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1.
Drug Discov Ther ; 14(2): 107-108, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321878

RESUMO

The recent clinical trial reports pertaining to the efficacy of chloroquine and hydroxychloroquine against COVID-19 albeit yet to be validated with larger clinical trials, have sparked much interest globally to evaluate whether this anti-malarial drug can be repurposed for the treatment of COVID-19. In addition to its anti-viral activity, the anti-inflammatory activity of chloroquine may also contribute to its efficacy. Based on our data obtained from an animal infection model of melioidosis (a disease caused by the bacteria Burkholderia pseudomallei), treatment with chloroquine can result in the phosphorylation and consequent inhibition of glycogen synthase kinase-3ß (GSK3ß). This serine/threonine protein kinase is now recognised as a point of convergence for host inflammatory response. In view of this, it is plausible that the mechanism for the anti-inflammatory effect of chloroquine against COVID-19 involves inhibition of host GSK3ß.


Assuntos
Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Modelos Animais de Doenças , Melioidose/tratamento farmacológico , Pandemias , Fosforilação
2.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 763-771, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32347070

RESUMO

The recombinant adenoviruses expressing miR-22 (Ad-miR-22) was constructed and the effect of Ad-miR-22 on insulin signal pathway and glucose uptake in HepG2 cells was analyzed. MiR-22 gene was amplified by PCR from human hepatocytes and cloned into the pAdTrack-CMV vector to generate the shuttle plasmid pAdT-22. The positive colonies were confirmed by PCR and sequencing. The resultant shuttle plasmid was linearized with Pme I, followed by co-transformation into competent BJ5183 cells containing an adenoviral backbone plasmid (pAdEasy-1) to create the recombinant plasmid pAd-miR-22. After digested with Pac I, the linearized pAd-miR-22 was transfected into 293A packaging cell line to generate recombinant adenoviruses Ad-miR-22. HepG2 cells were infected with Ad-miR-22 or control Ad-GFP (adenoviruses expressing green fluorescent protein), and then the miR-22 expression levels were analyzed by qPCR. The result shows that adenovirus-mediated overexpression of miR-22 significantly decreased insulin-induced glucose uptake in HepG2 cells. Moreover, overexpression of miR-22 markedly decreased insulin-induced phosphorylation of GSK-3ß. miR-22 also increased the mRNA levels of gluconeogenic genes in HepG2 cells. Furthermore, Western blotting results indicate that the protein expression of SIRT1 decreased in Ad-miR-22 infected HepG2 cells as compared with Ad-GFP infected HepG2 cells. In summary, overexpressing of miR-22 significantly increased gluconeogenesis while decreased glucose uptake in HepG2 cells. The effect of miR-22 on glucose metabolism may be mediated by SIRT1.


Assuntos
Adenoviridae , Glucose , MicroRNAs , Adenoviridae/genética , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais/genética , Transfecção
3.
Nat Cell Biol ; 22(4): 389-400, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231305

RESUMO

In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/ß and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/ß and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/ß and stabilize ß-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas do Tecido Nervoso/genética , Receptores de Netrina/genética , Netrina-1/genética , Receptores de Superfície Celular/genética , Via de Sinalização Wnt/genética , Animais , Linhagem Celular , Embrião de Mamíferos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina/metabolismo , Netrina-1/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores de Superfície Celular/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
4.
Life Sci ; 249: 117535, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151688

