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1.
Expert Opin Investig Drugs ; 28(11): 977-988, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31594388

RESUMO

Introduction: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase involved in several critical cellular pathways, including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 kinase (PI3K) is the key regulator of AKT activation, numerous stimuli and kinases initiate pro-proliferative AKT signaling which results in the activation of AKT pathway to drive cellular growth and survival. Activating mutations and amplification of components of the AKT pathway are implicated in the pathogenesis of many cancers including breast and ovarian. Given its importance, AKT, it has been validated as a promising therapeutic target.Areas covered: This article summarizes AKT's biological function and different classes of AKT inhibitors as anticancer agents. We also explore the efficacy of AKT inhibitors as monotherapies and in combination with cytotoxic and other targeted therapies.Expert opinion: The complex mechanism following AKT inhibition requires the addition of other therapies to prevent resistance and improve clinical response. Further studies are necessary to determine additional rational combinations that can enhance efficacy of AKT inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. The identification of biomarkers of response is essential for the development of successful therapeutics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Fosfatidilinositol 3-Quinase/metabolismo
2.
J Agric Food Chem ; 67(39): 10871-10879, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31517482

RESUMO

This study evaluated the effect of triterpenoids from edible mushroom Poria cocos on intestinal epithelium integrity and revealed the transcriptional regulatory pathways that underpin restorative mechanisms in the gut. Based on computational docking studies, transcriptional activation experiments and glucocorticoid receptor (GR) protein immunofluorescence localization assays in cultured cells, 16α-hydroxytrametenolic acid (HTA) was discovered as a novel GR agonist in this study. HTA ameliorates TNF-α-induced Caco-2 monolayer intestinal epithelial barrier damage and suppressed activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), which attenuated downstream IκB and nuclear factor kappa-B (NF-κB) phosphorylation through GR activation. Moreover, HTA prevented NF-κB translocation into the nucleus and binding to its cis-element and suppressed lipopolysaccharide-induced downstream NO production and pro-inflammatory cytokines at both protein and mRNA expression levels. In conclusion, HTA from P. cocos improves intestinal barrier function through a GR-mediated PI3K/Akt/NF-κB signaling pathway and may be potentially exploited as a supportive dietary therapeutic strategy for restoring gut health.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Glucocorticoides/metabolismo , Triterpenos/farmacologia , Wolfiporia/química , Células CACO-2 , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Mucosa Intestinal/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/genética , Fosfatidilinositol 3-Quinase/genética , Fosforilação , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/química , Verduras/química
3.
Expert Opin Ther Pat ; 29(11): 881-889, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530116

RESUMO

Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued. Areas covered: Here the authors provide recent updates to their previous publication on 'PTEN modulators: A patent review', and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson's disease, Alzheimer's disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn's disease, and several cancer types. Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.


Assuntos
Desenvolvimento de Medicamentos/métodos , PTEN Fosfo-Hidrolase/efeitos dos fármacos , Animais , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Patentes como Assunto , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
J Agric Food Chem ; 67(42): 11657-11664, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31549821

RESUMO

The therapeutic benefits of whole grains on diabetes mellitus have been continuously confirmed by in-depth research. To date, limited studies have investigated the effect of extruded products of whole grains on the insulin signaling pathway in vivo. This study investigated the effects of oral consumption of whole grain extrudate, including 97% brown rice and 3% defatted rice bran (w/w, BRD), on glucose metabolism and the hepatic insulin signaling pathway in C57BL/KsJ-db/db mice. BRD treatment induced a remarkable reduction in blood glucose. Moreover, glucose intolerance and insulin resistance were ameliorated in the BRD-treated group compared with those in the db/db control group. BRD also increased the hepatic glycogen content by reducing the expression and increasing the phosphorylation of glycogen synthase kinase 3ß (GSK3ß). The activities of glucose-6-phosphatase and phosphoenolpyruvate carboxylase and their respective mRNA expression levels in the liver were simultaneously decreased in the BRD-treated group. BRD also significantly upregulated the expression of phosphatidylinositol 3-kinase (PI3K) and increased the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT). These results indicate that BRD exhibits antidiabetic potential by activating the IRS1/PI3K/AKT signaling pathway, further regulating the expression of the FOXO1 gene and p-GSK3ß protein, thus inhibiting hepatic gluconeogenesis, increasing hepatic glycogen storage, and improving insulin resistance. Therefore, BRD could be used as a functional ingredient to alleviate the symptoms of hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Oryza/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Oryza/química , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
5.
Gene ; 716: 144031, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377314

