Search Results (246)

Cancer-associated fibroblasts (CAFs) are an abundant and diverse cell population within tumor microenvironments of solid tumors. Multiple subtypes of CAFs, defined by molecular and functional markers, have been described in the literature. CAFs contribute to tumor progression by remodeling the extracellular matrix, promoting immune evasion, and supporting angiogenesis and metastasis. Fibroblast activation protein (FAP) is a transmembrane serine protease minimally expressed in normal adult tissues but significantly upregulated in certain subtypes of CAFs across many solid tumors. High levels of FAP have been associated with poor prognosis in various cancers. FAP has increasingly emerged as a promising target for both imaging and therapy. Multiple FAP-targeting strategies, such as small molecules, monoclonal antibodies, drug conjugates, and radiolabeled ligands, are currently being investigated in preclinical and early clinical settings. This review provides a clinically focused overview of CAFs in the tumor microenvironment, highlighting key fibroblast markers, their associations with prognosis across various tumor types, and their utility in radiologic imaging and targeted therapy. We also discuss the potential of non-FAP fibroblast targeting molecules and the clinical rationale for more selective, subtype-specific strategies. By examining fibroblast biology through a radiologist’s lens, we aim to explore the evolving role of stromal targeting in imaging and the treatment of solid tumors. Full article

Skin aging, driven by oxidative stress, UV exposure, inflammation, and extracellular matrix degradation, necessitates the discovery of safer, multi-target natural products. We established an integrated pipeline combining UHPLC–MS/MS metabolomics, computational methods (network pharmacology, molecular docking, and dynamics simulation), and in vitro bioassays to efficiently discover and mechanistically characterize anti-aging compounds from novel botanical sources. We applied this pipeline to identify and evaluate Tephroseris flammea, a previously unassessed plant. Metabolomic profiling identified 21 compounds, including flavonoids, phenylpropanoids, and pyrrolizidine alkaloids. These compounds were linked via network pharmacology to 226 skin-aging-related targets, primarily involving inflammation (via AKT1, RELA) and matrix degradation (via MAPK3). Molecular docking and 100 ns molecular dynamics simulations confirmed stable ligand-target interactions with favorable binding energies. Validating these in silico predictions, the T. flammea extract demonstrated significant antioxidant activity and effectively suppressed key inflammatory mediators (IL-6, TNF-α, COX-2) and MMP-1 levels in UVB-exposed fibroblasts, notably without significant cytotoxicity. Collectively, this study validates the utility of our pipeline to mechanistically characterize complex botanicals, revealing that T. flammea contains multifunctional compounds modulating critical inflammatory and matrix-regulatory cascades. This work validates our pipeline for identifying novel, mechanistically defined ingredients from complex botanical sources. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article

Oxidative stress, UV exposure, inflammation, and extracellular matrix degradation collectively drive skin aging, underscoring the need for safe, multi-target therapeutic options. We developed and applied an integrated analytical pipeline combining UHPLC–MS/MS metabolomics, computational analyses (network pharmacology, molecular docking, and molecular dynamics simulation), and experimental bioassays to efficiently identify and characterize novel natural products with anti-aging potential. This workflow was applied to Melampyrum roseum Maxim., a previously unassessed hemiparasitic plant of the Orobanchaceae family, to elucidate its bioactive potential against skin aging. UHPLC–MS/MS profiling annotated 13 secondary metabolites, predominantly flavone aglycones, iridoid glycosides, and phenylpropanoid derivatives. Network pharmacology analysis linked these metabolites to 172 potential skin-aging-associated targets, mainly within inflammatory, ECM, and oxidative-stress pathways. Molecular docking and 100-ns molecular dynamics simulations confirmed stable ligand-target interactions with favorable binding energies, particularly with AKT1, EGFR, PTGS2 and XDH. Validating these predictions, the M. roseum extract demonstrated significant antioxidant activity and effectively suppressed key inflammatory mediators (IL-6, TNF-α, COX-2) and MMP-1 levels in UVB-exposed fibroblasts, notably without significant cytotoxicity. Collectively, these findings demonstrate that M. roseum harbors multifunctional metabolites that modulate key inflammatory and matrix-regulatory pathways, providing preliminary mechanistic evidence for its potential as a promising candidate for natural anti-aging applications. Full article

