This study aimed to systematically investigate the therapeutic effects and underlying mechanisms of ASIV against cerebral ischemia-reperfusion injury (CIRI) using an integrated approach combining network pharmacology and experimental validation.

Potential targets of Astragaloside IV (ASIV) were predicted using SwissTargetPrediction, PharmMapper and Comparative Toxicogenomics Database (CTD). Ischemic stroke-related targets were collected from GeneCards, DisGeNET and DrugBank. Overlapping targets were used to construct a protein-protein interaction (PPI) network via STRING and visualized in Cytoscape. Functional enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was performed using DAVID. The neuroprotective effects of ASIV were evaluated in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R), assessing neurological function, infarct volume, blood brain barrier (BBB) integrity, inflammatory markers, and PI3K/Akt/NF-κB pathway activity. In vitro, LPS-stimulated BV-2 microglia were used to examine the effects of ASIV on cell viability, inflammatory cytokine expression, and PI3K/Akt/NF-κB signaling.

Network pharmacology analysis identified 166 overlapping targets, and enrichment analysis emphasized the PI3K/Akt pathway as a key mechanism. In MCAO/R mice, ASIV significantly improved neurological function, reduced infarct volume and neuronal apoptosis, decreased Evans blue leakage, attenuated MMP-9 expression, and restored ZO-1 and Occludin levels. ASIV also suppressed the mRNA levels of IL-6, IL-1β, and TNF-α both in vivo and in LPS-stimulated BV-2 cells. Additionally, ASIV effectively upregulated the expression of Anti-inflammatory cytokines (IL-10 and Arg-1) in LPS-induced BV2 cells. Mechanistically, ASIV suppresses NF-κB activation through the stimulation of the PI3K/Akt signaling pathway.

ASIV exerts neuroprotective effects against CIRI by inhibiting neuroinflammation and preserving BBB integrity likely through modulation of the PI3K/Akt/NF-κB signaling pathway.

Invasive fungal infections (IFIs) are a leading cause of morbidity and mortality in children with hematological malignancies as well as those undergoing hematopoietic stem cell transplantation (HSCT). Extreme immunological dysregulation secondary to severe neutropenia, T-cell lymphopenia, graft-versus-host disease (GVHD), intensive chemotherapy regimens, and conditioning therapy for HSCT, as well as primary immunodeficiencies (PIDs), render these patients highly susceptible to both opportunistic and pathogenic fungal infections. Despite advances in antifungal drugs and diagnostic tools, it is very difficult in these children to provide timely diagnosis and optimal management of IFIs because of the nonspecific clinical manifestations, the invasiveness of present diagnostic modalities in pediatric patients, and biomarker kinetics differences in various pediatric age groups, along with a lack of incorporation of immunological-pharmacological maturity-associated variability in the existing scoring systems borrowed from adults. This narrative review provides a comprehensive and contemporary assessment of the epidemiology, host-related risk factors, clinical presentations, diagnostic criteria, and management practices for IFIs in children with hematological malignancies and following HSCT. It also highlights the role of EORTC/MSGERC criteria in defining IFIs as probable, proven, and possible infections and explores the sensitivity and specificity of noninvasive methods such as the galactomannan index, polymerase chain reaction (PCR), ß-D-glucan assay, high-resolution CT scans (HRCTs), and the latest approaches including next-generation sequencing (NGS) and metagenomics. This review points out significant gaps in pediatric research studies and supports efforts to optimize healthcare use with risk-prediction models rather than just relying on current algorithms.

The genus Salvia L. constitutes a core medicinal resource in China's diverse ethnic medical systems. However, a systematic and comparative understanding of how ecological adaptation-particularly among high-altitude ethnomedicinal species-translates into specific ethnomedicinal value remains lacking.

To address this gap, we developed and validated a "habitat-phytochemistry-pharmacological effect" linkage model, testing the hypothesis that environmental stressors driven by altitudinal gradients induce chemical differentiation among Salvia species, which in turn underlies their distinct pharmacological properties and traditional therapeutic uses.

We conducted a multidimensional analysis of 32 Salvia species documented in the Dictionary of Chinese Ethnic Medicine. This integrated systematic literature review, verification of altitudinal distributions using the Global Biodiversity Information Facility (GBIF), phenological characterization based on the Flora of China, and phytochemical profiling cross-referenced with the Human Metabolome Database (HMDB) and PubChem.

