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1.
Chem Biol Interact ; 319: 109024, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32097614

RESUMEN

Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-ß1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.


Asunto(s)
/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Células A549 , Animales , Antioxidantes/metabolismo , Línea Celular , Línea Celular Tumoral , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Dióxido de Silicio/farmacología
2.
Cell Physiol Biochem ; 54(2): 195-210, 2020 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-32083406

RESUMEN

BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-ß1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-ß1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. METHODS: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. RESULTS: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-ß1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-ß1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. CONCLUSION: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.


Asunto(s)
Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína smad3/metabolismo , Animales , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular , Transición Epitelial-Mesenquimal/efectos de los fármacos , Matriz Extracelular/metabolismo , Humanos , Isoquinolinas/farmacología , Cetonas/farmacología , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Piridinas/farmacología , Pirroles/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Proteína smad3/antagonistas & inhibidores , Proteína smad3/genética , Activación Transcripcional/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
3.
Yakugaku Zasshi ; 140(1): 15-22, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-31902879

RESUMEN

The development of serious lung diseases, such as pulmonary fibrosis, is associated with several drugs. A recent study has shown that the epithelial-mesenchymal transition (EMT) plays an essential role in the development of pulmonary fibrosis. However, the mechanisms underlying drug-induced EMT in alveolar epithelial cells have not been characterized. The present study showed that methotrexate (MTX), a drug known to cause lung injury, induced EMT-like phenotypic changes in an A549 cell model of the alveolar epithelium. We also found that the transforming growth factor (TGF)-ß1-mediated signaling pathway was associated with MTX-induced EMT. In addition, our results showed that certain secreted factors and microRNAs, a class of small noncoding RNAs, may be involved in MTX-induced EMT. The effects of COA-Cl, a novel synthetic small molecule, on TGF-ß1-induced EMT were evaluated to determine the therapeutic potential of COA-Cl against drug-induced lung injury. COA-Cl significantly suppressed TGF-ß1-induced EMT-like phenotypic changes, as evidenced by the inhibition of EMT-related transcription factors. Furthermore, MTX-induced EMT was completely suppressed by co-treatment with folic acid. Thus, these compounds may be promising therapeutic agents against drug-induced lung injury. In conclusion, the present study elucidated mechanisms underlying drug-induced EMT and highlighted a potential novel therapeutic approach to drug-induced lung diseases.


Asunto(s)
Lesión Pulmonar/inducido químicamente , Metotrexato/efectos adversos , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/uso terapéutico , Animales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ácido Fólico/administración & dosificación , Ácido Fólico/uso terapéutico , Humanos , Lesión Pulmonar/tratamiento farmacológico , MicroARNs , Terapia Molecular Dirigida , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta1/fisiología
4.
Anticancer Res ; 40(1): 9-26, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892549

RESUMEN

BACKGROUND/AIM: Inhibition of apoptosis is one of the hallmarks of cancer, and anti-apoptotic genes are often targets of genetic and epigenetic alterations. Cellular inhibitor of apoptosis 2 (cIAP2) has a role in degrading caspases by linking them to ubiquitin molecules, and is upregulated in triple-negative breast cancer (TNBC). Previous studies have demonstrated that cIAP2 may play a role in the epithelial-to-mesenchymal transition (EMT). MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was administered to triple-negative breast cancer (TNBC) cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. RESULTS: The compounds were able to decrease the expression of cIAP2 while increasing the expression of pro-apoptotic caspase 7. There were also changes in histone modifications, suggesting a role of epigenetic mechanisms in these changes in expression of cIAP2. These changes resulted in an increase in apoptosis. SAHA and EGCG were also capable of limiting TNBC cell migration across a fibronectin (FN) matrix. CONCLUSION: SAHA and EGCG reduce the metastatic potential of TNBC by inducing the apoptotic pathway.


Asunto(s)
Apoptosis/efectos de los fármacos , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Catequina/análogos & derivados , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/genética , Vorinostat/farmacología , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Caspasa 7/genética , Caspasa 7/metabolismo , Catequina/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
5.
Life Sci ; 244: 117343, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31978449

RESUMEN

AIMS: Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo. MAIN METHODS: The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model. KEY FINDINGS: In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-ß1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo. SIGNIFICANCE: ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.


