Alzheimer’s disease (AD) is increasingly recognized as a disorder with significant vascular involvement, with microvascular damage and thromboinflammation often preceding classical amyloid pathology by several years. Elevated levels of prothrombin and thrombin, along with aberrant platelet activation, have been reported in individuals with AD. We hypothesized that platelet hyperactivity in AD results from an exaggerated response to thrombin in the presence of elevated amyloid beta 1-40 (Aβ₁₋₄₀), a peptide that accumulates during the early stages of AD. Platelet activation in response to Aβ₁₋₄₀ and thrombin was assessed using aggregation assays with an aggregometer, adhesion measurements by confocal microscopy, and spreading via both confocal microscopy and scanning electron microscopy. Reactive oxygen species (ROS) production and integrin α IIbβ 3 activation were quantified by flow cytometry. The roles of NADPH oxidase (NOX), ROS, and integrin signaling were examined using selective inhibitors. Aβ₁₋₄₀ significantly enhanced thrombin-induced platelet adhesion, aggregation, and spreading via NOX-derived ROS and integrin α IIbβ 3 activation. Aβ₁₋₄₀ also promoted platelet binding to fibrinogen and cerebrovascular endothelial cells, accompanied by distinct morphological changes. Inhibition of NOX or integrin α IIbβ 3 significantly reduced these effects. These findings identify a novel Aβ₁₋₄₀–NOX–ROS–integrin α IIbβ 3 axis that drives platelet hyperactivation and cerebrovascular interactions in AD.Targeting this pathway with antithrombotic or antioxidative strategies may offer therapeutic potential in mitigating AD-associated vascular pathology.

Sleep deprivation (SD) disrupts homeostatic regulation and increases vulnerability to stress and mood disorders. This study investigated the duration-dependent effects of SD and elucidated the distinct roles of adenosine A1 receptors (A1R) and A2A receptors (A2AR) in behavioral and molecular alterations induced by 24, 48, and 72 h of SD in mice. SD for 48 h and 72 h, but not 24 h, significantly increased immobility time in the tail suspension test (TST) and forced swim test (FST), accompanied by elevated plasma corticosterone (CORT) levels, indicating a duration-dependent stress response. Hippocampal A1R mRNA expression was significantly reduced, whereas A2AR mRNA expression was markedly increased at 48 h and 72 h of SD. Pharmacological blockade of either A1R (DPCPX) or A2AR (SCH 58261) significantly attenuated SD-induced depression-like behaviors and CORT elevation, whereas activation of A1R with the agonist CPA exacerbated depression-like behavior at 24 h and 48 h of SD. These findings suggest that A2AR upregulation may represent a pathological response to prolonged SD, whereas A1R downregulation may reflect compensatory adaptation to sustained receptor activation. Taken together, our results demonstrate that A1R and A2AR play distinct roles in SD-induced depression-like behaviors.

Sleep–wake regulation is controlled by circadian and homeostatic processes, with adenosine acting as a key molecular mediator of homeostatic sleep pressure. Extracellular adenosine accumulates during wakefulness as a result of neuronal energy metabolism, particularly in the basal forebrain, and declines during recovery sleep, thereby reflecting the physiological need for sleep.The sleep-promoting effects of adenosine are mediated primarily by two G protein–coupled receptor subtypes, the adenosine A1 receptor and the adenosine A2A receptor. The adenosine A1 receptor, coupled to inhibitory Gi/o proteins and widely expressed in the cortex, hippocampus, thalamus, and basal forebrain, suppresses wake-promoting neuronal activity and facilitates slow-wave activity during non-rapid eye movement sleep. In contrast, the adenosine A2A receptor, coupled to stimulatory Golf proteins and enriched in the striatum and nucleus accumbens, promotes sleep by activating neurons in the preoptic hypothalamus and engaging the indirect basal ganglia pathway. Despite these well-established roles, the contributions of dysregulation of the adenosine A1 receptor and the adenosine A2A receptor to specific sleep disorders remain incompletely understood. This review examines how signaling of the adenosine A1 receptor and the adenosine A2A receptor is altered in insomnia, obstructive sleep apnea, narcolepsy, and restless legs syndrome, and evaluates the therapeutic potential of receptor-selective strategies for adenosine receptor–targeted treatment.

