Advancing age is associated with epicardial atherosclerosis and coronary microvascular dysfunction (CMD), complicating reliable assessment of CMD using coronary flow reserve (CFR). Whether prevalence of functional and structural CMD varies with age remains unclear.

The authors sought to evaluate the prevalence of CMD endotypes by age strata and compare CFR with microvascular resistance reserve (MRR) for diagnosis and stratification.

Data from 1,704 patients (2,283 lesions) with stable angina in the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry) were analyzed, including obstructive (fractional flow reserve ≤0.80) and nonobstructive (fractional flow reserve >0.80) lesions. CMD was classified as no CMD (MRR ≥3.0), functional CMD (MRR <3.0, normal resistance), or structural CMD (MRR <3.0, abnormal resistance). CMD classification was repeated using CFR (<2.5 abnormal). Patients were stratified per age decade: <50, 50-59, 60-69, 70-79, and ≥80 years.

CMD prevalence by MRR was 48.2%, and increased across age strata (37.2% to 78.0%; P < 0.001), driven by structural CMD (10.9% to 40.0%; P < 0.001), while functional CMD prevalence remained unchanged (26.3% to 38.0%; P = 0.220). Age independently predicted functional (OR/y: 1.02; P < 0.001) and structural CMD (OR/y: 1.05; P < 0.001). In obstructive lesions, age predicted structural CMD (OR/y: 1.03; P = 0.0055); in nonobstructive lesions, age predicted functional (OR/y: 1.02; P = 0.0032) and structural CMD (OR/y: 1.06; P < 0.001). Overall CMD prevalence by CFR exceeded MRR across groups (53.3% vs 48.2%; P < 0.001), irrespective of epicardial disease.

Structural CMD increases with age regardless of obstructive CAD, while functional CMD prevalence increases only in nonobstructive CAD. CFR may overestimate CMD in epicardial disease, whereas MRR provides a more consistent assessment regardless of obstructive CAD, underscoring the need for prospective studies on their clinical relevance.

The development and maturation of B lymphocytes are critical for adaptive immunity, relying on tightly regulated gene programs within specialized microenvironments shaped by extracellular matrix and neighboring cells. However, high-dimensional, integrated analyses of B cell heterogeneity, gene regulation, and external factors during development remain limited. Here, we analyze single-cell transcriptomic and B cell receptor (BCR) sequencing data from B cells and surrounding cells in bone marrow, tonsil, and peripheral blood. We reveal the dynamics of gene regulation, the heterogeneity of conventional B cells, and stage-specific cell-cell interactions along B cell development. Immature B cells display minimal transcriptional activity and low RNA velocity, whereas naïve B cell proliferation and activation are niche-confined and individualized. Two models for memory B cell subpopulation development appear compatible and warrant further study. Cell-cell interaction analysis highlights the role of myeloid cells and identifies TNF and adhesion signaling as dominant, stage-dependent pathways. Additionally, we identify two age-associated B cell subpopulations expressing S100A8/A9 and C1q, and experimentally confirm S100A8/A9 secretion from human B cells, indicating a senescence-associated secretory phenotype. This integrated analysis provides a comprehensive resource for understanding B cell development, gene regulation, and intercellular communication, offering insights into immune aging and potential therapeutic strategies.

Chronic overconsumption of high-fat diets contributes to obesity, with hyperlipidemia being a common comorbidity. The cardiovascular system is strongly influenced by circadian rhythms, which regulate key functions such as endothelial activity, thrombosis, and blood pressure. Circadian rhythms are central regulators of metabolic and physiological processes, and dietary pattern shifts can disrupt the synchronization of the internal clock within metabolic systems.

Using a hyperlipidemic mouse model, we investigated diurnal rhythm-related effects on the liver and intestine through transcriptomic, metagenomic, and metabolomic profiling. We identified several key genes-including CD36, Hmgcs1, Ehhadh, Cyp4a12b, Ifi27l2b, Ugt2b1, Ces2a, Cyp3a11, Selenbp2, and Gal3st1-that are regulated by the hepatic circadian clock and modulate metabolites via the gut-liver axis. The gut microbiota exhibited diurnal rhythmicity that coordinates intestinal digestion and metabolism, forming a synergistic circadian metabolic network. Hyperlipidemia disrupted normal circadian regulation in the liver and intestine, affecting lipid synthesis, transport, accumulation, and catabolism.

Our hepatic transcriptomic analysis revealed that a high-fat diet induces aberrant expression of lipid metabolism genes during the night. This diet also perturbs the circadian rhythm of the gut microbiota, leading to intestinal metabolic dysregulation. Metabolites entering the portal circulation act as signaling molecules that bind hepatic receptors and directly regulate the transcription of lipid metabolism genes. The loss of rhythmic metabolite secretion consequently disrupts circadian gene expression, contributing to hepatic lipid dysregulation via the gut-liver axis-a key mechanism in hyperlipidemia pathogenesis.