RESUMO

Circular RNAs (circRNAs), a novel class of widespread and diverse endogenous RNAs, have been identified as critical regulators of various cancers, including hepatocellular carcinoma (HCC). However, the specific roles of circRNAs in HCC are largely unknown. In this study, we identified a novel circRNA, circ-IGF1R, in HCC tumour tissues and cell lines. Circ-IGF1R levels were found to be significantly upregulated in HCC tissues compared with levels in paired peritumoural tissues. The high expression levels of circ-IGF1R in HCC were associated with tumour size. Moreover, knocking down circ-IGF1R with siRNA significantly attenuated cell proliferation and induced cell apoptosis and cell cycle arrest in vitro. Further investigation revealed that PI3K/AKT signalling pathway activation was involved in the oncogenic functions of circ-IGF1R in HCC. Our study suggests that circ-IGF1R may be a potential target for the prevention and treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA/metabolismo , Apoptose , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima
6.
Ecotoxicol Environ Saf ; 183: 109465, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31376806

RESUMO

Our group found that long-term low-dose exposure to hexavalent chromium [Cr(VI)] in L-02 hepatocytes resulted in premature senescence, which accompanied by the increased expression of Clusterin (CLU), but the functional role of CLU in premature senescence has never been explored. In the present study, the CLU overexpressed or silenced L-02 hepatocytes were established by lentiviral vector transfection. Cell viability assay, cell cycle analysis, western blotting, plate clone formation assay, and confocal microcopy were performed. The results indicated that Cr(VI)-induced premature senescence was associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition, and high expression of CLU in the senescent cells exerted its functional role of promoting cell proliferation. CLU could complex with eukaryotic translation initiation factor 3 subunit I (EIF3I) and prevent its degradation, leading to the increase of AKT activity in Cr(VI)-exposed senescent hepatocytes. Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of CLU on Cr(VI)-induced premature senescence. We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.


Assuntos
Senescência Celular/efeitos dos fármacos , Cromo/toxicidade , Clusterina/genética , Hepatócitos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Senescência Celular/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Life Sci ; 231: 116542, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176781

RESUMO

AIM: To compare the effect of 150 min vs. 300 min of weekly moderate intensity exercise training on the activation of the opioid system and apoptosis in the hearts of a diet-induced obesity model. METHODS: Male Wistar rats were fed with either control (CON) or high fat (HF) diet for 32 weeks. At the 20th week, HF group was subdivided into sedentary, low (LEV, 150 min·week-1) or high (HEV, 300 min·week-1) exercise volume. After 12 weeks of exercise, body mass gain, adiposity index, systolic blood pressure, cardiac morphometry, apoptosis biomarkers and opioid system expression were evaluated. RESULTS: Sedentary animals fed with HF presented pathological cardiac hypertrophy and higher body mass gain, systolic blood pressure and adiposity index than control group. Both exercise volumes induced physiological cardiac hypertrophy, restored systolic blood pressure and improved adiposity index, but only 300 min·week-1 reduced body mass gain. HF group exhibited lower proenkephalin, PI3K, ERK and GSK-3ß expression, and greater activated caspase-3 expression than control group. Compared to HF, no changes in the cardiac opioid system were observed in the 150 min·week-1 of exercise training, while 300 min·week-1 showed greater proenkephalin, DOR, KOR, MOR, Akt, ERK and GSK-3ß expression, and lower activated caspase-3 expression. CONCLUSION: 300 min·week-1 of exercise training triggered opioid system activation and provided greater cardioprotection against obesity than 150 min·week-1. Our findings provide translational aspect with clinical relevance about the critical dose of exercise training necessary to reduce cardiovascular risk factors caused by obesity.


