Inducers of the endothelial cell barrier identified through chemogenomic screening in genome-edited hPSC-endothelial cells.

The blood-retina barrier and blood-brain barrier (BRB/BBB) are selective and semipermeable and are critical for supporting and protecting central nervous system (CNS)-resident cells. Endothelial cells (ECs) within the BRB/BBB are tightly coupled, express high levels of Claudin-5 (CLDN5), a junctional protein that stabilizes ECs, and are important for proper neuronal function. To identify novel CLDN5 regulators (and ultimately EC stabilizers), we generated a CLDN5-P2A-GFP stable cell line from human pluripotent stem cells (hPSCs), directed their differentiation to ECs (CLDN5-GFP hPSC-ECs), and performed flow cytometry-based chemogenomic library screening to measure GFP expression as a surrogate reporter of barrier integrity. Using this approach, we identified 62 unique compounds that activated CLDN5-GFP. Among them were TGF-ß pathway inhibitors, including RepSox. When applied to hPSC-ECs, primary brain ECs, and retinal ECs, RepSox strongly elevated barrier resistance (transendothelial electrical resistance), reduced paracellular permeability (fluorescein isothiocyanate-dextran), and prevented vascular endothelial growth factor A (VEGFA)-induced barrier breakdown in vitro. RepSox also altered vascular patterning in the mouse retina during development when delivered exogenously. To determine the mechanism of action of RepSox, we performed kinome-, transcriptome-, and proteome-profiling and discovered that RepSox inhibited TGF-ß, VEGFA, and inflammatory gene networks. In addition, RepSox not only activated vascular-stabilizing and barrier-establishing Notch and Wnt pathways, but also induced expression of important tight junctions and transporters. Taken together, our data suggest that inhibiting multiple pathways by selected individual small molecules, such as RepSox, may be an effective strategy for the development of better BRB/BBB models and novel EC barrier-inducing therapeutics.

The impact of aromatherapy-based oral care on oral conditions, salivary pH, and halitosis in older adults with dementia: Pilot study.

Inadequate oral care and poor oral health in older adults are known to increase the risk of dementia. Dementia patients residing in long-term care facilities are especially vulnerable to oral diseases due to their care-resistant behavior. This study aimed to investigate the effects of a 7-day oral care program based on an aroma solution in 58 dementia patients (29 each in the experimental and control groups) admitted to a long-term care hospital in South Korea. The experimental group received oral care with a solution containing peppermint, tea tree, and lemon essential oils, and the control group with a saline solution. The effectiveness of oral care was assessed by the participants' oral condition, salivary pH, and halitosis. The experimental group showed significant improvements (P<.001) in all three outcomes, indicating that oral care with an aroma solution can improve the oral health of older dementia patients residing in long-term care facilities.

Large-area vertically aligned 2D MoS2layers on TEMPO-cellulose nanofibers for biodegradable transient gas sensors.

Crystallographically anisotropic two-dimensional (2D) molybdenum disulfide (MoS2) with vertically aligned (VA) layers is attractive for electrochemical sensing owing to its surface-enriched dangling bonds coupled with extremely large mechanical deformability. In this study, we explored VA-2D MoS2layers integrated on cellulose nanofibers (CNFs) for detecting various volatile organic compound gases. Sensor devices employing VA-2D MoS2/CNFs exhibited excellent sensitivities for the tested gases of ethanol, methanol, ammonia, and acetone; e.g. a high response rate up to 83.39% for 100 ppm ethanol, significantly outperforming previously reported sensors employing horizontally aligned 2D MoS2layers. Furthermore, VA-2D MoS2/CNFs were identified to be completely dissolvable in buffer solutions such as phosphate-buffered saline solution and baking soda buffer solution without releasing toxic chemicals. This unusual combination of high sensitivity and excellent biodegradability inherent to VA-2D MoS2/CNFs offers unprecedented opportunities for exploring mechanically reconfigurable sensor technologies with bio-compatible transient characteristics.

Efficient and additive-free synthesis of morphology variant iron oxyhydroxide nanostructures for phosphate adsorption application.

