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1.
FEBS Open Bio ; 14(7): 1192-1204, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38719785

ABSTRACT

Glioblastoma recruits various nontransformed cells from distant tissues. Although bone marrow-derived mesenchymal stem cells (MSCs) have been observed migrating to glioblastoma, the underlying mechanism driving MSC migration toward glioblastoma remains unclear. Tumor vascularity is critical in the context of recurrent glioblastoma and is closely linked to the expression of stromal cell-derived factor-1 (SDF-1). We demonstrated that cadherin-6 mediated MSC migration both toward SDF-1 and toward glioblastoma cells. Cadherin-6 knockdown resulted in the downregulation of MSCs capacity to migrate in response to SDF-1. Furthermore, MSCs with cadherin-6 knockdown exhibited impaired migration in response to conditioned media derived from glioblastoma cell lines (U87 and U373) expressing SDF-1, thus simulating the glioblastoma microenvironment. Moreover, MSCs enhanced the vasculogenic capacity of U87 cells without increasing the proliferation, cancer stem cell characteristics, or migration of U87. These results suggest that the current strategy of utilizing MSCs as carriers for antiglioblastoma drugs requires careful examination. Furthermore, cadherin-6 may represent a novel potential target for controlling the recruitment of MSCs toward glioblastoma.


Subject(s)
Cadherins , Cell Movement , Chemokine CXCL12 , Glioblastoma , Mesenchymal Stem Cells , Humans , Glioblastoma/metabolism , Glioblastoma/pathology , Glioblastoma/genetics , Mesenchymal Stem Cells/metabolism , Cadherins/metabolism , Cadherins/genetics , Cell Movement/genetics , Chemokine CXCL12/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Tumor Microenvironment
2.
Front Physiol ; 14: 1225118, 2023.
Article in English | MEDLINE | ID: mdl-37593235

ABSTRACT

The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.

3.
Heliyon ; 8(10): e10991, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36276728

ABSTRACT

A processing map is required for Ti alloys to find processing parameters securing a high formability. This study adopted the extreme gradient boosting (XGB) approach of machine learning to predict a flow curve and plot a processing map with less experiments for the first time. The optimum XGB model predicted flow curves of Ti-6Al-2Sn-2Zr-2Mo-2Cr-0.15Si at 1073-1273 K and 10 s-1. The predicted data were used to plot a processing map, which showed a higher accuracy in the instability map as compared with the map without XGB. The XGB model also anticipated the power dissipation map at low strain rates. The low accuracy at high strain rates would be improved by alleviating the bias towards a flow hardening. This work has successfully proven the potential usefulness of XGB for plotting an enhanced processing map in light of a higher accuracy with less experiments.

4.
Biomedicines ; 9(11)2021 Oct 29.
Article in English | MEDLINE | ID: mdl-34829800

ABSTRACT

The prostate tumor microenvironment plays important roles in the metastasis and hormone-insensitive re-growth of tumor cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into prostate tumors to facilitate tumor microenvironment formation. However, the specific intrinsic molecules mediating BM-MSCs' migration to prostate tumors are unknown. BM-MSCs' migration toward a conditioned medium (CM) of hormone-insensitive (PC3 and DU145) or hormone-sensitive (LNCaP) prostate tumor cells was investigated using a three-dimensional cell migration assay and a transwell migration assay. PC3 and DU145 expressed transforming growth factor-ß (TGF-ß), but LNCaP did not. Regardless of TGF-ß expression, BM-MSCs migrated toward the CM of PC3, DU145, or LNCaP. The CM of PC3 or DU145 expressing TGF-ß increased the phosphorylation of Smad2/3 in BM-MSCs. Inactivation of TGF-ß signaling in BM-MSCs using TGF-ß type 1 receptor (TGFBR1) inhibitors, SB505124, or SB431542 did not allow BM-MSCs to migrate toward the CM. The CM of PC3 or DU145 enhanced N-cadherin expression on BM-MSCs, but the LNCaP CM did not. SB505124, SB431542, and TGFBR1 knockdown prevented an increase in N-cadherin expression. N-cadherin knockdown inhibited the collective migration of BM-MSCs toward the PC3 CM. We identified N-cadherin as a mediator of BM-MSCs' migration toward hormone-insensitive prostate tumor cells expressing TGF-ß and introduced a novel strategy for controlling and re-engineering the prostate tumor microenvironment.

