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1.
Gan To Kagaku Ryoho ; 48(4): 476-485, 2021 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-33976029

RESUMO

Small cell lung cancer(SCLC)is one of the histological types of lung cancer showing the worst prognosis, and is often diagnosed as an inoperable advanced stage disease. Recently, several comprehensive genomic analyses for SCLC have shown that inactivating mutations of tumor suppressor genes such as TP53 and RB1 and MYC family gene amplifications are involved in the development and progression of SCLC. However, actionable gene alterations for targeted therapies have not yet been identified, and there has been no significant advance in the development of targeted therapies for SCLC. In a nationwide lung cancer genome screening project in Japan, LC‒SCRUM‒Japan, a large‒scale genomic analysis was prospectively performed for Japanese SCLC patients, and based on this genomic analysis, a clinical study to evaluate the efficacy of a targeted therapy for PI3K/AKT/mTOR pathway gene‒altered SCLC(EAGLE‒PAT trial)was conducted. In this article, we describe the results of the genomic analysis in LC‒SCRUM‒Japan and the EAGLE‒PAT trial, and also provide the overview of genetic alterations reported in SCLC and the current and future development of targeted therapies for SCLC.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Genômica , Humanos , Japão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
2.
Zhen Ci Yan Jiu ; 46(4): 272-7, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33931990

RESUMO

OBJECTIVE: To explore the effect of moxa-cone moxibustion at "Feishu" (BL13) and "Zhongfu" (LU1) on the contents of related inflammatory factors in serum and bronchoalveolar lavage fluid (BALF), and the expression of phosphatidy-linositol-3-kinase (PI3K), retinoic acid related orphan receptor γt (RORγt) and fork/wing helix transcription factor 3 (Foxp3) in lung tissue in asthma mice. METHODS: Sixty male Balb/c mice were divided into normal, model, LY294002 (an inhibitor of PI3K, LY), electroacupuncture (EA) and moxa-cone moxibustion (moxibustion) groups (n=12 in each group). The asthma model was established by intraperitoneal injection of ovalbumin sensitization. The mice in the LY group were injected with LY 294002 (7.5 mg/kg) via the tail vein. EA or moxa-cone moxibustion was applied at BL13 and LU1 in the EA or moxibustion group once daily for 2 weeks. The levels of immunoglobulin E (IgE), interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum and BALF were detected by enzyme-linked immunosorbent assay. The expressions of PI3K, RORγt and Foxp3 in lung tissue were detected by real-time fluorescent quantitative polymerase chain reaction (QRT PCR) and immunohistochemistry. RESULTS: Compared with the normal group, the levels of IgE and IL-4 in serum and BALF, the expressions of PI3K and RORγt mRNA and protein in lung tissue were significantly increased (P<0.01), while the levels of IFN-γ, and the expressions of Foxp3 mRNA and protein were significantly reduced (P<0.01) in the model group. Compared with the model group, the levels of IgE and IL-4 in serum and BALF, the expressions of PI3K and RORγt mRNA and protein in lung tissue were significantly decreased (P<0.01, P<0.05), and the levels of IFN-γ in serum and BALF, the expressions of Foxp3 mRNA and protein in lung tissue were significantly increased (P<0.01) in the LY, EA and moxibustion groups. CONCLUSION: Moxa cone moxibustion at Shu- and Mu-acupoints of the lung meridian can reduce airway inflammatory reaction and control asthma attacks in asthma mice, which is closely related to its effects in regulating the expressions of RORγt and Foxp3 through PI3K signaling pathway.