RESUMO

AIM: Schizophrenia is a chronic, disabling and one of the major neurological illnesses affecting nearly 1% of the global population. Currently available antipsychotic medications possess limited effects. The current research aimed at investigating potential therapeutic add-on benefit to enhance the effects of clozapine anti-schizophrenic. MAIN METHODS: To induce schizophrenia, ketamine was administered at a dose of 25 mg/kg i.p. for 14 consecutive days. Naringin was administered to Wistar rats at a dose of 100 mg/kg orally, alone or in combination with clozapine 5 mg/kg i.p from day 8 to day 14. Furthermore, behavioral tests were conducted to evaluate positive, negative and cognitive symptoms of schizophrenia. In addition, neurotransmitters' levels were detected using HPLC. Moreover, oxidative stress markers were assessed using spectrophotometry. Furthermore, apoptotic and wnt/ß-catenin pathway markers were determined using western blotting (Akt, GSK-3ß and ß-catenin), colorimetric methods (Caspase-3) and immunohistochemistry (Bax, Bcl2 and cytochrome c). KEY FINDINGS: Ketamine induced positive, negative and cognitive schizophrenia symptoms together with neurotransmitters' imbalance. In addition, ketamine treatment caused significant glutathione depletion, lipid peroxidation and reduction in catalase activity. Naringin and/or clozapine treatment significantly attenuated ketamine-induced schizophrenic symptoms and oxidative injury. Additionally, ketamine provoked apoptosis via increasing Bax/Bcl2 expression, caspase-3 activity, and Cytochrome C and Akt protein expression while naringin/clozapine treatment significantly inhibited this apoptotic effect. Moreover, naringin activated the neurodevelopmental wnt/ß-catenin signaling pathway evidenced by increasing pGSK-3ß and reducing pß-catenin protein expression. SIGNIFICANCE: These findings may suggest that naringin possesses a potential therapeutic add-on effect against ketamine-induced schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Flavanonas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ketamina/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esquizofrenia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Clozapina/administração & dosagem , Clozapina/farmacologia , Clozapina/uso terapêutico , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Flavanonas/uso terapêutico , Masculino , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente
5.
Zhen Ci Yan Jiu ; 45(3): 202-8, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32202711

RESUMO

OBJECTIVE: To explore the mechanism of electroacupuncture (EA) underlying improvement of cerebral infarction (CI) by investigating its influence on expression of cerebral Wnt7a, lymphoid enhancer factor-1 (LEF1), glycogen synthase kinase 3ß(GSK-3ß) and Dickkopf-1(DKK1) mRNA and proteins in CI rats. METHODS: A total of 280 male Wistar rats were randomly divided into blank control (n=10), sham-operation, model and EA groups,and 90 rats of the last 3 groups were further divided into 1, 3, 6, 9, 12 and 24 h, and 3, 7 and 12 d subgroups with 10 rats in each subgroup. The CI model was established by occlusion of the middle cerebral artery (MCAO). The sham-operation group received the same surgical operation but without thread embolus insertion. EA (2 Hz/15 Hz, 2 mA) was applied to "Shuigou" (GV26) for 20 min, once a day for 1, 3, 7 and 12 d, respectively. The neurological deficit was evaluated by using Neurological Severity Scores (NSS). The expression levels of Wnt7a,LEF1, GSK-3ß and DKK1 mRNAs and proteins in the right ischemic brain tissues were detected by Quantative real-time PCR and Western blot, respectively. RESULTS: After MCAO, the NSS score was significantly increased in the model and EA groups relevant to the blank control and sham-operation groups (P<0.01) and gradually decreased with the prolongation of ischemia time. After EA, the NSS scores were notably decreased on day 3, 7 and 12 in the EA group compared with the model group (P<0.05, P<0.01). After modeling, the expression levels of Wnt7a and LEF1 mRNAs from 3 h to 12 d, Wnt7a and LEF1 proteins from 6 h to 12 d were considerably increased (P<0.01, P<0.05), while those of GSK-3ß mRNA at 9, 12 and 24 h, GSK-3ß protein at 24 h and 3 d, and DKK1 mRNA at 24 h and 3 d and DKK1 protein at 3 d were obviously decreased in the model group relevant to the sham-operation group (P<0.05, P<0.01). After the intervention, the expression levels of Wnt7a mRNA at 12 h to 3 d, Wnt7α protein from 24 h to 12 d, LEF1 mRNA from 24 h to 12 d, and LEF1 protein from 3 d to 12 d were further apparently up-regulated (P<0.01, P<0.05), while those of GSK-3ß mRNA at 9 h, 3,7 and 12 d, and GSK-3ß protein at 12 h, 7 d and 12 d, and DKK1 mRNA at 12 h, 24 h and 3 d, and DKK1 protein at 24 h to 12 d were obviously down-regulated in the EA group relevant to the model group (P<0.01, P<0.05). No significant difference was found between the blank and sham-operation groups in the NSS scores and expression levels of Wnt7a, LEF1, GSK-3ß and DKK1 mRNAs and proteins at all the time points (P>0.05). CONCLUSION: EA of GV26 can significantly improve the neurological deficit symptoms in MCAO rats, which may be associated with its effects in up-regulating the expression of Wnt7a and LEF1 mRNAs and proteins, and in down-regulating the expression of GSK-3ß and DKK1 mRNAs and proteins.


