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2.
Cancer Prev Res (Phila) ; 15(4): 213-215, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35373259

RESUMO

The role of aspirin in cancer prevention has been well described for multiple cancers, with strong data for gastrointestinal cancers. Studies, primarily conducted in colorectal cancer, suggest that aspirin exerts its cancer-preventive effects through the inhibition of gastrointestinal inflammation. Compared with colorectal cancer, the role of aspirin in gastric cancer prevention is less well described, however it stands to reason that aspirin and/or other nonsteroidal anti-inflammatory drugs may inhibit gastric cancer progression through the inhibition of COX-2. As discussed in this issue of Cancer Prevention Research, aspirin may prevent gastric cancer, albeit it appears to exert a disparate effect in men and women, the reason for which remain unclear. These results expand upon prior studies by prospectively examining aspirin use at a wider range of doses and durations in non-Asian participants and lend support to observations from previously conducted studies in Asian populations. See related article, p. 265.


Assuntos
Neoplasias Gastrointestinais , Neoplasias Gástricas , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/farmacologia , Aspirina/uso terapêutico , Ciclo-Oxigenase 2 , Feminino , Neoplasias Gastrointestinais/prevenção & controle , Humanos , Masculino , Neoplasias Gástricas/prevenção & controle
3.
Eur Rev Med Pharmacol Sci ; 26(6): 2106-2116, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35363360

RESUMO

OBJECTIVE: Aspirin resistance is described as the failure of aspirin to decrease the production of thromboxane A2 by platelets, which is the mechanism by which aspirin decreases platelet activation and aggregation. This study was performed to assess the prevalence of aspirin resistance among cardiovascular patients in al-Qassim, Saudi Arabia. PATIENTS AND METHODS: The study used a survey of patients with first and recurrent attacks of ischemic heart disease (IHD) and available data from blood samples processed using a VerifyNow® kit, which measures aspirin reaction units (ARUs). RESULTS: A total of 119 patients were included: 45 with their first IHD episodes and 74 with recurrent episodes. Of the surveyed patients, 40% with a first episode were younger than 50 years old, and 75.6% of them have been diagnosed with IHD during the previous 5 years. Of the patients with recurrent attacks, 45.9% were older than 60 years, and 54.1% of them have been diagnosed more than 5 years before. The group with first episodes of IHD had 133.2 ARUs, whereas the group with recurrent episodes had 168.5 ARUs (p=0.105). In the recurrent-episode group, 77% had diabetes; in the first-episode group, only 37.8% had diabetes (p≤0.001). Overall, 46.2% were overweight, 54.6% were nonsmokers, and 82.4% underwent percutaneous coronary intervention. CONCLUSIONS: The study participants in both the new and recurrent IHD groups showed no sign of aspirin resistance. The presence of cardiovascular risk factors increased the likelihood of episode recurrence.


Assuntos
Isquemia Miocárdica , Inibidores da Agregação Plaquetária , Aspirina/farmacologia , Plaquetas , Resistência a Medicamentos , Humanos , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/epidemiologia , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Arábia Saudita/epidemiologia
4.
Ann Clin Lab Sci ; 52(2): 222-229, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35414501

RESUMO

OBJECTIVE: It has been demonstrated in vitro that acetylsalicylic acid (ASA) treatment halves hepatitis C virus (HCV) expression in hepatocarcinoma cells. However, the signaling pathway that promotes this ASA-induced antiviral effect has not yet been identified. AIM: The aim of this work was to identify alterations in the transcriptional profile of Huh-7-HCV-subgenomic replicon cells with vs. without ASA treatment. This comparison sheds light onto the signaling pathways and molecular mechanisms involved in the antiviral effects of ASA. METHODS: Human hepatocellular carcinoma (Huh-7) cells that express non-structural HCV proteins (Huh-7-HCV-replicon cells) were exposed to 4 mM ASA for 0, 24, 48, and 72 hours. Total RNA was isolated, and cDNA was synthesized. Transcripts were then tagged with biotin and purified. Thereafter, they were fragmented and hybridized on HG-U133 Plus 2 Gene Expression chips. Hybridization signals were captured using a GeneChip 3000 7G Scanner and analyzed via Expression Console and dChip Software. RESULTS: When exposed to ASA, hepatocarcinoma cells with non-structural HCV proteins were found to differentially regulate genes with oxidative roles in the cell. The most upregulated genes were interleukin 8 (IL-8), cytochrome P450 (CYP450), and metallothioneins (MTs), while the most downregulated genes were ribonucleotide reductases (RRs). CONCLUSION: These results show that ASA modulates the expression of genes with antioxidant functions. This suggests that ASA induces a remodeling of the antioxidant microenvironment, which may in turn interfere with the replication of HCV.