Iron oxyhydroxide (FeOOH) nanostructures of different shapes were successfully synthesized on flexible textile cloth of polyester using a novel and simple technique based on hydrolysis method. The technique used herein is newly designed specifically to improve the efficiency in terms of energy, simplicity and cost involved in large scale synthesis of nanostructured thin films. Additionally, the morphology of nano-sized iron oxyhydroxide could be tuned into different shapes through variation in the type of precursors used for synthesis. The uniformity and adhesion of the depositions were also found to be excellent as examined by qualitative techniques. The as-deposited samples exhibited monoclinic and orthorhombic structures of FeOOH. A significant variation in the shape of as-deposited FeOOH nanostructures with change in precursor was observed through morphological studies, which displayed lance-shaped, rounded clusters and rod-like growth features in different cases. The nanocrystalline FeOOH can be directly applied to attract and trap phosphate from water reservoirs, thus contributing to environmental solutions. The proposed technique can also be utilized to deposit larger areas, which could be suitable for practical applications.

Phosphatidylserine modulates response to oxidative stress through hormesis and increases lifespan via DAF-16 in Caenorhabditis elegans.

Phosphatidylserine is one of the phospholipids present in cell membranes, especially in brain and nervous system. The phosphatidylserine content is reduced with aging and age-related decrease in phosphatidylserine is known to contribute to cognitive impairment and Alzheimer's disease in the elderly. In the present study, we examined the effect of supplementation with phosphatidylserine on the response to oxidative stress and aging using C. elegans as a model system. Dietary supplementation with phosphatidylserine significantly increased resistance to oxidative stress and extended lifespan accompanying reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with phosphatidylserine. The cellular levels of reactive oxygen species and the expression of stress-responsive genes were increased by phosphatidylserine treatment, suggesting a hormetic effect. The extension of lifespan by phosphatidylserine overlaps with reduced insulin/IGF-1-like signaling and requires DAF-16. The effect of phosphatidylserine on age-related diseases was examined using animal model of disease. Supplementation with phosphatidylserine significantly suppressed amyloid beta-induced toxicity in Alzheimer's disease model. Reduced survival in diabetes mellitus due to high-glucose diet was reversed by supplementation with phosphatidylserine. This study reports the anti-oxidative stress and anti-aging effect of phosphatidylserine for the first time at the organismal level and proposes possible underlying mechanisms.

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery.

Protein-protein interactions (PPIs) are an effective means to orchestrate intricate biological processes required to sustain life. Approximately 650 000 PPIs underlie the human interactome; thus underscoring its complexity and the manifold signaling outputs altered in response to changes in specific PPIs. This minireview illustrates the growing arsenal of PPI assemblies and offers insights into how these varied PPI regulatory modalities are relevant to customized drug discovery, with a focus on cancer. First, known and emerging PPIs and PPI-targeted drugs of both natural and synthetic origin are categorized. Building on these discussions, the merits of PPI-guided therapeutics over traditional drug design are discussed. Finally, a compare-and-contrast section for different PPI blockers, with gain-of-function PPI interventions, such as PROTACS, is provided.

Modulation of Rat Hepatic CYP1A and 2C Activity by Honokiol and Magnolol: Differential Effects on Phenacetin and Diclofenac Pharmacokinetics In Vivo.

Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of Magnolia officinalis (Magnoliaceae) bark, which has been widely used in traditional Chinese medicine (Houpu Tang) for the treatment of various diseases, including anxiety, stress, gastrointestinal disorders, infection, and asthma. The aim of this study was to investigate the direct effects of honokiol and magnolol on hepatic CYP1A and 2C-mediated metabolism in vitro using rat liver microsomes and in vivo using the Sprague-Dawley rat model. Honokiol and magnolol inhibited in vitro CYP1A activity (probe substrate: phenacetin) more potently than CYP2C activity (probe substrate: diclofenac): The mean IC50 values of honokiol for the metabolism of phenacetin and diclofenac were 8.59 µM and 44.7 µM, while those of magnolol were 19.0 µM and 47.3 µM, respectively. Notably, the systemic exposure (AUC and Cmax) of phenacetin, but not of diclofenac, was markedly enhanced by the concurrent administration of intravenous honokiol or magnolol. The differential effects of the two phytochemicals on phenacetin and diclofenac in vivo pharmacokinetics could at least be partly attributed to their lower IC50 values for the inhibition of phenacetin metabolism than for diclofenac metabolism. In addition, the systemic exposure, CL, and Vss of honokiol and magnolol tended to be similar between the rat groups receiving phenacetin and diclofenac. These findings improve our understanding of CYP-mediated drug interactions with M. officinalis and its active constituents.

Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity.

Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56 µM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure-activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions.

Age at menarche and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The goal of this study was to examine the association between age at menarche and non-alcoholic fatty liver disease (NAFLD) in Korean women and to explore whether any observed associations were mediated by adult adiposity. METHODS: A cross-sectional study was performed for 95,183 Korean women, aged 30 or older, who underwent a regular health screening examination between March 2011 and April 2013. Information regarding age at menarche was collected using standardized, self-administered questionnaires. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association between age at menarche and NAFLD. RESULTS: Of the 76,415 women evaluated in this study, 9601 had NAFLD. Age at menarche was inversely associated with the prevalence of NAFLD. In a multivariable-adjusted model, the prevalence ratios (95% CIs) for NAFLD comparing menarche at <12, 12, 14, 15, and 16-18 years to menarche at 13 years were 1.31 (1.18-1.45), 1.05 (0.97-1.13), 0.93 (0.87-0.99), 0.87 (0.82-0.93), and 0.78 (0.73-0.84), respectively (p for trend <0.001). Adjusting for adult BMI or percent fat mass (%) substantially reduced these associations; however, they remained statistically significant. The association between age at menarche and NAFLD was modified by age. CONCLUSIONS: We identified an inverse association between age at menarche and NAFLD in a large sample of middle-aged women. This association was partially mediated by adiposity. The findings of this study suggest that obesity prevention strategies are needed in women who undergo early menarche to reduce the risk of NAFLD.

Metabolic syndrome, insulin resistance, and mammographic density in pre- and postmenopausal women.

Little is known about the association of metabolic syndrome (MetS) or insulin resistance (IR) with mammographic density, a strong risk factor for breast cancer. The goal of this study was to evaluate these associations in pre- and postmenopausal women. A cross-sectional study was performed in 73,974 adult women who underwent a comprehensive health screening examination that included a mammogram between 2011 and 2013 (mean age 42.6 years). MetS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III. IR was assessed with the homeostasis model assessment-insulin resistance (HOMA-IR). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for dense breast were estimated using logistic regression models after adjustment for potential confounders. In premenopausal women, MetS and all its components except waist circumference were associated with dense breast. After adjustment for potential confounders, the OR (95% CI) for dense breast in women with MetS compared with those without MetS was 1.22 (1.06-1.39). In postmenopausal women, however, there was positive but non-significant association between MetS and dense breast. In both pre- and postmenopausal women, high blood glucose and IR were positively associated with dense breast. The OR (95% CI) for dense breast between the highest and lowest quartiles of HOMA-IR was 1.29 (1.20-1.39) for premenopausal women and 1.44 (1.05-1.97) for postmenopausal women. In a large sample of Korean women, MetS and IR were associated with mammographic dense breast, demonstrating that IR, a potentially modifiable risk factor, may increase breast cancer risk, possibly through high mammographic density.

Thyroid hormones and coronary artery calcification in euthyroid men and women.

OBJECTIVE: Overt and subclinical hypothyroidism are risk factors for atherosclerosis. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC). APPROACH AND RESULTS: We conducted a cross-sectional study of 41 403 apparently healthy young and middle-aged men and women with normal thyroid hormone levels. Free thyroxin, free triiodothyronine, and thyroid-stimulating hormone levels were measured by electrochemiluminescent immunoassay. CAC score was measured by multidetector computed tomography. The multivariable adjusted CAC ratios comparing the highest versus the lowest quartile of thyroid hormones were 0.74 (95% confidence interval, 0.60-0.91; P for trend <0.001) for free thyroxin, 0.81 (0.66-1.00; P for trend=0.05) for free triiodothyronine, and 0.78 (0.64-0.95; P for trend=0.01) for thyroid-stimulating hormone. Similarly, the odds ratios for detectable CAC (CAC >0) comparing the highest versus the lowest quartiles of thyroid hormones were 0.87 (0.79-0.96; P for linear trend <0.001) for free thyroxin, 0.90 (0.82-0.99; P for linear trend=0.02) for free triiodothyronine, and 0.91 (0.83-1.00; P for linear trend=0.03) for thyroid-stimulating hormone. CONCLUSIONS: In a large cohort of apparently healthy young and middle-aged euthyroid men and women, low-normal free thyroxin and thyroid-stimulating hormone were associated with a higher prevalence of subclinical coronary artery disease and with a greater degree of coronary calcification.