Assuntos
Cardiomegalia/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores Opioides/fisiologia , Adiposidade , Animais , Apoptose/fisiologia , Pressão Sanguínea , Peso Corporal , Dieta Hiperlipídica , Encefalinas/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Coração/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismo , Condicionamento Físico Animal/métodos , Precursores de Proteínas/metabolismo , Ratos , Ratos Wistar
8.
Biol Pharm Bull ; 42(6): 968-976, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155593

RESUMO

Previously, we reported that adenosine N1-oxide (ANO), which is found in royal jelly, inhibited the secretion of inflammatory mediators by activated macrophages and reduced lethality in lipopolysaccharide (LPS)-induced endotoxin shock. Here, we examined the regulatory mechanisms of ANO on the release of pro-inflammatory cytokines, with a focus on the signaling pathways activated by toll-like receptor (TLR)4 in response to LPS. ANO inhibited both tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion from LPS-stimulated RAW264.7 cells without affecting cell proliferation. In this response, phosphorylation of mitogen-activated protein kinase (MAPK) family members (extracellular signal-regulated kinase (ERK)1/2, p38 and SAPK/c-Jun N-terminal kinase (JNK)) and nuclear factor-κB (NF-κB) p65 was not affected by treatment with ANO. In contrast, phosphorylation of Akt (Ser473) and its downstream molecule glycogen synthase kinase-3ß (GSK-3ß) (Ser9) was up-regulated by ANO, suggesting that ANO stimulated GSK-3ß phosphorylation via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The phosphorylation of GSK-3ß on Ser9 has been shown to negatively regulate the LPS-induced inflammatory response. Activation of PI3K/Akt signaling pathway has also been implicated in differentiation of mesenchymal stem cells into osteoblasts and adipocytes. As expected, ANO induced alkaline phosphatase activity and promoted calcium deposition in a mouse pre-osteoblastic MC3T3-E1 cell line. The ANO-induced differentiation into osteoblasts was abrogated by coincubation with Wortmannin. Furthermore, ANO promoted insulin/dexamethasone-induced differentiation of mouse 3T3-L1 preadipocytes into adipocytes at much lower concentrations than adenosine. The protective roles of PI3K/Akt/GSK-3ß signaling pathway in inflammatory disorders have been well documented. Our data suggest that ANO may serve as a potential candidate for the treatment of inflammatory disorders. Promotion of osteogenic and adipocyte differentiation further suggests its application for regenerative medicine.


Assuntos
Adenosina/análogos & derivados , Adipócitos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Óxidos N-Cíclicos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenosina/farmacologia , Adipócitos/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
J Agric Food Chem ; 67(20): 5754-5763, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31045365

RESUMO

Recently, although ginseng ( Panax ginseng C. A. Meyer) and its main component saponins (ginsenosides) have been reported to exert protective effects on cisplatin (CDDP)-induced acute kidney injury (AKI), the beneficial activities of non-saponin on CDDP-induced AKI is little known. This research was designed to explore the protective effect and underlying mechanism of arginyl-fructosyl-glucose (AFG), a major and representative non-saponin component generated during the process of red ginseng, on CDDP-caused AKI. AFG at doses of 40 and 80 mg/kg remarkably reversed CDDP-induced renal dysfunction, accompanied by the decreased levels of serum creatinine and blood urea nitrogen. Interestingly, all of oxidative stress indices were ameliorated after pretreatment with AFG continuously for 10 days. Importantly, AFG relieved CDDP-induced inflammation and apoptosis in part by mitigating the cascade initiation steps of nuclear factor κB signals and regulating the participation of the phosphatidylinositol 3-kinase/protein kinase B signal pathway. In conclusion, these results clearly provide strong rationale for the development of AFG to prevent CDDP-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Arginina/análogos & derivados , Cisplatino/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Glucose/administração & dosagem , Glicina/análogos & derivados , NF-kappa B/metabolismo , Panax/química , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Arginina/administração & dosagem , Arginina/química , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/química , Glucose/química , Glicina/administração & dosagem , Glicina/química , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Reação de Maillard , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
10.
Environ Pollut ; 252(Pt A): 39-50, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146237

