Objective The goal of this study is to investigate the role and mechanism of endoplasmic reticulum stress and apoptosis regulated by thrombospondin 1(TSP1)in human renal tubular epithelial cells(HK-2 cells).Methods HK...Objective The goal of this study is to investigate the role and mechanism of endoplasmic reticulum stress and apoptosis regulated by thrombospondin 1(TSP1)in human renal tubular epithelial cells(HK-2 cells).Methods HK-2 cells were exposed to high concentrations of glucose(HG).The endoplasmic reticulum stress inhibitor 4-phenylbutyric acid(4-PBA)was administered by transfecting TSP1 or an empty vector to explore the mechanism of the endoplasmic reticulum response regulated by TSP1 and stress in renal cell apoptosis.The effects of TSP1 and 4-PBA on the proliferation and apoptosis of HK-2 cells under HG conditions were assessed using Cell counting kit-8 and flow cytometry.Western blotting was used to detect the apoptosis-and endoplasmic reticulum stress-related protein expression regulated by TSP1 and 4-PBA.Results HG treatment induced high cell apoptosis,abundantly expressed TSP1 level and restrained viability in HK-2 cells.Overexpression of TSP1 significantly inhibited the proliferation of and facilitated apoptosis of HK-2 cells under HG conditions.Administration of endoplasmic reticulum stress inhibitor 4-PBA after overexpression of TSP1 antagonized the inhibitory proliferation and promoted apoptosis rate in HG-triggered HK-2 cells induced by TSP1 overexpression.4-PBA treatment significantly hindered the expression of endoplasmic reticulum stress markers,such as PERK,ATF4,ATF6,p-eIF2α,IRE1,CHOP and XBP1,suggesting that the administration of 4-PBA was successful.Conclusion Overexpression of TSP1 activated endoplasmic reticulum stress by regulating the ATF6-CHOP axis.TSP1 restrained cell proliferation,and promoted apoptosis and endoplasmic reticulum stress by activating the ATF6-CHOP axis.展开更多
BACKGROUND Osteoarthritis(OA),a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage,is one of the leading causes of disability.As a new strategy for treatment of OA,m...BACKGROUND Osteoarthritis(OA),a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage,is one of the leading causes of disability.As a new strategy for treatment of OA,mesenchymal stem cells(MSCs)have the potential for articular cartilage regeneration.Meanwhile,thrombospondin 2(TSP2)promotes the chondrogenic differentiation of MSCs.AIM To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs(hADMSCs)and potentiates the therapeutic effects of hADMSCs in OA rabbits.METHODS We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA(siRNA)-treated stem cells.Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits,and 8 wk later,hADMSCs(1.7×10^6 or 1.7×10^7 cells)were injected into the injured knees alone or in combination with intra-articular injection of TSP2(100 ng/knee)at 2-d intervals.OA progression was monitored by gross,radiological,and histological examinations.RESULTS In hADMSC culture,treatment with TSP2 increased the expression of chondrogenic markers(SOX9 and collagen Ⅱ)as well as NOTCH signaling genes(JAGGED1 and NOTCH3),which were inhibited by TSP2 siRNA treatment.In vivo,OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration,osteophyte formation,and extracellular matrix loss 8 wk after cell transplantation.Notably,such cartilage damage was further alleviated by the combination of hADMSCs and TSP2.In addition,synovial inflammatory cytokines,especially tumor-necrosis factor-α,markedly decreased following the combination treatment.CONCLUSION The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling,and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.展开更多
Chronic heart failure（CHF）remains a leading cause of morbidity and mortality.In the current study,we aimed to evaluate the predictive value of circulating fhrombospondin-2（TSP-2）for cumulative survival in patients...Chronic heart failure（CHF）remains a leading cause of morbidity and mortality.In the current study,we aimed to evaluate the predictive value of circulating fhrombospondin-2（TSP-2）for cumulative survival in patients with ischemic CHF due to coronary artery disease（CAD）.The results showed that during a median follow-up of2.18 years,21 participants died and 106 subjects were hospitalized repeatedly.The median circulating levels of TSP-2 in patients who survived and those who died were 0.63 ng/mL（95%CI=0.55-0.64 ng/mL）and 1.03 ng/mL（95%CI=0.97-1.07 ng/mL）（P〈0.001）.Circulating TSP-2 independently predicted all-cause mortality（OR=1.27;95%CI=1.08-1.59;P=0.002）,CHF-related death（OR=1.16;95%CI=1.02-1.50;P〈0.001）,and also CHF-related rehospitalization（OR=1.12;95%CI=1.07-1.25;P〈0.001）.In conclusion,among CAD patients with symptomatic CHF,increased circulating TSP-2 is correlated with increased 3-year CHF-related death,all-cause mortality,and risk for recurrent hospitalization.展开更多
基金This study was supported by a grant from Chinese Society of Nephrology(No.14050430580).