Asunto(s)
Proteína ADAM17/antagonistas & inhibidores , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Apoptosis , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Proliferación Celular , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188317, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31669587

RESUMEN

We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Ácido Tióctico/farmacología , Apoptosis/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos
7.
Food Chem Toxicol ; 135: 110915, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31669600

RESUMEN

Fibrogenesis is a common feature for all types of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells is one of the main processes involving renal fibrosis and its inhibition is considered as a preventive/therapeutic strategy for CKD. Trigonelline (TRIG), a plant alkaloid commonly found in herbs, coffee bean, soy bean and other edible food plants, has several beneficial effects on human health and has been proposed to reduce renal fibrosis but with unclear mechanisms. This study thus addressed cellular mechanism underlying the anti-fibrogenic effects of TRIG in renal tubular epithelial cells grown in vitro. EMT was successfully induced by oxalate treatment as indicated by morphological changes into spindle-shape cells, increased expression of mesenchymal proteins (fibronectin, vimentin and α-smooth muscle actin (α-SMA)), decreased expression of epithelial proteins (E-cadherin and zonula occludens-1 (ZO-1)) and increased activity of a profibrotic factor (matrix metalloproteinase-9 (MMP-9)). Interestingly, these oxalate-induced EMT features could be attenuated by TRIG pretreatment. Moreover, TRIG also prevented oxalate-induced cell migration, reactive oxygen species (ROS) overproduction, and down-regulation of Nrf-2 signaling molecule. These data indicated that TRIG could attenuate the effects of oxalate-induced EMT and thus may serve as the anti-fibrotic compound for prevention and/or treatment of CKD.


Asunto(s)
Alcaloides/farmacología , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Oxalatos/efectos adversos , Sustancias Protectoras/farmacología , Actinas/metabolismo , Animales , Cadherinas/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perros , Células Epiteliales/metabolismo , Fibronectinas/metabolismo , Células de Riñón Canino Madin Darby , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Vimentina/metabolismo , Proteína de la Zonula Occludens-1/metabolismo
8.
Toxicol Lett ; 320: 37-45, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31778776

RESUMEN

As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 µM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.


Asunto(s)
Benzo(a)pireno/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/metabolismo , Células A549 , Antígenos CD/genética , Antígenos CD/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Invasividad Neoplásica , ARN Largo no Codificante/genética , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia Arriba
9.
Life Sci ; 241: 117139, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31809714

RESUMEN

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious lung problem with advancing and diffusive pulmonary fibrosis as the pathologic basis, and with oxidative stress and inflammation as the key pathogenesis. Glycyl-L-histidyl-l-lysine (GHK) is a tripeptide participating into wound healing and regeneration. GHK-Cu complexes improve GHK bioavailability. Thus, the current study aimed to explore the therapeutic role of GHK-Cu on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. METHODS: BLM (3 mg/kg) was administered via tracheal instillation (TI) to induce a pulmonary fibrosis model in C57BL/6j mice 21 days after the challenge of BLM. GHK-Cu was injected intraperitoneally (i.p.) at different dosage of 0.2, 2 and 20 µg/g/day in 0.5 ml PBS on alternate day. The histological changes, inflammation response, the collagen deposition and epithelial-mesenchymal transition (EMT) was evaluated in the lung tissue. EMT was evaluated by ɑ-SMA and fibronectin expression in the lung tissue. NF-κB p65, Nrf2 and TGFß1/Smad2/3 signalling pathways were detected by immunoblotting analysis. RESULTS: GHK-Cu complex inhibited BLM-induced inflammatory and fibrotic pathological changes, alleviated the inflammatory response in the BALF by reducing the levels of the inflammatory cytokines, TNF-ɑ and IL-6 and the activity of MPO as well as reduced collagen deposition. In addition, the GHK-Cu treatment significantly reversed the MMP-9/TIMP-1 imbalance and partially prevented EMT via Nrf2, NF-κB and TGFß1 pathways, as well as Smad2/3 phosphorylation. CONCLUSIONS: GHK-Cu presented a protective effect in BLM-induced inflammation and oxidative stress by inhibiting EMT progression and suppressing TGFß1/Smad2/3 signalling in pulmonary fibrosis.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Bleomicina/toxicidad , Cobre/administración & dosificación , Oligopéptidos/administración & dosificación , Fibrosis Pulmonar/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/toxicidad , Colágeno/metabolismo , Cobre/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Oligopéptidos/química , Estrés Oxidativo/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología
10.
Cancer Sci ; 111(1): 59-71, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31729097

