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1.
Hum Genet ; 139(4): 483-498, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32055997

RESUMO

Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.


Assuntos
Doenças Genéticas Inatas/genética , Proteínas de Choque Térmico HSC70/genética , Mutação com Perda de Função , Membrana Nuclear/genética , Adulto , Feminino , Humanos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Isoformas de Proteínas
2.
Life Sci ; 248: 117465, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105707

RESUMO

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.


Assuntos
Fator 6 de Crescimento de Fibroblastos/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Músculo Esquelético/metabolismo , Traumatismos dos Nervos Periféricos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Regeneração/genética , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Fator 6 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 6 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Denervação Muscular/métodos , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Proteína MyoD/genética , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Mioblastos/patologia , Miogenina/genética , Miogenina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Nervo Isquiático/lesões
3.
Life Sci ; 236: 116899, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614145

RESUMO

AIMS: The aim of our study is to illustrate the role of amphiregulin in trophoblast invasiveness and underlying signal cascades. MAIN METHODS: An immortalized human early extravillous cell line, HTR-8/SVneo, was used for this investigation. Matrigel-transwell invasion assay was used for testing the effects of amphiregulin on cell invasiveness. MMP9 and MMP2 mRNA expression level and activity were measured using Rt-qPCR and zymographic analysis. Cell signals involved in the invasion process were verified using western blot and specific inhibitors. KEY FINDINGS: Our results showed that amphiregulin could promote HTR-8/SVneo cell invasiveness without interfering cell proliferation, and significantly upregulate the expression of MMP9 and TIMP-1 mRNAs as well as the ratio of MMP9/TIMP-1. Using specific inhibitors for MEK and PI3K signaling further indicated that, both ERK1/2 and Akt signal pathways were required for amphiregulin-induced cell invasiveness. The co-ordination between ERK1/2 and Akt signaling pathway was needed for the upregulation of MMP9 mRNA, while ERK1/2 was more essential for the upregulation of TIMP-1 mRNA. Meanwhile, we first put forward that the deficiency of amphiregulin expression in trophoblast might be compensated by the upregulation of epidermal growth factor receptor (EGFR) and heparin-binding EGF (HB-EGF) mRNA. SIGNIFICANCE: ERK1/2 and Akt signaling pathways mediate amphiregulin-induced upregulation of MMP9 mRNA and the MMP9/TIMP-1 ratio, which subsequently contribute to amphiregulin-promotion of HTR-8/SVneo cell invasion.


Assuntos
Anfirregulina/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Humanos , Metaloproteinase 9 da Matriz/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Gravidez , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-1/genética
4.
J Cancer Res Clin Oncol ; 145(11): 2649-2661, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31529191

RESUMO

PURPOSE: The incidence of Urothelial carcinoma of bladder (UBC) is gradually increasing by changing lifestyle and environment. The development of a tumor has been noted to be accompanied by modifications in the extracellular matrix (ECM) consisting of CD44, hyaluronic acid (HA) and its family members. The importance of CD44 splice variants and HA family members has been studied in UBC. METHODS: The cohort of study included 50 UBC patients undergoing radical cystectomy and 50 healthy subjects. The molecular expression of CD44 and HA family members was determined. Effect of CD44 variant-specific silencing on downstream signaling in HT1376 cells was investigated. Combinatorial treatment of 4-MU (4-methylumbelliferone) with cisplatin or doxorubicin on chemosensitivity was also explored. RESULTS: Higher expression of HA, HAS2, and CD44 was observed in Indian UBC patients which also showed the trend with severity of disease. Splice variant assessment of CD44 demonstrated the distinct role of CD44v3 and CD44v6 in bladder cancer progression. shRNA-mediated downregulation of CD44v3 showed an increase effect on cell cycle, apoptosis and multiple downstream signaling cascade including pAkt, pERK and pSTAT3. Furthermore, 4-MU, an HA synthesis inhibitor, observed to complement the effect of Cisplatin or Doxorubicin by enhancing the chemosensitivity of bladder cancer cells. CONCLUSIONS: Our findings exhibit involvement of CD44 splice variants and HA family members in UBC and significance of 4-MU in enhancing chemosensitivity suggesting their novel therapeutic importance in disease therapeutics.


