A Chronobiologic Approach to Ethanol and Acidified Aspirin Injury of the Gastric Mucosa in the Rat

Several models of erosive peptic disease have used drug-induced lesions to examine protective mechanisms of the gastric mucosa. Physiological processes such as acid secretion, motility, or epithelial cell turnover have circadian rhythms which may modulate the susceptibility of the gastric mucosa to injury. In this review are described recent studies which demonstrated that susceptibility to gastric mucosal injury by acidified aspirin and absolute ethanol varied with the phases of the light-dark cycle. Acidified aspirin caused significantly more gastric mucosal lesions when administered early in the light phase compared to administration early in the dark phase. The differences in susceptibility were not altered by pretreatment conditions such as immobilization or length of the fasting period. Absolute ethanol also caused significantly greater gastric mucosal injury when administered in the light than in the dark phase, but this difference was only evident in rats immobilized during the pretreatment fasting period. Further studies are needed to correlate circadian susceptibility to drug-induced gastric mucosal injury with physiological defense mechanisms. Careful attention to circadian timekeeping may allow us to refine therapy to optimize physiological defense mechanisms in the stomach.     

Effects of copper aspirinate and aspirin on tissue copper,zinc, and iron concentrations following chronic oral treatment in the adjuvant arthritic rat

Concentrations of copper, zinc, and iron were analyzed and compared in a number of tissues of adjuvant arthritic rats following 22 d of chronic treatment (per os) with either vehicle, aspirin or copper aspirinate, at doses of 100 mg/kg, 200 mg/kg, or 400 mg/kg. Such chronic treatment resulted in a negative balance in copper, zinc, and iron in many tissues. Among the tissues examined, liver and kidney exhibited the greatest changes in metal concentrations; brain and skeletal muscle exhibited the least. Arthritis-induced changes in the concentrations of all three metals in the liver were reversed upon treatment with aspirin. Treatment with copper aspirinate, on the other hand, resulted in an extremely high accumulation of copper in the liver. Arthritis-induced changes in copper, zinc, and iron concentrations in the pancreas and copper concentration in the plasma were generally not reversed upon treatment with either aspirin or copper aspirinate. Among the three metals examined, the degree of change observed as a result of drug treatments was greatest for iron and least for zinc. Finally, it appeared that the effects of aspirin and copper aspirinate on tissue metal concentrations were independent of the antiarthritic effects of these compounds.     

Aspirin changes the secretion rate and amino acid composition of human small intestinal mucin in subjects with ileal conduits

The effect of aspirin on the rate of secretion and amino acid composition of human ileal mucin was studied, using subjects with ileal conduits as a model system in which mucin secreted from the ileal conduit tissue is flushed out in the urine and can be measured and analysed. Aspirin (600 mg per day, administered orally) increased the daily mucin output by 37–104% in subjects by days 3 or 4, but thereafter the mucin output declined to below the baseline level by day 10. Mucin samples, purified from the ileal conduit urine during the control period and during aspirin administration, were compared. There were no discernible changes in the degree of polymerisation or the density, but during aspirin administration the amino acid composition was significantly changed, and in particular threonine and proline were enriched. One possible explanation, consistent with the compositional analyses, is that the N- and C-terminal regions of the mucin subunits have been cleaved off and lost during aspirin administration. The observed changes in mucin secretion may have implications for the mechanism of the toxic effects of aspirin on the small intestine by altering the barrier properties of the mucus layer.Abbreviations EGF epidermal growth factor - NSAID non-steroidal anti-inflammatory drug     

初始小剂量甲巯咪唑对Graves病甲亢患者甲状腺功能和Visfatin、TNF-α、IL-6水平的影响

目的:分析初始小剂量甲巯咪唑治疗对Graves病甲状腺功能亢进症(甲亢)患者甲状腺功能和内脂素(Visfatin)、肿瘤坏死因子-α(Tumor necrosis factor-alpha, TNF-α)、白介素-6(Interleukin-6, IL-6)水平的影响。方法:选择我院2017年1月-2018年6月诊治的125例Graves病甲亢患者,根据入院编号随机数字表法分为两组。对照组63例给予甲硫咪唑15 mg/次,2次/d;研究组62例给予甲硫咪唑10 mg/次,2次/d,两组均连续治疗6个月,对比两组治疗总有效率、治疗前后甲状腺功能和血清Visfatin、TNF-α、IL-6水平的变化。结果:治疗后,研究组的治疗总有效率显著高于对照组(90.32%vs. 77.78%,P<0.05);两组患者的甲状腺功能指标血清游离三碘甲状腺原氨酸(Free triiodothyronine, FT3)、血清游离甲状腺素(FT4)水平均显著降低、敏感促甲状腺激素(Sensitive thyroid stimulating hormone, s TSH)水平均显著升高,且研究组以上指标变化较对照组更显著(P<0.05);两组患者的血清Visfatin、TNF-α、IL-6水平均较治疗前显著下降,且研究组以上指标均显著低于对照组(P<0.05)。结论:初始小剂量(10 mg/次)甲巯咪唑治疗Graves病甲亢的疗效显著优于甲硫咪唑15 mg/次治疗,可能与其有效改善患者的甲状腺功能和血清Visfatin、TNF-α、IL-6等炎症因子水平有关。     

