Search Results (29,925)

The human genome produces a large repertoire of non-coding RNAs (ncRNAs) with important regulatory roles in development, physiology, and most of diseases. Among these, long non-coding RNAs (lncRNAs) have emerged as key modulators of gene expression, chromatin organization, and cellular homeostasis, despite displaying remarkably low primary-sequence conservation across species. This apparent evolutionary paradox questions the limitations of predicting biological function based on conservation, particularly across different biological domains. Here, we examine current evidence on lncRNA evolution, with a focus on their roles in metabolic regulation compared with neurobiological processes. We hypothesize that lncRNAs involved in ancient and conserved pathways such as metabolism may be under stronger evolutionary constraint than those associated with higher-order, species-specific traits, although available data support a more nuanced interpretation. Functional importance often correlates poorly with linear sequence conservation and instead appears to depend on higher-level features, including RNA secondary or tertiary structure, genomic context, regulatory architecture, and interactions with conserved molecular partners. We propose a systematic comparative framework to empirically assess conservation among metabolism- and neuro-associated lncRNAs using phylogenetic, syntenic, structural, and expression-based metrics. Finally, we discuss the therapeutic implications of lncRNA biology, highlighting how a deeper understanding of their evolutionary and mechanistic properties may inform the development of more precise and effective RNA-targeting strategies. Together, these insights underscore the non-coding transcriptome as a critical frontier for both fundamental biology and precision medicine. Full article

This narrative review examines topical anti-inflammatory therapies in veterinary medicine through the lens of the One Health framework, integrating pharmacology, dermatology, ecotoxicology, food safety, and regulatory science. It discusses the interconnected roles of veterinarians, pharmacists, environmental scientists, public health authorities, and regulatory bodies in addressing antimicrobial resistance, environmental contamination, zoonotic transmission, and drug residues in food-producing animals. By emphasising cross-sector collaboration, the review highlights how coordinated strategies can enhance animal welfare, safeguard human health, and reduce ecological burden. The article analyses inflammatory conditions in companion and farm animals and compares systemic versus topical anti-inflammatory approaches. Particular attention is given to corticosteroids, NSAIDs, immunomodulators, pro-resolving lipid mediators, and plant-derived bioactives, alongside advances in vehicles such as lipid nanocarriers and biodegradable film-forming systems designed to minimise systemic absorption and environmental dispersion. Regulatory considerations, residue control, pharmacovigilance gaps, and sustainability-oriented formulation strategies are critically addressed. Topical anti-inflammatory therapies, when rationally designed and monitored under One Health principles, represent a strategic opportunity to improve therapeutic precision while limiting systemic toxicity and ecological impact. Future directions should prioritise translational research, eco-compatible formulation design, and harmonised regulatory frameworks. Full article

Metabolic reprogramming plays a critical role in the pathogenesis of cardiovascular diseases. Historically regarded as a metabolic waste product, lactate has recently emerged as a critical regulator of vascular biology, exerting both metabolic and signaling functions. Moreover, the discovery of protein lactylation, a novel post-translational modification derived from lactate, has revealed a direct link between metabolic flux and gene regulation. This review provides a comprehensive overview of the evolving roles of lactate and lactylation in cardiovascular physiology and disease, offering insights into potential therapeutic interventions. It first provides a historical perspective of lactate and lactylation, followed by an overview of lactate metabolism, lactate shuttle theory and signaling pathways. It then discusses the mechanism and regulation of lactylation, focusing on its writers, erasers, and readers. Finally, this review summarizes clinical implications of lactate and lactylation in various cardiovascular diseases, including atherosclerosis, pulmonary hypertension, myocardial infarction, heart failure, and diabetic vascular complications. A deeper understanding of the mechanisms underlying the lactate–lactylation axis may facilitate the development of new therapeutic strategies to prevent or treat cardiovascular diseases. Full article

