Exercise is a recurrent multidimensional perturbation that initiates biological adaptation, yet responses to comparable training programmes remain heterogeneous. This critical narrative Review introduces the Adaptive Cellular State (ACS) Model as a heuristic framework for examining how the biological context present before training may contribute to variation in the subsequent processing and consolidation of exercise-induced perturbations. ACS is defined as a pre-existing, dynamic and multidimensional biological configuration that may condition how exercise-induced perturbations are received, decoded, executed and retained across repeated adaptive cycles. The model organizes nine interacting domains—mitochondrial quality, metabolic flexibility, nutrient sensing, redox responsiveness, inflammatory tone, microbiota-derived signalling, endothelial function, proteostasis and epigenetic readiness—and proposes four emergent properties: gain, fidelity, biological noise and memory. These domains and properties are theoretical constructs rather than validated ACS measurements or clinical categories. Exercise remains the indispensable initiating stimulus, whereas nutrition may act through distinct routes: acute nutritional conditions may modify the internal perturbation generated during exercise, habitual dietary quality may influence selected components of the pre-existing biological context, and recovery nutrition may provide substrates or modify conditions relevant to remodelling. Nutrient-adequate dietary patterns emphasizing minimally processed foods and a diverse plant-food component represent plausible candidate exposures, but current evidence does not establish superiority over appropriately constructed high-quality omnivorous patterns or demonstrate greater long-term training adaptation. The ACS Model should therefore be interpreted as a prospective and falsifiable research framework whose validity depends on whether prespecified baseline ACS-related measures provide reproducible information about durable adaptation beyond conventional metabolic, fitness and training-history variables.
3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly implicated in motor control, motivation, and reward mechanisms. In the cerebral cortex it participates in attention processes, working memory, long-term memory, etc. DA overproduction or deficits lead to neuronal circuit imbalance that underlies a number of neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, Huntington’s disease (HD), and substance use disorders (SUDs), to name a few. DA regulates neuronal excitability by modulating ion channels, the release of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters, and postsynaptic interactions with glutamate and GABA receptors. Together, these pre- and postsynaptic actions of DA underlie a number of synergistic or antagonistic actions that have important implications for setting membrane potentials, improving the signal-to-noise ratio, and directing the sign of synaptic plasticity. In this review, I will first provide a historical overview of the many studies exploring DA actions in the brain, with particular focus on the striatum. Then, I will emphasize some of the contributions of our laboratory to the understanding of DA modulatory effects from an electrophysiological perspective. Finally, I will discuss the mechanistic and therapeutic implications of DA function and dysfunction.
Collagen is the most abundant protein in the human body and a vital component of the extracellular matrix (ECM), where it maintains structural architecture, strength, and mechanical stability throughout the body. Collagen undergoes continuous turnover and remodeling mediated by matrix metalloproteinases (MMPs) and other proteases to generate collagen peptide fragments (CPFs). CPFs were long considered inert byproducts of collagen turnover but are now recognized to have two overlapping roles: as circulating and urinary biomarkers of ECM remodeling, and as beneficial or adverse bioactive matrikines that directly regulate inflammation, angiogenesis, fibrosis, immune responses, and tissue remodeling. This review focuses on current evidence regarding the biological activities of various CPFs across cardiovascular, cancer, and pulmonary systems. We conclude by discussing various perspectives, including clinical and therapeutic applications and future directions.
Vascular calcification is a hallmark of vascular aging that is accelerated by hyperlipidemia and contributes to adverse cardiovascular outcomes. Although vascular smooth muscle cells (VSMCs) are key mediators of vascular calcification, the signaling pathways linking aging-associated stress to osteogenic remodeling remain incompletely understood. To define the role of MAPK14 (p38α) in vascular aging, we integrated bulk RNA sequencing of young and aged mouse aortas with published single-nucleus RNA sequencing data from VSMC-specific Mapk14 knockout (KO) mice. Bulk RNA-seq identified age-associated activation of extracellular matrix remodeling, calcification, inflammatory, and senescence-associated gene programs, accompanied by increased p38 MAPK signaling. Single-nucleus RNA-seq further demonstrated that Mapk14 KO attenuated proliferative, inflammatory, fibrotic, and ossification-associated gene modules in VSMCs. Consistent with these transcriptomic findings, RUNX2 expression was markedly increased in aged aortas, whereas aged Mapk14 KO mice exhibited reduced RUNX2 expression together with attenuated vascular calcification, fibrosis, and inflammatory cell infiltration compared with wild-type controls. Collectively, these results identify VSMC MAPK14 as an important regulator of vascular calcification during hyperlipidemic aging and demonstrate that MAPK14 deficiency is associated with reduced RUNX2 expression and attenuated fibro-inflammatory vascular remodeling. These findings support MAPK14 as a potential therapeutic target for limiting vascular calcification and associated pathological remodeling during aging.