RESUMEN

Low vitamin D status is associated with progression in patients with renal cell carcinoma (RCC). The present study found that vimentin, a mesenchymal marker, was accordingly upregulated, and E-cadherin, an epithelial marker, was downregulated in RCC patients with low vitamin D status. Thus, we investigated the effects of calcitriol or vitamin D3, an active form of vitamin D, on epithelial-mesenchymal transition (EMT) in RCC cells. RCC cells were treated by two models. In model 1, three RCC cell lines, ACHN, 786-O and CAKI-2, were incubated with either LPS (2.0 µg/mL) or transforming growth factor (TGF)-ß1 (10 ng/mL) in the presence or absence of calcitriol (200 nmol/L). In model 2, two RCC cell lines, ACHN and CAKI-2, were incubated with calcitriol (200 nmol/L) only. Calcitriol inhibited migration and invasion not only in TGF-ß1-stimulated but also in TGF-ß1-unstimulated RCC cells. Moreover, calcitriol suppressed E-cadherin downregulation and vimentin upregulation not only in TGF-ß1-stimulated but also in TGF-ß1-unstimulated ACHN and CAKI-2 cells. Calcitriol attenuated LPS-induced upregulation of MMP-2, MMP-7, MMP-9, MMP-26 and urokinase-type plasminogen activator (u-PA) in ACHN cells. In addition, calcitriol blocked TGF-ß1-induced nuclear translocation of ZEB1, Snail and Twist1 in ACHN and CAKI-2 cells. Mechanistically, calcitriol suppressed EMT through different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF-ß1-stimulated RCC cells; (ii) calcitriol inhibited signal transducer and activator of transcription (STAT)3 activation in LPS-stimulated RCC cells; (iii) calcitriol inhibited ß-catenin/TCF-4 activation by promoting integration of VDR with ß-catenin in TGF-ß1-unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells partially by suppressing Smad2/3-, STAT3- and ß-catenin-mediated EMT.


Asunto(s)
Calcitriol/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Adulto , Anciano , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Renales/metabolismo , Masculino , Metaloendopeptidasas/metabolismo , Persona de Mediana Edad , Factor de Transcripción STAT3/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , beta Catenina/metabolismo
11.
Life Sci ; 241: 117108, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31786192

RESUMEN

AIMS: Telmisartan (TLM), a highly selective angiotensin II type 1 receptor blocker (ARB) and partial PPAR-γ agonist, has versatile beneficial effects against oxidative stress, apoptosis, inflammatory responses and epithelial-mesenchymal transition (EMT). However, its underlying mechanism of inhibiting oxalate and calcium oxalate (CaOx) crystal-induced EMT by activating the PPAR-γ pathway remains unclear. MAIN METHODS: CCK-8 assays were used to evaluate the effects of TLM on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were measured by the cell-permeable fluorogenic probe 2,7-dichlorofluorescein diacetate (DCFH-DA). Wound-healing and Transwell assays were used to evaluate the migration ability of HK2 cells exposed to oxalate. Moreover, immunofluorescence, immunohistochemistry and western blotting were used to examine the expression of E-cadherin, N-cadherin, vimentin and α-SMA and explore the underlying molecular mechanisms in HK2 cells and a stone-forming rat model. KEY FINDINGS: Our results showed that TLM treatment could protect HK2 cells from oxalate-induced cytotoxicity and oxidative stress injury. Additionally, TLM prevented EMT induction by oxalate and CaOx crystals via the PPAR-γ-AKT/STAT3/p38 MAPK-Snail pathway in vitro and in vivo. However, knockdown of PPAR-γ with small interfering RNA or the PPAR-γ-specific antagonist GW9662 abrogated these protective effects of TLM. SIGNIFICANCE: As a PPAR-γ agonist, TLM can ameliorate oxalate and CaOx crystal-induced EMT by exerting an antioxidant effect through the PPAR-γ-AKT/STAT3/p38 MAPK-Snail signaling pathway. Therefore, TLM can block EMT progression and could be a potential therapeutic agent for preventing and treating calcium oxalate urolithiasis formation and recurrence.


Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Oxalatos/toxicidad , PPAR gamma/metabolismo , Telmisartán/farmacología , Animales , Oxalato de Calcio/toxicidad , Línea Celular , Transición Epitelial-Mesenquimal/fisiología , Humanos , Túbulos Renales/citología , Masculino , Estrés Oxidativo/efectos de los fármacos , PPAR gamma/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Crecimiento Transformador beta1/toxicidad , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
12.
Toxicol Lett ; 318: 22-29, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31634547

RESUMEN

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R3SnX (R is butyl or phenyl, X is isothiocyanate), which are considered RXR ligands, were investigated in the human MDA-MB-231 breast cancer cell line. Studies were evaluated in the presence and absence of all-trans retinoic acid (ATRA), a natural RAR ligand. Vimentin represents the major protein associated with epithelial-mesenchymal transition (EMT), an essential process when the primary tumour transforms into a malignant one. mRNA and proteomic data obtained in this study, based on the PDQuest software protein evaluation and further quantification of proteins by iTRAQ analysis, suggest that vimentin was significantly reduced in the combination of RAR ligand and RXR ligand treatment. Both tested triorganotin compounds showed similarly reduced expression of vimentin, but tributyltin isothiocyanate (TBT-ITC) proved to be more effective than triphenyltin isothiocyanate (TPT-ITC). Furthermore, the effect of natural (9cRA) and synthetic RXR ligands, both chloride and isothiocyanate derivatives, on vimentin expression was compared.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteómica/métodos , Receptores X Retinoide/agonistas , Compuestos de Trialquiltina/farmacología , Vimentina/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Regulación hacia Abajo , Electroforesis en Gel Bidimensional , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Compuestos Orgánicos de Estaño/farmacología , Receptores X Retinoide/metabolismo , Transducción de Señal/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Tretinoina/farmacología
13.
Chem Biol Interact ; 316: 108926, 2020 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-31874164

RESUMEN

Grape seed proanthocyanidin extract (GSPE) has been reported to exhibit a variety of protective effects, such as antioxidant, anti-atherosclerosis and other pharmacological effects. As a member of the complement system, complement component 3 (C3) deposition in the glomerulus is recognized as an important causative mediator of various kidney diseases. In this study, we aimed to identify the effect of GSPE on C3 in the chronic kidney fibrosis and evaluate the possible mechanism. We observed that administration of GSPE relieves inflammation and chronic renal fibrosis in mouse models of UUO. GSPE inhibited C3 secreted by macrophages to relieve renal interstitial inflammation. In vitro, we found that C3 stimulated HMGB1 translocation form nucleus to cytoplasm and promote the expression of pro-inflammatory cytokines including TGF-ß1 in primary renal tubular epithelial cells (PTEC), which could be inhibited by GSPE. Meanwhile, GSPE could also decreased HMGB1-induced EMT of PTEC through suppresses the HMGB1/TLR4/p65/TGF-ß1 pathway. In addition, the myofibroblast activation was inhibited by GSPE via TGF-ß1/Smad2/3 signaling pathways in normal rat kidney fibroblast (NRK-49F) cells. Overall, these observations provide that GSPE alleviates renal fibrosis by inhibiting the C3/HMGB1/TGF-ß1 pathway and could thus lead to find the potential therapy for the suppression of renal fibrosis.


Asunto(s)
Extracto de Semillas de Uva/farmacología , Riñón/efectos de los fármacos , Proantocianidinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Células Cultivadas , Complemento C3/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis , Extracto de Semillas de Uva/uso terapéutico , Proteína HMGB1/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/prevención & control , Túbulos Renales/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Proantocianidinas/uso terapéutico , Ratas , Factor de Crecimiento Transformador beta1/metabolismo
14.
Int J Nanomedicine ; 14: 9665-9675, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31824158