RESUMO

Exposure to ultrafine particulate matter (PM0.1) is positively associated with the etiology of different acute and chronic disorders; however, the in-depth biological imprints that link these submicron particles with the disturbances in the epigenomic machinery are not well defined. Earlier, we showed that exposure to these particles causes significant disturbances in the mitochondrial machinery and triggers PI-3-kinase mediated DNA damage responses. In the present study, we aimed to further understand the epigenomic insights of the ultrafine PM exposure. The higher levels of intracellular reactive oxygen species and depleted Nrf-2 in ultrafine PM exposed cells reconfirmed its potential to induce oxidative stress. Importantly, the observed increase in the levels of NF-κß and associated cytokines among exposed cells suggested the activation of NF-κß mediated inflammatory loop which potentially serves as a platform for initiating epigenetic insinuations. This fact was strongly supported by the altered miRNA expression profile of the ultrafine PM exposed cells. These NF-κß induced miRNA alterations were also found to be associated with other epigenetic targets as the exposed cells showed higher expression levels of DNA methyltransferases which positively corresponded with the global changes in DNA methylation levels. Upon further analysis, significant alterations in histone code were also reported in ultrafine PM exposed cells. Conclusively our results suggested that NF-κß acts as an inflammatory switch that possesses the potential to induce genome-wide epigenetic modification upon ultrafine PM exposure.


Assuntos
Metilação de DNA/efeitos dos fármacos , Epigênese Genética/genética , Linfócitos/metabolismo , NF-kappa B/metabolismo , Material Particulado/toxicidade , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Metilases de Modificação do DNA/biossíntese , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Mitocôndrias/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Tamanho da Partícula , Material Particulado/análise , Fosfatidilinositol 3-Quinase/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
J Stroke Cerebrovasc Dis ; 28(7): 1832-1840, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078389

RESUMO

GOAL: The present study aimed to examine whether Am80 (tamibarotene) protects the hippocampus against cerebral ischemia-reperfusion (I/R) injury and whether phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway mediates this effect. MATERIALS AND METHODS: Rats were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. The animals were randomly divided into 7 groups: sham-operated group; I/R group; groups pretreated with 2 mg/kg, 6 mg/kg, and 10 mg/kg of Am80; Am80 (6 mg/kg) combined with the selective PI3K inhibitor wortmannin (0.6 mg/kg), and wortmannin (0.6 mg/kg) only group. After 24 hours of reperfusion, neurological deficits and infarct volume were measured. Pathological changes in hippocampal neurons were analyzed by transmission electron microscopy. Neuronal survival was examined by TUNEL staining. The expression of Bcl-2, Bax, and Akt, and Akt phosphorylation (p-Akt) were measured by Western blotting and quantitative real-time polymerase chain reaction. FINDINGS: The pretreatment with Am80 improved the neurologic deficit score, reduced infarct volume, and decreased the number of TUNEL-positive cells in the hippocampus. Moreover, Am80 pretreatment downregulated the expression of Bax, upregulated the expression of Bcl-2, and increased the level of p-Akt. Wortmannin abolished in part the increase in p-Act and the neuroprotective effect exerted on the ischemic by Am80 pretreatment. CONCLUSIONS: Our results documented that Am80 pretreatment protects ischemic hippocampus after cerebral I/R by regulating the expression of apoptosis-related proteins through the activation of the PI3K/Akt signaling pathway.


Assuntos
Benzoatos/farmacologia , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Tetra-Hidronaftalenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/enzimologia , Hipocampo/ultraestrutura , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/enzimologia , Neurônios/ultraestrutura , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
12.
Pancreas ; 48(4): 568-573, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946236

RESUMO

OBJECTIVES: The study aimed to investigate the involvement of the mammalian target of rapamycin (mTOR) signaling pathway in orexin-A/OX1 receptor-induced insulin secretion in rat insulinoma INS-1 cells. METHODS: Rat insulinoma INS-1 cells were grown and treated with various concentrations of orexin-A, with or without OX1 receptor-selective antagonist SB674042 or the phosphatidylinositol 3-kinase/mTOR antagonist PF-04691502. Insulin release experiments, Western blot analysis, and statistical analysis were conducted using INS-1 cells. RESULTS: Our results showed that treating cells with orexin-A increased the expression of the OX1 receptor and the phosphorylation of mTOR in a concentration-dependent manner. An increase in insulin secretion was also observed for cells treated with orexin-A. We further demonstrated that the increase in insulin secretion was dependent on the activation of the OX1 receptor and mTOR signaling pathway by using the OX1 receptor-selective antagonist SB674042 or the phosphatidylinositol 3-kinase/mTOR antagonist PF-04691502, which abolished the effects of orexin-A treatment. CONCLUSIONS: Our results concluded that orexin-A/OX1 receptor stimulates insulin secretion by activating AKT and its downstream target, mTOR. Therefore, orexins may regulate the energy balance for cell survival with the involvement of mTOR in this process.


