Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.594
Filtrar
1.
Commun Biol ; 5(1): 974, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109592

RESUMO

Leydig cells in fetal testes play crucial roles in masculinizing fetuses through androgen production. Gene knockout studies have revealed that growth factors are implicated in fetal Leydig cell (FLC) differentiation, but little is known about the mechanisms regulating this process. We investigate this issue by characterizing FLC progenitor cells using single-cell RNA sequencing. The sequence datasets suggest that thymosin ß10 (Tmsb10) is transiently upregulated in the progenitors. While studying the function of Tmsb10, we reveal that platelet-derived growth factor (PDGF) regulates ciliogenesis through the RAS/ERK and PI3K/AKT pathways, and thereby promotes desert hedgehog (DHH)-dependent FLC differentiation. Tmsb10 expressed in the progenitor cells induces their differentiation into FLCs by suppressing the RAS/ERK pathway. Through characterizing the transiently expressed Tmsb10 in the FLC progenitors, this study unveils the molecular process of FLC differentiation and shows that it is cooperatively induced by DHH and PDGF.


Assuntos
Androgênios , Sistema de Sinalização das MAP Quinases , Androgênios/metabolismo , Feto , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Timosina
2.
J Pharmacol Sci ; 150(2): 74-80, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055754

RESUMO

PURPOSE: Peficitinib and tofacitinib are known to suppress inflammation in rheumatoid arthritis (RA) by inhibiting Janus kinases (JAKs). However, these effects on tyrosine kinases other than JAKs have not yet been well investigated. We evaluated the effects of peficitinib and tofacitinib on platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) and on the activation of fibroblast-like synoviocytes (FLSs) and endothelial cells, main pathological causes of RA. METHODS: Peficitinib and tofacitinib were tested in PDGF and VEGF RTK assays. We then used FLSs derived from RA patient (RA-FLSs) and human umbilical vein endothelial cells (HUVECs) to study the effects of peficitinib and tofacitinib on PDGF- and VEGF-induced signal transduction and on the activation of RA-FLSs and endothelial cell tube formation. FINDINGS: Peficitinib, not tofacitinib, inhibited both PDGF and VEGF RTKs in addition to JAKs in cell-free assay system. Peficitinib and tofacitinib attenuated PDGF- and VEGF-induced intracellular signal transduction pathways in RA-FLSs and HUVECs to varying degrees. Only peficitinib potently inhibited PDGF-induced secretion of interleukin-6, VEGF, and matrix metalloproteinase-3 in RA-FLSs, and endothelial cell tube formation by HUVECs. CONCLUSION: Peficitinib may improve RA through inhibition of PDGF and VEGF signal transduction, in addition to JAK inhibition.


Assuntos
Artrite Reumatoide , Sinoviócitos , Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Células Cultivadas , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Janus Quinases , Niacinamida/análogos & derivados , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Transdução de Sinais , Sinoviócitos/patologia , Tirosina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/farmacologia
3.
Cell Rep ; 40(7): 111192, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35977484

RESUMO

Fibroblasts differentiate into myofibroblasts by acquiring new contractile function. This is important for tissue repair, but it also contributes to organ fibrosis. Platelet-derived growth factor (PDGF) promotes tissue repair and fibrosis, but the relationship between PDGF and myofibroblasts is unclear. Using mice with lineage tracing linked to PDGF receptor α (PDGFRα) gene mutations, we examine cell fates during skin wound healing. Elevated PDGFRα signaling increases proliferation but unexpectedly delays the fibroblast-to-myofibroblast transition, suggesting that PDGFRα must be downregulated for myofibroblast differentiation. In contrast, deletion of PDGFRα decreases proliferation and myofibroblast differentiation by reducing serum response factor (SRF) nuclear localization. Consequences of SRF deletion resemble PDGFRα deletion, but deletion of two SRF coactivators, MRTFA and MRTFB, specifically eliminates myofibroblasts. Our findings suggest a scenario where PDGFRα signaling initially supports proliferation of fibroblast progenitors to expand their number during early wound healing but, later, PDGFRα downregulation facilitates fibroblast differentiation into myofibroblasts.