文摘Objective The goal of this study is to investigate the role and mechanism of endoplasmic reticulum stress and apoptosis regulated by thrombospondin 1(TSP1)in human renal tubular epithelial cells(HK-2 cells).Methods HK-2 cells were exposed to high concentrations of glucose(HG).The endoplasmic reticulum stress inhibitor 4-phenylbutyric acid(4-PBA)was administered by transfecting TSP1 or an empty vector to explore the mechanism of the endoplasmic reticulum response regulated by TSP1 and stress in renal cell apoptosis.The effects of TSP1 and 4-PBA on the proliferation and apoptosis of HK-2 cells under HG conditions were assessed using Cell counting kit-8 and flow cytometry.Western blotting was used to detect the apoptosis-and endoplasmic reticulum stress-related protein expression regulated by TSP1 and 4-PBA.Results HG treatment induced high cell apoptosis,abundantly expressed TSP1 level and restrained viability in HK-2 cells.Overexpression of TSP1 significantly inhibited the proliferation of and facilitated apoptosis of HK-2 cells under HG conditions.Administration of endoplasmic reticulum stress inhibitor 4-PBA after overexpression of TSP1 antagonized the inhibitory proliferation and promoted apoptosis rate in HG-triggered HK-2 cells induced by TSP1 overexpression.4-PBA treatment significantly hindered the expression of endoplasmic reticulum stress markers,such as PERK,ATF4,ATF6,p-eIF2α,IRE1,CHOP and XBP1,suggesting that the administration of 4-PBA was successful.Conclusion Overexpression of TSP1 activated endoplasmic reticulum stress by regulating the ATF6-CHOP axis.TSP1 restrained cell proliferation,and promoted apoptosis and endoplasmic reticulum stress by activating the ATF6-CHOP axis.
基金Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to Y.B.K.,No.2017R1A2A2A05069417
文摘BACKGROUND Osteoarthritis(OA),a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage,is one of the leading causes of disability.As a new strategy for treatment of OA,mesenchymal stem cells(MSCs)have the potential for articular cartilage regeneration.Meanwhile,thrombospondin 2(TSP2)promotes the chondrogenic differentiation of MSCs.AIM To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs(hADMSCs)and potentiates the therapeutic effects of hADMSCs in OA rabbits.METHODS We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA(siRNA)-treated stem cells.Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits,and 8 wk later,hADMSCs(1.7×10^6 or 1.7×10^7 cells)were injected into the injured knees alone or in combination with intra-articular injection of TSP2(100 ng/knee)at 2-d intervals.OA progression was monitored by gross,radiological,and histological examinations.RESULTS In hADMSC culture,treatment with TSP2 increased the expression of chondrogenic markers(SOX9 and collagen Ⅱ)as well as NOTCH signaling genes(JAGGED1 and NOTCH3),which were inhibited by TSP2 siRNA treatment.In vivo,OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration,osteophyte formation,and extracellular matrix loss 8 wk after cell transplantation.Notably,such cartilage damage was further alleviated by the combination of hADMSCs and TSP2.In addition,synovial inflammatory cytokines,especially tumor-necrosis factor-α,markedly decreased following the combination treatment.CONCLUSION The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling,and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.
文摘Chronic heart failure（CHF）remains a leading cause of morbidity and mortality.In the current study,we aimed to evaluate the predictive value of circulating fhrombospondin-2（TSP-2）for cumulative survival in patients with ischemic CHF due to coronary artery disease（CAD）.The results showed that during a median follow-up of2.18 years,21 participants died and 106 subjects were hospitalized repeatedly.The median circulating levels of TSP-2 in patients who survived and those who died were 0.63 ng/mL（95%CI=0.55-0.64 ng/mL）and 1.03 ng/mL（95%CI=0.97-1.07 ng/mL）（P〈0.001）.Circulating TSP-2 independently predicted all-cause mortality（OR=1.27;95%CI=1.08-1.59;P=0.002）,CHF-related death（OR=1.16;95%CI=1.02-1.50;P〈0.001）,and also CHF-related rehospitalization（OR=1.12;95%CI=1.07-1.25;P〈0.001）.In conclusion,among CAD patients with symptomatic CHF,increased circulating TSP-2 is correlated with increased 3-year CHF-related death,all-cause mortality,and risk for recurrent hospitalization.
