Activation of cGAS-STING suppresses coxsackievirus replication via interferon-dependent signaling.

Coxsackievirus B3 (CVB3) is a non-enveloped, single-stranded, positive RNA virus known for its role in provoking inflammatory diseases that affect the heart, pancreas, and brain, leading to conditions such as myocarditis, pancreatitis, and meningitis. Currently, there are no FDA-approved drugs treating CVB3 infection; therefore, identifying potential molecular targets for antiviral drug development is imperative. In this study, we examined the possibility of activating the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that triggers a type-I interferon (IFN) response, in inhibiting CVB3 infection. We found that activation of the cGAS-STING pathway through the application of cGAS (poly dA:dT and herring testes DNA) or STING agonists (2'3'-cGAMP and diamidobenzimidazole), or the overexpression of STING, significantly suppresses CVB3 replication. Conversely, gene-silencing of STING enhances viral replication. Mechanistically, we demonstrated that cGAS-STING activation combats CVB3 infection by inducing IFN response. Notably, we discovered that knockdown of IFN-α/ß receptor, a key membrane receptor in type-I IFN signaling, or inhibition of the downstream JAK1/2 signaling with ruxolitinib, mitigates the effects of STING activation, resulting in increased viral protein production. Furthermore, we investigated the interplay between CVB3 and the cGAS-STING pathway. We showed that CVB3 does not trigger cGAS-STING activation; instead, it antagonizes STING and the downstream TBK1 activation induced by cGAMP. In summary, our results provide insights into the interaction of an RNA virus and the DNA-sensing pathway, highlighting the potential for agonist activation of the cGAS-STING pathway in the development of anti-CVB3 drugs.

AIBP: A New Safeguard against Glaucomatous Neuroinflammation.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

Machine learning-based predictive models for the occurrence of behavioral and psychological symptoms of dementia: model development and validation.

The behavioral and psychological symptoms of dementia (BPSD) are challenging aspects of dementia care. This study used machine learning models to predict the occurrence of BPSD among community-dwelling older adults with dementia. We included 187 older adults with dementia for model training and 35 older adults with dementia for external validation. Demographic and health data and premorbid personality traits were examined at the baseline, and actigraphy was utilized to monitor sleep and activity levels. A symptom diary tracked caregiver-perceived symptom triggers and the daily occurrence of 12 BPSD classified into seven subsyndromes. Several prediction models were also employed, including logistic regression, random forest, gradient boosting machine, and support vector machine. The random forest models revealed the highest area under the receiver operating characteristic curve (AUC) values for hyperactivity, euphoria/elation, and appetite and eating disorders; the gradient boosting machine models for psychotic and affective symptoms; and the support vector machine model showed the highest AUC. The gradient boosting machine model achieved the best performance in terms of average AUC scores across the seven subsyndromes. Caregiver-perceived triggers demonstrated higher feature importance values across the seven subsyndromes than other features. Our findings demonstrate the possibility of predicting BPSD using a machine learning approach.

Association between excessive alcohol consumption and hypertension control in hypertensive patients.

OBJECTIVES: The purposes of this study were to investigate the association between excessive alcohol consumption and control of hypertension and the associations stratified by sex, age, and duration of hypertension among Korean adults who were diagnosed with hypertension under medication. METHODS: This study was cross-sectional design with a secondary data analysis using national data from the Korea National Health and Nutrition Evaluation Survey (KNHANES) collected from 2013 to 2018, including 4278 participants who were diagnosed with hypertension under medication. A multiple logistic regression analysis was conducted to evaluate the associations between excessive alcohol consumption and hypertension control while controlling for potential confounding variables. RESULTS: The hypertensive patients who consumed excessive alcohol were more associated with uncontrolled hypertension (OR, 1.31; 95% CI, 1.04-1.65) than those who do not consumed excessive alcohol. Specially, Excessive consumption of alcohol in men and young adults (<65 years) and short duration of hypertension (<5 years) were significantly more associated with uncontrolled hypertension compared to their counterparts. DISCUSSION: To improve blood pressure (BP) control in hypertensive patients, healthcare plan should be focused to modifiable risk factors and the intervention for unhealthy alcohol consumption should be part of comprehensive treatment for hypertension.

Factors Associated With Behavioral and Psychological Symptoms of Dementia: Prospective Observational Study Using Actigraphy.

