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1.
J Immunol Res ; 2022: 7465353, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132983

RESUMO

Purpose: To investigate the function of C/EBPα in the development of aortic dissection (AD) and the underlying mechanism. Methods: Aortic vascular smooth muscle cells (VSMCs) were isolated, cultured, and identified from AD rats. Then, C/EBPα and PIK3C2A were knockdown or overexpressed by siRNA or plasmid transfection, respectively. Rapamycin or 3-MA was utilized to stimulate and restrain autophagy of VSMCs, respectively. Western blot was used to evaluate the expression levels of C/EBPα, PIK3C2A, LC3, Beclin-1, p62, MMP-2, MMP-9, α-SMA, SM-MHC, and OPN. The pathological status of aortic ring was evaluated by stretch stress, and ChIP assay was used to analyze the binding between C/EBPα and PIK3C2A. C/EBPα shRNA was injected into tail vein to observe the effect of C/EBPα knockdown in vivo on phenotype, autophagy of aortic vascular tissue by immunohistochemical staining and Western blot. Results: The protein levels of C/EBPα, PIK3C2A, MMP-2, MMP-9, and LC3 in the aorta of AD rats were all upregulated significantly. C/EBPα and rapamycin promoted notable upregulation of the synthesized proteins (OPN), PIK3C2A, matrix metalloproteinases, LC3, and Beclin-1 in VSMCs, while suppressed contractile proteins (α-SMA and SM-MHC) and p62. The opposite results were observed in the C/EBPα-knockdown VSMCs, PIK3C2A-knockdown VSMCs, or VSMCs treated with 3-MA. C/EBPα, PIK3C2A, and LC3 were dramatically upregulated by the stimulation of 3 g and 5 g stretch stress. The downregulated contractile proteins, upregulated synthetic proteins, activated autophagy, and aggravated pathological state in 5 g stretch stress-treated aortic rings were significantly reversed by the knockdown of C/EBPα. ChIP results indicated that there was a binding site for C/EBPα in the promoter of PIK3C2A. C/EBPα also downregulated α-SMA level and upregulated OPN levels in AD rats in vivo. Conclusion: Our data indicated that during the development of AD, C/EBPα regulated the transition of VSMC phenotype and extracellular matrix remodeling by activating autophagy through regulating the transcriptional activity of PIK3C2A promoter.


Assuntos
Aneurisma Dissecante , Músculo Liso Vascular , Aneurisma Dissecante/genética , Animais , Autofagia/genética , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/farmacologia , Células Cultivadas , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Fenótipo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Sirolimo/farmacologia , Ativação Transcricional
2.
Acta Biochim Pol ; 69(3): 613-618, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36099587

RESUMO

OBJECTIVES: Cerebral aneurysm (CA) is one of the most common cerebrovascular diseases. The study was conducted to investigate the effect of resveratrol (RES) on the CA formation and its possible mechanisms. MATERIALS AND METHODS: Murine model of CA was constructed by induced hypertension and fed without (model group) or with RES (RES group). A Sham group was used as a control. The CA formation and inflammatory response were examined morphologically and histochemically. The expression of nuclear factor-κB (NF-κB), matrix metalloproteinase (MMP)-2, and MMP-9 was analyzed using qRT-PCR and Western blots. RESULTS: CA was induced in mice after the left common carotid artery was ligated and fed with high sodium chloride. Compared with the model, mice fed with RES had significantly fewer CA with smaller size, normal thickness of the arterial wall (P<0.05), and fewer infiltrated macrophages in the aneurysm wall (P<0.05). qRT-PCR and Western blot analyses showed that the expression of MMP-2, MMP-9 and NF-κB was significantly elevated in the model as compared with the control and significantly decreased after RES treatments (P<0.05). CONCLUSIONS: RES can inhibit the CA formation in mice subjected to induced hypertension and this inhibition is likely mediated via downregulating the NF-κB pathway.


Assuntos
Hipertensão , Aneurisma Intracraniano , Estilbenos , Animais , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/metabolismo , Resveratrol/farmacologia , Cloreto de Sódio , Estilbenos/farmacologia , Estilbenos/uso terapêutico
3.
Dis Markers ; 2022: 5085183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118675

