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1.
Anticancer Res ; 39(10): 5541-5549, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570448

RESUMO

BACKGROUND/AIM: The connection between prostate cancer and inflammation has been proposed many years ago, but very little is known about the metabolic adaptations of prostate cells in case of infection or inflammation. The aim of this study was to examine the effect of the stimulation of Toll-like receptor 3 (TLR3) on the metabolism of prostate cancer (PCa) cell lines and benign prostate cells. MATERIALS AND METHODS: Cytofluorimetry, qRT-PCR, western blot and Gas-chromatography/Mass-spectrometry were used. RESULTS: Reprogramming of glucose utilization involving hypoxia-inducible factor 1-alpha (HIF-1α) and the extracellular adenosine axis was observed. TLR3 stimulation synergized with adenosine receptor A2b on PCa cells, and induced a strong production of lactate, exacerbating the Warburg effect. Moreover, stimulation of benign prostate cells with poly I:C reduced lactate secretion, a characteristic typical of the neoplastic transformation. CONCLUSION: TLR3 stimulation promotes metabolic adaptations likely involved in the mechanisms of disease onset and progression.


Assuntos
Glucose/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptor 3 Toll-Like/metabolismo , Adenosina/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Células PC-3 , Poli I-C/metabolismo , Neoplasias da Próstata/patologia , Receptores Purinérgicos P1/metabolismo
2.
Pol J Pathol ; 70(2): 84-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556558

RESUMO

The purpose of the study is to investigate the clinicopathological and prognostic features of dual hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth factor (VEGF) expression in oesophageal squamous cell carcinoma (OSCC) patients. A total of 73 patients were enrolled in this study. The positive expression of HIF-1a was identified in 69.9% of the cases. Hypoxia-inducible factor 1a expression was correlative with pT (p = 0.008) and pTNM stage (p = 0.002). The positive expression of VEGF was identified in 63.0% of the cases. Vascular endothelial growth factor expression was correlative with pT (p = 0.005), pN (p = 0.045), and pTNM stage (p < 0.05). HIF-1a and VEGF expressions had a significantly positive correlation (p = 0.010). Dual positive expression of HIF-1a and VEGF was identified in 50.7% (37/73) of the cases, and it was significantly correlative with pT (p = 0.025), pN (p = 0.008), and pTNM stage (p = 0.014). The OSCC patients' 5-year survival rate was correlative with pT (p < 0.05), pN (p < 0.01), pTNM stage (p < 0.01), VEGF expression (p < 0.01), and dual expressions of HIF-1a and VEGF (p < 0.01). Cox regression analysis showed that pN and dual HIF-1a and VEGF expression were independent prognostic factors for the 5-year survival rate of the patients. In conclusion, HIF-1a combined with VEGF could enable us to more accurately predict the prognosis of OSCC patients.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Prognóstico
3.
Sheng Li Xue Bao ; 71(4): 537-546, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440750

RESUMO

Intermittent hypoxia (IH) has preventive and therapeutic effects on hypertension, myocardial infarction, cerebral ischemia and depression, but its effect on post-traumatic stress disorder (PTSD) has not been known. In this study, we used inescapable electric foot shock combined with context recapture to build PTSD mouse model. The levels of fear and anxiety were valued by the open field, the elevated plus maze (EPM) and the fear conditioning tests; the level of spatial memory was valued by Y maze test; the number of Fos positive neurons in hippocampus, amygdala and medial prefrontal cortex was valued by immunohistochemical staining; and the protein expressions of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF) in these brain area were valued by Western blot. The results showed that IH and model (foot shock) had an interaction on percentage of entering open arms (OE%) in EPM and freezing time and the number of fecal pellets in fear conditioning test. IH increased OE% in EPM and reduced the freezing time and the number of fecal pellets in fear conditioning test in PTSD model mice. At the same time, IH reduced the number of Fos positive neurons in the hippocampus, amygdala and medial prefrontal cortex of PTSD model mice, and increased the protein expression levels of HIF-1α, VEGF and BDNF in these brain tissues. In conclusion, IH pretreatment can relieve fear and anxiety behavior in post-traumatic stress model mice, suggesting that IH may be an effective means of preventing PTSD.


