Aß dissociation by pectolinarin may counteract against Aß-induced synaptic dysfunction and memory impairment.

Alzheimer's disease (AD) is a degenerative brain disorder characterised by various neurological symptoms, including memory impairment and mood disorders, associated with the abnormal accumulation of amyloid b(Aß) and tau proteins in the brain. There is still no definitive treatment available for AD, and the Aß antibody drugs, which are expected to be approved by the FDA, have many limitations. Therefore, there is an urgent need to develop low-molecular-weight therapeutic agents for the management of AD. In this study, we investigated whether pectolinarin, a flavonoid, regulates Aß aggregation and Aß-induced toxicity. Pectolinarin demonstrated concentration-dependent inhibition of Aß aggregation and had the ability to break down pre-formed Aß aggregates, thereby reducing their neurotoxicity. Furthermore, pectolinarin suppressed Aß aggregates-induced reduction in long-term potentiation (LTP) in the hippocampus. Oral administration of pectolinarin in experimental animals inhibited memory impairment and LTP deficits induced by Aß injection in the hippocampus. These results indicate that pectolinarin may reduce toxic Aß species and Aß-induced memory impairments and synaptic dysfunction.

Antidepressants and the Risk of Ischemic Stroke in Older Adults According to the Degree of Serotonin Reuptake Inhibition: A Retrospective Cohort Study.

OBJECTIVE: The effects of serotonin reuptake inhibition induced by antidepressants on ischemic stroke and its pathophysiology remain unclear despite the frequent use of antidepressants and high fatality of ischemic stroke. We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition. DESIGN: Retrospective cohort study. PARTICIPANTS: The cohort consisted of older adult patients who were treated with antidepressants. MEASUREMENTS: We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition using Korea's National Health Insurance System-Senior Cohort. Exposure to antidepressants was categorized by type (strong, intermediate, or weak serotonin reuptake inhibitors [SRIs]) and by the mean prescribed dose per day and treatment duration. The risk for the strong and intermediate SRIs group was compared with that of the weak SRIs group using a Cox proportional hazards regression model. RESULTS: Of 97,411 were weak SRIs users, and 107,152 and 18,783 were users of strong and intermediate SRIs. The risk of ischemic stroke was 1.192- and 1.057-fold higher in strong and intermediate SRI users, respectively than in weak SRI users. Hazard ratios were increased in higher dose and shorter duration user groups. The risk increased 1.753-fold in strong SRI users with anticonvulsants and 1.387-fold in intermediate SRI users with PPIs. CONCLUSION: The use of strong and intermediate SRIs should be considered carefully in older adult patients, especially when high-dose antidepressants are prescribed even for a short duration.

Status of Patient Safety Culture in Community Pharmacy Settings: A Systematic Review.

OBJECTIVES: This systematic aimed to understand the global status using the results of survey studies based on the Community Pharmacy Survey on Patient Safety Culture and set the directions of development in terms of the patient safety culture of community pharmacies. METHODS: Electronic searches were performed in EMBASE, MEDLINE, PubMed, and CINAHL databases by using the words "patient safety," "culture," and "community pharmacy" with synonyms or associated words in the original English language research articles published between January 1, 2012, and March 2, 2023. This systematic review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Eleven surveys from 10 countries were selected. Five studies were conducted on pharmacists, whereas 6 studies were carried out on all pharmacy staff members such as pharmacists, technicians, clerks, and pharmacy students on apprenticeship. There was a considerable variation in the positive response rates across the dimensions of all the surveys. The highest positive response score was demonstrated for "teamwork" and "patient counseling," whereas the "staffing, work pressure, and pace" dimension was essential for improving patient safety culture in community pharmacy settings. For overall rating of the pharmacy on patient safety, 84.8% of pharmacy staff members gave good, very good, or excellent as their responses. CONCLUSIONS: Despite the differences among studies, findings of this study are expected to be used as valuable evidence to develop patient safety improvement strategies after reflecting each country's health care setting or community pharmacy practice. Furthermore, the results would offer meaningful assistance to achieve the goals of global campaigns such as the World Health Organization Patient Safety Challenge.

Blood-brain barrier breakdown is linked to tau pathology and neuronal injury in a differential manner according to amyloid deposition.

