EDIL3 regulates caveolin-1-dependent endothelial permeability in subchondral bone during osteoarthritis.

Highly virulent porcine reproductive and respiratory syndrome virus 1 (PRRSV-1) strains, such as the Rosalía strain, continue to emerge in the swine industry. The mechanisms by which these strains induce lung pathology are not clearly understood. This study aimed to characterise the lung histopathological lesions and immune responses induced by the highly virulent Rosalía strain in experimentally infected pigs. Infected animals developed severe lung lesions, including extensive interstitial pneumonia, multifocal proliferative and necrotising pneumonia (PNP), and to a lesser extent, bronchopneumonia. Marked expression of von Willebrand factor (vWF) and reactive morphological changes in endothelial cells was observed, suggesting endothelial activation and increased vascular permeability which contributed to local inflammation. Throughout the course of infection, dynamic shifts in immune cell populations were observed. At 10 days post-infection (dpi), lung infiltrate was dominated by T cells and calprotectin⁺ myeloid-like cells, with a moderate presence of CD20⁺ cells, alongside a marked depletion of CD163⁺ pulmonary alveolar macrophages. Interestingly, CD163⁺ septal macrophages infiltrated areas around PNP and bronchopneumonia lesions, with several cells displaying spindle-shaped morphology. By 35 dpi, there was a replenishment of CD163⁺ cells and a significant increase in CD20⁺ cells, indicating a shift from an early innate to an adaptive immune response. The presence of tertiary lymphoid structures (TLS) with abundant CD20⁺ cell aggregates at this stage further supports sustained local immune activation. Our findings highlight immunopathological mechanisms underlying the severity of disease caused by the highly virulent Rosalía PRRSV-1 strain, characterised by severe lung immune dysregulation, macrophage depletion, endothelial activation, and delayed B-cell lymphoid response.

Enzymatically-modified isoquercitrin alleviates skin inflammation, mast cell degranulation, and vascular hyperpermeability in a mouse model of plaque psoriasis.

Yolkin is an egg yolk-derived protein with immunoregulatory properties. In this work, yolkin was evaluated as a protective agent in endotoxemic BALB/c mice. The mice were pretreated with yolkin either orally in drinking water or intraperitoneally (i.p.) before i.p. injection of E. coli lipopolysaccharide (LPS). Circulating blood leukocyte number, blood cell composition, serum levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and haptoglobin, as well as histological changes in the spleen and the liver, were examined. Yolkin differentially regulated the values of these parameters, depending on the administration protocol; however, the serum levels of TNF-α and IL-6 were generally decreased, and the level of haptoglobin, an acute-phase protein, was elevated. The pretreatment of mice with yolkin led to improved histological architecture in the investigated organs of endotoxemic mice, particularly in the liver, where yolkin diminished an increased level of vascular permeability and reversed a decreased number of Kupffer cells. These changes were independent of the route of yolkin administration. In conclusion, yolkin proved effective in the amelioration of pathogenic consequences of LPS administration and may be considered a potential protective measure for patients at risk of endotoxemia.

Ceapin-A7 counteracts the protective effects of Lanreotide in endothelial cells.

Psoriasis is a prevalent dermatological condition characterized by chronic inflammation, affecting an estimated 2-3% of the global population. Current therapies for psoriasis can relieve symptoms, but their serious adverse effects and financial burdens are significant. Hence, it is urgent to focus on natural product-originated agents to develop much safer, more effective, and low-cost treatments. Here, we determined and compared the efficacy of sodium R-lipoate (NaRLA, 50 and 100mg/kg body weight/day), given orally for 8 consecutive days, in a BALB/c mouse model of imiquimod-induced psoriatic skin inflammation, in comparison with the synthetic drug methotrexate (MTX). Moreover, the vascular permeability (Evans blue) response was investigated. Our results revealed that NaRLA (especially at the high dose) exhibited better performance like MTX in alleviating (P < 0.05-0.001) the symptoms of psoriasis (erythema, scaling, and skin thickness), as well as the psoriasis area and severity index score, body weight loss, splenomegaly, the deteriorating histopathology, and oxidative stress. Most importantly, NaRLA decreased (P < 0.05-0.001) the elevated expression of interleukin (IL)-23 and IL-17A (key cytokines involved in psoriasis pathogenesis), markedly inhibited phosphorylation of nuclear factor-κBp65, and downregulated tumor necrosis factor-α, IL-1β, and cyclooxygenase-2 levels in mice skin tissues. Furthermore, NaRLA resulted in a significant improvement (P < 0.001) on both Evans blue extravasation and mast cell degranulation, suggesting a reduction in inflammation and edema. Thus, our observations imply that NaRLA may serve as an effective agent for alleviating psoriatic skin inflammation via targeting IL-23/IL-17A axis and mast cell degranulation.

