Testicular tissues are highly vulnerable to oxidative stress and external insults due to their unique physiological microenvironment; thus, developing protective interventions is critical. We reveal that preconditioning through short-term stress-induced sympathetic nervous system (SNS) activation effectively mitigates testicular ischemia-reperfusion injury (IRI) in mice. Pre-activation of the SNS via diverse stressors markedly reduced seminiferous tubular damage and oxidative biomarkers compared to untreated controls. Mechanistically, the protective effect is mediated by dopamine-beta hydroxylase-expressing neurons in the rostral ventrolateral medulla (DBH^RVLM), which enhance sympathetic innervation in the testes. Optogenetic and chemogenetic approaches confirmed that DBH^RVLM neuron activation elevates testicular norepinephrine levels and attenuates tissue damage. Furthermore, we identify testicular macrophages as one of key mediators of this protection, demonstrating their immunomodulatory response to sympathetic signaling. These results support the "good stress" hypothesis, underscoring the beneficial effects of acute stress. Since the short-term stress response is a conserved adaptive mechanism in mammals, our findings suggest that SNS-mediated preconditioning could extend beyond testicular protection, potentially offering therapeutic insights for other oxidative stress-sensitive organs.

Stroke is a major cause of disability and mortality worldwide, with ischemic stroke (IS) being the most common form. The blood-brain barrier (BBB) plays a critical role in protecting the brain, and its dysfunction after stroke exacerbates neuronal damage. Therefore, restoring BBB integrity is a promising therapeutic strategy. Tirzepatide (TZP), a dual GLP-1 and GIP receptor agonist, has demonstrated neuroprotective effects, but its role in BBB restoration post-stroke remains unclear.

This study aims to evaluate the potential of TZP in preventing BBB dysfunction and restoring its integrity in ischemic stroke models.

Using a middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke, we assessed the effects of TZP on neurological deficits, BBB permeability, and the expression of tight junction (TJ) proteins, particularly Claudin-1. In vitro, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemic conditions. The involvement of C/EBP-α, a key transcription factor regulating TJ proteins, was also investigated.

TZP treatment significantly improved neurological scores and reduced BBB permeability in MCAO mice. It also restored Claudin-1 expression, which was downregulated in stroke conditions. In vitro, TZP reduced endothelial permeability and enhanced Claudin-1 expression in OGD/R-treated HBMVECs. Silencing C/EBP-α abolished the protective effects of TZP on both BBB integrity and Claudin-1 expression, indicating that C/EBP-α signaling is crucial for TZP's action.

TZP ameliorates BBB dysfunction and protects against ischemic stroke by activating C/EBP-α signaling and restoring Claudin-1-mediated tight junction integrity. These findings suggest that TZP holds promise as a therapeutic agent for stroke, offering a novel strategy for maintaining BBB function and reducing neuronal damage. Further studies are needed to explore the detailed mechanisms underlying TZP's neuroprotective effects and its clinical potential in stroke therapy.

Atherosclerosis is a complex inflammatory disease driven by endothelial dysfunction. However, most in vitro studies rely on lipopolysaccharide (LPS) or oxidized LDL (oxLDL) as stimulants, overlooking the pathogenic role of lipoprotein(a) [Lp(a)]. Lp(a) is an independent and genetically determined risk factor for cardiovascular disease (CVD), but its precise mechanisms in promoting endothelial activation, inflammation, and monocyte adhesion remain poorly understood. The underlying mechanisms remain unclear despite clinical evidence that PCSK9 inhibitors (PCSK9i) lower plasma Lp(a) levels. This study explores the critical role of Lp(a) in driving PCSK9 expression and atherogenesis biomarkers, evaluates the protective effects of PCSK9i on endothelial activation, dysfunction and inflammation in Lp(a)-stimulated human coronary artery endothelial cells (HCAECs), and investigates their potential to mitigate monocyte adhesion, a key process in early atherogenesis.

HCAECs were stimulated with Lp(a) and treated with Alirocumab or Evolocumab. Cell viability was assessed using the MTS assay. The expression of PCSK9, inflammatory (IL-6, NF-κB p65), endothelial activation (E-selectin, ICAM-1), and endothelial function (eNOS) biomarkers were quantified using ELISA and QuantiGene plex assays. Monocyte adhesion to endothelial cells was measured using the Rose Bengal method.