Assuntos
Hepatite C , Neoplasias Hepáticas , Antioxidantes/farmacologia , Antivirais/farmacologia , Aspirina/farmacologia , Hepacivirus/genética , Hepatite C/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , RNA Viral/genética , Replicon/genética , Microambiente Tumoral , Replicação Viral/genética
5.
Asian Pac J Cancer Prev ; 23(4): 1405-1413, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35485703

RESUMO

Objective: Angiogenesis is new blood vessels formations that are necessary for certain physiological and pathologic conditions. Almond oil represents adjuvant therapies for numerous health benefits; It has ability for prevent the formation angiogenesis in tumour, due to its high concentration of unsaturated fatty acids, polyphenols, flavonoids and other ingredients content. Aspirin is non-steroidal ant-inflammatory drug; significantly reduce the angiogenesis of cancer. The aim of the study is to investigate the role of Prunus dulcis oil alone and in combination with aspirin, as an anti-angiogenic. Method: A sequential concentrations ex-vivo rat aorta ring assay, investigate the anti-angiogenic activity of Prunus dulcisoil in vivo. After three days of incubation, small holes were created on the fine pinpoint. Acute toxicity study was evaluated after administration of Prunus dulcis oil via intraperitoneal route. Results: the obtained results displayed that the serial concentration dose-response has a significant inhibition effect of blood vessels growth when compared to the negative control (DMSO 1%), the dose depended percentage of inhibition, sweet almond oil in combination with aspirin synergism effect to inhibition growth blood vessels as anti-angiogenic activity. The zone of inhibition was been measured as the mean of inhibition area of blood vessel on eggs in millimetre (mm) ± standard deviation. Conclusion: Almond oil dose has inhibition effect on cancer and can be used as (anti-angiogenesis), the activity of almond oil with Aspirin synergism can significantly reduce blood vessel's growth in rate aorta ring and CAM assay.


Assuntos
Prunus dulcis , Inibidores da Angiogênese/farmacologia , Animais , Aspirina/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Sementes
6.
Turk J Gastroenterol ; 33(3): 257-270, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35410859

RESUMO

BACKGROUND: Gastroesophageal reflux disease has a high incidence of 23%, with 29% of those with gastroesophageal reflux disease consuming nonsteroidal anti-inflammatory drugs. There are insufficient data concerning the effects of nonsteroidal anti-inflammatory drugs on the esophageal tissue. We aimed to examine the effects of well-known nonsteroidal anti-inflammatory drugs using electrophysiologic criteria on the rabbit esophageal epithelium. METHODS: Esophageal epithelium mounted on Ussing chambers enabled in vitro investigation of the electrophysiological properties. Doses of 1 mg/mL, 2.5 mg/mL, 5 mg/mL ibuprofen, naproxen, and aspirin were dissolved in dimethyl sulfoxide and added to the luminal side. Esophagi were cannulated from both sides for the administration of high-dose ibuprofen in vivo, and the potential difference was monitored. RESULTS: Ibuprofen and aspirin inhibited tissue transport functions in a dose-dependent manner. pH 4 acid and 0.1 mg/mL ibuprofen alone were not harmful; however, the combination of these agents had an additive and significance effect: 78% decrease in the potential difference and 85% decrease in the short-circuited current (Isc). The change in the potential difference in the in vivo experiments (5 mg/mL ibuprofen) was similar (52 ± 7% decrease) with in vitro experiments in the first 30 minutes. CONCLUSION: Nonsteroidal anti-inflammatory drugs were harmful to the rabbit esophageal epithelium in both the in vitro and in vivo experiments. Even though aspirin and ibuprofen affected the transport mechanisms of the esophageal epithelium, the dose-dependent decrease of tissue potential difference and Isc with ibuprofen was more pronounced than those with aspirin. The combination of harmless doses of ibuprofen and acid demonstrated that even low acidic conditions can create a disruptive environment.


Assuntos
Aspirina , Refluxo Gastroesofágico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Epitélio , Humanos , Ibuprofeno/farmacologia , Coelhos
7.
Elife ; 112022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35416770

RESUMO

Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.


Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/epidemiologia , Adenoma/prevenção & controle , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Humanos , Incidência , Cinética , Microambiente Tumoral
8.
Placenta ; 121: 61-69, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35279428

RESUMO

INTRODUCTION: Clinical studies suggest that early pregnancy is the critical window for the prevention of preeclampsia by low-dose aspirin (LDA). Abnormal extravillous trophoblast (EVT) cell invasion and spiral artery remodeling during early placentation have been observed in preeclampsia cases. Thus, we hypothesized LDA prevents preeclampsia by mitigating EVT migration/invasion and spiral artery remodeling dysfunction. METHODS: A single systemic lipopolysaccharide (LPS) (1 µg/kg) injection was administrated in pregnant mice at e14.5 to induce a preeclampsia-like pregnant mouse model. We administered LDA (2.5 µg/g body weight/day) and observed the effects on LPS-induced preeclampsia-like symptoms by examining the placental histology, protein expression, EVT invasion, and spiral artery remodeling. In human EVT cell line, HTR-8/SVneo, we investigated cell invasion and migration by matrigel and wound healing assays, respectively. Signaling pathways were surveyed using inhibitors, siRNA transfections, and Western blot. RESULTS: LDA treatment significantly reversed the preeclampsia-like phenotype induced by LPS, as observed by decreases in hypertension, proteinuria, and fetal growth retardation. The numbers of pathological lesions, including excessive extracellular matrix deposition, endotheliosis, and collapsed glomerular capillaries in kidneys, were significantly lower in the LDA+LPS vs. the LPS group. LDA pretreatment eliminated placental lesions, including calcification, edema, and narrowed uterine spiral arteries and reduced aquaporin-1 (AQP-1) protein expression. In HTR-8/SVneo cells, LDA rescued the decreased cell migration and invasion induced by LPS. The phosphorylation of ERK1/2 was up-regulated and AQP-1 expression was decreased by LPS, which were reversed by LDA treatments. The effects of LDA were inhibited when AQP-1 expression was downregulated by siRNA transfection. DISCUSSION: This study provides new evidence that supports the use of LDA for the prevention of preeclampsia and suggests that the effects of LDA are mediated through a novel mechanism of a water channel, AQP-1, and MAPK/ERK 1/2 signaling.


Assuntos
Pré-Eclâmpsia , Animais , Aquaporina 1/metabolismo , Aspirina/farmacologia , Movimento Celular , Feminino , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Camundongos , Fenótipo , Placenta/metabolismo , Pré-Eclâmpsia/induzido quimicamente , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/prevenção & controle , Gravidez , RNA Interferente Pequeno/farmacologia , Trofoblastos/metabolismo
9.
Neurochem Int ; 154: 105301, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35121011

RESUMO

Traumatic Brain Injury (TBI) is one of the leading causes of death and disability worldwide. Aspirin (ASA) and clopidogrel (CLOP) are antiplatelet agents that inhibit platelet aggregation. They are implicated in worsening the intracerebral haemorrhage (ICH) risk post-TBI. However, antiplatelet drugs may also exert a neuroprotective effect post-injury. We determined the impact of ASA and CLOP treatment, alone or in combination, on ICH and brain damage in an experimental rat TBI model. We assessed changes in platelet aggregation and measured serum thromboxane by enzyme immune assay. We also explored a panel of brain damage and apoptosis biomarkers by immunoblotting. Rats were treated with ASA and/or CLOP for 48 h prior to TBI and sacrificed 48 h post-injury. In rats treated with antiplatelet agents prior to TBI, platelet aggregation was completely inhibited, and serum thromboxane was significantly decreased, compared to the TBI group without treatment. TBI increases UCHL-1 and GFAP, but decreases hexokinase expression compared to the non-injured controls. All groups treated with antiplatelet drugs prior to TBI had decreased UCH-L1 and GFAP serum levels compared to the TBI untreated group. Furthermore, the ASA and CLOP single treatments increased the hexokinase serum levels. We confirmed that αII-spectrin cleavage increased post-TBI, with the highest cleavage detected in CLOP-treated rats. Aspirin and/or CLOP treatment prior to TBI is a double-edged sword that exerts a dual effect post-injury. On one hand, ASA and CLOP single treatments increase the post-TBI ICH risk, with a further detrimental effect from the ASA + CLOP treatment. On the other hand, ASA and/or CLOP treatments are neuroprotective and result in a favourable profile of TBI injury markers. The ICH risk and the neuroprotection benefits from antiplatelet therapy should be weighed against each other to ameliorate the management of TBI patients.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Clopidogrel/farmacologia , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Ratos
10.
Sci Adv ; 8(5): eabl5420, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35108049