Thoracic coupled motions of korean men in good health in their 20s.

[Purpose] The purpose of this study was to investigate thoracic coupled motions of 20 Korean young individuals. [Methods] Thoracic motion of twenty healthy male college students aged 23.2±3.1 was examined. The coupled motions of the thoracic regions T1-4, T4-8, T8-12 were measured using a three dimensional motion capture system. [Results] Coupled axial rotation in the same direction as lateral bending was observed in T1-T4 and T4-T8 in the neutral, flexed, and extended postures of the thoracic spine. In T8-T12, coupled axial rotation in the same direction as lateral bending were observed in the neutral and flexed postures, while coupled axial rotation in the opposite direction was observed in an extended posture. [Conclusion] The patterns of coupled motions in the thoracic spine demonstrated some variability between postures and regions in vivo. However, coupled motions in the same direction were predominantly lateral flexion or axial rotation in the three postures.

Metabolic factors and breast cancer risk in Korean women.

PURPOSE: Metabolic factors have been suggested to be associated with breast cancer. However, the findings are inconsistent among studies. We conducted a case-control study in Korean women to evaluate the association between metabolic factors and premenopausal and postmenopausal breast cancer. METHODS: Incident breast cancer cases (270 women) and their controls (540 women) matched by age and menopausal status were recruited from the recipients of a health examination at the same institution. Five relevant factors of metabolic syndrome were evaluated. Odds ratios (OR) and 95 % confidence intervals (CI) for the association were estimated by conditional logistic regression analysis. RESULTS: Proportions of cases and controls with each factors were 25.6 and 20.6 % for obesity (body mass index ≥ 25 kg/m(2)), 17.4 and 17.4 % for high fasting glucose (≥5.55 mmol/L or use of hypoglycemic medication), 13.0 and 18.9 % for high triglyceride (≥1.69 mmol/L), 26.3 % and 23.9 % for low high-density lipoprotein cholesterol (<1.29 mmol/L), and 29.6 and 30.6 % for high blood pressure (≥130/or 85 mmHg or use of antihypertensive medication), respectively. Although only the obesity was associated with an increased risk of postmenopausal breast cancer (OR = 2.24; 95 % CI 1.22-4.10) among individual metabolic factors, women with aggregation of three or more metabolic factors as defined by international diabetes federation criteria showed greater risk for postmenopausal breast cancer compared with women without any factor (OR = 2.36; 95 % CI 1.10-5.10). CONCLUSIONS: Although obesity was the only metabolic factor associated with postmenopausal breast cancer, the presence of other metabolic factors may further increase the risk of postmenopausal breast cancer when combined with obesity.

Automated Dual-Mode Cell Monitoring To Simultaneously Explore Calcium Dynamics and Contraction-Relaxation Kinetics within Drug-Treated Stem Cell-Derived Cardiomyocytes.