Transthyretin amyloidosis (ATTR) is a degenerative disease affecting the heart and other organs. Transthyretin (TTR) aggregation is a driver of ATTR pathology, but the mechanism is poorly understood. We used proteomics and tissue clearing technology on wild-type (WT) human cardiac (WT/WT) and V122I human cardiac (V122I/WT) tissue to better understand TTR cardiomyopathy. Flash-frozen cardiac tissue slices from human subjects with end-stage WT-TTR cardiomyopathy, end-stage V122I TTR cardiomyopathy, and an age-matched control were used. Fibrils and tissue proteomes were extracted and assessed by bottom-up proteomics. Tissue clearing was performed using a lauryl sulfate-based lipid removal strategy. Slices were stained using indirect immunofluorescence against targets identified by proteomics. TTR deposits were imaged by antibody and AmyTracker 480 staining. Structures of ATTR fibrils were characterized using cryogenic electron microscopy. Proteomic analysis revealed high abundance of TTR, proteins associated with amyloid fibrils, as well as angiogenic, hemostatic, and complement cascade-associated proteins. Three-dimensional imaging revealed loss of normal microvascular architecture, regions of hypervascularization and hypovascularization, and microvascular obstruction by capillary thrombosis. ATTR fibrils adopted the spearhead fold and were decorated with collagen VI, an extracellular matrix component. Based on our imaging and proteomic data, we hypothesize that ATTR cardiomyopathy is a microangiopathy driven by capillary bed thromboinflammation and dysregulated angiogenic revascularization. In this model, increased capillary permeability exposes components of the vascular basement membrane to misfolded TTR. These components promote aggregation and stabilize amyloid fibrils. Congestion of the vascular basement membrane prevents appropriate revascularization, reducing cardiac exertional capacityover time, leading to heart failure.

Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective benefits, reducing vascular leakage, enhancing blood oxygenation, and alleviating edema. We designed, synthesized, and preclinically evaluated cannabidiol-derived TRPV4 channel inhibitors for potential therapeutic application in ALI and future clinical translation. We identified a lead cannabidiol-derived TRPV4 inhibitor through specific in vitro screening assays. The lead compound was then tested in a series of animal models of ALI. Initial evaluation employed the lipopolysaccharide (LPS) induced lung injury model, followed by models involving TRPV4 overexpression in alveolar macrophages, as well as models featuring TRPV4 hyperactivation. These models were strategically chosen to replicate key pathological features of clinical ALI. Our investigation revealed that administration of the lead derivative CS-85(4j) demonstrated significant protective effects in a mouse model of ALI. CS-85 effectively prevented lung edema and maintained the integrity of pulmonary vascular barrier. Notably, it inhibited neutrophil influx into the lung, reduced proinflammatory cytokine production, and mitigated associated pathological changes. In additional relevant preclinical in vivo models, we further investigated how TRPV4 hyperactivation via pharmacological stimulation and overexpression in alveolar macrophages through liposome-mediated gene delivery exacerbated key features of ALI. CS-85 effectively reduced this exaggerated lung inflammation and alleviated the ALI features. In exploring the downstream mechanisms of CS-85, we found that its pharmacological efficacy is mediated through modulation of the NLRP3-caspase-1, NFAT, and NF-ĸB signaling pathways, all of which are crucial inflammatory cascades. We identified CS-85 as a potent and promising TRPV4 inhibitor that demonstrates strong preclinical efficacy in mitigating ALI by preserving vascular integrity and modulating key inflammatory signaling pathways. Its dual mechanism of action highlights its therapeutic potential for ALI and supports further clinical evaluation.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The vascular endothelial cells (VECs) play a pivotal role in the progression of sepsis-induced vascular leakage. While therapeutic strategies targeting pathogen elimination and inflammation exist, direct interventions on the endothelial barrier are limited. The mechanisms of endothelial damage related to mitochondrial dysfunction during sepsis require further elucidation. The study utilized a cecal ligation and puncture (CLP) rat model of sepsis and lipopolysaccharide (LPS)-stimulated VECs to investigate vascular leakage mechanisms. These models were utilized to investigate the changes in vascular permeability, mitochondrial function and protein crotonylation in VECs, aiming to identify potential therapeutic targets for sepsis. In septic rats, significant lung injury and increased vascular leakage were observed, linked to mitochondrial dysfunction and decreased survival rates. A marked downregulation of Platelet Activating Factor Acetylhydrolase 2 (PAFAH2) in VECs was identified post-sepsis, causing an upregulation of Enoyl-CoA Hydratase, Short Chain 1 (ECHS1), which inhibited crotonylation and compromised mitochondrial function, leading to increased apoptosis of VECs. Restoration experiments showed that modulating PAFAH2 and ECHS1 levels could mitigate these adverse effects. PAFAH2 overexpression alleviated sepsis-induced vascular leakage by downregulating ECHS1 and enhancing crotonylation. The study identifies the PAFAH2-ECHS1 pathway as a critical axis in sepsis-induced vascular leakage, influencing mitochondrial function and crotonylation, which leads to endothelial apoptosis. These insights could guide the development of new therapies targeting the endothelial barrier for treating sepsis.

