Osteoarthritis (OA) is the leading cause of disability worldwide. Due to its complex pathogenesis, no disease-modifying therapies currently exist to halt its progression. Consequently, there is an urgent clinical need to develop effective pharmacological interventions that attenuate cartilage damage and treat OA.

This study aimed to evaluate the therapeutic effects of Aloe-emodin (AE) in experimental models of OA and to investigate whether AE regulates chondrocyte cytoskeletal organization via Septin7-associated mechanisms.

A destabilization of the medial meniscus (DMM) rat model was established to evaluate the impact of AE on joint pathology and cartilage integrity. Concurrently, primary rat chondrocytes were stimulated with interleukin-1β (IL-1β) to establish an in vitro model of OA-like degeneration. Transcriptomic screening, biochemical assays, and molecular analyses were performed to identify AE-interacting targets and to examine cytoskeletal organization, ubiquitination-related mechanisms, and associated signaling pathways.

AE interacts with key amino acid residues (Ser59 and Asp119) of Septin7, promotes RNF20 binding to Septin7, and accelerates its ubiquitin-proteasome-mediated degradation. This targeted degradation suppresses GTP-RhoA activation and its downstream signaling cascades, including the ROCK/Cofilin and FAK/Src pathways, thereby achieving precise regulation of chondrocyte cytoskeletal remodeling and metabolic homeostasis. Notably, Septin7 expression is significantly elevated in both serum and macroscopically intact and highly degenerated cartilage tissue from OA patients, highlighting its dual potential as a biomarker and a therapeutic target. Furthermore, intra-articular injection of an adenovirus to silence Septin7 attenuated DMM-induced joint structural damage in vivo.

Our findings demonstrate that Septin7 serves as both a therapeutic target and a serum biomarker for OA. Furthermore, the natural compound AE effectively delays OA progression by restoring chondrocyte cytoskeletal homeostasis and promoting the degradation of Septin7 via the RNF20-mediated ubiquitin-dependent degradation pathway.

Chronic Venous Insufficiency (CVI) is a complex condition resulting from venous valve dysfunction or a loss of structural integrity in the vein walls, affecting 60% of the general population. Although traditionally regarded as a localized peripheral pathology, emerging evidence suggests that CVI may serve as an early indicator of systemic vascular disease. Our comprehensive review aims to analyzes the pathophysiological links between CVI and global cardiovascular risk, evaluating the clinical impact of venous disease on cardiovascular morbidity and mortality. The current literature highlights shared mechanisms between CVI and arterial diseases, including chronic low-grade inflammation, oxidative stress, and endothelial dysfunction. Clinical studies indicate that CVI is an independent predictor of major adverse cardiovascular events (MACE) and all-cause mortality. CVI should be reinterpreted as a peripheral marker of systemic vascular frailty. The integration of proactive cardiovascular screening is proposed for the management of patients with advanced CVI to improve long-term prognosis and reduce the risk of fatal events.

This is the official English summary of the Japanese 2025 guide. The first edition of the guide for the diagnosis and management of connective tissue disease (CTD) associated with interstitial lung disease (ILD) was published in 2020 as a joint initiative by the Japanese Respiratory Society and the Japanese College of Rheumatology. This updated edition reflects major advances over the past five years, incorporating the latest international guidelines, consensus statements, and considerations unique to the Japanese healthcare reimbursement system. The guide is structured to facilitate timely clinical decision-making by highlighting key diagnostic and therapeutic milestones. The newly added content includes a conceptual framework for understanding ILD in CTD, practical clinical flowcharts, screening strategies, and risk factors, an overview of acute exacerbations, and a comprehensive approach to rehabilitation. Notably, treatment algorithms for ILD associated with polymyositis/dermatomyositis and systemic sclerosis have been revised to align with the most recent evidence and disease-specific recommendations, thereby enhancing their relevance to real-world practice. In addition, a provisional algorithm was proposed for the management of rheumatoid arthritis-associated ILD. The updated guide aims to standardize the multidisciplinary management of CTD-associated ILD and offers future perspectives to guide research and improve patient outcomes.

This study aims to explore the relationship between aortic aneurysm and dissection (AAD) and cognitive impairment, with an emphasis on uncovering the potential biological mechanisms.