While glutamate, a key neurotransmitter in the central nervous system, is fundamental to neuronal viability and normal brain function, its excessive accumulation leads to oxidative stress, contributing to neuronal damage and neurodegenerative diseases. In this study, we investigated the effect of β-lapachone (β-Lap), a naturally occurring naphthoquinone, on glutamate-induced injury in HT22 cells and explored the underlying mechanism involved. Our results show that β-Lap significantly improved cell viability in a dose-dependent manner. Additionally, β-Lap exhibited a significant antioxidant activity, reducing intracellular reactive oxygen species levels and restoring glutathione levels. The antioxidant capacity of β-Lap was further demonstrated through 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assays. Western blot analysis revealed that β-Lap upregulated brain-derived neurotrophic factor (BDNF) and promoted the phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response elementbinding protein (CREB), which were downregulated by glutamate. Furthermore, β-Lap enhanced the cellular antioxidant molecules, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, β-Lap can protect HT22 cells against glutamate-induced injury by activating the BDNF/TrkB/ERK/CREB and ERK/Nrf2/HO-1 signaling pathways, suggesting its therapeutic potential for neurodegenerative diseases.

While glutamate, a key neurotransmitter in the central nervous system, is fundamental to neuronal viability and normal brain function, its excessive accumulation leads to oxidative stress, contributing to neuronal damage and neurodegenerative diseases. In this study, we investigated the effect of β-lapachone (β-Lap), a naturally occurring naphthoquinone, on glutamate-induced injury in HT22 cells and explored the underlying mechanism involved. Our results show that β-Lap significantly improved cell viability in a dose-dependent manner. Additionally, β-Lap exhibited a significant antioxidant activity, reducing intracellular reactive oxygen species levels and restoring glutathione levels. The antioxidant capacity of β-Lap was further demonstrated through 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assays. Western blot analysis revealed that β-Lap upregulated brain-derived neurotrophic factor (BDNF) and promoted the phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response elementbinding protein (CREB), which were downregulated by glutamate. Furthermore, β-Lap enhanced the cellular antioxidant molecules, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, β-Lap can protect HT22 cells against glutamate-induced injury by activating the BDNF/TrkB/ERK/CREB and ERK/Nrf2/HO-1 signaling pathways, suggesting its therapeutic potential for neurodegenerative diseases.

While glutamate, a key neurotransmitter in the central nervous system, is fundamental to neuronal viability and normal brain function, its excessive accumulation leads to oxidative stress, contributing to neuronal damage and neurodegenerative diseases. In this study, we investigated the effect of β-lapachone (β-Lap), a naturally occurring naphthoquinone, on glutamate-induced injury in HT22 cells and explored the underlying mechanism involved. Our results show that β-Lap significantly improved cell viability in a dose-dependent manner. Additionally, β-Lap exhibited a significant antioxidant activity, reducing intracellular reactive oxygen species levels and restoring glutathione levels. The antioxidant capacity of β-Lap was further demonstrated through 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical scavenging assays. Western blot analysis revealed that β-Lap upregulated brain-derived neurotrophic factor (BDNF) and promoted the phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response elementbinding protein (CREB), which were downregulated by glutamate. Furthermore, β-Lap enhanced the cellular antioxidant molecules, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, β-Lap can protect HT22 cells against glutamate-induced injury by activating the BDNF/TrkB/ERK/CREB and ERK/Nrf2/HO-1 signaling pathways, suggesting its therapeutic potential for neurodegenerative diseases.

Sleep is one of the most essential physiological phenomena for maintaining health. Sleep disturbances, such as insomnia, are often accompanied by psychiatric or physical conditions such as impaired attention, anxiety, and stress. Medication used to treat insomnia have concerns about potential side effects with long-term use, so interest in the use of alternative medicine is increasing. In this study, we investigated the hypnotic effects of β-lapachone (β-Lap), a natural naphthoquinone compound, using pentobarbital-induced sleep test, immunohistochemistry, real-time PCR, and western blot in mice. Our results indicated that β-Lap exerts a significant hypnotic effect by showing a decrease in sleep onset latency and an increase in total sleep time in pentobarbital-induced sleep model. The results of c-Fos immunostaining showed that β-Lap decreased neuronal activity in the basal forebrain and lateral hypothalamus, which are wakefulness-promoting brain regions, while increasing in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor (A1R) antagonist. Western blot analysis showed that β-Lap increased extracellular signalregulated kinase phosphorylation and nuclear factor-kappa B translocation from the cytoplasm to the nucleus; these effects were inhibited by DPCPX. Additionally, β-Lap increased the mRNA levels of A1R. Taken together, these results suggest that β-Lap exerts hypnotic effects, potentially through A1R.

