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1.
Crit Care ; 23(1): 300, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484582

RESUMO

RATIONALE: Our pilot study suggested that noninvasive ventilation (NIV) reduced the need for intubation compared with conventional administration of oxygen on patients with "early" stage of mild acute respiratory distress syndrome (ARDS, PaO2/FIO2 between 200 and 300). OBJECTIVES: To evaluate whether early NIV can reduce the need for invasive ventilation in patients with pneumonia-induced early mild ARDS. METHODS: Prospective, multicenter, randomized controlled trial (RCT) of NIV compared with conventional administration of oxygen through a Venturi mask. Primary outcome included the numbers of patients who met the intubation criteria. RESULTS: Two hundred subjects were randomized to NIV (n = 102) or control (n = 98) groups from 21 centers. Baseline characteristics were similar in the two groups. In the NIV group, PaO2/FIO2 became significantly higher than in the control group at 2 h after randomization and remained stable for the first 72 h. NIV did not decrease the proportion of patients requiring intubation than in the control group (11/102 vs. 9/98, 10.8% vs. 9.2%, p = 0.706). The ICU mortality was similar in the two groups (7/102 vs. 7/98, 4.9% vs. 3.1%, p = 0.721). Multivariate analysis showed minute ventilation greater than 11 L/min at 48 h was the independent risk factor for NIV failure (OR, 1.176 [95% CI, 1.005-1.379], p = 0.043). CONCLUSIONS: Treatment with NIV did not reduce the need for intubation among patients with pneumonia-induced early mild ARDS, despite the improved PaO2/FIO2 observed with NIV compared with standard oxygen therapy. High minute ventilation may predict NIV failure. TRIAL REGISTRATION: NCT01581229 . Registered 19 April 2012.

3.
Gen Comp Endocrinol ; 283: 113231, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31351053

RESUMO

Endothelins (EDNs) and their receptors (EDNRs) are reported to be involved in the regulation of many physiological/pathological processes, such as cardiovascular development and functions, pulmonary hypertension, neural crest cell proliferation, differentiation and migration, pigmentation, and plumage in chickens. However, the functionality, signaling, and tissue expression of avian EDN-EDNRs have not been fully characterized, thus impeding our comprehensive understanding of their roles in this model vertebrate species. Here, we reported the cDNAs of three EDN genes (EDN1, EDN2, EDN3) and examined the functionality and expression of the three EDNs and their receptors (EDNRA, EDNRB and EDNRB2) in chickens. The results showed that: 1) chicken (c-) EDN1, EDN2, and EDN3 cDNAs were predicted to encode bioactive EDN peptides of 21 amino acids, which show remarkable degree of amino acid sequence identities (91-95%) to their respective mammalian orthologs; 2) chicken (c-) EDNRA expressed in HEK293 cells could be preferentially activated by chicken EDN1 and EDN2, monitored by the three cell-based luciferase reporter assays, indicating that cEDNRA is a functional receptor common for both cEDN1 and cEDN2. In contrast, both cEDNRB and cEDNRB2 could be activated by all three EDN peptides with similar potencies, indicating that both receptors can function as common receptors for the three EDNs and share functional similarity. Moreover, activation of three EDNRs could stimulate intracellular calcium, MAPK/ERK, and cAMP/PKA signaling pathways. 3) qPCR assay revealed that cEDNs and cEDNRs are widely, but differentially, expressed in adult chicken tissues. Taken together, our data establishes a clear molecular basis to uncover the physiological/pathological roles of EDN-EDNR system in birds and helps to reveal the conserved actions of EDN-EDNR signaling across vertebrates.

4.
Virus Res ; 270: 197675, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351879

RESUMO

Administration of oncolytic viruses (OVs) is an emerging anticancer strategy that exploits the lytic nature of viral replication to enhance the killing of malignant cells. OVs can be used as tools to directly induce cancer cell death and to trigger local and/or systemic immune responses to metastatic cancer in vivo. The effectiveness of OV therapy was initially highlighted by the clinical use of the genetically modified herpes virus, talimogene laherparepvec, for melanoma therapy. A number of OVs are now being evaluated as potential treatments for cancer in clinical trials. In spite of being engineered to specifically target tumor cells, the safety and off-target effects of OV therapy are a concern. The potential safety concerns of OVs are highlighted by current clinical trial criteria, which exclude individuals harbouring other viral infections and people who are immunocompromised. Despite the potential for adverse effects, clinical trials to date revealed relatively minimal adverse immune-related effects, such as fever. With advances in our understanding of virus replication cycles, several novel OVs have emerged. Reverse genetic systems have facilitated the insertion of anticancer genes into a range of OVs to further enhance their tumor-killing capacity. In this review, we highlight the recent advances in OV therapy for a range of human cancers in in vitro and in in vivo animal studies. We further discuss the future of OVs as a therapeutic strategy for a range of life-threatening cancers.