RESUMO

Background: Chronic actinic dermatitis (CAD) is an abnormally proliferating photoallergic skin disease. Dysregulated inflammation and oxidative stress are the immediate factors in the abnormal proliferation of keratinocytes. This study aimed to investigate the effect of curcumin on the aberrant proliferation of keratinocytes in an in vitro (actinic dermatitis) AD model and the possible molecular mechanisms. Methods: The keratinocytes were irradiated with ultraviolet (UV) to construct an in vitro AD model and then processed with different concentrations of curcumin. Cell viability, oxidative stress markers (SOD, GSH-PX, and MDA), activated oxygen species (ROS), and inflammation markers (IL-1ß, IL-6, IL-18, and TNFα) were determined, respectively. Western blot was applied to assay the profiles of apoptosis-related proteins (Bax, Bcl-xL, Caspase3, Caspase8, and Caspase9), oxidative stress proteins (Keap1, Nrf2, HO-1, COX2, and iNOS), and inflammatory proteins (NF-κB, MMP1, and MMP9) and SPAG5/FOXM1. Functionally, SPAG5 or FOXM1 overexpression and knockdown models were constructed in keratinocytes to characterize their influence on UV irradiation-mediated keratinocyte dysfunction. Results: Curcumin weakened UV-mediated inflammation, proliferation, and oxidative stress and impaired apoptosis in keratinocytes. UV boosted SPAG5/FOXM1 expression in cells, while curcumin concentration-dependently retarded SPAG5/FOXM1 expression. Overexpression of SPAG5/FOXM1 fostered UV-mediated inflammation, proliferation, oxidative stress, and intensified apoptosis, whereas curcumin mostly reversed the SPAG5/FOXM1-mediated effects. In addition, knocking down SPAG5/FOXM1 ameliorated UV-mediated keratinocyte dysfunction, whereas curcumin failed to exert further protective effects in cells with knockdown of SPAG5/FOXM1. Conclusion: Curcumin modulated proliferation, inflammation, oxidative stress, and apoptosis of keratinocytes by restraining the SPAG5/FOXM1 axis.


Assuntos
Curcumina , Transtornos de Fotossensibilidade , Proteínas de Ciclo Celular , Proliferação de Células , Curcumina/metabolismo , Curcumina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Proteína Forkhead Box M1 , Humanos , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Queratinócitos/metabolismo , Metaloproteinase 1 da Matriz , Metaloproteinase 9 da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Oxigênio/metabolismo , Oxigênio/farmacologia , Transtornos de Fotossensibilidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia
4.
Physiol Rep ; 10(18): e15434, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36117462

RESUMO

Chronic consumption of Western-type diet (WD) induces cardiac structural and functional abnormalities. Previously, we have shown that WD consumption in male ATM (ataxia-telangiectasia mutated kinase) deficient mice associates with accelerated body weight (BW) gain, cardiac systolic dysfunction with increased preload, and exacerbation of hypertrophy, apoptosis, and inflammation. This study investigated the role of ATM deficiency in WD-induced changes in functional and biochemical parameters of the heart in female mice. Six-week-old wild-type (WT) and ATM heterozygous knockout (hKO) female mice were placed on WD or NC (normal chow) for 14 weeks. BW gain, fat accumulation, and cardiac functional and biochemical parameters were measured 14 weeks post-WD. WD-induced subcutaneous and total fat contents normalized to body weight were higher in WT-WD versus hKO-WD. Heart function measured using echocardiography revealed decreased percent fractional shortening and ejection fraction, and increased LV end systolic diameter and volume in WT-WD versus WT-NC. These functional parameters remained unchanged in hKO-WD versus hKO-NC. Myocardial fibrosis, myocyte hypertrophy, and apoptosis were higher in WT-WD versus WT-NC. However, apoptosis was significantly lower and hypertrophy was significantly higher in hKO-WD versus WT-WD. MMP-9 and Bax expression, and Akt activation were higher in WT-WD versus WT-NC. PARP-1 (full-length) expression and mTOR activation were lower in WT-WD versus hKO-WD. Thus, ATM deficiency in female mice attenuates fat weight gain, preserves heart function, and associates with decreased cardiac cell apoptosis in response to WD.


Assuntos
Ataxia Telangiectasia , Cardiopatias , Animais , Peso Corporal , Dieta Ocidental/efeitos adversos , Feminino , Hipertrofia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Proteína X Associada a bcl-2
5.
Cell Commun Signal ; 20(1): 146, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123693

RESUMO

BACKGROUND: Keratinocytes constitute a major part of the melanoma microenvironment, considering their protective role towards melanocytes in physiological conditions. However, their interactions with tumor cells following melanomagenesis are still unclear. METHODS: We used two in vitro models (melanoma-conditioned media and indirect co-culture of keratinocytes with melanoma cells on Transwell inserts) to activate immortalized keratinocytes towards cancer-associated ones. Western Blotting and qPCR were used to evaluate keratinocyte markers and mediators of cell invasiveness on protein and mRNA expression level respectively. The levels and activity of proteases and cytokines were analysed using gelatin-FITC staining, gelatin zymography, chemiluminescent enzymatic test, as well as protein arrays. Finally, to further study the functional changes influenced by melanoma we assessed the rate of proliferation of keratinocytes and their invasive abilities by employing wound healing assay and the Transwell filter invasion method. RESULTS: HaCaT keratinocytes activated through incubation with melanoma-conditioned medium or indirect co-culture exhibit properties of less differentiated cells (downregulation of cytokeratin 10), which also prefer to form connections with cancer cells rather than adjacent keratinocytes (decreased level of E-cadherin). While they express only a small number of cytokines, the variety of secreted proteases is quite prominent especially considering that several of them were never reported as a part of secretome of activated keratinocytes' (e.g., matrix metalloproteinase 3 (MMP3), ADAM metallopeptidase with thrombospondin type 1 motif 1). Activated keratinocytes also seem to exhibit a high level of proteolytic activity mediated by MMP9 and MMP14, reduced expression of TIMPs (tissue inhibitor of metalloproteinases), upregulation of ERK activity and increased levels of MMP expression regulators-RUNX2 and galectin 3. Moreover, cancer-associated keratinocytes show slightly elevated migratory and invasive abilities, however only following co-culture with melanoma cells on Transwell inserts. CONCLUSIONS: Our study offers a more in-depth view of keratinocytes residing in the melanoma niche, drawing attention to their unique secretome and mediators of invasive abilities, factors which could be used by cancer cells to support their invasion of surrounding tissues. Video abstract.