5.
Theranostics ; 11(14): 6786-6799, 2021.
Article in English | MEDLINE | ID: mdl-34093853

ABSTRACT

Rationale: Bone marrow-derived mesenchymal stem cells (BM-MSCs) recruited into breast tumors regulate the behavior of tumor cells via various mechanisms and affect clinical outcomes. Although signaling molecules, such as transforming growth factor ß (TGF-ß), are known to transmit signals between BM-MSCs and breast tumor cells for recruiting BM-MSCs, it is unclear which specific intrinsic molecules involved in cell motility mediate the migration of BM-MSCs into breast tumor. It is also unclear as to how specific intrinsic molecules contribute to the migration. Methods: Conditioned medium (CM) from breast tumor cells (MCF-7 and MDA-MB-231) that simulates breast tumor secreting TGF-ß was used to examine the migration of BM-MSCs into breast tumors. A three-dimensional migration assay was performed to investigate the collective migration of BM-MSCs, maintaining cell-cell adhesion, toward breast tumor cells. Results: N-cadherin formed adherens junction-like structures on the intercellular borders of BM-MSCs, and TGF-ß increased the expression of N-cadherin on these borders. Knockdown of Smad4 impaired the TGF-ß-mediated increase in N-cadherin expression in BM-MSCs, but inhibitors of non-canonical TGF-ß pathways, such as extracellular signal-regulated kinases, Akt, and p38, did not affect it. siRNA-mediated knockdown of N-cadherin and Smad4 impaired the migration of BM-MSCs in response to TGF-ß. Conditioned medium from breast tumor cells also enhanced the expression of N-cadherin in BM-MSCs, but inactivation of TGF-ß type 1 receptor (TGFBR1) with SB505124 and TGFBR1 knockdown abolished the increase in N-cadherin expression. BM-MSCs collectively migrated toward CM from MDA-MB-231 in vitro while maintaining cell-cell adhesion through N-cadherin. Knockdown of N-cadherin abolished the migration of BM-MSCs toward the CM from breast tumor cells. Conclusion: In the present study, we identified N-cadherin, an intrinsic transmembrane molecule in adherens junction-like structures, on BM-MSCs as a mediator for the migration of these cells toward breast tumor. The expression of N-cadherin increases on the intercellular borders of BM-MSCs through the TGF-ß canonical signaling and they collectively migrate in response to breast tumor cells expressing TGF-ß via N-cadherin-dependent cell-cell adhesion. We, herein, introduce a novel promising strategy for controlling and re-engineering the breast tumor microenvironment.


Subject(s)
Antigens, CD/metabolism , Breast Neoplasms/metabolism , Cadherins/metabolism , Mesenchymal Stem Cells/metabolism , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Transforming Growth Factor beta/pharmacology , Tumor Microenvironment/drug effects , Antigens, CD/genetics , Benzodioxoles/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cadherins/genetics , Cell Adhesion , Cell Line, Tumor , Cell Movement/drug effects , Culture Media, Conditioned/pharmacology , Female , Humans , Imidazoles/pharmacology , Immunohistochemistry , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/pharmacology , RNA, Small Interfering , Real-Time Polymerase Chain Reaction , Receptor, Transforming Growth Factor-beta Type I/genetics , Receptor, Transforming Growth Factor-beta Type I/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Smad4 Protein/genetics , Smad4 Protein/metabolism , Tumor Microenvironment/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
6.
Cancers (Basel) ; 13(5)2021 Mar 02.
Article in English | MEDLINE | ID: mdl-33801569

ABSTRACT

Cancer cachexia is a multifactorial systemic inflammation disease caused by complex interactions between the tumor and host tissues via soluble factors. However, whether cancer cachexia affects the bone marrow, in particular the hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), remains unclear. Here, we investigated the bone marrow and bone in a cancer cachexia animal model generated by transplanting Lewis lung carcinoma cells. The number of bone marrow mononuclear cells (BM-MNCs) started to significantly decrease in the cancer cachectic animal model prior to the discernable loss of muscle and fat. This decrease in BM-MNCs was associated with myeloid skewing in the circulation and the expansion of hematopoietic progenitors in the bone marrow. Bone loss occurred in the cancer cachexia animal model and accompanied the decrease in the bone marrow MSCs that play important roles in both supporting HSCs and maintaining bone homeostasis. Glucocorticoid signaling mediated the decrease in bone marrow MSCs in the cancer cachectic environment. The cancer cachexia environment also skewed the differentiation of the bone marrow MSCs toward adipogenic fate via JAK/STAT as well as glucocorticoid signaling. Our results suggest that the bone loss induced in cancer cachexia is associated with the depletion and the impaired differentiation capacity of the bone marrow MSCs.

