Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 13.643
Filtrar
1.
Invest Ophthalmol Vis Sci ; 61(1): 3, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31995154

RESUMO

Purpose: The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED). Methods: For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxia-inducible factor (HIF)-1α conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45+ cell apoptosis was determined with neutralizing TRAIL treatment. Results: Desiccating stress significantly increased HIF-1α expression in LG-acinar cells. Furthermore, HIF-1α deficiency significantly enhanced the infiltration of CD45+ inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1α CKO. Interestingly, the main source of TRAIL was the CD45- LG-acinar cells, but not CD45+ immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1α-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1α and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice. Conclusions: Our findings offer novel insight into the regulatory function of acinar cell-derived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.


Assuntos
Dacriocistite/metabolismo , Síndromes do Olho Seco/metabolismo , Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Aparelho Lacrimal/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Apoptose , Técnicas de Cocultura , Dacriocistite/patologia , Modelos Animais de Doenças , Síndromes do Olho Seco/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Marcação In Situ das Extremidades Cortadas , Aparelho Lacrimal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Reação em Cadeia da Polimerase em Tempo Real
2.
J Phys Chem Lett ; 11(3): 864-868, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31940206

RESUMO

The transcriptional adaptor zinc-binding 1 (TAZ1) domain of the transcriptional coactivator CBP/P300 and two disordered peptides, HIF-1α and CITED2, form a delicate protein switch that regulates cellular hypoxic response. In hypoxia, HIF-1α binds TAZ1 to control the transcription of adaptive genes critical for the recovery from hypoxic stress. CITED2 acts as the negative feedback regulator to rapidly displace HIF-1α and efficiently attenuate the hypoxic response. Though CITED2 and HIF-1α have the same dissociation constant (Kd = 10 nM) in their binary complexes with TAZ1, CITED2 is much more competitive than HIF-1α upon binding the same target TAZ1 in ternary ( Berlow et al. Nature 2017 , 543 , 447 - 451 ). Here we demonstrate that a simple coarse-grained model can recapitulate this negative allosteric effect and provide detailed physical insights into the displacement mechanism. We find that long-range electrostatic forces are essential for the efficient displacement of HIF-1α by CITED2. The strong electrostatic interactions between CITED2 and TAZ1, along with the unique binding mode, make CITED2 much more competitive than HIF-1α in binding TAZ1.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Proteínas Repressoras/química , Transativadores/química , Fatores de Transcrição de p300-CBP/química , Regulação Alostérica , Humanos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Eletricidade Estática
3.
Adv Exp Med Biol ; 1232: 131-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893404

RESUMO

Hypoxia, one of the hallmarks of cancer, is caused by an insufficient oxygen supply, mostly due to a chaotic, deficient tumor microcirculation. Apart from a hypoxia-mediated resistance to standard therapies, modulated gene and protein expression, genetic instability and malignant progression, hypoxia also plays a pivotal role in anti-cancer immune responses by (a) reducing survival, cytolytic and migratory activity of effector cells such as CD4+ cells, CD8+ cytotoxic T cells, natural killer-like T cells and natural killer cells, (b) reducing the production and release of effector cytokines, (c) supporting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, (d) increasing the production and release of immunosuppressive cytokines, and (e) inducing the expression of immune checkpoint inhibitors. In this minireview, immunosuppressive effects of hypoxia- and HIF-1a-driven traits in cancers are described.


Assuntos
Hipóxia , Células Supressoras Mieloides , Neoplasias , Humanos , Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia
4.
Adv Exp Med Biol ; 1232: 169-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893407