Assuntos
Miofibroblastos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Animais , Diferenciação Celular/fisiologia , Fibroblastos/metabolismo , Fibrose , Camundongos , Miofibroblastos/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Cicatrização
4.
Front Immunol ; 13: 907636, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967419

RESUMO

Tumor-associated macrophages (TAMs) are involved in the growth of prostate cancer (PrC), while the molecular mechanisms underlying the interactive crosstalk between TAM and PrC cells remain largely unknown. Platelet-derived growth factor (PDGF) is known to promote mesenchymal stromal cell chemotaxis to the tumor microenvironment. Recently, activation of spindle pole body component 25 (SPC25) has been shown to promote PrC cell proliferation and is associated with PrC stemness. Here, the relationship between SPC25 and PDGF in the crosstalk between TAM and PrC was investigated. Significant increases in both PDGF and SPC25 levels were detected in PrC specimens compared to paired adjacent normal prostate tissues. A significant correlation was detected between PDGF and SPC25 levels in PrC specimens and cell lines. SPC25 increased PDGF production and tumor cell growth in cultured PrC cells and in xenotransplantation. Mechanistically, SPC25 appeared to activate PDGF in PrC likely through Early Growth Response 1 (Egr1), while the secreted PDGF signaled to TAM through PDGFR on macrophages and polarized macrophages, which, in turn, induced the growth of PrC cells likely through their production and secretion of transforming growth factor ß1 (TGFß1). Thus, our data suggest that SPC25 triggers the crosstalk between TAM and PrC cells via SPC25/PDGF/PDGFR/TGFß1 receptor signaling to enhance PrC growth.


Assuntos
Proteínas Associadas aos Microtúbulos , Fator de Crescimento Derivado de Plaquetas , Próstata , Neoplasias da Próstata , Corpos Polares do Fuso , Macrófagos Associados a Tumor , Linhagem Celular Tumoral , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Receptor Cross-Talk/fisiologia , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Corpos Polares do Fuso/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo
5.
J Hypertens ; 40(10): 1935-1949, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35983805

RESUMO

OBJECTIVE: Increased central venous pressure in congestive heart failure is responsible for renal dysfunction, which is mediated by renal venous congestion. Pericyte detachment from capillaries after renal congestion might trigger renal fibrogenesis via pericyte-myofibroblast transition (PMT). Platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated in our recently established renal congestion model. This study was designed to determine whether inhibition of the PDGFR pathway could suppress tubulointerstitial injury after renal congestion. METHODS: The inferior vena cava between the renal veins was ligated in male Sprague-Dawley rats, inducing congestion only in the left kidney. Imatinib mesylate or vehicle were injected intraperitoneally daily from 1 day before the operation. Three days after the surgery, the effect of imatinib was assessed by physiological, morphological and molecular methods. The inhibition of PDGFRs against transforming growth factor-ß1 (TGFB1)-induced fibrosis was also tested in human pericyte cell culture. RESULTS: Increased kidney weight and renal fibrosis were observed in the congested kidneys. Upstream inferior vena cava (IVC) pressure immediately increased to around 20 mmHg after IVC ligation in both the imatinib and saline groups. Although vasa recta dilatation and pericyte detachment under renal congestion were maintained, imatinib ameliorated the increased kidney weight and suppressed renal fibrosis around the vasa recta. TGFB1-induced elevation of fibrosis markers in human pericytes was suppressed by PDGFR inhibitors at the transcriptional level. CONCLUSION: The activation of the PDGFR pathway after renal congestion was responsible for renal congestion-induced fibrosis. This mechanism could be a candidate therapeutic target for renoprotection against renal congestion-induced tubulointerstitial injury.