Assuntos
Processamento Alternativo , Receptores de Hialuronatos/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Apoptose , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
5.
Eur J Appl Physiol ; 119(10): 2237-2253, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420735

RESUMO

PURPOSE: Stressful training with insufficient recovery can impair muscle performance. Expression of mitogen-activated protein kinases (MAPK) has been reported at rest following overreaching and overtraining. The acute myocellular exercise response to stressful training with insufficient recovery has not been investigated. We investigated MAPK, androgen, and glucocorticoid receptor phosphorylation following a period of stressful training. METHODS: Sixteen resistance-trained men were matched on barbell squat 1 repetition maximum strength and randomized into a group that performed normal training or stressful training with insufficient recovery. The control group (CON) performed three speed-squat training sessions on non-consecutive days, while the stressful training group (NFOR) performed 15 training sessions over 7.5 days. Resting and post-exercise skeletal muscle biopsies were obtained prior to (T1) and after the training period (T2). Samples were analyzed for total and phosphorylated androgen receptor (AR), glucocorticoid receptor (GR), and MAPKs (ERK, JNK, and p38). RESULTS: Total AR were down-regulated post-exercise at T2 in NFOR only. Phospho-AR at ser515 increased in both groups post-exercise at T1; however, ser515 only increased at T2 in NFOR. Phosphorylated ERK, JNK, and p38 increased post-exercise in CON and NFOR at T1 and T2. Post-exercise phospho-p38 was blunted in NFOR at T2 compared to T1. After the training intervention, resting phospho-p38 was higher in NFOR compared to T1. At T2, post-exercise phospho-GR at ser226 was lower compared to T1, and resting levels increased in NFOR. CONCLUSION: Steroid receptors are phosphorylated after acute resistance exercise, and in addition to MAPKs, are differentially regulated after stressful training with insufficient recovery.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Treinamento de Resistência/métodos , Estresse Fisiológico , Regulação para Baixo , Humanos , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Fosforilação , Receptores Androgênicos/genética , Receptores de Glucocorticoides/genética , Recuperação de Função Fisiológica , Treinamento de Resistência/efeitos adversos , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382554

RESUMO

Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase family of signaling molecules. ERK is predominantly found in two forms, ERK1 (p44) and ERK2 (p42), respectively. There are also several atypical forms of ERK, including ERK3, ERK4, ERK5 and ERK7. The ERK1/2 signaling pathway has been implicated in many and diverse cellular events, including proliferation, growth, differentiation, cell migration, cell survival, metabolism and transcription. ERK1/2 is activated (i.e., phosphorylated) in the cytosol and subsequently translocated to the nucleus, where it activates transcription factors including, but not limited to, ETS, c-Jun, and Fos. It is not surprising that the ERK1/2 signaling cascade has been implicated in many pathological conditions, namely, cancer, arthritis, chronic inflammation, and osteoporosis. This narrative review examines many of the cellular events in which the ERK1/2 signaling cascade plays a critical role. It is anticipated that agents designed to inhibit ERK1/2 activation or p-ERK1/2 activity will be developed for the treatment of those diseases characterized by dysregulated gene expression through ERK1/2 activation.