Assuntos
Asma , Moxibustão , Pontos de Acupuntura , Animais , Asma/genética , Asma/terapia , Fatores de Transcrição Forkhead/genética , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais
3.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809015

RESUMO

B cell activation is an early event in the development of systemic sclerosis (SSc). The classical activation of B cells downstream of the B-cell receptor (BCR) involves the phosphatidylinositol-3 kinase (PI3K) pathway that integrates the effects of multiple co-stimulatory receptors. Our analysis of PI3K pathway associated molecules in peripheral blood B cells of early diffuse cutaneous SSc (dcSSc) patients showed altered mRNA expression of Toll-like receptor (TLR) homolog CD180, TLR4, complement component 3, IL-4 receptor and secreted phosphoprotein 1 (SPP1). Parallel to this, we found elevated basal SPP1 secretion in dcSSc B cells, but, with BCR + IL-4 receptor co-stimulation, we could not induce further secretion. CD180 stimulation alone resulted in NF-κB activation in more B cells than CD180 + BCR co-stimulation both in dcSSc and healthy control (HC), but the co-engagement increased the phosphorylation of NF-κB only in dcSSc B cells. Additionally, in contrast with HC B cells, the lower basal production of IL-10 by dcSSc B cells could not be elevated with CD180 stimulation. Furthermore, activation via CD180 increased the percentage of CD86+ switched memory (CD27+IgD-) B cells in dcSSc compared to HC. Our results suggest that alternative B cell activation and CD180 dysfunction cause imbalance of regulatory mechanisms in dcSSc B cells.


Assuntos
Linhagem da Célula/genética , Complemento C3/genética , Fosfatidilinositol 3-Quinases/genética , Esclerodermia Difusa/genética , Antígenos CD/genética , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem da Célula/imunologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Interleucina-10/genética , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Osteopontina/genética , Receptores de Interleucina-4/genética , Esclerodermia Difusa/metabolismo , Esclerodermia Difusa/patologia , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética
4.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804063

RESUMO

Besides its insulinotropic actions on pancreatic ß cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Exenatida/farmacologia , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Animais , Movimento Celular/genética , Sobrevivência Celular/genética , Cromonas/farmacologia , Técnicas de Cocultura , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Exenatida/genética , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Morfolinas/farmacologia , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Células de Schwann/citologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Nervo Isquiático/lesões
5.
J Agric Food Chem ; 69(15): 4446-4452, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33822608

RESUMO

The hypoglycemic activities of the hydrophobic branched-chain amino acid (BCAA) peptides from seabuckthorn seed protein were preliminarily characterized in type 2 diabetic db/db mice. Four novel BCAA peptides (18.27 ± 0.26% (w/w): Leu/Ile-Pro-Glu-Asp-Pro, Asp-Leu/Ile-Val-Gly-Glu, Leu/Ile-Pro, and Leu/Ile-Pro-Leu/Ile) were identified in seabuckthorn seed protein. The protein content in seabuckthorn seed protein hydrolysate, obtained using 80% ethanol, was 78.8 ± 1.4% (w/w). Animal experiments revealed that oral administration of BCAA peptides (all four) significantly reversed the diabetic symptoms. Compared to the db/db group (control), body weight and insulin resistance were ameliorated after treatment with BCAA peptides (0.5, 1.0, 2.0 mg/(g d)). Also, the treatment remarkably reduced the fasting blood glucose (FBG) levels by upregulation of glucose transporter 4 (GULT4). Moreover, BCAA peptides significantly increased the muscle glycogen content (22.6 ± 0.9 nmol/mg) via the downregulation of protein kinase B (AKT) and glycogen synthase kinase-3ß (GSK-3ß) while increasing the activity of glycogen synthase (GS). BCAA peptides also significantly upregulated the protein levels of phosphatidylinositol 3-kinase (PI3K). We show that BCAA peptides alleviated insulin resistance associated with altered PI3K/Akt protein expression in the skeletal muscle of db/db mice.


Assuntos
Hipoglicemiantes , Fosfatidilinositol 3-Quinase , Aminoácidos de Cadeia Ramificada , Animais , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
6.
Adv Exp Med Biol ; 1280: 219-230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791985

RESUMO

Head and neck squamous cell carcinoma (HNSCC) glycolysis is an important factor for the advancement of the disease and metastasis. Upregulation of glycolysis leads to decreased sensitivity to chemotherapy and radiation. HNSCC cells maintain constitutive glycolytic flux generating metabolic intermediates for the synthesis of amino acids, nucleotides, and fats for cell survival and disease progression. There are several pathways such as PI3K/Akt, EGFR, and JAK-STAT that contribute a major role in metabolic alteration in HNSCC. Recent studies have demonstrated that cancer-associated fibroblasts abundant in the HNSCC tumor microenvironment play a major role in HNSCC metabolic alteration via hepatocyte growth factor (HGF)/c-Met cross signaling. Despite therapeutic advancement, HNSCC lacks broad range of therapeutic interventions for the treatment of the disease. Thus, understanding the different key players involved in glucose metabolism and targeting them would lead to the development of novel drugs for the treatment of HNSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Glicólise , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/genética , Microambiente Tumoral
7.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668685

RESUMO

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.


