AIM:To evaluate the effect of exogenous recombinant human bone morphogenic protein-7(rhBMP-7)on transforming growth factor-β(TGF-β)-induced epithelial mesenchymal cell transition(EMT)and assessed its antifibrotic ef...AIM:To evaluate the effect of exogenous recombinant human bone morphogenic protein-7(rhBMP-7)on transforming growth factor-β(TGF-β)-induced epithelial mesenchymal cell transition(EMT)and assessed its antifibrotic effect via topical application.METHODS:The cytotoxic effect of rhBMP-7 was evaluated and the EMT of human corneal epithelial cells(HECEs)was induced by TGF-β.HECEs were then cultured in the presence of rhBMP-7 and/or hyaluronic acid(HA).EMT markers,fibronectin,E-cadherin,α-smooth muscle actin(α-SMA),and matrix metaloproteinase-9(MMP-9),were evaluated.The level of corneal fibrosis and the reepithelization rate were evaluated using a rabbit keratectomy model.Expression ofα-SMA in keratocytes were quantified following treatment with different concentrations of rhBMP-7.RESULTS:Treatment with rhBMP-7 attenuated TGF-β-induced EMT in HECEs.It significantly attenuated fibronectin secretion(31.6%;P〈0.05),theα-SMA protein level(72.2%;P〈0.01),and MMP-9 expression(23.6%,P〈0.05)in HECEs compared with cells grown in the presence of TGF-βalone.E-cadherin expression was significantly enhanced(289.7%;P〈0.01)in the presence of rhBMP-7.Topical application of rhBMP-7 combined with 0.1%HA significantly reduced the amount ofα-SMA~+cells by 43.18%(P〈0.05)at a concentration of 2.5μg/mL and by 47.73%(P〈0.05)at 25μg/mL,compared with the control group,without disturbing corneal reepithelization.CONCLUSION:rhBMP-7 attenuates TGF-β-induced EMT in vitro,and topical application of rhBMP-7 reduces keratocyte myodifferentiation during the early wound healing stages in vivo without hindering reepithelization.Topical rhBMP-7 application as biological eye drops seems to be feasible in diseases involving TGF-β-related corneal fibrosis with corneal reepithelization disorders.展开更多
A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indi...A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-βsignaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP-7). This enhancement of BMP-7 in the context of TGF-β in the tumor microenvironment is shown to enhance the mesenchymal-to-epithelial transition. Most importantly, we show that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic differentiation program is also up-regulated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-β signaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic setting.展开更多
Coordinated morphogenic adaptation of growing plants is critical for their survival and propagation under fluctuating environments.Plant morphogenic responses to light and warm temperatures,termed photomorphogenesis a...Coordinated morphogenic adaptation of growing plants is critical for their survival and propagation under fluctuating environments.Plant morphogenic responses to light and warm temperatures,termed photomorphogenesis and thermomorphogenesis,respectively,have been extensively studied in recent decades.During photomorphogenesis,plants actively reshape their growth and developmental patterns to cope with changes in light regimes.Accordingly,photomorphogenesis is closely associated with diverse growth hormonal cues.Notably,accumulating evidence indicates that light-directed morphogenesis is profoundly affected by two recently identified phytochemicals,karrikins(KARs)and strigolactones(SLs).KARs and SLs are structurally related butenolides acting as signaling molecules during a variety of developmental steps,including seed germination.Their receptors and signaling mediators have been identified,and associated working mechanisms have been explored using gene-deficient mutants in various plant species.Of particular interest is that the KAR and SL signaling pathways play important roles in environmental responses,among which their linkages with photomorphogenesis are most comprehensively studied during seedling establishment.In this review,we focus on how the phytochemical and light signals converge on the optimization of morphogenic fitness.We also discuss molecular mechanisms underlying the signaling crosstalks with an aim of developing potential ways to improve crop productivity under climate changes.展开更多
