Search Results (493)

Cardiovascular diseases (CVDs) have emerged as a common health problem. However, despite their prevalence, little progress has been made in their treatment. In recent years, neurotrophic factors (NTFs) have been discovered to exert cardioprotective functions for CVDs. NTFs can modulate vascular integrity, myocardial remodeling, angiogenesis, and autonomic regulation, playing the roles of maintaining cardiovascular homeostasis and influencing disease progression. Under pathological conditions, the supplement of NTFs can induce substantial adaptations to mitigate adverse cardiac responses. Several NTFs have been investigated in this regard. This review briefly elaborates on present insights into the expression, signaling pathways, and regulatory effects of NTFs on the development of CVDs, and also discusses emerging therapeutic strategies based on NTFs, ranging from exercise to advanced modalities including stem cell therapy, gene transfer, recombinant protein therapy and NTF mimetics, among which the mimetics and exercise interventions emerge as the most promising avenues for clinical translation. Full article

(1) Background: The transcription factor p73 exists in multiple isoforms with divergent functions in cancer. While DNp73 promotes stemness, epithelial–mesenchymal transition (EMT), and metastasis, the tumor-suppressive isoform TAp73 can also switch to promoting cancer progression. How isoforms sharing the same DNA-binding domain produce divergent outcomes remains unclear. (2) Methods: Here, we performed CUT&RUN in combination with JASPAR, transcriptomics, proteomics, patient survival and gene expression data to map genome-wide and promoter-associated DNA-binding and coregulatory transcription factor (coTF) profiles of TAp73α and DNp73β in melanoma cells. (3) Results: Systematic screening for motif enrichment in cancer hallmark gene sets revealed TAp73- and DNp73-specific coTF repertoires with distinct functions. We identified a coregulator signature for EMT genes enriched for both isoforms that has tumor context-dependent effects on survival and correlates with unfavorable patient prognosis. Of these EMT-associated coTFs, PATZ1 was validated as a novel direct interactor of DNp73β. (4) Conclusions: Our results provide a comprehensive reference map of p73 isoform-specific binding and coregulator recruitment and establish a workflow to model their influence on cancer reprogramming with implications for AI-based individualized therapy. Full article

Kynurenic acid (KYNA), a small molecule derived from the tryptophan–kynurenine pathway, can readily diffuse across biological membranes and act as an endogenous ligand for receptors such as the aryl hydrocarbon receptor (Ahr). While KYNA dysregulation is implicated in neurodegenerative disorders, the role of the KYNA–Ahr-IL-6 axis in MSC proliferation and differentiation remains poorly defined. We investigated the impact of KYNA on murine bone marrow-derived MSCs (BM-MSCs) at various concentrations (10–200 μM) and time points (8–48 h). The BM-MSC phenotype was assessed via flow cytometry; proliferation, via cell counting; and the gene expression of Ahr, Cyp1a1, Cyp1b1, and Il-6, via quantitative real-time PCR. Multipotency was evaluated through adipogenic, osteogenic, and chondrogenic differentiation assays with histochemical confirmation. KYNA significantly upregulated Ahr mRNA expression. Among the tested concentrations, 100 μM KYNA induced the highest Ahr expression (~19.1 ± 1.5-fold greater than that of the untreated controls, p < 0.005). Notably, 10 and 50 μM KYNA caused moderate induction, whereas compared with 100 μM KYNA, 200 μM did not further increase expression. In addition, KYN treatment increased Cyp1a1, Cyp1b1, and Il-6 expression, with increases of ~64.6 ± 4.5-fold, ~43.6 ± 2.3-fold, and ~41.6 ± 1.2-fold, respectively. Compared with no treatment, 100 µM KYNA enhanced BM-MSC proliferation by 1.210 ± 0.02, 1.189 ± 0.03, and 1.242 ± 0.02-fold across passages P3, P4, and P5, respectively (p < 0.05), without altering Sca-1, CD90, or CD45 expression or impairing trilineage differentiation potential. KYNA may activate the AHR–IL-6 signaling axis to promote BM-MSC expansion. This controlled proliferative effect, without loss of phenotypic or functional integrity, highlights the pharmacological potential of KYNA as a small-molecule modulator for stem cell-based therapies. Full article