Assuntos
Carcinogênese/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Serina-Treonina Quinases TOR/genética
8.
Life Sci ; 274: 119354, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737087

RESUMO

AIMS: Gigantol is a bibenzyl compound isolated from orchids of the genus Dendrobium. Gigantol has been demonstrated to possess various pharmacologic (including anticancer) effects. Cisplatin (DDP) has been used and studied as the first-line agent for breast cancer (BC) treatment. Often, its efficacy is jeopardized due to intolerance and organ toxicity. We investigated if gigantol could enhance the anticancer effects of DDP in BC cells and its underlying mechanism of action. MAIN METHODS: The potential pathway of gigantol in BC cells was detected by network-pharmacology and molecular-docking studies. The proliferation and apoptosis of BC cell lines were measured by the MTT assay, colony formation, Hoechst-33342 staining, and flow cytometry. Protein expression was measured by western blotting. KEY FINDINGS: Gigantol could inhibit proliferation of BC cells and enhance DDP-induced apoptosis. According to the results of western blotting, gigantol reinforced DDP-induced anticancer effects through downregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in BC cells. The effects were consistent with those of the pathway inhibitor LY294002. SIGNIFICANCE: Our data might provide new insights into the underlying antitumor effect of gigantol in BC cells. This enhancement effect in the combination of gigantol and DDP may provide many therapeutic benefits in clinical treatment regimens against BC.


Assuntos
Bibenzilas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Sinergismo Farmacológico , Guaiacol/análogos & derivados , Fosfatidilinositol 3-Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Guaiacol/farmacologia , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
9.
Crit Rev Oncol Hematol ; 160: 103284, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33675910

RESUMO

A systematic review (SR) and meta-analysis were conducted to determine the prevalence of PI3K-AKT-mTOR signaling pathway mutations in patients with head and neck cancer (HNC). Overall, 105 studies comprising 8630 patients and 1306 mutations were selected. The estimated mutations prevalence was 13 % for PIK3CA (95 % confidence interval [CI] = 11-14; I2 = 82 %; p < 0.0001), 4% for PTEN (95 % CI = 3-5; I2 = 55 %; p < 0.0001), 3% for MTOR (95 % CI = 2-4; I2 = 5%; p = 0.40), and 2% for AKT (95 % CI = 1-2; I2 = 50 %; p = 0.0001). We further stratified the available data of the participants according to risk factors and tumor characteristics, including HPV infection, tobacco use, alcohol exposure, TNM stage, and histological tumor differentiation, and performed subgroup analysis. We identified significant associations between PI3K-AKT-mTOR pathway-associated mutations and advanced TNM stage (odds ratio [OR] = 0.20; 95 % CI = 0.09-0.44; I² = 71 %; p = 0.0001) and oropharyngeal HPV-positive tumors and PIK3CA mutations (OR = 17.48; 95 % CI = 4.20-72.76; I² = 69 %; p < 0.0002). No associations were found between alcohol and tobacco exposure, and tumor differentiation grade. This SR demonstrated that the PI3K-AKT-mTOR pathway emerges as a potential prognostic factor and could offer a molecular basis for future studies on therapeutic targeting in HNC patients.


Assuntos
Neoplasias de Cabeça e Pescoço , Fosfatidilinositol 3-Quinases , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Prevalência , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética
10.
Life Sci ; 273: 119297, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689686

RESUMO

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 ß (IL-1ß) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.


