Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute t...Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.展开更多
BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role...BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.展开更多
Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in...Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.展开更多
BACKGROUND Heart diseases are the primary cause of death all over the world.Following myocardial infarction,billions of cells die,resulting in a huge loss of cardiac function.Stem cell-based therapies have appeared as...BACKGROUND Heart diseases are the primary cause of death all over the world.Following myocardial infarction,billions of cells die,resulting in a huge loss of cardiac function.Stem cell-based therapies have appeared as a new area to support heart regeneration.The transcription factors GATA binding protein 4(GATA-4)and myocyte enhancer factor 2C(MEF2C)are considered prominent factors in the development of the cardiovascular system.AIM To explore the potential of GATA-4 and MEF2C for the cardiac differentiation of human umbilical cord mesenchymal stem cells(hUC-MSCs).METHODS hUC-MSCs were characterized morphologically and immunologically by the presence of specific markers of MSCs via immunocytochemistry and flow cytometry,and by their potential to differentiate into osteocytes and adipocytes.hUC-MSCs were transfected with GATA-4,MEF2C,and their combination to direct the differentiation.Cardiac differentiation was confirmed by semiquant itative real-time polymerase chain reaction and immunocytochemistry.RESULTS hUC-MSCs expressed specific cell surface markers CD105,CD90,CD44,and vimentin but lack the expression of CD45.The transcription factors GATA-4 and MEF2C,and their combination induced differentiation in hUC-MSCs with significant expression of cardiac genes i.e.,GATA-4,MEF2C,NK2 homeobox 5(NKX2.5),MHC,and connexin-43,and cardiac proteins GATA-4,NKX2.5,cardiac troponin T,and connexin-43.CONCLUSION Transfection with GATA-4,MEF2C,and their combination effectively induces cardiac differentiation in hUC-MSCs.These genetically modified MSCs could be a promising treatment option for heart diseases in the future.展开更多
目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7...目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7月南阳市中心医院收治的214例Hp阳性早期胃癌患者进行前瞻性研究,所有患者均行内镜黏膜下剥离术(ESD),采用实时荧光定量聚合酶链反应(qRT-PCR)法检测肿瘤组织、癌旁组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平,并分析其与临床病理特征相关性。依据ESD术后是否复发分为复发组、未复发组,采用q RT-PCR法检测两组患者的TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平。采用偏相关性分析肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平与复发的关系。采用受试者工作特征(ROC)曲线分析TGF-β_(1)m RNA、MMP-2 mRNA、PBP1A m RNA表达水平对复发的预测价值。结果肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.04±0.26、1.45±0.31,明显高于癌旁组织的0.85±0.14、1.18±0.25,PBP1A m RNA表达水平为0.31±0.10,明显低于癌旁组织的0.43±0.12,差异均有统计学意义(P<0.05);列联相关系数C分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平与临床分期、浸润深度、淋巴结转移呈正相关(P<0.05),与分化程度呈负相关(P<0.05),而PBP1A m RNA表达水平与临床分期、浸润深度、淋巴结转移呈负相关(P<0.05),与分化程度呈正相关(P<0.05);复发组患者的TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.31±0.25、1.74±0.31,明显高于未复发组的1.01±0.20、1.42±0.25,PBP1A mRNA表达水平为0.18±0.05,明显低于未复发组的0.32±0.10,差异均有统计学意义(P<0.05);偏相关性分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2m RNA、PBP1A m RNA表达水平与复发显著相关(P<0.05);TGF-β_(1)mRNA、MMP-2 mRNA、PBP1A mRNA单项及联合预测复发的曲线下面积(AUC)分别为0.755、0.742、0.795、0.915,敏感度为75.00%、70.00%、75.00%、80.00%,特异度为72.25%、67.54%、76.95%、95.81%,且预测效能显著高于各指标单独预测价值(Z=2.376、2.413、1.997,P=0.018、0.016、0.046)。结论Hp阳性早期胃癌患者肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA表达水平升高,PBP1A m RNA表达水平降低,且与临床病理特征、复发密切相关,联合检测其水平对复发具有较高的预测价值。展开更多
The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane pr...The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.展开更多
基金supported by a grant from the Heart and Stroke Foundation of Canada(HHC,AFRS)a grant from the Natural Science&Engineering Research Council of Canada(HHC,AFRS)a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario,Canada(HHC)
文摘Ischemic brain injury triggers an inflammatory response. tissue but can also exacerbate brain injury. Microglia are This response is necessary to clear damaged brain the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused syn- apses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery.
