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Dipicolylamine derivatives and their pharmaceutical uses
No full text[[abstract]]Dipicolylamine compounds of Formula (I) set forth herein. Also disclosed are pharmaceutical compositions containing metal ions and these compounds. Further disclosed is a method for treating a condition associated with cells containing inside-out phosphatidylserine, with these compounds
ピラゾール化合物
No full text[[abstract]]Compounds of formula (I): wherein R1, R2, R3, R4, R5, and X are defined herein. Also disclosed are pharmaceutical compositions and methods related to use of these compounds
Heterocyclic compounds and use thereof
No full text[[abstract]]Heterocyclic compounds of Formula (I) shown herein. Also disclosed are pharmaceutical compositions containing the heterocyclic compounds and methods of using the heterocyclic compounds to mobilize hematopoietic stem cells and endothelial progenitor cells into the peripheral circulation. Further provided are methods for treating tissue injury, cancer, inflammatory disease, and autoimmune disease with the heterocyclic compounds
Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction
No full text[[abstract]]Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions
Dose-response analysis of music intervention for improving delirium in intensive care unit patients: A systematic review and meta-analysis
No full text[[abstract]]BackgroundDelirium is a common and severe condition among adult intensive care unit (ICU) patients. Music intervention, as a non-pharmacological approach, has the potential to reduce delirium, but the optimal dosage and type of intervention remain unclear.AimTo explore the effects of music intervention at different doses and types on reducing delirium in ICU patients.Study DesignThis study was conducted as a systematic review and meta-analysis. Databases including Cochrane Library, EBSCO, Embase, PubMed, Web of Science, Airiti Library, China National Knowledge Infrastructure and Wanfang Data were searched until 29 February 2024. Study quality was assessed using the Cochrane Risk of Bias 2.0 criteria. Data were analysed using RevMan 5.4.1 and Comprehensive Meta-Analysis 3.0.ResultsFourteen studies involving 1434 ICU patients were included. Four studies were of good quality (low risk of bias), seven were of moderate quality (unclear risk) and three were of low quality (high risk). Pooled analysis showed that music interventions significantly reduced the risk of delirium (12 studies, RR = .49, 95% confidence interval [CI] [.40, .61]). Slow-tempo music had the strongest effect (11 studies, RR = .46, 95% CI [.37, .57]). The optimal intervention dosage involves conducting music interventions twice daily (12 studies, RR = .46, 95% CI [.34, .63]), with each session lasting 30 min (12 studies, RR = .41, 95% CI [.30, .55]). Additionally, a pooled analysis showed that a 7-day music intervention (6 studies, RR = .43, 95% CI [.26, .71]) was the most effective in reducing the risk of delirium.ConclusionsMusic intervention reduces delirium in ICU patients, especially with two 30-min sessions daily for 7 days. However, the certainty of evidence is low, highlighting the need for further high-quality research.Relevance to Clinical PracticeMusic intervention is a simple, non-invasive method that may help reduce delirium in ICU patients. However, given the low certainty of the current evidence, it should be used cautiously, and further research is needed to validate its effectiveness before routine implementation
Disrupted HIV care during COVID-19 pandemic associated with increased disabilities among people living with HIV in Belize
No full text[[abstract]]The COVID-19 pandemic may have impacted disabilities among people living with HIV; however, data on the association between COVID-19 pandemic-related healthcare disruptions and disabilities among people living with HIV is limited. We aimed to evaluate the association between COVID-19-affected HIV care behaviors and disability domains among people living with HIV in Belize. A cross-sectional study was conducted at the Western Regional Hospital and Southern Regional Hospital between August and October 2021 among people living with HIV in Belize aged ≥ 21 years and on antiretroviral therapy. A self-reported questionnaire captured data on demographic and clinical characteristics (gender, age, ethnicity, marital status, employment, education, CD4 count, and viral load), COVID-19-affected HIV care behaviors, and disability across six domains (physical, cognitive, and mental-emotional symptoms and impairments; uncertainty; difficulties carrying out day-to-day activities; and social inclusion challenges) using the Short-Form HIV Disability Questionnaire. Univariate and multivariate logistic regression analyses were employed to analyze the data. Of the 489 participants, 276 (56.4%) were women and 213 (43.6%) were men. After adjusting for covariates, (age, gender, employment, CD4 count, viral load, COVID-19-affected HIV care behaviours), our results showed that people living with HIV, whose HIV care behaviors were greatly affected by COVID-19, were more likely to have disabilities across various domains: physical (adjusted odds ratio (AOR): 1.61, 95% confidence interval (CI): 1.08-2.41, p = 0.018), cognitive (AOR: 2.49, 95% CI: 1.58-3.94, p < 0.001), uncertainty (AOR: 2.94, 95% CI: 1.68-5.12, p < 0.001), difficulties carrying out day-to-day activities (AOR: 1.69, 95% CI: 1.06-2.69, p = 0.027), and social inclusion challenges (AOR: 1.89, 95% CI: 1.27-2.81, p = 0.002). Mitigating disruptions in care behaviors through the implementation of more accessible and comprehensive healthcare services may potentially address the multifaceted nature of HIV disabilities
Neurofilament light chain level is associated with lifetime suicidal behaviors
No full text[[abstract]]BACKGROUND: Suicide is among the severe outcomes of mental illness and has been reported to be associated with neurodegeneration and cognitive impairment. The blood neurofilament light chain (NfL) level is a biomarker of neuronal damage in neuropsychiatric disorders. This study investigated whether the NfL levels are associated with lifetime suicidal behaviors and whether this level is higher in patients with major depressive disorder (MDD) compared with healthy controls. METHODS: In this cross-sectional study, we included 73 patients with MDD and 40 age- and sex-matched controls. The blood NfL levels were measured using an enzyme-linked immunosorbent assay. We compared the NfL levels between patients with MDD and controls and performed regression analysis to evaluate the association between the NfL levels and suicidal behaviors. RESULTS: Nearly half of the patients with MDD (43.80%) reported lifetime suicide attempts. Those with MDD had higher blood NfL levels, but their levels did not significantly differ from those of the healthy controls. Logistic regression results revealed higher risks of lifetime suicide planning (Odds ratio (OR) = 1.64) and suicide attempts (OR = 1.94) with every 10 pg/mL increase in the NfL levels. CONCLUSIONS: Our results demonstrate that higher serum NfL levels were associated with lifetime suicidal behavior
Development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection
No full text[[abstract]]Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSD1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSD1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSD1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSD1 and beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment
做為蛋白激酶抑制劑的稠合多環化合物
No full text[[abstract]]Fused multicyclic compounds of formula (I): wherein R′, R″, X, Y, Z, A, B, C, D, and n are defined herein. Also disclosed are a method for inhibiting protein kinase (e.g., Aurora kinase) activity and a method for treating a protein kinase mediated disorder (e.g., cancer) with these compounds
[[alternative]]Benzimidazole compounds and use thereof for treating alzheimer's disease or huntington's disease
No full text[[abstract]]揭露了以下所示式(I)的苯并咪唑化合物，該化合物是有效的人類麩酸胺環化酶抑制劑。還揭露的是一種含有該等化合物中之一化合物及醫藥上可接受載體的醫藥組合物、以及一種藉由對需要治療阿茲海默症或亨丁頓氏症的個體投予有效量的該化合物來治療阿茲海默症或亨丁頓氏症的方法