Assuntos
Ansiedade/terapia , Medo , Hipóxia , Transtornos de Estresse Pós-Traumáticos/terapia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
J Agric Food Chem ; 67(32): 8855-8867, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343893

RESUMO

Abalone (Haliotis discus hannai) is a precious seafood in the market. It has been reported that biological active substances derived from abalone have anti-oxidative, anti-inflammatory, anti-bacterial, and anti-thrombosis potential. However, there were few studies to assess whether they have anti-cancer potential. In this study, we evaluated the anti-metastasis and anti-pro-angiogenic factors and mechanism of action of boiled abalone byproduct peptide (BABP, EMDEAQDPSEW) in human fibrosarcoma (HT1080) cells and human umbilical vein endothelial cells (HUVECs). The results demonstrated that BABP treatment significantly lowers migration and the invasion of HT1080 cells and HUVECs. BABP inhibits phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase (MMP) expression and activity by blocking mitogen-activated protein kinases (MAPKs) and NF-κB signaling and hypoxia-induced vascular endothelial growth factor (VEGF) secretion and hypoxia inducible factor (HIF)-1α accumulation through suppressing the AKT/mTOR signal pathway. BABP treatment inhibits VEGF-induced VEGFR-2 expression and tube formation in HUVECs. The effect of BABP on anti-metastatic and anti-vascular activity in HT1080 cells and HUVECs revealed that BABP may be a potential pharmacophore for tumor therapy in the future.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Gastrópodes/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Peptídeos/farmacologia , Resíduos/análise , Inibidores da Angiogênese/química , Inibidores da Angiogênese/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Peptídeos/química , Peptídeos/isolamento & purificação , Frutos do Mar/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Gene ; 712: 143956, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31271843

RESUMO

Gastric cancer represents a common malignancy of digestive tract with high incidence and mortality. Increasing evidence suggests that the growth of gastric tumor cells relies largely on aerobic glycolysis. Currently, many potential anti-cancer candidates are derived from natural products. Here, we evaluated the effects of oleanolic acid (OA), a triterpenoid component widely found in the plants of Oleaceae family, on aerobic glycolysis and proliferation in human MKN-45 and SGC-7901 gastric cancer cells. Our results demonstrated that OA reduced the viability and proliferation of gastric cancer cells and inhibited the expression of cyclin A and cyclin-dependent kinase 2. OA blocked glycolysis in these cells evidenced by decreases in the uptake and consumption of glucose, intracellular lactate levels and extracellular acidification rate. Glycolysis inhibitor 2-deoxy-d-glucose, similar to OA, suppressed gastric cancer cell proliferation. OA also decreased the expression and intracellular activities of glycolysis rate-limiting enzymes hexokinase 2 (HK2) and phosphofructokinase 1 (PFK1). Moreover, OA downregulated the expression of hypoxia inducible factor-1α (HIF-1α) and decreased its nuclear abundance. Upregulation of HIF-1α by deferoxamine rescued OA-inhibited HK2 and PFK1. Furthermore, OA reduced the nuclear abundance of yes-associated protein (YAP) in gastric tumor cells. YAP inhibitor verteporfin, similar to OA, downregulated the expression of HIF-1α and glycolytic enzymes in gastric cancer cells; whereas overexpression of YAP abrogated all these effects of OA. Collectively, inhibition of YAP was responsible for OA blockade of HIF-1α-mediated aerobic glycolysis and proliferation in human gastric tumor cells. OA could be developed as a promising candidate for gastric cancer treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Oleanólico/farmacologia , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/metabolismo , Neoplasias Gástricas/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Ciclo do Ácido Cítrico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise , Humanos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 199-203, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257798