This manuscript proposes a new dual-mode cell imaging system for studying the relationships between calcium dynamics and the contractility process of cardiomyocytes derived from human-induced pluripotent stem cells. Practically, this dual-mode cell imaging system provides simultaneously both live cell calcium imaging and quantitative phase imaging based on digital holographic microscopy. Specifically, thanks to the development of a robust automated image analysis, simultaneous measurements of both intracellular calcium, a key player of excitation-contraction coupling, and the quantitative phase image-derived dry mass redistribution, reflecting the effective contractility, namely, the contraction and relaxation processes, were achieved. Practically, the relationships between calcium dynamics and the contraction-relaxation kinetics were investigated in particular through the application of two drugs─namely, isoprenaline and E-4031─known to act precisely on calcium dynamics. Specifically, this new dual-mode cell imaging system enabled us to establish that calcium regulation can be divided into two phases, an early phase influencing the occurrence of the relaxation process followed by a late phase, which although not having a significant influence on the relaxation process affects significantly the beat frequency. In combination with cutting-edge technologies allowing the generation of human stem cell-derived cardiomyocytes, this dual-mode cell monitoring approach therefore represents a very promising technique, particularly in the fields of drug discovery and personalized medicine, to identify compounds likely to act more selectively on specific steps that compose the cardiomyocyte contractility.

Development of anti-coxsackievirus agents targeting 3C protease.

Peptidomimetic anti-viral agents against Coxsackievirus B3 (CVB3) were developed using a strategy involving the inhibition of 3C protease (CVB3 3C(pro)), a target for CVB3-mediated myocarditis or pericarditis. In an attempt to improve the inhibitory activity against CVB3, a variety of hetero-aromatic groups were incorporated into the α,ß-unsaturated ester as Michael acceptor moiety, which is the position of interaction with the cysteine moiety in the P1' active site of CVB3 3C(pro). Among these hetero-aromatic groups, the quinoline analogs 9c and 9e, with IC(50) values of 250 and 130 nM as determined from an enzyme assay, significantly inhibited the CVB3-mediated cell cytotoxicity, indicating parallel anti-viral activities. A comparison of the binding modes of the potent inhibitor 9e and the relatively weak inhibitor 9n was explored in a molecular docking study, which revealed that compound 9n lacked hydrogen bonds in its interactions with Gly129, 128, and 145.

Psychometric Properties and Effects on Health Outcomes of the Patient Assessment of Chronic Illness Care (PACIC) in Korean Hemodialysis Patients.

BACKGROUND: The satisfaction of patients receiving integrated care with End-Stage Renal Disease (ESRD) is widely advocated and patients with ESRD have special health needs, but few studies have investigated whether integrated care was associated with health outcomes. Our aims were to evaluate the psychometric properties of the Korean-translated patient assessment of chronic illness care (PACIC) in patients with ESRD, and to evaluate whether PACIC evaluated by patients was associated with health outcomes. METHODS: ESRD patients on hemodialysis (n = 172) at 2 dialysis centers. Data quality, internal consistency and correlation between items and scales were assessed. To test the external validity, the association between PACIC and the health behaviour and outcomes of hemodialysis patients was analyzed. RESULTS: The mean score of the PACIC items was 3.0. The item-scale correlation (0.67-0.85) and test-retest correlation (0.72-0.82) regarding scales for internal consistency showed excellent consistency. Total PACIC score was significantly associated with dietary self-efficacy (ß = 0.22) and serum potassium (Exp(B) = 1.65). Higher overall PACIC score was significantly associated with higher physical health status (ß = 3.52). CONCLUSIONS: The Korean-translated PACIC questionnaire is a tool with reliability and validity. Comprehensive treatment strategies for ESRD patients may improve their health behaviors and outcomes.

Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans.

Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid abundant in various fruits and vegetables, including apple, strawberry, and onion, shows several beneficial effects such as anti-oxidant, anti-inflammatory, and anti-tumor effects. The free radical theory of aging suggests that age-related accumulation of oxidative damage is the major cause of aging and that decreasing cellular oxidative stress can regulate aging. Here, we investigated the effects of dietary supplementation with fisetin on the stress response, aging, and age-related diseases. Fisetin reduced the cellular ROS levels and increased the resistance to oxidative stress. However, the response to UV irradiation was not affected by fisetin. Both the mean and maximum lifespans were significantly extended by fisetin; lifespan extension by fisetin was accompanied by reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin. Amyloid beta-induced toxicity was markedly decreased by fisetin, which required DAF-16 and SKN-1. Reduced motility induced by a high-glucose diet was completely recovered by supplementation with fisetin, which was dependent on SKN-1. Using a Parkinson's disease model, we showed that degeneration of dopaminergic neurons was significantly inhibited by treatment with fisetin. Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy. These findings support the free radical theory of aging and suggest that fisetin can be a strong candidate for use in novel anti-aging anti-oxidant nutraceuticals.