Critical-sized bone defect repair in patients with diabetes mellitus remains a challenge in clinical treatment because of dysfunction of macrophage polarization and the inflammatory microenvironment in the bone defect...Critical-sized bone defect repair in patients with diabetes mellitus remains a challenge in clinical treatment because of dysfunction of macrophage polarization and the inflammatory microenvironment in the bone defect region.Three-dimensional(3D)bioprinted scaffolds loaded with live cells and bioactive factors can improve cell viability and the inflammatory microenvironment and further accelerating bone repair.Here,we used modified bioinks comprising gelatin,gelatin methacryloyl(GelMA),and 4-arm poly(ethylene glycol)acrylate(PEG)to fabricate 3D bioprinted scaffolds containing BMSCs,RAW264.7 macrophages,and BMP-4-loaded mesoporous silica nanoparticles(MSNs).Addition of MSNs effectively improved the mechanical strength of GelMA/gelatin/PEG scaffolds.Moreover,MSNs sustainably released BMP-4 for long-term effectiveness.In 3D bioprinted scaffolds,BMP-4 promoted the polarization of RAW264.7 to M2 macrophages,which secrete anti-inflammatory factors and thereby reduce the levels of pro-inflammatory factors.BMP-4 released from MSNs and BMP-2 secreted from M2 macrophages collectively stimulated the osteogenic differentiation of BMSCs in the 3D bioprinted scaffolds.Furthermore,in calvarial critical-size defect models of diabetic rats,3D bioprinted scaffolds loaded with MSNs/BMP-4 induced M2 macrophage polarization and improved the inflammatory microenvironment.And 3D bioprinted scaffolds with MSNs/BMP-4,BMSCs,and RAW264.7 cells significantly accelerated bone repair.In conclusion,our results indicated that implanting 3D bioprinted scaffolds containing MSNs/BMP-4,BMSCs,and RAW264.7 cells in bone defects may be an effective method for improving diabetic bone repair,owing to the direct effects of BMP-4 on promoting osteogenesis of BMSCs and regulating M2 type macrophage polarization to improve the inflammatory microenvironment and secrete BMP-2.展开更多
Spinal cord injury(SCI)is a debilitating injury that results from traumatic or non-traumatic insults to the spinal cord,causing significant impairment of the patient's activity and quality of life.Bone morphogenic...Spinal cord injury(SCI)is a debilitating injury that results from traumatic or non-traumatic insults to the spinal cord,causing significant impairment of the patient's activity and quality of life.Bone morphogenic proteins(BMPs)are a group of polyfunctional cytokines belonging to the transforming growth factor beta superfamily that regulates a wide variety of cellular functions in healthy and disease states.Recent studies suggest that dysregulation of BMP signaling is involved in neuronal demyelination and death after traumatic SCI.The focus of this article is to describe our current understanding of the role of BMP signaling in the regulation of cell fate,proliferation,apoptosis,autophagy,and inflammation in traumatic SCI.First,we will describe the expression of BMPs and pattern of BMP signaling before and after traumatic SCI in rodent models and in vitro.Next,we will discuss the role of BMP in the regulation of neuronal and glial cell differentiation,survival,functional recovery from traumatic SCI,and the gap in knowledge in this area that requires further investigation to improve SCI prognosis.展开更多
During embryo development in many metazoan animals, the first differentiated cell type to form is anepithelial cell. This epithelial layer is modified by developmental cues of body axes formation to give rise to vario...During embryo development in many metazoan animals, the first differentiated cell type to form is anepithelial cell. This epithelial layer is modified by developmental cues of body axes formation to give rise to various tissues. The cells that arise are mesenchymal in nature and are a source of other tissue types. This epithelial to mesenchymal transition is used for tissue type formation and also seen in diseases such as cancer. Here we discuss recent findings on the cellular architecture formation in the Drosophila embryo and how it affects the developmental program of body axes formation. In particular these studies suggest the presence of compartments around each nucleus in a common syncytium. Despite the absence of plasma membrane boundaries, each nucLeus not only has its own endoplasmic reticulum and Golgi complex but also its own compartmentalized plasma membrane domain above it. This architecture is potentially essential for morphogen gradient restriction in the syncytial Drosophila embryo. We discuss various properties of the dorso-ventral and the antero-posterior morphogen gradients in the Drosophila syncytium, which are likely to depend on the syncytial architecture of the embryo.展开更多
In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen trans...In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion？ Developmental Cell 2 （2002） 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimension region.展开更多
In this study, a capillary electrophoresis immunoassay(CEIA) method based on the enhanced chemiluminescence(CL) detection was developed. A horseradish peroxidase(HRP) label catalyzing the luminol/H 2O 2/p-iodophenol(P...In this study, a capillary electrophoresis immunoassay(CEIA) method based on the enhanced chemiluminescence(CL) detection was developed. A horseradish peroxidase(HRP) label catalyzing the luminol/H 2O 2/p-iodophenol(PIP) reaction was performed, and the HRP was detected with detection limit(S/N=3) of 4.4 pmol/L(53 zmol), which is one of the highest sensitivity of HRP reported yet. The HRP was linked to bone morphogenic protein-2(BMP-2) in rat vascular smooth muscle(VSM) cells in noncompetitive format and first detected by CL. HRP-Ab 2-mAb-BMP-2 complexes were baseline separated from free HRP label in 3 min. The detection limit(S/N=3) of BMP-2 is 6.2 pmol/L(75 zmol). This technique has been applied to arteriosclerosis pathology research. The change of BMP-2 contentin VSM cells which were stimulated by angiotensin Ⅱ(AgⅡ) for different hours was investigated in the concentration range of 1.0-10.0 pmol/L. The results are in accord with that obtained by common used Pathology image analysis system.展开更多
基金Supported by the Soonchunhyang University Research Fund,the WPM project,Ministry of trade,industry&energy(No.10037842)the National Research Foundation of Korea(No.NRF-2016R1C1B2015622)Recombinant human BMP-7 protein was kindly provided by Cellumed Co.,Ltd
文摘AIM:To evaluate the effect of exogenous recombinant human bone morphogenic protein-7(rhBMP-7)on transforming growth factor-β(TGF-β)-induced epithelial mesenchymal cell transition(EMT)and assessed its antifibrotic effect via topical application.METHODS:The cytotoxic effect of rhBMP-7 was evaluated and the EMT of human corneal epithelial cells(HECEs)was induced by TGF-β.HECEs were then cultured in the presence of rhBMP-7 and/or hyaluronic acid(HA).EMT markers,fibronectin,E-cadherin,α-smooth muscle actin(α-SMA),and matrix metaloproteinase-9(MMP-9),were evaluated.The level of corneal fibrosis and the reepithelization rate were evaluated using a rabbit keratectomy model.Expression ofα-SMA in keratocytes were quantified following treatment with different concentrations of rhBMP-7.RESULTS:Treatment with rhBMP-7 attenuated TGF-β-induced EMT in HECEs.It significantly attenuated fibronectin secretion(31.6%;P〈0.05),theα-SMA protein level(72.2%;P〈0.01),and MMP-9 expression(23.6%,P〈0.05)in HECEs compared with cells grown in the presence of TGF-βalone.E-cadherin expression was significantly enhanced(289.7%;P〈0.01)in the presence of rhBMP-7.Topical application of rhBMP-7 combined with 0.1%HA significantly reduced the amount ofα-SMA~+cells by 43.18%(P〈0.05)at a concentration of 2.5μg/mL and by 47.73%(P〈0.05)at 25μg/mL,compared with the control group,without disturbing corneal reepithelization.CONCLUSION:rhBMP-7 attenuates TGF-β-induced EMT in vitro,and topical application of rhBMP-7 reduces keratocyte myodifferentiation during the early wound healing stages in vivo without hindering reepithelization.Topical rhBMP-7 application as biological eye drops seems to be feasible in diseases involving TGF-β-related corneal fibrosis with corneal reepithelization disorders.
文摘A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-βsignaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP-7). This enhancement of BMP-7 in the context of TGF-β in the tumor microenvironment is shown to enhance the mesenchymal-to-epithelial transition. Most importantly, we show that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic differentiation program is also up-regulated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-β signaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic setting.