RESUMO

Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPMs), including AT-lipoxin A4 and AT-resolvin D1, in colonic tissues during inflammation-associated CRC (I-CRC). Aspirin also down-regulated the expression of the checkpoint protein programmed cell death protein-1 in macrophages and CD8+ T cells from the colonic mucosa. Inhibition of AT-SPM biosynthesis or knockout of the AT-SPM receptor Alx/Fpr2 reversed the immunomodulatory actions of aspirin on macrophages and CD8+ T cells and abrogated its protective effects during I-CRC. Furthermore, treatment of mice with AT-SPM recapitulated the immune-directed actions of aspirin during I-CRC. Together, these findings elucidate a central role for AT-SPM in mediating the immune-directed actions of aspirin in regulating I-CRC progression.


Assuntos
Aspirina , Neoplasias Associadas a Colite , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Receptores de Formil Peptídeo/metabolismo
12.
Food Funct ; 13(4): 2336-2353, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35142767

RESUMO

Alzheimer's disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been widely studied in the prevention and treatment of neurodegenerative diseases. However, there is a controversy about the efficacy as well as the adverse effects of aspirin. 10-Hydroxydecanoic acid (10-HDAA) is a characteristic fatty acid found in the honey bee product royal jelly. In this study, we found that 10-HDAA attenuated the activation of the NF-κB pathway, then targeted Ptgs-1/2, the well-known target of aspirin. Hence, combined therapy of 10-HDAA and aspirin was conducted. In vitro assays suggested that this combinatory group alleviated LPS-induced inflammation in BV-2 cells, as assessed by the downregulation of nitric oxide, COX-2, and IL-6 compared to 10-HDAA or aspirin treatment alone. In vivo assays showed that the combined treatment synergistically inhibited the overactivation of glial cells and decreased the levels of pro-inflammatory mediators. Moreover, 10-HDAA alleviated the adverse effects of aspirin on gastrointestinal injuries and microbiota dysbiosis. The Morris water maze test indicated that neither 10-HDAA nor aspirin effectively improved LPS-induced memory dysfunction, but the combined therapy showed synergistic effects. Altogether, our findings support 10-HDAA and aspirin combinatory therapy as the basis for future therapeutics for AD and other neuroinflammation-related diseases with minimal adverse effects.


Assuntos
Aspirina/farmacologia , Ácidos Decanoicos/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Administração Oral , Animais , Aspirina/administração & dosagem , Aspirina/química , Astrócitos/efeitos dos fármacos , Abelhas , Ácidos Decanoicos/administração & dosagem , Ácidos Decanoicos/química , Modelos Animais de Doenças , Sinergismo Farmacológico , Ácidos Graxos , Alimento Funcional , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Distribuição Aleatória
13.
Atherosclerosis ; 345: 7-14, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35183904

RESUMO

BACKGROUND AND AIMS: The platelet inhibitor aspirin reduces inflammation and atherosclerosis in both apolipoprotein E deficient (apoE-/-) mice and low-density lipoprotein receptor deficient (Ldlr-/-) mice. Similarly, the factor Xa inhibitor rivaroxaban reduces atherosclerosis in both apoE-/- and Ldlr-/- mice. We tested the hypothesis that the combination of aspirin and rivaroxaban reduces atherosclerosis in mice to a greater extent than either agent alone. METHODS: Male Ldlr-/- mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Cohorts of mice received aspirin in the water and/or rivaroxaban in the diet. Atherosclerosis and lesion composition were measured in the aortic sinus and the aorta. Expression of 55 proteins in the aorta and plasma was determined using multiplex ELISA assays. RESULTS: Aspirin alone, rivaroxaban alone, and the combination of both agents significantly reduced atherosclerosis in the Ldlr-/- mice compared with control Ldlr-/- mice fed a western-type diet. However, there were no significant differences in atherosclerosis in the group receiving aspirin and rivaroxaban compared with the groups that received aspirin or rivaroxaban alone. Aspirin, rivaroxaban and the combination reduced macrophage content and apoptosis in the lesions compared with controls but there was no difference between the three treatment groups. We observed statistically significant changes in the expression of a small number of proteins in the aorta and plasma in mice treated with aspirin and/or rivaroxaban. CONCLUSIONS: Contrary to our expectation, the combination of aspirin and rivaroxaban did not further reduce atherosclerosis in Ldlr-/- mice beyond the level observed with each agent alone.


