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1.
Life Sci ; 259: 118383, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896555

RESUMO

AIMS: Previous studies have shown that the widespread use of estrogen preparations can cause adverse outcomes such as thrombosis and cardiovascular disease. Autophagy is a biochemical process necessary to maintain cell homeostasis. The present study investigated whether E-2 mediates autophagy-induced endothelial cell dysfunction. The role of aspirin in this process was then studied. MAIN METHODS: Western blot, fluorescence microscopy, electron transmission microscopy, plasma construction and transfection, vasoreactivity study in wire myograph are all used in this study. KEY FINDINGS: We found that E-2 activated the PI3K/mTOR signaling pathway and inhibited the formation of the Atg14L-Beclin1-Vps34-Vps15 complex, thereby inhibiting autophagy. Aspirin promoted Beclin1 phosphorylation in autophagy initiation complexes and enhanced autophagy. Furthermore, E-2 treatment of HAECs resulted in endothelial dysfunction by inhibiting autophagy and leading to accumulation of α-smooth muscle actin (α-SMA). E-2 inhibited the activation of eNOS and reduced the expression of eNOS protein. In the mouse aortic vascular function test, E-2 disrupted endothelium-dependent vasodilation. An α-SMA-shRNA lentivirus eliminated the disruption to endothelium-dependent vasodilation by E-2. Aspirin inhibited α-SMA accumulation by enhancing autophagy, reversed endothelial functional impairment caused by E-2, and promoted endothelium-dependent vasodilation. SIGNIFICANCE: This study provides new evidence that E-2 inhibits autophagy and induces abnormal accumulation of α-SMA, resulting in endothelial cell dysfunction and affecting vasodilation. Aspirin can effectively restore the endothelial cell function disrupted E-2.


Assuntos
Actinas/metabolismo , Aspirina/farmacologia , Autofagia/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estradiol/metabolismo , Proteína VPS15 de Distribuição Vacuolar/metabolismo , Animais , Western Blotting , Células Cultivadas , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Fosforilação/efeitos dos fármacos
2.
Medicine (Baltimore) ; 99(31): e21446, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756162

RESUMO

Aspirin (ASA) exerts an anti-tumor effect via the COX pathway. Clinical studies on the chemopreventive effects of ASA on uterine cancer (UC) remain inconsistent. We used population-based retrospective cohort study to evaluate the UC in ASA users in Taiwanese women. From insurance claims data, we identified 23,342 women received ASA treatment between 2000 and 2010 and a comparison group of same sample size randomly selected from the same database matched by the propensity score. The incidence of UC in the ASA cohort was 10% of that in the comparison group (0.28 vs 2.73 per 10,000 person-years). The Poisson regression analysis estimated adjusted incidence rate ratio (IRR) was 0.10 (95% confidence interval (CI) = 0.09-0.11) for ASA users relatives to comparisons after controlling for covariates. The UC incidence in ASA users decreased with age, from 0.61 per 10,000 person-years in the 20 to 39 years old (adjusted IRR = 0.21, 95% CI = 0.15-0.29) to 0.21 per 10,000 person-years in the 65 to 80 years old (adjusted IRR = 0.15, 95% CI = 0.12-0.16). The incidence was higher in longer term users. Hormone therapy of estradiol was associated with the increase of UC risk in both cohorts, but less in ASA users than comparisons (1.34 vs 4.75 per 10,000 person-years). This study suggests that ASA use was associated with a decreased risk of UC. Further prospective randomized clinical trials are warranted to confirm the association.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Neoplasias Uterinas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Estudos de Casos e Controles , Quimioprevenção , Estudos de Coortes , Inibidores de Ciclo-Oxigenase/administração & dosagem , Estradiol/efeitos adversos , Estrogênios/efeitos adversos , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Taiwan/epidemiologia
3.
Int J Food Microbiol ; 334: 108807, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-32835997