Assuntos
Biomarcadores/análise , Gastrite/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Estresse Fisiológico , Zeaxantinas/farmacologia , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Gastrite/etiologia , Gastrite/metabolismo , Gastrite/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Fator Trefoil-1/genética , Fator Trefoil-1/metabolismo
11.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(1): 18-24, 2021 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33678632

RESUMO

OBJECTIVES: To investigate the effects of propofol on the proliferation and invasion of glioma U87 cells and to explore the possible anti-tumor mechanisms. METHODS: The glioma U87 cells was divided into a blank group, a positive control group, and the propofol groups (1.00, 2.00 or 5.00 mmol/L). Cell counting kit-8 (CCK-8) was used to detect cell proliferation; Transwell method was used to detect the effect of propofol on invasion and migration of U87 cells; real-time PCR was used to detect the expression of microRNA-134 (miR-134); Western blotting was used to detect the expression levels of reproduction-related protein Ki-67, invasion-related protein metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway-related protein. RESULTS: Compared with the blank group, the proliferation, invasion and migration capacity of U87 cells were reduced in the positive control group and the propofol groups after 48 hours (all P<0.05), along with the decreased expression of Ki-67, MMP-2 and MMP-9 and the ratio of p-PI3K/PI3K and p-Akt/Akt (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). Compared with the positive control group and the 1.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours (all P<0.05), while the level of miR-134 was increased significantly in the 2.00 and 5.00 mmol/L propofol-treated groups (both P<0.05). Compared with the 2.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours in the 5.00 mmol/L propofol-treated group (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). CONCLUSIONS: Propofol can decrease the proliferation rate, and the invasion and migration abilities of U87 cells, which may be achieved by up-regulation of miR-134 and suppression of PI3K/Akt signaling pathway.


Assuntos
Glioma , MicroRNAs , Propofol , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glioma/genética , Humanos , Metaloproteinase 2 da Matriz/genética , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/genética , Propofol/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética
12.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760104

RESUMO

Gastric cancer (GC) is a common malignant tumor in the digestive system, which presents without specific symptoms. Circular RNAs (circRNAs) play important roles in tumor progression and cellular functions; however, the relationship between GC and hsa_circ_0072309 remains unclear. The aim of the present study was to investigate the molecular mechanisms of hsa_circ_0072309 and the role that hsa_circ_0072309 plays in proliferation, invasion and migration of GC cells. The expression of hsa_circ_0072309 was evaluated using reverse transcription­quantitative PCR. A series of functional experiments were performed to study the role that hsa_circ_0072309 has in survival and metastasis of GC cells. In the present study, hsa_circ_0072309 was downregulated in GC cell lines and its overexpression inhibited the proliferation, migration and invasion of GC cells. In addition, hsa_circ_0072309 overexpression induced activation of the peroxisome proliferator­activated receptor γ (PPARγ)/PTEN pathway and inhibition of PI3K/AKT signaling. Moreover, pioglitazone, a PPARγ agonist, strengthened the effects of abundant hsa_circ_0072309 on the proliferative, migratory and invasive capabilities of GC cells, while GW9662, a PPARγ antagonist, abolished the effects of hsa_circ_0072309 overexpression on cell proliferation, migration and invasion. The present findings suggested that hsa_circ_0072309 inhibited proliferation, invasion and migration of gastric cancer cells via the inhibition of PI3K/AKT signaling by activating the PPARγ/PTEN signaling pathway. Targeting hsa_circ_0072309 may be an innovative therapeutic strategy for the treatment of GC.


Assuntos
PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , RNA Circular/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Neoplasias Gástricas/patologia
13.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760114