These species are used by 17 ethnic minority groups in China, primarily for cardiovascular and cerebrovascular diseases, gynecological disorders, and wound healing, guided by the principles of "activating blood circulation to resolve stasis" and "clearing heat and detoxifying." Our findings support the habitat-adaptation hypothesis: biologically, species diverge into spring-flowering types (low-altitude, used predominantly by Miao and Zhuang communities) and summer-flowering types (high-altitude; widely employed in Tibetan medicine). Chemically, this divergence corresponds to marked compositional differences-low-altitude species are enriched in flavonoids, whereas high-altitude species accumulate higher levels of phenolic acids, consistent with adaptive responses to intense UV radiation at elevation. Functional compartmentalization was also observed: roots preferentially accumulate lipophilic diterpenoid quinones (associated with antitumor and antiplatelet effects) and hydrophilic phenolic acids (linked to antioxidant and antifibrotic activities), while aerial parts are rich in flavonoids (antibacterial and antitussive) and triterpenoids (immunomodulatory). Pharmacologically, Salvia species exhibit broad bioactivities - including anticancer, anti - inflammatory, hepatoprotective, and cardioprotective effects - mediated by multiple compound classes (terpenoids, phenolic acids, polysaccharides) acting through diverse pathways. Clinical evidence further corroborates a direct alignment between traditional efficacy concepts and molecular mechanisms: "activating blood circulation to resolve stasis" corresponds to diterpenoid quinone-mediated antitumor activity, and "clearing heat and detoxifying" aligns with phenolic acid-driven anti-inflammatory effects.

This study successfully validates the "habitat-phytochemistry-pharmacological effect" linkage model, demonstrating a strong correlation between the ethnomedicinal value of Salvia species and their ecological traits, phytochemical profiles, and pharmacological actions. The model provides a robust framework for ethnopharmacology-guided natural product discovery. Future work should prioritize mechanistic studies of key active constituents and rigorous pharmacological validation of their traditional uses.

Nerve injury-induced protein 1 (Ninjurin 1) is a cell surface adhesion molecule that contains one extracellular adhesion domain and two transmembrane domains. Originally discovered in nerve injury, it has been extensively studied for its role in nerve regeneration. Ninj1 mediates the transendothelial migration of myeloid cells mainly through the extracellular adhesion domain, thereby aggravating the inflammation of the central nervous system. In addition to regulating the inflammatory phenotype of cells, Ninj1 actively mediates the rupture of the plasma membrane and regulates the programmed death of inflammatory cells, thereby participating in the host defense against exogenous infection. In recent years, Ninj1, an important protein associated with inflammasome activation, has garnered increasing attention from researchers regarding its mechanistic role and pathophysiological significance in cardiovascular diseases. Accumulating evidence suggests that Ninj1 not only participates in the regulation of inflammatory responses and cell death processes but also plays a critical role in the onset and progression of various cardiovascular conditions, including atherosclerosis, myocardial ischemia-reperfusion injury, and heart failure. Therefore, an in-depth exploration of the specific functions of Ninj1 in the cardiovascular system holds significant scientific and clinical value for elucidating the molecular mechanisms underlying these diseases and for developing novel therapeutic strategies. This review aims to summarize the research progress on Ninj1 in cardiovascular diseases and to outline its mechanisms in pathological processes.

Our main aim was to explore and elucidate whether metabolic equivalents of task (METs), as a measure of cardiorespiratory fitness (CRF), was associated with dementia.

A symptom-limited bicycle standard exercise test was performed in 4030 patients with no cardiovascular events. Dementia was classified according to International Classification of Diseases, Ninth and Tenth Revision codes. One MET corresponds to an oxygen uptake of 3.5 mL/kg/min.

During a median follow-up of 26.5 years, 104 cases of dementia occurred. In a fully adjusted model subjects with CRF of >9 METS had a 53% (hazard ratio (HR) 0.47, 95% CI (0.22, 0.99), p = 0.048) decreased risk of incidencec dementia compared to those CRF <6 METS.

Exercise training is an important modifiable factor that improves CRF and may help in dementia risk.