RESUMO

OBJECTIVE: To analyze the expression and relationship of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR) in local skin tissues of pressure injury and investigate the possible mechanism of stage 3 pressure injury refractory wound. METHODS: Forty male SD rats were randomly divided into normal control group, compressed 3 d, 5 d, 7 d, and 9 d groups. Stage 3 pressure injury animal model were established by magnet compression. The morphology of skin was observed by HE staining. The expression of VEGF was detected by immunohistochemistry. The expression levels of HIF-1α, VEGF and KDR protein in skin tissue were detected by Western blot. One-way analysis of variance and LSD test were performed on the data. RESULTS: ①The HE results showed that compared with the normal control group, the epidermis of the compressed group was gradually thickened, the number of blood vessels was decreased, the collagen arrangement disordered and inflammatory cells infiltration were increased. ②Immunohistochemical results showed that the expression of VEGF protein in the 3 d group was significantly higher than that in the normal control group (P<0.01). The expression of VEGF protein in the skin tissue of 5 d, 7 d and 9 d groups was lower than that in normal control group (P<0.05). WB results were consistent with immunohistochemistry results. ③WB results showed that the expression of HIF-1α in the skin tissues of the rats in 3 d, 5 d and 7 d groups was higher than that in the normal control group (P<0.01 or P<0.05). The expression of KDR protein was lower than that of the normal control group (P<0.05 or P<0.01). CONCLUSION: HIF-1α mediated reduction of VEGF and KDR protein expression and decreased tissue angiogenesis may be one of the important causes of chronic dysfunction of stage 3 pressure injury.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pressão/efeitos adversos , Pele/lesões , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
7.
Cell Biochem Funct ; 37(6): 443-451, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317578

RESUMO

Renal cells need oxygen for homeostasis; it is known for adjusting cellular functioning and the energy obtainment have a broad relationship with cellular respiration, through the O2 bioavailability. O2 homeostasis regulation in the kidney is mediated by hypoxia-inducible factors (HIFs). HIF is divided into three α isoforms, represented by HIF-1α, HIF-2α, and HIF-3α in addition to three paralogs of HIF-1ß; these are involved in some metabolic processes, as well as in the pathogenesis of several diseases. Renal biopsy analyses of patients and experimental animal models aim to understand the relationship between HIF and protection against developing renal diseases or the induction of their onset, being thus this molecule can be considered a potential biomarker of renal disease. We carried out a systematic review to which we included studies on HIF-1α and renal disease in the last 5 years (2013-2018) in researches with humans and/or animal model through searches in three databases: LILACS, PubMed, and SciELO by two researchers. We obtained 22 articles that discussed the relationship with HIF as inductor or protector against renal disease and no relation between HIF and renal. We observed controversies remain regarding the relation between of HIF with renal diseases; this may be related to the different intracellular pathways mediated by HIF-1α, thereby determining differentiated cellular responses.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nefropatias/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Nefropatias/patologia
8.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
9.
Anticancer Res ; 39(6): 2739-2747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177109

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-ß. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.


Assuntos
Antígenos CD34/metabolismo , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Astragalus propinquus/química , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Medicina Tradicional Chinesa , Camundongos , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos
10.
Nat Commun ; 10(1): 2824, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249305

RESUMO

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


Assuntos
Fibrose/metabolismo , Hipóxia/metabolismo , Macrófagos/metabolismo , Oncostatina M/metabolismo , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oncostatina M/genética , Fosforilação , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
11.
Gene ; 711: 143938, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31220580

RESUMO

BACKGROUND AND PURPOSE: The pathogenesis of endometrial cancer (EC) involves many regulatory pathways including transcriptional regulatory networks supported by transcription factors and microRNAs only in part known. The aim of this retrospective study was to explore the possible correlation in the EC microenvironment between master regulators of complex phenomena such as steroid responsiveness through estrogen receptor alpha (ERα) and progesterone receptor (PR), epithelial-to-mesenchymal transition (supported by SLUG transcription factor), hypoxia (with hypoxia inducible factor-1 alpha, HIF-1α), and obesity that has been recognized as a EC risk factor. METHODS: Formalin-Fixed Paraffin-Embedded (FFPE) blocks from University of Ferrara Pathology Archive were used and allocated into 2 groups according to their immunohistochemical positivity to ERα and PR, distinguishing the samples with a more benign prognosis (ERα+/PR+) from those with a poorer prognosis (ERα-/PR-). Immunohistochemistry for HIF1-α and SLUG was also performed. Body mass index (BMI) was registered at the time of diagnosis: patients with BMI ≥ 30 kg/m2 were defined obese (OB). Total RNA was isolated for miR-221 analysis. RESULTS: We showed a comparable percentage of HIF1-α and SLUG positive samples in the ERα+/PR+ and ERα-/PR- groups. However, the obesity factor impacted more in the ERα+/PR+ group since the ratio between OB and non-obese (NOB) patients with high expression of HIF1-α and SLUG was higher in ERα+/PR+ than in the ERα-/PR- group. miR-221 levels were significantly higher in the OB than NOB patients, and, also in this case, obesity impacted more in the ERα+/PR+ group. CONCLUSIONS: A molecular circuit of mutual regulation between ERα, PR, HIF1-α, SLUG and miR-221 is feasible in the EC and was firstly suggested by our research. In this interplay miR-221 seems to be in a nodal point of the regulatory system that is particularly strengthened by the metabolic changes in obesity.


Assuntos
Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Obesidade/genética , Receptores de Progesterona/metabolismo , Fatores de Transcrição da Família Snail/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Obesidade/metabolismo , Estudos Retrospectivos , Fatores de Risco , Fatores de Transcrição da Família Snail/metabolismo , Microambiente Tumoral
12.
J Agric Food Chem ; 67(28): 7844-7854, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31241937

RESUMO

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 µM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isotiocianatos/administração & dosagem , Neoplasias da Bexiga Urinária/fisiopatologia , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
13.
Int Heart J ; 60(4): 924-937, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204374

RESUMO

Our previous studies have revealed that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and genes were abnormally expressed in the pulmonary artery tissues of the chronic thromboembolic pulmonary hypertension (CTEPH) patients. We aim to establish the CTEPH-related miRNA-gene-lncRNA network for finding the core genes and associated miRNA and lncRNA in CTEPH patients.Firstly, the target genes of differential miRNAs were predicted by searching TargetScan databases, and the predicted target genes were intersected with the mRNAs from the gene chip. Secondly, the intersective genes were analyzed by the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway software for obtaining differential intersective genes and then establish the miRNA-gene networks. Thirdly, the possible genes regulated by the differential lncRNAs from the gene chip were intersected with the above-screened mRNA to build the lncRNA-mRNA networks. Subsequently, the miRNA-gene-lncRNA networks were constructed according to the two networks above (miRNA-gene networks and lncRNA-mRNA networks). Finally, the core genes of the networks in the experimental group were screened according to Diffk > 0.6 and used to construct the miRNA-core gene-lncRNA networks of CTEPH.The pathway network, miRNA-mRNA network, lncRNA-mRNA networks, and miRNA-gene-lncRNA networks were successfully constructed. The core genes of the miRNA-gene-lncRNA networks (Diffk > 0.6) were the human Beta-type platelet-derived growth factor receptor (PDGFRB) and hypoxia-inducible factor-1a (HIF-1A), the miRNAs-PDGFRB-lncRNAs and miRNAs-HIF1A-lncRNAs networks were constructed. Finally, miRNA-149-5p-PDGFRB-TCONS_l2_00020587-XLOC_l2_010723 and miRNA-338-5p/miRNA-199b-5p-HIF1A- TCONS_l2_00020587-XLOC_l2_010723 were found in the analysis of the network.miRNA-149-5p-PDGFRB-lncRNA CTEPH-associated 1 (CTEPHA1) (TCONS_l2_00020587-XLOC_l2_010723) and miRNA-338-5p/miRNA-199b-5p-HIF1A-lncRNA CTEPHA1 are related to the development of CTEPH.