Assuntos
Metaloproteinase 3 da Matriz , Melanoma , Caderinas/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core , Meios de Cultivo Condicionados/farmacologia , Citocinas , Fluoresceína-5-Isotiocianato , Galectina 3 , Gelatina , Humanos , Queratinócitos/patologia , Queratinas , Metaloproteinase 14 da Matriz , Metaloproteinase 9 da Matriz/metabolismo , Melanoma/patologia , RNA Mensageiro/metabolismo , Trombospondinas , Inibidores Teciduais de Metaloproteinases
6.
Eur Rev Med Pharmacol Sci ; 26(16): 5710-5717, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36066144

RESUMO

OBJECTIVE: The aim of this study was to investigate the correlations of cluster of differentiation 147 (CD147) with plaque stability of carotid atherosclerosis (AS), degree of stenosis, inflammatory factors, matrix metalloproteinase-9 (MMP-9) expression and vascular endothelial function in patients with cerebral infarction. PATIENTS AND METHODS: A total of 50 patients diagnosed with cerebral infarction (cerebral infarction group), 70 patients diagnosed with AS plaque (plaque group, with no infarction but plaques only) and 30 healthy people receiving physical examination (control group) in our hospital from March 2018 to July 2019 were collected. The levels of biochemical indexes, CD147, MMP-9, vascular endothelial function indexes [endothelin-1 (ET-1) and C-reactive protein (CRP)] and inflammatory factors [interleukin-10 (IL-10), IL-16 and tumor necrosis factor-alpha (TNF-α)] in the blood of each group of patients were detected via radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). Moreover, ultrasonic examination and Gensini score system were applied to score the degree of carotid stenosis in cerebral infarction group. Finally, the differences in various parameters were compared among the three groups, and the correlations of CD147 with different indexes were evaluated using Spearman method. RESULTS: Compared with those in control group, the levels of CD147, MMP-9, hemoglobin, platelets, total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A, apolipoprotein B, IL-10, IL-13 and TNF-α in the blood were remarkably elevated in cerebral infarction group and plaque group (p<0.05). Cerebral infarction group had notably higher levels of CD147, hemoglobin, triglyceride, apolipoprotein B, IL-10, IL-13 and TNF-α in the blood than plaque group (p<0.05). The plaque score was markedly higher in cerebral infarction group than that in plaque group [(3.27±2.86) points vs. (0.93±1.44) points] (p<0.05). In comparison with control group, plaque group and cerebral infarction group exhibited evidently raised levels of blood ET-1 and CRP (p<0.05). The serum CD147 level was significantly associated with MMP-9 (p=0.003, r=0.616), Gensini score (p=0.006, r=0.656), plaque score (p=0.027, r=0.396), IL-10 (p=0.004, r=0.603), TNF-α (p=0.001, r=0.746) and CRP (p=0.037, r=0.450) in cerebral infarction group. CONCLUSIONS: CD147 level is prominently increased in carotid AS and closely related to inflammatory responses, and CD147 may become a new reference for the prediction and treatment of AS and cerebral infarction.


Assuntos
Aterosclerose , Doenças das Artérias Carótidas , Placa Aterosclerótica , Proteína C-Reativa , Infarto Cerebral , Humanos , Interleucina-10 , Interleucina-13 , Metaloproteinase 9 da Matriz/metabolismo , Placa Aterosclerótica/patologia , Triglicerídeos , Fator de Necrose Tumoral alfa
7.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955918