Assuntos
Proliferação de Células/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Inflamação/genética , Sistema de Sinalização das MAP Quinases/genética , Diferenciação Celular/genética , Condrócitos/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Inflamação/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Osteócitos/metabolismo , Osteócitos/patologia
7.
Mol Med Rep ; 20(2): 1575-1582, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257493

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and exhibits a high mortality rate. Sirtuin (SIRT)6 is a member of the sirtuin family, which may be useful targets in the treatment of tumors. The present study aimed to explore the expression of SIRT6 in numerous HCC cell lines and investigate the role of SIRT6 in the proliferation and apoptosis of the HCC cells, and the underlying mechanisms. Overexpression and silencing of SIRT6 were performed by transfection of Huh­7 cells with synthetic overexpression and small interfering RNA (siRNA) plasmids. Cell proliferation was evaluated using a Cell Counting Kit­8 assay. The apoptosis rate was measured via flow cytometry. Cloning efficiency was assessed using plate clone formation assays. The expression of mRNAs and proteins were determined via reverse transcription­quantitative PCR and western blot analyses, respectively. SIRT6 was overexpressed in Hep3B, Huh­7, MHCC­97H, MHCC­97L, MHCC­LM6, MHCC­LM3, YY­8103 and SK­hep­1 cell lines, compared with MIHA and HL­7702 normal liver cell lines. Overexpression of SIRT6 increased the proliferation of Huh­7 cells, upregulated the expression of Bcl­2 and phosphorylation of extracellular­signal regulated protein kinase (ERK), and decreased the expression of cleaved­caspase­3 and Bcl­2­associated X protein (Bax) in Huh­7 cells. siRNA­mediated silencing of SIRT6 decreased the proliferation and increased the apoptosis of Huh­7 cells, downregulated the expression of Bcl­2 and phosphorylated­ERK, and promoted the expression of cleaved­caspase­3 and Bax. The proliferation of Huh­7 cells was decreased using the ERK1/2 inhibitor U0126. The results suggested that SIRT6 affected the proliferation and apoptosis of HCC cells via the regulation of the ERK1/2 pathway, altering the activation of the intrinsic apoptosis pathway. SIRT6 may be a potential target for the treatment of HCC; however, its role requires further investigation.


Assuntos
Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Sirtuínas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Clonais , Hepatócitos/patologia , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirtuínas/antagonistas & inibidores , Sirtuínas/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
8.
Mol Med Rep ; 20(2): 1583-1592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257496

RESUMO

Propofol is a general anesthetic used in surgical operations. Phosphoprotein enriched in astrocytes 15(PEA15) was initially identified in astrocytes. The present study examined the role of PEA15 in the damage induced by propofol in hippocampal neurons. A model of hippocampal neuron damage was established using 50 µmol/l propofol. Cell viability, proliferation and apoptosis of hippocampal neurons were tested by Cell Counting Kit­8 and flow cytometry. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were performed to measure the expression levels of PEA15, and additional factors involved in apoptosis or in the signaling pathway downstream of PEA15. The present results suggested that propofol significantly decreased PEA15 expression levels in hippocampal neurons. Furthermore, overexpression of PEA15 significantly increased the cell viability and cell proliferation of cells treated with propofol. Additionally, PEA15 overexpression decreased apoptosis, which was promoted by propofol. Treatment with propofol significantly decreased the protein expression levels of pro­caspase­3, B­cell lymphoma-2, phosphorylated extracellular signal­regulated kinases (ERK)1/2, ribosomal S6 kinase 2 (RSK2) and phosphorylated cAMP responsive element binding protein 1 (CREB1). However, propofol upregulated active caspase­3 and Bax expression levels. Notably, PEA15 overexpression was able to reverse the effects of propofol. Collectively, overexpression of PEA15 was able to attenuate the neurotoxicity of propofol in rat hippocampal neurons by increasing proliferation and repressing apoptosis via upregulation of the ERK­CREB­RSK2 signaling pathway.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Propofol/toxicidade , Animais , Animais Recém-Nascidos , Apoptose/genética , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , Gravidez , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Transfecção , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
9.
Med Sci Monit ; 25: 5143-5149, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31293277

