Store-operated Cat+ entry (SOCE), mediated by stromal interaction molecule (STIM) and Orai proteins, plays a key role in smooth muscle contraction. We previously demonstrated that docosahexaenoic acid (DHA) inhibits Orai1-dependent SOCE and suppresses contraction in guinea pig gastric fundus smooth muscle. However, whether this effect is specific to DHA or shared by other fatty acids remains unclear. In the present study, we examined the effects of thirteen fatty acids on cyclopiazonic acid (CPA)-induced contraction in gastric fundus smooth muscle and SOCE-associated Cat+ responses in 293T cells. Among the fatty acids tested, 7-linolenic acid, pinolenic acid, eicosapentaenoic acid (EPA), and DHA significantly inhibited CPA-induced contraction. These fatty acids also suppressed SOCE-associated Cat+ entry in wild-type 293T cells, with DHA showing the greatest effect. In STIM2-overexpressing 293T cells, pinolenic acid, EPA, and DHA inhibited SOCE-associated Cat+ responses, whereas the inhibitory effect of 7-linolenic acid was lost. A structure-activity relationship was suggested, with inhibitory effects associated with the position of the first double bond relative to the carboxyl group (04-06). These findings suggest that fatty acids differentially inhibit SOCE, with pinolenic acid, EPA, and DHA showing consistent inhibitory effects across both 293T cell models, whereas 7-linolenic acid shows greater context dependence.
Hepatotoxicity is a major adverse effect of high-dose methotrexate (HD-MTX) therapy. Although preclinical studies have highlighted the potential of angiotensin receptor blockers (ARBs) to reduce the risk of MTX-induced hepatotoxicity, their clinical effects remain unknown. Therefore, we aimed to ascertain whether the preventive effect of ARBs on HD-MTX-induced hepatotoxicity is evident in a real-world setting using medical Big Data analysis. This study involved patients who received ≥1.5 g MTX as a single dose by injection between April 1, 2014 and August 31, 2022, and were registered in the JMDC hospital-based database. Factors potentially associated with the development of MTX-induced hepatotoxicity, in addition to concomitant use of ARBs, were selected as explanatory variables and analyzed using a Fine-Gray subdistribution hazard model, accounting for death as a competing event. A total of 243 patients received a single MTX dose of ≥1.5 g during the observation period; among them, 34 patients presented hepatotoxicity grades 3-4. Female sex, concomitant use of anticancer drugs, and a high baseline alanine aminotransferase value were associated with the development of MTX-induced hepatotoxicity. Although concomitant ARB use was associated with a hazard ratio below 1, this was not statistically significant (subdistribution hazard ratio: 0.249, 95% confidence interval: 0.031-1.990). Similar trends were observed in the sensitivity analysis with grade ≥2 hepatotoxicity as the outcome. While the concomitant use of ARBs had a potential preventive effect against HD-MTX-induced hepatotoxicity, its clinical significance appears to be lower than the effect of other known risk factors.
Although parents of young children are often anxious about administering medication to their wards, they tend to hesitate about consulting with pharmacists. The purpose of this study was to evaluate parent satisfaction with pharmacist services and pharmacy use, identify items for improvement, and explore the reasons reported by parents who would not consult a pharmacist. An online cross-sectional survey of 1788 parents (aged ≥18 years) of children aged <6 years was conducted. A customer satisfaction analysis comprising 11 items from the survey was also carried out. The mean overall satisfaction score was 3.97. The analysis identified "explanation of medication," "time spent on explanation," "answers to questions," and "pharmacist attitude" as priority maintenance areas. Conversely, "explanation of daily precautions" and "ease of consultation" were identified as priority improvement areas. Additionally, the analysis identified "consideration for privacy" as an area with substantial room for improvement. Further, 20.2% of respondents answered that they would not consult a pharmacist, primarily because they had "already consulted a doctor" or perceived the pharmacists as "too busy." These results suggest that consideration for privacy may be one area in which pharmacy services could be improved, and perceived pharmacist busyness was one of the reasons reported by respondents as a barrier. Although parents expressed high satisfaction with direct medication guidance, pharmacies may be able to provide services that lead to even higher satisfaction among parents by ensuring physical privacy, actively explaining precautions regarding daily care, and creating a welcoming environment.