Assuntos
Isquemia Encefálica , Eletroacupuntura , Animais , Encéfalo , Infarto Cerebral , Glicogênio Sintase Quinase 3 beta , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Via de Sinalização Wnt
6.
Zhonghua Gan Zang Bing Za Zhi ; 28(1): 43-46, 2020 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-32023698

RESUMO

Objective: To investigate the differential expression of serum-and-glucocorticoid-inducible-kinase-2 (SGK2) in hepatocellular carcinoma (HCC) and normal liver tissues and the related mechanism mediating signal transduction of GSK-3 ß / ß catenin in HCC cells. Methods: Twenty pairs of matched HCC and normal tissues were collected and the situation of expression of SGK2 mRNA was detected by real-time fluorescence quantitative PCR. Western blot was used to detect the levels of SGK2 protein in human HCC cell lines (Huh-7, SMMC-7721) and normal human liver cell line (L02). SGK2 siRNA was used to transfect human HCC cell lines (SMMC-7721 and Huh-7), and then the protein expression levels of GSK-3 ß/ ß - catenin was successfully detected with the above-mentioned transfected cell line by western blot. Measurement data were expressed as mean ± standard deviation (x±s), and the Student t -test was used as the statistical method. Results: SGK2 mRNA expression was up-regulated in all 20 HCC samples than that of the expression of matched normal liver tissues. SGK2 protein levels were significantly higher in Huh-7 and SMMC-7721 than normal human liver cell lines (P < 0.01). The downregulation of SGK2 expression in human HCC cell lines (SMMC-7721 and Huh-7) had inhibited the expression of unphosphorylated GSK-3 ß. In addition, the downregulation of SGK2 expression in HCC cell lines had decreased the dephosphorylation of ß - catenin to prevent degradation of the ß - catenin proteasome. Conclusion: SGK2 is overexpressed in HCC and mediates GSK-3ß/ß- catenin signaling in HCC cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Linhagem Celular Tumoral , Glucocorticoides , Quinase 3 da Glicogênio Sintase , Glicogênio Sintase Quinase 3 beta , Humanos , Transdução de Sinais , beta Catenina
7.
Adv Clin Exp Med ; 29(1): 135-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011832

RESUMO

BACKGROUND: Anesthetics, such as isoflurane, sevoflurane, ketamine, and desflurane, are commonly used in clinics. Specifically, isoflurane is one of the most commonly used inhalational anesthetics, which can be used in surgery patients of all ages, including children. OBJECTIVES: The aim of the study was to investigate the mechanisms of vitexin against isoflurane-induced neurotoxicity. MATERIAL AND METHODS: Reference memory testing was performed for 5 days (4 trials, 2 per day) before anesthesia. Reversal testing was performed on the 3rd day after anesthesia. The cell viability and apoptosis of PC-12 cells were detected using MTT and TUNEL assays, respectively. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure serum tumor necrosis factor α (TNF­α), interleukin 6 (IL­6), glutathione (GSH), and superoxide dismutase (SOD) concentrations. The concentration of reactive oxygen species (ROS) was detected using ROS measurement. Expression of miR-409 was determined using quantitative reverse-transcription polymerase chain reaction (qPT-PCR). Protein expression levels were detected using western blotting. RESULTS: Rats treated with isoflurane showed significant increases in the escape latency periods (ELP) and the apoptosis of hippocampus neuron cells; this effect was reversed by 3 mg/kg or 10 mg/kg of vitexin (p < 0.05). Further testing showed that isoflurane could significantly decrease the cell viability and increase the apoptosis of PC-12, the expression of inflammatory cytokines (TNF­α and IL­6) and ROS (p < 0.05). However, these results were reversed by 10/100 µM of vitexin. In addition, vitexin could significantly increase the expression of miR-409 (p < 0.05). Further studies showed that overexpression of miR-409 could significantly promote the effect of vitexin on isoflurane-induced neurotoxicity (p < 0.05). Finally, overexpression miR-409 could significantly increase the expression of p-AMPK/t-AMPK and p-GSK3ß/t-GSK3ß. CONCLUSIONS: Vitexin has protective effects against isoflurane-induced neurotoxicity by targeting miR-409 and the AMPK/GSK3ß pathway.