RESUMO

BACKGROUND In present study, we explored the function of the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) gene in the development of non-small cell lung cancer (NSCLC). MATERIAL AND METHODS qRT-PCR was used to detect the MALAT1 mRNA expression level in cancer tissues and adjacent normal tissues of 115 NSCLC patients and in cell lines. MALAT1-mimic, MALAT1-inhibitor, and corresponding negative controls (NC) were utilized to transfect the H460 cells. Proliferation, migration, and invasion of H460 cells were evaluated by MTT method and Transwell assay. Expression levels of proteins in the ERK/MAPK signaling pathway were assessed by Western blot analysis. RESULTS MALAT1 mRNA was upregulated in NSCLC tissues and cell lines compared to that in adjacent tissues and normal human bronchial cell line (BEAS-2B), respectively. Overexpression of MALAT1 significantly strengthened the proliferation, migration, and invasion ability of H460 cells. In comparison with the NC group, expression levels of CXCL5 and p-JNK proteins were elevated, while p-MAPK and p-ERK proteins were decreased in the MALAT1-mimic group. MALAT1 targets the 3'- untranslated region (UTR) fragment of the CXCL5 gene and inhibits its translation. Disturbance of the CXCL5 gene can reduce the protein expression of MAPK, p-MEK1/2, p-ERK1/2, and p-JNK, and inhibit the proliferation, migration, and invasion of MALAT1-mimic cells. CONCLUSIONS High MALAT1 expression promotes the proliferation, migration, and invasion of non-small cell lung cancer via the ERK/MAPK signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Invasividade Neoplásica/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
10.
Biomater Sci ; 7(8): 3307-3319, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204746

RESUMO

Small interfering RNA (siRNA)-based therapy is an emerging treatment to address serious cardiovascular disease. It is essential to construct highly efficient vehicles for therapeutic siRNA intracellular delivery. Extracellular signal-regulated kinase-2 (ERK2) siRNA (abbreviated as ERK2-siRNA) is known as a type of siRNA to selectively silence the expression of ERK2. Herein, a type of ternary delivery system characterized by an endosome-selective-self-accelerating-escape ability was designed and prepared for the purpose of inhibiting the migration of vascular smooth muscle cells (VSMCs) in vitro. This system was called ternary ERK2-siRNA complexes (abbreviated as TRCs-Aco), which were fabricated via sequential electrostatic self-assembly of a star-shaped cell-penetrating peptide based on polyhedral oligomeric silsesquioxane (POSS-(C-G-R8-G-W)16), ERK2-siRNA and a pH-sensitive anionic polymer of cis-aconitic anhydride grafted ε-poly(l-lysine). Importantly, TRCs-Aco could break down the obstacle of biocompatibility-silencing efficiency. In comparison with the parent binary siRNA complexes (abbreviated as BRCs), which are composed of POSS-(C-G-R8-G-W)16 and ERK2-siRNA, our designed TRCs-Aco revealed more excellent biocompatibility including hemocompatibility and cytocompatibility. Unexpectedly, TRCs-Aco exhibited stronger ERK2 silencing efficiency at the level of mRNA and protein, which was mainly due to its remarkable self-accelerating endosomal escape. Definitive evidence demonstrated that this ternary ERK2-siRNA delivery system significantly prevented the migration of VSMCs and decreased the dermal thickness in bleomycin-treated mice. In brief, this unique structured system could provide a valuable nanoplatform for highly efficient siRNA delivery in VSMCs, and it might hold great potential in guiding ERK2-siRNA-based proliferative disease therapy.


Assuntos
Portadores de Fármacos/química , Endossomos/metabolismo , Hiperplasia/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Nanoestruturas/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Sequência de Aminoácidos , Animais , Transporte Biológico , Membrana Celular/metabolismo , Movimento Celular/genética , Feminino , Fibrose , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/deficiência , Músculo Liso Vascular/patologia , Peptídeos/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Eletricidade Estática
11.
Nat Commun ; 10(1): 2824, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249305

RESUMO

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-ß1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-ß1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-ß1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.