BACKGROUND: Perioperative adverse cardiac events (PACEs) in elderly patients with hip fractures are associated with perioperative mortality. We investigated the relationship of PACE with post-discharge mortality and further explored whether it differs between patients with and without cardiovascular disease (CVD). METHODS: We retrospectively analyzed data from patients aged ≥ 65 years who underwent fragility hip fracture surgery from September 2016 to December 2021. PACE was defined as a composite of congestive heart failure, cardiogenic shock, myocardial injury after non-cardiac surgery, arrhythmic event, ischemic stroke, or acute pulmonary thromboembolism during hospitalization or within the 30-day postoperative period. Patients with 30-day mortality were excluded. The primary endpoint was all-cause mortality after hospital discharge. RESULTS: Of the 446 patients (133 patients in the CVD group and 313 patients in the non-CVD group), 14.8% experienced PACE, and overall mortality during a median of 15.9 months (interquartile range: 6.6-27.0 months) was 20.9% [CVD (26.3%) vs. non-CVD (18.5%), P = 0.064]. Patients with PACE demonstrated a significantly worse survival rate than those without PACE in both groups (all log-rank P < 0.05). After adjustment for confounders, PACE was an independent predictor of mortality in the overall population [hazard ratio (HR) = 3.01, 95% CI: 1.69-5.35, P < 0.001]. Its prognostic impact was significant in patients without CVD (HR = 2.69, 95% CI: 1.35-5.38, P = 0.005) but not in those with CVD (HR = 1.20, 95% CI: 0.41-3.50, P = 0.735). CONCLUSIONS PACE was associated with increased post-discharge mortality after fragility hip fracture, especially in elderly patients without CVD.

Background: The increasing rate of excess body weight (EBW) in the global population has led to growing health concerns, including cancer-related EBW. We aimed to estimate the population attributable fraction (PAF) of cancer incidence and deaths linked to EBW in Korean individuals from 2015 to 2030 and to compare its value with various body mass index cutoffs. Methods: Levin’s formula was used to calculate the PAF; the prevalence rates were computed using the Korean National Health and Nutrition Examination Survey data, while the relative risks of specific cancers related to EBW were estimated based on the results of Korean cohort studies. To account for the 15-year latency period when estimating the PAF in 2020, the prevalence rates from 2015 and attributable cases or deaths from 2020 were used. Results: The PAF attributed to EBW was similar for both cancer incidence and deaths using either the World Health Organization (WHO) Asian-Pacific region standard or a modified Asian standard, with the WHO standard yielding the lowest values. In the Korean population, the PAFs of EBW for cancer incidence were 2.96% in men and 3.61% in women, while those for cancer deaths were 0.67% in men and 3.06% in women in 2020. Additionally, PAFs showed a gradual increase in both sexes until 2030. Conclusion The EBW continues to have a significant impact on cancer incidence and deaths in Korea. Effective prevention strategies targeting the reduction of this modifiable risk factor can substantially decrease the cancer burden.

Background: The increasing rate of excess body weight (EBW) in the global population has led to growing health concerns, including cancer-related EBW. We aimed to estimate the population attributable fraction (PAF) of cancer incidence and deaths linked to EBW in Korean individuals from 2015 to 2030 and to compare its value with various body mass index cutoffs. Methods: Levin’s formula was used to calculate the PAF; the prevalence rates were computed using the Korean National Health and Nutrition Examination Survey data, while the relative risks of specific cancers related to EBW were estimated based on the results of Korean cohort studies. To account for the 15-year latency period when estimating the PAF in 2020, the prevalence rates from 2015 and attributable cases or deaths from 2020 were used. Results: The PAF attributed to EBW was similar for both cancer incidence and deaths using either the World Health Organization (WHO) Asian-Pacific region standard or a modified Asian standard, with the WHO standard yielding the lowest values. In the Korean population, the PAFs of EBW for cancer incidence were 2.96% in men and 3.61% in women, while those for cancer deaths were 0.67% in men and 3.06% in women in 2020. Additionally, PAFs showed a gradual increase in both sexes until 2030. Conclusion The EBW continues to have a significant impact on cancer incidence and deaths in Korea. Effective prevention strategies targeting the reduction of this modifiable risk factor can substantially decrease the cancer burden.