Assuntos
Anestésicos Inalatórios , Apigenina/farmacologia , Isoflurano/farmacologia , MicroRNAs/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP , Animais , Apoptose/efeitos dos fármacos , Criança , Ensaio de Imunoadsorção Enzimática , Glutationa/sangue , Glicogênio Sintase Quinase 3 beta , Humanos , Interleucina-6/sangue , MicroRNAs/genética , Ratos , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/sangue , Fator de Necrose Tumoral alfa/sangue
8.
Anticancer Res ; 40(2): 653-664, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014906

RESUMO

BACKGROUND/AIM: Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial biogenesis and metabolism. We investigated the effect of PGC-1α knockdown in the human colorectal cancer cell line SW620, which highly expresses PGC-1α. MATERIALS AND METHODS: We established the PGC-1α shRNA-silenced SW620 stable cell line (PGC-1α shRNA-SW620 cells) and examined cell proliferation by cell counts and carboxyfluorescein succinimidyl ester (CFSE) staining, migration by wound-healing and transwell migration assay, and invasion by transwell assays. RESULTS: PGC-1α knockdown inhibited cell proliferation, migration, and invasion in SW620 cells. Western blot analysis showed that p-AKT, p-GSK-3ß, ß-catenin, N-cadherin and vimentin expression were all reduced, but E-cadherin had increased expression in PGC-1α shRNA-SW620 cells. We also examined cell proliferation, migration, invasion and the expression of p-AKT, p-GSK-3ß, ß-catenin, N-cadherin, vimentin, and E-cadherin in PGC-1α overexpressing SW480 cells (a low PGC-1α expressing line). We observed a complete reversal of the results seen in the knockdown. CONCLUSION: PGC-1α might regulate cell proliferation and invasion via AKT/GSK-3ß/ß-catenin pathway in SW620 and SW480 cells.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Técnicas de Silenciamento de Genes , Humanos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais , Transfecção
9.
Life Sci ; 245: 117328, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954162

RESUMO

AIMS: Atrial fibrosis is a common feature of atrial fibrillation (AF). Recently, it is reported that osteopontin (OPN) can induce fibrosis in lungs, livers and kidneys. However, its role in atrial fibrosis remains unclear. Here, we sought to determine the involvement of OPN in atrial fibrosis and the underlying mechanisms during this pathological remodeling process. MATERIALS AND METHODS: Protein expressions were determined by enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining and immunoblotting. mRNA expressions were detected by qRT-PCR. Cell proliferation was assessed by CCK-8. Left atrial electroanatomical voltage maps were created using PentaRay catheters and a 3-dimensional mapping system. KEY FINDINGS: OPN was highly expressed in the circulation of AF patients and was further increased with the progression of AF. In addition, correlation analysis showed that circulating OPN positively related with low-voltage areas (LVAs, a marker of atrial fibrosis) in AF patients. Immunohistological staining and immunoblotting revealed an increased expression of OPN in AF patients who present a higher degree of atrial fibrosis. Furthermore, in vitro studies in cultured human atrial fibroblasts (hAFs) demonstrated that OPN promoted the proliferation of fibroblasts and increased production of collagen I and fibronectin. Mechanistically, the profibrotic effects of OPN on atrial fibroblasts were determined via activating Akt/GSK-3ß/ß-catenin signaling and suppressing autophagy. SIGNIFICANCE: This study uncovered a previously unrecognized profibrotic role of OPN in atrial fibrosis, which was achieved through activation of Akt/GSK-3ß/ß-catenin signaling pathway and suppression of autophagy, implying a promising therapeutic target in atrial fibrosis and AF.