Background: Liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition, driven by activated hepatic stellate cells (aHSCs). Effective therapeutic strategies require targeting aHSCs and agents capable of reversing their activated phenotype. Methods: In this study, we developed chitosan nanoparticles loaded with atorvastatin (AS) and JQ1 and functionalized them with varying densities of retinol (Rt) to exploit aHSC targeting. Results: In vitro, Rt-NPs demonstrated enhanced uptake in GRX cells, with optimal performance observed at high Rt density (HRt-NPs). In vivo biodistribution in CCl₄-induced fibrotic and healthy mice revealed that LRt-NPs achieved superior hepatic accumulation in fibrotic livers compared to unmodified and HRt-NPs, underscoring the importance of optimal ligand density for targeting. Western blot analysis showed that treatment of GRX cells with Rt-AS-NPs and Rt-JQ1-NPs either individually or combined significantly reduced the expression of fibronectin, vimentin, and PDGFR-β, key markers of HSC activation, with combination therapy providing more significant effects. Conclusions: This work highlights the potential of Rt-chitosan NPs loaded with AS and JQ1 as an effective dual-drug system for targeted antifibrotic therapy, offering enhanced hepatic selectivity, improved safety, and potent aHSC deactivation. Full article

Background/Objectives: Pulmonary fibrosis (PF) and lung cancer (LC) are major global health challenges that share several pathogenic mechanisms despite their distinct clinical features. PF leads to progressive fibrotic remodeling and respiratory decline, while LC is characterized by uncontrolled proliferation, invasion, and metastasis. Growing evidence shows that PF markedly increases the risk of LC development. This review aims to clarify the convergent molecular and cellular mechanisms that link fibrogenesis to tumorigenesis. Methods: Published studies exploring shared pathogenic pathways, molecular signaling networks, immune microenvironment alterations, and mitochondrial and genomic disturbances in PF and LC were systematically examined and integrated to identify common mechanisms contributing to fibrosis-associated carcinogenesis. Results: Findings highlight several overlapping processes between PF and LC, including oxidative stress, genomic instability, dysregulated DNA damage repair, immune microenvironment remodeling, mitochondrial dysfunction, and alterations in the ubiquitin–proteasome system. These aberrations drive chronic inflammation, epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and other hallmarks shared by both diseases. Key signaling pathways—such as transforming growth factor-β (TGF-β), programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1), and tumor microenvironment–mediated immune evasion—further contribute to disease progression and increased LC risk in PF patients. Conclusions: Integrating molecular and pathological insights reveals a strong biological continuum between PF and LC. Understanding these convergent mechanisms may facilitate the identification of diagnostic biomarkers and therapeutic targets, ultimately helping to mitigate PF-associated lung carcinogenesis. Full article

The Receptor for Advanced Glycation End-Products (RAGE) is a cell surface receptor of the immunoglobulin-like receptor superfamily. RAGE is a pattern-recognition, multi-ligand receptor that binds glycated proteins, specific non-glycated proteins, and nucleic acids. RAGE ligands are typically part of the group of damage-associated molecular patterns (DAMPs) or alarmins. As such, RAGE is a receptor for molecular products of cellular stress, abnormal metabolism, and inflammation. Activation of RAGE by its ligands leads to pro-inflammatory signaling, often resulting in persistent RAGE activation in various disease states. Consequently, RAGE has been investigated as a potential drug target in the treatment of diabetic complications, vascular disease, Alzheimer’s disease, and multiple types of cancer. An underexplored aspect of RAGE is its role in cell adhesion. Structural comparison of the extracellular domain of RAGE has revealed structural similarity to the activated leukocyte cell adhesion molecule (ALCAM). The present study reveals the role and mechanism of RAGE in regulating cell adhesion. We investigated the role of individual RAGE domains in cell adhesion to extracellular matrix proteins and the changes in protein expression resulting from RAGE upregulation. Key findings include that RAGE displays substrate-specific adhesion to extracellular matrix proteins, that the intracellular domain of RAGE is required for modulating cell spreading, and that regulation of ITGA8 depends on the cytoplasmic domain of RAGE. Full article