7.
Membranes (Basel) ; 11(3)2021 Mar 09.
Article in English | MEDLINE | ID: mdl-33803122

ABSTRACT

Organic solvent nanofiltration (OSN) has been recognized as an eco-friendly separation system owing to its excellent cost and energy saving efficiency, easy scale-up in the narrow area and mild operation conditions. Membrane properties are the key part in terms of determining the separation efficiency in the OSN system. In this review paper, the recently reported OSN thin-film composite (TFC) membranes were investigated to understand insight of membrane materials and performance. Especially, we highlighted the representative study concepts and materials of the selective layer of OSN TFC membranes for non-polar solvents. The proper choice of monomers and additives for the selective layer forms much more interconnected voids and the enhanced microporosity, which can improve membrane performance of the OSN TFC membrane with reducing the transport resistance. Therefore, this review paper could be an important bridge to connect with the next-generation OSN TFC membranes for non-polar solvents.

8.
Int J Mol Sci ; 21(22)2020 Nov 13.
Article in English | MEDLINE | ID: mdl-33202862

ABSTRACT

Endogenous bone marrow-derived mesenchymal stem cells are mobilized to peripheral blood and injured tissues in response to changes in the expression of various growth factors and cytokines in the injured tissues, including substance P (SP), transforming growth factor-beta (TGF-ß), and stromal cell-derived factor-1 (SDF-1). SP, TGF-ß, and SDF-1 are all known to induce the migration of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, it is not yet clear how these stimuli influence or interact with each other during BM-MSC mobilization. This study used mouse bone marrow-derived mesenchymal stem cell-like ST2 cells and human BM-MSCs to evaluate whether SP, TGF-ß, and SDF-1 mutually regulate their respective effects on the mobilization of BM-MSCs. SP pretreatment of ST2 and BM-MSCs impaired their response to TGF-ß while the introduction of SP receptor antagonist restored the mobilization of ST2 and BM-MSCs in response to TGF-ß. TGF-ß pretreatment did not affect the migration of ST2 and BM-MSCs in response to SP, but downregulated their migration in response to SDF-1. SP pretreatment modulated the activation of TGF-ß noncanonical pathways in ST2 cells and BM-MSCs, but not canonical pathways. These results suggest that the migration of mesenchymal stem cells is regulated by complex functional interactions between SP, TGF-ß, and SDF-1. Thus, understanding the complex functional interactions of these chemotactic stimuli would contribute to ensuring the development of safe and effective combination treatments for the mobilization of BM-MSCs.


Subject(s)
Bone Marrow Cells/immunology , Chemotaxis/immunology , Mesenchymal Stem Cells/immunology , Signal Transduction/immunology , Animals , Bone Marrow Cells/cytology , Cell Line , Chemokine CXCL12/immunology , Humans , Mesenchymal Stem Cells/cytology , Mice , Transforming Growth Factor beta/immunology
9.
Biochem Biophys Res Commun ; 522(4): 917-923, 2020 02 19.
Article in English | MEDLINE | ID: mdl-31806373

ABSTRACT

Diabetes induces cellular dysfunction in dermal fibroblasts, such as impairment in migration, which is a major cause of chronic wound. Here, we demonstrated that the migration of human dermal fibroblasts was impaired under a high glucose culture condition. Substance P (SP) rescued the impaired migration of the fibroblasts. The activity of Rac1, Rho-associated kinase (ROCK), and Src was required for SP-mediated rescue of fibroblast migration. SP activated Rac1 and Src, whereas, NSC23766, a Rac1 inhibitor, and PP1 and PP2, Src inhibitors, inhibited SP-mediated enhancement of fibroblast migration. Y-27632, a ROCK inhibitor, inhibited the SP-mediated rescue of fibroblast migration. Senescence-associated ß-galactosidase activity increased in human dermal fibroblasts cultured in a high glucose environment, but SP inhibited the ß-galactosidase activity of the fibroblasts. These results suggest that SP promotes the migration of human dermal fibroblasts in diabetic-condition-mimicking cultures via the activity of Rac1, ROCK, and Src, and inhibits fibroblast senescence in hyperglycemic cultures.


Subject(s)
Cell Movement/drug effects , Cellular Senescence/drug effects , Dermis/pathology , Fibroblasts/pathology , Hyperglycemia/pathology , Substance P/pharmacology , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Glucose/toxicity , Humans , rac1 GTP-Binding Protein/metabolism , rho-Associated Kinases/metabolism , src-Family Kinases/metabolism
10.
Sci Rep ; 9(1): 11724, 2019 08 13.
Article in English | MEDLINE | ID: mdl-31409851

ABSTRACT

Bone morphogenetic protein (BMP) signaling and Notch signaling play important roles in tumorigenesis in various organs and tissues, including the breast. BMP-4 enhanced epithelial mesenchymal transition (EMT) and stem cell properties in both mammary epithelial cell line and breast carcinoma cell line. BMP-4 increased the expression of EMT biomarkers, such as fibronectin, laminin, N-cadherin, and Slug. BMP-4 also activated Notch signaling in these cells and increased the sphere forming efficiency of the non-transformed mammary epithelial cell line MCF-10A. In addition, BMP-4 upregulated the sphere forming efficiency, colony formation efficiency, and the expression of cancer stem cell markers, such as Nanog and CD44, in the breast carcinoma cell line MDA-MB-231. Inhibition of Notch signaling downregulated EMT and stem cell properties induced by BMP-4. Down-regulation of Smad4 using siRNA impaired the BMP-4-induced activation of Notch signaling, as well as the BMP-4-mediated EMT. These results suggest that EMT and stem cell properties are increased in mammary epithelial cells and breast cancer cells through the activation of Notch signaling in a Smad4-dependent manner in response to BMP-4.


Subject(s)
Bone Morphogenetic Protein 4/genetics , Epithelial-Mesenchymal Transition/genetics , Neoplasms/etiology , Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Receptors, Notch/metabolism , Signal Transduction , Animals , Bone Morphogenetic Protein 4/metabolism , Cell Line, Tumor , Cell Movement/genetics , Disease Models, Animal , Female , Humans , Mice , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Smad4 Protein/genetics , Smad4 Protein/metabolism , Xenograft Model Antitumor Assays
11.
Biochem Biophys Res Commun ; 508(2): 361-367, 2019 01 08.
Article in English | MEDLINE | ID: mdl-30502084

ABSTRACT

Endogenous bone marrow-derived mesenchymal stem cells (BM-MSCs) are mobilized into peripheral blood and injured tissues by various growth factors and cytokines that are expressed in the injured tissues, such as substance P (SP), stromal cell derived factor-1 (SDF-1), and transforming growth factor-beta (TGF-ß). Extracellular bioactive lipid metabolites such as ceramide-1-phosphate and sphingosine-1-phosphate also modulate BM-MSC migration as SP, SDF-1, and TGF-ß. However, the roles of intrinsic lipid kinases of BM-MSCs in the stem cell migration are unclear. Here, we demonstrated that ceramide kinase mediates the chemotactic migration of BM-MSCs in response to SP, SDF-1, or TGF-ß. Furthermore, a specific inhibitor of ceramide kinase inhibited TGF-ß-induced migration of BM-MSCs and N-cadherin that is necessary for BM-MSCs migration in response to TGF-ß. Therefore, these results suggest that the intracellular ceramide kinase is required for the BM-MSCs migration and the roles of the intrinsic ceramide kinase in the migration are associated with N-cadherin regulation.


Subject(s)
Cell Movement/physiology , Mesenchymal Stem Cells/physiology , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Animals , Antigens, CD/genetics , Cadherins/genetics , Cell Line , Ceramides/metabolism , Chemokine CXCL12/metabolism , Chemotaxis/physiology , Gene Expression Regulation , Humans , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Substance P/metabolism , Transforming Growth Factor beta/metabolism
12.
J Cell Physiol ; 233(1): 201-213, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28213973

ABSTRACT

Transforming growth factor-beta (TGF-ß) induces the migration and mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF-ß mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM-MSCs mediated by TGF-ß are unclear. In this study, we showed that TGF-ß activated noncanonical signaling molecules, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF-ß type I receptor in human BM-MSCs and murine BM-MSC-like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF-ß-mediated migration. These results suggested that the Smad-independent, noncanonical signals activated by TGF-ß were necessary for migration. We also showed that N-cadherin-dependent intercellular interactions were required for TGF-ß-mediated migration using functional inhibition of N-cadherin with EDTA treatment and a neutralizing antibody (GC-4 antibody) or siRNA-mediated knockdown of N-cadherin. However, N-cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF-ß. Therefore, these results suggested that the migration of BM-MSCs in response to TGF-ß was mediated through N-cadherin and noncanonical TGF-ß signals.


Subject(s)
Antigens, CD/metabolism , Bone Marrow Cells/drug effects , Cadherins/metabolism , Cell Movement/drug effects , Mesenchymal Stem Cells/drug effects , Signal Transduction/drug effects , Transforming Growth Factor beta1/pharmacology , Animals , Antigens, CD/genetics , Bone Marrow Cells/metabolism , Cadherins/antagonists & inhibitors , Cadherins/genetics , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/metabolism , Focal Adhesion Kinase 1/metabolism , Humans , Mesenchymal Stem Cells/metabolism , Mice , Neuropeptides/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/agonists , Receptors, Transforming Growth Factor beta/metabolism , Transfection , p38 Mitogen-Activated Protein Kinases/metabolism , rac1 GTP-Binding Protein/metabolism , src-Family Kinases/metabolism
13.
Mol Med Rep ; 15(5): 3035-3040, 2017 May.
Article in English | MEDLINE | ID: mdl-28339006

ABSTRACT

Wound healing is delayed in diabetes due to a number of factors, including impaired angiogenesis and poor dermal healing. The present study demonstrated that subcutaneous administration of substance P (SP) accelerates wound healing in db/db type 2 diabetic mice (db/db mice). SP injection (10 nM/kg, subcutaneously) enhanced angiogenesis, induced the mobilization of endothelial progenitor cells (EPCs) and increased the number of EPC­colony forming units (EPC­CFUs) in the bone marrow of db/db mice. Immunohistochemistry was performed to check the effects of SP on the cellular proliferation and the subcellular localization of Yes-associated protein (YAP) in the wound dermis. SP also upregulated cellular proliferation in the injured dermis of db/db mice. Compared with the control group, an increased number of cells in the wound dermis of SP-treated mice exhibited nuclear localization of YAP, which induces cellular proliferation. The results of the current study indicate that subcutaneous administration of SP may be a promising therapeutic strategy to treat diabetic wounds exhibiting impaired angiogenesis and dysfunctional dermal wound healing.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cell Movement/drug effects , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Endothelial Progenitor Cells/drug effects , Phosphoproteins/metabolism , Substance P/pharmacology , Wound Healing/drug effects , Animals , Bone Marrow/drug effects , Bone Marrow/pathology , Cell Cycle Proteins , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Disease Models, Animal , Endothelial Progenitor Cells/pathology , Immunohistochemistry , Injections, Subcutaneous , Male , Mice , Neovascularization, Physiologic/drug effects , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Random Allocation , YAP-Signaling Proteins
14.
Tissue Eng Regen Med ; 14(1): 49-55, 2017 Feb.
Article in English | MEDLINE | ID: mdl-30603461

ABSTRACT

Dermal fibroblasts play essential roles in wound healing and their dysfunction has been shown to be associated with impaired wound healing in diabetes. In the present study, we aimed at investigating whether Yes-associated protein (YAP), a mediator of mechanotransduction in dermal fibroblasts, is associated with impaired wound healing in diabetic mice. Compared with that in the control, the rate of wound contraction was decreased twofold in db/db type 2 diabetic mice (db/db mice). To mimic diabetic pathological condition, dermal fibroblasts were cultured under high glucose conditions (25.5 mM glucose). Further, dermal fibroblast-mediated contraction of wound was evaluated by in vitro collagen gel contraction assay. Dermal fibroblasts cultured under hyperglycemic condition showed impaired gel contraction and mitochondrial dysfunction, compared to the cells cultured under normoglycemic conditions (5.5 mM glucose). Importantly, compared with the normal dermal fibroblasts, diabetic db/db dermal fibroblasts expressed lower levels of growth factors and cytokines that enhance wound healing, such as insulin-like growth factor-1, stromal cell-derived factor-1, connective tissue growth factor, and transforming growth factor-ß (TGF-ß). The quantity of YAP mRNA was also lower in diabetic db/db dermal fibroblasts, compared with that in the control fibroblasts. These results indicate that impaired wound healing in diabetics is associated with the dysfunction of dermal fibroblasts, including downregulation of YAP, which plays essential roles in extracellular matrix remodeling and TGF-ß-mediated wound healing.