基金Supported by the National Natural Science Foundation of China,No.61802350
文摘BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.
基金supported by grant from Alize PharmaⅢand the Harrington Scholar Program of Harrington Research Foundation
文摘Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.
基金Supported by the Higher Education Commission(HEC),Pakistan Scholarship for Ph.D.Studies to Razzaq SS,No.520-148390-2BS6-011.
文摘BACKGROUND Heart diseases are the primary cause of death all over the world.Following myocardial infarction,billions of cells die,resulting in a huge loss of cardiac function.Stem cell-based therapies have appeared as a new area to support heart regeneration.The transcription factors GATA binding protein 4(GATA-4)and myocyte enhancer factor 2C(MEF2C)are considered prominent factors in the development of the cardiovascular system.AIM To explore the potential of GATA-4 and MEF2C for the cardiac differentiation of human umbilical cord mesenchymal stem cells(hUC-MSCs).METHODS hUC-MSCs were characterized morphologically and immunologically by the presence of specific markers of MSCs via immunocytochemistry and flow cytometry,and by their potential to differentiate into osteocytes and adipocytes.hUC-MSCs were transfected with GATA-4,MEF2C,and their combination to direct the differentiation.Cardiac differentiation was confirmed by semiquant itative real-time polymerase chain reaction and immunocytochemistry.RESULTS hUC-MSCs expressed specific cell surface markers CD105,CD90,CD44,and vimentin but lack the expression of CD45.The transcription factors GATA-4 and MEF2C,and their combination induced differentiation in hUC-MSCs with significant expression of cardiac genes i.e.,GATA-4,MEF2C,NK2 homeobox 5(NKX2.5),MHC,and connexin-43,and cardiac proteins GATA-4,NKX2.5,cardiac troponin T,and connexin-43.CONCLUSION Transfection with GATA-4,MEF2C,and their combination effectively induces cardiac differentiation in hUC-MSCs.These genetically modified MSCs could be a promising treatment option for heart diseases in the future.
文摘目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7月南阳市中心医院收治的214例Hp阳性早期胃癌患者进行前瞻性研究,所有患者均行内镜黏膜下剥离术(ESD),采用实时荧光定量聚合酶链反应(qRT-PCR)法检测肿瘤组织、癌旁组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平,并分析其与临床病理特征相关性。依据ESD术后是否复发分为复发组、未复发组,采用q RT-PCR法检测两组患者的TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平。采用偏相关性分析肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平与复发的关系。采用受试者工作特征(ROC)曲线分析TGF-β_(1)m RNA、MMP-2 mRNA、PBP1A m RNA表达水平对复发的预测价值。结果肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.04±0.26、1.45±0.31,明显高于癌旁组织的0.85±0.14、1.18±0.25,PBP1A m RNA表达水平为0.31±0.10,明显低于癌旁组织的0.43±0.12,差异均有统计学意义(P<0.05);列联相关系数C分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平与临床分期、浸润深度、淋巴结转移呈正相关(P<0.05),与分化程度呈负相关(P<0.05),而PBP1A m RNA表达水平与临床分期、浸润深度、淋巴结转移呈负相关(P<0.05),与分化程度呈正相关(P<0.05);复发组患者的TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.31±0.25、1.74±0.31,明显高于未复发组的1.01±0.20、1.42±0.25,PBP1A mRNA表达水平为0.18±0.05,明显低于未复发组的0.32±0.10,差异均有统计学意义(P<0.05);偏相关性分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2m RNA、PBP1A m RNA表达水平与复发显著相关(P<0.05);TGF-β_(1)mRNA、MMP-2 mRNA、PBP1A mRNA单项及联合预测复发的曲线下面积(AUC)分别为0.755、0.742、0.795、0.915,敏感度为75.00%、70.00%、75.00%、80.00%,特异度为72.25%、67.54%、76.95%、95.81%,且预测效能显著高于各指标单独预测价值(Z=2.376、2.413、1.997,P=0.018、0.016、0.046)。结论Hp阳性早期胃癌患者肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA表达水平升高,PBP1A m RNA表达水平降低,且与临床病理特征、复发密切相关,联合检测其水平对复发具有较高的预测价值。
文摘The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.