Background: Acute brain injury (ABI) is a frequent complication of extracorporeal membrane oxygenation (ECMO), but early detection is limited by sedation, imaging constraints, and low sensitivity of conventional neuroimaging. We hypothesized that plasma metabolomics could identify ECMO-mode-specific metabolic shifts and biomarkers preceding ABI. Methods: Untargeted plasma metabolomics was performed in 70 participants across two centers: 30 healthy controls, 17 critically ill controls, and 23 ECMO patients [14 venovenous (VV) and 9 venoarterial (VA)]. Plasma was collected within 24 h and 7 days after cannulation. Fold-change analyses and partial least squares discriminant analysis were used to define metabolic differences and identify metabolites associated with subsequent ABI. Results: ABI occurred in seven ECMO patients, including five venoarterial and two venovenous ECMO patients. ECMO support was associated with broad alterations in circulating lipid metabolism, including changes in sphingomyelins, lysophospholipids, and monoacylglycerols. PLS-DA demonstrated metabolomic separation between ECMO patients and controls. Among ECMO patients, three structurally related glycerophospholipids—GPI (18:0/18:2), GPC (16:0/18:2), and GPE (16:0/18:2)—were significantly decreased before ABI diagnosis. ABI was also associated with broader reductions in phosphatidylethanolamines, phosphatidylinositols, lysophospholipids, and polyunsaturated fatty acids. Conclusions: Early reductions in membrane-associated phospholipids were associated with subsequent ABI during ECMO support, suggesting that alterations in circulating lipid homeostasis may identify neurological vulnerability before clinical or radiographic recognition of injury. Plasma metabolomics may provide a complementary approach for early neurological risk stratification and support future biomarker development.
Osteoarthritis (OA) is the leading cause of disability worldwide. Although rodent models are widely used in OA research, the disease is often artificially accelerated in these systems, and joint biomechanics differ substantially from those of humans. In contrast, canine models offer greater translational relevance due to similarities in joint size, cartilage thickness, and physiological mechanical loading of the knee, making them suitable surrogates for evaluating regenerative therapies. In this study, we assessed the therapeutic efficacy of allogeneic dedifferentiated fat (DFAT) cells, which exhibit greater cellular homogeneity and enhanced osteochondrogenic potential compared with conventional mesenchymal stem cells (MSCs), in a canine monoiodoacetate (MIA)-induced OA model. OA was induced by intra-articular (i.a.) injection of MIA into the knee joints of beagles. Animals were allocated to three groups: an implant group receiving allogeneic DFAT cells via i.a. injection, a vehicle group, and a sham group. Therapeutic outcomes were evaluated through macroscopic scoring of cartilage surfaces and histological assessment using toluidine blue staining to examine proteoglycan depletion and structural integrity. The implant group demonstrated significantly lower Osteoarthritis Research Society International (OARSI) scores for cartilage erosion and osteophyte formation compared with the vehicle group, indicating preservation of joint surface integrity. Toluidine blue staining further showed that DFAT cell implantation significantly preserved extracellular matrix components, with greater proteoglycan retention relative to vehicle-treated controls. A key rationale for employing a canine model was the high prevalence of spontaneous OA in dogs, which closely resembles human disease in clinical presentation, radiographic findings, and molecular pathways. Unlike rodent models, dogs naturally develop OA with progressive degenerative features that mirror human conditions. By utilizing a large animal model, this study bridges the gap between preclinical in vitro findings and potential human clinical application. Collectively, these results provide strong evidence supporting the therapeutic potential of allogeneic DFAT cells and suggest that DFAT-based therapy may represent a promising treatment strategy for chronic, naturally occurring OA in both veterinary and human patients.