基金supported by the Leaping Research Program(NRF-2021R1A2B5B03001476 to C.M.P.)provided by the National Research Foundation(NRF)of Koreaa grant from Kyung Hee University in 2023(KHU-20230886 to Y.J.P.).
文摘Coordinated morphogenic adaptation of growing plants is critical for their survival and propagation under fluctuating environments.Plant morphogenic responses to light and warm temperatures,termed photomorphogenesis and thermomorphogenesis,respectively,have been extensively studied in recent decades.During photomorphogenesis,plants actively reshape their growth and developmental patterns to cope with changes in light regimes.Accordingly,photomorphogenesis is closely associated with diverse growth hormonal cues.Notably,accumulating evidence indicates that light-directed morphogenesis is profoundly affected by two recently identified phytochemicals,karrikins(KARs)and strigolactones(SLs).KARs and SLs are structurally related butenolides acting as signaling molecules during a variety of developmental steps,including seed germination.Their receptors and signaling mediators have been identified,and associated working mechanisms have been explored using gene-deficient mutants in various plant species.Of particular interest is that the KAR and SL signaling pathways play important roles in environmental responses,among which their linkages with photomorphogenesis are most comprehensively studied during seedling establishment.In this review,we focus on how the phytochemical and light signals converge on the optimization of morphogenic fitness.We also discuss molecular mechanisms underlying the signaling crosstalks with an aim of developing potential ways to improve crop productivity under climate changes.
基金supported by National Key R&D Program of China(2018YFB1105600/2018YFC2002300/2018YFA0703000)National Natural Science Foundation of China(81772326/81702124/81902195)+3 种基金Fundamental research program funding of Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine(JYZZ070)Project of Shanghai Science and Technology Commission(18441903700/19XD1434200/18431903700/19441908700/19441917500)Translational Medicine Innovation Project of Shanghai Jiao Tong University School of Medicine(TM201613/TM201915)Project of Shanghai Jiading National Health and Family Planning Commission(KYXM 2018-KY-03).
文摘Critical-sized bone defect repair in patients with diabetes mellitus remains a challenge in clinical treatment because of dysfunction of macrophage polarization and the inflammatory microenvironment in the bone defect region.Three-dimensional(3D)bioprinted scaffolds loaded with live cells and bioactive factors can improve cell viability and the inflammatory microenvironment and further accelerating bone repair.Here,we used modified bioinks comprising gelatin,gelatin methacryloyl(GelMA),and 4-arm poly(ethylene glycol)acrylate(PEG)to fabricate 3D bioprinted scaffolds containing BMSCs,RAW264.7 macrophages,and BMP-4-loaded mesoporous silica nanoparticles(MSNs).Addition of MSNs effectively improved the mechanical strength of GelMA/gelatin/PEG scaffolds.Moreover,MSNs sustainably released BMP-4 for long-term effectiveness.In 3D bioprinted scaffolds,BMP-4 promoted the polarization of RAW264.7 to M2 macrophages,which secrete anti-inflammatory factors and thereby reduce the levels of pro-inflammatory factors.BMP-4 released from MSNs and BMP-2 secreted from M2 macrophages collectively stimulated the osteogenic differentiation of BMSCs in the 3D bioprinted scaffolds.Furthermore,in calvarial critical-size defect models of diabetic rats,3D bioprinted scaffolds loaded with MSNs/BMP-4 induced M2 macrophage polarization and improved the inflammatory microenvironment.And 3D bioprinted scaffolds with MSNs/BMP-4,BMSCs,and RAW264.7 cells significantly accelerated bone repair.In conclusion,our results indicated that implanting 3D bioprinted scaffolds containing MSNs/BMP-4,BMSCs,and RAW264.7 cells in bone defects may be an effective method for improving diabetic bone repair,owing to the direct effects of BMP-4 on promoting osteogenesis of BMSCs and regulating M2 type macrophage polarization to improve the inflammatory microenvironment and secrete BMP-2.