RESUMO

Inhospitable conditions within the tumor microenvironment (TME) are a characteristic feature ('hallmark') of most solid malignancies. Regional tumor hypoxia is a primary deficiency since it plays a key role in malignant progression. Severe hypoxia is often associated with other detrimental conditions in the TME as a consequence of hypoxia-/HIF-1α-induced (with/without oncogene-direction and/or reciprocal interaction of cancer cells with TME cells) metabolic re-programming, exorbitant extracellular adenosine (ADO) generation and VEGF overexpression/VEGF-R activation. Re-programming of the tumor metabolism inter alia includes a 'selfish' upregulation of aerobic glycolysis/glycolytic flux ('Warburg effect'), a strongly enhanced glutaminolysis in tumor cells, ketogenesis in cancer-associated fibroblasts, and an acceleration of the tryptophan uptake/intensified catabolism yielding kynurenine, which can support the malignant phenotype. Aerobic glycolysis and glutaminolysis result in lactate accumulation (up to 40 mM), and together with the enhanced ketogenesis and CO2/carbonic acid production lead to extracellular acidosis (pHe < 6.8). These traits of the TME individually or collectively operate towards cancer progression via e.g. promotion of genetic instability and mutation, resistance to apoptosis, clonal selection, limitless cell survival and sustained proliferation, continuous angiogenesis and tumor growth, local invasion and distant metastasis, anti-tumor immunosuppression and resistance to therapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias , Hipóxia Tumoral , Microambiente Tumoral , Linhagem Celular Tumoral , Progressão da Doença , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/fisiopatologia , Fenótipo
5.
Adv Exp Med Biol ; 1232: 271-276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893420

RESUMO

Adaptation to hypoxia is essential for regulating the survival and functions of hypoxic cells; it is mainly mediated by the hypoxia-inducible factor 1 (HIF1). The alpha subunit of HIF1 (HIF1α) is a well-known regulatory component of HIF1, which is tightly controlled by various types of HIF1α-regulating processes. Previous research has shown that microtubule-regulated HIF1α nuclear translocation is a key factor for HIF1 activation under hypoxia. In this review, we summarize experimental reports on the role of microtubule-associated factors, such as microtubule, dynein, and dynein adaptor protein, in nuclear translocation of HIF1α. Based upon scientific evidence, we propose a bicaudal D homolog (BICD) as a novel HIF1α translocation regulating factor. A deeper understanding of the mechanism of the action of regulatory factors in controlling HIF1α nuclear translocation will provide novel insights into cell biology under hypoxia.


Assuntos
Transporte Ativo do Núcleo Celular , Subunidade alfa do Fator 1 Induzível por Hipóxia , Transporte Ativo do Núcleo Celular/genética , Hipóxia Celular/fisiologia , Núcleo Celular/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Microtúbulos/metabolismo , Transporte Proteico/genética
6.
J Appl Oral Sci ; 28: e20190140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31800874

RESUMO

OBJECTIVE: The goal of the present study was to determine the effect of systemic and topical ozone application on alveolar bone loss (ABL) by evaluating the effect of Hypoxia-inducible factor -1 alpha (HIF-1-α) and receptor activator of NF-kB ligand (RANKL)-positive cells on histopathological and immunohistochemical changes in a rat periodontitis model. METHODOLOGY: Thirty male Wistar rats were divided into three groups: 1) Group C (control group); 2) Group SO (systemic ozone group) and 3) Group TO (topical ozone group). Experimental periodontitis was induced with a 3/0 silk suture placed at the mandibular left first molars of rats, and the suture was removed 14 days later. Ozone gas was injected intraperitoneally (0.7 mg/kg) in SO group. Topical ozone application protocol was performed using an ozone generator at 80% concentration (4th grade) 90- degree probe for the duration of 30 s. Both ozone applications were carried out for two weeks at intervals of two days. Histomorphometric and immunohistochemical analysis were performed. RESULTS: ABL was significantly lower in Group SO compared to Group C (p: 0.0052). HIF-1α- positive cells were significantly lower in Group TO than in Group C (p: 0.0043). RANKL-positive cells were significantly lower in Group SO and in Group TO compared to the control group (p: 0.0033, p: 0.0075, respectively). CONCLUSION: Both ozone applications decreased RANKL-positive cell counts, TO application decreased HIF-1-α positive cells counts, and SO application was found to be more effective in reducing ABL compared to control group.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Ozônio/administração & dosagem , Periodontite/tratamento farmacológico , Periodontite/patologia , Administração Tópica , Animais , Contagem de Células , Imuno-Histoquímica , Masculino , Ligante RANK/análise , Ratos Wistar , Reprodutibilidade dos Testes , Resultado do Tratamento
7.
Cancer Sci ; 111(1): 239-252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31729096