Assuntos
Fibrilação Atrial/patologia , Autofagia , Glicogênio Sintase Quinase 3 beta/metabolismo , Átrios do Coração/patologia , Osteopontina/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Idoso , Fibrilação Atrial/metabolismo , Autofagia/fisiologia , Estudos de Casos e Controles , Colágeno/metabolismo , Feminino , Fibronectinas/metabolismo , Fibrose , Átrios do Coração/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transdução de Sinais/fisiologia
10.
PLoS One ; 15(1): e0227340, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910234

RESUMO

The PI3K/Akt pathway is interconnected to protein kinase CK2, which directly phosphorylates Akt1 at S129. We have previously found that, in HK-2 renal cells, downregulation of the CK2 regulatory subunit ß (shCK2ß cells) reduces S129 Akt phosphorylation. Here, we investigated in more details how the different CK2 isoforms impact on Akt and other signaling pathways. We found that all CK2 isoforms phosphorylate S129 in vitro, independently of CK2ß. However, in HK-2 cells the dependence on CK2ß was confirmed by rescue experiments (CK2ß re-expression in shCK2ß HK-2 cells), suggesting the presence of additional components that drive Akt recognition by CK2 in cells. We also found that CK2ß downregulation altered the phosphorylation ratio between the two canonical Akt activation sites (pT308 strongly reduced, pS473 slightly increased) in HK-2 cells. Similar results were found in other cell lines where CK2ß was stably knocked out by CRISPR-Cas9 technology. The phosphorylation of rpS6 S235/S236, a downstream effector of Akt, was strongly reduced in shCK2ß HK-2 cells, while the phosphorylation of two Akt direct targets, PRAS40 T246 and GSK3ß S9, was increased. Differently to what observed in response to CK2ß down-regulation, the chemical inhibition of CK2 activity by cell treatment with the specific inhibitor CX-4945 reduced both the Akt canonical sites, pT308 and pS473. In CX-4945-treated cells, the changes in rpS6 pS235/S236 and GSK3ß pS9 mirrored those induced by CK2ß knock-down (reduction and slight increase, respectively); on the contrary, the effect on PRAS40 pT246 phosphorylation was sharply different, being strongly reduced by CK2 inhibition; this suggests that this Akt target might be dependent on Akt pS473 status in HK-2 cells. Since PI3K/Akt and ERK1/2/p90rsk pathways are known to be interconnected and both modulated by CK2, with GSK3ß pS9 representing a convergent point, we investigated if ERK1/2/p90rsk signaling was affected by CK2ß knock-down and CX-4945 treatment in HK-2 cells. We found that p90rsk was insensitive to any kind of CK2 targeting; therefore, the observation that, similarly, GSK3ß pS9 was not reduced by CK2 blockade suggests that GSK3ß phosphorylation is mainly under the control of p90rsk in these cells. However, we found that the PI3K inhibitor LY294002 reduced GSK3ß pS9, and concomitantly decreased Snail1 levels (a GSK3ß target and Epithelial-to-Mesenchymal transition marker). The effects of LY294002 were observed also in CK2ß-downregulated cells, suggesting that reducing GSK3ß pS9 could be a strategy to control Snail1 levels in any situation where CK2ß is defective, as possibly occurring in cancer cells.


Assuntos
Caseína Quinase II/genética , Glicogênio Sintase Quinase 3 beta/genética , Proteína Oncogênica v-akt/genética , Fatores de Transcrição da Família Snail/genética , Sistemas CRISPR-Cas/genética , Linhagem Celular , Cromonas/farmacologia , Transição Epitelial-Mesenquimal/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Morfolinas/farmacologia , Naftiridinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais/efeitos dos fármacos
11.
Cancer Sci ; 111(2): 429-440, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808966

RESUMO

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3ß, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3ß in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3ß (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3ß activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3ß inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3ß in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3ß as a new and promising therapeutic target for these STS types.


Assuntos
Fibrossarcoma/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Indóis/administração & dosagem , Maleimidas/administração & dosagem , Sarcoma Sinovial/tratamento farmacológico , Tiazóis/administração & dosagem , Ureia/análogos & derivados , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Indóis/farmacologia , Injeções Intraperitoneais , Maleimidas/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Tiazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Toxicol Lett ; 320: 95-102, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760062

RESUMO

Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that "Axon" and "Neurotrophin Signaling Pathway" was the top significant GO term and pathway, respectively. 7 miRNAs both related to "Axon" and "Neurotrophin Signaling Pathway" were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3ß, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.