Assuntos
Secreção de Insulina/efeitos dos fármacos , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Insulinoma/metabolismo , Insulinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Piridonas/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tiazóis/farmacologia
13.
Med Sci Monit ; 25: 2352-2360, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30930461

RESUMO

BACKGROUND High-mobility group box 1 (HMGB1) is an essential contributor towards initiation and progression of many kinds of cancers. Nevertheless, our understanding of the molecular etiology of HMGB1-modulated vasculogenesis, as well as invasion, of breast cancer is poor. This study explored HMGB1 expression in breast cancer and its role in the development and spread of malignancy. MATERIAL AND METHODS We enrolled 15 patients with breast cancer who received primary surgery at the Department of Thyroid and Breast Surgery in our hospital. HMGB1 was recorded and analyzed. RESULTS Our investigation successfully proves that HMGB1 is upregulated in breast cancer tissues in comparison to the surrounding non-malignant tissues. HMGB1 enhanced vessel formation in breast cancer tissues by regulating hypoxia-inducible factor 1 (HIF-1alpha), which in turn upregulates the expression of VEGF. Furthermore, HMGB1-mediated upregulation of HIF-1alpha relies on its ability to stimulate the phosphatidylinositol 3-kinase (PI3K) pathway to reinforce AKT subunit phosphorylation. HMGB1 overexpression reinforces the vasculogenesis in malignancies not only in vivo but also in vitro. Additionally, shRNA knockdown of HMGB1 prohibited the vessel-forming and invasive capabilities, downregulated VEGF and HIF-1alpha, and suppressed AKT phosphorylation in breast cancer cells. Most importantly, PI3K/AKT axis suppression eliminated the effect of HMGB1-modulated vascularization and invasion in breast cancer cells. CONCLUSIONS Our research indicates that HMGB1 serves as a crucial regulator of malignant cell-modulated vessel formation and is involved in the development of malignancy. Our findings indicate that HMGB1 is a promising target for breast cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/fisiologia , Indutores da Angiogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , China , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Oncol ; 54(6): 2211-2221, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942425

RESUMO

Emerging reports have revealed that several microRNAs (miRNAs) are abnormally expressed in non­small cell lung cancer (NSCLC). miRNAs have been identified as oncogenes or tumor suppressors, and regulate various biological processes including oncogenesis and development. miR­802 is dysregulated in multiple types of human cancer, and exerts tumor­suppressive or promoting roles. However, the expression levels and functional roles of miR­802 in NSCLC remain largely unknown. In the present study, miR­802 expression was demonstrated to be decreased in NSCLC tissues and cell lines. A low miR­802 expression was significantly correlated with the tumor stage, lymph node metastasis and brain metastasis in NSCLC patients. Restoring miR­802 expression inhibited NSCLC cell proliferation and colony formation, induced cell apoptosis, decreased cell migration and invasion in vitro, and hindered in vivo tumor growth. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) was confirmed as the target gene of miR­802 in NSCLC cells. In addition, FGFR1 silencing mimicked the tumor­suppressing roles of miR­802 upregulation in NSCLC cells. Furthermore, rescue experiments revealed that FGFR1 reintroduction rescued the miR­802­induced inhibition of the malignant phenotypes in NSCLC cells. Notably, miR­802 was able to deactivate the phosphoinositide 3­kinase (PI3K)/AKT serine/threonine kinase (Akt)/mammalian target of rapamycin (mTOR) pathway in NSCLC cells in vitro and in vivo. Overall, these results demonstrated that miR­802 could downregulate FGFR1 expression, thereby deactivating the PI3K/Akt/mTOR pathway and inhibiting the malignant development of NSCLC. Thus, miR­802 may be a therapeutic candidate for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinase/metabolismo , Pneumonectomia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Med Rep ; 19(6): 4673-4684, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957185