RESUMO

Hypoxia-inducible factor 1 (HIF-1) is a critical heterodimeric transcription factor for tumor malignancy. Recently, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) has been reported to function as a deubiquitinating enzyme for the stabilization of its α subunit (HIF-1α). In the present study, we showed that UCHL1 inhibition can be an effective therapeutic strategy against HIF-1-dependent tumor malignancy. In 2D monolayer culture, a UCHL1 inhibitor suppressed HIF activity and decreased the transcription of HIF downstream genes by inhibiting the UCHL1-mediated accumulation of HIF-1α. Phenotypically, UCHL1 inhibition remarkably blocked cell migration. In 3D spheroid culture models, ectopic expression of UCHL1 significantly upregulated malignancy-related factors such as solidity, volume, as well as viable cell number in an HIF-1α-dependent manner. Conversely, inhibition of the UCHL1-HIF-1 pathway downregulated these malignancy-related factors and also abolished UCHL1-mediated cell proliferation and invasiveness. Finally, inhibition of UCHL1 promoted HIF-1α degradation and lowered the expression of HIF-1 target genes in the 3D model, as also observed in 2D monolayer culture. Our research indicates that the UCHL1-HIF-1 pathway plays a crucial role in tumor malignancy, making it a promising therapeutic target for cancer chemotherapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Esferoides Celulares/patologia , Ubiquitina Tiolesterase/genética , Ubiquitinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação da Expressão Gênica/genética , Células HeLa , Humanos , Regulação para Cima/genética
8.
Food Chem Toxicol ; 135: 110968, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31738984

RESUMO

This October, the Nobel Prize in Physiology or Medicine 2019 was jointly awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for their discoveries of "how cells sense and adapt to oxygen availability." Importantly, the protein named hypoxia-inducible factors (HIF) were revealed in the molecular machinery that how cells regulate the activity of genes in response to hypoxia. Hypoxia has a close relationship with oxidative stress and its related diseases including cancer. Actually, accumulating evidence and recent advances show that mycotoxins, including ochratoxin A, trichothecene mycotoxins T-2 toxin, deoxynivalenol, and diacetoxyscirpenol have the potential of triggering hypoxia in cells. Moreover, HIF-1α activation is involved in the mycotoxin-induced oxidative stress response. As is known, oxidative stress is considered to be a common mechanism of various toxicities of mycotoxins; however, an in-depth molecular mechanism, especially the molecular target in this context is not fully understood. Therefore, in this work, we have discussed the underlying mechanism(s) of hypoxia and HIF-1α in the mycotoxin-induced oxidative stress effect. We believe that the explanation of hypoxia and HIF-1α would open up new avenues for early diagnosis and treatment of mycotoxicosis. More importantly, under these circumstances, we compile a special issue, "Mycotoxins in Food: New Determination Methods, Toxic Mechanisms, and Control Strategies" for Food and Chemical Toxicology. Researchers are encouraged to submit their newest research articles and excellent work within this topic for the readers of Food and Chemical Toxicology.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Micotoxinas/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Humanos , Estresse Oxidativo/fisiologia
9.
Gut ; 69(1): 158-167, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30833451

RESUMO

OBJECTIVE: Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent. DESIGN: Here, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection. RESULTS: Functional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ESR1) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N-(phosphonoacetyl)-L-aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets. CONCLUSION: The discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.


Assuntos
Aspartato Carbamoiltransferase/genética , Ácido Aspártico/análogos & derivados , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética , Di-Hidro-Orotase/genética , Receptor alfa de Estrogênio/metabolismo , Fulvestranto/farmacologia , Hepatite D Crônica/tratamento farmacológico , Ácido Fosfonoacéticos/análogos & derivados , Pirimidinas/biossíntese , Antivirais/farmacologia , Aspartato Carbamoiltransferase/antagonistas & inibidores , Aspartato Carbamoiltransferase/metabolismo , Ácido Aspártico/farmacologia , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/antagonistas & inibidores , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo , Linhagem Celular , Di-Hidro-Orotase/antagonistas & inibidores , Di-Hidro-Orotase/metabolismo , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Inativação Gênica , Hepatite D Crônica/genética , Hepatite D Crônica/metabolismo , Vírus Delta da Hepatite/fisiologia , Hepatócitos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Resistência à Insulina , Estágios do Ciclo de Vida , Mutação com Perda de Função , Ácido Fosfonoacéticos/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Viral/metabolismo , Transdução de Sinais , Replicação Viral
10.
Immunology ; 159(1): 121-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606895