The blood-brain barrier (BBB) breakdown has been suggested as an early marker for Alzheimer's disease (AD); yet the relationship between BBB breakdown and AD-specific biomarkers based on the amyloid/tau/neurodegeneration framework is not clear. This study investigated the relationship between BBB permeability, AD-specific biomarkers, and cognition in patients with cognitive impairment. In this prospective study, we enrolled 62 participants with mild cognitive impairment or dementia between January 2019 and October 2020. All participants were assessed through cognitive tests, amyloid positron emission tomography (PET), dynamic contrast-enhanced magnetic resonance imaging (MRI) for BBB permeability (Ktrans), cerebrospinal fluid studies for Aß42/40 ratio, phosphorylated-tau Thr181 protein (p-tau), total tau protein (t-tau), and structural MRI for neurodegeneration. In amyloid PET (+) group, higher cortical Ktrans was associated with lower Aß40 (r = -0.529 p = 0.003), higher Aß42/40 ratio (r = 0.533, p = 0.003), lower p-tau (r = -0.452, p = 0.014) and lower hippocampal volume (r = -0.438, p = 0.017). In contrast, cortical Ktrans was positively related to t-tau level. (r = 0.489, p = 0.004) in amyloid PET (-) group. Our results suggest that BBB permeability is related to AD-specific biomarkers, but the relationship can vary by the presence of Aß plaque accumulation.

Ethyl pyruvate prevents long-term stress-induced cognitive decline and modulates Akt/GSK-3ß signaling.

Stress is an inevitable part of life and, simultaneously, a stimulus that can trigger various neuropsychiatric disorders. Therefore, proper stress management is essential for maintaining a healthy life. In this study, we investigated the suppression of stress-induced cognitive deficit by controlling changes in synaptic plasticity caused by stress and confirmed that ethyl pyruvate (EP) has such an effect. Corticosterone, a stress hormone, suppresses long-term potentiation (LTP) in mouse acute hippocampal slices. EP blocked the LTP inhibitory effect of corticosterone by regulating GSK-3ß function. Restraint stress for 2 weeks increased the anxiety levels and caused the cognitive decline in the experimental animals. Administration of EP for 14 days did not affect the increase in anxiety caused by stress but improved cognitive decline caused by stress. In addition, the decrease in neurogenesis and synaptic function deficits in the hippocampus, which cause of cognitive decline due to stress, were improved by EP administration. These effects appear via regulation of Akt/GSK-3ß signaling, as in in vitro studies. These results suggest that EP prevents stress-induced cognitive decline through the modulation of Akt/GSK-3ß-mediated synaptic regulation.

Phyllodulcin improves hippocampal long-term potentiation in 5XFAD mice.

Alzheimer's disease (AD) is a well-known neurodegenerative brain disease, and no curative treatment has yet been developed. The main symptoms include various brain lesions, caused by amyloid ß (Aß) aggregation, and cognitive decline. Therefore, it is believed that substances that control Aß will inhibit the onset of Alzheimer's disease and slow its progression. In this study, the effect of phyllodulcin, a major component of hydrangea, on Aß aggregation and brain pathology in an animal model of AD was studied. Phyllodulcin inhibited the aggregation of Aß and decomposed the pre-aggregated Aß in a concentration-dependent manner. In addition, it inhibited the cytotoxicity of Aß aggregates. Oral administration of phyllodulcin improved Aß-induced memory impairments in normal mice, reduced Aß deposition in the hippocampus, inhibited the activation of microglia and astrocytes, and improved synaptic plasticity in 5XFAD mice. These results suggest that phyllodulcin may be a candidate for the treatment of AD.

Investigation of Phospholipid Differences in Valproic Acid-Induced Autistic Mouse Model Brain Using Mass Spectrometry Imaging.

Autism is a neurodevelopmental disorder for which the cause and treatment have yet not been determined. The polyunsaturated fatty acid (PUFA) levels change rapidly in the blood or cerebrospinal fluid of autistic children and PUFAs are closely related to autism spectrum disorder (ASD). This finding suggests that changes in lipid metabolism are associated with ASD and result in an altered distribution of phospholipids in cell membranes. To further understand ASD, it is necessary to analyze phospholipids in organs consisting of nerve cells, such as the brain. In this study, we investigated the phospholipid distribution in the brain tissue of valproic acid-induced autistic mice using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Phospholipids including phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine were identified in each brain region and exhibited differences between the ASD and control groups. These phospholipids contain docosahexaenoic acid and arachidonic acid, which are important PUFAs for cell signaling and brain growth. We expect that the differences in phospholipids identified in the brain tissue of the ASD model with MALDI-MSI, in conjunction with conventional biological fluid analysis, will help to better understand changes in lipid metabolism in ASD.