Background: Cultured primary mouse hepatocytes undergo drastic phenotypic and metabolic reprogramming, while the temporal rules and regulatory machinery of membrane phospholipid remodeling remain elusive. Methods: Relying on a 0–72 h time-series in vitro culture system, this study integrated multi-omics technologies to dissect the temporal dynamics of phospholipid remodeling in hepatocytes. Through phosphatidylethanolamine N-methyltransferase (PEMT) knockout, exogenous PEMT expression, and methionine deprivation, we examined the association of PEMT status and methionine availability with phospholipid remodeling. Results: In vitro cultivation reduces intracellular total phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) through three coordinated events: suppressed transcription of phospholipid synthetic genes hinders de novo synthesis, elevated lipid hydrolysis consumes cellular phospholipids, and extracellular phospholipids accumulate in the culture medium from 12 to 48 h. These jointly trigger ordered remodeling of PC/PE balance, acyl chain length and fatty acid unsaturation. PEMT knockout was associated with PE retention without worsening hepatocyte dedifferentiation, PEMT exogenous expression raises PC content and PC/PE ratio yet cannot rescue culture-dominated lipid structural shifts. Methionine depletion depleted cellular methionine, S-adenosylmethionine (SAM) and S-adenosyl-L-homocysteine (SAH), producing selected lipid changes that partially overlapped with lipid phenotypes of PEMT knockout. Conclusion: In short, culture duration was the dominant factor associated with the fundamental phospholipid remodeling trajectory, and PEMT status and methionine availability, were associated with selective differences in lipid composition.
CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions.
Neuroinflammation within the tumor microenvironment (TME) of central nervous system (CNS) neoplasms, particularly glioblastoma (GBM), is no longer viewed merely as a reactive phenomenon but rather as a major driver of gliomagenesis and malignant transformation. This process involves a shift from acute immune activation to a chronic, sterile state that reshapes the CNS borders and immune niches to favor tumor evasion. This narrative review provides a comprehensive mechanistically focused analysis of the mechanisms governing the inflammatory stroma in primary and metastatic brain neoplasms. It critically examines the ontogeny and transcriptomic profile of myeloid and glial populations, dismantling the binary M1/M2 polarization model in favor of a continuum of functional states determined by metabolic and oxygenation gradients. It also analyzes intracellular signaling cascades, the subversion of innate immunity sensors such as the cGAS-STING pathway, the epigenetic reprogramming of stromal cells, and the role of extracellular vesicles. The electrochemical integration of tumor cells into neuronal circuits via glutamatergic synapses and connexin 43 gap junction coupling is addressed in detail, defining the mitogenic impact of neuronal activity on the tumor. The inflammatory profiles of IDH-wildtype and IDH-mutant gliomas and of secondary brain metastases are contrasted. Finally, the correlates of functional neuroimaging, liquid biopsies, and resistance mechanisms to conventional therapies are analyzed, including the GIANT and SENIPERA clinical trials, CARv3-TEAM-E bivalent cellular immunotherapy preconditioned with the LDC + R regimen, and the accelerated approval of dordaviprone (Modeyso) in H3 K27M-mutant diffuse midline gliomas.
While the chaperonin-containing TCP-1 (CCT) complex is essential for proteostasis, the distinct roles of individual subunits in tumor immune regulation remain unclear. Here, we identify CCT7 as a previously unrecognized regulator of immune evasion in lung adenocarcinoma (LUAD). Integrative analyses of TCGA and GEO cohorts revealed that CCT7 is markedly upregulated in LUAD and is associated with poor patient prognosis. Functional studies demonstrated that CCT7 knockdown inhibited tumor cell proliferation and migration and enhanced cisplatin-induced apoptosis, yet paradoxically impaired T-cell activation. Mechanistically, transcriptomic and biochemical analyses revealed that CCT7 depletion activated the DR5–MKK4–JNK–c-Jun signaling cascade, resulting in the transcriptional upregulation of PD-L1. Disruption of DR5 or JNK signaling effectively abrogated PD-L1 induction. In contrast, CCT2 depletion exerted the opposite effect by suppressing the DR5–JNK–c-Jun–PD-L1 signaling axis and enhancing T-cell activation. Collectively, these findings reveal unexpected functional divergence among TRiC/CCT subunits and identify the CCT7–DR5–JNK–c-Jun signaling axis as a previously unrecognized mechanism regulating PD-L1-mediated immune evasion, highlighting the potential therapeutic relevance of this signaling axis in LUAD.
Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Although lysosomal substrate storage represents the primary molecular defect, accumulating evidence indicates that disease progression is driven by interconnected mechanisms, including chronic inflammation, oxidative stress, endothelial dysfunction, and impaired autophagy, leading to progressive multisystem involvement. The marked clinical heterogeneity of Fabry disease, together with nonspecific early manifestations, frequently delays diagnosis and complicates patient stratification and therapeutic decision-making. While advances in biomarkers, genetic testing, and imaging have improved disease recognition, current diagnostic approaches remain insufficient to fully capture disease complexity. Precision medicine is therefore emerging as a promising strategy through the integration of clinical, molecular, imaging, and multi-omics data. In this context, artificial intelligence (AI) offers novel opportunities for early diagnosis, biomarker discovery, risk stratification, and prediction of therapeutic response. This review provides an integrated overview of the molecular mechanisms, inflammatory pathways, clinical manifestations, and precision diagnostic strategies underlying Fabry disease, highlighting how AI-driven approaches may accelerate the transition toward more accurate, personalized, and predictive disease management.
Leukemia progression is increasingly shaped by reciprocal interactions between leukemic cells and the bone marrow microenvironment, yet the extracellular regulatory networks associated with these interactions remain incompletely understood. Here, we investigated the biological context associated with the antileukemic activity of LCC-10 (NSC765599), a synthetic biphenyl benzamide derivative, using an integrated pharmacogenomic and structure-guided computational framework. Antiproliferative activity was first characterized using the NCI-60 screen and subsequently integrated with pharmacogenomic response similarity analysis, baseline transcriptomic profiling, similarity-based target prediction, systems-level network analysis, molecular docking, coarse-grained molecular dynamics simulations, comparative in silico ADMET evaluation, and zebrafish embryo developmental toxicity assessment. LCC-10 exhibited potent antiproliferative activity across leukemia cell lines, with submicromolar GI50 values in five of six models. Computational analyses converged on a matrix metalloproteinase (MMP)-associated extracellular matrix (ECM) regulatory network, with MMP2 and MMP9 among the recurrently implicated candidates. Structure-guided analyses suggested structural compatibility of LCC-10 with representative MMP catalytic domains but did not establish direct biochemical inhibition or target engagement. Comparative in silico ADMET analyses supported the predicted developability profile of LCC-10, whereas zebrafish embryo assays indicated concentration-dependent developmental tolerability within the tested range. Collectively, these findings associate LCC-10 with an MMP-associated ECM regulatory network in leukemia while defining this relationship as a hypothesis requiring direct experimental validation. This integrated framework provides a rationale for subsequent biochemical, target-engagement, and functional studies to clarify the molecular basis of LCC-10 activity.
This study utilized a genetically engineered mouse model deficient in the small GTPase Rap1A (knockout/Rap1A-null) to understand the biological role of Rap1A in the heart. We examined differential protein expression in the left ventricle of Rap1A-null versus wild-type control C57BL/6 male mice (~5 months) using proteomics (nanoLC-MS/MS quantitative analysis), and in the whole heart of aged male mice (~16 months) using MAL-DI-TOF/TOF mass spectrometry. Additionally, we used an experimental model of acute cardiovascular stress and assessed the impact on heart tissue histology, gene expression and mortality risk. Rap1A-deficient hearts showed reduced size and reduced heart and left ventricular weights. Significantly reduced gene expression of extracellular matrix collagen type I and collagen type III was present under baseline and cardiovascular stress conditions. Assessment of the proteomic profile identified a crucial role of Rap1A in promoting healthy ventricular myocardium, as its deficiency exhibited increased impact on cytoskeletal, mitochondrial, metabolic and contractile protein expression in young and aged mice. In young Rap1A-deficient mice, overrepresentation analysis revealed markers myosin heavy chain 7 (β-MHC) and alpha-actinin-2 (α-actinin-2) associated with cardiomyopathies, and upon cardiac stress, showed mortality risk compared to controls. Altogether, these findings provide important insights into the role of Rap1A in cardiac structure and remodeling under basal and stress conditions in male mice.