RESUMO

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of the response and function of myeloid cells in hypoxic and inflammatory microenvironments. To define the role of HIF-1α in tuberculosis, the progression of aerosol Mycobacterium tuberculosis infection was analysed in mice deficient in HIF-1α in the myeloid lineage (mHIF-1α-/- ). We show that myeloid HIF-1α is not required for the containment of the infection, as both wild-type (WT) and mHIF-1α-/- mice mounted normal Th1 responses and maintained control of bacterial growth throughout infection. However, during chronic infection mHIF-1α-/- mice developed extensive lymphocytic inflammatory involvement of the interstitial lung tissue and died earlier than WT mice. These data support the hypothesis that HIF-1α activity coordinates the response of myeloid cells during M. tuberculosis infection to prevent excessive leucocyte recruitment and immunopathological consequences to the host.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células Mieloides/metabolismo , Pneumonia/metabolismo , Tuberculose Pulmonar/metabolismo , Animais , Carga Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Interações Hospedeiro-Patógeno , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/microbiologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
11.
Toxicol Lett ; 318: 74-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654802

RESUMO

Metabolic flexibility defines the capacity of cells to respond to changes in nutrient status. Mitochondria are important mediators of metabolic flexibility and dysfunction is associated with metabolic inflexibility and pathology. Foodborne toxins are often overlooked as potential factors contributing to metabolic toxicity. Fusaric acid (FA), a neglected mycotoxin, is known to disrupt mitochondrial function. The aim of this study was to investigate the molecular mechanisms underlying a metabolic switch in response to FA. This study investigated the effects of FA on energy homeostasis in cultured human liver (HepG2) cells. HepG2 cells poised to undergo oxidative and glycolytic metabolism were exposed to a range of FA concentrations (4, 63 and 250 µg/mL) for 6 h. We determined mitochondrial toxicity, acetyl CoA levels and cell viability using luminometric, fluorometric and spectrophotometric methods. Expression of metabolic proteins (PDK1, PKM2, phosphorylated-PDH E1α and HIF-1α) and mRNAs (HIF-1α, PKM2, LDHa and PDK1) were determined using western blot and qPCR respectively. Our data connects a constitutive expression of HIF-1α in response to FA, to the inhibition of pyruvate decarboxylation through up-regulation of PDK-1 and phosphorylation of Pyruvate Dehydrogenase E1α subunit. Moreover, we highlight the potential of FA to induce a glucose "addiction" and phenotype reminiscent of the Warburg effect. The findings provide novel insights into the impact of this neglected foodborne mycotoxin in the dysregulation of energy metabolism.


Assuntos
Plasticidade Celular/efeitos dos fármacos , Microbiologia de Alimentos , Ácido Fusárico/toxicidade , Glicólise/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase (Lipoamida)/metabolismo
12.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(6): 577-582, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31875433

RESUMO

OBJECTIVE: To observe the effect of protein kinase D1 (PKD1) on the growth and metabolism of oral squamous cell carcinoma HSC-4 cells and related molecular mechanisms in the tumor microenvironment. METHODS: HSC-4 cell lines were transfected with shRNA plasmids. Three groups (Wild, control-shRNA, and PKD1-shRNA) were cultured under acidic or hypoxic environment for a certain time. Western blot was used to detect the expression of autophagy-related and glycolytic-related proteins. The proliferation changes were detected by CCK-8 kits. RESULTS: The PKD1-knockdown HSC-4 cell line was established. PKD1 silencing increased autophagy activity. Under hypoxic and acidic conditions, the PKD1-knockdown HSC-4 cells showed lower proliferation than the parental cells. PKD1-knockdown also decreased the expression of hypoxia induciblefactor 1α (HIF-1α) and pyruvate kinase M2 (PKM2). CONCLUSIONS: Under hypoxic and acidic conditions, PKD1 gene silencing can increase apoptotic autophagy activity. Downregulated PKD1 gene expression can reduce the glycolysis of oral squamous cell carcinoma cells and inhibit tumor cell proliferation. This study revealed the important role of PKD1 in the metabolism and growth of oral squamous cell carcinoma, making it a possible target for the treatment of oral squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Proteínas Quinases , Microambiente Tumoral
13.
Stomatologiia (Mosk) ; 98(5): 60-65, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31701931