Assuntos
Fibrose/metabolismo , Hipóxia/metabolismo , Macrófagos/metabolismo , Oncostatina M/metabolismo , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oncostatina M/genética , Fosforilação , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Oxid Med Cell Longev ; 2019: 7285434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249649

RESUMO

The aim of this study was to investigate the cardioprotective effect of mangiferin (MAF) in vitro and in vivo. Oxidative stress and inflammatory injury were detected in coronary artery ligation in rats and also in hypoxia-reoxygenation- (H/R-) induced H9c2 cells. MAF inhibited myocardial oxidative stress and proinflammatory cytokines in rats with coronary artery occlusion. The ST segment of MAF treatment groups also resumed. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that MAF could significantly reduce myocardial injury. In vitro data showed that MAF could improve hypoxia/reoxygenation- (H/R-) induced H9c2 cell activity. In addition, MAF could significantly reduce oxidative stress and inflammatory pathway protein expression in H/R-induced H9c2 cells. This study has clarified the protective effects of MAF on myocardial injury and also confirmed that oxidative stress and inflammation were involved in the myocardial ischemia-reperfusion injury (I/R) model.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Xantonas/farmacologia , Animais , Cardiotônicos/farmacologia , Heme Oxigenase (Desciclizante)/genética , Técnicas In Vitro , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley
13.
BMC Cancer ; 19(1): 530, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151422

RESUMO

BACKGROUND: Histone H2AX phosphorylation at the site of Tyr-142 can participates in multiple biological progressions, which is including DNA repair. Ras pathway is closely involved in human cancers. Our study investigated the effects of Ras pathway via regulating H2AX.Y142ph. METHODS: Gastric cancer cell line SNU-16 and MKN1 cells were transfected with Ras for G12D and T35S site mutation. The phosphorylation of H2A.XY142 and ERK1/2, WSTF and MDM2 was detected by western blot. Cell viability, cell colonies and migration was analyzed by MTT assay, soft-agar colony formation assay, and Transwell assay, respectively. The expression of Ras pathway related downstream factors, EYA3 and WSTF was detected by qRT-PCR. The relationship between Ras and downstream factors were detected by ChIP. The cell cycle progression was measured by flow cytometry. RESULTS: RasG12D/T35V transection decreased the phosphorylation of H2A.XY142 and activated phosphorylation of ERK-1/2. H2A.XY142 inhibited cell viability, colonies and migration. H2A.XY142ph altered the expression of Ras downstream factors. CHIP assay revealed that RasG12D/T35V could bind to the promoters of these Ras pathway downstream factors. Silence of EYA3 increased H2A.XY142ph and inhibited cell viability, migration and percent cells in S stage. Furthermore, silence of EYA3 also changed the downstream factors expression. WSTF and H2A.XY142ph revealed the similar trend and MDM2 on the opposite. CONCLUSION: Ras/ERK signal pathway decreased H2A.XY142ph and promoted cell growth and metastasis. This Ras regulation process was down-regulated by the cascade of MDM2-WSTF-EYA3 to decrease H2A.XY142ph in SNU-16 cells.


Assuntos
Histonas/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Inativação Gênica , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Gástricas/patologia , Fatores de Transcrição/genética
14.
Life Sci ; 229: 173-179, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103606