RESUMO

Steroid­induced avascular necrosis of the femoral head (SANFH) is a common orthopaedic disease that is difficult to treat. The present study investigated the effects of total flavonoids of Rhizoma drynariae (TFRD) on SANFH and explored its underlying mechanisms. The SANFH rat model was induced by intramuscular injection of lipopolysaccharides and methylprednisolone. Osteoblasts were isolated from the calvariae of neonatal rats and then cultured with dexamethasone (Dex). TFRD was used in vitro and in vivo, respectively. Haematoxylin and eosin staining was used to assess the pathological changes in the femoral head. Terminal deoxynucleotidyl transferase­mediated deoxyuridine triphosphate nick end labelling assay and flow cytometry were conducted to detect apoptosis of osteoblasts. The 2',7'­dichlorofluorescein­diacetate staining method was used to detect reactive oxygen species (ROS) levels in osteoblasts and the 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay was used to detect osteoblast proliferation. The expression of caspase­3, Bax, Bcl­2, VEGF, runt­related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (OCN), receptor activator of nuclear factor κB ligand (RANKL) and phosphoinositide 3­kinase (PI3K)/AKT pathway related­proteins were detected via western blotting. It was found that TFRD reduced the pathological changes, inhibited apoptosis, increased the expression of VEGF, RUNX2, OPG and OCN, decreased RANKL expression and activated the PI3K/AKT pathway in SANFH rats. TFRD promoted proliferation, inhibited apoptosis and reduced ROS levels by activating the PI3K/AKT pathway in osteoblasts. In conclusion, TFRD protected against SANFH in a rat model. In addition, TFRD protected osteoblasts from Dex­induced damage through the PI3K/AKT pathway. The findings of the present study may contribute to find an effective treatment for the management of SANFH.


Assuntos
Flavonoides/farmacologia , Osteonecrose/tratamento farmacológico , Extratos Vegetais/farmacologia , Polypodiaceae/química , Animais , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Cabeça do Fêmur/patologia , Flavonoides/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Osteoblastos/efeitos dos fármacos , Osteogênese por Distração/métodos , Osteonecrose/induzido quimicamente , Osteonecrose/patologia , Osteoprotegerina/genética , Fosfatidilinositol 3-Quinases/genética , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Ligante RANK/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroides/efeitos adversos
14.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760204

RESUMO

Cisplatin (DDP)­based chemotherapy is a standard treatment for cervical cancer, although chemotherapy resistance remains a major concern. Hypoxia­inducible factor­2 α (HIF­2α) plays an important role in chemotherapy resistance. MicroRNAs (miRs) can inhibit gene expression by binding to the 3'­untranslated region of the target gene. The authors' previous study showed that miR­519d­3p plays an important role in the regulation of HIF­2α expression under hypoxic conditions in cervical cancer. However, the function and regulatory mechanisms of the miR­519d­3p/HIF­2α axis in DDP­resistance in cervical cancer are not fully understood. Therefore, the aim of the present study was to investigate whether the miR­519d­3p/HIF­2α axis increased DDP resistance by regulating the PI3K/AKT signaling pathway. It was found that the expression of miR­519d­3p was lower in DDP­resistant cervical cancer cells (CaSki/DDP and HeLa/DDP) compared with CaSki and HeLa cells under hypoxic conditions. Additionally, miR­519d­3p overexpression decreased the IC50 value in CaSki/DDP and HeLa/DDP cells, and inhibited HIF­2α protein expression and the PI3K/AKT signaling pathway under hypoxic conditions. Furthermore, it was demonstrated that HIF­2α overexpression reduced the effect of miR­519d­3p overexpression on HeLa/DDP and CaSki/DDP cells. Moreover, the present results suggested that HIF­2α overexpression increased the IC50 value in CaSki/DDP and HeLa/DDP cells. It was also found that HIF­2α overexpression reduced the effect of miR­519d­3p overexpression on the PI3K/AKT signaling pathway. Therefore, the present results indicated that the miR­519d­3p/HIF­2α axis increased DDP resistance of cervical cancer cells by suppressing the PI3K/AKT signaling pathway under hypoxic conditions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cisplatino/farmacologia , MicroRNAs/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Hipóxia Tumoral/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
15.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760124