Lp(a) stimulation increased PCSK9, IL-6, ICAM-1, E-selectin, NF-κB p65, and reduced eNOS in HCAECs. Both Alirocumab and Evolocumab lowered PCSK9 protein levels, with Alirocumab showing more potent effects. Evolocumab consistently reduced PCSK9 gene expression, whereas Alirocumab elicited variable effects. IL-6 and NF-κB p65 were elevated by both inhibitors, especially Alirocumab. Both treatments reduced ICAM-1 and E-selectin proteins, but gene expression varied. eNOS expression improved only at high concentrations (100 µg/ml), particularly with Evolocumab. Monocyte adhesion decreased at lower doses of both inhibitors, suggesting protective effects against early atherogenesis.

PCSK9i exhibits pleiotropic effects beyond lipid-lowering by modulating endothelial activation, inflammation, and monocyte adhesion in Lp(a)-stimulated HCAECs. These findings provide mechanistic insights into the potential atheroprotective properties of PCSK9i, highlighting their role in early atherogenesis prevention.

Not applicable.

Awareness of obesity's causes and risks remains limited, affecting management and support efforts. This review evaluates evidence on obesity awareness across adults and children living with obesity, the general public and healthcare professionals.

A systematic literature search was conducted across three electronic databases: PubMed, Embase, and Web of Science Core Collection, from inception until November 19, 2023. Studies were included if they met the following criteria: (1) children or adults living with overweight or obesity, (2) healthcare providers, (3) general public, and (4) assessed awareness of obesity as a disease, including its complications, causes, and symptoms, using either qualitative or quantitative research methods. Meta-analyses were conducted using the Metafor package in R.

In total, 47 out of 14,871 unique records could be included. Meta-analysis revealed that 83% [0.75, 0.92] of healthcare professionals viewed obesity as a disease, compared to 75% [0.61, 0.89] of adults living with obesity and 68% [0.51, 0.85] of the general public. Cardiovascular diseases (0.83 [0.69, 0.96]) and Type 2 diabetes (0.81 [0.67, 0.95]) were the most commonly recognised complications of obesity. Lack of physical activity (0.82 [0.76, 0.82]) and excessive or unhealthy food intake (0.74 [0.63, 0.85]) were identified as the leading perceived causes. Only 49% [0.35, 0.63] acknowledged the role of genetic factors in contributing to obesity.

Although healthcare professionals were more likely to perceive obesity as a disease compared to the general public, significant awareness gaps persisted across all groups regarding its causes and complications. To bridge these gaps, future interventions focusing on knowledge and awareness concerning obesity should prioritise educating people on the pathophysiology of obesity, as well as the extensive range of its symptoms and complications.

Pyroptosis is an inflammatory form of programmed cell death (PCD), driven by the activation of inflammasomes and inflammatory caspases. These molecular events trigger the proteolytic cleavage of gasdermin proteins, leading to membrane pores formation, cell lysis, and the subsequent release of cellular contents. Induction of pyroptosis amplifies inflammation, contributing to severe inflammatory responses and accelerating the pathogenesis of various chronic inflammation-related diseases. Myocardial fibrosis (MF) is characterized by the deposition of scar tissue in the heart, stemming from an aberrant wound healing response to inflammatory damage. It is a prevalent pathological feature in a range of cardiovascular diseases. Given the complex nature of wound repair and fibrosis following myocardial injury, treatments that target only specific contributors to disease pathogenesis show limited efficacy in mitigating fibrosis. While significant progress has been made in understanding the mechanisms underlying pyroptosis, its regulatory processes in MF remain incompletely understood, and strategies to improve clinical outcomes are still lacking. This review provides an in-depth examination of the latest insights into the regulatory mechanisms of pyroptosis, newly identified influencing factors, and its role in myocardial inflammation and fibrosis. Additionally, we discuss potential anti-fibrotic therapies targeting pyroptosis for the management of MF, highlighting challenges and future directions in this field.