The efficacy of the host antiviral response against Influenza A virus (IAV), a leading cause of global pandemics, hinges upon the rapid recognition of the pathogen and the prompt activation of immune mechanisms. Nevertheless, the epigenetic landscape that orchestrates this antiviral response remains largely elusive. Here, we identify histone demethylase JMJD2D as a critical regulator in defense against IAV infection. A significant upregulation of JMJD2D expression was observed clinically in response to IAV infection, indicating that JMJD2D may play a role in regulating IAV infection. Indeed, JMJD2D-deficient mice exhibit increased susceptibility to IAV, characterized by elevated viral loads, severe lung tissue damage, and reduced survival rates, suggesting that JMJD2D plays an essential role in defense against IAV infection. Consistently, knockdown or pharmacological inhibition of JMJD2D in lung cells suppressed IAV replication and the IAV-triggered innate immune response. Mechanistically, JMJD2D suppressed IAV infection by removing H3K9me3 at the promoter region of retinoic acid inducible gene-I (RIG-I) and cooperating with NF-κB to enhance the expression of RIG-I, a critical sensor for IAV RNA. This study identifies JMJD2D as an epigenetic rheostat that governs RIG-I-mediated antiviral signaling, highlighting its potential as a therapeutic target for mitigating severe IAV infection. Full article

Neuropsychiatric conditions constitute a major and growing global health burden, with prevalence rates that continue to rise worldwide. Although these disorders have traditionally been studied primarily from a neuronal perspective, accumulating evidence indicates that immune dysregulation and inflammatory processes play a central role in their pathophysiology. In this review, we advance the hypothesis that nitric oxide (NO)-mediated alterations in blood–brain barrier (BBB) integrity represent a critical mechanistic link between inflammation and central nervous system dysfunction in neuropsychiatric disorders. NO is a gaseous multifunctional signaling molecule involved in vascular homeostasis and immune responses, and its dysregulated production, together with aberrant protein S-nitrosylation, has been implicated in several neuropsychiatric conditions. However, the specific mechanisms by which NO signaling contributes to BBB dysfunction remain incompletely defined. Here, we synthesize current evidence supporting a role for NO-dependent vascular and inflammatory pathways in BBB disruption and discuss how these processes may contribute to the onset and progression of neuropsychiatric conditions. Clarifying these mechanisms may provide novel insights into disease pathogenesis and identify therapeutic targets aimed at preserving BBB integrity and limiting neuroinflammation. Full article

Breast carcinoma is a major cause of cancer-related mortality among women worldwide. Identifying novel molecular targets remains essential, particularly for aggressive triple-negative breast cancer (TNBC). Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been linked to tumor progression and angiogenesis, but its molecular mechanisms in breast cancer are poorly defined. We evaluated the effects of recombinant human LRG1 (rhLRG1) on cell viability and migration in MDA-MB-231 TNBC cells and performed transcriptomic profiling followed by functional enrichment analyses using GenArise, Cytoscape, and R-based tools. RhLRG1 treatment significantly increased cell viability and migration. Transcriptomic analysis revealed activation of key oncogenic cascades, including the PI3K/AKT, MAPK, and RAS signaling pathways. Hub-gene analysis identified upregulated genes involved in proliferation (NRAS, STAT5B, IGF2), angiogenesis (PGF, ANGPT2), and apoptosis (CASP8, BAD), whereas downregulated genes were associated with apoptotic resistance (BCL2, MCL1) and adhesion (LAMB1, ITGB4). Functional enrichment highlighted LRG1’s role in the bioinformatic analysis of differentially expressed genes that were obtained from microarray assays. LRG1 remodels the tumor microenvironment by promoting proliferation, angiogenesis, and apoptotic sensitivity while repressing resistance-related genes. These findings position LRG1 as a potential diagnostic biomarker and therapeutic target for advanced breast carcinoma. Full article

Background and Clinical Significance: Mechanical complications and intracavitary thrombus are both recognized causes of clinical deterioration following acute myocardial infarction, yet they require fundamentally different therapeutic approaches. Distinguishing between these entities is critical, as misdiagnosis may lead to unnecessary surgical intervention or delayed anticoagulation with serious consequences. Left ventricular (LV) thrombus typically appears as a well-defined mass; however, atypical and highly mobile morphologies may closely mimic catastrophic post-infarction mechanical complications, creating significant diagnostic uncertainty. This case highlights the pivotal role of contrast-enhanced echocardiography in resolving such ambiguity and guiding appropriate management in a high-stakes clinical setting. Case Presentation: A 60-year-old man presented with acute dyspnea and pulmonary edema ten days after an anterior myocardial infarction treated with percutaneous coronary intervention, complicated by ischemic stroke. Transthoracic echocardiography demonstrated severe LV systolic dysfunction with moderate-to-severe mitral regurgitation and an unexpected, highly mobile, irregular mass protruding into the LV apex. The mass exhibited a shredded, tissue-like appearance, raising urgent concern for post-infarction mechanical complications, including papillary muscle rupture or apical myocardial disruption, and prompting immediate consideration of surgical intervention. Contrast-enhanced echocardiography was performed and revealed a mobile LV apical thrombus. Surgical management was avoided, and systemic anticoagulation was initiated, followed by transition to rivaroxaban in combination with ongoing dual antiplatelet therapy. The patient demonstrated rapid clinical improvement with optimized heart failure treatment and was discharged after four days, with planned follow-up imaging to assess thrombus resolution. Conclusions: Left ventricular thrombus may present with atypical, misleading morphologies that closely resemble life-threatening mechanical complications after myocardial infarction. Full article