Assuntos
Hiperemia , Nefropatias , Animais , Fibrose , Humanos , Mesilato de Imatinib/metabolismo , Mesilato de Imatinib/farmacologia , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos , Ratos Sprague-Dawley
6.
Biochem Biophys Res Commun ; 623: 51-58, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35872542

RESUMO

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.


Assuntos
Músculo Liso Vascular , Lesões do Sistema Vascular , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Dantroleno/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/patologia
7.
J Mol Biol ; 434(16): 167709, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35777468

RESUMO

As a member of PDGF/VEGF (Platelet-derived growth factor/ Vascular endothelial growth factor) growth factors, PDGF-D regulates blood vessel development, wound healing, innate immunity, and organogenesis. Unlike PDGF-A and PDGF-B, PDGF-D has an additional CUB (Complement C1r/C1s, Uegf, Bmp1) domain at the N-terminus of its growth factor domain, and thus it is secreted in a latent, inactive complex, which needs to be proteolytically activated for its biological activities. However, how the CUB domain contributes to the latency and activation of the growth factor remains elusive. In this study, we modeled the dimeric structure of PDGF-D pro-complex and studied the inhibitory functions of PDGF-D prodomain on PDGF-B and PDGF-D signaling. In our model, the growth factor domain of PDGF-D forms a VEGF-D-like dimer through their ß1 and ß3 interactions. The hinge and CUB domains of PDGF-D bind at the opposite sides of the growth factor domain and exclude the PDGFR-ß (PDGF Receptor ß) D2 and D3 domains from recognizing the growth factor. In addition, we verified that PDGF-D prodomain could inhibit both PDGF-B and PDGF-D mediated PDGFR-ß transphosphorylation in a dose-dependent manner. However, PDGF-D prodomain could only inhibit the proliferation of NIH 3T3 cells stimulated by PDGF-D but not by PDGF-B, indicating its differential inhibitory activities toward PDGF-B and PDGF-D signaling.


Assuntos
Linfocinas , Fator de Crescimento Derivado de Plaquetas , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Linfocinas/química , Linfocinas/metabolismo , Linfocinas/farmacologia , Camundongos , Células NIH 3T3 , Fator de Crescimento Derivado de Plaquetas/química , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Domínios Proteicos , Multimerização Proteica , Receptor beta de Fator de Crescimento Derivado de Plaquetas/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/farmacologia , Transdução de Sinais , Fator D de Crescimento do Endotélio Vascular/química
8.
Sci Rep ; 12(1): 9532, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680971

RESUMO

Hormones and growth factors stimulate vascular smooth muscle cells (VSMC) invasive capacities during the progression of atherosclerosis. The GTPase ARF6 is an important regulator of migration and proliferation of various cell types, but whether this small G protein can be activated by a variety of stimuli to promote invasion of VSMC remains unknown. Here, we aimed to define whether Platelet-derived growth factor (PDGF), a mitogenic stimulant of vascular tissues, and Angiotensin II (Ang II), a potent vasoactive peptide, can result in the activation of ARF6 in a human model of aortic SMC (HASMC). We demonstrate that these two stimuli can promote loading of GTP on this ARF isoform. Knockdown of ARF6 reduced the ability of both PDGF and Ang II to promote invasion suggesting that this GTPase regulates key molecular mechanisms mediating degradation of the extracellular matrix and migration. We report that PDGF-BB-mediated stimulation of ARF6 results in the activation of the MAPK/ERK1/2, PI3K/AKT and PAK pathways essential for invasion of HASMC. However, Ang II-mediated stimulation of ARF6 only promotes signaling through the MAPK/ERK1/2 and PAK pathways. These ARF6-mediated events lead to activation of MMP14, a membrane-bound collagenase upregulated in atherosclerosis. Moreover, ARF6 depletion decreases the release of MMP2 in the extracellular milieu. Altogether, our findings demonstrate that the GTPase ARF6 acts as a molecular switch to regulate specific signaling pathways that coordinate invasiveness of HASMC.