5.
Front Immunol ; 10: 1235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214189

RESUMO

Immune checkpoint blockade (ICB) immunotherapy increases antitumor immunity by blocking cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and displays robust clinical responses in various cancers. However, ICB immunotherapy also triggers severe inflammatory side effects, known as immune-related adverse effects (irAEs). One of the most common toxicities is immune checkpoint blockade-associated colitis (ICB associated colitis). The exact mechanism of ICB associated colitis remains to be explored. Here, we combined ICB (anti-CTLA-4 and anti-PD-1) treatment with a standard colitis model, in which a more severe form of colitis is induced in mice, to recapitulate the clinical observations in patients receiving combined ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy, during which colitis is the most frequent complication encountered. We found that the composition of the gut microbiota changed in ICB associated colitis. Principal component analysis of the gut microbiome showed an obvious reduction in the abundance of Lactobacillus in severe ICB associated colitis. Lactobacillus depletion completely by vancomycin augmented the immunopathology of ICB. Furthermore, we found that the ICB toxicity could be totally eliminated via the administration of a widely available probiotic Lactobacillus reuteri (L.reuteri). Oral administration of L. reuteri therapeutically inhibited the development and progression of colitis, thus ameliorating the loss of body weight and inflammatory status induced by ICB treatment. Mechanistically, the protective effect of L. reuteri was associated with a decrease in the distribution of group 3 innate lymphocytes (ILC3s) induced by ICB associated colitis. In conclusion, our study highlights the immunomodulatory mechanism of the gut microbiota and suggests that manipulating the gut microbiota by administrating L. reuteri can mitigate the autoimmunity induced by ICB, thus allowing ICB immunotherapy to stimulate the desired immune response without an apparent immunopathology.

6.
Cell Biol Toxicol ; 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31102011

RESUMO

Fructose is an important alternative carbon source for several tumors, and GLUT5 is the major fructose transporter which mediates most of fructose uptake in cells. So far, it is unclear whether GLUT5-mediated fructose utilization is important for clear cell renal cell carcinoma (ccRCC). Here, we demonstrated that GLUT5 was highly expressed in a panel of ccRCC cell lines. High GLUT5 expression exacerbated the neoplastic phenotypes of ccRCC cells, including cell proliferation and colony formation. On the other hand, deletion of the GLUT5-encoding gene SLC2A5 dramatically attenuated cellular malignancy via activating the apoptotic pathway. Moreover, administration of 2,5-anhydro-D-mannitol (2,5-AM), a competitive inhibitor of fructose uptake, could markedly suppress ccRCC cell growth. Together, we provide a new mechanistic insight for GLUT5-mediated fructose utilization in ccRCC cells and highlight the therapeutic potential for targeting this metabolic pathway against ccRCC.

7.
Heart Fail Rev ; 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044326

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

8.
Heart Fail Rev ; 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31087212

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is an established long-term complication of pulmonary thromboembolism (PTE). However, studies have shown that many patients with a definitive CTEPH diagnosis have no history of symptomatic PTE, suggesting that PTE is not the only cause of CTEPH. Despite extensive progress in research on pulmonary hypertension in recent years, due to a lack of relevant studies on the pathophysiology of CTEPH, implementing pulmonary endarterectomy (PEA) in patients has many challenges, and the prognosis of patients with CTEPH is still not optimistic. Therefore, revealing the pathogenesis of CTEPH would be of great significance for understanding the occurrence and development of CTEPH, developing relevant drug treatment studies and formulating intervention strategies, and may provide new preventive measures. This article summarizes the current research progress in CTEPH pathogenesis from the perspective of risk factors related to medical history, abnormal coagulation and fibrinolytic mechanisms, inflammatory mechanisms, genetic susceptibility factors, angiogenesis, in situ thrombosis, vascular remodeling, and other aspects.