15.
Tissue Eng Regen Med ; 13(2): 155-161, 2016 Apr.
Article in English | MEDLINE | ID: mdl-30603395

ABSTRACT

Dermal fibroblasts play essential roles in wound healing. However, they lose their normal regenerative functions under certain pathologic conditions such as in chronic diabetic wounds. Here, we show that substance P (SP) rescues the malfunctions of dermal fibroblasts in diabetes. SP increased the proliferation of diabetic dermal fibroblasts dose-dependently, although the effect was lower compared to the SP-stimulated proliferation of normal dermal fibroblasts. In contrast to normal dermal fibroblasts, SP increased the expression level of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) in diabetic dermal fibroblast hence, rescuing their angiogenic potential. The cellular characteristics of diabetic dermal fibroblasts modulated by SP would be able to accelerate the wound healing process through faster wound contraction and improved angiogenesis in diabetic chronic wounds. Moreover, SP pretreatment into dermal fibroblasts isolated from diabetic patients would be a promising strategy to develop autologous cell therapy for treating diabetic chronic wounds.

16.
Tissue Eng Regen Med ; 13(2): 149-154, 2016 Apr.
Article in English | MEDLINE | ID: mdl-30603394

ABSTRACT

Impaired angiogenesis is a common pathological characteristic of chronic wounds. Therefore, the regulation of angiogenesis is important for proper tissue repair. It was reported that substance P (SP) accelerates wound healing in a skin injury model. SP is degraded by neutral endopeptidase (NEP). Our study shows that systemic co-treatment of SP and thiorphan, an inhibitor of NEP synergically increased the number of α-smooth muscle actin positive-blood vessels in skin wounds. However, there was no synergic improvement in wound contraction and extracellular matrix deposition. Therefore, inhibition of endogenous NEP activity by thiorphan treatment might modulate the effects of SP treatment specifically on accelerating angiogenesis during wound healing. However, the molecular mechanism(s) of the synergic increase in angiogenesis by SP and thiorphan treatment is still unknown.

17.
J Thorac Dis ; 7(3): 433-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25922722

ABSTRACT

BACKGROUND: Tegafur-uracil (UFT) is an anticancer agent that inhibits thymidylate synthase (TS). The degree of TS expression in primary lung cancer (LC) is different according to histologic cell type. In this study, we examined the variability of the anti-tumor efficacy of UFT monotherapy depending on histological subtypes of LC. METHODS: In the current single-institution, retrospective study, we assigned the patients with LC to three histologic groups [the squamous (Sq) non-small cell lung cancer (NSCLC)] group, the non-Sq NSCLC group and the SCLC group] and then compared the clinical response to UFT monotherapy between the three groups. RESULTS: Our clinical series of 149 patients include 54 cases of Sq NSCLC, 67 cases of non-Sq NSCLC and 28 cases of SCLC. For Sq NSCLC, non-Sq NSCLC and SCLC group, the overall response rates (ORRs) were 1%, 1% and 0% (P=0.522), respectively. The disease control rates (DCRs) were 38.9%, 31.3% and 10.7% (P=0.012), respectively. The median progression-free survivals (PFSs) were 2.68, 2.25 and 1.46 months (P=0.004 for three groups and P=0.773 for two groups except for the SCLC group at the log-rank test), respectively. There was no significant difference between the groups in median overall survival (OS). CONCLUSIONS: Our results indicate that the degree of the anti-tumor effect of UFT was higher in patients with NSCLC as compared with SCLC. But it showed no significant difference between the patients with Sq NSCLC and those with non-Sq NSCLC.