Assuntos
Axônios/efeitos dos fármacos , Hexanonas/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , Nervo Isquiático/efeitos dos fármacos , Solventes/toxicidade , Medula Espinal/efeitos dos fármacos , Animais , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Transcriptoma
13.
Cancer Sci ; 111(1): 186-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746077

RESUMO

Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3ß/ß-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Ácido Láctico/metabolismo , Estresse Oxidativo/genética , Transativadores/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Espécies Reativas de Oxigênio/metabolismo
14.
Mol Immunol ; 118: 153-164, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31884387

RESUMO

BACKGROUND: Accumulating evidence suggests a regulatory role of Wnt proteins in innate immune responses. However, the effects of Wnt3a signaling on TLR4-mediated inflammatory responses are controversial and the signaling crosstalk between TLR4 and Wnt3a remains uncertain. METHODS: Gain- and Loss- of function approaches were utilized to determine the function of Wnt3a signaling in TLR4-mediated inflammatory responses. Cytokine production at protein and mRNA levels and phosphorylation of signaling molecules were measured by ELISA, qRT-PCR, and Western Blot, respectively. Endotoxemia mouse model was employed to assess the effect of Wnt3a on systemic inflammatory cytokine levels and neutrophil infiltration. RESULTS: LPS stimulation leads to an increase of Wnt3a expression and its downstream molecule, Dvl3, in primary monocytes. Inhibition or silence of Wnt3a or Dvl3 significantly increases the production of pro-inflammatory cytokines (IL-12, IL-6, TNFα), robustly reduces ß-catenin accumulation, and enhances the phosphorylation of NF-κB P65 and its DNA binding activity. These results were confirmed by multiple gain- and loss- of function approaches including specific siRNA and ectopic expression of Dvl3, GSK3ß, and ß-catenin in monocytes. Moreover, in vivo relevance was established in a murine endotoxin model, in which Wnt3a inhibition enhances the inflammatory responses by augmenting the systemic pro-inflammatory cytokine levels and neutrophil infiltration. CONCLUSIONS: TLR4 activation promotes Wnt3a-Dvl3 signaling, which acts as rheostats to restrain the intensity of inflammation through regulating GSK3ß-ß-catenin signaling and NF-κB activity. GENERAL SIGNIFICANCE: Wnt3a-Dvl3-ß-catenin signaling axis could be a potential interventional target for manipulating the direction and intensity of inflammatory responses.


Assuntos
Proteínas Desgrenhadas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Inflamação/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Animais , Citocinas/metabolismo , Endotoxinas/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Fosforilação/fisiologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-31846691

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) plays a crucial role in regulating lipid metabolism, endoplasmic reticulum (ER) stress and apoptosis in mammals, however, its gene structure and function is little known about in fish. Here, its two paralogs, grass carp (Ctenopharyngodon idella) GSK-3ß1 and GSK-3ß2 were isolated and characterized, encoding peptides of 421 and 457 amino acids, respectively. These two paralogs may have originated from the teleost-specific genome duplication (TSGD) event. Alignment of grass carp GSK-3ß deduced amino acid sequences with select teleost species showed that the protein is conserved. However, two paralogs of the GSK-3ß had great variation in gene structure: the GSK-3ß1 contained eleven exons while the GSK-3ß2 contained nine exons. The two paralogs were expressed in a wide range of tissues, GSK-3ß1 was most expressed in adipose tissue, GSK-3ß2 was most expressed in liver. In OA-induced adipocytes and hepatocytes, we found that GSK-3ß1 mRNA expression was significantly increased only in adipocytes, while the mRNA expression of GSK-3ß2 was dramatically increased both in adipocytes and hepatocytes. These results provide evidence that the GSK-3ß may participate in the process of lipid accumulation in OA-induced adipocytes and hepatocytes of grass carp.


Assuntos
Adipócitos/metabolismo , Carpas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hepatócitos/metabolismo , Ácido Oleico/farmacologia , Sintenia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Carpas/genética , Células Cultivadas , Clonagem Molecular , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/genética , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Filogenia , Homologia de Sequência de Aminoácidos , Distribuição Tecidual
16.
Phytomedicine ; 66: 153130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790897