RESUMO

AIMS: The innate immune response induced by bacterial peptidoglycan peptides, such as γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP), is an important host defense system. However, little is known about the innate immune response in the lung alveolar region. In this study, we examined induction of the innate immune response by iE-DAP in human alveolar epithelial cell lines, NCI-H441 (H441) and A549. MAIN METHODS: Induction of the innate immune response was evaluated by measuring the mRNA expression of cytokines and their release into the culture medium. KEY FINDINGS: iE-DAP treatment increased the mRNA expression of interleukin (IL)-6 and IL-8, and increased release of these pro-inflammatory cytokines into the culture medium in H441 cells, but not in A549 cells. Lack of release of these cytokines in A549 cells may have been due to lack of peptide transporter 2 (PEPT2) function. Intracellular nucleotide-binding oligomerization domain 1 (NOD1) recognizes iE-DAP and activates downstream signaling pathways to initiate the immune response. Therefore, the role of mitogen-activated protein kinase (MAPK) signaling pathways was examined in H441 cells. As a result of inhibition studies, receptor-interacting serine/threonine-protein kinase 2 and MAPK signaling pathways, such as p38 MAPK and extracellular signal-regulated kinase, but not c-Jun N-terminal kinase, were determined to be involved in the innate immune response in H441 cells. In addition, the nuclear factor κB pathway also played a role in the innate immune response. SIGNIFICANCE: These findings indicated that the innate immune response induced by bacterial peptides could occur in a PEPT2- and NOD1-dependent manner in alveolar epithelial cells.


Assuntos
Células Epiteliais Alveolares/imunologia , Ácido Diaminopimélico/análogos & derivados , Imunidade Inata/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simportadores/metabolismo , Células A549 , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Citocinas/metabolismo , Ácido Diaminopimélico/farmacologia , Humanos , Imunidade Inata/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Transdução de Sinais , Simportadores/genética
15.
Mol Immunol ; 112: 103-114, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31082644

RESUMO

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (M.tb). New cases are now mainly caused by the progression of latent tuberculosis infection (LTBI). Thus, methods to diagnose and treat LTBI are urgently needed to prevent the development of active TB in infected individuals and the subsequent spread of the disease. In this study, a systems biology approach was utilized to obtain numerous microarray data sets for mRNAs and microRNAs (miRNAs) expressed in the peripheral blood mononuclear cells (PBMCs) of TB patients and individuals with LTBI. Within these data sets, we identified the differentially expressed mRNAs and miRNAs and further investigated which differentially expressed genes and miRNAs were uniquely expressed during LTBI. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was employed to analyze the functional annotations and pathway classifications of the identified genes. To further understand the unique miRNA-gene regulatory network of LTBI, we constructed a protein-protein interaction (PPI) network for the targeted genes. The PPI network included 39 genes that were differentially and uniquely expressed in PBMCs of individuals with LTBI, and KEGG pathway enrichment analysis showed that these genes were predominantly involved in the PI3K-Akt signaling pathway, which plays an important role in chronic inflammation. DIANA TOOLs-mirPath analysis revealed that the identified miRNAs in the miRNA-gene regulatory network for LTBI were mainly associated with the Hippo signaling pathway, which functions in the development of inflammation. Quantitative real-time PCR verified the up expression of hsa-miR-212-3p and its predicted target gene -MAPK1 which had low expression and was a major component of the PPI network, and MAPK1 expression was correlated with the clinicopathological characteristics of LTBI by receiver operating characteristic (ROC) curve analysis. Therefore, MAPK1 has potential to be a new investigable marker during LTBI, which merits our further study and solution. The unique aberrant miRNA-gene regulatory network and the related PPI network identified in this study provide insight into the molecular mechanisms of the immune response to LTBI, and thus, may aid in the development of a novel treatment strategy.


Assuntos
Redes Reguladoras de Genes/genética , Tuberculose Latente/genética , MicroRNAs/genética , Biomarcadores/metabolismo , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/genética , Inflamação/microbiologia , Proteínas de Ligação a TGF-beta Latente/genética , Tuberculose Latente/microbiologia , Leucócitos Mononucleares/microbiologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Mycobacterium tuberculosis/patogenicidade , RNA Mensageiro/genética , Transdução de Sinais/genética , Transcriptoma/genética
16.
Braz J Psychiatry ; 41(6): 485-493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116258