RESUMO

The main goal of this study was to describe impact of preharvest application of methyl salicylate (MeSA), acetyl salicylic acid (ASA) and salicylic acid (SA) on the reduction of disease caused by Botrytis cinerea in two table grape cultivars ('Crimson' and 'Magenta'). Based on previous studies, MeSA and SA were applied at 0.1 and 0.01 mM for both cultivars, while ASA was applied at 1 mM in 'Crimson' and 0.1 mM in 'Magenta'. At time of harvest, berry maturity-quality attributes, bioactive compounds and antioxidant enzymes were determined. In addition, grapes were artificially inoculated with B. cinerea spores, and the berries were ranked for visual decay incidence after 5 days of inoculation. Salicylates preharvest treatments led to higher total acidity, content of bioactive compounds and activity of antioxidant enzymes in treated than in control berries. The application of salicylate derivatives induced resistance to B. cinerea spoilage, since higher percentage of berries with no symptoms was observed and on the contrary, the highest percentages of berries were obtained in control grapes. All preharvest treatments with SA, ASA and MeSA alleviated postharvest disease caused by B. cinerea probably due to increasing levels of phenolic compounds and activity of antioxidant enzymes, although the best results were obtained with MeSA at 0.1 mM. Also, for this treatment and dose, higher quality properties, such as higher concentrations of ascorbic, succinic and fumaric acids, were observed compared with no treated-grapes.


Assuntos
Antioxidantes/metabolismo , Botrytis/efeitos dos fármacos , Doenças das Plantas/prevenção & controle , Ácido Salicílico/farmacologia , Vitis/microbiologia , Aspirina/farmacologia , Resistência à Doença/efeitos dos fármacos , Conservação de Alimentos/métodos , Fenóis/metabolismo , Doenças das Plantas/microbiologia , Salicilatos/farmacologia , Vitis/efeitos dos fármacos , Vitis/metabolismo
5.
Drugs ; 80(14): 1383-1396, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32705604

RESUMO

Severe Acute Respiratory Syndrome-Coronavirus-2 is responsible for the current pandemic that has led to more than 10 million confirmed cases of Coronavirus Disease-19 (COVID-19) and over 500,000 deaths worldwide (4 July 2020). Virus-mediated injury to multiple organs, mainly the respiratory tract, activation of immune response with the release of pro-inflammatory cytokines, and overactivation of the coagulation cascade and platelet aggregation leading to micro- and macrovascular thrombosis are the main pathological features of COVID-19. Empirical multidrug therapeutic approaches to treat COVID-19 are currently used with extremely uncertain outcomes, and many others are being tested in clinical trials. Acetylsalicylic acid (ASA) has both anti-inflammatory and antithrombotic effects. In addition, a significant ASA-mediated antiviral activity against DNA and RNA viruses, including different human coronaviruses, has been documented. The use of ASA in patients with different types of infections has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality. However, safety issues related both to the risk of bleeding and to that of developing rare but serious liver and brain damage mostly among children (i.e., Reye's syndrome) should be considered. Hence, whether ASA might be a safe and reasonable therapeutic candidate to be tested in clinical trials involving adults with COVID-19 deserves further attention. In this review we provide a critical appraisal of current evidence on the anti-inflammatory, antithrombotic, and antiviral effects of ASA, from both a pre-clinical and a clinical perspective. In addition, the potential benefits and risks of use of ASA have been put in the context of the adult-restricted COVID-19 population.


Assuntos
Aspirina/farmacologia , Betacoronavirus , Coagulação Sanguínea , Infecções por Coronavirus , Inflamação , Pandemias , Pneumonia Viral , Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Medição de Risco , Resultado do Tratamento
7.
Clin Hemorheol Microcirc ; 76(1): 33-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538826