Postacute coronavirus disease 2019 (COVID-19) syndrome (PACS), or long COVID, encompasses a range of symptoms persisting beyond the acute phase of severe acute respiratory syndrome coronavirus 2 infection. Although acute-phase coagulation disturbances in COVID-19 are well documented, these abnormalities during recovery and their association with PACS remain inadequately explored. Our study aimed to investigate the long-term changes in coagulation function and inflammatory markers in patients with PACS, elucidating their pathological mechanisms and providing insights for patient management. This retrospective cohort study included 3783 adult inpatients in Jinan, China, divided into COVID-19-positive and -negative groups, with 363 patients with COVID-19 further diagnosed with PACS. Coagulation and inflammatory markers were collected at baseline and during 1-year follow-up, and changes over time were analyzed using generalized estimating equations. Most inflammatory markers and some coagulation parameters showed significant recovery, including lymphocyte counts and fibrinogen. However, several parameters remained abnormal even at 7 to 12 months after infection. Of note, D-dimer (Z = 5.692, P < .001, abnormal rate 65.79%) and erythrocyte sedimentation rate (Z = 2.749, P = .006, abnormal rate 57.32%) remained elevated above the normal upper limit. Additionally, certain coagulation parameters, particularly prothrombin time (β = -0.10 [95% confidence interval, -0.88 to 0.69]; P = .81, prolonged rate 17.29%) and platelet counts, did not normalize by 7 to 12 months. Our findings in survivors of severe COVID-19 pneumonia support the concept of PACS as a chronic thromboinflammatory syndrome characterized by sustained coagulation abnormalities. The prolonged elevation of D-dimer and incomplete recovery of coagulation parameters highlight the need for long-term monitoring and personalized management strategies to mitigate thrombotic risks in survivors of COVID-19.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Although conventional treatments such as surgery and transplantation have improved patient survival, they are subject to major limitations. Three-dimensional (3D) bioprinting presents new opportunities for treating CVDs, with the long-term objective of fabricating functional tissues that faithfully replicate native cardiac structure and key physiological functions, including contractile force, electrical conduction, and mechanical integrity. This review outlines the use of 3D bioprinting in modeling principal cardiac disorders, such as arrhythmias, structural heart defects, myocardial infarction, cardiac fibrosis, and heart failure. It further assesses the utility of bioprinting in developing disease models and advancing clinical therapies for these conditions. Finally, we address the ongoing challenges in implementing bioprinting and cardiac tissue engineering for CVDs and suggest possible avenues for improvement. Future studies should prioritize clinical translation and long-term follow-up to evaluate the durability and viability of bioprinted cardiac tissues.

Insomnia is one of the most prevalent diseases observed in clinical practice, contributing to increased death and a range of chronic diseases. While numerous studies have explored the relationship between insomnia and cardiovascular disease, research on its association with atrial fibrillation (AF) remains limited. This study aimed to investigate the association between insomnia and incident AF in the general population by comprehensive, nationwide, real-world data in Japan.

A total of 1 780 764 individuals without prior cardiovascular disease including AF from the DeSC database were included between April 2014 and August 2023. Insomnia was defined by International Classification of Diseases, Tenth Revision (ICD-10) codes (F510, G470) before the baseline health checkup. The primary outcome was incident AF (I480-I482 and I489). Cox proportional hazards models were used to estimate hazard ratios of AF according to present insomnia (versus absent).

Insomnia was observed in 216 919 individuals (12.2%), showing a significant association with incident AF after adjusting for potential confounding factors (adjusted hazard ratio, 1.14 [95% CI, 1.10-1.18]). Among subgroups, a similar pattern in the association between insomnia and incident AF was seen, while the association was stronger in younger individuals aged <65 years (versus ≥65 years) and women (versus men) (P for interaction=0.01 and 0.03, respectively).

Insomnia was significantly associated with the risk of AF. It highlighted the importance of recognizing insomnia as a risk factor for AF, given its high prevalence in the general population and the substantial impact of AF on quality of life and prognosis.

Atrial fibrillation (AF) is the most common arrhythmia and is associated with high morbidity and mortality, particularly in the aging population. Current treatment and prevention strategies remain suboptimal, highlighting the urgent need to better understand the mechanisms underlying aging-associated AF. We recently reported a causal role of the stress-activated kinase JNK2 (c-Jun N-terminal kinase 2) in aging-associated AF pathogenesis, mediated by JNK2-driven sarcoplasmic reticulum Ca²⁺ dysfunction. However, the mechanisms by which cardiac JNK2 is activated during aging to promote AF remain unclear. Emerging evidence suggests that interorgan crosstalk contributes critically to the development of cardiovascular diseases. A hyperpermeable gastrointestinal epithelial barrier ("leaky gut"), commonly observed in aged individuals, is associated with elevated levels of proinflammatory cytokines and an increased risk of AF. Although proinflammatory cytokines have been proposed as predisposing factors for AF, clinical and experimental studies have yielded inconsistent results, underscoring the complexity of inflammation-associated AF pathogenesis. Here, we investigated whether cardiac JNK2 integrates diverse stress stimuli, including proinflammatory cytokines and lipopolysaccharide, to drive AF pathogenesis.