RESUMO

Glycyrrhizin (GA) is the most essential active ingredient in licorice root, and has a wide range of biological and pharmacological activities. The present study aimed to conduct a detailed analysis of the effects of GA on liver cancer (LC) cell proliferation and the Warburg effect. Hexokinase­2 (HK2) is a glycolytic enzyme that catalyzes the Warburg effect. To this end, the LC HepG2 cell line was transfected with small interfering RNA­HK2 or pCDNA3.1­HK2, followed by GA treatment. A Cell Counting Kit­8 assay and EdU staining were employed to evaluate the proliferation rate of LC cells. The expression levels of HK2 and the phosphorylation level of AKT were measured by reverse transcription­quantitative PCR and western blotting, respectively. Furthermore, the glucose uptake capacity and lactic acid content were assessed by kits, and the glycolysis level was evaluated by assessing the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR). A pronounced increase in the OCR, and decreases in the cell proliferation, glucose uptake capacity, lactic acid content, ECAR and HK2 expression were detected in LC cells subjected to GA treatment or HK2­knockdown. Conversely, overexpression of HK2 reversed these trends, indicating that glycyrrhizin may inhibit LC cell proliferation and the Warburg effect through suppression of HK2. In addition, it was revealed that the PI3K/AKT signaling pathway was associated with LC cell proliferation and the Warburg effect; notably, treatment of LC cells with the AKT agonist SC79 induced elevation of the ECAR, cell proliferation, glucose uptake capacity, lactic acid content, phosphorylated­AKT and HK2 expression, and suppressed the OCR. In conclusion, GA may inhibit the Warburg effect and cell proliferation in LC by suppressing HK2 through blockade of the PI3K/AKT signaling pathway.


Assuntos
Ácido Glicirrízico/farmacologia , Hexoquinase/genética , Neoplasias Hepáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/efeitos dos fármacos , /efeitos dos fármacos
16.
Life Sci ; 276: 119412, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33774025

RESUMO

AIMS: The effects of PFKFB4 on glycolysis during the cancer progression has been investigated, while its role in glioma remains unclear. The present study evaluated the molecular mechanism of PFKFB4 in glycolysis of glioma progression. MATERIALS AND METHODS: The pan-cancer platform SangerBox was inquired to investigate the E2F2 expression in tumors. The E2F2 expression was studied by qRT-PCR and immunohistochemistry in collected glioma and normal brain tissues and by qRT-PCR and western blot in glioma cells. The relationship between the E2F2 expression in glioma tissues and patients' prognosis was analyzed. The cell malignant phenotype, glycolysis, growth and metastasis were examined by CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, ELISA kits, and tumorigenesis and metastasis assays. Downstream targets of E2F2 were searched in hTFtarget, followed by pathway enrichment analysis. The expression of these targets and their correlation with E2F2 expression in gliomas were investigated through the GEPIA website. After ChIP and luciferase assays, the effect of the target on glioma was investigated. KEY FINDINGS: E2F2 was overexpressed in glioma patients and predicted poor prognoses. E2F2 promoted cell proliferation, colony formation, DNA synthesis, migration, invasion and glycolysis, and inhibited apoptosis. Meanwhile, inhibition of E2F2 suppressed the growth and metastasis of gliomas. E2F2 elevated the PFKFB4 expression transcriptionally by binding to its promoter and activated PI3K/AKT pathway. The promotion of glioma metastasis and glycolysis by E2F2 was mitigated by PFKFB4 knockdown. SIGNIFICANCE: E2F2-mediated transcriptional enhancement of PFKFB4 expression regulated the phosphorylation of PI3K/AKT to promote glioma malignancy progression.


Assuntos
Biomarcadores Tumorais/metabolismo , Fator de Transcrição E2F2/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfofrutoquinase-2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Fator de Transcrição E2F2/genética , Feminino , Glioma/genética , Glioma/metabolismo , Glicólise , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Fosfofrutoquinase-2/genética , Fosforilação , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Life Sci ; 276: 119367, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33775691