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis¹. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine intermediate orotidine 5'-monophosphate, and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we observed that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Moreover, unopposed NAA from adipocytes greatly enhanced whole-body glucose disposal exclusively in WAT. Exogenous NAA also increased plasma pyrimidines and lowered body temperature. These data place WAT-derived NAA as an endocrine regulator of postprandial body temperature and define broader roles for metabolic homeostasis.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism, inflammation and haemostasis. Pathogenic gain-of-function variants in the PCSK9 gene are causative of autosomal-dominant form of familial hypercholesterolemia, while several PCSK9 alleles have been associated with elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of cardiovascular disease. Elevated lipoprotein(a) (Lp(a)) levels, regardless of LDL-C levels, as well as functional and morphological changes in the arterial vessel wall predict future cardiovascular events. In our study, we aimed to identify whether treatment with statins nullifies the effect of four gain-of-function gene variants in PCSK9 on lipoproteins and arterial wall properties in high-risk post-myocardial infarction patients with severely elevated Lp(a) levels. We included 68 patients after myocardial infarction with elevated Lp(a) levels on maximal statin therapy. Biochemical analysis of lipid parameters and total PCSK9 levels were performed. Arterial wall properties were measured by ultrasound. Genotyping was performed for four gain-of-function, i.e. rs11206510, rs2479409, rs2479408 and rs1711503, and one intergenic, rs11591147 PCSK9 single nucleotide polymorphisms. The results showed no association between studied PCSK9 gene variants and lipid parameters, PCSK9 levels and arterial wall properties in our patient cohort. Clinical, biochemical and arterial wall parameters did not differ between the group with lower compared to group with higher number of PCSK9 alleles. Our results suggest that in high-risk patients after myocardial infarction with increased Lp(a) levels treated with statins the studied PCSK9 gain-of-function gene variants are associated neither with lipoproteins nor with arterial wall properties.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovitis and presenting as symmetrical arthritis that primarily affects the small joints of the limbs. PIWI-interacting RNAs, a class of small noncoding RNAs, have garnered significant attention due to their critical involvement in various pathological conditions, including reproductive diseases, cancers and other disorders. Here we observe elevated levels of macrophage-derived piENOX2 in the synovial tissues of both patients with RA and mice with collagen-induced arthritis (CIA). It was found that transfection with a piENOX2 mimic promoted M1 macrophage polarization, while a piENOX2 inhibitor facilitated M2 polarization. In vivo, a piENOX2 inhibitor significantly alleviated disease progression, reduced systemic inflammation and preserved the integrity of articular cartilage in CIA mice. Mechanistic analyses indicated that the piENOX2 effects were due to its targeting Alkbh5 mRNA for degradation. In a Alkbh5 conditional-knockout mouse model of CIA, the therapeutic effects of a piENOX2 inhibitor, including inflammation suppression and cartilage protection, were reduced compared with control mice. A comprehensive analyses using methylated RNA immunoprecipitation sequencing and methylated RNA immunoprecipitation and quantitative PCR revealed that piENOX2 regulated ALKBH5-mediated m⁶A modification of Itga4 mRNA, thereby influencing macrophage polarization through the PI3K-AKT signaling pathway. These findings provide important insights into the complex roles of PIWI-interacting RNAs in RA progression and indicate potential avenues for therapeutic intervention.

Stroke rehabilitation movements are significantly influenced by patient subjectivity, leading to challenges in capturing subtle differences and temporal characteristics of patient motions. Existing methods typically focus on adjacent joint movements, overlooking the intricate interdependencies among body joints. Moreover, they lack the capacity to assess motion quality based on diverse temporal characteristics. To address these challenges, we propose a Frame Topology Fusion Hierarchical Graph Convolution Network (FTF-HGCN). This method aims to provide a more precise assessment of rehabilitation movement quality by effectively modeling both spatial and temporal features. First, this method combines nearby and distant keypoints to construct a fused topology structure for obtaining the enhanced motion representation. This allows the network to focus on joints with larger motion amplitudes. Second, based on the fused topology structure, a learnable topological matrix is established for each action frame to capture subtle differences between patient movements. Finally, a hierarchical temporal convolution attention module is employed to integrate motion feature information across different time sequences. Subsequently, a fully connected layer is used to output the predicted quality score of rehabilitation movements. Extensive experiments were conducted on KIMORE and UI-PRMD datasets, achieving best performance on relevant evaluation metrics (MAD: 13.4[Formula: see text], RMSE: 39.8[Formula: see text], MAPE: 7.6[Formula: see text]). This shows that the proposed FTF-HGCN method is capable of delivering accurate evaluations and offering superior support for the home-based rehabilitation of stroke patients.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of neonatal mortality and developmental disabilities. It has been revealed that the temporal behavior of the cerebral blood volume (CBV) carries information on the degree of hypoxia-ischemia. CBV can be estimated by means of near-infrared spectroscopy. The change of CBV after the insult is related to the change of CBV during the insult. In this paper, we consider a mathematical model which governs the time evolution of CBV after the insult. We show that the temporal behavior of CBV can be predicted with the Kalman filter which is based on the mathematical model. Finding a governing equation opens up possibilities for a more quantitative diagnosis of HIE.