RESUMO

Lidocaine injection is a common treatment for tendon injuries. However, the evidence suggests that lidocaine is toxic to tendon cells. This study investigated the effects of lidocaine on cultured tendon cells, focusing on the molecular mechanisms underlying cell proliferation and extracellular matrix (ECM) production. Tendon cells cultured from rat Achilles tendons were treated with 0.5, 1.0, or 1.5 mg/mL lidocaine for 24 h. Cell proliferation was evaluated by Cell Counting Kit 8 (CCK-8) assay and bromodeoxyuridine (BrdU) assay. Cell apoptosis was assessed by Annexin V and propidium iodide (PI) stain. Cell cycle progression and cell mitosis were assessed through flow cytometry and immunofluorescence staining, respectively. The expression of cyclin E, cyclin A, cyclin-dependent kinase 2 (CDK2), p21, p27, p53, matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), type I collagen, and type III collagen were examined through Western blotting, and the enzymatic activity of MMP-9 was determined through gelatin zymography. Lidocaine reduced cell proliferation and reduced G1/S transition and cell mitosis. Lidocaine did not have a significant negative effect on cell apoptosis. Lidocaine significantly inhibited cyclin A and CDK2 expression but promoted p21, p27, and p53 expression. Furthermore, the expression of MMP-2 and MMP-9 increased, whereas that of type I and type III collagen decreased. Lidocaine also increased the enzymatic activity of MMP-9. Our findings support the premise that lidocaine inhibits tendon cell proliferation by changing the expression of cell-cycle-related proteins and reduces ECM production by altering levels of MMPs and collagens.


Assuntos
Colágeno Tipo III , Metaloproteinase 9 da Matriz , Animais , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Colágeno Tipo III/genética , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo , Matriz Extracelular/metabolismo , Lidocaína/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Tendões/metabolismo , Proteína Supressora de Tumor p53/metabolismo
8.
Biomed Pharmacother ; 154: 113562, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35994813

RESUMO

BACKGROUND: Hypoxic microenvironment of colon cancer is associated with HIF-1α upregulation. HIF-1α response elements are responsible for autophagy induction that promotes tumor proliferation. Moreover, HIF-1α induces tumor cell proliferation via maintaining cancer stem cells (CSCs) survival. Siah2 is E3 ubiquitin ligase that indirectly stabilizes HIF-1α. We hypothesized that dual inhibition of Siah2 as well as autophagy could be a promising approach that may inhibit CSCs growth. AIM OF THE WORK: This study investigated the possible effect of vitamin K3 as a Siah2 inhibitor and hydroxychloroquine as an autophagy inhibitor in colon cancer management. The effect (if any) of these agents on CSCs growth will be also manipulated. METHODS: Colon cancer was induced by dimethylhydrazine. MDA and GSH were selected as oxidative stress markers, Expression of HIF-1α, Caspase-3, VEGF, MMP-9, EpCAM, SCF, and CA19.9 were assayed using immunoassay. The Western blot technique was used to assess LC3Ⅰ, CD44, and CD133 whereas RT-PCR was used to investigate PHD3 and CD44 in colon tissues. Additionally, Ki-67 and Siah2 were detected immunohistochemically. RESULTS: vitamin K3 and hydroxychloroquine either alone or in combination downregulated the expression of Siah2 and HIF-1α through upregulating PHD3 in colon tissues. This combination significantly downregulated MDA, Ki-67, VEGF, and MMP-9 expression and upregulated the expression of GSH and caspase-3. LC3Ⅰ was also upregulated. Interestingly, these therapeutic options were correlated with down-regulation of the cancer stem cell marker such as CD44 and EpCAM. CONCLUSION: Our results suggested that suppression of both Siah2-PHD3-HIF-1α axis and autophagy retard colon cancer proliferation and dampened CSCs.


Assuntos
Neoplasias do Colo , Autofagia , Caspase 3/metabolismo , Hipóxia Celular/fisiologia , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Molécula de Adesão da Célula Epitelial , Humanos , Hidroxicloroquina , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Antígeno Ki-67/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Neoplásicas/metabolismo , Microambiente Tumoral , Ubiquitina-Proteína Ligases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vitamina K 3
9.
Cancer Treat Res Commun ; 32: 100617, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36027697

RESUMO

INTRODUCTION: Osteosarcoma (OS) is the most common primary osseous malignant tumour, with high propensity to metastasise in lungs. Pulmonary micro-metastases are present in up to 80% of patients at initial diagnosis and they are associated with significantly worse prognosis. Doxycycline (Dox) is a synthetic tetracycline that has been shown to have anti-cancer properties in vitro and in vivo, and inhibit angiogenesis - effects that may prove beneficial for several types of cancer. The aim of the present work was to study how Dox affects OS cell growth in vitro and in vivo and OS-driven pulmonary metastasis in vivo. METHODS: In vitro, the effect of Dox was measured in MG-63 and 143B human OS cell viability, apoptosis, invasion and migration. In vivo, highly metastatic 143B cells were orthotopically implanted into the tibia of SCID mice. The tumour growth and pulmonary metastases between Dox treated and untreated, non-amputated and early amputated xenografts were examined. RESULTS: In vitro, Dox decreased viability, inhibited invasion, migration, and induced the apoptosis of OS cells. In vivo, Dox significantly enhanced tumour necrosis at primary OS sites, similarly to its in vitro effect, and downregulated the expression of Ki67, MMP2, MMP9, VEGFA and ezrin. It also decreased circulating VEGFA and MMP9 protein levels, in line with the decreased metastatic burden in Dox-treated mice (non-amputated and early-amputated). CONCLUSIONS: Reprofiling of Dox can prevent the evolvement of pulmonary micro-metastases to clinically detectable macro-metastases and suppress the lethal progress of OS by inhibiting the expression of MMPs, VEGFA and ezrin at primary sites.


Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Animais , Neoplasias Ósseas/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas do Citoesqueleto , Doxiciclina , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos SCID , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fator A de Crescimento do Endotélio Vascular
10.
J Mol Model ; 28(9): 266, 2022 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-35987945

RESUMO

Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κß are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κß system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-ƙß. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.


Assuntos
Metaloproteinase 9 da Matriz , Xantonas , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Xantonas/química , Xantonas/farmacologia
11.
Mol Med ; 28(1): 92, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941589

RESUMO

BACKGROUND: The forkhead box O3a protein (FoxO3a) has been reported to be involved in the migration and invasion of trophoblast, but its underlying mechanisms unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development. METHODS: Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC-MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed. RESULTS: We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells. CONCLUSIONS: Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.


Assuntos
Proteína Forkhead Box O3/metabolismo , Pré-Eclâmpsia , Trofoblastos , Aminoácidos Aromáticos/metabolismo , Linhagem Celular , Movimento Celular/genética , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/genética , Gravidez , Trofoblastos/metabolismo
12.
Front Immunol ; 13: 935545, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935949

RESUMO

Background: Accumulating evidence supports the predisposition of systemic lupus erythematosus (SLE) to atherosclerosis (AS). However, the common pathogenesis of these two diseases remains unclear. This study aimed to explore the mechanisms of SLE complicated by AS. Methods: Gene expression profiles of SLE (GSE50772) and AS (GSE100927) were downloaded from the Gene Expression Omnibus. We analyzed differentially expressed genes (DEGs) of SLE and AS and performed enrichment analyses separately. After analyzing the common DEGs (CDEGs), we performed functional enrichment analysis, protein-protein interaction (PPI) network analysis, and hub genes (HGs) identification of CDEGs. Then, we performed a co-expression analysis of HGs and verified their expression and diagnostic value. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells (IICs). Finally, we verified the reliability of the screening pathway. Results: We obtained 530 DEGs from the GSE50772 dataset and 448 DEGs from the GSE100927 dataset. The results of the enrichment analysis showed that there were many similar immune- and inflammation-related processes between the two diseases. We analyzed 26 CDEGs (two downregulated genes and 24 upregulated genes) and enrichment analysis highlighted the important role of the IL-17 signaling pathway. We identified five HGs (CCR1, CD163, IL1RN, MMP9, and SIGLEC1) using the CytoHubba plugin and HGs validation showed that the five HGs screened were reliable. Co-expression networks showed that five HGs can affect mononuclear cell migration. Immune cell infiltration analysis indicated monocytes in SLE and M0 macrophages in AS accounted for a high proportion of all IICs, and the difference in infiltration was obvious. We also found a significant positive correlation between CCR1, CD163, IL1RN, and MMP9 and monocytes in SLE, and a significant positive correlation between CCR1, IL1RN, MMP9, and SIGLEC1 and M0 macrophages in AS. Pathway validation also demonstrated that the IL-17 signaling pathway was a key pathway for the differentiation of monocytes into macrophages. Conclusions: The five HGs may promote the differentiation of monocytes into macrophages by influencing the IL-17 signaling pathway, leading to SLE complicated by AS. Our study provides insights into the mechanisms of SLE complicated by AS.


Assuntos
Aterosclerose , Lúpus Eritematoso Sistêmico , Aterosclerose/genética , Humanos , Interleucina-17/genética , Metaloproteinase 9 da Matriz/metabolismo , Reprodutibilidade dos Testes , Transcriptoma
13.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(6): 602-607, 2022 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-35924515