9.
Rev Sci Instrum ; 90(4): 043104, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31042969

RESUMO

A compact laser system for a portable 87Rb atom interferometry gravimeter has been demonstrated in this work. This laser system is based on frequency doubling of a single seed laser at the wavelength of 1560 nm. The frequency of the seed laser is controlled by a digital unit with an analog feedback circuit. By using this frequency control method, the frequency of the laser system can be shifted over 1 GHz. Based on this method, the Raman frequency can be locked on the F = 3 → F' = 4 transition of 85Rb atoms. Moreover, the Raman sideband and the repumping laser are generated by a phase modulator, and it can generate different laser frequencies to meet the requirements of a typical atom interferometer. Additional sidebands in the Raman beam produced from the phase modulator are optimized and reduced, allowing us to observe atom interference with a free evolution time of 320 ms. The control unit including the laser system has been integrated into a box with a volume of 1.5 m × 0.6 m × 0.6 m, and the weight of which is only 150 kg. Using this compact optical scheme, our atomic gravimeter has achieved a sensitivity of 53 µGal/Hz1/2 and a resolution of better than 1 µGal (1 µGal = 1 × 10-8 m/s2) in an integration time of 3000 s.

10.
Clin Immunol ; 205: 29-34, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121287

RESUMO

Identification of new therapeutic targets for the treatment of sepsis is imperative. We report here that cytokine IL-28 (IFN-λ) levels were elevated in clinical and experimental sepsis. Neutralization of IL-28 protected mice from lethal sepsis induced by cecal ligation and puncture (CLP), which was associated with improved bacterial clearance and enhanced neutrophil infiltration. Conversely, administration of recombinant IL-28 aggravated mortality, facilitated bacterial dissimilation and limited neutrophil recruitment, in the model of sepsis induced by CLP. This study defines IL-28 as a detrimental mediator during sepsis and identifies a potential therapeutic target for the immune therapy in sepsis.

11.
Int J Cardiovasc Imaging ; 35(8): 1499-1508, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31037475

RESUMO

Resting two-dimensional speckle tracking echocardiography (2D-STE) identified right ventricular (RV) systolic function were reported to predict exercise capacity in pulmonary hypertension (PH) patients, but little attention had been payed to 2D-STE detected RV diastolic function. Therefore, we aim to elucidate and compare the relations between 2D-STE identified RV diastolic/systolic functions and peak oxygen consumption (PVO2) determined by cardiopulmonary exercise testing (CPET) in pre-capillary PH. 2D-STE was performed in 66 pre-capillary PH patients and 28 healthy controls. Linear correlation and multivariate regression analyses were performed to evaluate and compare the relations between RV 2D-STE parameters and PVO2. Receiver operating characteristic curves were used to compare the predictive value of 2D-STE parameters in predicting the cut-off-PVO2 < 11 ml/min/kg. There were significant differences of all the 2D-STE parameters between PH patients and healthy controls. In patients, RV-peak global longitudinal strain (GLS, rs = - 0.498, P < 0.001), RV- peak systolic strain rate (GSRs, rs = - 0.537, P < 0.001) and RV- peak early diastolic strain rate (GSRe, rs = 0.527, P < 0.001) significantly correlated with PVO2, but no significant correlation was observed between RV- peak late diastolic strain rate (GSRa, rs = 0.208, P = 0.093) and PVO2. The first multivariate regression analysis of clinical data without echocardiographic parameters identified WHO functional class, NT-proBNP and BMI as independent predictors of PVO2 (Model-1, adjusted r2 = 0.421, P < 0.001); Then we added conventional echocardiographic parameters and 2D-STE parameters to the clinical data, identified S,(Model-2,adjusted r2 = 0.502, P < 0.001), RV-GLS (Model-3, adjusted r2 = 0.491, P < 0.001), RV-GSRe (Model-4, adjusted r2 = 0.500, P < 0.001) and RV-GSRs (Model-5, adjusted r2 = 0.519, P < 0.001) as independent predictors of PVO2, respectively. The predictive power was increased, and Model-5 including RV-GSRs showed the highest predictive capability. ROC curves found RV-GSRs expressed the strongest predictive value (AUC = 0.88, P < 0.001), and RV-GSRs > - 0.65/s had a 88.2% sensibility and 82.2% specificity to predict PVO2 < 11 ml/min/kg. 2D-STE assessed RV function improves the prediction of exercise capacity represented by PVO2 in pre-capillary PH.


Assuntos
Ecocardiografia Doppler/métodos , Tolerância ao Exercício , Hipertensão Pulmonar/diagnóstico por imagem , Função Ventricular Direita , Adulto , Estudos de Casos e Controles , Estudos Transversais , Teste de Esforço , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Adulto Jovem
12.
Mol Cancer ; 18(1): 77, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943988

RESUMO

Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition.


Assuntos
Ciclopentanos/uso terapêutico , Proteína NEDD8/metabolismo , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular , Ensaios Clínicos como Assunto , Ciclopentanos/farmacologia , Humanos , Proteína NEDD8/antagonistas & inibidores , Neoplasias/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
13.
Gut ; 68(9): 1653-1666, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30902885

RESUMO

OBJECTIVE: In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN: We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS: The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS: OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

14.
Medicine (Baltimore) ; 98(6): e14493, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732222

RESUMO

High mobility group box 1 (HMGB1) is a kind of proinflammatory mediator that acts as an alarmin when released by dying, injured or activated cells. Previous studies have reported that HMGB1 are closely linked to antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The present study aimed to evaluate whether serum HMGB1 levels were associated with systemic vasculitis (VAs).The study population consisted of 51 patients with VAs, 46 patients with essential hypertension (EH) and 46 healthy controls (HC). Thirty-five patients with VAs had in active stage and 16 patients with VAs in an inactive stage. Furthermore, 31 patients with VAs had renal involvement, the other 20 patients were selected for without renal involvement. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. Associations between serum HMGB1 levels with clinical and laboratory parameters were analyzed.Serum HMGB1 levels in patients with VAs were significantly higher than in EH and HC (all P < .05), and no difference regarding serum HMGB1 levels could be found between EH and HC (P = .208). Serum HMGB1 levels in VAs patients with active stage were significantly higher than those in HC and VAs patients with inactive stage (all P < .05). Patients with renal involvement and non-renal involvement had increased HMGB1 levels compared with HC (all P < .05). In addition, serum HMGB1 levels were significantly higher in patients with renal involvement compared with non-renal involvement patients (P = .001). Correlation analysis showed that serum HMGB1 levels were positive significant correlated with the Birmingham Vasculitis Activity Score, hypersensitive C reactive protein (Hs-CRP), serum creatinine (Scr) and 24-hour proteinuria (all P < .05). Among the subsets of VAs, serum HMGB1 levels were significantly higher in AAV, polyarteritis nodosa (PAN) and takayasu arteritis (TA) than in HC (all P < .05). More interestingly, serum HMGB1 were significantly higher in patients with PAN compared with AAV and TA patients (all P < .05). Furthermore, there was positive correlation between serum HMGB1 levels and Hs-CRP, Scr, and 24-hour proteinuria in patients with PAN (all P < .05).Serum HMGB1 levels are increased in patients with VAs compared with HC and EH and can reflect the disease activity and renal involvement.


Assuntos
Proteína HMGB1/sangue , Nefropatias/epidemiologia , Vasculite Sistêmica/sangue , Vasculite Sistêmica/epidemiologia , Adulto , Fatores Etários , Biomarcadores , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores Sexuais , Vasculite Sistêmica/fisiopatologia
15.
Clin Exp Rheumatol ; 37 Suppl 117(2): 79-85, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30620279