Utilizing the UK Biobank database, a matched cohort study was performed to assess the association between AAD and the risk of Alzheimer's disease. Cognitive function was evaluated in a β-aminopropionitrile (BAPN)-induced AAD mouse model through a series of behavioral assays. Drug-target Mendelian randomization analysis was conducted to identify candidate genes implicated in this association. Expression levels of PRDX6 were examined in brain tissues from Alzheimer's disease patients using datasets from the Gene Expression Omnibus (GEO), as well as in aortic tissues and blood samples obtained from both AAD patients and AAD model mice. Correlative analyses between PRDX6 and pro-inflammatory cytokines (IL-1β and TNF-α) were performed in mouse hippocampal tissues of the mouse model. Additionally, in vitro experiments employing SH-SY5Y cells were carried out to investigate the functional role of PRDX6 in modulating synaptic protein expression and inflammatory responses.

Competing risk regression analysis indicated that AAD is significantly associated with an increased incidence of cognitive impairment. Behavioral testing revealed that AAD model mice exhibited deficits in cognitive performance. Mendelian randomization prioritized PRDX6 was prioritized as a candidate gene of interest. Elevated PRDX6 expression was observed in brain tissues from Alzheimer's disease patients. Both AAD patients and AAD model mice demonstrated markedly increased PRDX6 levels in aortic tissues and circulating blood; notably, PRDX6 expression was also upregulated in the hippocampus of AAD mice. In the hippocampus, PRDX6 expression positively correlated with levels of IL-1β and TNF-α expression in AAD mice. In SH-SY5Y cells, silencing of PRDX6 resulted in increased expression of synaptic proteins, reduced pro-inflammatory cytokine production, and decreased apoptosis, whereas overexpression of PRDX6 elicited inverse effects.

The present findings establish a significant association between AAD and heightened risk of cognitive impairment. PRDX6 has been identified as a potential mediator in this relationship, and PRDX6-related neuroinflammation is proposed as a plausible mechanistic pathway linking AAD to cognitive dysfunction.

Micro- and nanoplastics (MNP) are ubiquitous environmental stressors increasingly detected in human tissues and directly linked to clinical cardiovascular events. This review proposes immunometabolic reprogramming as the central nexus through which MNP drive systemic immune dysregulation and chronic inflammation. Upon entering via multiple routes, MNP selectively sequester in immune organs, disrupting mitochondrial quality control via Drp1-mediated fission and activating the cGAS-STING pathway. Furthermore, MNP induce a pseudohypoxic state that stabilizes HIF-1a, driving a glycolytic "Warburg-like" shift that promotes pro-inflammatory macrophage polarization. These intracellular perturbations are further amplified by "lipid corona" formation and gut microbiota dysbiosis, which depletes anti-inflammatory short-chain fatty acids. Collectively, this systemic immunometabolic remodeling provides a mechanistic framework for understanding MNP-related risks for cardiovascular, metabolic, and neurodegenerative disorders.  This review emphasizes the necessity of integrating immunometabolic parameters into future environmental health risk assessment frameworks.

Heart transplantation (HT) remains the reference therapy for selected eligible patients with advanced heart failure (HF), recent developments in drug and device therapies notwithstanding. The majority of heart transplants are performed in Europe and the USA. However, the rate of heart transplants varies greatly among European countries, ranging from <1 to >10 per million population per annum. Due to donor organ shortage, durable mechanical circulatory support (MCS) became a practical solution for many advanced HF patients, either as a bridge to transplant or as destination therapy. The aim of the present clinical consensus statement of the European Society of Cardiology -Heart Failure Association is to provide a perspective on important issues regarding HT, in particular patient selection, pre-transplant work-up, matching of donor heart and recipient, strategies of bridging patients to transplant with temporary or durable MCS, as well as how to increase the donor organ pool. Furthermore, surgical techniques and complications are discussed, as well as immediate post-transplant, and long-term management including the main aspects of long-term follow up such as rejection surveillance, personalized immunosuppression and managing comorbidities. Cellular and antibody mediated rejection, early cardiac allograft failure, and indications for retransplantation are described. An emphasis is given on the most important post-HT complications, such as cardiac allograft vasculopathy, infections and malignancies. Finally, the need for tailored physical rehabilitation and psychosocial support, and impact of post-transplant status on reproductive health are discussed.

No recommended therapy exists for chronic fibrosing interstitial lung diseases (CF-ILD) with disease progression despite ongoing treatment with nintedanib or pirfenidone. Pamufetinib (also known as TAS-115) is a novel oral antifibrotic tyrosine kinase inhibitor in development for CF-ILD with a progressive phenotype.

We sought to evaluate the dose-response of pamufetinib monotherapy in patients with CF-ILD including idiopathic pulmonary fibrosis (IPF) with a progressive phenotype despite an antifibrotic treatment.

