Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated h...Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated homolog 2(JPT2)is a critical molecule in Ca^(2+)mobilization,and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear.This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones.Genetic approaches were used to control JPT2 expression in cells and mice,and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics.The results showed that oxalate exposure triggered the upregulation of JPT2,which is involved in nicotinic acid adenine dinucleotide phosphate(NAADP)-mediated Ca^(2+)mobilization.Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown,and these were dominated by phosphatidylinositol 3-kinase(PI3K)/AKT signaling,respectively.Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde(SSA)in macrophages.Furthermore,JPT2 deficiency in mice inhibited kidney stones mineralization.In conclusion,this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion,and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.展开更多
Ovarian cancer(OC)is the deadliest gynecologic malignancy,with platinum-based chemotherapy,such as carboplatin,remaining the standard first-line treatment.However,resistance to carboplatin poses a major therapeutic ch...Ovarian cancer(OC)is the deadliest gynecologic malignancy,with platinum-based chemotherapy,such as carboplatin,remaining the standard first-line treatment.However,resistance to carboplatin poses a major therapeutic challenge,and its mechanisms are not fully understood.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82070723,82270797)Nature Science Foundation of Hubei Province,China(Grant No.:2022CFC020).
文摘Oxalate is an organic dicarboxylic acid that is a common component of plant foods.The kidneys are essential organs for oxalate excretion,but excessive oxalates may induce kidney stones.Jupiter microtubule associated homolog 2(JPT2)is a critical molecule in Ca^(2+)mobilization,and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear.This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones.Genetic approaches were used to control JPT2 expression in cells and mice,and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics.The results showed that oxalate exposure triggered the upregulation of JPT2,which is involved in nicotinic acid adenine dinucleotide phosphate(NAADP)-mediated Ca^(2+)mobilization.Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown,and these were dominated by phosphatidylinositol 3-kinase(PI3K)/AKT signaling,respectively.Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde(SSA)in macrophages.Furthermore,JPT2 deficiency in mice inhibited kidney stones mineralization.In conclusion,this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion,and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.
基金supported by the US National Institutes of Health(No.1R01GM120156-01A1,R03CA223906-01,1R03CA283225-A1 to T.L.)the Kay Yow Cancer Fund(V Foundation for Cancer Research)(USA)(No.4486242 to T.L.)+1 种基金Showalter Scholar fund from Indiana University School of Medicine(USA)(No.2286263 to T.L.)the Indiana University Melvin and Bren Simon Comprehensive Cancer Center(IUSCCC)fund(USA)(No.2987664 to T.L.).
文摘Ovarian cancer(OC)is the deadliest gynecologic malignancy,with platinum-based chemotherapy,such as carboplatin,remaining the standard first-line treatment.However,resistance to carboplatin poses a major therapeutic challenge,and its mechanisms are not fully understood.