RESUMO

BACKGROUND: Analysis of responsiveness to antiplatelet therapy is crucial in the management of patients with cardiovascular diseases. OBJECTIVE: This study aimed to evaluate a new platelet function analysis system (Anysis-200) and to compare it with VerifyNow (Accumetrics, San Diego, CA, USA) in cardiology patients. METHODS: Overall, 125 citrated blood samples were collected from 85 cardiology patients referred for platelet function testing. In Anysis-200, platelet function was measured as blood migration distance (MD) until clogging of flow passage, which is comparable to aspirin resistance units obtained using VerifyNow. The two devices were simultaneously used and compared. RESULTS: The MDs before and after taking aspirin were 175±51 and 247±27 mm, respectively (p < 0.0001). Compared with VerifyNow (reference), the sensitivity and specificity of Anysis-200 was 91.5% and 75.5%, respectively (area under the curve, 0.829). Further, the true positive rate in patients newly taking aspirin was 85% for VerifyNow and 92.5% for Anysis-200, respectively. The Cohen's kappa coefficient between the two devices was 0.682, indicating a relatively high agreement. CONCLUSIONS: Anysis-200, a novel system for assessing platelet aggregation, has accuracy and precision equivalent to that of, and significant agreement with, VerifyNow. Anysis-200 may be useful in screening patients with abnormal platelet reactivity and aspirin nonresponsiveness.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Doenças Cardiovasculares/sangue , Testes de Função Plaquetária/métodos , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Int J Clin Pharmacol Ther ; 58(8): 457-464, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32469305

RESUMO

OBJECTIVE: To perform a comparative bioavailability study between a test (re-formulation) and a reference acetylsalicylic acid formulation (Ecasil-81, 81 mg coated tablet) in healthy subjects under fed condition. MATERIALS AND METHODS: Healthy subjects (n = 48) were included in this monocentric, open-label, randomized, two-way crossover pharmacokinetic study. They received a single 81-mg oral dose of a test or a reference formulation of acetylsalicylic acid under fed condition, with a 7-day washout period between the treatments. Blood samples were collected over a period of 36 hours. The salicylic acid plasma concentration was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis was performed using WinNonlin software. RESULTS: The geometric mean and 90% confidence interval of test/reference formulation ratios were 109.32% (102.54 - 116.54%) and 106.94% (102.97 - 111.07%) for salicylic acid Cmax and AUC0-last, respectively. Food decreased the AUC and Cmax (p < 0.001) and delayed the tmax (p = 0.0077). The investigated women presented higher AUC0-∞ and Cmax values (p < 0.001) than men. The clinical and laboratory exams did not show significant alterations. CONCLUSION: The re-formulation is bioequivalent to the reference formulation regarding the absorption extent and rate in fed healthy subjects. The administration of acetylsalicylic acid with food decreased its bioavailability. Moreover, differences in salicylic acid disposition related to sex were observed. The treatments were well tolerated by the investigated subjects.


Assuntos
Aspirina/farmacologia , Administração Oral , Área Sob a Curva , Aspirina/efeitos adversos , Disponibilidade Biológica , Cromatografia Líquida , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica
9.
PLoS One ; 15(5): e0233012, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469878

RESUMO

Leukocyte migration is controlled by a membrane-based chemosensory pathway on the leading edge pseudopod that guides cell movement up attractant gradients during the innate immune and inflammatory responses. This study employed single cell and population imaging to investigate drug-induced perturbations of leading edge pseudopod morphology in cultured, polarized RAW macrophages. The drugs tested included representative therapeutics (acetylsalicylic acid, diclofenac, ibuprofen, acetaminophen) as well as control drugs (PDGF, Gö6976, wortmannin). Notably, slow addition of any of the four therapeutics to cultured macrophages, mimicking the slowly increasing plasma concentration reported for standard oral dosage in patients, yielded no detectable change in pseudopod morphology. This finding is consistent with the well established clinical safety of these drugs. However, rapid drug addition to cultured macrophages revealed four distinct classes of effects on the leading edge pseudopod: (i) non-perturbing drug exposures yielded no detectable change in pseudopod morphology (acetylsalicylic acid, diclofenac); (ii) adaptive exposures yielded temporary collapse of the extended pseudopod and its signature PI(3,4,5)P3 lipid signal followed by slow recovery of extended pseudopod morphology (ibuprofen, acetaminophen); (iii) disruptive exposures yielded long-term pseudopod collapse (Gö6976, wortmannin); and (iv) activating exposures yielded pseudopod expansion (PDGF). The novel observation of adaptive exposures leads us to hypothesize that rapid addition of an adaptive drug overwhelms an intrinsic or extrinsic adaptation system yielding temporary collapse followed by adaptive recovery, while slow addition enables gradual adaptation to counteract the drug perturbation in real time. Overall, the results illustrate an approach that may help identify therapeutic drugs that temporarily inhibit the leading edge pseudopod during extreme inflammation events, and toxic drugs that yield long term inhibition of the pseudopod with negative consequences for innate immunity. Future studies are needed to elucidate the mechanisms of drug-induced pseudopod collapse, as well as the mechanisms of adaptation and recovery following some inhibitory drug exposures.