RESUMO

Non­alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and has high rates of morbidity and mortality worldwide. Daphnetin (DAP) possesses notable antioxidative, anti­inflammatory and anticoagulant activities; DAP is an active ingredient extracted from Daphne Koreana Nakai. To investigate the effects and the underlying mechanism of DAP on NAFLD, we treated HepG2 cells with oleic acid (OA) and DAP simultaneously and non­simultaneously. In the simultaneous treatment condition, HepG2 cells were co­treated with 0.5 mM OA and DAP (5, 20, and 50 µM) for 24 h. In the non­simultaneous treatment conditions, HepG2 cells were pretreated with 0.5 mM OA for 24 h, and then treated with DAP (5, 20 and 50 µM) for 24 h. Following the aforementioned treatments, the biochemical indexes associated with NAFLD were measured as follows: i) The intracellular contents of triglyceride (TG), reactive oxygen species (ROS) and fluorescent glucose 2­[N­(7­nitrobenz­2­oxa­1,3­diazol­4­yl) amino]­2­deoxyglucose were analyzed with corresponding detection kits; and ii) the cellular expression levels of glycolipid metabolism­ and oxidative stress­related genes, including 5'AMP­activated protein kinase (AMPK), sterol regulatory element­binding protein­1C (SREBP­1C), patatin­like phospholipase domain­containing protein 3 (PNPLA3), peroxisome proliferator­activated receptor α (PPARα), phosphoinositide 3­kinase (PI3K), protein kinase B (AKT), nuclear factor­like 2 (Nrf2), cytochrome P450 (CYP) 2E1 and CYP4A were determined by reverse transcription­quantitative polymerase chain reaction and western blotting. The results revealed the potential mechanism underlying the effects of DAP on NAFLD in vitro: i) By increasing the phosphorylation of AMPK, DAP inhibited the expression of SREBP­1C and PNPLA3, and induced that of PPARα. Lipid accumulation within hepatocytes was reduced; ii) by upregulating PI3K expression and pAKT/AKT levels, DAP may alleviate insulin resistance and promote hepatocellular glucose uptake; and iii) by upregulating the expression of Nrf2, DAP downregulated the expression of CYP2E1 and CYP4A, and the levels of reactive oxygen species in hepatocytes.


Assuntos
Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Oleico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Umbeliferonas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP4A/genética , Citocromo P-450 CYP4A/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/genética , PPAR alfa/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
16.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013639

RESUMO

The epithelial-mesenchymal transition (EMT) is a phenomenon that facilitates epithelial cells to acquire invasive potential to induce the initiation the metastatic spread of tumor cells. Here, we determined if brassinin (BSN) can affect the EMT process and deciphered its anti-cancer effects. BSN attenuated the levels of EMT linked genes and suppressed transforming growth factor beta (TGF-ß)-mediated regulation of diverse mesenchymal markers. Additionally, BSN did increase the expression of various epithelial marker proteins in lung cancer cells. TGF-ß-induced morphological changes and induction of invasive ability of tumor cells was also found to be abrogated by BSN treatment. Finally, BSN not only suppressed constitutive, but also inducible phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation in tumor cells.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Indóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tiocarbamatos/farmacologia , Células A549 , Humanos , Neoplasias Pulmonares/patologia
17.
Nutrients ; 11(4)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935076

RESUMO

The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin's ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-mediated leptin responsiveness in DIO mice. Overall, these findings indicate that UGN improves leptin sensitivity in DIO mice.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Leptina/metabolismo , Peptídeos Natriuréticos/metabolismo , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Dieta/efeitos adversos , Hipotálamo/metabolismo , Camundongos , Camundongos Obesos , Obesidade/etiologia , Fosfatidilinositol 3-Quinase/metabolismo , Fator de Transcrição STAT3/metabolismo
18.
Int J Mol Sci ; 20(8)2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022972

RESUMO

Stem cells are undifferentiated cells that can give rise to several different cell types and can self-renew. Given their ability to differentiate into different lineages, stem cells retain huge therapeutic potential for regenerative medicine. Therefore, the understanding of the signaling pathways involved in stem cell pluripotency maintenance and differentiation has a paramount importance in order to understand these biological processes and to develop therapeutic strategies. In this review, we focus on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation. Precisely, in human stem cells, the PI3K cascade is involved in different processes from pluripotency and induced pluripotent stem cell (iPSC) reprogramming to mesenchymal and oral mesenchymal differentiation, through different and interconnected mechanisms.