Diagnostic Tools for Alzheimer's Disease: A Narrative Review Based on Our Own Research Experience.

Alzheimer's disease (AD), one of the most representative neurodegenerative diseases, has diverse neurobiological and pathophysiological mechanisms. Treatment strategies targeting a single mechanism have repeated faced failures because the mechanism of neuronal cell death is very complex that is not fully understood yet. Since complex mechanisms exist to explain AD, a variety of diagnostic biomarkers for diagnosing AD are required. Moreover, standardized evaluations for comprehensive diagnosis using neuropsychological, imaging, and laboratory tools are needed. In this review, we summarize the latest clinical, neuropsychological, imaging, and laboratory evaluations to diagnose patients with AD based on our own experience in conducting a prospective study.

Minoxidil Regulates Aging-Like Phenotypes in Rat Cortical Astrocytes In Vitro.

Mainly due to the slanted focus on the mechanism and regulation of neuronal aging, research on astrocyte aging and its modulation during brain aging is scarce. In this study, we established aged astrocyte culture model by long-term culturing. Cellular senescence was confirmed through SA-ß-gal staining as well as through the examination of morphological, molecular, and functional markers. RNA sequencing and functional analysis of astrocytes were performed to further investigate the detailed characteristics of the aged astrocyte model. Along with aged phenotypes, decreased astrocytic proliferation, migration, mitochondrial energetic function and support for neuronal survival and differentiation has been observed in aged astrocytes. In addition, increased expression of cytokines and chemokine-related factors including plasminogen activator inhibitor -1 (PAI-1) was observed in aged astrocytes. Using the RNA sequencing results, we searched potential drugs that can normalize the dysregulated gene expression pattern observed in long-term cultured aged astrocytes. Among several candidates, minoxidil, a pyrimidine-derived anti-hypertensive and anti-pattern hair loss drug, normalized the increased number of SA-ß-gal positive cells and nuclear size in aged astrocytes. In addition, minoxidil restored up-regulated activity of PAI-1 and increased mitochondrial superoxide production in aged astrocytes. We concluded that long term culture of astrocytes can be used as a reliable model for the study of astrocyte senescence and minoxidil can be a plausible candidate for the regulation of brain aging.

H2O2-Driven Hydroxylation of Steroids Catalyzed by Cytochrome P450 CYP105D18: Exploration of the Substrate Access Channel.

CYP105D18 supports H2O2 as an oxygen surrogate for catalysis well and shows high H2O2 resistance capacity. We report the hydroxylation of different steroids using H2O2 as a cosubstrate. Testosterone was regiospecifically hydroxylated to 2ß-hydroxytestosterone. Based on the experimental data and molecular docking, we predicted that hydroxylation of methyl testosterone and nandrolone would occur at position 2 in the A-ring, while hydroxylation of androstenedione and adrenosterone was predicted to occur in the B-ring. Further, structure-guided rational design of the substrate access channel was performed with the mutagenesis of residues S63, R82, and F184. Among the mutants, S63A showed a marked decrease in product formation, while F184A showed a significant increase in product formation in testosterone, nandrolone, methyl testosterone, androstenedione, and adrenosterone. The catalytic efficiency (kcat/Km) toward testosterone was increased 1.36-fold in the F184A mutant over that in the wild-type enzyme. These findings might facilitate the potential use of CYP105D18 and further engineering to establish the basis of biotechnological applications. IMPORTANCE The structural modification of steroids is a challenging chemical reaction. Modifying the core ring and the side chain improves the biological activity of steroids. In particular, bacterial cytochrome P450s are used as promiscuous enzymes for the activation of nonreactive carbons of steroids. In the present work, we reported the H2O2-mediated hydroxylation of steroids by CYP105D18, which also overcomes the use of expensive cofactors. Further, exploring the substrate access channel and modifying the bulky amino acid F184A increase substrate conversion while modifying the substrate recognizing amino acid S63 markedly decreases product formation. Exploring the substrate access channel and the rational design of CYP105D18 can improve the substrate conversion, which facilitates the engineering of P450s for industrial application.

Novel Therapeutics for Treating Sleep Disorders: New Perspectives on Maydis stigma.