RESUMEN

Purpose: Vitamin D is a novel potential therapeutic agent for peritoneal dialysis (PD)-related peritoneal fibrosis, but it can induce hypercalcemia and vascular calcification, which limits its applicability. In this study, we create nanotechnology-based drug delivery systems to investigate its therapeutics and side effects. Materials and methods: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) and L-α-phosphatidylcholine (PC), which packages with 1α,25(OH)2D3, were used to construct vitamin D nanoliposomes. To confirm the function and safety of vitamin D nanoliposomes, peritoneal mesothelial cells were treated with TGF-ß1 and the reverse was attempted using vitamin D nanoliposomes. Antibodies (Ab) against the peritoneum-glycoprotein M6A (GPM6A) Ab were conjugated with vitamin D nanoliposomes. These particles were implanted into mice by intraperitoneal injection and the animals were monitored for the distribution and side effects induced by vitamin D. Results: Vitamin D nanoliposomes were taken up by the mesothelial cells over time without cell toxicity and it also provided the same therapeutic effect in vitro. In vivo study, fluorescent imaging showed vitamin D nanoliposomes allow specific peritoneum target effect and also ameliorate vitamin D side effect. Conclusion: Nanoliposomes vitamin D delivery systems for the prevention of PD-related peritoneal damage may be a potential clinical strategy in the future.


Asunto(s)
Nanomedicina , Diálisis Peritoneal/efectos adversos , Peritoneo/patología , Vitamina D/farmacología , Animales , Anticuerpos/farmacología , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Liberación de Fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Cinética , Liposomas , Ratones , Nanopartículas/química , Nanopartículas/ultraestructura , Peritoneo/efectos de los fármacos , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Factor de Crecimiento Transformador beta1/metabolismo
15.
Biochemistry (Mosc) ; 84(11): 1424-1432, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31760928

RESUMEN

A large body of evidence suggests that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), as well as expression and function of retinoid receptors, are pivotal features of tumor initiation, progression, and chemoresistance. This is also true for pancreatic ductal adenocarcinoma (PDAC), which represents a clinical challenge due to poor prognosis and increasing incidence. Understanding the above features of cancer cells could open new avenues for PDAC treatment strategies. The aim of this study was to investigate the relation between CSCs, EMT, and retinoid receptors in PDAC after treatment with the chemotherapeutic agents - gemcitabine and 5-fluorouracil. First, we demonstrated the difference in the expression levels of CSC and EMT markers and retinoid receptors in the untreated Mia PaCa-2 and Panc1 cells that also differed in the frequency of spontaneous apoptosis and distribution between the cell cycle phases. Chemotherapy reduced the number of cancer cells in the S phase. Gemcitabine and 5-fluorouracil modulated expression of CSC markers, E-cadherin, and RXRß in Panc1 but not in Mia PaCa-2 cells. We suggest that these effects could be attributed to the difference in the basal levels of expression of the investigated genes. The obtained data could be interesting in the context of future preclinical research.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor beta X Retinoide/metabolismo , Apoptosis/efectos de los fármacos , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Fluorouracilo/farmacología , Humanos , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Receptor beta X Retinoide/genética , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos
16.
J Agric Food Chem ; 67(50): 13939-13947, 2019 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-31769973

RESUMEN

The effect of a novel semi-natural derivative of naringenin, 6-C-(E-phenylethenyl)naringenin (6-CEPN) on hepatocellular carcinoma (HCC) stemness was evaluated both in vitro and in vivo. 6-CEPN reduced HCC cell viability, inhibited sphere formation, cell migration and invasion, and blocked epithelial-mesenchymal transition. It was equally effective against NANOG+ cells sorted from cultured HCC cells that was accompanied by downregulation of stemness-associated transcription factors and attenuated HIF-1 activity. Furthermore, 6-CEPN significantly enhanced the sensitivity of HCC cells to therapeutic drugs, and inhibited HCC tumor growth and lung metastasis of HCC cells. 6-CEPN suppressed Wnt/ß-catenin signaling by inducing ß-catenin degradation and inhibiting its nuclear translocation. Upregulation of GSK3ß appeared to be crucial for 6-CEPN's inhibitory activity in the signaling pathway. These findings indicate that 6-CEPN has a strong effect against liver cancer, which is mediated, at least in part, by suppressing the stemness of HCC cells through an action mechanism involving Wnt/ß-catenin signaling.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Autorrenovación de las Células/efectos de los fármacos , Flavanonas/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , beta Catenina/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatología , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatología , Ratones , Ratones Endogámicos BALB C , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/genética
17.
Adv Clin Exp Med ; 28(11): 1441-1450, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31778596