Assuntos
Fator 6 de Ribosilação do ADP , Aterosclerose , Metaloproteinase 14 da Matriz , Miócitos de Músculo Liso , Fator 6 de Ribosilação do ADP/genética , Fator 6 de Ribosilação do ADP/metabolismo , Angiotensina II/metabolismo , Aterosclerose/metabolismo , Movimento Celular , Células Cultivadas , Humanos , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo
9.
Dev Cell ; 57(12): 1466-1481.e6, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35659339

RESUMO

Dysregulated growth factor receptor pathways, RNA modifications, and metabolism each promote tumor heterogeneity. Here, we demonstrate that platelet-derived growth factor (PDGF) signaling induces N6-methyladenosine (m6A) accumulation in glioblastoma (GBM) stem cells (GSCs) to regulate mitophagy. PDGF ligands stimulate early growth response 1 (EGR1) transcription to induce methyltransferase-like 3 (METTL3) to promote GSC proliferation and self-renewal. Targeting the PDGF-METTL3 axis inhibits mitophagy by regulating m6A modification of optineurin (OPTN). Forced OPTN expression phenocopies PDGF inhibition, and OPTN levels portend longer survival of GBM patients; these results suggest a tumor-suppressive role for OPTN. Pharmacologic targeting of METTL3 augments anti-tumor efficacy of PDGF receptor (PDGFR) and mitophagy inhibitors in vitro and in vivo. Collectively, we define PDGF signaling as an upstream regulator of oncogenic m6A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adenosina/análogos & derivados , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Metiltransferases/metabolismo , Mitofagia , Células-Tronco Neoplásicas/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia
10.
Biomed Res Int ; 2022: 6738959, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35647192

RESUMO

Objective: Currently, autologous fat transplantation (AFT) still has a low graft survival rate. Elevation of the AFT graft survival rate is a challenge. This study investigated the effect of hyperbaric oxygen (HBO) on AFT. Methods: Twelve adult male SD rats were randomly divided into two groups after AFT: the control group (n = 6) and the HBO group (n = 6). The rats were killed at 7, 14, and 28 days after transplantation to take the transplanted adipose tissues. The volume and weight of the tissues were detected. The pathological changes in the adipose tissues were observed after H&E staining. Microvessel density and levels of transforming growth factor- (TGF-) ß, tumor necrosis factor- (TNF-) α, and malondialdehyde (MDA) in the transplanted adipose tissues were measured with CD31 immunohistochemical stain, ELISA, and biochemical reagents, respectively. Additionally, the protein expression levels of vascular endothelial growth factor- (VEGF-) A and platelet-derived growth factor- (PDGF) A in the adipose tissues were detected by Western blot. Results: HBO significantly preserved the volume and weight of the transplanted adipose tissue (p < 0.01) and maintained the pathological structure of the transplanted adipose tissue. HBO therapy was effective in reducing inflammatory factor (TGF-ß and TNF-α) levels and oxidative stress (MDA) in the transplanted adipose tissue (p < 0.01) and significantly increased the level of CD31 and angiogenesis-related factors including VEGF-A and PDGF-A (p < 0.01) to promote angiogenesis. Conclusion: HBO therapy regulated the immune response of fat grafts, stimulated their angiogenesis, and ultimately promoted their survival after AFT.


Assuntos
Tecido Adiposo , Oxigenoterapia Hiperbárica , Tecido Adiposo/transplante , Animais , Masculino , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley , Transplante Autólogo , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Biomed Res Int ; 2022: 6496382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35586817

RESUMO

Objectives: The texture of the autologous platelet-rich plasma (PRP) that is used in treating degenerative joint diseases such as knee osteoarthritis (OA) is usually in liquid form. However, the turnover rate of protein metabolism in the knee synovial fluid (SF) is less than one hour. This study examined the feasibility of the thermal oscillation technique in converting the liquid-form PRP into an injectable viscous paste-like PRP that may delay the degradation of PRP and continuously release growth factors in the knee joint for a longer period of time. Methods: This study was conducted in the rehabilitation department of a tertiary hospital. A total of 10 elderly patients with an average age of greater than 65 years and diagnosed with moderate degree of knee OA were recruited. The RegenPRP (RegenLab, Le Mont-sur-Lausanne, Switzerland) test tube chamber was used for PRP generation. A total of 60 milliliters (mL) of blood was drawn from each patient. 10 mL of blood was injected into each PRP test tube chamber. As a result, a total of 6 test tube chambers were obtained and each chamber was centrifuged for 15 minutes. Approximately 5 mL of PRP supernatant (the liquid-form end product) was aspirated and sent for thermal oscillation treatment. Five temperatures were tested: 55, 65, 75, 85, and 95 degrees Celsius. Oscillation was set at 200 revolutions per minute (rpm) for 15 minutes. The enzyme-linked immunosorbent assay (ELISA) was applied in measuring the concentration of platelet-derived growth factor (PDGF) in picogram/milliliter (pg/mL). Repeated measures ANOVA followed by the Bonferroni post hoc test was used to compare the PDGF concentrations between each testing condition. Results: Under 75 degrees Celsius of heating, the resultant paste-like PRP end product had the highest concentration of PDGF in picograms per milliliter (pg/mL) as compared with other heating conditions (p < 0.05). The viscosity of the paste-like PRP was measured to be 70,000 centipoise (cP), which is similar to the viscosity of a toothpaste. The paste-like PRP end product was able to release PDGF continuously for about 14 days, with the highest concentration achieved on the 8th day with an average of 35646 ± 2499 pg/mL. In nonthermally treated liquid-form PRP sample, the highest number of PRP was observed on the 4th day with an average value of 8444 ± 831 pg/mL. Under the heating conditions of 55 and 95 degrees Celsius, the highest concentration of PDGF was observed on the 5th day (13346 ± 764 pg/mL and 3440 ± 303 pg/mL, respectively). Under the heating conditions of 65 and 85 degrees Celsius, the highest concentration of PDGF was observed on the 7th day (15468 ± 744 pg/mL and 20432 ± 1118 pg/mL, respectively). Conclusion: Through thermal oscillation, liquid-form PRP can be converted to paste-like PRP end product with a viscosity similar to that of a toothpaste. The best heating condition was discovered to be 75 degrees Celsius. The paste-like PRP was able to release PDGF continuously for about 2 weeks, with the highest concentration obtained on the 8th day. The findings in this study suggested that paste-like PRP may be a viable option in treating degenerative knee joint diseases.


Assuntos
Osteoartrite do Joelho , Plasma Rico em Plaquetas , Idoso , Humanos , Articulação do Joelho/metabolismo , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/terapia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Plasma Rico em Plaquetas/metabolismo , Cremes Dentais
12.
Oncogene ; 41(20): 2860-2872, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35422475

RESUMO

RNA N6-methyladenosine (m6A) is an emerging regulator of mRNA modifications and represents a novel player in tumorigenesis. Although it has functional significance in both pathological and physiological processes, the role of m6A modification in pancreatic ductal cancer (PDAC) remains elusive. Here, we showed that high fat mass and obesity-associated gene (FTO) expression was associated with a poor prognosis in PDAC patients and that suppression of FTO expression inhibited cell proliferation. Here, m6A sequencing (m6A-seq) was performed to screen genes targeted by FTO. The effects of FTO stimulation on the biological characteristics of pancreatic cancer cells, including proliferation and colony formation, were investigated in vitro and in vivo. The results indicate that FTO directly targets platelet-derived growth factor C (PDGFC) and stabilizes its mRNA expression in an m6A-YTHDF2-dependent manner. m6A-methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to validate the specific binding of FTO to PDGFC. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting cell growth. Overall, our study reveals that FTO downregulation leads to increased m6A modifications in the 3' UTR of PDGFC and then modulates the degradation of its transcriptional level in an m6A-YTHDF2-dependent manner, highlighting a potential therapeutic target for PDAC treatment and prognostic prediction.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Neoplasias Pancreáticas , Fator de Crescimento Derivado de Plaquetas , Proteínas de Ligação a RNA , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Humanos , Linfocinas , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
13.
J Biol Chem ; 298(6): 101981, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35472332

RESUMO

Mesenchymal stem cells (MSCs) are adult stem cell populations and exhibit great potential in regenerative medicine and oncology. Platelet-derived growth factors (PDGFs) are well known to regulate MSC biology through their chemotactic and mitogenic properties. However, their direct roles in the regulation of MSC lineage commitment are unclear. Here, we show that PDGF D promotes the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) into osteoblasts and inhibits hBMSC differentiation into adipocytes. We demonstrate that PDGF D-induced ß-actin expression and polymerization are essential for mediating this differential regulation of osteoblastogenesis and adipogenesis. Interestingly, we found that PDGF D induces massive upward molecular weight shifts of its cognate receptor, PDGF receptor beta (ß-PDGFR) in hBMSCs, which was not observed in fibroblasts. Proteomic analysis indicated that the E3 ubiquitin ligase HECT, UBA, and WWE domain-containing protein 1 (HUWE1) associates with the PDGF D-activated ß-PDGFR signaling complex in hBMSCs, resulting in ß-PDGFR polyubiquitination. In contrast to the well-known role of ubiquitin in protein degradation, we provide evidence that HUWE1-mediated ß-PDGFR polyubiquitination delays ß-PDGFR internalization and degradation, thereby prolonging AKT signaling. Finally, we demonstrate that HUWE1-regulated ß-PDGFR signaling is essential for osteoblastic differentiation of hBMSCs, while being dispensable for PDGF D-induced hBMSC migration and proliferation as well as PDGF D-mediated inhibition of hBMSC differentiation into adipocytes. Taken together, our findings provide novel insights into the molecular mechanism by which PDGF D regulates the commitment of hBMSCs into the osteoblastic lineage.


Assuntos
Linfocinas/metabolismo , Células-Tronco Mesenquimais , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ubiquitina-Proteína Ligases , Diferenciação Celular , Proliferação de Células , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteômica , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
14.
J Nanobiotechnology ; 20(1): 201, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35473604

RESUMO

Chronic wounds represent a major challenge to the present healthcare system. In recent decades, many topical therapies have been investigated for the treatment of chronic wounds, including different types of wound dressings, antimicrobial agents, and cell therapy. Platelet-derived growth factor (PDGF) plays an important role in wound healing and has been approved for treatment of wounds related to diabetes mellitus. However, the high cost and short retention time of PDGF protein have limited its wide application. To overcome this challenge, we designed a PDGF-mimicking peptide by connecting PDGF epitope VRKIEIVRKK and self-assembling motif derived from ß-amyloid peptide. The resultant peptide can self-assemble into a fibril-rich network and leads to supramolecular hydrogelation with good stability. The hydrophilic epitope can be exposed on the surface of nanofibrils, which might contribute to the binding and activation of PDGF receptors. The forming hydrogel is able to induce the growth and migration of vascular endothelial cells and promote the formation of vascular branches. In the full-thickness skin wounds of healthy mice, after the application of the hydrogel, the density of neovascularization marked by CD31 was greater than that in the control group on Day 3. Larger collagen deposition and a thicker epidermis were observed on Day 12. These results demonstrate that the hydrogel can stimulate collagen deposition and angiogenesis, enhance skin regeneration, and show an excellent therapeutic effect. Taken together, this work not only provides new insight into the design of bioactive peptides but also offers a promising biomaterial for wound healing.


Assuntos
Células Endoteliais , Hidrogéis , Animais , Becaplermina , Colágeno/metabolismo , Células Endoteliais/metabolismo , Epitopos , Camundongos , Fator de Crescimento Derivado de Plaquetas/metabolismo , Cicatrização
15.
Biochem Biophys Res Commun ; 606: 94-99, 2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35339758

RESUMO

Valproic acid (VPA) has been used to treat epilepsy and bipolar disorder. Although the abnormal proliferation of vascular smooth muscle cells (VSMCs) is a well-established contributor to the development of various vascular diseases including atherosclerosis, the effect of VPA on VSMC proliferation and its mechanism of action have not been fully revealed. Herein, we investigated the molecular mechanism by which VPA inhibits rat VSMC proliferation. VPA dose-dependently decreased VSMC proliferation, which was accompanied by the dose-dependent decrease in phosphorylation of p70 S6 kinase (p70S6K) at Thr389 (p-p70S6K-Thr389), and overexpression of the p70S6K-T389E mutant gene significantly reversed VPA-inhibited VSMC proliferation. Co-treatment with okadaic acid, a specific protein phosphatase 2A (PP2A) inhibitor, significantly restored p-p70S6K-Thr389. Furthermore, knockdown of PP2Ac gene expression by siRNA significantly reversed VPA-inhibited p-p70S6K-Thr389 and VSMC proliferation. Confocal microscopic analyses and co-immunoprecipitation results clearly showed that the physical binding of p70S6K and PP2Ac was promoted by VPA. Valpromide, a VPA's structural derivative with no histone deacetylase (HDAC) inhibition activity, as well as VPA and sodium butyrate, an HDAC inhibitor similar to VPA, decreased VSMC proliferation and p-p70S6K-Thr389, indicating that HDAC is not involved in VPA-inhibited VSMC proliferation. Finally, the inhibitory effects of VPA on p-p70S6K-Thr389 and VSMC proliferation were reiterated in a platelet-derived growth factor (PDGF)-induced in vitro atherosclerosis model. In conclusion, our results demonstrate that VPA decreased cell proliferation via PP2A-mediated inhibition of p-p70S6K-Thr389 in basal and PDGF-stimulated VSMCs. The results suggest that VPA could be used in the treatment and prevention of atherosclerosis and in-stent restenosis.


Assuntos
Aterosclerose , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Aterosclerose/metabolismo , Proliferação de Células , Células Cultivadas , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Fosfatase 2/metabolismo , Ratos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Ácido Valproico/farmacologia
17.
Commun Biol ; 5(1): 197, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241778

RESUMO

The nitric oxide-cGMP (NO-cGMP) pathway is of outstanding importance for vascular homeostasis and has multiple beneficial effects in vascular disease. Neointimal hyperplasia after vascular injury is caused by increased proliferation and migration of vascular smooth muscle cells (VSMCs). However, the role of NO-cGMP signaling in human VSMCs in this process is still not fully understood. Here, we investigate the interaction between platelet derived growth factor (PDGF)-signaling, one of the major contributors to neointimal hyperplasia, and the cGMP pathway in vascular smooth muscle, focusing on NO-sensitive soluble guanylyl cyclase (sGC). We show that PDGF reduces sGC expression by activating PI3K and Rac1, which in turn alters Notch ligand signaling. These data are corroborated by gene expression analysis in human atheromas, as well as immunohistological analysis of diseased and injured arteries. Collectively, our data identify the crosstalk between PDGF and NO/sGC signaling pathway in human VSMCs as a potential target to tackle neointimal hyperplasia.


Assuntos
Guanilato Ciclase , Músculo Liso Vascular , GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Músculo Liso Vascular/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais
18.
Recent Pat Anticancer Drug Discov ; 17(4): 427-434, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35319391