In this double-blind, multicenter, active-controlled phase 2 b study, patients with CF-ILD with a progressive phenotype (defined as ≥ 5% decline in the annual percent predicted forced vital capacity [%FVC] despite treatment with nintedanib or pirfenidone and an %FVC ≥ 50%) were randomized 1:1:1 to pamufetinib 50 mg, 100 mg, or control (nintedanib or pirfenidone) for ≥ 26 weeks. The primary endpoint was the 26-week rate of decline in FVC.

Of the 243 patients randomized, approximately 70% had IPF. The 26-week rate of change in FVC was -157.8 mL, -95.9 mL, and -63.6 mL in patients receiving pamufetinib 100 mg, pamufetinib 50 mg, and control, respectively; as such, no clear dose-response relationship was observed. The most frequent adverse event in the pamufetinib groups was rash, which was mostly mild or moderate in severity.

While the safety profile was acceptable, pamufetinib failed to decelerate FVC decline in patients with CF-ILD with a progressive phenotype who had previously been treated with nintedanib or pirfenidone. No benefits were demonstrated by switching from standard antifibrotic treatment to pamufetinib monotherapy.Clinical trial registered with the Japan Registry of Clinical Trials (https://jrct.mhlw.go.jp/en-top; jRCT2051210050).

Obesity is a chronic condition leading to increased risk for premature cardiovascular diseases and mortality. The study aims to compare body mass index (BMI) classifications (as per the World Health Organization (WHO) and Asian Indian Guidelines (AIG), 2024) and gender in relation to fasting blood sugar (FBS) and lipid profile parameters, with the goal of gaining a better understanding and facilitating the early identification of at-risk groups.

To compare the association between BMI (as per WHO and AIG) and biochemical metabolites in gender-matched healthy individuals.

A cross-sectional study involving 150 healthy individuals aged 21-40, excluding those with chronic medical conditions and BMI <18.5 kg/m 2 , used body weight and height to calculate BMI and biochemical analysis (AGD 2020 clinical chemistry analyzer).

The study involving 150 subjects categorized into WHO BMI and AIG showed significant differences in triglyceride levels (in both genders) and FBS levels (in females). While statistical significance for very low-density lipoprotein (VLDL) was attained in the AIG classification only. However mild positive correlation with statistical significance was found between BMI and triglycerides (TGL), VLDL, and FBS.

The comparative study of biochemical metabolites for BMI as per two different classifications yielded VLDL as one parameter, other than TGL and FBS, in a healthy Indian population. The findings need to be explored with a larger population before an agreement can be reached on using AIG as a valuable criterion for the early detection of metabolic syndrome in the Indian population.

Long non-coding RNAs (lncRNAs) play key roles in gene regulation. One potential regulation mechanism involves the formation of RNA•DNA:DNA triplexes. In these triplexes, the lncRNA binds in the major groove of a target DNA via Hoogsteen base pair formation. Here, we investigated the impact of the underlying RNA binding on the on the stability of the DNA duplex target to gain insights into the triplex stability at base pair resolution. Quantification of the temperature-dependent exchange of imino hydrogen atoms with solvent of the target DNA duplex allows determination of the changes of the stability of individual DNA duplex base pairs upon triplex formation. The data shown here investigates an antiparallel triplex, formed between the lncRNA hypoxia-inducible factor 1-alpha Antisense RNA 1 (HIF1α-AS1) and the DNA target Adrenomedullin (ADM), important in cardiovascular diseases. Triplex formation alters DNA structure and stability by affecting both hydrogen bonding strength and nucleobase-stacking interactions. These thermodynamic insights support bioinformatic methods to predict triplex stability and enhance our understanding of RNA•DNA:DNA triplex formation.

Patulin (PAT) is a mycotoxin that grows on various fruits and grains, and its toxicity research mainly focuses on organ toxicity. However, the research on its impact on nutritional metabolism is still unclear. Vitamin D is an important nutrient and has been reported to have multiple physiological functions. Vitamin D deficiency has been reported to be associated with the risk of developing diseases such as fatal cancers, autoimmune disorders, cardiovascular disease, neurocognitive function impairment, and type 2 diabetes. However, vitamin D need to be converted into biologically active forms through two steps of hydroxylation in the liver or kidney by 25-hydroxylase (CYP2R1) and 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1). In this study, we found that PAT can cause liver and kidney injury, and affect the levels of activated vitamin D products 25(OH)D and 1,25(OH)₂D. Specifically, we demonstrated that PAT affects the hydroxylation of vitamin D by downregulating 25-hydroxylase (CYP2R1) and 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1) expression and interfering their substrate binding sites. This study can provide a basis for a more comprehensive assessment of the impact of environmental pollution, food safety, and other issues on human health.