RESUMO

OBJECTIVES: Lysosomal-associated membrane protein-2 (LAMP-2) is a highly glycosylated type I glycoprotein ex- pressed on the membranes of neutrophils, endothelial cells and other cells, which are closely linked to subsets of systematic vasculitis. The aim of this study was to investigate whether serum LAMP-2 can be used as a biomarker in small and medium vessel vasculitis (SMVV). METHODS: Serum samples from 39 patients with SMVV (including ANCA-associated vasculitis (AAV) and polyarteritis nodosa (PAN)) confirmed by angiography and/or biopsy and 78 healthy controls (HC) were collected. Serum LAMP-2 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Serum LAMP-2 levels in SMVV patients were increased compared with HC (p<0.001). Serum LAMP-2 levels were significantly different between patients with active stage and those with inactive stage (p=0.024). Patients with renal involvement had higher LAMP-2 levels than patients with non-renal involvement at presentation (p=0.022). Furthermore, serum LAMP-2 levels were correlated with Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), hypersensitive CRP (Hs-CRP), serum creatinine (Scr) and 24-hour proteinuria (all p<0.05). Among SMVV subsets, serum LAMP-2 levels were signi cantly higher in PAN compared with AAV (p=0.003). In PAN patients, serum LAMP-2 levels were correlated with BVAS and Hs-CRP (all p<0.05). CONCLUSIONS: Serum LAMP-2 levels can reflect the disease activity and renal involvement of SMVV. Furthermore, serum LAMP-2 levels were significantly higher in PAN compared with AAV, and associated with disease activity. LAMP-2 might be a potential biomarker for SMVV, especially in PAN.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Proteína 2 de Membrana Associada ao Lisossomo/sangue , Poliarterite Nodosa , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos , Biomarcadores/sangue , Feminino , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/imunologia , Masculino , Poliarterite Nodosa/sangue , Poliarterite Nodosa/imunologia
16.
Biomed Pharmacother ; 111: 813-820, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616080

RESUMO

Breast cancer is one of the most common malignancies and the leading cause of women's death, most of breast cancers are estrogen receptor-positive (ER+) breast cancer which can develop into advanced stage from early stage with treatment resistance. The purpose of this study was to investigate anti-ER+ breast cancer effects of 1,2,3,4,6-penta-O-galloyl-ß-d-glucose (PGG) and its possible mechanisms. Cell viability was analyzed by MTT assay. The cell cycle distribution and apoptosis were detected by Flow cytometry. The expressions of cell proliferation- and apoptosis-related proteins were determined by western blot and immunofluorescence staining. The results showed PGG induced cytotoxicity and decreased viability of ER+ breast cancer T-47D and BT-474 cells. Flow cytometry analysis revealed that cell cycle was blocked in S phase at lower dose (25 µM PGG), and G1 phase at higher dose (50 or 75 µM PGG). One of the underlying mechanisms of the anti-cancer effect exerted by PGG was owed to inhibition of the expression of HURP, an up-regulated protein in human hepatocellular carcinoma which is closely related to tumor proliferation, invasion and metastasis. PGG affected cell cycle- or apoptosis-related proteins such as cyclin D1, Bcl-2 and Bax. These data suggest that PGG exerts anti-ER+ breast cancer effects. In this sense, our study provides new alternative therapies to treat breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Taninos Hidrolisáveis/uso terapêutico
17.
J Org Chem ; 84(4): 1999-2011, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30652868

RESUMO

A general and concise method was developed for the synthesis of 2-amino-4,6-diarylpyridine derivatives 4-6 through the cascade reaction, which includes Michael addition, intramolecular cyclization, aromatization, and/or loss of HNO2, of different types of α,ß-unsaturated ketones 1 and 1,1-enediamines 2 and 3 in 1,4-dioxane promoted by the base Cs2CO3 or piperidine. This method is suitable for the efficient parallel synthesis of pyridines. A library of highly functional 2-amino-4,6-diarylpyridine derivatives was easily constructed using the cascade reaction described in this study.

18.
Fitoterapia ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521857

RESUMO

Two new nucleoside derivatives, named asponguanosines A and B (1 and 2), three new N-acetyldopamine analogues, aspongamides C-E (3-5), one new sesquiterpene, aspongnoid D (6), and three known compounds were isolated from the medicinal insect Aspongopus chinensis. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD and 13C NMR calculations. Biological activities of compounds 3-7 towards human cancer cells, COX-2, ROCK1, and JAK3 were evaluated.