基金The work was supported,in part,by an investigator-initiated research grant(SCIRF-2015-I-01)from the South Carolina Spinal Cord Injury Research Fund(Columbia,SC,USA)an award from the Soy Health Research Program(SHRP,United Soybean Board,Chester昀eld,MO,USA)earlier R01 grants(CA-091460 and NS-057811)from the National Institutes of Health(Bethesda,MD,USA).
文摘Spinal cord injury(SCI)is a debilitating injury that results from traumatic or non-traumatic insults to the spinal cord,causing significant impairment of the patient's activity and quality of life.Bone morphogenic proteins(BMPs)are a group of polyfunctional cytokines belonging to the transforming growth factor beta superfamily that regulates a wide variety of cellular functions in healthy and disease states.Recent studies suggest that dysregulation of BMP signaling is involved in neuronal demyelination and death after traumatic SCI.The focus of this article is to describe our current understanding of the role of BMP signaling in the regulation of cell fate,proliferation,apoptosis,autophagy,and inflammation in traumatic SCI.First,we will describe the expression of BMPs and pattern of BMP signaling before and after traumatic SCI in rodent models and in vitro.Next,we will discuss the role of BMP in the regulation of neuronal and glial cell differentiation,survival,functional recovery from traumatic SCI,and the gap in knowledge in this area that requires further investigation to improve SCI prognosis.
文摘During embryo development in many metazoan animals, the first differentiated cell type to form is anepithelial cell. This epithelial layer is modified by developmental cues of body axes formation to give rise to various tissues. The cells that arise are mesenchymal in nature and are a source of other tissue types. This epithelial to mesenchymal transition is used for tissue type formation and also seen in diseases such as cancer. Here we discuss recent findings on the cellular architecture formation in the Drosophila embryo and how it affects the developmental program of body axes formation. In particular these studies suggest the presence of compartments around each nucleus in a common syncytium. Despite the absence of plasma membrane boundaries, each nucLeus not only has its own endoplasmic reticulum and Golgi complex but also its own compartmentalized plasma membrane domain above it. This architecture is potentially essential for morphogen gradient restriction in the syncytial Drosophila embryo. We discuss various properties of the dorso-ventral and the antero-posterior morphogen gradients in the Drosophila syncytium, which are likely to depend on the syncytial architecture of the embryo.
文摘In biological development, morphogens are locally produced and spread to other regions in organs, forming gradients that control the inter-related pattern and growth of developing organs. Mechanisms of morphogen transport were built and investigated by numerical simulations in [A. D. Lander, Q. Nie and F. Y. M. Wan, Do morphogen gradients arise by diffusion？ Developmental Cell 2 （2002） 785-796]. In that paper, model C, which considers endocytosis, exocytosis and receptor synthesis and degradation, is in a one-dimensional spatial region and couples a partial differential equation with ordinary differential equations. Here, this model is promoted to an arbitrary dimension bounded region. We prove existence, uniqueness and non-negativity of a global solution for this advanced model, of its steady-state solution and linear stability of steady state by operator semigroup, the Schauder theorem and local perturbation method. Our results improve previous results for this model in a one dimension region.
文摘In this study, a capillary electrophoresis immunoassay(CEIA) method based on the enhanced chemiluminescence(CL) detection was developed. A horseradish peroxidase(HRP) label catalyzing the luminol/H 2O 2/p-iodophenol(PIP) reaction was performed, and the HRP was detected with detection limit(S/N=3) of 4.4 pmol/L(53 zmol), which is one of the highest sensitivity of HRP reported yet. The HRP was linked to bone morphogenic protein-2(BMP-2) in rat vascular smooth muscle(VSM) cells in noncompetitive format and first detected by CL. HRP-Ab 2-mAb-BMP-2 complexes were baseline separated from free HRP label in 3 min. The detection limit(S/N=3) of BMP-2 is 6.2 pmol/L(75 zmol). This technique has been applied to arteriosclerosis pathology research. The change of BMP-2 contentin VSM cells which were stimulated by angiotensin Ⅱ(AgⅡ) for different hours was investigated in the concentration range of 1.0-10.0 pmol/L. The results are in accord with that obtained by common used Pathology image analysis system.
