Background: Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression.Hypothesis/Purpose: In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents.Methods: ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured in vitro, and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses.Results: Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of Il1b, Il6, iNos, ccl2, and cxcl10 in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, Irf7, ccl12, and Irg1 also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide.Conclusion: Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent.

Clazosentan, a selective endothelin receptor antagonist, is used to prevent cerebral vasospasm. We investigated patient characteristics and concomitant medications associated with an increased risk of clazosentan-induced fluid retention, the risk factors of which remain unknown. We retrospectively reviewed cases of clazosentan-induced adverse drug reactions from the Japanese Adverse Drug Event Report (JADER) database, published by the Pharmaceuticals and Medical Devices Agency. We investigated the time course of fluid retention onset following clazosentan administration before analyzing whether specific patient characteristics and concomitant medications were associated with an increased risk of clazosentan-induced fluid retention. Among 241 cases of clazosentan use identified, fluid retention occurred in 114 (47.3 %). The median time interval from clazosentan initiation to onset of fluid retention was 3 days, and 88.7 % of fluid retention cases were reported within 1 week of initiation. Patients with fluid retention were older than those without; patients >70 years old accounted for 63.16 % of the cohort with fluid retention vs 44.1 % of the cohort without fluid retention. Fluid retention occurred more frequently in patients with concomitant use of fasudil hydrochloride, a conventional vasospasm drug in Japan, than in those without. Multivariate logistic regression analysis revealed that older age (>70 years) and concomitant use of fasudil hydrochloride remained independent risk factors for fluid retention. Clazosentan-induced fluid retention occurred more frequently in older adult patients. Clazosentan combined with fasudil hydrochloride increased the incidence of fluid retention. These findings can guide pharmacological treatment of cerebral vasospasm in patients with subarachnoid hemorrhage.

Background and Objectives: Vitamin D supplementation is effective for allergic rhinitis; however, its usefulness is unclear. We conducted a systematic review and meta-analysis to examine the conditions in which vitamin D supplementation was effective in allergic rhinitis management. Materials and Methods: Randomized controlled trials of vitamin D supplementation used for patients with allergic rhinitis were searched for across different databases. We extracted scores on patients’ symptoms and the medication types used as the baseline treatments and performed a meta-analysis to evaluate the effect of vitamin D supplementation on allergic rhinitis symptoms. Meta-regression and subgroup analyses were performed for the average age, proportion of female participants, concomitant medications, vitamin D administration durations, and baseline serum 25-hydroxyvitamin D levels. Results: In total, 2389 articles were screened, and 5 randomized controlled trials (RCTs) were included in the meta-analysis. Compared with placebos, vitamin D supplementation alleviated allergic rhinitis symptoms, although the difference was not significant; there was significant heterogeneity among studies (standardized mean difference [SMD] = −2.69, 95% confidence interval [CI]: −6.20 to 0.82, I2 = 98%, p < 0.01). The proportion of female participants in the RCTs (slope: 0.21, p = 0.026) and concomitant corticosteroid use (slope: −9.16, p = 0.005) influenced the vitamin D response. Compared with the placebos, vitamin D supplementation without corticosteroids alleviated the allergic rhinitis symptoms (SMD = −0.56, 95% CI: −0.90 to −0.23). Combination treatment with corticosteroids also non-significantly alleviated symptoms. Additionally, the heterogeneity between studies was significant (SMD = −5.97, 95% CI: −13.55 to 1.16, I2 = 99%, p < 0.01). Conclusions: The study results suggest that vitamin D supplementation alleviates allergic rhinitis symptoms, although the effects differ according to the patient’s sex and concomitant medications.

Background/Objectives: Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR)-derived exosome-like nanoparticles (ALR-ELNs) exhibit anti-neuroinflammatory effects in microglial cells. However, the associated mechanisms and pathways are unknown. We aimed to characterize the effects of ALR-ELNs on inflammatory responses of BV-2 microglial cells to lipopolysaccharide (LPS) using RNA sequencing. Methods: ALR-ELNs were fractionated from ALR. BV-2 microglial murine cells were stimulated with LPS after treatment with ALR-ELNs. RNA sequencing was performed to analyze variations in mRNA levels. Ingenuity pathway analysis (IPA) was performed to investigate the mechanism of action of ALR-ELNs. mRNA expression was assessed using real-time quantitative polymerase chain reaction (qPCR). Results: The expression of 651 genes was downregulated, whereas that of 1204 genes was upregulated in LPS-stimulated BV2 cells pretreated with ALR-ELNs. The IPA showed that the effects of ALR-ELNs on inflammation took place through pathogen-influenced signaling. Network analysis via IPA showed that the Toll-like receptor (TLR) is involved in the suppression of inflammation by ALR-ELNs. The qPCR analysis showed that pretreatment with ALR-ELNs significantly reduced TLR4 mRNA expression. Conclusions: ALR-ELNs suppress the release of inflammatory mediators by downregulating TLR4 expression, which is a novel mechanism by which ALR-ELNs act on microglia. Identifying active ingredients in ALR-ELNs that downregulate TLR4 expression can advance the development of therapeutic drugs for neuroinflammatory diseases.

Introduction: Guideline-directed medical therapy with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved the survival of patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, it is unclear whether RAS inhibitors and beta-blockers can be administered to older patients with HF. Therefore, this study aimed to investigate the effects of beta-blockers and RAS inhibitors on the prognosis of older patients with HFrEF.Methods: Demographic, clinical, and pharmacological data from 1,061 patients with acute decompensated HF, enrolled in the Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI study), were analyzed to assess their impact on mortality. Additionally, a machine learning approach was applied to complement the conventional statistical model for analysis. Patients with HFrEF (n = 314) were divided into the all-cause mortality within 2 years group (n = 80) and the survivor group (n = 234).Results: Overall, 41.1% (129/314) of the patients were aged ≥80, and 25.5% (80/314) experienced all-cause mortality within 2 years. Furthermore, 57.6% (181/314) and 79.0% (248/314) were prescribed RAS inhibitors and beta-blockers, respectively. Our analysis showed that RAS inhibitor use was associated with reduced all-cause mortality and cardiac death in patients with HFrEF of all ages (P < 0.001), and beta-blocker use had an interaction with age. Machine learning revealed that the use of beta-blockers altered the risk of mortality, with a threshold of approximately 80 years of age. Beta-blocker use was associated with lower all-cause mortality and cardiac death in patients with HFrEF aged <80 years (P < 0.001) but not in those aged ≥80 years (P = 0.319 and P = 0.246, respectively). These results suggest that beta blockers may differ in their all-cause mortality benefits according to age.Conclusions: RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.