributes to the complex inflammatory context that results in the treatment of AD and psoriasis.In the present study,the modulatory effects of benvitimod on treating AD and psoriasis.