Assuntos
Hipertensão Pulmonar/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-sis/genética , Embolia Pulmonar/complicações , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Embolia Pulmonar/genética , Embolia Pulmonar/metabolismo
14.
Int J Nanomedicine ; 14: 3705-3722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190820

RESUMO

Hypoxia is a hallmark of malignant tumors and often correlates with increasing tumor aggressiveness and poor treatment outcomes. Therefore, early diagnosis and effective killing of hypoxic tumor cells are crucial for successful tumor control. There has been a surge of interdisciplinary research aimed at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. These mainly include hypoxia-active nanoparticles, anti-hypoxia agents, and agents that target biomarkers of tumor hypoxia. Hypoxia-active nanoparticles have been intensively investigated and have demonstrated advanced effects on targeting tumor hypoxia. In this review, we present an overview of the reports published to date on hypoxia-activated prodrugs and their nanoparticle forms used in tumor-targeted therapy. Hypoxia-responsive nanoparticles are inactive during blood circulation and normal physiological conditions but are activated by hypoxia once they extravasate into the hypoxic tumor microenvironment. Their use can enhance the efficiency of tumor chemotherapy, radiotherapy, fluorescence and photoacoustic intensity, and other imaging and therapeutic strategies. By targeting the broad habitats of tumors, rather than tumor-specific receptors, this strategy has the potential to overcome the problem of tumor heterogeneity and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.


Assuntos
Nanopartículas/química , Nanomedicina Teranóstica , Hipóxia Tumoral , Diagnóstico por Imagem , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/tratamento farmacológico
15.
Nat Commun ; 10(1): 2711, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221993

RESUMO

Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.


Assuntos
Inflamassomos/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sepse/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Seguimentos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/imunologia , Monócitos/citologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores Purinérgicos P2X7/imunologia , Sepse/sangue , Sepse/microbiologia , Sepse/mortalidade , Regulação para Cima/imunologia
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(2): 165-168, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31250610

RESUMO

OBJECTIVE: To investigate the effects of Notch signal on hypoxic induction factor (HIF-1α) and autophagy-associated genes Beclin1, LC3I, LC3II in oxygen-glucose deprivation (OGD) induced myocardial cell injury. METHODS: The OGD model was established using hypoxic culture box and hypoglycemic DMEM medium. The cells were divided into normal control group, OGD group, OGD + NC siRNA group, OGD + Notch1 siRNA group and OGD + HIF-1α siRNA group. Western blot was used to detect the interference effects of HIF-1α siRNA and Notch1 siRNA. The effects of Notch1 siRNA and HIF-1α siRNA on the activity of myocardial cells in OGD model were detected by the CCK-8 assay. The effects of Notch1 siRNA and HIF-1α siRNA on autophage-associated genes Beclin1, LC3I and LC3II expression were detected by Western blot. RESULTS: The results of Western blot showed that HIF-1α siRNA could effectively knock down the expression of HIF-1α in myocardial cells in OGD model, and Notch1 siRNA could effectively knock down the expression of Notch1 and HIF-1α in myocardial cells in OGD model. The result of CCK-8 assay showed that Notch1 siRNA and HIF-1α siRNA reduced the activity of myocardial cells in OGD model, and there was no statistical difference between the two groups. Western blot results showed that Notch1 siRNA and HIF-1α siRNA could reduce the expressions of the autophagy-associated genes Beclin1, LC3I and LC3II, and reduce the ratio of LC3II to LC3I at mRNA level. CONCLUSION: Notch1 plays a role in myocardial protection by regulating the expression of HIF-1α to regulate the autophagy in OGD model cells.


Assuntos
Autofagia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Miócitos Cardíacos/citologia , Receptores Notch/metabolismo , Transdução de Sinais , Proteína Beclina-1/metabolismo , Hipóxia Celular , Células Cultivadas , Glucose , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/patologia , Oxigênio
17.
Nat Commun ; 10(1): 2679, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213603

RESUMO

The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from islet amyloid polypeptide (IAPP), a protein co-expressed with insulin by ß-cells. In common with amyloidogenic proteins implicated in neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers implicated in misfolded protein stress. Here, we establish that hIAPP misfolded protein stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged from oxidative phosphorylation with mitochondrial fragmentation and perinuclear clustering, considered a protective posture against increased cytosolic Ca2+ characteristic of toxic oligomer stress. In contrast to tissues with the capacity to regenerate, ß-cells in adult humans are minimally replicative, and therefore fail to execute the second pro-regenerative phase of the HIF1α/PFKFB3 injury pathway. Instead, ß-cells in T2D remain trapped in the pro-survival first phase of the HIF1α injury repair response with metabolism and the mitochondrial network adapted to slow the rate of cell attrition at the expense of ß-cell function.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Estresse do Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Adulto , Animais , Animais Geneticamente Modificados , Apoptose , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Glicólise/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Masculino , Pessoa de Meia-Idade , Degradação Mitocondrial/fisiologia , Fosforilação Oxidativa , Fosfofrutoquinase-2/metabolismo , Agregados Proteicos/fisiologia , Ratos
18.
Neoplasma ; 66(5): 776-784, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31169018

RESUMO

Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.


Assuntos
Acetanilidas , Adamantano/análogos & derivados , Cisplatino , Células A549 , Acetanilidas/farmacologia , Adamantano/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Neoplasias Pulmonares/fisiopatologia
19.
Life Sci ; 232: 116601, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31252000

RESUMO

AIMS: Tet1, Tet2, and interleukin-6 (IL-6) have been linked to atherosclerosis. Whether Tet3 has a relationship with atherosclerosis and IL-6 was unknown. This study aims to determine the link between Tet3 and IL-6, and the role of Tet3 in prenatal hypoxia-induced atherosclerosis in offspring rats. MAIN METHODS: Pregnant rats were divided into hypoxia and control group. Their male offspring were tested at 20 months old. Hematoxylin-eosin staining and transmission electron microscopic staining were used. Gene mRNA and protein levels were measured with q-PCR or Western blotting. Cell viability and migration was tested with MTT or cell scratch assay. 5-hmC and 5-mC expression were obtained by qGlucMS-PCR; 5-hmC and 5-mC activity were obtained by dot blotting. KEY FINDINGS: Chronic prenatal hypoxia increased Tet3 and IL-6 expression, and decreased Tet3 activity in offspring rats. GlucMS-qPCR showed the percentage of 5-hmC was significantly up-regulated in the promoter of IL-6 in both the rats and cells. Moreover, 5-hmC percentage also was increased in the A7r5 cells transfected with Tet3. Furthermore, Tet3 promoted proliferation and migration of A7r5 cells. However, Tet3 was not sensitive to acute hypoxia, while influenced by HIF-1α DNA element. SIGNIFICANCE: Tet3 enhanced IL-6 expression though up-regulating 5-hmC percentage in the IL-6 promoter.


Assuntos
Aterosclerose/metabolismo , Desoxicitidina/análogos & derivados , Dioxigenases/metabolismo , Hipóxia/metabolismo , Interleucina-6/biossíntese , Animais , Aterosclerose/genética , Aterosclerose/patologia , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Desoxicitidina/metabolismo , Epigênese Genética , Feminino , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Oxigenases de Função Mista/metabolismo , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ativação Transcricional , Regulação para Cima
20.
Biochemistry (Mosc) ; 84(5): 529-539, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234767

RESUMO

Hypoxia plays a critical role in progression of atherosclerosis. Local oxygen deficiency in a plaque creates a specific microenvironment that alters the transcriptome of resident cells, particularly of macrophages. Reverse cholesterol transport from plaque to liver is considered a main mechanism for regression of atherosclerosis. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver- and small intestine-derived apolipoprotein A-1 (ApoA-1) are two main actors in this process. We recently reported endogenous apoA-1 expression in human macrophages. While ABCA1 and ApoA-1 have antiatherogenic properties, the role of complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases. On the other hand, C3 gene knockout in a murine atherosclerosis model increases both plaque size and triglycerides level in blood. In the present study, we show for the first time that a hypoxia-mimicking agent, CoCl2, induces the upregulation of the apoA-1 and C3 genes and the accumulation of intracellular and membrane protein ApoA-1 in THP-1 macrophages. The MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in upregulation of ABCA1 and C3 via activation of transcription factor NF-κB, which interacts with the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1). The three major MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) and the NF-κB transcription factor are involved in the hypoxia-induced expression of the apoA-1 gene in THP-1 macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Hipóxia Celular , Complemento C3/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Linhagem Celular Tumoral , Cobalto/farmacologia , Complemento C3/análise , Complemento C3/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos
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