We used aged mice, intestinal epithelium-specific tight junction OD (occludin) knockdown (OD^+/-) mice, and a well-established dextran sulfate sodium-induced leaky gut mouse model characterized by reduced gastrointestinal epithelial occludin expression. A series of physiological and molecular approaches was applied to assess cardiac and gastrointestinal responses.

We found that leaky gut significantly activates atrial JNK2, which, in turn, drives Ca²⁺-triggered arrhythmic activity and increases AF inducibility in aged, dextran sulfate sodium-treated, and OD^+/- mouse models. Restoration of gut barrier function in dextran sulfate sodium mice, a clinically relevant model, reduced AF susceptibility. Similarly, either JNK2 inhibition or TNF-α (tumor necrosis factor α) blockade abolished the increased AF risk associated with leaky gut. Furthermore, we demonstrate, for the first time, that leaky gut-associated proinflammatory cytokines, including TNF-α and IL-17A (interleukin-17A), together with lipopolysaccharide, activate cardiac JNK2. This activation promotes AF pathogenesis through JNK2-mediated arrhythmogenic mechanisms, including diastolic sarcoplasmic reticulum Ca²⁺ leak, Ca²⁺ waves, and delayed afterdepolarizations.

Activated JNK2 functions as a pathological nodal integrator of leaky gut-associated stress signals, mediating gut-to-heart crosstalk and driving inflammation-induced AF pathogenesis. Targeting JNK2 may represent a novel therapeutic strategy for AF.

Prescription stimulant use among the United States' (US) older adult population is increasing, yet little is known about the cardiovascular safety profiles of the two major prescription stimulant classes, methylphenidate (MPD) and amphetamine (AMP).

To compare the hazard of major adverse cardiovascular (CV) events between new users of prescription MPD and AMP products in US older adults.

We employed a new user comparative safety study from a 5% random sample of fee-for-service Medicare beneficiaries. Continuously enrolled beneficiaries (Parts A/B/D) aged ≥ 66 years who initiated MPD or AMP (1/1/17-12/31/21) were included. We required a 1-year washout before the first prescription claim (index date) and excluded those with contraindications based on diagnosis codes. The primary outcome was incident modified 4-Point Major Adverse Cardiovascular Event (4-P MACE), including acute myocardial infarction, stroke or transient ischemic attack, ventricular arrhythmia, or all-cause mortality; secondary outcomes included all-cause mortality and CV events (all MACE excluding death). We used a 1-year follow up after index date that was censored at change in insurance coverage, therapeutic switch, addition of the comparator drug, or end of the study (12/31/21). Confounders included demographics, healthcare utilization indicators, comorbidities, and other medications. We used trimmed propensity scores (PS) to create stabilized inverse probability of treatment weights (IPTW) and Cox proportional hazard regression to estimate the effect of MPD vs. AMP initiation on the first occurrence of 4-P MACE.

We identified 2526 Medicare beneficiaries initiating MPD (N = 1340, mean [SD] age = 76.7 [7.4] years, 54.3% female sex) or AMP (N = 1186, mean [SD] age = 72.3 [5.4] years, 60.6% female sex). After PS trimming and applying IPTW, the groups were well-balanced based on absolute standardized mean differences. During 2021.6 person-years follow up (MPD [1009.9 years] vs. AMP [1011.8 years]), 339 4-P MACE events occurred (MPD [N = 280] vs. AMP [N = 59]), of which 225 were deaths (MPD [N = 192] vs. AMP [N = 33]), and 114 were CV events (MPD [N = 88] vs. AMP [N = 26]). In the primary analysis, MPD vs. AMP initiation was associated with an increased risk of 4-P MACE (HR = 1.73, 95% CI [1.36, 2.19]). The secondary analysis showed a statistically significant increased risk of all-cause mortality (HR = 2.20, 95% CI [1.62, 3.00]), but not adverse CV events (HR = 1.14, 95% CI [0.77, 1.67]).

Initiation of MPD vs. AMP among older adults was associated with an increase in the hazard of 4-P MACE. Secondary analysis suggested that this increase was driven by all-cause mortality as opposed to adverse CV events.