19.
J Thorac Dis ; 10(10): 5804-5812, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30505488

RESUMO

Background: Due to its effects, like an exaggerated negative intrathoracic pressure, sympathetic activation, systemic inflammation, oxidative stress, and endothelial dysfunction, obstructive sleep apnea (OSA) has been involved as a cause in multiple cardiovascular diseases. These diseases include coronary artery disease, hypertension, heart failure, and pulmonary hypertension (PH). Furthermore, OSA often coexists with chronic thromboembolic pulmonary hypertension (CTEPH) in clinical practice. However, few studies focus on OSA and its relationship with CTEPH. This study aims to determine whether OSA has an influence on the clinic status of patients with CTEPH, and to identify what possible factors are associated with OSA in CTEPH. Methods: Patients who were newly diagnosed with CTEPH and received overnight polysomnography (PSG) monitoring from September 2015 to December 2017 were enrolled. OSA was defined as apnea-hypopnea index (AHI) of ≥5/h and the obstructive events at ≥50%. Baseline clinical characteristics and parameters were collected and compared between CTEPH patients with and without OSA. In addition, logistic regression analysis was performed to identify possible factors associated with OSA in CTEPH. Results: Fifty-seven patients with CTEPH were eventually enrolled. Among them, 32 patients were diagnosed with OSA by PSG. CTEPH patients with OSA showed an older age, a higher body mass index (BMI), a higher hemoglobin level, a lower oxygen saturation and a worse World Health Organization functional class (WHO FC) (all P<0.05) when compared to CTEPH patients without OSA. In addition, sleep data including AHI, oxygen desaturation index and minimum oxygen saturation were also statistically different between two groups (all P<0.05). Adjusted for age, sex and BMI, hemoglobin [odd ratio (OR) =1.057, 95% confidence interval (CI): 1.001-1.117, P=0.046], oxygen saturation (OR =0.718, 95% CI: 0.554-0.929, P=0.012), N-terminal pro-brain natriuretic peptide (OR =1.001, 95% CI: 1.000-1.002, P=0.016), mean right atrium pressure (OR =1.284, 95% CI: 1.030-1.600, P=0.026), mean pulmonary arterial pressure (mPAP) (OR =1.087, 95% CI: 1.001-1.180, P=0.048), cardiac index (CI) (OR =0.058, 95% CI: 0.008-0.433, P=0.037), pulmonary vascular resistance (OR =1.004, 95% CI: 1.001-1.007, P=0.014) and WHO FC III-IV (OR =18.550, 95% CI: 2.363-144.128, P=0.005) were associated with OSA in CTEPH. Multivariate logistic regression analysis demonstrated CI (OR =0.051, 95% CI: 0.003-0.868, P=0.040) was independently associated with OSA in CTEPH in addition to age, sex and BMI. Conclusions: OSA may aggravate the clinical status of CTEPH patients to some degree. In turn, a worse hemodynamics, oxygenation state and cardiac function are associated with OSA in CTEPH after being adjusted for age, sex and BMI. Among them, CI is the most important parameter in indicating the coexistence of OSA and CTEPH.

20.
Cell Physiol Biochem ; 51(5): 2421-2433, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30537743

RESUMO

BACKGROUND/AIMS: Excessive fluoride intake can induce cytotoxicity, DNA damage and cell-cycle changes in many tissues and organs, including the kidney. However, the underlying molecular mechanisms of fluoride-induced renal cell-cycle changes are not well understood at present. In this study, we used a mouse model to investigate how sodium fluoride (NaF) induces cell-cycle changes in renal cells. METHODS: Two hundred forty ICR mice were randomly assigned to four equal groups for intragastric administration of NaF (0, 12, 24 and 48 mg/kg body weight/day) for 42 days. Kidneys were taken to measure changes of the cell-cycle at 21 and 42 days of the experiment, using flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods. RESULTS: NaF, at more than 12 mg/kg body weight, induced G2/M phase cell-cycle arrest in the renal cells, which was supported by the finding of significantly increased percentages of renal cells in the G2/M phase. We found also that G2/M phase cell-cycle arrest was accompanied by up-regulation of p-ATM, p-Chk2, p-p53, p-Cdc25C, p-CDK1, p21, and Gadd45a protein expression levels; up-regulation of ATM, Chk2, p53, p21, and Gadd45a mRNA expression levels; down-regulation of CyclinB1, mdm2, PCNA protein expression levels; and down-regulation of CyclinB1, CDK1, Cdc25C, mdm2, and PCNA mRNA expression levels. CONCLUSION: In this mouse model, NaF, at more than 12 mg/ kg, induced G2/M phase cell-cycle arrest by activating the ATM-Chk2-p53/Cdc25C signaling pathway, which inhibits the proliferation of renal cells and development of the kidney. Activation of the ATM-Chk2-p53/Cdc25C signaling pathway is the mechanism of NaF-induced renal G2/M phase cell-cycle arrest in this model.


Assuntos
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Rim/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fluoreto de Sódio/efeitos adversos , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Feminino , Rim/citologia , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Endogâmicos ICR , Proteína Supressora de Tumor p53/metabolismo , Fosfatases cdc25/metabolismo
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