RESUMO

OBJECTIVE: To study interrelation of maintenance of α-defensins 1-3 and a hypoxia-inducible factor 1-alpha (HIF-1α) in gingival liquid of patients with caries. MATERIAL AND METHODS: 75 patients with the diagnosis dentine caries were enrolled in the study and divided into two groups: in group 1 (n=30) caries was diagnosed in earlier untreated tooth, the 2nd group (n=45) included patients with the recurrence of carious process (in earlier treated tooth). Controls involved 25 caries-free individuals. The level of α-defensins 1-3 was studied in gingival fluid by ELISA method. RESULTS: The level of α-defensins 1-3 and antimicrobic peptide in gingival liquid in group 2 was 28 and 36% higher than in the 1st group, correspondingly (p<0.001). Concentration of HIF-1α in gingival liquid in the 2nd group was almost twice higher (p<0.001) than in group 1 and 82% higher than in controls (p<0.001), while in group 1 it decreased by 11% when compared to controls (p<0.001). All controls showed a close correlation between the level of α-defensins 1-3 and HIF-1α in gingival fluid (R=0.78, p<0.001), not observed in group 1 (R=0.32, p>0.05) but statistically significant in group 2 (R=0.78, p<0.001). Thus, the recurrence of carious process in caries-associated tooth is associated with the hypoxia-dependent activation of a congenital antimicrobial immunity by means of accumulation of HIF-1α and pronounced increase of α-defensins 1-3 in gingival fluid.


Assuntos
Anti-Infecciosos , Cárie Dentária , Dentina , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia
14.
Anticancer Res ; 39(11): 6025-6033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704828

RESUMO

BACKGROUND/AIM: Carbohydrate antigen 19-9 (CA19-9) is a poor prognostic marker in intrahepatic cholangiocarcinoma (IHCC). Previous studies have shown a link between hypoxia and CA19-9 in cancer, and we have previously demonstrated a correlation between HDAC1 and HIF-1α in IHCC. Here, we evaluated the expression and correlation of CA19-9 with HIF-1 and HDAC in IHCC. PATIENTS AND METHODS: This study included 62 patients with IHCC who underwent primary hepatectomy at our department. Clinicopathological characteristics were examined. Immunohistochemical expression of HIF-1 and HDAC1 in specimens was quantitatively evaluated. RESULTS: Patients with high preoperative serum CA19-9 levels showed clinicopathological characteristics associated with tumour progression. High CA19-9 levels were associated with worse overall and recurrence-free survival. Univariate and multivariate analysis detected high CA19-9 levels as an independent poor prognostic factor for IHCC. Serum CA19-9 was significantly correlated with both HIF-1α and HDAC1 expression. CONCLUSION: High serum CA19-9 level is a poor prognostic factor for overall survival in IHCC and correlates with HIF-1α and HDAC1 expression.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Antígeno CA-19-9/metabolismo , Colangiocarcinoma/patologia , Histona Desacetilase 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/cirurgia , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida
15.
Rev Assoc Med Bras (1992) ; 65(10): 1295-1299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721962

RESUMO

AIM: To examine the relationship between treatment response and hypoxia-inducible factor-1 alpha (HIF-1α) levels in patients with locally advanced non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT). METHODS: Eighty patients with NSCLC were included in the study and treated at Acibadem Mehmet Ali Aydinlar University Medical Faculty. HIF-1 α levels were measured before and after CRT by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Patients' stages were as follows; stage IIIA (65%) and stage IIIB (35%). Squamous histology was 45%, adenocarcinoma was 44%, and others were 11%. Chemotherapy and radiotherapy were given concurrently to 80 patients. Forty-five (56%) patients received cisplatin-based chemotherapy, and 35 (44%) received carboplatin-based chemotherapy. Serum HIF-1α levels (42.90 ± 10.55 pg/mL) after CRT were significantly lower than the pretreatment levels (63.10 ± 10.22 pg/mL, p<0.001) in patients with locally advanced NSCLC. CONCLUSION: The results of this study revealed that serum HIF-1α levels decreased after CRT. Decrease of HIF-1α levels after the initiation of CRT may be useful for predicting the efficacy of CRT.