RESUMO

OBJECTIVE: To investigate whether signal transducer and activator of transcription (STAT1/3/5) have a protective effect on hyperoxia-induced acute lung injury (HALI) and its mechanism. METHODS: Seventy C57BL/6J mice were randomly divided into five groups: normoxia control group, HALI group, and STAT1/3/5 inhibitor groups, with 14 mice in each group. The HALI model was established by exposure to more than 90% hyperoxia for 48 hours; three STAT inhibitor groups were pretreated by intraperitoneal injection of STAT1 inhibitor 40 mg/kg and STAT3 inhibitor 5 mg/kg, and STAT5 inhibitor 10 mg/kg for 1 week. Six blood samples were randomly collected from each group, and microRNA-21 (miR-21) expression was measured by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). Lung tissue of the sacrificed mice was obtained, and enzyme linked immunosorbent assay (ELISA) was used to detect the contents of tumor necrosis factor-α (TNF-α), interleukins (IL-6, IL-1ß), superoxide dismutase (SOD), malonic dialdehyde (MDA), and matrix metalloproteinase 9 (MMP9). The water content of lung tissue was calculated. The pathological changes in lung tissue were observed under the light microscope, and the pathological score of lung injury was performed. Western blotting was used to detect the expression of phosphorylated STAT (p-STAT1, p-STAT3, p-STAT5) in lung tissue. The 7-day cumulative survival rates of the remaining 8 mice in each group were analyzed using Kaplan-Meier survival curves. RESULTS: Under the light microscope, the alveolar structures in the HALI group and the STAT1 inhibitor group were destroyed, a large number of neutrophils (NEU) infiltrated in the alveoli and lung interstitium, which were thickened. The pathological score of lung injury and the water content of the lung tissue was significantly increased. In STAT3 inhibitor and STAT5 inhibitor groups, the alveolar cavity was clear, the degree of NEU infiltration and the thickness of lung interstitium were lower than those in HALI group, the pathological score of lung injury and the water content of lung tissue were significantly decreased, especially in STAT3 inhibitor group. Compared with the normoxia control group, the contents of TNF-α, IL-6, IL-1ß, MDA, and MMP9, and the expression levels of p-STAT3 and p-STAT5 in the HALI group were significantly increased. In contrast, the content of SOD and the expression of miR-21 were significantly decreased. Compared with the HALI group, the contents of TNF-α, IL-6, IL-1ß, MDA, and MMP9 in the STAT3 inhibitor group and STAT5 inhibitor group were significantly decreased. At the same time, the content of SOD and the expression of miR-21 were significantly increased, especially in STAT3 inhibitor group [TNF-α (µg/L): 42.53±3.25 vs. 86.36±5.48, IL-6 (ng/L): 68.46±4.28 vs. 145.00±6.89, IL-1ß (µg/L): 28.74±3.53 vs. 68.00±5.64, MDA (µmol/g): 20.33±2.74 vs. 42.58±3.45, and MMP9 (ng/L): 128.55±6.35 vs. 325.13±6.65, SOD (kU/g): 50.53±4.19 vs. 22.53±3.27, miR-21 (2-ΔΔCt): 0.550±0.018 vs. 0.316±0.037, all P < 0.05]. Kaplan-Meier survival curve analysis showed that the 7-day cumulative survival rates of the STAT3 inhibitor group and STAT5 inhibitor group were significantly higher than those of the HALI group [62.5% (5/8), 37.5% (3/8) vs. 12.5% (1/8), both P < 0.05]. CONCLUSIONS: Inhibition of STAT3 hyperactivation may suppress the inflammatory response, regulate oxidative stress, improve lung permeability through regulating the expression of miR-21, which exert lung protection in HALI.


Assuntos
Lesão Pulmonar Aguda , Hiperóxia , MicroRNAs , Animais , Hiperóxia/complicações , Interleucina-6/metabolismo , Pulmão/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Água
14.
Cell Physiol Biochem ; 56(4): 353-366, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35959709

RESUMO

BACKGROUND/AIMS: Aging is accompanied by progressive and adverse cardiac remodeling characterized by myocardial hypertrophy, fibrosis, and dysfunction. We previously reported that galectin-3 (Gal-3) is a critical regulator of inflammation and fibrosis associated with hypertensive heart disease and myocardial infarction. Nevertheless, the role and mechanism of Gal-3 in age-related cardiac remodeling have not been previously investigated. We hypothesized that Gal-3 plays a critical role in cardiac aging and that its deficiency exacerbates the underlying mechanisms of myocardial hypertrophy and fibrosis. METHODS: Male C57BL/6 (control) (n=24) and Gal-3 knockout (KO) (n=29) mice were studied at 24 months of age to evaluate the role of Gal-3 in cardiac aging. We assessed 1) survival rate; 2) systolic blood pressure (SBP) by plethysmography; 3) myocardial hypertrophy, apoptosis, and fibrosis by quantification of histological and immunohistochemical analysis; 4) cardiac expression of angiotensin (Ang) II, Ang (1-7) by Radioimmunoassay; 5) transforming growth factor-ß (TGF-ß), sirtuin (SIRT) 1, SIRT 7 and metalloproteinase 9 (MMP-9) by RT-qPCR and 6) ventricular remodeling and function by echocardiography. RESULTS: We found that aged Gal-3 KO mice had a lower survival rate and exhibited exacerbated myocardial hypertrophy and fibrosis without changes in SBP. Similarly, myocardial apoptosis and MMP-9 mRNA expression was significantly increased in the hearts of Gal-3 KO mice compared to controls. Additionally, cardiac Ang II and TGF-ß expression were higher in aged Gal-3 KO mice while SIRT1 and SIRT7 expression were reduced. CONCLUSION: Our findings strongly suggest that Gal-3 is involved in age-related cardiac remodeling by regulating critical mechanisms associated with the development of pathological hypertrophy. The gene deletion of Gal-3 reduced the lifespan and markedly increased age-dependent mechanisms of myocardial hypertrophy, apoptosis, and fibrosis, including Ang-II, TGF-ß, and MMP-9. At the same time, there was diminished cardiac-specific expression of SIRT1 and SIRT7, which are extensively implicated in delaying age-dependent cardiomyopathies.