Assuntos
Macrófagos/efeitos dos fármacos , Pseudópodes/efeitos dos fármacos , Acetaminofen/farmacologia , Adaptação Fisiológica , Animais , Aspirina/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Diclofenaco/farmacologia , Humanos , Ibuprofeno/farmacologia , Imunidade Inata/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/fisiologia , Camundongos , Pseudópodes/fisiologia , Pseudópodes/ultraestrutura , Células RAW 264.7 , Imagem com Lapso de Tempo
10.
Life Sci ; 255: 117854, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470453

RESUMO

Chronic inflammation and hyperglycaemia are well-established aspects in the pathogenesis of type 2 diabetes mellitus (T2D), including the progression of its associated complications such as cardiovascular diseases (CVDs). In fact, emerging evidence shows that dysfunctional immune responses due to dysregulated T-cell function aggravates CVD-related complications in T2D. However, there is a lack of specific therapeutic interventions that protect patients with diabetes who are at risk of heart failure. Metformin and aspirin are among the leading therapies being used to protect or at the very least slow the progression of CVD-related complications. The current review made use of major electronic databases to identify and systematically synthesise emerging experimental data on the impact of these pharmacological drugs on T-cell responses. The quality and risk of bias of include evidence were independently assessed by two reviewers. Overwhelming evidence showed that both metformin and aspirin can ameliorate T-cell mediated inflammation by inducing regulatory T-cells (Tregs) polarisation, inhibiting T-cell trafficking and activation as well as signal transducer and activator of transcription (STAT)3 signalling. As a plausible mechanism to mediate T-cell function, metformin showed enhanced potential to regulate mechanistic targets of rapamycin (mTOR), STAT5 and adenosine-monophosphate-activated protein kinase (AMPK) signalling pathways. Whilst aspirin modulated nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and co-stimulatory signalling pathways and induced T-cell anergy. Overall, synthesised data prompt further investigation into the combinational effect of metformin and aspirin for the management of T2D-related cardiovascular complications.


Assuntos
Aspirina/farmacologia , Inflamação/tratamento farmacológico , Metformina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Inflamação/patologia , Metformina/administração & dosagem , Linfócitos T/imunologia
11.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188379, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439311

RESUMO

Breast cancer is the most ubiquitous type of neoplasms among women worldwide. Molecular aberrations associated with breast development and progressions have been extensively investigated in recent years. An AMP-activated kinase (AMPK) initially identified as a cellular energy sensor that plays a crucial role in cellular energy homeostasis. Intensive research over the last decade about the molecular mechanisms of AMPK has demonstrated that AMPK mediated diverse biological functions are achieved through phosphorylation and regulation of multiple downstream signaling molecules in normal tissue. Downregulation of AMPK activity or decreased level involved in the promotion of breast tumorigenesis, and thus activation of AMPK found to oppose tumor progression. In this review, we epitomize the recent advances in exploring the tumor suppressor function of AMPK pathways. Besides, we discuss the developments in the area of AMPK activator and its molecular mechanisms for breast cancer treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Ativadores de Enzimas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Aspirina/farmacologia , Aspirina/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias da Mama/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Ativadores de Enzimas/farmacologia , Feminino , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Resultado do Tratamento
12.
J Cancer Res Clin Oncol ; 146(8): 2161-2171, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32328776