Cancer immunotherapy has transformed the treatment of multiple malignancies; however, primary and acquired resistance remain major clinical challenges. Because effective immune recognition depends on the repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules, increasing attention has focused on the antigen processing and presentation pathway as a therapeutic target to enhance tumor immunogenicity. Among its key regulators, the endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 shape the MHC-I immunopeptidome by trimming peptide precursors before antigen presentation. Beyond this canonical function, accumulating evidence indicates that ERAP aminopeptidases are multifunctional proteins involved in inflammation, angiogenesis, ER stress responses, cell migration, and tumor-intrinsic signaling. These moonlighting activities suggest that ERAP enzymes influence cancer progression through both immune-dependent and immune-independent mechanisms. Recent advances in medicinal chemistry have enabled the development of selective ERAP1 inhibitors, leading to the first clinical evaluation of this therapeutic strategy and providing early clinical evidence that pharmacological modulation of antigen processing may complement existing immunotherapies. In this review, we summarize the multiple functions of ERAP aminopeptidases in cancer, discuss their role in regulating adaptive and innate immune responses, and highlight emerging therapeutic strategies and future challenges for exploiting ERAP-targeted interventions in precision immuno-oncology.
This manuscript is the corrected version of a previously published paper. Glucose uptake by mammalian cells is a key mechanism to maintain cell and tissue homeostasis and relies mostly on plasma membrane-localized glucose transporter proteins (GLUTs). Two main cellular mechanisms regulate GLUT proteins in the cell: first, expression of GLUT genes is under dynamic transcriptional control and is used by cancer cells to increase glucose availability. Second, GLUT proteins are regulated by membrane traffic from storage vesicles to the plasma membrane (PM). This latter process is triggered by signaling mechanisms and is well studied in the case of insulin-responsive cells, which activate protein kinase AKT to phosphorylate TBC1D4, a RAB-GTPase–activating protein involved in membrane traffic regulation. Previously, we identified protein kinase WNK1 as another kinase able to phosphorylate TBC1D4 and regulate the surface abundance of the constitutive glucose transporter GLUT1. Here we describe that downregulation of WNK1 through RNA interference in HEK293 cells led to a two-fold decrease in cell-surface GLUT1 abundance, concomitant with a 40% decrease in glucose uptake. By mass spectrometry, we identified serine (S) 704 in TBC1D4 and also S565 in its paralogue TBC1D1 as candidate WNK1 phosphorylation sites. Transfection of the respective phosphomimetic or unphosphorylatable TBC1D mutants into cells revealed that both affected the cell-surface abundance of GLUT1. The results reinforce a regulatory role for WNK1 in GLUT1 trafficking and glucose uptake and may have potential impact for the understanding of metabolic dysregulation, as observed in many cancer cells or insulin-responsive cell types.
Background: Differences in gene expression between inflammatory-like (iEOS-like) and resident-like (rEOS-like) eosinophil subtypes, and in eosinophil-derived serum mediators, may reflect eosinophil functional activity and their potential role in the pathogenesis of allergic asthma (AA). Methods: Twenty-three patients with non-severe AA and thirteen healthy subjects (HS) were examined. AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus and were re-evaluated 24 h later. Blood eosinophils were isolated by gradient centrifugation and magnetic separation, followed by subtyping based on CD62L expression. Gene expression was assessed by TaqMan-based quantitative PCR. Serum eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Galectin-10 (Gal10), and NADPH oxidase 2 (NOX2) were measured using ELISA. Results: Blood eosinophil subtypes from AA patients showed significantly higher expression of CLC, ECP, EPX, EDN, MBP, ALOX5, NOX2, and TGF-β1 compared to those from HS (p < 0.05), with no significant changes in LTA4H and LTC4S. iEOS-like cells in AA patients exhibited higher CLC and EPX expression compared to rEOS-like cells, (p < 0.05). Following BAC, CLC, MBP, and TGF-β1 expression increased in both eosinophil subtypes, while EPX and NOX2 increased only in iEOS-like cells (all p < 0.05). Serum ECP, EDN, and Gal10 concentrations were elevated in AA compared to HS and further increased after BAC (all p < 0.05); serum NOX2 remained unchanged. Conclusions: BAC induces a late-phase eosinophilic response in AA characterized by a partially eosinophil subtype-specific increase in gene expression and in circulating eosinophil-derived mediators. An increase in Gal10, observed at the CLC transcript level in eosinophils and in serum—but not in ECP or EDN—suggests the existence of mediator-specific mechanisms that regulate gene expression and extracellular release.
Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3′UTR (“del2.5”) that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as an important class of medications for managing type 2 diabetes and obesity, with cardiovascular outcome trials demonstrating reductions in major adverse cardiovascular events (MACEs) for several agents. The SELECT trial, which enrolled 17,604 participants with established cardiovascular disease and overweight or obesity but without diabetes, showed a 20% reduction in MACEs with semaglutide compared with placebo. Importantly, mediation analyses indicated that weight loss accounted for approximately one-third of this cardiovascular benefit, suggesting that additional mechanisms contribute substantially to the observed risk reduction. The temporal dissociation between weight loss and early MACEs reduction supports the hypothesis that GLP-1RAs exert direct vascular protective effects independent of their metabolic actions. This review synthesizes current evidence on the thromboinflammatory mechanisms through which GLP-1RAs may exert their cardiovascular benefits, with particular emphasis on the neutrophil–NET axis, platelet function, and plaque stabilization. Overall, thromboinflammation represents a biologically reasonable candidate mechanism, but its contribution to the cardiovascular benefit of GLP-1RAs treatment is an open question. Still, residual treatment effects cannot be attributed specifically to thromboinflammation, because metabolic, renal, hemodynamic, and vascular pathways, among others, may also contribute.
SLAMF1 encodes CD150, an immunoregulatory receptor involved in lymphocyte activation, T–B-cell interactions, and humoral immune responses. The SLAMF1 promoter polymorphism rs2295613(G>A) was previously associated with systemic lupus erythematosus (SLE) susceptibility in a Chinese case–control cohort. Here, we investigated the regulatory activity of rs2295613 in the transformed B-cell lines Raji and MP1 and in primary human CD19+ B cells. The rs2295613(A)-containing reporter showed higher promoter activity than the rs2295613(G)-containing reporter in all three cellular systems. Bioinformatic analysis predicted that the G to A substitution strengthens a pre-existing MYC-compatible motif. Substitutions disrupting the motif-containing region attenuated the rs2295613(A)-associated increase in reporter activity and reduced enrichment of the promoter fragment in anti-c-MYC DNA pull-down assays. Partial siRNA-mediated reduction in MYC mRNA also decreased the activity of the rs2295613(A)-containing reporter in Raji cells. Together, these findings identify rs2295613 as a functional SLAMF1 promoter variant in B-cell reporter systems and support a contribution of c-MYC-associated regulation to the enhanced activity of the rs2295613(A)-containing promoter.
Hispanics of Mexican American descent in South Texas show a very high prevalence of MASLD, with some studies reporting rates as high as 50% in adults. However, assessment of genetic risk factors underlying this prevalence is complicated by a high co-occurrence of other metabolic disorders and variable endogenous and exogenous environmental risk factors. To map the transcriptomic architecture of MASLD hepatic steatosis risk, we conducted an epidemiological-scale investigation using human induced pluripotent stem cell (iPSC)-derived hepatocyte cultures from 193 participants in our longitudinal South Texas Family Study (STFS). iPSC-based models offer greater power to map genetic risk factors by experimentally controlling for confounding organismal and environmental factors. We combined transcriptome-wide gene expression analysis with high-content cellular measurements of neutral lipids to define a core hepatic steatosis MASLD phenotype at baseline (vehicle-treated) and following a lipid challenge. The additive genetic heritability of hepatic steatosis measures was 0.44 (p-value = 0.03) at baseline and 0.42 (p-value = 0.03) at post-lipid challenge. Multivariable linear regression comparing each gene’s expression against hepatic steatosis measures identified 1070 genes at baseline and 1229 genes post-lipid challenge, whose expression showed a transcriptome-wide statistically significant association (standardized |β| ≥ 0.24; Bonferroni-corrected p-value ≤ 0.001) with baseline and post-lipid challenge hepatic steatosis measures, respectively. Functional annotation and pathway enrichment analyses of these genes implicated a broad range of hepatocellular functions, mapping an overall transcriptomic architecture of MASLD-associated steatosis risk in Mexican Americans. The genes whose expression was positively correlated with hepatic steatosis measures suggest a direct role of variation in fatty acid (FA) and cholesterol uptake, de novo lipogenesis (DNL), and carbohydrate shunts in hepatic steatosis risk, as well as a cellular stress-associated and high-turnover metabolic state marked by elevated FA-oxidation and ketogenesis. In contrast, the genes whose expression was inversely correlated with hepatic steatosis measures suggest a significant role of the cellular cytoskeleton, hepatocyte epithelial integrity, and endosomal and autophagic clearance machinery in steatosis risk.