Advances in research on the role of VEGF family members in ischemic stroke.

Heme-induced ITAM signaling exacerbates malaria-associated neuropathogenesis through activation of platelet mTOR.

The IL-33/ST2 axis promotes sepsis-induced lung injury by modulating NETs formation via the ATF4/REDD1 signaling pathway.

Lipedema has long been misclassified as a cosmetic concern or a subtype of obesity, leading to delayed diagnosis and suboptimal surgical outcomes. Growing molecular, histopathologic, and imaging evidence supports lipedema as a systemic disorder involving adipose tissue, connective matrix, vascular-lymphatic integrity, and neuroimmune regulation. To integrate these findings into a clinically actionable model, we introduce the concept of Adipoconnective Fragility Syndrome (AFS), framing lipedema as a multisystem condition with direct implications for surgical planning and perioperative management. A narrative review of the literature was conducted, integrating evidence from adipose biology, connective tissue pathology, endocrine signaling, vascular-lymphatic dysfunction, and pain neurobiology relevant to lipedema. Emphasis was placed on mechanisms with established clinical correlations, including disease progression, symptom severity, and surgical outcomes. Lipedema tissue demonstrates early adipocyte hyperplasia, immune dysregulation, hypoxia-driven fibrosis, and abnormal sodium handling, resulting in a fragile adipoconnective microenvironment. Alterations in caveolar biology particularly involving CAVEOLIN-1 and its interaction with matrix remodeling pathways emerge as a key molecular mechanism contributing to hormonal hypersensitivity, vascular permeability, lymphatic overload, and pain. Within the AFS framework, these processes explain the resistance to weight-loss strategies, the propensity for recurrence, and the heterogeneity of surgical outcomes observed in clinical practice. Reframing lipedema as an Adipoconnective Fragility Syndrome provides a clinically relevant framework that enhances surgical decision-making rather than diminishing the role of surgery. This model supports earlier diagnosis, improved patient selection, individualized perioperative optimization, and structured long-term follow-up, aimed at reducing complications and recurrence. By linking molecular vulnerability to clinical behavior, AFS facilitates a more precise, multidisciplinary, and mechanism-based approach to the surgical management of lipedema. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Characterization of missense variants in the signal peptide of the C1-esterase inhibitor.