Preventing VEGF-Mediated Vascular Permeability by Experimentally Potentiating BBB Characteristics in Endothelial Cells.

Difficulties with poor reproducibility and translatability of animal model-based research, along with increased efforts to abide by the 3Rs tenet of animal welfare, are driving demand for more relevant human cellular systems. This is especially true for central nervous system (CNS) vasculatures with specialized properties and barriers, namely the blood-brain and blood-retinal barriers (BBB and BRB, respectively) which are difficult to model in vitro. The BBB and BRB protect neurovascular units by regulating nutrient homeostasis, maintaining local ion levels, protecting against exposure from circulating toxins and pathogens, and restricting passage of peripheral immune factors. In this manuscript, we will describe transgenic and pharmacological-based protocols to generate relevant BBB and BRB models both from human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and from primary human umbilical vein endothelial cells (HUVECs). When followed, researchers can expect to generate well-characterized, anatomical and functional BBB and BRB EC monolayers in 36-48 h that are stable up to 90 h. The ability to generate more relevant BBB and BRB EC cultures will improve drug discovery efforts and inform future therapies for neurovascular disorders.

Factors Associated with Gastrointestinal Symptoms among Rotating Shift Nurses in South Korea: A Cross-Sectional Study.

Rotating shift work places a serious burden on nurses' physical and psychological health. Gastrointestinal (GI) symptoms are a common complaint among shift workers. This study assessed GI symptoms and identified the associations between dietary habits, psychological status, and sleep quality among rotating shift nurses. Data from 125 female nurses in rotating shifts who worked at two tertiary hospitals in South Korea were collected using a questionnaire that included the Gastrointestinal Symptoms Questionnaire; the Dietary Habit Questionnaire; the Depression, Anxiety, Stress Scale (DASS)-21; and the Pittsburgh Sleep Quality Index (PSQI). All participants experienced various GI symptoms, and 47% of them complained of at least one severe GI symptom. There were significant differences in GI symptom scores according to the status of depression, anxiety, stress, and sleep quality. In multiple linear regression analysis, the factors associated with an increase in the occurrence and severity of GI symptoms were poor sleep quality and morbid anxiety and stress. The model explained power at 43.2%. As most nurses in rotating shifts experience GI symptoms, they should receive counseling and training programs at work to alleviate psychological symptoms, improve sleep quality, and pay more attention to their health status as well as GI symptom management.

Supplementation with phosphatidylethanolamine confers anti-oxidant and anti-aging effects via hormesis and reduced insulin/IGF-1-like signaling in C. elegans.

Phosphatidylethanolamine is a major component of phospholipids with both structural and metabolic functions in cells. Previous studies have revealed that phosphatidylethanolamine can modulate autophagy with a protective effect against age-related diseases. We examined the effect of dietary supplementation with phosphatidylethanolamine on stress response and aging in Caenorhabditis elegans. Phosphatidylethanolamine increased resistance to oxidative stress without effect on heat stress or ultraviolet irradiation. Both mean and maximum lifespans were significantly increased by phosphatidylethanolamine while fertility was reduced as a trade-off. Age-related decline of muscle function was delayed in animals treated with phosphatidylethanolamine. Supplementation with phosphatidylethanolamine suppressed toxic effect of amyloid ß and high-glucose diet. Increased ROS levels and induction of stress-responsive genes after dietary supplementation with phosphatidylethanolamine suggest that anti-oxidative stress and anti-aging effects of phosphatidylethanolamine might be though hormesis. Genetic analysis using long-lived mutants and knockdown by RNAi revealed that the lifespan-extending effect of phosphatidylethanolamine overlapped with that of reduced insulin/IGF-1-like signaling and required DAF-16, a downstream transcription factor known to regulate the expression of many stress-responsive genes. These findings indicate that phosphatidylethanolamine has anti-oxidative stress and anti-aging activities with its underlying mechanisms involving hormesis and reduced insulin/IGF-1-like signaling in C. elegans.