Hyun Joung Lim

Background: Biological sex is a fundamental determinant of the pathogenesis and progression of cardiovascular disease (CVD). Despite extensive research on sex differences in human populations and whole-animal preclinical models, studies directly comparing male- and female-derived cells within defined cardiovascular cell types remain limited. Although human and in vivo studies have clearly highlighted the importance of sex differences, their complex systemic environments can make it difficult to disentangle cell-associated effects from the effects of circulating hormones and interactions among multiple cell types. Accordingly, this narrative review integrates evidence primarily from studies of isolated cardiovascular cells, supplemented where appropriate by relevant in vivo and clinical findings, to examine the reported contributions of hormonal signaling, sex chromosome complement, and related pathophysiological mechanisms. Main body: The reviewed studies report sex-associated cellular differences related to hormonal signaling and, in specific experimental models, sex chromosome complement. Across three major pathophysiological domains—oxidative stress, nitric oxide signaling, and inflammatory responses—the direction and magnitude of the reported differences vary according to cell type, tissue or vascular origin, species, and experimental conditions. Conclusion: Collectively, this review provides an integrated overview of reported sex-associated differences in cardiovascular cells and the hormonal, chromosomal, and pathophysiological factors that may contribute to them. The available evidence highlights the need for further direct male–female comparisons at the cellular level relevant to CVD, while complementary multicellular and in vivo approaches remain necessary to determine the relevance of cellular findings at the tissue and organ levels. Such studies may provide a stronger foundation for developing sex-informed precision therapies for CVD.

Background: Meal timing has emerged as a potential determinant of healthy aging; however, evidence linking temporal dietary patterns (TDPs) with frailty remains limited. We aimed to identify distinct TDPs among older adults and examine their associations with frailty and its components. Methods: In this cross-sectional study, 4184 adults aged ≥ 65 years from the Korea National Health and Nutrition Examination Survey (2016–2018) were analyzed. Temporal energy-intake trajectories from 24 h recalls were clustered using dynamic time warping-based kernel k-means. Frailty was defined using a modified Fried phenotype, and diet quality was assessed employing the Healthy Eating Index. Survey-weighted logistic regression and mediation analyses were performed. Results: Five distinct patterns were identified as follows: balanced (n = 1665, 38.8%), steady (n = 735, 17.8%), midday (n = 737, 18.0%), evening (n = 627, 15.2%), and morning–evening (n = 420, 10.2%). Among these, the evening-skewed (characterized by a disproportionate concentration of energy intake in the late evening; adjusted odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.03–2.10) and morning–evening (characterized by higher energy intake in both the morning and evening; OR = 1.43, 95% CI = 1.01–2.03) patterns were associated with higher frailty risk than the balanced pattern. Mediation analysis showed that higher total energy intake had a protective role in the evening-skewed pattern; however, this benefit was offset by the adverse impact of late-night eating, resulting in increased frailty risk. In the morning–evening pattern, both a direct association with frailty and an indirect pathway mediated by lower energy intake and poorer diet quality contributed to the increased frailty risk. Conclusions: Older adults with evening-skewed or morning–evening TDPs had greater frailty risk than those with balanced eating patterns. Optimizing meal timing—by reducing late-day energy loading and ensuring adequate overall intake and dietary quality—may represent a feasible chrono-nutrition strategy for frailty prevention.

Inflammation is critical in the development of acute liver failure (ALF). Peroxisome proliferator-activated receptor delta (PPARδ) regulates anti-inflammatory responses and is protective in several diseases such as obesity and cancer. However, the beneficial effects and underlying mechanisms of PPARδ agonist GW501516 in ALF remain unclear. This study investigated the molecular mechanisms underlying the anti-inflammatory effects of GW501516 in macrophages and assessed its protective potential against lipopolysaccharide (LPS)/galactosamine (GalN)-induced ALF. In vivo administration of GW501516 significantly reduced LPS/GalN-induced hepatotoxicity, as evidenced by lower mortality, decreased liver damage, and attenuated secretion of IL-1β, IL-6, and TNF-α. GW501516 treatment also decreased LPS-induced nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) production in RAW264.7 cells, an effect reversed by PPARδ siRNA. Additionally, GW501516 inhibited LPS-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), suggesting that inactivation of these MAPKs contributes to its effects. The secretion of IL-6, TNF-α, and NF-κB DNA-binding activity were also suppressed by GW501516, while the nuclear translocation of the NF-κB p65 subunit was unaffected. In conclusion, our findings suggest that GW501516 exerts protective effects in ALF by inhibiting the production of inflammatory mediators. Therefore, GW501516 may act as a potential agent for developing anti-inflammatory therapies for ALF.

Particulate matter 2.5 (PM_2.5) induces lung injury by increasing the generation of reactive oxygen species (ROS) and inflammation. ROS aggravates NLRP3 inflammasome activation, which activates caspase-1, IL-1β, and IL-18 and induces pyroptosis; these factors propagate inflammation. In contrast, treatment with exogenous 8-hydroxydeoxyguanosine (8-OHdG) decreases RAC1 activity and eventually decreases dinucleotide phosphate oxidase (NOX) and ROS generation. To establish modalities that would mitigate PM_2.5-induced lung injury, we evaluated whether 8-OHdG decreased PM_2.5-induced ROS generation and NLRP3 inflammasome activation in BEAS-2B cells. CCK-8 and lactate dehydrogenase assays were used to determine the treatment concentration. Fluorescence intensity, Western blotting, enzyme-linked immunosorbent assay, and immunoblotting assays were also performed. Treatment with 80 μg/mL PM_2.5 increased ROS generation, RAC1 activity, NOX1 expression, NLRP3 inflammasome (NLRP3, ASC, and caspase-1) activity, and IL-1β and IL-18 levels in cells; treatment with 10 μg/mL 8-OHdG significantly attenuated these effects. Furthermore, similar results, such as reduced expression of NOX1, NLRP3, ASC, and caspase-1, were observed in PM_2.5-treated BEAS-2B cells when treated with an RAC1 inhibitor. These results show that 8-OHdG mitigates ROS generation and NLRP3 inflammation by inhibiting RAC1 activity and NOX1 expression in respiratory cells exposed to PM_2.5.

Exposure to fine particulate matter increases the risk of cardiovascular morbidity and mortality. Few studies have tested the beneficial effect of indoor air filtration intervention in patients with cardiovascular disease. The aim of this study is to investigate the effect of air filtration on mitigating cardiovascular health in patients with coronary artery disease. This randomized, double-blind, crossover study is conducted with 38 coronary artery disease patients. The intervention consists of the following three periods: two-week active and sham air filtration interventions, with a two-week washout period. The indoor PM_2.5 concentration is continuously monitored during the entire study period. We measure the blood pressure, heart rate variability, baroreflex sensitivity, autonomic function test results, and endothelial function. The two-week active air filtration intervention for two weeks reduces the average indoor concentration of PM_2.5 by 33.9%. The indoor PM_2.5 concentration is significantly correlated to cross-correlation baroreflex sensitivity. Active air filtration is significantly associated with a decrease in the indicator of oxidative stress represented as 8-hydroxy-2′-deoxyguanosine. This study shows that a short-term air filtration intervention improved baroreflex sensitivity and might reduce oxidative stress in coronary artery disease patients. These findings suggest that the use of an air purifier could mitigate the recurrence of cardiovascular disease events in patients with coronary artery disease.

There is growing evidence that the accumulation of DNA damage induced by fine particulate matter (PM_2.5) exposure is an underlying mechanism of pulmonary disease onset and progression. However, there is a lack of experimental evidence on whether common factors (age, gender) affect PM_2.5 induced genomic damage. Here, we assessed the DNA damage potency of PM_2.5 using conventional genotoxicity testing in old male and female mice aged 8 and 40 weeks. Mice were intratracheally instilled with diesel exhaust PM_2.5 (DEP, NIST SRM 1650b), twice a week for 4 weeks. Exposure to DEP was not associated with an increase in the frequency of micronucleated polychromatic erythrocytes and did not induce a systemic genotoxic effect in the bone marrow. Meanwhile, the results from the comet assay showed a significant increase in DNA damage in DEP exposed mouse lung specimens. The positive relationship between DEP exposure and DNA damage is stronger in the older than in the younger group. Statistical analysis showed that there was a modifying effect of age on the association between PM_2.5 exposure and DNA damage. Our results suggest that the age factor should be considered to better understand the cellular adverse effects of PM_2.5.

Several epidemiological studies concluded that inhalation of diesel exhaust particles (DEP) is associated with an increase in the relative risk of lung cancer. In vitro research evaluating the genetic damage and/or changes in gene expression have been attempted to explain the relationship between DEP exposure and carcinogenicity. However, to date, investigations have been largely confined to studies in immortalized or tumorigenic epithelial cell models. Few studies have investigated damage at the chromosomal level to DEP exposure in normal cell lines. Here, we present the genotoxic effects of DEP in normal cells (embryonic human lung fibroblasts) by conventional genotoxicity testing (micronuclei (MN) and comet assay). We show the differentially expressed genes and enriched pathways in DEP-exposed WI-38 cells using RNA sequencing data. We observed a significant increase in single-strand DNA breaks and the frequency of MN in DEP-exposed cells in a dose-dependent manner. The differentially expressed genes following DEP exposure were significantly enriched in the pathway for responding to xenobiotics and DNA damage. Taken together, these results show that DEP exposure induced DNA damage at the chromosomal level in normal human lung cells and provide information on the expression of genes associated with genotoxic stress.

Alzheimer’s disease (AD) is characterized by amyloid plaques and pathologic cerebrovascular remodeling. Cerebrovascular abnormalities may contribute to the pathology of AD, but the molecular mechanisms are not fully understood. In this study, we evaluated blood–brain barrier (BBB) disruption and the role of VE-cadherin in the progression of amyloid pathology. Here, we determined that levels of VE-cadherin are decreased in brain vessels of AD patients and mouse model of AD. In vitro experiments showed that the disappearance of VE-cadherin by beta-amyloid at the endothelial cell surface was due to cleavage of VE-cadherin. VE-cadherin cleavage was inhibited by a γ-secretase and ADAM10 inhibitor. The disappearance of VE-cadherin in brain vessels was also seen in amyloid precursor protein transgenic mice. In the postmortem brain of individuals with AD, furthermore, levels of VE-cadherin were significantly reduced in vessels. Dementia patients showed a distinct blood biochemical profile characterized by high soluble VE-cadherin (sVEC). There was a strong association between plasma sVEC (adjusted odds ratio = 3.41, P < 0.001) and dementia. These results suggest that measurements of plasma VE-cadherin could have the potential for predicting the risk of progressive AD.