RESUMO

OBJECTIVE: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. METHODS: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. RESULTS: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. CONCLUSION: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/sangue , Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína Crack , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Adulto , Estudos de Casos e Controles , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade/genética , Histona Desacetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Modelos Lineares , MAP Quinase Quinase 1/genética , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Estatísticas não Paramétricas , Adulto Jovem
17.
J Biol Chem ; 294(24): 9416-9429, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31036565

RESUMO

The human complement component, C5a, binds two different seven-transmembrane receptors termed C5aR1 and C5aR2. C5aR1 is a prototypical G-protein-coupled receptor that couples to the Gαi subfamily of heterotrimeric G-proteins and ß-arrestins (ßarrs) following C5a stimulation. Peptide fragments derived from the C terminus of C5a can still interact with the receptor, albeit with lower affinity, and can act as agonists or antagonists. However, whether such fragments might display ligand bias at C5aR1 remains unexplored. Here, we compare C5a and a modified C-terminal fragment of C5a, C5apep, in terms of G-protein coupling, ßarr recruitment, endocytosis, and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activation at the human C5aR1. We discover that C5apep acts as a full agonist for Gαi coupling as measured by cAMP response and extracellular signal-regulated kinase 1/2 phosphorylation, but it displays partial agonism for ßarr recruitment and receptor endocytosis. Interestingly, C5apep exhibits full-agonist efficacy with respect to inhibiting lipopolysaccharide-induced interleukin-6 secretion in human macrophages, but its ability to induce human neutrophil migration is substantially lower compared with C5a, although both these responses are sensitive to pertussis toxin treatment. Taken together, our data reveal that compared with C5a, C5apep exerts partial efficacy for ßarr recruitment, receptor trafficking, and neutrophil migration. Our findings therefore uncover functional bias at C5aR1 and also provide a framework that can potentially be extended to chemokine receptors, which also typically interact with chemokines through a biphasic mechanism.


Assuntos
Complemento C5a/metabolismo , Endocitose , Receptor da Anafilatoxina C5a/metabolismo , beta-Arrestinas/metabolismo , Sequência de Aminoácidos , Movimento Celular , Complemento C5a/genética , Células HEK293 , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neutrófilos/metabolismo , Fosforilação , Ligação Proteica , Receptor da Anafilatoxina C5a/genética , Homologia de Sequência , Transdução de Sinais , beta-Arrestinas/genética
18.
Biomed Pharmacother ; 115: 108953, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075732

RESUMO

OBJECTIVE: Preeclampsia is a pregnancy-specific syndrome characterized by hypertension and proteinuria. Impaired trophoblast invasion partly modulated by abnormal MAPK1/ERK2 signaling played important roles in the pathological process of preeclampsia. The objective of this study is to investigate miR-141-5p regulate ATF2 via effecting MAPK1/ERK2 signaling to promote preeclampsia. STUDY DESIGN: The maternal placentae and clinical data of 30 patients with preeclampsia and 30 healthy pregnant women were collected in the Second Hospital of Shanxi Medical University from July 2015 to April 2016. Transcriptional levels of miR-141-5p in placentae were monitored using quantitative real-time reverse transcription-polymerase chain reaction. The target gene of miR-141-5p was analyzed with "TargetScanHuman Release 7.2″. To evaluate the pathways of this response, MAPK1 and ERK1/2 in placentae were detected using immunohistochemistry and Western Blot. Transfection experiment was used to verify the function of miR-141-5p regulating ATF2 to effect MAPK1/ERK2 signaling in JEG-3 cells. RESULTS: miR-141-5p was significantly down-regulated in placentae of patients with preeclampsia, in comparison to the healthy pregnant women groups. There was no difference in MAPK1 expression between placentae of patients with preeclampsia and healthy pregnant women groups. While p-MAPK1 expression was lower in preeclampsia placentae, in comparison to the healthy pregnant women groups. Moreover, inhibition and activation experiments also validate the function of miR-141-5p in effecting p-MAPK1 level in JEG-3 cells. Bioinformatic analysis identified that ATF2 was a target gene of miR-141-5p, which was one DNA-binding protein to effect phosphatase DUSP1 transcription. DUSP1 effect MAPK1/ERK2 signaling in preeclampsia. CONCLUSION: miR-141-5p up-regulated transcription factor ATF2 to promote phosphatase DUSP1 expression. DUSP1 expression reduces p-MAPK1 and ERK1/2 expression to promote preeclampsia.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/genética , Fator 2 Ativador da Transcrição/genética , Adulto , Linhagem Celular , Progressão da Doença , Fosfatase 1 de Especificidade Dupla/genética , Feminino , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Placenta/patologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Transdução de Sinais/genética
19.
Virology ; 533: 34-44, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31082732