Assuntos
Galectina 3 , Remodelação Ventricular , Angiotensina II/metabolismo , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Fibrose , Galectina 3/genética , Galectina 3/metabolismo , Deleção de Genes , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo
15.
Eur J Med Res ; 27(1): 153, 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-35978364

RESUMO

The migration, proliferation, and inflammatory factor secretion of vascular smooth muscle cells (VSMCs) are involved in the important pathological processes of several vascular occlusive diseases, including coronary atherosclerosis (CAS). Interleukin 1ß(IL-1ß), as a bioactive mediator of VSMC synthesis and secretion, can promote the pathological progress of CAS. In this study, we further explored the underlying molecular mechanisms by which IL-1ß regulates VSMC migration, invasion. We pretreated A7r5 and HASMC with IL-1ß for 24 h, and measured the expression of IL-1ß, proliferating cell nuclear antigen (PCNA), cyclin D1, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 2 (MMP9) in the cells by Western blotting. Cell migration and invasion ability were measured by Transwell and wound healing assays. Cell viability was measured by an MTT assay. We found that IL-1ß upregulated the expression of proliferation-related proteins (PCNA and Cyclin D1) in A7r5 and HASMC, and induces the secretion of MMP2 and MMP9, promotes cell invasion and migration. In addition, in A7r5 and HASMCs treated with IL-1ß, the expression of Angiopoietin-2 (Angpt-2) increased in a time-dependent manner, transfection with si-Angpt-2 suppressed cell migration and invasion, with downregulated MMP2 and MMP9 expression. Parallelly, we further found that the p38-MAPK pathway is activated in cells induced by IL-1ß, p38-MAPK inhibitors can down-regulate the expression of Angpt-2. Collectively, these data demonstrated that IL-1ß promotes A7r5 and HASMC migration and invasion via the p38-MAPK/Angpt-2 pathway.


Assuntos
Metaloproteinase 2 da Matriz , Proteínas Quinases p38 Ativadas por Mitógeno , Angiopoietina-2 , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Humanos , Interleucina-1beta/farmacologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Antígeno Nuclear de Célula em Proliferação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Front Immunol ; 13: 936995, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36003376

RESUMO

Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1ß, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP+ osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.


Assuntos
Antígenos CD , Artrite , Imunoglobulinas , Glicoproteínas de Membrana , Osteólise , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antígenos CD/metabolismo , Artrite/metabolismo , Humanos , Imunoglobulinas/metabolismo , Inflamação/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Osteoclastos/metabolismo , Osteólise/metabolismo , Receptor 4 Toll-Like/metabolismo
17.
Sci Rep ; 12(1): 14552, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008454

RESUMO

Primary Sjögren's syndrome (pSS) patients exhibit enhanced degradation of the salivary epithelium initially through MMP9 overexpression. We assessed the expression of MMP9 and an associated transcription factor, ETS1, in primary salivary gland epithelial cells (SGECs) and investigated potential regulatory mechanism(s) in immortalized SGECs. SGECs and iSGECs were derived from pSS and/or xerostomic "sicca" patients. siRNA knockdown of ETS1 in iSGECs was performed to determine MMP9 mRNA (qRT-PCR) and protein expression (ELISA). ETS1 binding to MMP9 promoter was assessed by luciferase activity and binding confirmed by mutagenesis and ChIP. Effects of ETS1 overexpression on progenitor and Epithelial-Mesenchymal transition (EMT) associated markers were determined by Western blot. Expression of ETS1 and its phosphorylated form in iSGECs was determined by immunofluorescence microscopy. ETS1 and MMP9 were overexpressed in SGECs of pSS and non-pSS sicca patients with salivary gland lymphocytic infiltration compared to non-pSS sicca patients without infiltration. ETS1 siRNA knockdown reduced both MMP9 mRNA and protein levels. ETS1 overexpression affected the expression of EMT and progenitor cell markers. Lastly, ETS1 bound the MMP9 promoter within the DNA region of -296 bp to -339 bp. ETS1 may impair salivary function through direct transcriptional control of the MMP9 promoter. ETS1 upregulation may also affect other factors involved in repair of the dysfunctional pSS salivary epithelium.


Assuntos
Glândulas Salivares/metabolismo , Síndrome de Sjogren , Células Epiteliais/metabolismo , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Síndrome de Sjogren/genética , Síndrome de Sjogren/metabolismo
18.
Cells ; 11(16)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-36010685

RESUMO

Tumor metastasis is a complex process modulated by both intrinsic and extrinsic factors that ultimately result in poorer patient outcomes, including diminished survival. Pseudogene-derived long non-coding RNAs (lncRNA) play important roles in cancer progression. In the current study, we found that the pseudogene-derived lncRNA LPAL2 is downregulated in hepatocellular carcinoma (HCC) tissues, and further showed that elevated LPAL2 expression is positively correlated with survival outcome. The knockdown of LPAL2 in hepatoma cells induced tumor formation, migration, invasion, sphere formation, and drug resistance. Metalloproteinase 9 (MMP9) was identified as an LPAL2-regulated target gene, consistent with clinical findings that LPAL2 expression is significantly associated with MMP9 expression. Furthermore, patients with a higher expression of LPAL2 and lower expression of MMP9 (LPAL2-high/MMP9-low) had a higher survival rate than those with other combinations. Collectively, our findings establish LPAL2 as a novel tumor suppressor in HCC, and suggest targeting LPAL2 and MMP9 as a therapeutic approach for the treatment of HCC.