Assuntos
Adenocarcinoma/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Neoplasias Pulmonares/sangue , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade
17.
J Photochem Photobiol B ; 201: 111634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715551

RESUMO

Skin Flap is used in reconstructive plastic surgery. However, complications such as ischemia followed by local necrosis may occur, requiring a new surgical procedure. It is well known that photobiomodulation therapy (PBMT) is an effective technique for improving microcirculation and neoangiogenesis, which contributes positively to the blood supply in the pre and post surgical period. Thus, the objective of the present study was to investigate the effects of preemptive treatment with laser PBMT with different energies on the viability in skin flaps in rats. Sixty-three Wistar rats, male, were randomized into five groups: Control Group (CG) (n = 15): PBMT simulation; Preemptive group 1.1 J laser (GP1) (n = 15): preemptive laser PBMT with 1.1 J of energy per point; Preemptive group 4 J laser (GP4) (n = 15): preemptive PBMT with 4 J of energy per point; Laser group 11 J (G1) (n = 9): PBMT immediately after surgery with 1.1 J of energy per point; Laser group 4 J (G4) (n = 9): TFMB immediately after surgery with 4 J of energy per point. The CG, GP1 and GP4 groups started treatment 72 h prior to surgery and were subdivided into two experimental periods, one of them on the day of the flap and the other along with the other groups on the seventh postoperative day. Three days after the randomization, the animals underwent random skin flap surgery. PBMT was performed with a 660 nm laser at three points. In the first experimental period, a greater number of vessels were found, as well as mast cells in GP1 compared to the CG and greater expression of fibroblast growth factor and vascular endothelial growth factor in the GP1 and GP4 groups compared to the CG. In the second experimental period, GP1 presented a lower percentage of necrotic tissue, a higher number of vessels and a percentage of cells labeled with both VEGF and hypoxia indicible factor alpha (HIF-1α) compared to the CG, FGF in GP1, GP4 and G4 when compared to the CG. Thus, it was concluded that preemptive treatment with PBMT with the application of 1.1 J of energy per point is effective in improving the viability of the skin flap.


Assuntos
Lasers Semicondutores , Retalhos Cirúrgicos/patologia , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/efeitos da radiação , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/metabolismo , Mastócitos/efeitos da radiação , Necrose , Distribuição Aleatória , Ratos , Ratos Wistar , Retalhos Cirúrgicos/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
BMC Complement Altern Med ; 19(1): 318, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744486

RESUMO

BACKGROUND: Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4-17, 2014; Kim and Bae, Curr Opin Hematol 25:52-59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism. METHODS: Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a-/- mouse model (Spicer etal., J Biol Chem 275:21555-21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a-/-mice. RESULTS: In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a-/- mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05). CONCLUSIONS: Conclusively, WPL could ameliorate GPLs in Atp4a-/- mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Mucosa Gástrica/efeitos dos fármacos , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
19.
Zhonghua Shao Shang Za Zhi ; 35(9): 676-682, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594186

RESUMO

Objective: To investigate the expressions of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1α), and epidermal growth factor receptor (EGFR) in different morphological regions of Marjolin ulcer and their clinical relationship with angiogenesis. Methods: From January 2012 to December 2017, the patients admitted to our hospital who met the inclusion criteria were selected, including 92 patients with Marjolin ulcer [56 males and 36 females, aged (55±15) years], 100 patients with chronic non-cancerous skin ulcer [59 males and 41 females, aged (51±16) years], and 100 patients performed with other skin-related surgery [58 males and 42 females, aged (52±15) years], and they were enrolled into Marjolin ulcer group (MU), chronic non-cancerous ulcer group (CNU), and other skin surgery group (OSS) respectively. The etiology, pathogenic site, ulcer diameter, and course of patients in group MU were retrospectively analyzed. Ulcer tissue specimens from patients of group MU and group CNU and specimens of normal skin tissue attached to the tissue resected during operation from patients of group OSS were collected. The expressions of VEGF, HIF-1α, EGFR, and CD34 in the above-mentioned tissue and the surrounding normal skin, ulcer, epitheliomatous hyperplasia, and canceration areas in Marjolin ulcer tissue were detected by immunohistochemical method, and the positive expression rate and protein expression level were calculated. Data were processed with Pearson chi-square test, Mann-Whitney U test, Bonferroni method, and Bonferroni correction, and Spearman correlation analysis was used to analyze the relationship among the total protein expression levels. Results: In group MU, burns accounted for 91.3% (84/92) of the causes of patients, 44.6% (41/92) of the patients had tumors in the lower extremities, 62.0% (57/92) of the patients had skin ulcer diameter of 2.1-5.0 cm, and 75.0% (69/92) of the patients had a course of disease of more than 20 years. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group CNU were 41.0% (41/100), 77.0% (77/100), and 83.0% (83/100), respectively, significantly higher than those of normal skin tissue of patients in group OSS [12.0% (12/100), 45.0% (45/100), and 67.0% (67/100), χ(2)=21.589, 21.522, 6.827, P<0.01]. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group MU were 91.3% (84/92), 100.0% (92/92), and 100.0% (92/92), respectively, which were significantly higher than those in corresponding tissue of patients in group CNU and group OSS (χ(2)=53.372, 24.772, 17.159; 120.543, 72.777, 36.661, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of VEGF in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=87.120, 42.368, 89.624, P<0.01); the positive expression rates of VEGF in canceration and ulcer areas were significantly higher than the rate in epitheliomatous hyperplasia area (χ(2)=22.586, 16.060, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=21.679, 27.600, 27.600, P<0.01), but the positive expression rates of HIF-1α in four morphological areas were similar (χ(2)=3.008, P>0.05). In ulcer tissue of patients in group MU, the protein expression levels of VEGF and CD34 in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.765, -6.819; -6.765, -6.640; -6.765, -6.819, P<0.01), the protein expression levels of VEGF and CD34 in epitheliomatous hyperplasia area were significantly lower than those in ulcer area (Z=-4.484, -5.266, P<0.01), and the protein expression levels of VEGF and CD34 in canceration area were significantly higher than those in ulcer area (Z=-6.427, -6.723, P<0.01) and epitheliomatous hyperplasia area (Z=-6.427, -6.462, P<0.01). In ulcer tissue of patients in group MU, the protein expression levels of HIF-1α and EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.819, -6.393; -6.819, -6.393; -6.819, -6.393, P<0.01), the protein expression levels of HIF-1α and EGFR in ulcer area were significantly lower than those in epitheliomatous hyperplasia and canceration areas (Z=-6.118, -5.638; -6.640, -6.393, P<0.01), and the protein expression levels of HIF-1α and EGFR in canceration area were significantly higher than those in epitheliomatous hyperplasia area (Z=-6.558, -6.819, P<0.01). In ulcer tissue of patients in group MU, the total protein expression levels of VEGF, HIF-1α, and EGFR were significantly positively correlated with the total protein expression level of CD34 (r=0.772, 0.415, 0.502, P<0.01) respectively; the total protein expression level of EGFR was significantly positively correlated with that of HIF-1α (r=0.839, P<0.01), both of which were significantly positively correlated with the total protein expression level of VEGF (r=0.531, 0.440, P<0.01) respectively. Conclusions: The expressions of VEGF, HIF-1α, and EGFR are the highest in Marjolin ulcer canceration area, and EGFR may promote angiogenesis through HIF-1α or directly increasing the expression of VEGF.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neovascularização Patológica/genética , Úlcera Cutânea/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Estudos Retrospectivos , Úlcera Cutânea/patologia
20.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3441-3447, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602907

RESUMO

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 µg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.


Assuntos
Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/farmacologia , Tripterygium/química , Inibidores da Angiogênese/farmacologia , Angiotensina I/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Membrana Sinovial/efeitos dos fármacos , Comprimidos , Fator A de Crescimento do Endotélio Vascular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA