To explore the role of a novel Obg-like ATPase 1 （OLA1） in cancer metastasis, small interference RNA （siRNA） was used to knockdown the protein, and the cells were subjected to in vitro cell migration and invasion ...To explore the role of a novel Obg-like ATPase 1 （OLA1） in cancer metastasis, small interference RNA （siRNA） was used to knockdown the protein, and the cells were subjected to in vitro cell migration and invasion assays. Knockdown of OLA 1 significantly inhibited cell migration and invasion in breast cancer cell line MDA-MB-231. The knockdown caused no changes in cell growth but affected ROS production. In wound-healing assays, decreased ROS in OLA1-knockdown cells were in situ asso- ciated with the cells＇ decreased motile morphology. Further, treatment ofN-acetylcysteine, a general ROS scavenger, blunted the motility and invasiveness of MDA-MB-231 cells, similar to the effect of OLAl-knockdown. These results suggest that knock- down of OLA1 inhibits breast cancer cell migration and invasion through a mechanism that involves the modulation of intracellular ROS levels.展开更多
Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated mode...Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages,T cells,and dendritic cells.These immune cells are at the center stage to orchestrate cellular proliferation,migration,and interactions of themselves and other vascular cells including endothelial cells(ECs),vascular smooth muscle cells(VSMCs),and fibroblasts.These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling.Mineralocorticoid receptor(MR)is a classic nuclear receptor.MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling.Conversely,MR antagonists have the opposite effects.MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress.Recent studies using genetic mouse models have revealed that MR in myeloid cells,VSMCs and ECs all contribute to vascular remodeling.In conclusion,data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling.Studies will continue to provide evidence with more detailed mechanisms to support this notion.展开更多
Acrolein,known as one of the most common reactive carbonyl species,is a toxic small molecule affecting human health in daily life.This study is focused on the scavenging abilities and mechanism of ferulic acid and som...Acrolein,known as one of the most common reactive carbonyl species,is a toxic small molecule affecting human health in daily life.This study is focused on the scavenging abilities and mechanism of ferulic acid and some other phenolic acids against acrolein.Among the 13 phenolic compounds investigated,ferulic acid was found to have the highest efficiency in scavenging acrolein under physiological 8nditions.Ferulic acid remained at(3.04±1.89)%and acrolein remained at(29.51±4.44)%after being incubated with each other for 24 h.The molecular mechanism of the detoxifying process was also studied.Detoxifying products,namely 2-methoxy-4-vinyIphenol(product 21)and 5-(4-hydroxy-3-methoxyphenyl)pent-4-enal(product 22),were identified though nuclear magnetic resonanee(NMR)and gas chromatography-mass spectrometry(GC-MS),after the scavenging process.Ferulic acid showed significant activity in scavenging acrolein under physiological conditions.This study indicates a new method for inhibiting damage from acrolein.展开更多
A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident i...A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident in atherosclerotic plaques,characterized by reduced cell proliferation,irreversible growth arrest and apoptosis,and telomere attrition.As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress,shortened LTL in patients with atherosclerosis might stem from the two sources,one is an accelerated rate in hematopoietic stem cells(HSCs)replication to replace leukocytes consumed in the inflammatory process,and another is the increase in the loss of telomere repeats per replication.Thus,diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood.In addition,the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication.Atherosclerosis is an aging-related disease,and practically all humans develop atherosclerosis if they live long enough.Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis,and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.展开更多
