Search Results (4,508)

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

Background and Clinical Significance: Breast hemangioma is an extremely rare benign vascular tumor of the breast. Its imaging findings are nonspecific, and differentiation from malignant tumors such as encapsulated papillary carcinoma, mucinous carcinoma or angiosarcoma is often difficult. We report a case of breast hemangioma that showed slow growth over an 11-year period. Case Presentation: A woman in her 50s presented with a well-defined 11 mm mass in the upper outer quadrant of the left breast detected by ultrasonography. A core needle biopsy revealed a benign lesion, and follow-up was recommended. Eleven years later, the mass had increased to 27 mm. Magnetic resonance imaging showed high signal intensity on T2-weighted images and a fast-plateau enhancement pattern extending from the periphery to the center. Although malignancy was suspected, vacuum-assisted biopsy revealed a hemangioma. Conclusions: Breast hemangioma can show slow enlargement over a long period. Recognition of a characteristic peripheral-to-central enhancement pattern may aid in distinguishing this benign vascular lesion from malignant tumors. Full article

RECK was first reported as a transformation suppressor gene in 1998 and gradually gained attention as evidence indicating its reduced expression in a wide variety of human cancers accumulated. RECK encodes a membrane-anchored glycoprotein exhibiting protease inhibitor activity against matrix metalloproteases. Restored expression of RECK in cancer xenograft models suggests it suppresses tumor growth and/or metastasis. RECK was also found to be essential for mammalian embryogenesis, especially in the maintenance of tissue integrity as well as the development of neural and vascular systems. Due to its functional versatility during animal development, we only recently began to obtain formal experimental evidence that RECK is a bona fide tumor suppressor. In the meantime, mechanisms by which RECK expression is reduced in cancer cells have been explored. Various stimuli that alter RECK expression have also been described. Furthermore, recent findings in the clinic as well as in animal studies indicate the involvement of RECK in disorders other than cancer. The aim of this article is to summarize our current knowledge of RECK and assist future efforts to understand its nature and functions and to develop useful applications. Full article

Background: Coffin–Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. Case Description: We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient’s systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. Conclusions: This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development. Full article

Colorectal cancer (CRC) therapy faces challenges due to limited drug penetration across the blood–tumor barrier. Neutrophils, with their natural ability to migrate to inflamed and tumor sites, offer a promising cell-mediated delivery strategy. This study developed albumin nanoparticles loaded with 6-shogaol (NPs/6-shogaol) and utilized activated neutrophils as carriers to transport the nanoparticles across vascular barriers for colon cancer therapy. The physicochemical properties, biocompatibility, and targeting efficiency of the NPs were evaluated in vitro and in vivo. The formulated NPs/6-shogaol exhibited favorable physicochemical properties, including a uniform nano-scale size (~150 nm), negative zeta potential, and high drug loading efficiency. In both subcutaneous and orthotopic colon cancer models, neutrophil-mediated delivery significantly enhanced tumor accumulation of 6-shogaol, inhibited tumor growth, and induced apoptosis by suppressing neutrophil elastase (NE) expression. Notably, no significant systemic toxicity was observed. This neutrophil-hitchhiking albumin nanoplatform provides a targeted and biocompatible strategy for effective colon cancer therapy. Full article

Vascular endothelial growth factor 165 (VEGF₁₆₅) stands out as a pivotal isoform of the VEGF-A protein and is critically involved in various angiogenesis-related diseases. Consequently, it has emerged as a promising target for diagnosing and treating such conditions. Structurally, VEGF₁₆₅ forms a homodimer, and each of its constituting monomers comprises a receptor-binding domain (RBD) and a heparin-binding domain (HBD). These two domains are linked by a flexible linker, and thus the overall structure of VEGF₁₆₅ remains incompletely understood. Aptamers are known as potent drugs that interact with VEGF₁₆₅, and dimeric aptamers that can simultaneously interact with two distant domains are frequently adopted to improve the potency. However, designing such aptamer dimers faces challenges in regard to determining the appropriate length of the linker connecting the two aptamer fragments. To gain insight into this distance information, we here employ biased molecular dynamics (MD) simulations with the umbrella sampling method, with the distance between the two HBDs serving as a reaction coordinate. Our simulations reveal an overall preference for compact conformations with HBD-HBD distances below 3 nm, with the minimum of the potential of mean force located at 1.1 nm. We find that VEGF₁₆₅ with the optimal HBD-HBD distance forms hydrogen bonds with its receptor VEGFR-2 that well match experimentally known key hydrogen bonds. We then try to computationally design aptamer homodimers consisting of two del5-1 aptamers connected by various linker lengths to target VEGF₁₆₅. Collectively, our findings may provide quantitative guidelines for rationally designing high-affinity aptamers for targeting VEGF₁₆₅. Full article

Quercetin (Q), a bioactive flavonoid, exerts potent antioxidant and redox-modulating effects by activating the nuclear factor erythroid 2-related factor 2/antioxidant response Element (Nrf2/ARE) pathway and upregulating endogenous antioxidant defenses, including enzymatic antioxidants such as superoxide dismutase (SOD) and catalase (CAT), as well as non-enzymatic glutathione (GSH) and lipid peroxidation (MDA). Gemcitabine (Gem), a widely used antimetabolite chemotherapeutic, often shows limited efficacy under hypoxic and oxidative stress conditions driven by hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF)-mediated angiogenesis. This study investigated the redox-mediated synergistic effects of Q and Gem in MDA-MB-231 human breast cancer cells. Combination treatment significantly reduced cell viability beyond the expected Bliss value, indicating a synergistic interaction and enhanced apoptosis compared with single-agent treatments. Increased reactive oxygen species (ROS) production was accompanied by depletion of GSH and accumulation of MDA, establishing a pro-apoptotic oxidative stress environment. Q alone enhanced SOD and CAT activities, whereas the combination induced exhaustion of antioxidant defenses under oxidative load, reflecting a redox-adaptive response. Molecular analyses revealed downregulation of HIF-1α and VEGF, alongside upregulation of Bax and Caspase-3, confirming suppression of hypoxia-driven survival and activation of the intrinsic apoptotic pathway. Transcriptomic and enrichment analyses further identified modulation of oxidative stress- and apoptosis-related pathways, including phosphoinositide-3-kinase–protein kinase B/Akt (PI3K/Akt), HIF-1 and VEGF signaling. Collectively, these results indicate that Q potentiates Gem cytotoxicity via redox modulation, promoting controlled ROS elevation and apoptosis while suppressing hypoxia-induced survival mechanisms, highlighting the therapeutic potential of redox-based combination strategies against chemoresistant breast cancer. Full article

Lateral Organ Boundaries Domain (LBD) proteins are plant-specific transcription factors characterized by a typical N-terminal LOB domain and are critical for plant growth, development, and stress response. Currently, LBD genes have been investigated in various plant species, but they have yet to be identified in Neolamarckia cadamba, known as a ‘miracle tree’ for its fast growth and acknowledged for its potential medicinal value in tropical and subtropical areas of Asia. In this study, a total of 65 NcLBD members were identified in N. cadamba by whole-genome bioinformatics analysis. Phylogenetic analysis revealed their classification into two clades with seven distinct groups, and their uneven distribution across 18 chromosomes, along with 6 tandem repeats and 58 segmental duplications. Furthermore, enrichment analysis of transcription factor binding motifs within NcLBD promoters identified the MYB-related and WRKY families exhibited the most significant enrichment in the NcLBD promoter. Protein interaction network analysis revealed potential interactions among NcLBD proteins, as well as their interactions with various transcription factors. RNA-seq and qRT-PCR analyses of NcLBDs transcript levels showed distinct expression patterns both across various tissues and under different hormone and abiotic stress conditions. Specifically, NcLBD3, NcLBD37, and NcLBD47 were highly expressed in vascular cells and induced by abiotic stress, including cold, drought, and salt, suggesting their significant role in the processes. In summary, our genome-wide analysis comprehensively identified and characterized LBD gene family in N. cadamba, laying a solid foundation for further elucidating the biological functions of NcLBD genes. Full article

Vascular remodeling and progressive lung vessel obliteration are a histopathological cornerstone for the onset of pulmonary arterial hypertension (PAH). However, the role of vascular endothelial growth factor (VEGF) signaling pathways in the development of histopathological vascular changes in PAH is still incompletely understood. This educational review aims to untangle the opposing and heterogeneous actions of VEGF and the receptors it engages in triggering lung angio-proliferative lesions, driving hemodynamic changes in PAH. A proposed ‘VEGF-oriented’ approach attempts to untangle some of the contrasting and complementary actions of VEGF in the pathogenesis of the disease. Experimental models provide a cogent explanation for dysfunctional angiogenesis and the paradox of VEGF-receptor-blockade-induced PAH. The multifaced properties of VEGF, whether angiogenic or nonangiogenic, vary depending on the nature of the ligand, receptor-dependent and -independent signaling pathways, and the duration of the ligand–receptor engagement. Further investigation is needed to translate the knowledge acquired to human subjects and to confirm the pathogenic mechanisms surrounding the phenotypic shift to apoptosis-resistant, hyperproliferative cellular subset and the development of angio-obliterative lesions in PAH. Full article

Doppler assessment of fetal cerebral circulation has become a cornerstone of modern fetal medicine. It is used to evaluate cerebral vascular malformations, brain anomalies, fetal growth restriction due to placental insufficiency, fetal anemia, and hemodynamic complications arising from placental vascular anastomoses in monochorionic pregnancies. Emerging research also explores the predictive value of Doppler parameters for perinatal outcomes and long-term neurodevelopment. To review the anatomy and physiology of fetal cerebral vessels accessible to Doppler evaluation, outline key technical aspects, and summarize current obstetric applications. A PubMed search identified 113 relevant publications, published between 1984 and 2025. Three book chapters by authors recognized internationally within the scientific community were included. A total of 116 publications were critically analyzed in this narrative review. Strong evidence supports the use of Doppler ultrasound in obstetrics, particularly for evaluating fetal cerebral hemodynamics, where it contributes to reducing fetal morbidity and mortality. Doppler assessment of fetal brain circulation is a valuable tool for evaluating brain vascular malformations, other structural abnormalities, and for assessing fetuses with growth restriction, anemia, and twin-to-twin transfusion syndrome. It allows targeted fetal monitoring and timely interventions, providing critical prognostic information and aiding parental counseling. Ongoing advances in Doppler technology and understanding of fetal brain physiology are likely to broaden its clinical uses, improving both perinatal outcomes and long-term neurological health. Full article

Diabetes mellitus severely impairs skeletal muscle regeneration after injury, limiting satellite cell activation and angiogenesis and disrupting barrier integrity while increasing fibrosis. Hypobaric hypoxia has been proposed to improve the regenerative microenvironment through hypoxia-responsive signaling, but its temporal effects and the coordination between vascular and myogenic programs in diabetic muscle remain unclear. To clarify these processes, adult male mice were divided into five groups: diabetes mellitus control (DM), cardiotoxin-injured (CTX) diabetes assessed on days 7 and 14 (CTX7, CTX14), and hypobaric-hypoxia-treated diabetic injury assessed on days 7 and 14 (H+CTX7, H+CTX14). Animals in the hypoxia groups were exposed to a hypobaric hypoxia chamber for 8 h per day for 14 days. Fibrosis, angiogenic and myogenic markers, and endothelial junctional genes were examined using histology, immunofluorescence, immunoblotting, and qRT-PCR (Quantitative Real-Time PCR). Hypobaric hypoxia on day 7 enhanced HIF-1α (hypoxia-inducible factor 1 alpha), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthas), Kdr (kinase insert domain receptor, VEGFR-2), and Angpt2 (angiopoietin-2) expression, accompanied by simultaneous endothelial sprouting and early myogenic stimulation compared to CTX7. Improvements were observed in Angpt1 (angiopoietin-1), Cdh5 (cadherin-5, VE-cadherin), Emcn (endomucin), the Angpt1/Angpt2 ratio, and CD31 density. Myogenin and MyHC (myosin heavy chain) were induced with a reduction in eMyHC (embryonic myosin heavy chain) in accordance with stabilization of endothelium and maturation of fibers, which occurred by day 14. A decrease in fibrosis and an increase in the myofiber cross-sectional area occurred. These findings suggest that hypobaric hypoxia modulates HIF-1α signaling, which in turn induces the VEGF-Kdr-eNOS pathway and the angiopoietin–Tie2–VE-cadherin pathway. Together, these pathways coordinate vascular remodeling and myogenic regeneration, ultimately improving the structural and functional recovery of diabetic muscle. Full article

Background/Objectives: The cardiac hypoxia- and inflammation-associated processes in patients with chronic coronary artery disease remain unknown. The coronary sinus (CS) can be used to explore changes in cardiac microenvironment. This study sought to evaluate acute changes in the CS concentration of hypoxia and inflammation-associated biomarkers after the percutaneous revascularization of chronic total occlusions (CTO-PCI). Additionally, we explored changes in systemic inflammation and the potential of CS biomarkers to predict left ventricular ejection fraction (LVEF) improvement on follow-up. Methods: Thirty-three patients undergoing CTO-PCI were included. Samples from CS were collected before and after the revascularization. Twenty-six protein biomarkers associated with hypoxia and inflammation were measured using proximity extension assay technology. Systemic inflammation markers and LVEF on cardiac magnetic resonance imaging were assessed at baseline and 6-month follow-up. Results: CTO-PCI yielded a significant decrease in the concentration of CS pro-angiogenic biomarkers (angiopoietin-1, vascular endothelial growth factors). In addition, there was a significant increase in the anti-inflammatory biomarker interleukin-10 and a decrease in several pro-inflammatory biomarkers like interleukin-1β. The acute response in cardiac microenvironment was followed by a mid-term reduction in systemic inflammatory markers, particularly high-sensitivity C-reactive protein. Notably, interleukin-10 showed good performance to identify patients achieving LVEF improvement on follow-up in our cohort. Conclusions: Our results suggest that CTO-PCI might attenuate cardiac hypoxic and inflammatory stress. These exploratory findings warrant confirmation in larger, controlled studies. Full article

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment. Full article

Background: The anterior cruciate ligament (ACL) and medial collateral ligament (MCL) display strikingly different healing behaviors, despite their similar structural roles within the knee. The epiligament (EL)—a vascular and cellular envelope surrounding each ligament—has emerged as a critical determinant of repair capacity. The aim of this study was to perform a region-specific, comparative analysis of EL molecular profiles in the ACL and MCL to elucidate the mechanisms underlying their contrasting reparative outcomes. Methods: Human ACL and MCL specimens were obtained from 12 fresh knee joints. Immunohistochemical labeling for CD34, α-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) was performed across proximal, mid-substance, and distal EL regions. Quantitative image analysis using IHC Profiler for ImageJ generated semiquantitative (negative, low-positive, positive) distributions, and inter-ligament comparisons were quantified using t-tests (p  <  0.05). Results: Distinct, region-specific EL signatures were identified. The ACL EL exhibited strong proximal α-SMA expression (0% neg/66.8% low+/33.2%+) and notable distal CD34 positivity (0% neg/83.3% low+/16.7%+), while VEGF expression was confined to the mid-substance (≈55% low+/26%+). In contrast, the MCL EL was largely negative for CD34 and VEGF across all regions, showing a homogeneous but functionally oriented α-SMA profile: proximally negative, sparse mid positivity, and high distal low-positive staining (93.4% low+). Differences in proximal and distal CD34 and α-SMA expression between the ACL and MCL were highly significant (p  <  0.0001–0.001), confirming a mechanistic divergence in EL organization. Conclusions: The ACL EL is regionally heterogeneous, vascularly biased, and enriched in contractile α-SMA+ cells, suggesting localized but poorly coordinated reparative potential. In contrast, the MCL EL is structurally uniform, with distributed α-SMA activity supporting stable wound contraction and tissue continuity, despite limited angiogenic signaling. These findings indicate that the ACL’s failure to heal is not attributable to the absence of progenitor or angiogenic factors, but rather to its fragmented spatial organization and dominant contractile phenotype. Therapeutically, preserving and modulating the EL, particularly its CD34+ and α-SMA+ compartments, could be key to enhancing intrinsic ACL repair and improving outcomes in ligament reconstruction and regeneration. Full article