Assuntos
Aterosclerose , Rivaroxabana , Animais , Aorta/patologia , Apolipoproteínas E , Aspirina/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/prevenção & controle , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL , Rivaroxabana/metabolismo , Rivaroxabana/farmacologia
14.
Int J Mol Sci ; 23(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35162965

RESUMO

Ischemic stroke is a disease related to abnormal blood flow that leads to brain dysfunction. The early and late phases of the disease are distinguished. A distinction is made between the early and late stages of the disease, and the best effect in treating an ischemic stroke is usually achieved within the first hours after the onset of symptoms. This review looked at studies platelet activity monitoring studies to determine the risks and benefits of various approaches including antiplatelet therapy. A study was conducted on recently published literature based on PRISMA. This review includes 32 research articles directly addressing the importance of monitoring platelet function during antiplatelet therapy (dual or monotherapy) after ischemic stroke. In patients with transient ischemic attack or ischemic stroke, antiplatelet therapy can reduce the risk of stroke by 11-15%, assuming that patients respond well. Secondary prevention results are dependent on platelet reactivity, meaning that patients do not respond equally to antiplatelet therapy. It is very important that aspirin-resistant patients can benefit from the use of dual antiplatelet therapy. The individualized approach to secondary stroke prevention is to administer the most appropriate drug at the correct dose and apply the optimal therapeutic procedure to the individual patient.


Assuntos
Plaquetas/efeitos dos fármacos , AVC Isquêmico/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Aspirina/farmacologia , Aspirina/uso terapêutico , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , AVC Isquêmico/sangue , Inibidores da Agregação Plaquetária/farmacologia
15.
Molecules ; 27(3)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35164195

RESUMO

Aspirin (also known as acetylsalicylic acid) is a drug intended to treat fever, pain, or inflammation. Treatment of moderate to severe cases of COVID-19 using aspirin along with dexamethasone has gained major attention globally in recent times. Thus, the purpose of this study was to use High-Performance Liquid Chromatography (HPLC) to evaluate the in vitro inhibition of CYP3A2 enzyme activity using aspirin in rat liver microsomes (RLMs). In this study, an efficient and sensitive HPLC method was developed using a reversed phase C18 column (X Bridge 4.6 mm × 150 mm, 3.5 µm) at 243 nm using acetonitrile and water (70:30 v/v). The linearity (r2 > 0.999), precision (<15%), accuracy and recovery (80-120%), limit of detection (5.60 µM and 0.06 µM), limit of quantification (16.98 µM and 0.19 µM), and stability of the newly developed method were validated for dexamethasone and 6ß-hydroxydexamethasone, respectively, following International Conference on Harmonization (ICH) guidelines. This method was applied in vitro to measure CYP3A2 activity. The results showed that aspirin competitively inhibits 6ß-hydroxylation (CYP3A2 activity) with an inhibition constant (Ki) = 95.46 µM and the concentration of the inhibitor causing 50% inhibition of original enzyme activity (IC50) = 190.92 µM. This indicated that there is a minimal risk of toxicity when dexamethasone and aspirin are co-administrated and a very low risk of toxicity and drug interaction with drugs that are a substrate for CYP3A2 in healthcare settings.


Assuntos
Aspirina/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Citocromo P-450 CYP3A/metabolismo , Animais , Aspirina/química , COVID-19/tratamento farmacológico , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dexametasona/análogos & derivados , Dexametasona/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade
16.
Exp Eye Res ; 218: 108938, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35120872