RESUMO

BACKGROUNDS: Estrogen and its metabolites often lead to intrahepatic cholestasis in susceptible women with pregnancy, administration of oral contraceptives and postmenopausal hormone replacement therapy. Recently, dysfunction of the gut-liver axis has been suggested to play a pivotal role in the progression of cholestasis, but details about estrogen cholestasis (EC)-induced gut and liver injury are still largely unknown. This study aims to gain insight into EC-induced gut and liver injury and cell signaling implicated. METHODS: Male rats were exposed to 5 and 10 mg/kg of 17α-ethinylestradiol via subcutaneous injection for 5 successive days to simulate human EC. RESULTS: By detection of these estrogen cholestatic rats, we found that EC induced inflammation in the liver but not in the intestine through activating NF-κB signaling pathway. EC strongly induced oxidative stress in both the liver and intestine, and activated the hepatic Nrf2/Gclm/Gclc pathway and the intestinal Nrf2/Ho-1 pathway, respectively, for adaptively regulating oxidative stress. EC increased cell apoptosis in both the liver and intestine. Additionally, EC elevated phosphorylation of Akt, ERK1/2, and p38 in the liver and increased phosphorylation of p38 in the intestine. CONCLUSIONS: EC induces liver inflammation, both gut and liver oxidative stress and apoptosis, involving in activating PI3K/Akt and MAPK signaling pathways. Investigation of EC-induced gut and liver injury contributes to the development of new potential therapeutic strategies.


Assuntos
Colestase/complicações , Estrogênios/toxicidade , Gastroenteropatias/patologia , Hepatopatias/patologia , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Colestase/induzido quimicamente , Colestase/patologia , Gastroenteropatias/etiologia , Gastroenteropatias/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley
18.
Life Sci ; 276: 119439, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785338

RESUMO

AIMS: Our study aimed to investigate the function of GALNT2 in lung adenocarcinoma (LUAD). MAIN METHODS: We used network tools and tissue microarray immunohistochemistry to measure the expression levels of GALNT2 in LUAD. Kaplan-Meier curves and Cox regression methods were used in survival analysis. We detected the role of GALNT2 in cell lines by Cell Counting Kit-8, colony formation, transwell, and wound healing assays. We performed Western blotting to evaluate downstream protein levels. KEY FINDINGS: GALNT2 was highly expressed in LUAD samples and indicated a poor prognosis. Knockdown of GALNT2 suppressed cell line proliferation, migration, and invasion abilities, while overexpression of GALNT2 enhanced those phenotypes. Moreover, GALNT2 activated Notch/Hes1-PTEN-PI3K/Akt signaling axis. SIGNIFICANCE: Our data confirmed the cancer-promoting effect of GALNT2, and might provide a new approach for LUAD therapy.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , N-Acetilgalactosaminiltransferases/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Idoso , Apoptose , Biomarcadores Tumorais/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , N-Acetilgalactosaminiltransferases/genética , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Taxa de Sobrevida , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Células Tumorais Cultivadas
19.
J Biol Regul Homeost Agents ; 35(2): 473-484, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33687910

RESUMO

Exosomes are involved in a range of processes in lung cancer such as cell proliferation, metastasis, and angiogenesis. Tumor-derived exosomes participate in the formation and progression of lung cancer by delivering functional biomolecules, including microRNAs (miRNA). The purpose of the present study was to determine the role of lung cancer cell-derived exosomal miR-210 in the proliferation and invasion of lung cancer cells and its underlying mechanism. Initially, exosomes were isolated from A549 cells and characterized by transmission electron microscopy and assessment of exosomal marker expression. RT-qPCR determined that miR-210 expression was elevated in exosomes as well as lung cancer cells. As reflected by dual-luciferase reporter assay, miR-210 negatively regulated RUNX3 expression. Following loss- and gain- function assay, it was found that miR-210 inhibition suppressed biological properties of A549 and H460 cells, which could be reversed by the silencing of RUNX3. miR-210 elevation induced the p-PI3K/PI3K and p-AKT/AKT levels, suggesting the activation of PI3K/AKT signaling pathway. Collectively, exosomal miR-210 targeted and negatively regulated RUNX3 expression to promote malignant properties of lung cancer cells by potentiating PI3K/AKT signaling pathway.


Assuntos
Neoplasias Pulmonares , MicroRNAs , Linhagem Celular Tumoral , Proliferação de Células , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
20.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673180

RESUMO

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32-/- mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32-/- mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32-/- neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32-/- mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quimiocinas/metabolismo , Lipoproteínas/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Quimiocinas/genética , Lipoproteínas/genética , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo
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