Sleep is a restorative period that plays a crucial role in the physiological functioning of the body, including that of the immune system, memory processing, and cognition. Sleep disturbances can be caused by various physical, mental, and social problems. Recently, there has been growing interest in sleep. Maydis stigma (MS, corn silk) is a female maize flower that is traditionally used as a medicinal plant to treat many diseases, including hypertension, edema, and diabetes. It is also used as a functional food in tea and other supplements. ß-Sitosterol (BS) is a phytosterol and a natural micronutrient in higher plants, and it has a similar structure to cholesterol. It is a major component of MS and has anti-inflammatory, antidepressive, and sedative effects. However, the potential effects of MS on sleep regulation remain unclear. Here, we investigated the effects of MS on sleep in mice. The effects of MS on sleep induction were determined using pentobarbital-induced sleep and caffeine-induced sleep disruption mouse models. MS extracts decreased sleep latency and increased sleep duration in both the pentobarbital-induced sleep induction and caffeine-induced sleep disruption models compared to the positive control, valerian root extract. The butanol fraction of MS extracts decreased sleep latency time and increased sleep duration. In addition, ß-sitosterol enhances sleep latency and sleep duration. Both MS extract and ß-sitosterol increased alpha activity in the EEG analysis. We measured the mRNA expression of melatonin receptors 1 and 2 (MT1/2) using qRT-PCR. The mRNA expression of melatonin receptors 1 and 2 was increased by MS extract and ß-sitosterol treatment in rat primary cultured neurons and the brain. In addition, MS extract increased the expression of clock genes including per1/2, cry1/2, and Bmal1 in the brain. MS extract and ß-sitosterol increased the phosphorylation of ERK1/2 and αCaMKII. Our results demonstrate for the first time that MS has a sleep-promoting effect via melatonin receptor expression, which may provide new scientific evidence for its use as a potential therapeutic agent for the treatment and prevention of sleep disturbance.

Rodent Models of Post-Stroke Dementia.

Post-stroke cognitive impairment is one of the most common complications in stroke survivors. Concomitant vascular risk factors, including aging, diabetes mellitus, hypertension, dyslipidemia, or underlying pathologic conditions, such as chronic cerebral hypoperfusion, white matter hyperintensities, or Alzheimer's disease pathology, can predispose patients to develop post-stroke dementia (PSD). Given the various clinical conditions associated with PSD, a single animal model for PSD is not possible. Animal models of PSD that consider these diverse clinical situations have not been well-studied. In this literature review, diverse rodent models that simulate the various clinical conditions of PSD have been evaluated. Heterogeneous rodent models of PSD are classified into the following categories: surgical technique, special structure, and comorbid condition. The characteristics of individual models and their clinical significance are discussed in detail. Diverse rodent models mimicking the specific pathomechanisms of PSD could provide effective animal platforms for future studies investigating the characteristics and pathophysiology of PSD.

Hyperoside improves learning and memory deficits by amyloid ß1-42 in mice through regulating synaptic calcium-permeable AMPA receptors.

Alzheimer's disease (AD) is the most common degenerative disease and is indicative of dementia. The cerebral accumulation of amyloid ß (Aß), a crucial factor in AD, initiates synaptic and cognitive dysfunction. Therefore, the elevation of synaptic and cognitive functions may help manage dementia in AD. In this study, we suggest hyperoside as a synaptic function- and memory-enhancing agent. Hyperoside enhanced learning and memory in passive avoidance and object recognition tasks. Hyperoside facilitated synaptic long-term potentiation (LTP) in acute hippocampal slices. IEM-1460, a calcium-permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) antagonist, blocked the facilitation effect of hyperoside. Hyperoside also induced N-methyl-d-aspartate receptor (NMDAR)-independent LTP, which was blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the synaptic effects of hyperoside-mediated LTP. PKI (a PKA inhibitor) or SQ22536 (adenylyl cyclase, an AC inhibitor) blocked hyperoside-facilitated LTP and hyperoside-induced NMDAR-independent LTP. Hyperoside-enhanced learning and memory were blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the effect of hyperoside on learning and memory. Finally, hyperoside ameliorated Aß-induced memory impairments in an AD mouse model. These results suggest that hyperoside enhances learning and memory, and this may be due to the effect of CP-AMPARs.

Role of extracellular signal-regulated kinase in rubrofusarin-enhanced cognitive functions and neurite outgrowth.

Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.

Incidence of osteoporosis and ambient air pollution in South Korea: a population-based retrospective cohort study.