Injury to tissue induces the normal wound healing process to repair damage. This is a normal and critical response developed by the body to maintain short-term organ function, and therefore, survival. Should this process become aberrant, then fibrosis can develop. Fibrosis is the excess accumulation of extracellular matrix proteins. Unlike normal wound healing that is designed to maintain organ/tissue function, fibrosis interferes with the normal architecture of the organ and has long-term functional implications. Fibroblasts are the cells responsible for producing extracellular matrix in both wound healing and fibrosis. Substance P is the cognate ligand for the neurokinin-1 receptor, and both substance P and the neurokinin-1 receptor have been demonstrated to be involved in organ remodeling; this includes regulation of fibroblast function. In this review we will focus on substance P/neurokinin-1 receptor regulation of fibroblast function in the setting of both wound healing and fibrosis. This review describes actions of substance P and the neurokinin-1 receptor on fibroblasts from multiple organs, thus identifying central actions common to all fibroblasts studied. This review also identifies gaps in the literature and future directions needed to improve understanding of substance P and the neurokinin-1 receptor regulation of fibroblast phenotype. Full article

Background/Objectives: Naegleria fowleri is a free-living protozoan that causes primary amoebic meningoencephalitis, a rapidly progressing central nervous system infection with high mortality rates and limited treatment options. Targeting virulence-associated proteins is essential for effective drug development. Fowlerpain-1 (FWP1), a papain-like cysteine protease (CP) implicated in extracellular matrix degradation and host–cell cytotoxicity, has been investigated as a therapeutic target. This study aimed to evaluate the FWP1 pocket geometry and stefin binding using an integrated in silico structural biology approach. Methods: A computational pipeline was used, including AlphaFold2-Multimer modeling of FWP1–stefin complexes, 20-ns molecular dynamics simulations under NPT conditions for conformational sampling, and molecular mechanics Poisson–Boltzmann surface area free energy calculations. Three natural CP inhibitors (stefins) were investigated. Structural stability was assessed using root mean square deviations, and binding profiles were characterized using protein–protein interaction analysis. Results: Stable FWP1–stefin interaction interfaces were predicted, with human stefin A showing favorable binding free energy. Two conserved motifs (PG and QVVAG) were identified as critical mediators of active-site recognition. Druggability analysis revealed a concave pocket with both hydrophobic and polar characteristics, consistent with a high-affinity ligand-binding site. Conclusions: This computational study supports a structural hypothesis for selective FWP1 inhibition and identifies stefins as promising scaffolds for developing structure-guided protease-targeted therapeutics against N. fowleri. Full article

During embryonic development, angiogenesis and arteriogenesis are responsible for vast growth and remodeling. These processes have distinct mechanisms, like budding, cord hollowing, cell hollowing, cell wrapping, and intussusception. This review discusses the diversity of morphogenetic mechanisms contributing to vessel assembly and angiogenic sprouting in blood vessels and how molecular pathways regulate some complex cell behaviors concerning the VEGFR pathway. Also, a particular part is dedicated to the HIF 1α gene. The key components of the VEGFR pathway are VEGF receptors VEGFR1, VEGFR2, and VEGFR3. VEGFR2 plays a central role in vascular morphogenesis. VEGF is the primary ligand involved in angiogenesis and arteriogenesis. Various types of VEGF are being studied in terms of their therapeutic use. The ultimate goal of the vascular morphogenesis study is to enable the development of organized vascular tissue that presumably might be used to replace the diseased one. Cellular chirality—the intrinsic “handedness” of cells in movement, structure, and organization—plays a crucial role in angiogenesis, the process by which new blood vessels develop from old ones. This chiral activity is essential for the directed and patterned organization of endothelial cells during vascular formation and remodeling. In angiogenesis, cellular chirality directs endothelial cells to adopt specific orientations and migratory patterns, which are crucial for the formation of functionally organized blood vessels that provide tissues with the necessary nutrients and oxygen. Cellular chirality in this environment is affected by multiple mechanisms, including VEGF/VEGFR signaling, mechanical pressures, interactions with the extracellular matrix (ECM), and cytoskeletal movements. Lately, researchers have focused on the molecular control of blood vessel morphogenesis, the study of signaling circuitry implied in vascular morphogenesis, the emerging mechanism of vascular stabilization, and helical vasculogenesis driven by cell chirality. Full article