Acute lung injury (ALI) is a severe inflammatory syndrome characterized by epithelial and endothelial injury, increased pulmonary vascular permeability, and impaired gas exchange. ALI often involves ferroptosis, an iron-dependent form of oxidative cell death. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of antioxidant defenses, but its role in ALI-related ferroptosis is not well understood. In this study, NRF2 knockout (KO) mice were utilized for transcriptomic analysis to investigate the role of NRF2 in ALI. NRF2 deficiency significantly exacerbated lung injury and ferroptosis, and upregulated the expression of the calcium transporter gene solute carrier family 24 member 2 (SLC24A2). Calcium overload was closely associated with increased SLC24A2 expression and contributed to the development of ferroptosis. These findings were validated in vitro: knockdown of NRF2 in lung epithelial cells enhanced susceptibility to ferroptosis, whereas overexpression of NRF2 attenuated ferroptotic cell death. Conversely, silencing SLC24A2 reduced intracellular calcium overload and suppressed ferroptosis. These results suggest that there may be a regulatory axis between NRF2 and SLC24A2, which has a potential association with inflammation and ferroptosis signals related to acute lung injury (ALI). However, further studies are required to clarify the causal relationship and its consistency across different models, thereby evaluating the feasibility of this axis as a potential therapeutic target.

Identification of the adhesion GPCR ADGRL4/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease.

Ginsenoside Rg1 Ameliorates LPS-Induced Sepsis-Associated Lung Injury in Mice via VEGFC/D-VEGFR3 Signaling-Mediated Lymphangiogenesis and Lymphatic Remodeling.

Ischemic stroke (IS) remains a major cause of global disability and mortality. Currently, neuroprotection, angiogenesis, and repair of injured blood brain barrier (BBB) are common regenerative therapy strategies for IS. The primary challenge remains how to integrate these processes into a synergistic tissue repair program in response to microenvironmental cues. In the present study, a functional ECM hydrogel was constructed by combining with specific ECM-binding bFGF (EBP-bFGF) for neuroprotection and chemically modifying with a matrix metalloproteinase-2 (MMP-2)-cleavable motif to control the release of angiopoietin-1 mimetic peptide (AMP), thereby promoting angiogenesis and BBB repair. After verification of the biological activity in vitro, the EBP-bFGF/ECM/TIMP-AMP hydrogel was transplanted into ischemic brain following IS. The findings indicated that the application of the innovative EBP-bFGF/ECM/TIMP-AMP hydrogel facilitated the preservation of neuronal integrity and conferred potent neuroprotection. Additionally, the therapeutic intervention significantly stimulated angiogenesis and achieved stabilization of the blood brain barrier through inhibition of MMP-2 overactivity, thereby diminishing vascular permeability. Collectively, these findings establish the targeted, stimulus-responsive co-delivery of bFGF and TIMP-AMP as a promising regenerative strategy, which orchestrates neuroprotection, angiogenesis, and BBB stabilization to synergistically promote repair and recovery after ischemic stroke.

Chronic rhinosinusitis (CRS) is a complex disorder influenced by both environmental and genetic factors. Due to incomplete understanding of its pathophysiology, effective treatment remains challenging. Microribonucleic acids (miRNAs) have emerged as one of the promising epigenetic regulators, with increasing evidence supporting their role in modulating multiple diseases. This insight might inform future research directions toward the development of miRNA-based biomarkers and therapies. This comprehensive scoping review summarizes the current literature on the functions of miRNAs as epigenetic regulators in CRS. A comprehensive literature review from PubMed database, focusing on chronic rhinosinusitis/nasal polyps and microRNA/miRNA. Numerous clinical, in vivo, and in vitro studies have identified altered miRNA levels in CRS, and distinct profiles between type 2 and non-type 2 endotypes of CRS. Several studies revealed positive correlations between miRNAs and symptom scores, objective disease measurements, and polyp recurrence. Certain in vivo and in vitro studies also demonstrated the effects of miRNAs changes mainly on inflammation and tissue remodeling, such as epithelial-mesenchymal transition, or fibrin deposition in nasal polyps. The most researched miRNAs in which involved these mechanisms include miR-125b, miR-155, miR-21, and miR-145-5p. miRNAs also have been shown to contribute to other CRS-related processes, including increased mucus secretion and vascular permeability. Collectively, these findings support the effects of miRNA on CRS development. However, a few studies indicated contradictory results, suggesting that miR-21 has a role in anti-inflammation. Increasing evidence highlights the role of miRNAs in CRS pathogenesis. Further research on miRNA-based biomarkers and therapies is warranted.

Resection of the Clinoidal Meningioma Encasing the Carotid Artery: A Complex and Delicate Surgical Procedure.