Assuntos
Diferenciação Celular , Reprogramação Celular , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Mesenquimais/citologia , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Mesenquimais/metabolismo
19.
Cardiovasc Pathol ; 41: 11-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31004933

RESUMO

Atherosclerosis is a chronic inflammatory disease with lipid accumulation. Apolipoprotein C3 (APOC3), which is an important regulator of human lipid metabolism, is associated with multiple vascular mechanisms in atherosclerosis and proinflammatory responses. We have previously reported that the expression of inflammatory cytokine TNF-α is elevated in human endothelial cells (HUVECs) after APOC3 treatment. This study investigates the APOC3 signaling pathway involved in TNF-α-mediated expression of JAM-1 in HUVECs. Cultured HUVECs were exposed to APOC3 (50 µg/ml) for 16 h. Mechanistic studies were carried out by silencing TNF-α gene with lentiviral TNF-α-shRNA. Our study was based on the eight signaling pathway inhibitors to block the effect of APOC3 in HUVECs. The expression of JAM-1 was determined by qRT-PCR, Western blotting, and flow cytometry. IKK2 degradation and NF-κB p65 phosphorylation were determined by Western blotting. Our results showed that APOC3 significantly promoted the TNF-α-induced expression of JAM-1 in HUVECs. Inhibiting APOC3 reversed the TNF-α-induced overexpression of JAM-1. Moreover, APOC3 induced the expression of NF-κB p65 and degraded IκB. In conclusion, APOC3 promoted the expression of JAM-1 via the NF-κB, IKK2, and PI3K signaling pathway.


Assuntos
Apolipoproteína C-III/farmacologia , Moléculas de Adesão Celular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Receptores de Superfície Celular/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Moléculas de Adesão Celular/genética , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Fosforilação , Proteólise , Interferência de RNA , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/enzimologia , Fator de Necrose Tumoral alfa/genética
20.
Mol Med Rep ; 19(5): 3633-3641, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864725

RESUMO

Ginsenoside Rb1 (GRb1), one of the major active saponins isolated from ginseng, has recently been reported to protect various organs against ischemia/reperfusion (IR) injury; however, the mechanisms underlying these protective effects following intestinal IR (IIR) remain unclear. The present study aimed to evaluate the effects of GRb1 on IIR injury and determine the mechanisms involved in these effects. Sprague Dawley rats were subjected to 75 min of superior mesenteric artery occlusion, followed by 3 h of reperfusion. GRb1 (15 mg/kg) was administered intraperitoneally 1 h prior to the induction of IIR, with or without intravenous administration of Wortmannin [WM; a phosphoinositide 3­kinase (PI3K) inhibitor, 0.6 mg/kg]. The degree of intestinal injury and oxidative stress­induced damage was determined by histopathologic evaluation and measurement of the serum activity levels of D­lactate, diamine oxidase and endotoxin, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and 8­iso­prostaglandin F2α (8­iso­PGF2α). The protein expression levels of p85, phosphorylated (p)­p85, protein kinase B (Akt), p­Akt and nuclear factor erythroid 2­related factor 2 (Nrf2) were determined via western blotting, and the concentrations of tumor necrosis factor­α (TNF­α), interleukin (IL)­1ß and IL­6 were measured via ELISA. It was revealed that IIR led to severe intestinal injury (as determined by significant increases in intestinal Chiu scores), which was accompanied with disruptions in the integrity of the intestinal mucosal barrier. IIR also increased the expression levels of TNF­α, IL­1ß, IL­6, MDA and 8­iso­PGF2α in the intestine, and decreased those of SOD. GRb1 reduced intestinal histological injury, and suppressed inflammatory responses and oxidative stress. Additionally, the protective effects of GRb1 were eliminated by WM. These findings indicated that GRb1 may ameliorate IIR injury by activating the PI3K/protein kinase B/Nrf2 pathway.


Assuntos
Ginsenosídeos/farmacologia , Inflamação/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Malondialdeído/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/metabolismo
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