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NKX6.3 protects against gastric mucosal atrophy by downregulatingβ-amyloid production 预览
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作者 Jung Hwan Yoon Yeon Soo Lee +4 位作者 Olga Kim Hassan Ashktorab Duane T Smoot Suk Woo Nam Won Sang Park 《世界胃肠病学杂志:英文版》 SCIE CAS 2019年第3期330-345,共16页
BACKGROUND Atrophic gastritis is characterized by loss of appropriate glands and reduction in gastric secretory function due to chronic inflammatory processes in gastric mucosa.Moreover,atrophic gastritis is considere... BACKGROUND Atrophic gastritis is characterized by loss of appropriate glands and reduction in gastric secretory function due to chronic inflammatory processes in gastric mucosa.Moreover,atrophic gastritis is considered as a precancerous condition of gastric cancer.However,little is known about the molecular mechanism underlying gastric mucosal atrophy and its contribution to gastric carcinogenesis.Thus,we hypothesized that transcription factor NKX6.3 might be involved in maintaining gastric epithelial homeostasis by regulating amyloidβ(Aβ)production.AIM To determine whether NKX6.3 might protect against gastric mucosal atrophy by regulating Aβproduction.METHODS We identified NKX6.3 depletion induced cell death by cell count and Western blot assay.Production and mechanism of Aβoligomer were analyzed by enzymelinked immunosorbent assay,Western blot,immunoprecipitation,real-time quantitative polymerase chain reaction and immunofluorescence analysis.We further validated the correlation between expression of NKX6.3,Helicobacter pylori CagA,Aβoligomer,apolipoprotein E(ApoE),andβ-secretase 1(Bace1)in 55 gastric mucosae.RESULTS NKX6.3 depletion increased both adherent and floating cell populations in HFE-145 cells.Expression levels of cleaved caspase-3,-9,and poly ADP ribose polymerase were elevated in floating HFE-145shNKX6.3 cells.NKX6.3 depletion produced Aβpeptide oligomers,and increased expression of ApoE,amyloid precursor protein,Aβ,Bace1,low-density lipoprotein receptor,nicastrin,high mobility group box1,and receptor for advanced glycosylation end product proteins.In immunoprecipitation assay,γ-secretase complex was stably formed only in HFE-145shNKX6.3 cells.In gastric mucosae with atrophy,expression of Aβpeptide oligomer,ApoE,and Bace1 was detected and inversely correlated with NKX6.3 expression.Treatment with recombinant Aβ1-42 produced Aβoligomeric forms and decreased cell viability in HFE-145shNKX6.3 cells.Additionally,NKX6.3 depletion increased expression of inflammatory cytokines and cyclooxygena 展开更多
关键词 NKX6.3 GASTRIC MUCOSA ATROPHY AMYLOID β Gastrokine 1
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