RESUMO

BACKGROUND: Angiogenesis is a hallmark of cancer, which is regulated by diverse factors, including long non-coding RNAs (lncRNAS). Our previous study showed that the long non-coding RNA H22954 inhibits tumor growth, albeit whether it is involved in the angiogenesis of cancer re-mains unknown. OBJECTIVES: This study aimed to investigate the role of lncRNA H22954 in angiogenesis of acute myeloid leukemia (AML) and the underlying molecular mechanism. METHODS: Bioinformatics analysis was conducted to screen the targeted molecule of H22954. Western blot and ELISA analysis detected PDGFA protein expression, and RT-qPCR detected H22954 and PDGFA expression in cell lines and AML samples. Dual-luciferase reporter gene assay and half-life assay were applied to validate the relationship between H22954 and PDGFA. The functional experi-ment was conducted to investigate the role of H22954 in tube formation. RESULTS: Overexpression of H22954 inhibited angiogenesis in mouse xenograft tumors and cultured acute myeloid leukemia (AML) cells. Bioinformatics analysis and luciferase assay revealed that H22954 targeted the 3' untranslated region (UTR) of the platelet-derived growth factor subunit A (PDGFA) gene. In transfected cells, H22954 overexpression reduced PDGFA expression and protein levels. Tube formation was rescued following the addition of exogenous human PDGFA to the con-ditioned medium from cells overexpressing H22954. The expression of H22954 in K562 cells re-duced the half-life of PDGFA mRNA. Furthermore, H22954 expression was inversely correlated with PDGFA expression in patient samples. CONCLUSION: These findings indicate that H22954 inhibits angiogenesis in AML through the down-regulation of PDGFA expression. Administering recombinant lncRNA H22954 may be a therapeutic approach for patients with AML.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , RNA Longo não Codificante , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/genética , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
19.
Comput Math Methods Med ; 2022: 6221673, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295202

RESUMO

This research examines the association between the platelet-derived growth factor/platelet-derived growth factor receptor (PDGF/PDGFR) system and rheumatoid arthritis (RA) susceptibility through a comprehensive search of the PubMed database to study the expression of the PDGF/PDGFR system in RA. Review Manager software version 5.3 was used for statistical analysis. Six eligible studies published in the English language were included, including 108 rheumatoid arthritis cases and 85 controls with the corresponding 126 and 97 tests, respectively, relating the expression of the PDGF/PDGFR system to the risk of RA. The overall results indicated a significant association between the PDGF/PDGFR system expression and RA (OR = 5.25, 95% CI: 3.00-9.18, p < 00001), RA patients in Asian countries (OR = 4.13, 95% CI = 2.04-8.39, p < 0.0001) and in Western countries (OR = 9.18, 95% CI = 2.04-8.39, p = 0.03), and only PDGF expression in RA patients (OR = 5.28, 95% CI = 2.73-10.21, p < 0.00001). Thus, only the PDGFR expression was insignificantly associated with RA susceptibility (OR = 9.25, 95% CI = 0.63-136.30, p = 0.11). Hence, the PDGF/PDGFR system most likely contributes to susceptibility to RA.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Suscetibilidade a Doenças , Humanos , Razão de Chances , Fatores de Risco
20.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(2): 349-354, 2022 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-35332741

RESUMO

Osteoarthritis (OA) is a chronic degenerative disease involving the entire joint. The pathogenesis and progression of OA bear close connection to the destruction and the abnormal metabolism of cartilage, subchondral bones and synovium. Platelet derived growth factor-AA (PDGF-AA) is a critical mitogenic and chemotactic factor for a variety of cells, including chondrocytes, mesenchymal stem cells, osteoclasts and osteoblasts, and PDGF-AA promotes effective wound repair. This paper reviewed the pathological changes of cartilage, subchondral bones and synovium in the process of OA development, and summarized research progress regarding the effect of PDGF-AA on the tissues and related cells mentioned above. Current studies have basically clarified the pathological changes of cartilage, subchondral bones and synovium in OA patients, and have shown that PDGF-AA serves critical regulatory function in the tissues or cells involved in OA, the internal mechanism of which remains unclear, though. More studies should be done to find ways to apply PDGF-AA for clinic purpose and to diagnose and treat OA on the cellular basis.


Assuntos
Cartilagem Articular , Osteoartrite , Cartilagem Articular/patologia , Condrócitos/patologia , Humanos , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...