Studies on the chaperone protein α-hemoglobin stabilizing protein （AHSP） reveal that abundant AHSP in erythroid cells en-hance the cells＇ tolerance to oxidative stress imposed by excess a-hemoglobin in pathologica...Studies on the chaperone protein α-hemoglobin stabilizing protein （AHSP） reveal that abundant AHSP in erythroid cells en-hance the cells＇ tolerance to oxidative stress imposed by excess a-hemoglobin in pathological conditions. However, the poten-tial intracellular modulation of AHSP expression itself in response to oxidative stress is still unknown. The present study ex-amined the effect and molecular mechanism of STAT3, an oxidative regulator, on the expression of AHSP. AHSP expression increased in K562 cells upon cytokine IL-6-induced STAT3 activation and decreased in STAT3 knock-down K562 cells. Reg-ulation of AHSP in oxidative circumstance was then examined in α-globin-overloaded K562 cells, and real-time PCR showed strengthened expression of both AHSP and STAT3. ChIP analysis showed binding of STAT3 to AHSP promoter and binding was significantly augmented with IL6 stimulation and upon α-globin overexpression. Dual luciferase reporter assays of the wildtype and mutated SB3 element, an IL-6RE site, in the AHSP promoter in K562 cells highlighted the direct regulatory ef-fect of STAT3 on AHSP gene. Finally, direct binding of STAT3 to SB3 site of AHSP promoter was confirmed with EMSA as-says. Our work reveals an adaptive AHSP regulation mediated by the redox-sensitive STAT3 signaling pathway, and provides clues to the therapeutic strategy for AHSP enhancement.展开更多
Ischemia occurs in diabetic retinopathy with neuronal loss, edema, glial cell reactivity and oxidative stress. Epacs, consisting of Epac 1 and Epac2, are cAMP mediators playing important roles in maintenance of endoth...Ischemia occurs in diabetic retinopathy with neuronal loss, edema, glial cell reactivity and oxidative stress. Epacs, consisting of Epac 1 and Epac2, are cAMP mediators playing important roles in maintenance of endothelial barrier and neuronal functions To investigate the roles of Epacs in the pathogenesis of ischemic retinopathy, transient middle cerebral artery occlusion （tMCAO） was performed on Epacl-deficient （Epacl-/- ） mice, Epac2-deficient （Epac2-/-） mice, and their wild type counter-parts （Epacl＋/＋ and Epac2＋/＋）. Two-hour occlusion and 22-hour reperfusion were conducted to induce ischemia/reperfusion injury to the retina. After tMCAO, the contralateral retinae displayed similar morphology between different genotypes. Neu-ronal loss, retinal edema and increase in immunoreactivity for aquaporin 4 （AQP4）, glial fibrillary acidic protein （GFAP）, peroxiredoxin 6 （Prx6） were observed in ipsilateral retinae. Epac2 / ipsilateral retinae showed more neuronal loss in retinal ganglion cell layer, increased retinal thickness and stronger immunostaining of AQP4, GFAP, and Prx6 than those of Epac2＋/＋. However, Epacl-/- ipsilateral retinae displayed similar pathology as those in Epacl＋/＋ mice. Our observations suggest that Epac2-deficiency led to more severe ischemic retinopathy after retinal ischemia/reperfusion injury.展开更多
基金Project supported by the National Basic Research Program (973) of China (No. 2004CB518707) the Methodist Hospital Research Institute, USA
文摘To explore the role of a novel Obg-like ATPase 1 （OLA1） in cancer metastasis, small interference RNA （siRNA） was used to knockdown the protein, and the cells were subjected to in vitro cell migration and invasion assays. Knockdown of OLA 1 significantly inhibited cell migration and invasion in breast cancer cell line MDA-MB-231. The knockdown caused no changes in cell growth but affected ROS production. In wound-healing assays, decreased ROS in OLA1-knockdown cells were in situ asso- ciated with the cells＇ decreased motile morphology. Further, treatment ofN-acetylcysteine, a general ROS scavenger, blunted the motility and invasiveness of MDA-MB-231 cells, similar to the effect of OLAl-knockdown. These results suggest that knock- down of OLA1 inhibits breast cancer cell migration and invasion through a mechanism that involves the modulation of intracellular ROS levels.
基金supported by grants from the One Hundred Talents Program of the Chinese Academy of Sciences(2012OHTP06)the National Basic Research Program of China(2012CB524900)the National Natural Science Foundation of China(91339110,31371153,31171133)
文摘Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages,T cells,and dendritic cells.These immune cells are at the center stage to orchestrate cellular proliferation,migration,and interactions of themselves and other vascular cells including endothelial cells(ECs),vascular smooth muscle cells(VSMCs),and fibroblasts.These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling.Mineralocorticoid receptor(MR)is a classic nuclear receptor.MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling.Conversely,MR antagonists have the opposite effects.MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress.Recent studies using genetic mouse models have revealed that MR in myeloid cells,VSMCs and ECs all contribute to vascular remodeling.In conclusion,data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling.Studies will continue to provide evidence with more detailed mechanisms to support this notion.
基金Project supported by the National Natural Science Foundation of China(Nos.21327010 and 21372199)
文摘Acrolein,known as one of the most common reactive carbonyl species,is a toxic small molecule affecting human health in daily life.This study is focused on the scavenging abilities and mechanism of ferulic acid and some other phenolic acids against acrolein.Among the 13 phenolic compounds investigated,ferulic acid was found to have the highest efficiency in scavenging acrolein under physiological 8nditions.Ferulic acid remained at(3.04±1.89)%and acrolein remained at(29.51±4.44)%after being incubated with each other for 24 h.The molecular mechanism of the detoxifying process was also studied.Detoxifying products,namely 2-methoxy-4-vinyIphenol(product 21)and 5-(4-hydroxy-3-methoxyphenyl)pent-4-enal(product 22),were identified though nuclear magnetic resonanee(NMR)and gas chromatography-mass spectrometry(GC-MS),after the scavenging process.Ferulic acid showed significant activity in scavenging acrolein under physiological conditions.This study indicates a new method for inhibiting damage from acrolein.
文摘A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident in atherosclerotic plaques,characterized by reduced cell proliferation,irreversible growth arrest and apoptosis,and telomere attrition.As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress,shortened LTL in patients with atherosclerosis might stem from the two sources,one is an accelerated rate in hematopoietic stem cells(HSCs)replication to replace leukocytes consumed in the inflammatory process,and another is the increase in the loss of telomere repeats per replication.Thus,diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood.In addition,the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication.Atherosclerosis is an aging-related disease,and practically all humans develop atherosclerosis if they live long enough.Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis,and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.
基金supported by the National Natural Science Foundation of China(31030026,31021091)the National Basic Research Program of China(2011CB965203,2011CB964803)
文摘Studies on the chaperone protein α-hemoglobin stabilizing protein （AHSP） reveal that abundant AHSP in erythroid cells en-hance the cells＇ tolerance to oxidative stress imposed by excess a-hemoglobin in pathological conditions. However, the poten-tial intracellular modulation of AHSP expression itself in response to oxidative stress is still unknown. The present study ex-amined the effect and molecular mechanism of STAT3, an oxidative regulator, on the expression of AHSP. AHSP expression increased in K562 cells upon cytokine IL-6-induced STAT3 activation and decreased in STAT3 knock-down K562 cells. Reg-ulation of AHSP in oxidative circumstance was then examined in α-globin-overloaded K562 cells, and real-time PCR showed strengthened expression of both AHSP and STAT3. ChIP analysis showed binding of STAT3 to AHSP promoter and binding was significantly augmented with IL6 stimulation and upon α-globin overexpression. Dual luciferase reporter assays of the wildtype and mutated SB3 element, an IL-6RE site, in the AHSP promoter in K562 cells highlighted the direct regulatory ef-fect of STAT3 on AHSP gene. Finally, direct binding of STAT3 to SB3 site of AHSP promoter was confirmed with EMSA as-says. Our work reveals an adaptive AHSP regulation mediated by the redox-sensitive STAT3 signaling pathway, and provides clues to the therapeutic strategy for AHSP enhancement.
基金supported by the Research Grants Council of Hong Kong(RGC)HKU 764008M to Sookja Kim Chung
文摘Ischemia occurs in diabetic retinopathy with neuronal loss, edema, glial cell reactivity and oxidative stress. Epacs, consisting of Epac 1 and Epac2, are cAMP mediators playing important roles in maintenance of endothelial barrier and neuronal functions To investigate the roles of Epacs in the pathogenesis of ischemic retinopathy, transient middle cerebral artery occlusion （tMCAO） was performed on Epacl-deficient （Epacl-/- ） mice, Epac2-deficient （Epac2-/-） mice, and their wild type counter-parts （Epacl＋/＋ and Epac2＋/＋）. Two-hour occlusion and 22-hour reperfusion were conducted to induce ischemia/reperfusion injury to the retina. After tMCAO, the contralateral retinae displayed similar morphology between different genotypes. Neu-ronal loss, retinal edema and increase in immunoreactivity for aquaporin 4 （AQP4）, glial fibrillary acidic protein （GFAP）, peroxiredoxin 6 （Prx6） were observed in ipsilateral retinae. Epac2 / ipsilateral retinae showed more neuronal loss in retinal ganglion cell layer, increased retinal thickness and stronger immunostaining of AQP4, GFAP, and Prx6 than those of Epac2＋/＋. However, Epacl-/- ipsilateral retinae displayed similar pathology as those in Epacl＋/＋ mice. Our observations suggest that Epac2-deficiency led to more severe ischemic retinopathy after retinal ischemia/reperfusion injury.