This study identifies critical temporal windows and core microbial taxa involved in microbiota-metabolite-gene crosstalk via the gut-liver axis, offering a theoretical foundation for circadian rhythm-targeted interventions in metabolic diseases.

Macrophages play a pivotal role in tissue regeneration and immune regulation through efferocytosis and other mechanisms, with their intracellular communication largely dependent on second messengers (e.g., cyclic adenosine monophosphate, cAMP). However, the broad-spectrum nature of these second messengers renders related interventions susceptible to uncontrollable systemic and off-target effects. Here, we developed an injectable apoptosis-mimicking hybrid hydrogel (PAS@Gel) that enables specific and coordinated macrophage intervention of both first and second messengers involved in efferocytosis, thereby optimizing macrophage communication and promoting tissue regeneration. First, the hybrid hydrogel forms an ECM-mimicking 3D structure through a thermosensitive copolymer and incorporates apoptosis-mimicking vesicles (PAS), enabling the first messenger regulation of macrophage efferocytosis Find-me/Eat-me processes specifically. Subsequently, Rolipram delivered by PAS inhibits cAMP phosphodiesterase (PDE4), synergistically enhancing the second messenger-mediated pathway to amplify intracellular signaling. In vitro experiments demonstrated that PAS@Gel synergistically activates macrophage Tyro3-Axl-Mer receptors, RAC1, and cAMP-related signaling pathways, significantly enhancing efferocytosis-related macrophage communication. In vivo studies using a myocardial ischemia/reperfusion (MI/R) injury model further confirmed that in-situ injection of PAS@Gel effectively alleviated inflammation via second messenger amplification, and significantly promoted myocardial tissue repair. This study presents a novel strategy for guiding tissue regeneration by enhancing macrophage second messenger regulation.

In recent years, the application of estrogen in skin health and disease prevention has garnered significant attention, and it is now widely involved in the intervention and study of various skin conditions. Experimental evidence shows that estrogen has profound effects on the structure and function of the skin, including the synthesis of collagen and elastin, regulation of skin pigmentation, and control of sebum secretion. This review systematically summarizes the multifaceted effects of estrogen on skin health and diseases, with a focus on the mechanisms by which different types of estrogen influence skin aging, pigmentation, and other related issues. Additionally, we explore how estrogen exerts its effects on the skin through various signaling pathways, such as estrogen receptor-mediated signaling, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) pathways. Through a comprehensive analysis of the existing studies, this review aims to provide a deeper understanding of the complex interactions between estrogen and the skin, offering a comprehensive perspective on estrogen's role in skin physiology and pathology.

The pathogenesis of atherosclerosis (AS) is a chronic disease marked by inflammation, and there are intimate associations with various forms of programmed cell death (PCD). Recently, the mechanisms of pyroptosis and autophagy in AS have attracted much attention. Pyroptosis is a form of PCD mediated by inflammasomes, which worsens local inflammatory responses by releasing proinflammatory factors (e.g., IL-18 and IL-1β) and favors plaque instability and thrombosis. Autophagy is a process that helps to keep cells healthy by breaking down damaged cell structures and abnormal proteins. Mitophagy, a specialized form of autophagy, is of major importance to redox homeostasis and the regulation of inflammation. However, the dysregulation of autophagy may disturb the cellular homeostasis, which then accelerates the progression of AS. Studies have found a complex mutual regulation between pyroptosis and autophagy. Autophagy can block the occurrence of pyroptosis by degrading the components of such as NLRP3. The inflammatory mediators released during pyroptosis may cause the disorder of autophagy, which aggravates the cell death and inflammatory response. The disorder of autophagy will also promote pyroptosis' occurrence and progress. Both of them play a vital role in AS. This study is mainly focused on clarifying the relationship and molecular mechanism between pyroptosis and autophagy in the context of AS. These findings pave the way for new avenues for understanding its pathogenesis and potentially therapeutic decision-making.

Aim: To evaluate nephroprotective effects of Silibinin in renal ischemia -reperfusion injury in rats by regulation of Notch-1 and Jagged-1.

Materials and Methods: 28 male Wistar albino rats were randomly divided into four groups, (seven rats / group): sham group (laparotomy only), control group (ischemia for 30 min / 2 hrs reperfusion), DMSO vehicle group (rats were injected intraperitoneally with 10% DMSO 1 hour before ischemia, then ischemia for 30 min / 2 hrs reperfusion, Silibinin treatment group (rats were injected with Silibinin (60 mg/kg) intraperitoneally 1 hour before ischemia, then "ischemia for 30 min / 2 hrs reperfusion. The kidneys were harvested after 2 hours of reperfusion for assessment of kidney injury molecule-1 (KIM-1), interleukin 1 β (IL-1β), TNF-α, F2-Isoprostane, and glutathione (GSH) by ELISA technique; Notch-1 and Jagged-1 mRNA levels were assessed by reverse transcription-polymerase chain reaction (RT-PCR), BAX and Bcl2 protein expression were assessed by immunohistochemistry (IHC).