RESUMO

BACKGROUND: Numerous studies have reported the preventive and protective effects of aspirin in patients with rectal cancer. However, it is not clear whether aspirin can be used as an assistance drug in preoperative neoadjuvant chemoradiotherapy. Therefore, this study will explore the efficacy of aspirin as an adjuvant agent in rectal cancer neoadjuvant chemoradiotherapy. METHODS: A literature search was performed using the electronic platforms to obtain relevant research studies published up to Jan 2020. The search was limited to papers published in English or Chinese language. Confidence intervals of research endpoints in each study were extracted and merged. The meta-analysis was performed using Stata12.0 software. Furthermore, we performed trial sequential analysis (TSA) to evaluate the robustness of our findings and to obtain a more conservative estimation. RESULTS: A total of 5 studies including 977 patients were identified to be eligible for this meta-analysis. Compared with control group, aspirin group significantly increased pathologic complete response rate from 16.5 to 22.3% (RR 1.41, 95% CI 1.01-1.96, P = 0.041), partial remission rate from 21.8 to 45.7% (RR 1.87, 95% CI 1.37-2.54, P < 0.001), and tumor down-staging rate from 44.4 to 63.8% (RR 1.43, 95% CI 1.17-1.75, P = 0.001). Moreover, aspirin group can reduce local recurrence rate (RR 0.37, 95% CI 0.17-0.84, P = 0.017), improve 3-year survival rate (RR 1.24, 95% CI 1.12-1.36, P < 0.001), and 5-year survival rate (RR 1.29, 95% CI 1.14-1.46, P < 0.001). TSA shows that the meta-analysis results of pathologic complete response rate and local recurrence rate may be a false positive. Furthermore, the meta-analysis results of other study endpoints were further confirmed by TSA. CONCLUSION: Aspirin, as an adjuvant agent, can enhance the effect of neoadjuvant chemoradiotherapy and improve the prognosis of patients with rectal cancer. Neoadjuvant therapy combined with aspirin may be considered a better option for preoperative rectal cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aspirina/administração & dosagem , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aspirina/farmacologia , Quimiorradioterapia Adjuvante , Sinergismo Farmacológico , Humanos , Terapia Neoadjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Biol Pharm Bull ; 43(4): 649-662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238706

RESUMO

Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D2 and thromboxane B2, a metabolite of thromboxane A2, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.


Assuntos
Restrição Calórica , Citocinas/imunologia , Prostaglandinas/imunologia , Células Th1/imunologia , Células Th2/imunologia , Timo/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Citocinas/genética , Dieta , Etodolac/farmacologia , Masculino , Camundongos Endogâmicos ICR , Tamanho do Órgão/efeitos dos fármacos , Timo/anatomia & histologia , Timo/efeitos dos fármacos
14.
Int J Gynaecol Obstet ; 150(1): 77-82, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32293031

RESUMO

OBJECTIVE: To evaluate differences in Doppler parameters and pregnancy outcomes, if any, and to determine the predictive accuracy of such indices, as well as the effects of low-dose aspirin (LDA) in unexplained recurrent pregnancy loss (URPL). METHODS: An observational study was conducted at Ren Ji Hospital, Shanghai, China, from May 2015 to December 2016. The endometrial thickness, and the pulsatility index (PI), resistive index (RI), and systolic-to-diastolic ratio (S/D) values of endometrial and uterine artery blood flow were collected. Receiver operating characteristic (ROC) curve analysis was used to analyze data from URPL patients (three or more first-trimester spontaneous abortions with unknown etiology) and patients with normal fertility. A second ultrasonography examination was performed in URPL patients who had received daily LDA for 2 months. RESULTS: There were 190 URPL patients and 35 control patients. Endometrial thickness was significantly thinner in URPL patients than control patients (P=0.005). The PI, RI, and S/D values for endometrial blood flow and the mean PI, RI, and S/D values for uterine arteries were significantly higher in URPL patients (P<0.001). The predictive accuracy of the indices mentioned above were 0.660, 0.802, 0.852, 0.837, 0.784, 0.929, and 0.929, respectively. Following LDA supplementation, URPL patients showed a significant reduction in resistance to endometrial and uterine artery blood flow (P<0.001). CONCLUSION: URPL patients had impaired uterine perfusion. Doppler parameters are valuable in predicting women at high risk of URPL. LDA could be effective in improving endometrial receptivity.