18.
J Thorac Dis ; 6(9): 1209-17, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25276362

ABSTRACT

BACKGROUND: With the recent increased use of new anti-neoplastic agents, molecular-targeted drugs and radiation in patients with lung cancer, there has been an increase in the occurrence drug-induced or radiation-induced pulmonary toxicities. We conducted this study to evaluate the clinical characteristics of patients with lung cancer who presented with treatment-related pulmonary toxicities and to analyze the dosage pattern of corticosteroid therapy against them. METHODS: To collect the baseline data from the patients with lung cancer who developed treatment-related pulmonary toxicities, we initially selected those who were prescribed corticosteroids between January 1, 2008 and December 31, 2012. Depending on clinical and radiological diagnoses, we classified pulmonary toxicities into drug-induced interstitial lung disease (DILD), radiation pneumonitis, acute exacerbation of chronic obstructive pulmonary disease (AE COPD) and others. RESULTS: We divided total patients (n=398) into four groups, and these include 88 cases (22%) of DILD, 189 cases (47%) of radiation pneumonitis, 47 cases (12%) of AE COPD and 74 cases (19%) of others. The prescribed rate of pulse or high-dose steroid was measured as 73%, 20%, 40% and 38%, respectively (P<0.001). In DILD radiologic findings, the 2-month mortality was significantly higher in the patients with the diffuse alveolar damage (DAD) pattern (100%) as compared with those with the non-specific interstitial pneumonia (NSIP) or bronchiolitis obliterans with organizing pneumonia (BOOP) one (62% or 42%, respectively) (P=0.032). CONCLUSIONS: This study showed that the natural course of DILD had more unfavorable outcome requiring higher dose steroid therapy as compared with those with radiation pneumonitis or AE COPD. According to a subgroup analysis of the patients with DILD, BOOP and NSIP radiographic patterns showed more favorable outcomes.

19.
J Korean Med Sci ; 29(6): 825-30, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24932085

ABSTRACT

Chronic sputum is a troublesome symptom in many respiratory diseases. The prevalence of chronic sputum varies from 1.2% to 13% according to the country. The purpose of this study was to estimate the prevalence of chronic sputum and to find its associated factors in a general Korean population. We analyzed the data of the Korea National Health and Nutrition Examination Survey 2010 and 2011. A total number of 6,783 subjects aged 40 yr or more were enrolled in this study with 3,002 men and 3,781 women. As a result, the prevalence of chronic sputum was 6.3% (n=430). Significant risk factors for chronic sputum by multivariate analysis were: age (≥ 70 yr) (odds ratio [OR], 1.954; 95% confidence interval [CI], 1.308-2.917), current smoking (OR, 4.496; 95% CI, 3.001-6.734), chronic obstructive pulmonary disease (COPD) (OR, 1.483; 95% CI, 1.090-2.018), and tuberculosis (OR, 1.959; 95% CI, 1.307-2.938). In conclusion, the prevalence of chronic sputum in Korea was in the intermediate range compared with other countries. Smoking is a preventable risk factor identified in this study, and major respiratory diseases, such as COPD and tuberculosis, should be considered in subjects with chronic sputum.


Subject(s)
Pulmonary Disease, Chronic Obstructive/epidemiology , Sputum , Tuberculosis/epidemiology , Adult , Aged , Chronic Disease , Demography , Female , Humans , Logistic Models , Lung/physiopathology , Male , Middle Aged , Odds Ratio , Prevalence , Pulmonary Disease, Chronic Obstructive/physiopathology , Republic of Korea , Risk Factors , Smoking , Sputum/microbiology , Surveys and Questionnaires , Tuberculosis/physiopathology
20.
Thorac Cancer ; 5(6): 525-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-26767047

ABSTRACT

BACKGROUND: Platinum doublets are standard first-line treatment for stage IV non-small cell lung cancer (NSCLC) without targetable driver mutations. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity. The objective of this study was to evaluate the efficacy and safety of oxaliplatin combined with docetaxel as a first-line treatment for stage IV NSCLC. METHODS: This was a prospective, single-center, phase II trial. Patients with chemotherapy-naive NSCLC received 60 mg/m(2) docetaxel (day 1) and 70 mg/m(2) oxaliplatin (day 2) every three weeks for up to six cycles. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Treatment response was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Thirty-three patients were enrolled and a response evaluation was available in 31 patients. There were 11 patients with a partial response, 15 with stable disease, and five with progressive disease. Two patients ceased further treatment after the first cycle of chemotherapy. Thus, the ORR was 33.3% in the 33 patients of the intention-to-treat population. Median PFS was 3.6 months (95% confidence interval [CI], 2.8-4.5), and median OS was 10.9 months (95% CI, 8.2-13.6). The most common hematologic toxicity was neutropenia. Grade 3-4 neutropenia occurred in 51.5% of patients. CONCLUSION: The results suggest that the combination of oxaliplatin and docetaxel is effective in patients with NSCLC with reasonable toxicity.

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