Assuntos
Apolipoproteína A-II/metabolismo , Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Processos Neoplásicos , RNA Longo não Codificante/genética
19.
Cell Mol Biol (Noisy-le-grand) ; 68(4): 134-143, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35988280

RESUMO

In recent years, anti-cancer plant food development and research have received increasing attention, and cauliflower is one of the vegetables with anti-cancer effects. Sulforaphane (SFN) is one of the main anti-cancer components in cauliflower. In this study, the mechanism of action of SFN in anti-breast cancer was investigated using SFN, a bioactive compound extracted from cauliflower. For this purpose, SFN was extracted from cauliflower using rotary evaporation and silica gel chromatography, and the extracted SFN was used for in vitro and in vivo experiments. Breast cancer cells MCF-7, MDA-MB-231 and MDA-MB-231 xenograft tumor model mice were treated with SFN, pcDNA3.1-MMP-9, Si-RNA- MMP-9 and Si-RNA-NF-κB, respectively, and the corresponding saline treatment or blank plasmid treatment was used as control. The gene expression of NF-κB and MMP-9 in each group was detected by RT-PCR, and the protein phosphorylation level of MMP-9 was measured by Western bloting assay. WST 1 assay, MTT assay and flow cytometric analysis were used to detect the activity, proliferation and apoptosis levels of breast cancer cells. The tumor histopathology of the xenograft tumor model mice after SFN treatment was examined by HE staining. Results showed that Breast cancer cells treated with SFN showed reduced cell proliferation, decreased cell activity, increased apoptosis ratio, and inhibited gene expression and protein phosphorylation of MMP-9 as well as gene expression of NF-κB (P < 0.05). The same effect occurred with transfection of Si-RNA- MMP-9 and Si-RNA-NF-κB in breast cancer cells, while transfection of pcDNA3.1-MMP-9 plasmid significantly redeemed the inhibitory effect of SFN on breast cancer cells (P < 0.05). MDA-MB-231 xenograft tumor model mice treated with SFN showed significant improvement in the pathological condition of the tumor tissue. Then, SFN may inhibit breast cancer development by regulating the NF-κB /MMP-9 signaling pathway.


Assuntos
Neoplasias da Mama , Isotiocianatos , Sulfóxidos , Animais , Apoptose , Brassica/genética , Brassica/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Isotiocianatos/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , RNA , Transdução de Sinais , Sulfóxidos/farmacologia
20.
J Am Heart Assoc ; 11(15): e026378, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35904197

RESUMO

Background The endothelium is essential for maintaining vascular physiological homeostasis and the endothelial injury leads to the neointimal hyperplasia because of the excessive proliferation of vascular smooth muscle cells. Endothelial Foxp1 (forkhead box P1) has been shown to control endothelial cell (EC) proliferation and migration in vitro. However, whether EC-Foxp1 participates in neointimal formation in vivo is not clear. Our study aimed to investigate the roles and mechanisms of EC-Foxp1 in neointimal hyperplasia. Methods and Results The wire injury femoral artery neointimal hyperplasia model was performed in Foxp1 EC-specific loss-of-function and gain-of-function mice. EC-Foxp1 deletion mice displayed the increased neointimal formation through elevation of vascular smooth muscle cell proliferation and migration, and the reduction of EC proliferation hence reendothelialization after injury. In contrast, EC-Foxp1 overexpression inhibited the neointimal formation. EC-Foxp1 paracrine regulated vascular smooth muscle cell proliferation and migration via targeting matrix metalloproteinase-9. Also, EC-Foxp1 deletion impaired EC repair through reduction of EC proliferation via increasing cyclin dependent kinase inhibitor 1B expression. Delivery of cyclin dependent kinase inhibitor 1B-siRNA to ECs using RGD (Arg-Gly-Asp)-peptide magnetic nanoparticle normalized the EC-Foxp1 deletion-mediated impaired EC repair and attenuated the neointimal formation. EC-Foxp1 regulates matrix metalloproteinase-9/cyclin dependent kinase inhibitor 1B signaling pathway to control injury induced neointimal formation. Conclusions Our study reveals that targeting EC-Foxp1-matrix metalloproteinase-9/cyclin dependent kinase inhibitor 1B pathway might provide future novel therapeutic interventions for restenosis.


Assuntos
Metaloproteinase 9 da Matriz , Neointima , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Endotélio/metabolismo , Fatores de Transcrição Forkhead , Hiperplasia/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo
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