Brain metastases remain a major problem for cancer patients, impacting their treatment and survival. The pathogenesis of brain metastases is largely unknown. Recent reports indicate that the adhesion molecule protocadherin γ C3 (PCDHGC3) is differentially expressed in various cancer cells and endothelial cells of the blood–brain barrier (BBB), suggesting its involvement in the development of brain metastases. Therefore, we generated a PCDHGC3 knockout (KO) in the triple-negative breast cancer cell line HCC1806 and the malignant melanoma cell line A2058. Control and KO cells were compared using cell proliferation, adhesion and invasion assays, gene expression analyses and matrix metalloproteinase (MMP) activity assays. While the PCDHGC3 KO mutation led to increased proliferation in HCC1806 cells, with no difference observed in A2058, it significantly increased adhesion to in vitro BBB models as well as invasion in both HCC1806 and A2058 KO cell lines. Although changes in mRNA expression of genes involved in metastasis, angiogenesis and cell adhesion were found in PCDHGC3 KO breast cancer and melanoma cells, the number of genes with significantly increased mRNA expression was higher in A2058 KO cells than in HCC1806 KO cells. While the mRNA expression of MMP1 and 2 was increased in A2058 KO cells, no significant changes were found in HCC1806 KO cells. However, increased MMP activity in the cell culture medium was detected in HCC1806 KO cells, while A2058 KO cells showed lower MMP-activity compared to control. These findings provide insights into the role of PCDHGC3 in cancer cell extravasation during metastatic process and identify potential therapeutic targets for further investigation. Full article

Background: The role of immune checkpoint inhibition in treating head and neck squamous cell carcinoma (HNSCC) is expanding, yet response rates to PD-L1 therapy remain inconsistent and generally poor. Although several studies have examined heterogeneous intratumoral PD-L1 expression, the disparity in response to PD-L1 therapy between primary tumors and their associated lymph node metastases remains unclear. Methods: Primary tumor samples and two matching lymph node metastases were obtained from a cohort of 50 patients and immunohistochemically stained with a PD-L1 antibody. PD-L1 expression, assessed using the combined positive score (CPS) and tumor proportion score (TPS), and immune infiltration, measured with an immunoreactive score (IRS), were compared between the primary tumor and lymph node metastases. These measures were then correlated with other histopathological and clinical features. Results: PD-L1 expression, evaluated by CPS and TPS, showed no significant differences between the primary tumor and matched lymph node metastases. Discordance relative to established regulatory cut-offs was observed in a subset of patients, affecting 18% (CPS; 95% CI, 8.0–30.0%) and 4% (TPS; 95% CI, 0.0–10.0%) of cases. CPS and TPS values were not influenced by primary tumor subsite or HPV status. Conversely, immune infiltration measured by IRS was significantly affected by primary tumor subsite location. Both HPV tumor status and primary tumor subsite were statistically significantly associated with overall survival. Conclusions: Our findings highlight variability in PD-L1 expression in HNSCC and may offer context for differential responses of primary tumors and lymph node metastases to immune checkpoint therapy reported in recent clinical studies. These observations support the need for a more comprehensive characterization of PD-L1 expression across tumor sites in head and neck cancer. Further investigation is required to determine whether, and in which settings, reassessment of PD-L1 status in metastatic lesions—including lymph node metastases—may provide additional clinically relevant information when initial testing does not meet established therapeutic cut-offs. Full article