This narrative review examines degenerative disc disease (DDD), a major cause of chronic back pain and disability worldwide. It is a multifactorial condition resulting from a complex interplay of genetic, mechanical, metabolic, and environmental factors that progressively impair disc structure and function. The pathophysiology of DDD involves disruption of extracellular matrix homeostasis, cellular senescence, oxidative stress, and chronic inflammation mediated by cytokines such as IL-1β, TNF-α, and IL-6. These processes are further modulated by signalling pathways including NF-κB, MAPK, and Wnt/β-catenin, leading to matrix degradation, dehydration, and loss of disc height. Epidemiological studies highlight the contribution of lifestyle and metabolic disorders, such as obesity, smoking, and diabetes, to disease progression. Traditional conservative and surgical treatments primarily alleviate symptoms but do not halt or reverse degeneration. In contrast, recent advances in molecular biology and regenerative medicine have opened new therapeutic avenues. Mesenchymal stem cell therapy, biomaterial scaffolds, and gene-based interventions aim to restore disc homeostasis by promoting matrix synthesis and suppressing catabolic activity. Despite promising experimental results, clinical translation remains limited by challenges in cell viability, delivery methods, and long-term efficacy. Future research integrating molecular, biomechanical, and regenerative strategies offers the potential for true biological repair and disc regeneration. Full article

Haemoglobinopathies, including β-thalassaemia and sickle cell disease (SCD), are among the most common monogenic disorders worldwide and remain major causes of morbidity and early mortality. Historically, management of these life-altering diseases has relied on supportive treatment and symptom management and, although these treatments reduce symptoms and ease disease burden, they do not correct the underlying genetic defect. Allogenic haematopoietic stem cell transplantation (HSCT) has been the only established curative option; however, it comes with substantial risks that significantly restrict its applicability. Over the past two decades, haematopoietic stem cell (HSC) gene therapy for haemoglobinopathies has rapidly progressed from experimental proof-of-concept to approved therapies. Lentiviral gene addition approaches have demonstrated durable expression of functional β-like globin transgenes, achieving transfusion independence in β-thalassaemia patients and significant reductions in vaso-occlusive events in SCD patients. Alternative therapeutic approaches to promote HbF expression have proved to be highly successful. Gene silencing strategies targeting BCL11A have been successful clinically and, more recently, gene editing technologies such as CRISPR/Cas9 have enabled precise disruption of regulatory elements controlling γ-globin repression, leading to the approval of the first CRISPR-based therapy for SCD and β-thalassaemia. Emerging base editing technologies promise even more precise genetic modification and are advancing through clinical evaluation. Despite these advances, access to gene therapy remains restricted due to the need for highly specialised manufacturing, toxic myeloablative conditioning regimens, and high treatment costs. Ongoing improvements and adaptations in these areas are essential to ensure that gene therapies fulfil their potential as accessible, curative treatments for patients suffering from haemoglobinopathies worldwide. Full article