RESUMO

Coronavirus infection induces the generation of autophagosomes, and certain host proteins regulating cellular autophagy are hijacked by some coronaviruses to facilitate the formation of double membrane vesicles. However, mechanisms underlying coronavirus-induced autophagy remain largely unknown. In this study, we demonstrate that autophagosome formation and apparent autophagic flux are induced in cells infected with infectious bronchitis virus (IBV) - a gammacoronavirus. Notably, IBV-induced autophagy was dependent on autophagy related 5 (ATG5) but not beclin1 (BECN1), although both are essential proteins in the canonical autophagy pathway. Moreover, the ER stress sensor inositol requiring enzyme 1 (IRE1), but not its substrate X-box protein 1 (XBP1), was also essential for the induction of autophagy during IBV infection. Finally, the anti-apoptotic extracellular signal-regulated kinase 1/2 (ERK1/2) also contributed to IBV-induced autophagy. Our findings add new knowledge to the regulatory mechanisms governing coronavirus-induced autophagy, highlighting an extensive cross-talk among cellular signaling pathways during coronavirus infection.


Assuntos
Autofagia , Infecções por Coronavirus/metabolismo , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Vírus da Bronquite Infecciosa/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Endorribonucleases/genética , Humanos , Vírus da Bronquite Infecciosa/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteínas Serina-Treonina Quinases/genética
20.
J BUON ; 24(2): 449-455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31127990

RESUMO

PURPOSE: To study the effect of transforming growth factor (TGF)-ß1 on apoptosis of colon cancer cells via the ERK signaling pathway. METHODS: Human chemosensitive colon cancer cell line HT- 29 was used in this study. VEGF mRNA and protein level were detected using PCR and western blot. Enzyme-linked immunosorbent assay (ELISA) was used for prostaglandin (PG) detection. Cell proliferation was determined via MTT assay. RESULTS: TGF-ß1 had a significant effect on blocking the cancer cell growth (p<0.05). TGF-ß1 significantly reduced the VEGF mRNA level (p<0.05) and eliminated the COX-2 expression in a dose-dependent manner, while p53 expression was increased (p<0.05). TGF-ß1-induced inhibitory effect on COX-2 was significantly eliminated by the ERK inhibitor Compound C (p<0.05). The basal PGE2 production was eliminated in cells treated with TGF-ß1 (p<0.05). N-acetylcysteine (NAC) treatment almost completely eliminated the reactive oxygen species (ROS) produced by TGF-ß1 and ERK activation. Compared with administration of 5-FU or etoposide alone, TGF-Β1 combined with 5-FU or etoposide significantly administration the viability of colon cancer HT-29 cells. CONCLUSION: ERK is a newly-identified cancer target molecule, which can significantly control COX-2 in colon cancer cells treated with TGF-ß1.


Assuntos
Apoptose/genética , Neoplasias do Colo/genética , Ciclo-Oxigenase 2/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Fator de Crescimento Transformador beta1/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Etoposídeo/farmacologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Espécies Reativas de Oxigênio/metabolismo
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