BACKGROUND: This study investigated the associations between exposure to ambient air pollutants and the incidence of osteoporosis using the Korean National Insurance Service-National Sample Cohort. METHODS: This nationwide, population-based, retrospective cohort study included 237,149 adults aged ≥40 years that did not have a diagnosis of osteoporosis at baseline between January 1, 2003, and December 31, 2015. Osteoporosis was defined as claim codes and prescriptions of bisphosphonates or selective estrogen receptor modulators at least twice annually. After matching values for PM10, NO2, CO, and SO2 during the 2002-2015 time period and PM2.5 in 2015 with residential areas, the incidence of osteoporosis was analyzed using a Cox proportional hazards regression model according to the quartile of average yearly concentrations of pollutants. RESULTS: Overall 22.2% of the study subjects, 52,601 (male: 5.6%, female: 37.6%) adults in total, were newly diagnosed with osteoporosis and treated. Exposure to PM10 was positively associated with incidence of osteoporosis (Q4: 1798 per 100,000 person-years vs. Q1: 1655 per 100,000 person-years). The adjusted hazard ratio (HR) with 95% confidence interval (CI) of Q4 in PM10 was 1.034 (1.009-1.062). The effect of PM10 on osteoporosis incidence was distinct in females (adjusted sub-HR: 1.065, 95% CI: 1.003-1.129), subjects aged < 65 years (adjusted sub-HR: 1.040, 95% CI: 1.010-1.072), and for residents in areas with low urbanization (adjusted sub-HR: 1.052, 95% CI: 1.019-1.087). However, there was no increase in osteoporosis based on exposure to NO2, CO, SO2, or PM2.5. CONCLUSIONS: Long-term exposure to PM10 was associated with newly diagnosed osteoporosis in Korean adults aged ≥40 years. This finding can aid in policy-making that is directed to control air pollution as a risk factor for bone health.

Late Passage Cultivation Induces Aged Astrocyte Phenotypes in Rat Primary Cultured Cells.

Astrocytes play various important roles such as maintaining brain homeostasis, supporting neurons, and secreting inflammatory mediators to protect the brain cells. In aged subjects, astrocytes show diversely changed phenotypes and dysfunctions. But, the study of aged astrocytes or astrocytes from aged subjects is not yet sufficient to provide a comprehensive understanding of their important processes in the regulation of brain function. In this study, we induced an in vitro aged astrocyte model through late passage cultivation of rat primary cultured astrocytes. Astrocytes were cultured until passage 7 (P7) as late passage astrocytes and compared with passage 1 (P1) astrocytes as early passage astrocytes to confirm the differences in phenotypes and the effects of serial passage. In this study, we confirmed the morphological, molecular, and functional changes of late passage astrocytes showing aging phenotypes through SA-ß-gal staining and measurement of nuclear size. We also observed a reduced expression of inflammatory mediators including IL-1ß, IL-6, TNFα, iNOS, and COX2, as well as dysregulation of wound-healing, phagocytosis, and mitochondrial functions such as mitochondrial membrane potential and mitochondrial oxygen consumption rate. Culture-conditioned media obtained from P1 astrocytes promoted neurite outgrowth in immature primary cultures of rat cortices, which is significantly reduced when we treated the immature neurons with the culture media obtained from P7 astrocytes. These results suggest that late passage astrocytes show senescent astrocyte phenotypes with functional defects, which makes it a suitable model for the study of the role of astrocyte senescence on the modulation of normal and pathological brain aging.

Associations of truncal body composition with cognitive status in patients with dementia.

BACKGOUND: Central obesity in midlife is a risk factor of cognitive decline and dementia, and also one of the factors that make cognitive functions deteriorate rapidly. OBJECTIVE: The objective of this study is to investigate the relationship between truncal body composition (fat and muscle) and cognitive impairment in patients with dementia. METHODS: A total of 81 female over 60 years of age with probable Alzheimer's disease were recruited between November 2014 and September 2015. The Mini-Mental State Examination, Global Deterioration Scale, and Clinical Dementia Rating Scale were used to assess the cognitive functions. Both truncal fat and muscle mass were measured using body dual-energy X-ray absorptiometry and used as a percentage of body weight (TMM% and TFM%). Correlations between truncal composition and cognitive status were assessed by simple correlation analysis, which was followed by partial correlation analysis with age and educational years. RESULTS: TFM% was not related to cognitive impairment. In contrast, TMM% had a significantly negative correlation with all three cognitive assessment scores. After further adjusting for age, educational years, and vascular factors, there was still a relationship between TMM% and cognitive functions. CONCLUSIONS: Unlike truncal fat mass that showed no relevance with cognitive functions, the truncal muscle mass was negatively correlated with cognitive status. The truncal muscle mass is thought to affect cognitive status in dementia patients somehow.