Assuntos
Aborto Habitual/fisiopatologia , Aspirina/farmacologia , Endométrio/efeitos dos fármacos , Aborto Habitual/prevenção & controle , Adulto , Aspirina/administração & dosagem , Estudos de Casos e Controles , China , Endométrio/irrigação sanguínea , Endométrio/diagnóstico por imagem , Feminino , Humanos , Gravidez , Curva ROC , Ultrassonografia Doppler , Artéria Uterina/diagnóstico por imagem , Artéria Uterina/efeitos dos fármacos
15.
Nucleic Acids Res ; 48(9): 4858-4876, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32313942

RESUMO

High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that plays essential roles in embryonic development and cancer progression. However, the mechanism of HMGA2 regulation remains largely uncharacterized. Here, we demonstrate that HMGA2 can be modulated by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, in esophageal squamous cell carcinoma (ESCC). HMGA2 expression was positively associated with HBXIP expression in clinical ESCC tissues, and their high levels were associated with advanced tumor stage and reduced overall and disease-free survival. We found that oncogenic HBXIP could posttranslationally upregulate HMGA2 protein level in ESCC cells. HBXIP induced HMGA2 acetylation at the lysine 26 (K26), resulting in HMGA2 protein accumulation. In this process, HBXIP increased the acetyltransferase p300/CBP-associated factor (PCAF) phosphorylation and activation via the Akt pathway, then PCAF directly interacted with HMGA2, leading to HMGA2 acetylation in the cells. HMGA2 K26 acetylation enhanced its DNA binding capacity and blocked its ubiquitination and then inhibited proteasome-dependent degradation. Functionally, HBXIP-stabilized HMGA2 could promote ESCC cell growth in vitro and in vivo. Strikingly, aspirin suppressed ESCC growth by inhibiting HBXIP and HMGA2. Collectively, our findings disclose a new mechanism for the posttranslational regulation of HMGA2 mediated by HBXIP in ESCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteína HMGA2/metabolismo , Acetilação , Animais , Aspirina/farmacologia , Linhagem Celular Tumoral , DNA/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/química , Humanos , Lisina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Ligação Proteica , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ubiquitinação , Fatores de Transcrição de p300-CBP/metabolismo
16.
Fertil Steril ; 113(3): 601-608.e1, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32192592

RESUMO

OBJECTIVE: To estimate the association between physical activity and risk of subclinical and clinical pregnancy loss among women with a history of pregnancy loss. DESIGN: Prospective cohort study as a secondary analysis of the Effects of Aspirin in Gestation and Reproduction randomized controlled trial of preconception-initiated low-dose aspirin among women with one or two prior pregnancy losses. SETTING: Four U.S. clinical centers, 2007-2011. PATIENT(S): Women with confirmed pregnancy (n = 785) as determined from hCG testing in longitudinally collected biospecimens. MAIN OUTCOME MEASURE(S): Subclinical loss of pregnancy detected only by hCG testing and clinically recognized loss. RESULT(S): Among 785 women (mean [SD] age, 28.7 [4.6] years) with an hCG-confirmed pregnancy, 188 (23.9%) experienced pregnancy loss. In multivariable models adjusted for confounders, compared with the first tertile of physical activity (median = 7.7 metabolic equivalent of task hours/week), there was a roughly twofold higher risk of subclinical loss in the second (risk ratio = 2.06; 95% confidence interval, 1.03-4.14) and third tertiles (risk ratio = 1.92; 95% confidence interval, 0.94-3.90), with median metabolic equivalent of task hours/week of 27.8 and 95.7, respectively. No relations were observed between physical activity and clinically recognized loss. CONCLUSION(S): Risk related to physical activity is different for pregnancy failure close to the time of implantation compared with that for later, clinical pregnancy loss. Higher physical activity levels were associated with an elevated risk of subclinical loss (i.e., pregnancies detected only by hCG, n = 55); however, no relationship was observed with clinically recognized loss. Further work is required to confirm these findings, assess generalizability to women without prior losses, and evaluate mechanisms. ETHICAL APPROVAL: Each participating center's Institutional Review Board approved the study, and participants provided written informed consent. The trial was registered on ClinicalTrials.gov (NCT00467363), and a Data Safety and Monitoring Board provided oversight.