Glioblastoma (GBM) is one of the most common and aggressive primary malignant tumors of the central nervous system, accounting for about half of all gliomas in adults. Despite intensive research and advances in molecular biology, genomics, and modern neuroimaging techniques, the prognosis for patients with GBM remains extremely poor. Despite the implementation of multimodal treatment involving surgery, radiotherapy, and chemotherapy with temozolomide, the average survival time of patients is only about 15 months. This is primarily due to the complex biology of this cancer, which involves numerous genetic and epigenetic abnormalities, as well as a highly heterogeneous tumor structure and the presence of glioblastoma stem cells with self renewal capacity. Mutations and abnormalities in genes such as IDH-wt, EGFR, PTEN, TP53, TERT, and CDKN2A/B are crucial in the pathogenesis of GBM. In particular, IDH-wt status (wild-type isocitrate dehydrogenase) is one of the most important identification markers distinguishing GBM from other, more favorable gliomas with IDH mutations. Frequent EGFR amplifications and TERT gene promoter mutations lead to the deregulation of tumor cell proliferation and increased aggressiveness. In turn, the loss of function of suppressor genes such as PTEN or CDKN2A/B promotes uncontrolled cell growth and tumor progression. The immunosuppressive tumor microenvironment also plays an important role, promoting immune escape and weakening the effectiveness of systemic therapies, including immunotherapy. The aim of this review is to summarize the current state of knowledge on the epidemiology, classification, pathogenesis, diagnosis, and treatment of glioblastoma multiforme, as well as to discuss the impact of recent advances in molecular and imaging diagnostics on clinical decision-making. A comprehensive review of recent literature (2018–2025) was conducted, focusing on WHO CNS5 classification updates, novel biomarkers (IDH, TERT, MGMT, EGFR), and modern diagnostic techniques such as liquid biopsy, radiogenomics, and next-generation sequencing (NGS). The results of the review indicate that the introduction of integrated histo-molecular diagnostics in the WHO 2021 classification has significantly increased diagnostic precision, enabling better prognostic and therapeutic stratification of patients. Modern imaging techniques, such as advanced magnetic resonance imaging (MRI), positron emission tomography (PET), and radiomics and radiogenomics tools, allow for more precise assessment of tumor characteristics, prediction of response to therapy, and monitoring of disease progression. Contemporary molecular techniques, including DNA methylation profiling and NGS, enable in-depth genomic and epigenetic analysis, which translates into a more personalized approach to treatment. Despite the use of multimodal therapy, which is based on maximum safe tumor resection followed by radiotherapy and temozolomide chemotherapy, recurrence is almost inevitable. GBM shows a high degree of resistance to treatment, which results from the presence of stem cell subpopulations, dynamic clonal evolution, and the ability to adapt to unfavorable microenvironmental conditions. Promising preclinical and early clinical results show new therapeutic strategies, including immunotherapy (cancer vaccines, checkpoint inhibitors, CAR-T therapies), oncolytic virotherapy, and Tumor Treating Fields (TTF) technology. Although these methods show potential for prolonging survival, their clinical efficacy still needs to be confirmed in large studies. The role of artificial intelligence in the analysis of imaging and molecular data is also increasingly being emphasized, which may contribute to the development of more accurate predictive models and therapeutic decisions. Despite these advancements, GBM remains a major therapeutic challenge due to its high heterogeneity and treatment resistance. The integration of molecular diagnostics, artificial intelligence, and personalized therapeutic strategies that may enhance survival and quality of life for GBM patients. Full article

Mesenchymal stromal/stem cells (MSCs) appear in many studies, and their utilization is a developing area of study. Scientists are investigating the abilities of MSCs and the possibilities of using them in anticancer therapies, as well as combining such therapies with those currently used clinically. This article provides an overview of MSC-based therapeutic strategies, assessing their potential in the context of cancer treatment. These are engineering or biotechnological approaches that utilize the natural properties of MSCs in a targeted and therapeutically effective manner. The review focuses on innovative methods such as genetic modifications to express desired therapeutic molecules, highlighting their potential applications in clinical practice. Innovative strategies include modifications to express anticancer proteins, miRNA (microRNA), siRNA (small interfering RNA), lncRNA (long non-coding RNA), and circRNA (circular RNA) that induce specific effects, as well as the delivery of therapeutic genes and oncolytic viruses. However, further studies are required to address the existing impediments, which are also discussed in this review. A major challenge in the clinical application of MSCs is their bidirectional role, an issue that remains a central focus of current research and is examined in this article. Full article

Hypertrophic cardiomyopathy (HCM) is a common and deadly cardiac disease characterized by enlarged myocytes, increased myocardial wall thickening, and fibrosis. A majority of HCM cases are associated with mutations in the β-myosin heavy chain (MYH7) converter domain locus, which leads to varied pathophysiological and clinical manifestations. Using base-editing technology, we generated mutant human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harboring HCM-causing myosin converter domain mutations (MYH7 c.2167C>T [R723C]; MYH6 c.2173C>T [R725C]) to define HCM pathogenesis in vitro. In this study, we integrated transcriptomic analysis with phenotypic and molecular analyses to dissect the HCM disease mechanisms using MYH6/7 myosin mutants. Our KEGG analysis of bulk RNA-sequencing data revealed significant upregulation of transcripts associated with HCM in the mutant hiPSC-CMs. Further, in-depth transcriptomic analysis using Gene-Ontology (GO-term) analysis for biological process showed upregulation of several transcripts associated with heart development and disease. Notably, our analysis showed robust upregulation of cytoskeletal transcripts, including actin-cytoskeleton networks, sarcomere components, and other structural proteins in the mutant CMs. Furthermore, cellular and nuclear morphological analysis showed that the MYH6/7 mutation induced cellular hypertrophy and increased aspect ratio compared to the isogenic control. Immunostaining experiments showed marked sarcomere disorganization with lower sarcomeric order and higher dispersion in the mutant hiPSC-CMs, highlighting the remodeling of the myofibril arrangement. Notably, the MYH6/7 mutant showed reduced cortical F-actin expression and increased central F-actin expression compared to the isogenic control, confirming the cytoskeletal remodeling and sarcomeric organization during HCM pathogenesis. These pathological changes accumulated progressively over time, underscoring the chronic and evolving nature of HCM driven by the MYH6/7 mutations. Together, our findings provide critical insights into the cellular and molecular underpinnings of MYH6/7-mutation-associated disease. These findings offer valuable insights into HCM pathogenesis, aiding in future therapies. Full article

Background/Objectives: Sickle cell disease (SCD) and β-thalassemia are autosomal recessive disorders of erythroid cells due to gene mutations occurring at the level of the β-globin gene. The severe forms of these hemoglobinopathies observed in individuals homozygous for these defective genes need intensive treatments, are associated with a poor quality of life, and allogeneic hematopoietic stem cell represents the only curative treatment option that can be offered to a limited proportion of patients. Methods: This work is a narrative review supported by a systematic literature search and analysis. Results: To bypass this limitation, autologous hematopoietic stem cell transplantation has been developed in these patients, in which patients’ HSCs are harvested and genetically modified ex vivo, then transplanted back into patients after conditioning for stem cell transplantation. There are two different approaches for gene therapy of hemoglobinopathies, one based on gene addition or gene silencing using lentiviruses as vectors and the other based on gene editing strategies using CRISPR-Caspase 9 technology or base editing. Several gene therapy products have been successfully evaluated in these patients, achieving transfusion independence and correction of hematological abnormalities durable over time. Conclusions: Several gene therapy products have been approved for the treatment of SCD and β-thalassemic patients and offer potentially curative treatment for these patients. Full article

Organ fibrosis is a progressive and often irreversible pathological process characterized by excessive deposition of extracellular matrix, leading to tissue dysfunction and failure. Despite its significant impact on various organ systems, available antifibrotic therapies remain limited. This review focuses on novel therapeutic approaches to inhibit fibrosis and improve clinical outcomes. Current strategies include small molecule inhibitors, monoclonal antibodies targeting fibrosis mediators, gene therapies, and cell-based approaches, including mesenchymal stem cells and induced pluripotent stem cells. In addition, the development of innovative drug delivery systems and combination therapies involving pulsed magnetic fields (PMFs) opens new possibilities for increasing the precision and efficacy of treatment. In recent years, multiomic approaches have enabled a better understanding of fibrosis mechanisms, facilitating the personalization of therapy. The role of artificial intelligence in drug discovery has also increased, as exemplified by models that support the design of small-molecule inhibitors currently undergoing clinical evaluation. This review discusses key signaling pathways involved in fibrosis progression, such as TGF-β, p38 MAPK, and fibroblast activation, as well as novel therapeutic targets. Although clinical trial results indicate promising potential for new therapies, challenges remain in optimizing drug delivery, considering patient heterogeneity, and ensuring long-term safety. The future of fibrosis therapy relies on integrating precision medicine, combination therapies, and molecularly targeted strategies to inhibit or even reverse the fibrosis process. Further intensive interdisciplinary collaboration is required to successfully implement these innovative solutions in clinical practice. Full article

Background: Cancer-associated fibroblasts (CAFs) are key components of the glioblastoma (GBM) microenvironment and contribute to tumor progression, immune evasion, and therapy resistance. However, their heterogeneity and clinical impact in GBM remain poorly defined. Methods: We performed an integrative transcriptomic analysis combining bulk and single-cell RNA sequencing (scRNA-seq) datasets to characterize CAF subtypes in GBM. Four CAF-associated transcriptional programs were defined based on canonical gene signatures: immune CAFs, myofibroblastic CAFs (myoCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). Prognostic relevance was assessed using survival analyses, and hub genes were identified through network analysis. Results: CAF subtype-specific gene signatures were significantly associated with poor overall survival. Single-cell analysis revealed spatial heterogeneity of CAF activation, with immune and inflammatory CAF markers enriched in low-stemness tumor cells. SYK was identified as a central hub gene shared across CAF subtypes, suggesting its role in stromal signaling. Conclusions: Our study reveals CAF subtype-associated patterns with prognostic and functional relevance in GBM. Targeting CAF subpopulations and key mediators such as SYK may represent a promising therapeutic strategy in GBM. Full article

This article aims to point out new perspectives opened by genomics and epigenomics in skin rejuvenation strategies which target the main hallmarks of the ageing. In this respect, this article presents a concise overview on: the clinical relevance of the most important clocks and biomarkers used in skin anti-ageing strategy evaluation, the fundamentals, the main illustrating examples preclinically and clinically tested, the critical insights on knowledge gaps and future research perspectives concerning the most relevant skin anti-ageing and rejuvenation strategies based on novel epigenomic and genomic acquisitions. Thus the review dedicates distinct sections to: senolytics and senomorphics targeting senescent skin cells and their senescent-associated phenotype; strategies targeting genomic instability and telomere attrition by stimulation of the deoxyribonucleic acid (DNA) repair enzymes and proteins essential for telomeres’ recovery and stability; regenerative medicine based on mesenchymal stem cells or cell-free products in order to restore skin-resided stem cells; genetically and chemically induced skin epigenetic partial reprogramming by using transcription factors or epigenetic small molecule agents, respectively; small molecule modulators of DNA methylases, histone deacetylases, telomerases, DNA repair enzymes or of sirtuins; modulators of micro ribonucleic acid (miRNA) and long-non-coding ribonucleic acid (HOTAIR’s modulators) assisted or not by CRISPR-gene editing technology (CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats); modulators of the most relevant altered nutrient-sensing pathways in skin ageing; as well as antioxidants and nanozymes to address mitochondrial dysfunctions and oxidative stress. In addition, some approaches targeting skin inflammageing, altered skin proteostasis, (macro)autophagy and intercellular connections, or skin microbiome, are very briefly discussed. The review also offers a comparative analysis among the newer genomic/epigenomic-based skin anti-ageing strategies vs. classical skin rejuvenation treatments from various perspectives: efficacy, safety, mechanism of action, evidence level in preclinical and clinical data and regulatory status, price range, current limitations. In these regards, a concise overview on senolytic/senomorphic agents, topical nutrigenomic pathways’ modulators and DNA repair enzymes, epigenetic small molecules agents, microRNAs and HOTAIRS’s modulators, is illustrated in comparison to classical approaches such as tretinoin and peptide-based cosmeceuticals, topical serum with growth factors, intense pulsed light, laser and microneedling combinations, chemical peels, botulinum toxin injections, dermal fillers. Finally, the review emphasizes the future research directions in order to accelerate the clinical translation of the (epi)genomic-advanced knowledge towards personalization of the skin anti-ageing strategies by integration of individual genomic and epigenomic profiles to customize/tailor skin rejuvenation therapies. Full article

Tumor stemness represents a key biological process that drives tumor progression and therapeutic resistance across various cancer types. To systematically elucidate the regulatory roles of long non-coding RNAs (lncRNAs) in this process, we integrated bulk transcriptomic data from The Cancer Genome Atlas (TCGA) with publicly available pan-cancer single-cell transcriptomic atlases. Using machine-learning-based stemness metrics, we successfully quantified stemness features and identified unique lncRNA gene sets for each cancer type at the bulk data level. The high-stemness subtype exhibited enhanced proliferation, an immunosuppressive microenvironment, and profound metabolic reprogramming. Based on these findings, we constructed a robust prognostic model with remarkable predictive performance across multiple cancer types. At the single-cell resolution, we reconstructed the dynamic trajectory of stemness evolution, uncovering distinctive metabolic and cell-communication patterns within cancer stem cells (CSCs). This multi-scale analysis consistently nominated a core set of regulatory lncRNAs, including NEAT1 and MALAT1. Our work not only nominates potential targets for stemness-directed therapy but also provides a comprehensive framework for understanding lncRNA-driven mechanisms of cancer aggressiveness and resistance. Full article

Demyelinating diseases comprise a group of chronic and debilitating neurological disorders, with the destruction of the myelin sheath serving as the core pathological hallmark. The central pathogenesis involves immune-mediated damage to oligodendrocytes (Ols) and myelin breakdown, accompanied by a vicious cycle of neuroinflammation and impaired epigenetic repair. Current therapeutic strategies, including conventional immunomodulatory agents to targeted monoclonal antibodies, effectively control disease relapses but exhibit limited efficacy in promoting neural repair. Consequently, research focus is increasingly shifting towards neuroprotective and remyelination strategies. In this context, Emerging therapeutic promise stems primarily from two fronts: the advent of novel pharmaceuticals, such as remyelination-promoting drugs targeting oligodendrocyte maturation, interventions inhibiting epigenetic silencing, signal pathway inhibitors, and natural products derived from traditional Chinese medicine; the development of innovative technologies, including cell therapies, gene therapy, exosome and nanoparticle-based drug delivery systems, as well as extracellular protein degradation platforms. Nevertheless, drug development still faces challenges such as disease heterogeneity, limited blood–brain barrier penetration, long-term safety, and difficulties in translating findings from preclinical models. Future efforts should emphasize precision medicine, multi-target synergistic therapies, and the development of intelligent delivery systems, with the ultimate goal of achieving a paradigm shift from delaying disability progression to functional neural reconstruction. Full article

Background/Objectives: High-grade gliomas (HGGs), including glioblastomas, are among the most aggressive brain tumors due to their high intratumoral heterogeneity and extensive infiltration. Glioma stem-like cells (GSCs) frequently invade along white matter tracts such as the corpus callosum, but the molecular programs driving this region-specific invasion remain poorly defined. The aim of this study was to identify transcriptional signatures associated with GSC infiltration into the corpus callosum. Methods: We established an orthotopic xenograft model by implanting fluorescently labeled human GSCs into nude mouse brains. Tumor growth and invasion patterns were assessed using tissue clearing, light-sheet fluorescence microscopy, and histological analyses. To characterize region-specific molecular profiles, we performed microfluidic-based single-cell RNA expression analysis of 48 invasion- and stemness-related genes in cells isolated from the tumor bulk (TB) and corpus callosum (CC). Results: By six weeks post-implantation, GSCs displayed marked tropism for the corpus callosum, with distinct infiltration patterns captured by three-dimensional imaging. Single-cell gene expression profiling revealed significant differences in 7 of the 48 genes (14.6%) between TB- and CC-derived GSCs. These genes—NES, CCND1, GUSB, NOTCH1, E2F1, EGFR, and TGFB1—collectively defined a “corpus callosum invasion signature” (CC-Iv). CC-derived cells showed a unimodal, high-expression profile of CC-Iv genes, whereas TB cells exhibited bimodal distributions, suggesting heterogeneous transcriptional states. Importantly, higher CC-Iv expression correlated with worse survival in patients with low-grade gliomas. Conclusions: This multimodal approach identified a corpus callosum-specific invasion signature in glioma stem-like cells, revealing how local microenvironmental cues shape transcriptional reprogramming during infiltration. These findings provide new insights into the spatial heterogeneity of gliomas and highlight potential molecular targets for therapies designed to limit tumor spread through white matter tracts. Full article