Aspirin inhibits osteoclast formation and wear-debris-induced bone destruction by suppressing mitogen-activated protein kinases

Excessive osteoclast recruitment and activation is the chief cause of periprosthetic osteolysis and subsequent aseptic loosening, so blocking osteolysis may be useful for protecting against osteoclastic bone resorption. We studied the effect of aspirin on titanium (Ti)-particle-induced osteolysis in vivo and in vitro using male C57BL/6J mice randomized to sham (sham surgery), Ti (Ti particles), low-dose aspirin (Ti/5 mg·kg⁻¹·d⁻¹ aspirin), and high-dose aspirin (Ti/30 mg·kg⁻¹·d⁻¹ aspirin). After 2 weeks, a three-dimensional reconstruction evaluation using micro-computed tomography and histomorphology assessment were performed on murine calvariae. Murine hematopoietic macrophages and RAW264.7 lineage cells were studied to investigate osteoclast formation and function. Aspirin attenuated Ti-particle-induced bone erosion and reduced osteoclasts. In vitro, aspirin suppressed osteoclast formation, osteoclastic-related gene expression, and osteoclastic bone erosion in a dose-dependent manner. Mechanically, aspirin reduced osteoclast formation by suppressing receptor activator of nuclear factor kappa-B ligand-induced activation of extracellular signal-related kinase, p-38 mitogen-activated protein kinase, and c-Jun N-terminal kinase. Thus, aspirin may be a promising option for preventing and curing osteoclastic bone destruction, including peri-implant osteolysis.     

Spectroscopic and DFT investigation of interactions between cyclophosphamide and aspirin with lysozyme as binary and ternary systems

Multi-spectroscopic and density functional theory (DFT) calculations was used to study the interaction between cyclophosphamide (CYP) and aspirin (ASA) with lysozyme (LYS). The experimental results showed that fluorescence quenching of LYS by drug was a result of the formation of drug–LYS complex; static quenching was confirmed to result in fluorescence quenching. Modified Stern–Volmer plots of interaction between CYP and ASA with protein in the binary and ternary systems were used to determine the binding parameters. Molecular distances between the donor (LYS) and acceptor (CYP and ASA) for all systems were estimated according to Forster’s theory. The quantitative analysis obtained by CD spectra suggested that the presence of ASA and CYP decreased the α-helical content of LYS and induced the destabilizing of it. Theoretical studies on the interaction between LYS with ASA and CYP have been carried out using DFT at the B3LYP/6-31G level in the solvent phase. Binding energy of the mentioned complexes was calculated. It showed that tryptophan (Trp) 62 had the most affinity toward ASA and CYP. Analyzing the calculated results revealed that the five member ring of Trp has a key role in interaction of LYS with ASA and CYP.     

Design,green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents*

The aim of this research work was to investigate a series of novel 5,6-diaryl-1,2,4-triazines (3a–3q) containing 3-morpholinoethylamine side chain, and to address their antiplatelet activity by in vitro, ex vivo and in vivo methods. All compounds were synthesized by environment benign route and their structures were unambiguously confirmed by spectral data. Compounds (3l) and (3m) were confirmed by their single crystal X-ray structures. Out of all the synthesized compounds, 10 were found to be more potent in vitro than aspirin; six of them were found to be prominent in ex vivo assays and one compound (3d) was found to have the most promising antithrombotic profile in vivo. Moreover, compound (3d) demonstrated less ulcerogenicity in rats as compared to aspirin. The selectivity of the most promising compound (3d) for COX-1 and COX-2 enzymes was determined with the help of molecular docking studies and the results were correlated with the biological activity.     

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation

Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox-1 and Cox-2) inhibition. In addition, aspirin-induced Cox-dependent and -independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell-cycle arrest. Exogenous prostaglandin E₂ significantly increased cell proliferation but did not abrogate the aspirin-mediated growth inhibition, suggesting a Cox-independent mechanism. These effects appear to be mediated by the increase of p21 ^waf1 and p27 ^Kip1, associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients.