Osteoporosis constitutes a severe public health problem marked by an unbalanced homeostasis between bone formation and bone resorption.Due to the considerable side effects associated with existing clinical medications...Osteoporosis constitutes a severe public health problem marked by an unbalanced homeostasis between bone formation and bone resorption.Due to the considerable side effects associated with existing clinical medications,the development of safe and efficient natural bioactive components has become increasingly urgent.This study is the first to verify that the osteogenic activity of lactoferrin-derived hydrophobic peptides(LF-HD)is significantly higher than that of hydrophilic peptides(LF-HY),and the key functional hydrophobic peptide YIYT(tyrosine-isoleucine-tyrosine-threonine)was successfully isolated and purified.In vitro assays using MC3T3-E1 subclone 14 indicated that YIYT enhanced osteoblast proliferation,cell cycle progression,differentiation,and matrix mineralization,and synergistically activated the Wnt/β-catenin and BMP/Smad signaling pathways,with the expression of BMP-2 increased by approximately 1 fold and RUNX-2 by about 0.5 fold.In vivo studies using ovariectomized mice further revealed that YIYT notably improved bone metabolism,increasing bone mineral density by roughly 40%,bone volume fraction(BV/TV)by more than 15%,trabecular number(Tb.N)by nearly 1 fold,and trabecular thickness by approximately 0.05 mm,while decreasing trabecular separation and improving trabecular microarchitecture.Meanwhile,YIYT modulated the RANKL/OPG axis and reduced the number of TRAP-positive osteoclasts,thus attenuating excessive bone resorption.Collectively,YIYT exerts a dual regulatory function by promoting bone formation and inhibiting bone resorption with remarkable efficacy,making it a safe and promising bioactive peptide candidate for the prevention and treatment of osteoporosis.展开更多
Intestinal barrier dysfunction and NLRP3 inflammasome-mediated pyroptosis are critical pathological drivers of dextran sulfate sodium(DSS)-induced colitis,with limited targeted therapies available.Herein,the therapeut...Intestinal barrier dysfunction and NLRP3 inflammasome-mediated pyroptosis are critical pathological drivers of dextran sulfate sodium(DSS)-induced colitis,with limited targeted therapies available.Herein,the therapeutic potential of geniposide and its core mechanism were explored.Geniposide was found to ameliorate colitis in a dose-dependent manner,with 50/100 mg/kg doses showing the most efficacy.This was reflected by restored body weight,reduced DAI score and alleviated histological damage in colonic tissues.Notably,the NF-κB-NLRP3-pyroptosis axis was uniquely suppressed by geniposide.Specifically,NF-κB activation was inhibited.The mRNA expression of NLRP3 and CASPASE-1 were downregulated,and the assembly process of the inflammasome was blocked.GSDMD-mediated pyroptosis in intestinal epithelial cells was also abrogated both in vivo and in vitro.Concomitantly,intestinal barrier integrity was synergistically restored.This restoration was achieved via upregulation of tight junction mRNA expression(OCCLUDIN,ZO-1,CLAUDIN-1)and enhanced MUC-2 secretion.Minor reduction in pro-inflammatory cytokines and inhibition of myeloperoxidase activity were observed as secondary effects.Collectively,geniposide exerts therapeutic effects by targeting the NF-κB-NLRP3-GSDMD pathway.It synergistically inhibits pyroptosis and repairs intestinal barrier,with its innovative value for colitis treatment highlighted.展开更多
基金supported by the National Natural Science Foundation of China(32472274)Liaoning Provincial Science and Technology Plan Joint Program Project(2024-MSLH-035)the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology,Ministry of Education(RK202302).
文摘Osteoporosis constitutes a severe public health problem marked by an unbalanced homeostasis between bone formation and bone resorption.Due to the considerable side effects associated with existing clinical medications,the development of safe and efficient natural bioactive components has become increasingly urgent.This study is the first to verify that the osteogenic activity of lactoferrin-derived hydrophobic peptides(LF-HD)is significantly higher than that of hydrophilic peptides(LF-HY),and the key functional hydrophobic peptide YIYT(tyrosine-isoleucine-tyrosine-threonine)was successfully isolated and purified.In vitro assays using MC3T3-E1 subclone 14 indicated that YIYT enhanced osteoblast proliferation,cell cycle progression,differentiation,and matrix mineralization,and synergistically activated the Wnt/β-catenin and BMP/Smad signaling pathways,with the expression of BMP-2 increased by approximately 1 fold and RUNX-2 by about 0.5 fold.In vivo studies using ovariectomized mice further revealed that YIYT notably improved bone metabolism,increasing bone mineral density by roughly 40%,bone volume fraction(BV/TV)by more than 15%,trabecular number(Tb.N)by nearly 1 fold,and trabecular thickness by approximately 0.05 mm,while decreasing trabecular separation and improving trabecular microarchitecture.Meanwhile,YIYT modulated the RANKL/OPG axis and reduced the number of TRAP-positive osteoclasts,thus attenuating excessive bone resorption.Collectively,YIYT exerts a dual regulatory function by promoting bone formation and inhibiting bone resorption with remarkable efficacy,making it a safe and promising bioactive peptide candidate for the prevention and treatment of osteoporosis.
基金supported by Liaoning Provincial Science and Technology Plan Joint Project(Grant No.2024-MSLH-026)Dalian Science and Technology Bureau(2023RG005).
文摘Intestinal barrier dysfunction and NLRP3 inflammasome-mediated pyroptosis are critical pathological drivers of dextran sulfate sodium(DSS)-induced colitis,with limited targeted therapies available.Herein,the therapeutic potential of geniposide and its core mechanism were explored.Geniposide was found to ameliorate colitis in a dose-dependent manner,with 50/100 mg/kg doses showing the most efficacy.This was reflected by restored body weight,reduced DAI score and alleviated histological damage in colonic tissues.Notably,the NF-κB-NLRP3-pyroptosis axis was uniquely suppressed by geniposide.Specifically,NF-κB activation was inhibited.The mRNA expression of NLRP3 and CASPASE-1 were downregulated,and the assembly process of the inflammasome was blocked.GSDMD-mediated pyroptosis in intestinal epithelial cells was also abrogated both in vivo and in vitro.Concomitantly,intestinal barrier integrity was synergistically restored.This restoration was achieved via upregulation of tight junction mRNA expression(OCCLUDIN,ZO-1,CLAUDIN-1)and enhanced MUC-2 secretion.Minor reduction in pro-inflammatory cytokines and inhibition of myeloperoxidase activity were observed as secondary effects.Collectively,geniposide exerts therapeutic effects by targeting the NF-κB-NLRP3-GSDMD pathway.It synergistically inhibits pyroptosis and repairs intestinal barrier,with its innovative value for colitis treatment highlighted.