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis. Full article

The cluster of differentiation 44 (CD44) is a member of the hyaluronic acid (HA) receptor family of cell adhesion molecules. Besides HA, this transmembrane protein also serves as a receptor for other components of the extracellular matrix (ECM), including fibronectin, collagen, and osteopontin (OPN). The CD44-HA axis is involved in a wide range of physiological and cancer-related processes, particularly in cell adhesion and migration, lymphocyte activation, as well as tumour progression and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor has therefore been recognized as an emerging anti-cancer strategy. With its expression in a wide variety, CD44 has also become the most common surface biomarker of cancer stem cells. Due to the rapid progress of research on this crucial receptor, some published and deposited variants were often poorly described or lacked accession numbers in the available protein databases, which created confusion and hindered relevant research. In this work, we attempted to examine the protein sequences of the known CD44 variants and match them between the two UniProt and the National Centre for Biotechnology Information (NCBI) Protein databases. The deposited sequences were aligned to the CD44 canonical sequence and grouped based on the observed differences. Analysis of CD44–ligand experimental structures available in the Protein Data Bank (PDB) was also performed to identify the most promising small-molecule inhibitors of the CD44-HA interaction. Full article

Glioblastoma (GBM) is an aggressive and lethal malignant brain tumor. Cell–cell interactions (CCIs) in the tumor microenvironment, mediated by ligand–receptor (LR) pairs, are known to contribute to its poor prognosis. However, the prognostic influence of CCIs on patients with GBM and the spatial expression profiles of such LR pairs within tumor tissues remain incompletely understood. This study aimed to identify prognostic LR pairs in GBM and their intratumoral localization via multitranscriptomic analysis. The CCIs among GBM cells as well as between GBM and niche cells were comprehensively evaluated using 40,958 cells in single-cell RNA sequencing datasets. They were found to form intercellular networks in GBM by specific LR pairs, which were mainly implicated in extracellular matrix (ECM)-related biological processes. Survival analysis revealed that 13 LR pairs related to ECM biological processes contributed to poor prognosis (p < 0.05, and 95% confidence intervals > 1). Notably, our spatial transcriptomic analysis using three independent GBM cohorts revealed that the identified poor prognostic LR pairs were localized in specific regions within GBM tissues. Although the clinical importance of these LR pairs requires further investigation, our findings suggest potential therapeutic targets for GBM. Full article

Therapy resistance is a major obstacle to cancer treatment, and transforming growth factor-beta (TGF-β) signaling has emerged as a major instigator across many cancer types and therapeutic regimens. Solid tumors overexpress TGF-β ligands, and canonical and non-canonical TGF-β signaling pathways drive molecular changes in most cell types within the tumor to hijack therapeutic responses. Cancer therapies further stimulate TGF-β release to potentiate this problem. Molecular mechanisms of TGF-β action supporting resistance include upregulation of drug efflux pumps, enhanced DNA Damage Repair, elaboration of stiffened extracellular matrix, and decreased neoantigen presentation. TGF-β also activates pro-survival pathways, such as epidermal growth factor receptor, B-cell lymphoma-2 expression, and AKT-mTOR signaling. TGF-β-induced epithelial-to-mesenchymal transformation leads to tumor heterogeneity and acquisition of stem-like states. In the tumor microenvironment, TGF-β induces extracellular matrix production, contractility, and secretion of immunosuppressive cytokines by cancer-associated fibroblasts that contribute to drug resistance. TGF-β also blunts cytotoxic T and NK cell activities and stimulates recruitment and differentiation of immunosuppressive cells, including T-regulatory cells, M2 macrophages, and myeloid-derived suppressor cells. The importance of TGF-β signaling in development of drug resistance cannot be understated and should be further explored mechanistically to identify novel molecular approaches and combinatorial drug dosing strategies to prevent drug-resistance. Full article

Multipotent hematopoietic stem cells (HSC) reside in specialized niches of the bone marrow (BM). The maintenance of their stemness requires a precisely regulated bone marrow microenvironment (BMM), supported by mesenchymal stem cells (MSCs), stromal reticular cells, and endothelial and nerve cells located within the vascular and endosteal niches. The heterogeneity of the niche environment is caused by the diversity of cell populations from HSCs to more mature hematopoietic cell types and MSCs, which collectively influence the complex intercellular interactions involved in hematopoiesis. MSC subclusters in BM are characterized by the phenotypes of CXC-chemokine ligand 12, leptin receptor, neuron-glial antigen 2, and Nestin+ cells. The article presents a detailed characterization of individual stem cell types in the BM, their reciprocal interaction, and the possibility of in vitro simulation of the bone marrow niche as a dynamic structure. Development of a suitable simulation of the BMM is essential for advancing research into both physiological and pathological processes of hematopoiesis. The main goal is to simulate 3D cell culture using biomaterials that mimic the BM niche in the form of hydrogels and scaffolds, in combination with extracellular matrix components. Full article