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver diseases. Cyclocarya paliurus (C. paliurus), an edible and medicinal plant in Chinese folk, has been demonstrated to ameliorate diabetes, obesity and lipid metabolism disorders. However, its effects on NAFLD and its potential molecular mechanism have not been clearly expounded. PURPOSE: The present study was designed to explore the therapeutic potential of triterpenic acids-enriched fraction from C. paliurus (CPT), as well as its underlying mechanism in vivo and in vitro models of NAFLD. METHODS: The metabolic effects and possible molecular mechanism of CPT were examined using HepG2 cells and primary hepatocytes (isolated from C57BL/6 J mice) models of fatty liver induced by palmitic acid (PA) and a high fat diet mouse model. RESULTS: In high fat diet-induced C57BL/6 J mice, CPT significantly reduced liver weight index, serum alanine transaminase (ALT), aspartate transaminase (AST), triacylglycerol (TG), total cholesterol (TC) and hepatic TG, TC levels. Moreover, CPT dramatically decreased the contents of blood glucose, insulin, and insulin resistance (HOMA-IR) index. Meanwhile, CPT significantly increased the tyrosine phosphorylation level of IRS and the uptake of 2-deoxyglucose (2DG) in PA-induced HepG2 cells and primary hepatocytes fatty liver models. Furthermore, in PA-induced HepG2 cells and primary hepatocytes, CPT significantly decreased the number of lipid droplets and intracellular TG content. In addition, mechanism investigation showed that CPT increased the phosphorylation of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase-3ß (GSK3ß) in vivo and in vitro models, which were abrogated by PI3K inhibitor LY294002 in vitro models. CONCLUSION: These findings indicate that CPT may exert the therapeutic effects on NAFLD via regulating PI3K/Akt/GSK3ß pathway.


Assuntos
Juglandaceae/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Extratos Vegetais/química , Plantas Medicinais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triglicerídeos/metabolismo , Triterpenos/química
17.
Proc Natl Acad Sci U S A ; 117(1): 584-594, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31843895

RESUMO

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.


Assuntos
Proteína 7 com Repetições F-Box-WD/metabolismo , Melanoma/patologia , Fator de Transcrição STAT2/metabolismo , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Estabilidade Proteica , Proteólise , Fator de Transcrição STAT2/química , Fator de Transcrição STAT2/genética , Serina/metabolismo , Transdução de Sinais , Pele/patologia , Treonina/metabolismo , Análise Serial de Tecidos , Ubiquitinação , Repetições WD40
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(10): 1180-1185, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31801717

RESUMO

OBJECTIVE: To investigate the inhibitory effect of polysaccharide of Atractylodes macrocephala (PAM) on the proliferation and invasion of hepatocellular carcinoma cells and the underlying mechanism. METHODS: Hepatocellular carcinoma HepG2 cells were treated with different concentrations of PAM, and their proliferation and invasive ability were examined using CCK-8 assay and Transwell assay. Immunofluorescence assay was performed to detect the expression level of ß-catenin, and real-time PCR and Western blotting were used to detect the mRNA and protein expressions of AKT, GSK-3ß and MMP-2 in the cells. The changes in the proliferation, invasiveness and the expressions of pGSK-3ß and MMP2 were examined in the cells following treatment with LiCl/PAM/LiCl plus PAM. RESULTS: PAM treatment significantly reduced the cell viability, the number of migration cells, and the expression levels of ß-catenin and MMP-2 (P < 0.05), and obviously inhibited the phosphorylation of AKT and GSK-3ß in the cells (P < 0.05) in a dose-dependent manner. The rescue experiment showed that LiCl reversed the inhibition of cell proliferation, invasiveness, and the Wnt/ß-catenin pathway induced by PAM. CONCLUSIONS: PAM can inhibit the proliferation and invasion of hepatocellular carcinoma cells in vitro possibly by inhibiting the Wnt/ß-catenin signaling pathway.


Assuntos
Atractylodes/química , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Polissacarídeos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Invasividade Neoplásica , Compostos Fitoquímicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
19.
Biomed Res Int ; 2019: 9203934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886264

