Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the...Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.展开更多
Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affe...Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin(m TOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1(m TORC1) and m TOR Complex 2(m TORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase(PI 3-K),protein kinase B(Akt),AMP activated protein kinase(AMPK),silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1),Wnt1 inducible signaling pathway protein 1(WISP1),and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.展开更多
The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing publ...The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing public health concern worldwide,and novel therapeutics that target both the liver and the GI tract(gut-liver axis)are much needed.In addition to aiding fat digestion,bile acids act as important signaling molecules that regulate lipid,glucose and energy metabolism via activating nuclear receptor,G protein-coupled receptors(GPCRs),Takeda G protein receptor 5(TGR5)and sphingosine-1-phosphate receptor 2(S1PR2).Sphingosine-1-phosphate(S1P)is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver,in-flammatory bowel disease(IBD)and colorectal cancer.In this review,we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.展开更多
Objective To study the role and mechanism of sphingosine-phosphate(S1P)/sphingosine-1-phosphate receptor 1(S1P1)signal pathway during post conditioning of hypertrophic cardiomyocytes.Methods Neonatal rat cardiomyocyte...Objective To study the role and mechanism of sphingosine-phosphate(S1P)/sphingosine-1-phosphate receptor 1(S1P1)signal pathway during post conditioning of hypertrophic cardiomyocytes.Methods Neonatal rat cardiomyocytes were isolated and cultured,then stimulated by norepinephrine(NE)to induce cardiomyocytes hypertrophy.Using tri-gas incubator to create展开更多
Osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic ...Osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1 P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1 P via microRNA-21-PI3 K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.展开更多
基金This work is supported in part by SmartState Cancer Stem Cell Biology&Therapy Program and by R01 grants from the National Institutes of Health,including AI118305,HL140953 and CA258440(X.-Z.Y.).
文摘Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.
基金supported by American Diabetes Association,American Heart Association,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin(m TOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1(m TORC1) and m TOR Complex 2(m TORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase(PI 3-K),protein kinase B(Akt),AMP activated protein kinase(AMPK),silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1),Wnt1 inducible signaling pathway protein 1(WISP1),and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
基金This work was supported by the USA National Institutes of Health(NIH)grants R01 DK104893 and R01DK-057543VA Merit Award I01BX004033 and 1I01BX001390Research Career Scientist Award(IK6BX004477)from the Department of Veterans Affairs.
文摘The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing public health concern worldwide,and novel therapeutics that target both the liver and the GI tract(gut-liver axis)are much needed.In addition to aiding fat digestion,bile acids act as important signaling molecules that regulate lipid,glucose and energy metabolism via activating nuclear receptor,G protein-coupled receptors(GPCRs),Takeda G protein receptor 5(TGR5)and sphingosine-1-phosphate receptor 2(S1PR2).Sphingosine-1-phosphate(S1P)is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver,in-flammatory bowel disease(IBD)and colorectal cancer.In this review,we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.
文摘Objective To study the role and mechanism of sphingosine-phosphate(S1P)/sphingosine-1-phosphate receptor 1(S1P1)signal pathway during post conditioning of hypertrophic cardiomyocytes.Methods Neonatal rat cardiomyocytes were isolated and cultured,then stimulated by norepinephrine(NE)to induce cardiomyocytes hypertrophy.Using tri-gas incubator to create
基金the National Natural Science Foundation of China Grants (No. 81302764)the Science and Technology Grant for Excellent Talents of Harbin (No.2017RAXXJ060)。
文摘Osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1 P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1 P via microRNA-21-PI3 K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.