Assuntos
Aborto Espontâneo/epidemiologia , Aspirina/uso terapêutico , Exercício Físico/fisiologia , Cuidado Pré-Concepcional/métodos , Gravidez/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Aborto Espontâneo/etiologia , Adolescente , Adulto , Aspirina/farmacologia , Doenças Assintomáticas , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Recém-Nascido , Complicações na Gravidez/prevenção & controle , Resultado da Gravidez , Fatores de Risco , Adulto Jovem
17.
PLoS One ; 15(3): e0230197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163488

RESUMO

Since hypobaric hypoxia significantly affects metabolic characteristics of intestinal flora, which plays an important role in the biotransformation of aspirin, high altitudes may influence the pharmacokinetics and therapeutic effects of aspirin in the intestines. In the present study, to test alterations of intestinal microbiota at high altitude comparing to that at low altitude, we analyzed rat feces from plain group and high-altitude group by 16S rRNA analysis. To detect concentrations of aspirin and salicylic acid, we established a reliable liquid chromatography tandem mass spectrometry method to measure aspirin and salicylic acid concentrations in fecal suspensions and plasma. Our study found that the plateau hypoxic environment caused a significant increase in Bacteroides in rat feces, while Corynebacterium, Prevotella, and Coprococcus were declined. In addition, compared with the plain group, the metabolic activity of fecal suspensions from the plateau group on aspirin was significantly reduced. More importantly, these changes in the intestinal microbiota led to increasing absorption of aspirin in the rats after rapidly ascent to the plateau, and a reduction in the pharmacodynamic index TXB2, which would possibly result in bleeding. In conclusion, our research provides new ideas for changes in plateau pharmacokinetics, and then guide the corresponding reduction in aspirin dose for the population quickly entering the plateau.


Assuntos
Aspirina/farmacologia , Aspirina/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Altitude , Doença da Altitude/microbiologia , Animais , Fezes/microbiologia , Hipóxia/microbiologia , RNA Ribossômico 16S/genética , Ratos , Ratos Wistar
18.
Eur J Med Chem ; 192: 112200, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32163816

RESUMO

Aspirin is a widely used medicine for a variety of indications. It is unique amongst non-steroidal anti-inflammatory drugs (NSAIDs) in that it causes irreversible acetylation of COX enzymes. Like all NSAIDs however, aspirin causes severe gastrointestinal side-effects, in particular with chronic administration. Prodrugs of aspirin have been proposed as a solution to these side-effects. However, identifying true prodrugs of aspirin, rather than salicylic acid, has proven challenging. This review details the challenges and highlights recent progress in the development of such prodrugs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Aspirina/farmacologia , Neoplasias/tratamento farmacológico , Pró-Fármacos/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Aspirina/efeitos adversos , Aspirina/química , Humanos , Óxido Nítrico/metabolismo , Pró-Fármacos/efeitos adversos , Pró-Fármacos/química
19.
J Cardiovasc Pharmacol ; 75(4): 314-320, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32040035