RESUMO

PURPOSE: To investigate the effect of Aspirin Triggered-Resolvin D1 (AT-RvD1) as an anti-pyroptosis and anti-inflammatory agent on lipopolysaccharide (LPS) induced acute keratitis in Wistar rats. METHODS: Acute keratitis in rats were induced by LPS stromal injection. Inflammatory reaction was measured by clinical score and histological observations. The non-canonical pyroptosis, the role of AT-RvD1 and Docosahexaenoic Acid (DHA) on non-canonical pyroptosis, were verified by quantification real-time PCR (qRT-PCR) and Western-blot. Besides, Human corneal epithelial cells (HCECs) primed with LPS, were stimulated with Nigericin, AT-RvD1 and necrosulfonamide (NSA), a Gasdermin-D (GSDMD) inhibitor separately. CCK-8 tests and flow cytometry were conducted to evaluate the cell viability and death ratio. And the marker of non-canonical pyroptosis were verified by Western blot. RESULTS: AT-RvD1 and DHA both alleviated the inflammation of rat cornea through inhibiting the expression of Caspase-11 and p30 which was triggered by LPS. Meanwhile, the activation of Caspase-4 and p30 were also significantly suppressed by AT-RvD1 in vitro, which is consistent with the results in rats. CONCLUSIONS: The non-canonical pyroptosis signaling pathways played an important role in rats with acute keratitis. In addition, AT-RvD1 can exert as an anti-inflammatory activity by inhibiting the non-canonical pyroptosis. Hence, it may be a promising and safe agent in treating acute keratitis.


Assuntos
Ácidos Docosa-Hexaenoicos , Ceratite , Animais , Anti-Inflamatórios , Aspirina/farmacologia , Caspases , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação , Ceratite/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Piroptose , Ratos , Ratos Wistar
17.
Pharm Biol ; 60(1): 175-184, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35014931

RESUMO

CONTEXT: Dehydroandrographolide succinate (DAS) is mainly used in the clinical treatment of various infectious diseases. Its potential effects on platelet aggregation and blood coagulation systems have not been reported systematically. OBJECTIVE: To explore whether DAS exerts an antithrombotic effect and its internal mechanism. MATERIALS AND METHODS: Human blood samples and Sprague-Dawley (SD) rats divided into control, aspirin (30 mg/kg), and DAS groups (200, 400 and 600 mg/kg) were used to measure the platelet aggregation rate, coagulation function, coagulation factor activity, and contents of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α). The histopathology of the SD rat gastric mucosa was also observed. All rats were administered intragastric or intraperitoneal injections once a day for 3 consecutive days. RESULTS: Compared to control group, DAS significantly inhibited the platelet aggregation rate (ED50 = 386.9 mg/kg) by decreasing TXB2 levels (1531.95 ± 649.90 pg/mL to 511.08 ± 411.82 pg/mL) and activating antithrombin III (AT-III) (103.22 ± 16.22% to 146.46 ± 8.96%) (p < 0.05). In addition, DAS significantly enhanced the coagulation factors FV (304.12 ± 79.65% to 443.44 ± 75.04%), FVII (324.19 ± 48.03% to 790.66 ± 225.56%), FVIII (524.79 ± 115.47% to 679.92 ± 143.34%), FX (34.90 ± 7.40% to 102.76 ± 29.41%) and FXI (38.12 ± 10.33% to 65.47 ± 34.08%), increased the content of Fg (2.18 ± 0.39 to 3.61 ± 0.37 g/L), shorten the PT (10.42 ± 0.44 to 9.22 ± 0.21 s), APTT (16.43 ± 1.4 to 14.07 ± 0.75 s) and TT time (37.04 ± 2.13 to 32.68 ± 1.29 s) (p < 0.05), while the aspirin group showed no such effect on these items but showed reduced activity of FII (89.21 ± 21.72% to 61.83 ± 8.95%) and FVIII (524.79 ± 115.47% to 306.60 ± 29.96%) (p < 0.05). Histopathological changes showed aspirin-induced gastric mucosa haemorrhage and the protective effect of DAS in the gastric mucosa. CONCLUSIONS: DAS is more suitable than aspirin in thromboprophylaxis treatment, which provides a reliable theoretical and experimental basis for its clinical application.


Assuntos
Diterpenos/farmacologia , Fibrinolíticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Aspirina/efeitos adversos , Aspirina/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Diterpenos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Fibrinolíticos/administração & dosagem , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Ratos , Ratos Sprague-Dawley , Succinatos
18.
Mol Biol Rep ; 49(4): 3007-3014, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35000048