RESUMEN

BACKGROUND: Human cytomegalovirus (HCMV) infection is one of the risk factors of cardiovascular disease; the most important pathological change is the change of vascular endothelial cell (VEC) function, but its mechanism is still unclear. Transforming growth factor ß1 (TGF-ß1) is an important cytokine associated with fibrosis; it can induce the occurrence of endothelial mesenchymal transition (EndMT) in VECs, which means endothelial cells acquire the characteristics and phenotypes of mesenchymal cells and secrete molecules associated with the deposition and remodeling of the extracellular matrix. Many in vivo and in vitro studies have shown that HCMV infection promotes the secretion and activation of TGF-ß1. OBJECTIVES: This study aims to observe the changes of endothelial cells after HCMV infection and EndMT occurrence induced by TGF-ß1 and to explore the possible mechanism of HCMV infection in the pathogenesis of cardiovascular disease. MATERIAL AND METHODS: Immunofluorescence staining, reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunoprecipitation methods were used in this study to analyze the changes in morphology and gene expression. RESULTS: We found that EndMT-related morphological and gene expression changes occurred in human umbilical vein endothelial cells (HUVECs) infected and uninfected with HCMV after treatment with TGF-ß1. Human umbilical vein endothelial cells infected with HCMV, which are treated with TGF-ß1, can activate the extracellular potential TGF-ß1 by activating matrix metalloproteinase 2 (MMP-2). CONCLUSIONS: Our findings provide a molecular basis for the association between HCMV infection, TGF-ß1 and cardiovascular disease.


Asunto(s)
Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus , Transición Epitelial-Mesenquimal , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Metaloproteinasa 2 de la Matriz , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Venas Umbilicales/metabolismo , Venas Umbilicales/virología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Infecciones por Citomegalovirus/diagnóstico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Transducción de Señal
18.
BMC Complement Altern Med ; 19(1): 290, 2019 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-31666058

RESUMEN

BACKGROUND: Nigella sativa or commonly known as black seed or black cumin is one of the most ubiquitous complementary medicine. Epithelial to mesenchymal transition (EMT) of type 2 is defined by the balance between wound healing and tissue fibrosis, which is dependent to the state of inflammation. This systematic review is conducted to provide an overview regarding the reported effect of Nigella sativa and its bioactive compound on the type 2 EMT. METHODS: A search was done in EBSCOHOST, OVID and SCOPUS database to obtain potentially relevant articles that were published between 1823 and August 2019. This review includes studies that focus on the effect of Nigella sativa and its bioactive compound on the events related to type 2 EMT. RESULTS: A total of 1393 research articles were found to be potentially related to the effect of Nigella sativa and its bioactive compound, thymoquinone on Type 2 EMT. After screening was done, 22 research articles met inclusion criteria and were included in this review. Majority of the studies, reported better wound healing rate or significant prevention of tissue inflammation and organ fibrosis following Nigella sativa or thymoquinone treatments. In terms of wound healing, studies included reported progression of EMT related pathological changes after treatment with Nigella sativa or thymoquinone. Alternatively, in terms of fibrosis and inflammation, studies included reported reversal of pathological changes related to EMT after treatment with Nigella sativa or thymoquinone. CONCLUSION: Through this review, Nigella sativa and thymoquinone have been associated with events in Type 2 EMT. They have been shown to promote wound healing, attenuate tissue inflammation, and prevent organ fibrosis via regulation of the EMT process.


Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Nigella sativa/química , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Heridas y Traumatismos/tratamiento farmacológico , Animales , Benzoquinonas/análisis , Benzoquinonas/uso terapéutico , Humanos , Fitoterapia , Resultado del Tratamiento , Heridas y Traumatismos/fisiopatología
19.
Invest Ophthalmol Vis Sci ; 60(14): 4748-4758, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31731295

RESUMEN

Purpose: Lens fibrosis involves aberrant growth, migration, and transforming growth factorß (TGFß)-induced epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). In this study, we investigated the role of the bromo- and extra-terminal domain (BET) inhibitor in lens fibrotic disorder to identify drug-based therapies. Methods: Rat lens explants, rabbit primary lens epithelial cells (rLECs), human lens explants and human SRA01/04 cells were treated with TGFß2 in the presence or absence of the BET bromodomain inhibitor JQ1 or the MYC inhibitor 10058-F4. Proliferation was determined by MTS assay. Cell migration was measured by wound healing and transwell assays. The expression levels of fibronectin (FN), α-smooth muscle actin (α-SMA), E-cadherin, and phosphorylated downstream Smads were analyzed by Western blot, qRT-PCR, and immunocytochemical experiments. Transcriptome analysis was conducted to explore the molecular mechanism. Results: Blockage of BET bromodomains with JQ1 significantly suppressed rLECs proliferation by inducing G1 cell cycle arrest. Furthermore, JQ1 attenuated TGFß2-dependent upregulation of mesenchymal gene expression and phosphorylation of Smad2/3 during the progression of EMT, whereas E-cadherin expression was preserved. JQ1 repressed MYC expression, which was dose- and time-dependently upregulated by TGFß2. Inhibiting MYC with either the small-molecule inhibitor 10058-F4 or genetic knockdown phenocopied the effects of JQ1 treatment. MYC overexpression partially reversed the JQ1-regulated EMT-related alteration of gene expression. Both JQ1 and 10058-F4 blocked the expression of TGFß receptor II and integrin αv in rLECs and abolished TGFß2-induced opacification and subcapsular plaque formation in rat lens explants. Conclusions: Our results demonstrate the antifibrotic role of JQ1 in maintaining the epithelial characteristics of LECs and blocking TGFß2-induced EMT, possibly by downregulating MYC, thereby providing new avenues for treating lens fibrosis.


Asunto(s)
Azepinas/farmacología , Regulación hacia Abajo , Células Epiteliales/efectos de los fármacos , Cristalino/patología , Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Triazoles/farmacología , Actinas/metabolismo , Adulto , Animales , Western Blotting , Cadherinas/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibronectinas/metabolismo , Fibrosis/prevención & control , Humanos , Conejos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Tiazoles/farmacología , Factor de Crecimiento Transformador beta2/antagonistas & inhibidores , Factor de Crecimiento Transformador beta2/farmacología
20.
Chem Biol Interact ; 314: 108846, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31606474

RESUMEN

Matrix metalloproteinases (MMPs) have been implicated in EMT but their role in the regulation of cigarette smoke-induced EMT in airway epithelium is not clear. We have therefore investigated the potential role of MMP-2 and -9 in cigarette smoke extract (CSE) induced EMT using A549 lung epithelial cells and human small airway epithelial cells (SAEC). The cells were treated with different concentration of CSE, and MTT and trypan blue assays, acridine orange-ethidium bromide assay, gelatin zymography, Western blotting, immunofluorescence studies, Boyden-chamber assay, wound healing assay and air-liquid interface (ALI) culture were used to assess different cellular and molecular changes associated with EMT. The results depict that CSE increased the cytotoxicity along with a concurrent increase in the expression and activity of MMP-2 and -9. CSE further altered EMT markers like E-cadherin, N-cadherin, vimentin, and the molecular modulators of EMT such as ß-catenin and pGSK-3ß. Further, CSE also upregulated EGFR, AKT, and ERK1/2 in airway epithelial cells. SB-3CT, a known inhibitor of MMP-2 and -9, altered and reversed the expression of markers of EMT and kinases, validating the role of MMP-2 and -9 in CSE-induced EMT. Fisetin, a plant-derived bioflavonoid, also reversed the expression of EMT markers and molecular regulators in a similar fashion as SB-3CT. In summary, this study highlights the role of MMP-2 and -9 in CSE-induced EMT and curate its molecular cascade through EGFR/AKT/ERK/ß-catenin axis, which could be restored by MMP-2 and -9 inhibitor and fisetin. Fisetin is hitherto unknown to modulate CSE-induced MMPs activity in airway epithelial cells, and our study suggests its potential role as a therapeutic approach in CSE-induced EMT in lung epithelial cells.


Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Flavonoides/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Transducción de Señal/efectos de los fármacos , Humo/efectos adversos , Tabaco/química , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Receptores ErbB/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismo
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