Results: Silibinin demonstrated considerable amelioration of renal ischemia reperfusion injury as evidenced by the significant reduction of KIM-1, IL-1β, TNF α, F2-Isoprostane, in rat kidneys pretreated with Silibinin, GSH level was significantly elevated in rat kidneys pretreated with silibinin. Furthermore silibinin pretreatment significantly reduced Notch-1 and Jagged-1 mRNA expression after renal ischemia reperfusion.

Conclusions: Silibinin offers protection against renal ischemia reperfusion injury due to its antioxidant, anti-inflammatory, and anti-apoptotic effects, those effects are associated with the downregulation of Notch-1 and its ligand, Jagged-1.

The aim of this repeated cross-sectional study was to estimate polypharmacy prevalence and trends in Australian adults between 2013 and 2024.

Dispensing records of medicines subsidised by the Australian Pharmaceutical Benefits Scheme (PBS) were analysed for a nationally representative 10% sample of PBS-eligible beneficiaries.

The outcomes for this study were annual polypharmacy and hyperpolypharmacy prevalence, defined as ≥5 and ≥10 regular medicines, respectively, and average annual percentage change (AAPC), overall and by gender-stratified age groups. These groups are defined broadly as adult (18-64 years) and older adult (≥65 years), and as younger adulthood (18-39 years), middle (40-64 years), early older (65-84 years) and later older (85+ years) age.

Polypharmacy prevalence rose from 8.0% in 2013 to 9.2% (AAPC+1.4%), with two million Australians exposed in 2024. Although prevalence was initially higher among women, by 2024 men had surpassed women from middle age onward. Increasing AAPC was observed among adult and older adult men (+1.0%, +1.3%), while remaining stable among women. Finer age strata showed growth among men in middle, early older, and later older age (+1.7%, +1.0%, +3.4%) and divergent trends among women, with increases in younger adulthood (+1.8%) and declines in early older age (- 0.7%).

Shifting gender trends appear driven by stabilising or declining prevalence among women alongside sustained growth among men. By 2024, men exceeded women from middle age onward, suggesting a changing prescribing landscape. These patterns highlight the need for targeted interventions, and gender-stratified monitoring to ensure prescribing is appropriate. The long-term consequences of increasing polypharmacy in younger and middle-aged adults remain unclear and warrant further investigation.

This systematic review synthesizes empirical research on organizational strategies that support the sustainability and scale-up of community-based interventions designed to promote youth psychological well-being. While research has established the effectiveness of youth mental health interventions in community contexts, less is understood about the processes that ensure their long-term sustainability and scale-up. A search across seven databases yielded 27 eligible empirical studies (2003-2025) including peer-reviewed and grey literature. The Synthesis without Meta-analysis (SWiM) and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) standards provided a framework for conducting and documenting the review. Evaluations of methodological quality were carried out using Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), Consolidated Standards of Reporting Trials (CONSORT), and the Critical Appraisal Skills Programme (CASP). Two dominant strategies for intervention retention and effectiveness were identified: training and technical assistance (12 studies, 44%) and capacity building with implementation support (12 studies, 44%). The main barriers to sustainability and scale-up were reported as staffing as well as other resource limitations (financial, human, and technical), while facilitators included strong communication and leadership, sufficient funding and partnerships, and access to training and technology. Eleven studies (41%) sustained interventions beyond the initial funding period, with key factors including intervention fidelity, agency incentives, organizational support, therapist retention, and stakeholder engagement. The findings highlight the potential benefits of embedding sustainability and scale-up strategies in the pre-implementation phase, anticipating foreseeable barriers, and considering intervention fidelity, workforce stability, and organizational readiness as important precursors to sustainability and scale-up.

Telemedicine became a vital tool during the COVID-19 pandemic, a time marked by increased social isolation and mental health challenges among adolescents. Using data from 7,998 U.S. adolescents collected in early 2021 via the Adolescent Behavior Experience Survey, this study examined intersectional disparities in telemental health use. Stratified multivariable logistic regression models revealed significantly lower odds of telemedicine use for mental health care among marginalized groups who experienced suicidal thoughts or behaviors. These included Black, Hispanic/Latino, and multi-racial Latino female adolescents; Black heterosexual adolescents; and sexual minority multi-racial non-Latino adolescents. Notably, sexual minority multi-racial non-Latino adolescents showed higher odds of telemental health care use in some cases. The findings highlight critical gaps in access and underscore the need for targeted strategies to improve equitable mental health service delivery, particularly for racially diverse sexual and gender minority youth navigating intersecting structural and identity-based inequities.