RESUMO

BACKGROUND: In some stent implanted patients, cardiovascular events (CE) may occur. Acetylsalicylic acid (ASA) is routinely administered to these patients in order to prevent the occurrence of CE. CE may be related to gene variations which cause ASA resistance (AR). Therefore, it was aimed to investigate the relationship between COX-1, COX-2, CYP2C9 and CYP2C19 variations with CE due to AR. MATERIALS AND RESULTS: Seventy-four stent implanted patients, using 100 mg of ASA per day during five years were enrolled into the study. Following stent implantation, thirty-eight patients who had a CE within five years due to AR and 36 patients without CE were enrolled in patient and control group, respectively. AR was confirmed by platelet aggregation testing. After DNA isolation from blood; COX-1, COX-2, CYP2C19 and CYP2C9 variations were investigated with real-time polymerase chain reaction. At the end of this study, heterozygous genotype of COX-1 was found statistically high in patients whereas heterozygous genotype of CYP2C19*17 was found statistically high in controls. The presence of C and G allele in COX-1 and COX-2 were found statistically high in patients, respectively. The presence of T allele in CYP2C19*17 was found statistically high in controls. Heterozygous genotype of COX-1 variation was found statistically high in patients who have AR. Additionally heterozygous genotype of CYP2C19*17 was found statistically high in patients who have low thrombosis risk. CONCLUSIONS: COX-1 and COX-2 gene mutations may increase the risk of CE due to AR whereas CYP2C19*17 may have a protective effect in this process.


Assuntos
Trombose , Ticlopidina , Aspirina/farmacologia , Clopidogrel , Ciclo-Oxigenase 2/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Genótipo , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Stents/efeitos adversos , Trombose/genética
19.
Neurotoxicology ; 89: 20-30, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34979192

RESUMO

Benzo[a]pyrene (B[a]P) is neurotoxic, however, the mechanisms remain unclear and there is no effective prevention. Available evidence suggests a role of DNA methylation in B[a]P-induced neurotoxicity. This study investigated the brain-derived neurotrophic factor (BDNF) IV methylation in the development of and aspirin intervention against B[a]P's neurotoxicity in mice and HT22 cells. Mice were intraperitoneally treated with solvent or B[a]P (0.5, 2, and 10 mg/kg b.w.) for 60 days. An intervention group was treated simultaneously with B[a]P (10 mg/kg, i.p.) and aspirin (10 mg/kg, daily water-drinking). The treated mice showed a dose-dependent cognitive and behavioral impairment, and cerebral cell apoptosis, which were alleviated by aspirin co-treatment. Following B[a]P treatment, DNA methyltransferase (DNMTs) and BDNF IV hypermethylation were increased in the cerebral cortex of mice compared to controls, while significant decreases were found in BDNF IV and BDNF mRNA, and BDNF protein levels. Aspirin co-treatment rescued DNMTs activation and BDNF IV hypermethylation, and mitigated the recession in BDNF mRNA and protein induced by B[a]P treatment. Similar results were shown in HT22 cells. These findings reveal a critical role of BDNF IV methylation in the neurotoxicity of B[a]P, and demonstrate a promising prevention of aspirin against B[a]P-induced cognitive impairment via inhibiting BDNF IV hypermethylation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Animais , Aspirina/metabolismo , Aspirina/farmacologia , Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/metabolismo , Metilação de DNA , Hipocampo , Camundongos
20.
Clin Pharmacokinet ; 61(4): 465-479, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35060092

RESUMO

Aspirin is one of the most widely used medicines. Although aspirin is commonly utilized for the treatment of several medical conditions, its broadest uptake is for the prevention of recurrent ischemic events in patients with atherosclerotic disease. Its mechanism of action of inhibiting platelet activation via blockade of thromboxane A2 production is unique and is not covered by any other antiplatelet agents. While plain, uncoated, immediate-release aspirin is used in acute settings to help assure rapid absorption, enteric-coated aspirin formulations dominate current chronic use, particularly in North America, including for secondary prevention of cardiovascular events. The unmet needs with current aspirin formulations include a high risk of gastrointestinal (GI) adverse events with plain aspirin, which enteric-coated formulations are not able to overcome, and subject to erratic absorption leading to reduced drug bioavailability. These observations underscore the need for aspirin formulations with a more favorable safety and efficacy profile. Phospholipid-aspirin complex (PL-ASA) is a novel formulation designed to address these needs. It is associated with reduced local acute GI injury compared with plain aspirin, and predictable absorption resulting in more reliable platelet inhibition compared with enteric-coated tablets. This review explores the rationale and pharmacologic profile of PL-ASA intended to address the unmet needs for aspirin therapy.


Assuntos
Aspirina , Fosfolipídeos , Aspirina/farmacologia , Plaquetas , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Comprimidos com Revestimento Entérico
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