BACKGROUND: Although disclosing the predictors of different behavioral and psychological symptoms of dementia (BPSD) is the first step in developing person-centered interventions, current understanding is limited, as it considers BPSD as a homogenous construct. This fails to account for their heterogeneity and hinders development of interventions that address the underlying causes of the target BPSD subsyndromes. Moreover, understanding the influence of proximal factors-circadian rhythm-related factors (ie, sleep and activity levels) and physical and psychosocial unmet needs states-on BPSD subsyndromes is limited, due to the challenges of obtaining objective and/or continuous time-varying measures. OBJECTIVE: The aim of this study was to explore factors associated with BPSD subsyndromes among community-dwelling older adults with dementia, considering sets of background and proximal factors (ie, actigraphy-measured sleep and physical activity levels and diary-based caregiver-perceived symptom triggers), guided by the need-driven dementia-compromised behavior model. METHODS: A prospective observational study design was employed. Study participants included 145 older adults with dementia living at home. The mean age at baseline was 81.2 (SD 6.01) years and the sample consisted of 86 (59.3%) women. BPSD were measured with a BPSD diary kept by caregivers and were categorized into seven subsyndromes. Independent variables consisted of background characteristics and proximal factors (ie, sleep and physical activity levels measured using actigraphy and caregiver-reported contributing factors assessed using a BPSD diary). Generalized linear mixed models (GLMMs) were used to examine the factors that predicted the occurrence of BPSD subsyndromes. We compared the models based on the Akaike information criterion, the Bayesian information criterion, and likelihood ratio testing. RESULTS: Compared to the GLMMs with only background factors, the addition of actigraphy and diary-based data improved model fit for every BPSD subsyndrome. The number of hours of nighttime sleep was a predictor of the next day's sleep and nighttime behaviors (odds ratio [OR] 0.9, 95% CI 0.8-1.0; P=.005), and the amount of energy expenditure was a predictor for euphoria or elation (OR 0.02, 95% CI 0.0-0.5; P=.02). All subsyndromes, except for euphoria or elation, were significantly associated with hunger or thirst and urination or bowel movements, and all BPSD subsyndromes showed an association with environmental change. Age, marital status, premorbid personality, and taking sedatives were predictors of specific BPSD subsyndromes. CONCLUSIONS: BPSD are clinically heterogeneous, and their occurrence can be predicted by different contributing factors. Our results for various BPSD suggest a critical window for timely intervention and care planning. Findings from this study will help devise symptom-targeted and individualized interventions to prevent and manage BPSD and facilitate personalized dementia care.

Consumption of a Blueberry-Enriched Diet by Women for 6 Weeks Alters Determinants of Human Muscle Progenitor Cell Function.

BACKGROUND: Human muscle progenitor cell (hMPC) function facilitates skeletal muscle regeneration and is influenced by circulating factors. Yet it is unknown whether dietary interventions impact hMPC function. Blueberry consumption was examined due to the pro-proliferative and antioxidant effects of blueberries and blueberry-derived compounds. OBJECTIVES: This study measured indicators of hMPC function in young and old cultures treated with serum collected from a blueberry-enriched diet (BED) intervention. METHODS: Younger (21-40 y, n = 12) and older (60-79 y, n = 10) women consumed a 6-wk BED (38 g of freeze-dried blueberries daily). Fasting serum was collected at 0, 4, and 6 wk, and a fed serum sample at 1.5 h (acute) after starting the BED intervention. Young and old hMPCs, derived from 3-5 distinct donors (biological replicates), were individually cultured in media containing pooled, age-group-matched serum from each time point. Determinants of hMPC function (e.g., hMPC number, oxidative stress resistance, and upregulation of metabolic pathways) were measured and compared within age groups. RESULTS: Culturing young hMPCs in acute (compared with 0 wk) BED serum did not alter hMPC number or oxidative stress-induced cell death, but increased cellular oxygen consumption (29%, P = 0.026). Culturing young hMPCs in 6-wk (compared with 0-wk) BED serum increased hMPC number (40%, P = 0.0024), conferred minor resistance to oxidative stress-induced cell death (12.6 percentage point decrease, P = 0.10), and modestly increased oxygen consumption (36%, P = 0.09). No beneficial effect of the acute or long-term BED serum was observed in old hMPCs. CONCLUSIONS: In younger women, dietary interventions could be a feasible strategy to improve hMPC function and thus muscle regeneration, through altering the serum environment.This study was registered at clinicaltrials.gov (NCT04262258).

Inhibitory Effect of Lycopene on Amyloid-ß-Induced Apoptosis in Neuronal Cells.

Alzheimer's disease (AD) is a fatal neurodegenerative disease. Brain amyloid-ß deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-κB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress-induced cell damage. We investigated whether lycopene inhibits amyloid-ß-stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-κB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-ß-induced apoptosis. The amyloid-ß increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid-ß-induced alterations. However, amyloid-ß did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF-κB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration.

Lycopene inhibits regulator of calcineurin 1-mediated apoptosis by reducing oxidative stress and down-regulating Nucling in neuronal cells.

SCOPE: Regulator of calcineurin 1 (RCAN1) is located on the Down syndrome critical region (DSCR) locus in human chromosome 21. Oxidative stress and overexpression of RCAN1 are implicated in neuronal impairment in Down's syndrome (DS) and Alzheimer's disease (AD). Serum level of lycopene, an antioxidant pigment, is low in DS and AD patients, which may be related to neuronal damage. The present study is to investigate whether lycopene inhibits apoptosis by reducing ROS levels, NF-κB activation, expression of the apoptosis regulator Nucling, cell viability, and indices of apoptosis (cytochrome c release, caspase-3 activation) in RCAN1-overexpressing neuronal cells. METHODS AND RESULTS: Cells transfected with either pcDNA or RCAN1 were treated with or without lycopene. Lycopene decreased intracellular and mitochondrial ROS levels, NF-κB activity, and Nucling expression while it reversed decrease in mitochondrial membrane potential, mitochondrial respiration, and glycolytic function in RCAN1-overexpressing cells. Lycopene inhibited cell death, DNA fragmentation, caspase-3 activation, and cytochrome c release in RCAN1-overexpressing cells. CONCLUSION: Lycopene inhibits RCAN1-mediated apoptosis by reducing ROS levels and by inhibiting NF-κB activation, Nucling induction, and the increase in apoptotic indices in neuronal cells. Consumption of lycopene-rich foods may prevent oxidative stress-associated neuronal damage in some pathologic conditions such as DS or AD.