RESUMO

BACKGROUND: The current light transmission aggregation method is a recognized conventional method for platelet function evaluation, but it is time-consuming and poor in parallelism and cannot simultaneously monitor multiple inducers at multiple levels. The microtiter plate method has been established because of the high-throughput characteristic, but it needs more practical applications. OBJECTIVES: To evaluate the microtiter plate method by using aspirin and clopidogrel in vivo and in vitro. METHODS: In vitro, the platelet aggregations inhibited by aspirin (0.3, 1, 3, 10, 30, 90 µM) and clopidogrel (1, 3, 10, 30, 100, 300 µM) were evaluated with the presence of arachidonic acid (AA) and adenosine diphosphate (ADP) agonists. Using the combination index (CI), the effect of the combination of aspirin and clopidogrel on platelet aggregation was evaluated. In vivo, New Zealand rabbits (n = 18) were randomly divided into 3 groups, aspirin group (5 mg/kg, intragastrical gavage [i.g.]), clopidogrel group (14 mg/kg at the first day, followed by 4 mg/kg, i.g.), and the combination of these two drugs, administered (i.g.) continuously for 7 days. Then, the blood was collected to measure platelet aggregation. RESULTS: Different concentrations of AA (12.5, 25, 50, 100 µM) and ADP (1.25, 2.5, 5, 10 µM) could promote platelet aggregation in concentration-dependent manner, and the most stable induction concentrations of AA and ADP were 50 and 5 µM. In vitro, with the above optimized detection system, aspirin and clopidogrel alone or in combination had concentration-dependent antiplatelet aggregation. The combination of aspirin and clopidogrel also showed synergistic inhibition effect within the concentration range studied. In vivo, aspirin and clopidogrel alone or in combination inhibited platelet aggregation induced by multiple concentrations of AA and ADP agonists, and the combined inhibition was more significant during the administration than aspirin or clopidogrel alone. CONCLUSIONS: The improved microtiter plate method combining the use of multiple levels of multiple agonists avoids the variation of the effective inducer concentrations due to individual different response of platelets to agonists. It may be a potential approach in the detection of platelet aggregation.


Assuntos
Aspirina/farmacologia , Clopidogrel/farmacologia , Monitoramento de Medicamentos/instrumentação , Ensaios de Triagem em Larga Escala/instrumentação , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária/instrumentação , Animais , Relação Dose-Resposta a Droga , Terapia Antiplaquetária Dupla , Humanos , Masculino , Valor Preditivo dos Testes , Coelhos , Fatores de Tempo
20.
Vascul Pharmacol ; 127: 106651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32044414

RESUMO

Aspirin is a widely used drug with anti-coagulating and anti-inflammatory effects on atherosclerotic vascular disease. The goal of this study was to investigate expression of microRNA (miR) in association with changes in arachidonic acid (AA) metabolism in cardiac and surrounding fat mesenchymal stem cells (MSCs) treated with or without aspirin. Aspirin-targeted endogenous lipid metabolites that impact specific miRNA expression were examined by mass spectrometry. The pattern of miR expression was characterized using a microarray of 1100 miRs. There were a dozen miRs expressed differentially in MSCs from human myocardium and peri-myocardial fat tissue at baseline, including hsa-miR-1307-3p, 765, 4739, 3613-3p, 4281, 6816-5p, 2861, and 146b-5p. After exposure to aspirin, cardiac MSCs expressed an array of of miRs (eg, hsa-miR-4734, 10a-5p, 4267, 3197, and 3182), while generation of their endogenous AA metabolites was depressed. However, in the peri-cardiac adipose tissue-derived MSCs, treatment with the same doses of aspirin caused mild changes in the miR expression levels. In conclusion, MSCs from human myocardium and peri-myocardial fat tissue respond differentially to aspirin treatment by alterations in miR expression and AA metabolism. The study further raises an intriguing issue as to whether the copious amounts of aspirin taken worldwide by patients with cardiovascular disease may have direct impacts on their heart repair processes by regulation of stromal cell miR expression and AA metabolism.


Assuntos
Tecido Adiposo/citologia , Anticoagulantes/farmacologia , Ácido Araquidônico/metabolismo , Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/metabolismo , Miocárdio/citologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Fenótipo , Transcriptoma
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