Gypenoside XLIX is a bioactive saponin with reported diverse biological activities, including antioxidant, regulation of cell growth, immune responses, and metabolic regulatory properties. The increasing global prevalence of non-alcoholic fatty liver disease (NAFLD) underscores the importance of exploring novel therapeutic agents such as Gypenoside XLIX. NAFLD pathogenesis involves lipotoxicity, oxidative stress, and mitochondrial dysfunction, in which mitochondria-associated endoplasmic reticulum membranes (MAMs) play a critical role in organelle communication, calcium signaling, and lipid metabolism. This narrative review summarizes current evidence indicating that Gypenoside XLIX may modulate oxidative stress, restore mitochondrial membrane potential, and regulate calcium homeostasis, thereby indirectly influencing MAM integrity and function. These effects can reduce lipid accumulation, improve hepatocellular metabolism, and attenuate inflammatory responses. This review evaluates the mechanistic impact and function of Gypenoside XLIX on MAM integrity and its effects on NAFLD. However, there is limited direct experimental evidence linking Gypenoside XLIX to MAM regulation, and further studies are required to validate its mechanisms and therapeutic potential in clinical settings. Full article

Non-small-cell lung cancer (NSCLC) constitutes approximately all lung cancers (LCs), and metastasis remains a major challenge in its treatment, thus necessitating the detection of novel molecular players involved in this process. In this study, we performed a comprehensive analysis of microarray and RNA-seq cohorts extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) and associated them with metastasis-related genes involved in brain metastasis (BM) in NSCLC. We thus identified differentially expressed metastatic genes (DEMGs) and constructed a protein–protein interaction network (PPIN) using these DEMGs. These DEMGs were further analyzed for associations with patient age, gender, and tumor stage, and the significant impact of specific genes on overall survival (OS) was assessed to determine the prognostic significance of the identified targets. We finally constructed a three-node microRNA (miRNA) feed-forward loop (FFL) involving miR-23b-3p, CD44, and five transcription factors (TFs) [EOMES, FOS, FOSL1, GLIS3, TP63] specific to NSCLC metastasis. Further mutational analysis of these FFL elements revealed that all were altered in the patient samples analyzed. Thus, our study identified potential genomic drivers that may play crucial roles in NSCLC BM. Overall, it provides valuable insights for the discovery of novel therapeutic targets in the management of NSCLC metastasis. However, further in vitro and in vivo experimentations are needed to justify the prognostic role of NSCLC biomarkers in BM pathogenesis. Full article

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy. Full article

Vascular diseases impose a heavy global burden, yet existing therapies have limitations, necessitating novel drug targets. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, acts not only as an initiator of metabolic collapse but also as a sterile inflammatory trigger by releasing damage-associated molecular patterns (DAMPs) and activating pro-inflammatory pathways. In this paper, we propose the “ferroptosis–inflammation circuit” as a self-amplifying loop where ferroptosis fuels inflammation and the inflammatory microenvironment reciprocally promotes ferroptosis via cell type-specific mechanisms. Although ferroptosis in cardiovascular diseases has been reviewed, its immunopathological role in specific vascular diseases and how macrophages, neutrophils, T cells, and vascular cells collaboratively drive pathology through this circuit remains underexplored. The unique perspective of this review is a systematic focus on the dynamic interplay between ferroptosis and immune responses within the vascular wall, moving beyond static metabolic descriptions. We synthesize evidence linking ferroptosis to atherosclerosis, pulmonary hypertension, stroke, aneurysms, and aortic dissection, emphasizing its immunological dimension across cell types. By defining the ferroptosis–inflammation circuit and its cell type-specific patterns, we reposition ferroptosis as a core pathological hub that couples metabolic dysregulation, immune activation, and vascular remodeling. Understanding this circuit may open novel therapeutic avenues for targeting the ferroptosis–immune interface. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article

Accounting for over 1.2 million new diagnoses worldwide in 2022, non-melanoma skin cancer (NMSC) represents the most common human cancer, predominantly manifesting as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). NMSC serves as a powerful natural model for studying how environmental exposure, the exposome, reprograms the epigenome to drive carcinogenesis. Chronic ultraviolet radiation (UVR), the dominant risk factor, induces DNA damage and inflammation that dysregulate epigenetic enzymes (e.g., DNMTs, HDACs). These effects are layered with perturbations from β-HPV infection and cutaneous dysbiosis, altering DNA methylation, histone modifications, and non-coding RNA and miRNA expression in a multistep carcinogenic process. This review synthesizes the central role of epigenetic regulation as the critical interface between genetic susceptibility and cumulative exposome factors in NMSC pathogenesis. We integrate how UVR, HPV, and inflammation converge to remodel the keratinocyte epigenome. Finally, we evaluate the translational potential of this knowledge for refined risk stratification through epigenetic biomarkers and discuss emerging therapeutic strategies, including epidrugs, that target these dysregulated pathways for advanced NMSC management. Full article