RESUMO

Metformin, an effective hypoglycemic, can modulate different points of malignant mass, polycystic ovary syndrome (PCOS), cardiovascular diseases, tuberculosis, and nerve regeneration. Recently, the effect of metformin on bone metabolism has been analyzed. Metformin relies on organic cation transporters (OCT1), a polyspecific cell membrane of the solute carrier 22A (SLC22A) gene family, to facilitate its intracellular uptake and action on complex I of the respiratory chain of mitochondria. These changes activate the cellular energy sensor AMP-activated protein kinase (AMPK). Thus, the increased cellular AMP/ATP ratio causes a dramatic and progressive activation of insulin and lysosomes, resulting in a decrease in intracellular glucose level, which promotes osteoblast proliferation and differentiation. AMPK also phosphorylates runt-related transcription factor 2 (Runx2) at S118, the lineage-specific transcriptional regulators, to promote osteogenesis. Metformin phosphorylates extracellular signal-regulated kinase (ERK), stimulates endothelial and inducible nitric oxide synthases (e/iNOS), inhibits the GSK3ß/Wnt/ß-catenin pathway, and promotes osteogenic differentiation of osteoblasts. The effect of metformin on hyperglycemia decreases intracellular reactive oxygen species (ROS) and advanced glycation end-products (AGEs) in collagen, and reduced serum levels of insulin-like growth factors (IGF-1) were beneficial for bone formation. Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism. The aim of this review was to elucidate the mechanisms of metformin on osteoblasts in insulin-deficient diabetes.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Metformina/farmacologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Hiperglicemia/metabolismo , Óxido Nítrico Sintase/metabolismo , Osteoporose , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
20.
Wei Sheng Yan Jiu ; 48(6): 964-975, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31875823

RESUMO

OBJECTIVE: To study the effect of glycogen synthase kinase 3ß(GSK3ß) in BPA-induced adipose tissue inflammation in high fat diet(HFD) fed mice. METHODS: Four-week-old male C57 BL/6 mice were randomly divided into normal diet(ND) group, HFD group, HFD + GSK3ß inhibitor group, HFD + 1000 nmol/L BPA group, HFD+1000 nmol/L BPA+GSK3ß inhibitor group. The mice were exposed to BPA via drinking water. From the 14 th week of BPA exposure to the end of 16 weeks, the GSK3ß inhibitor group was intraperitoneally injected with 21. 5 mg/kg lithium chloride(Li Cl) every two days for a total of 10 times. At the end of 16 weeks, the mice were sacrificed after anesthesia, and the epididymal fat tissue was taken aseptically. The pathological changes were observed by H&E staining. The expressions of interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) were detected by immunohistochemistry(IHC). The expression of GSK3ß protein and its S9 serine(GSK3ß-S9) phosphorylation were detected by western blot. RESULTS: Compared with the ND group, the body weight [(34. 97±1. 91) g]and epididymal fat pad coefficient [(3. 25±0. 39) %]of HFD group was significantly up-regulated(P < 0. 05), the adipose tissue inflammatory cell infiltration was increased, the expression of TNF-α(F = 73. 157, P < 0. 05) and IL-1ß(F = 42. 788, P < 0. 05) was significantly enhanced, and the phosphorylation degree of GSK3ß-S9(F = 57. 991, P < 0. 05) was decreased. The inflammatory cell infiltration of adipose tissue in the HFD+1000 nmol/L BPA group was significantly increased, the body weight [(38. 49±1. 34) g]and epididymal fat pad coefficient [(4. 41±0. 33) %] of the mice were significantly increased, the phosphorylation of GSK3ß-S9(F = 57. 991, P <0. 05) was significantly down-regulated, and the expression of TNF-α(F = 73. 157, P <0. 05) and IL-1ß(F = 42. 788, P <0. 05) was significantly enhanced compared with that in the HFD group. Compared with the HFD + 1000 nmol/L BPA group, the HFD + 1000 nmol/L BPA+GSK3 inhibitor group was decreased inflammatory cell infiltration in adipose tissue, significantly decreased body weight [(32. 61 ± 3. 34) g] and epididymal fat pad coefficient [(3. 33±0. 66) %], significantly increased GSK3-S9(F = 57. 991, P < 0. 05)phosphorylation, and significantly decreased TNF-α(F = 73. 157, P < 0. 05) and IL-1ß(F = 42. 788, P<0. 05) expression. CONCLUSION: GSK3ß inhibitor can down-regulate BPA-induced adipose tissue inflammation, inflammatory cytokine expression and upregulate GSK3ß-S9 phosphorylation in HFD-fed mice, suggesting that BPA exposure may regulate the expression of inflammatory cytokines mediating adipose tissue inflammation by affecting the degree of phosphorylation of GSK3ß-S9.


Assuntos
Dieta Hiperlipídica , Tecido Adiposo , Animais , Glicogênio Sintase Quinase 3 beta , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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