Search Results (45)

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody–drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC. Full article

Vascular remodeling is a characteristic pathological feature of various vascular diseases, including atherosclerosis, restenosis following vascular injury, hypertension, and aneurysms. The phenotypic switching of vascular smooth muscle cells (VSMCs) acts as a key driver of vascular remodeling. Under specific pathological stimuli, VSMCs rapidly transition from a contractile to a dedifferentiated phenotype, characterized by enhanced proliferation, migration, and secretory activity. Chromatin remodeling, a core mechanism of epigenetic regulation, orchestrates dynamic changes in chromatin structure and function through ATP-dependent remodeling complexes, histone-modifying enzymes, and DNA methyltransferases. These components collectively translate mechanical stress, metabolic disturbances, and inflammatory signals into reversible epigenetic modifications, thereby precisely regulating VSMC phenotypic switching. As such, chromatin remodeling represents a critical node for therapeutic intervention in vascular remodeling-related diseases. In recent years, a growing body of research has focused on the role of chromatin remodelers in regulating VSMC phenotype. In this review, we focus on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression of VSMC phenotype switching. Firstly, we summarize the latest insights into chromatin remodeling and VSMC phenotypic switching, and then discuss recent advances in the identification and functional characterization of chromatin remodeling molecules, emphasizing their implications for VSMC behavior. Finally, we highlight the translational potential of targeting chromatin remodelers in the development of clinical therapies for vascular remodeling diseases and outline future directions for research in this field. Full article

The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53’s tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53’s functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment. Full article

The dedifferentiation of smooth muscle cells (SMCs) is the main cause of atherosclerosis and vascular calcification. This study integrated the gene expression data of multiple microarrays to identify relevant marker molecules. A total of 72 Gene Expression Omnibus (GEO) samples (GSM) were collected from 10 gene expression data series (GSE) and divided into five groups: non-SMC, SMC, atherosclerotic SMC (SMC-ath), calcified SMC (SMC-calc), and treated SMC (SMC-t). The SMC-t group included synthetic SMCs that had undergone treatment to inhibit proliferation, migration, or inflammation. The gene expression data were merged, normalized, and batch effects were removed before differential gene expression (DGE) analysis was performed via linear models for microarray data (limma) and statistical analysis of metagenomic profiles (STAMPs). The genes with expressions that significantly differed were subsequently subjected to protein-protein interaction (PPI) and functional prediction analyses. In addition, the random forest method was used for classification. Twelve proteins that may be marker molecules for SMC differentiation and dedifferentiation were identified, namely, Proprotein convertase subtilisin/kexin type 1 (PCSK1), Transforming growth factor beta-induced (TGFBI), Complement C1s (C1S), Phosphomannomutase 1 (PMM1), Claudin 7 (CLDN7), Calcium binding and coiled-coil domain 2 (CALCOCO2), SAC3 domain-containing protein 1 (SAC3D1), Natriuretic peptide B (NPPB), Monoamine oxidase A (MAOA), Regulator of the Cell Cycle (RGCC), Alpha-crystallin B Chain (CRYAB), and Alcohol dehydrogenase 1B (ADH1B). Finally, their possible roles in SMCs are discussed. This study highlights the feasibility of bioinformatics analysis for studying SMC dedifferentiation. Full article

Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC. Full article

Molecules involved in the activation of regeneration in reptiles are almost unknown. MARCK-like proteins are indicated to activate regeneration in some amphibians and fish, and it would be important to know whether this is a general process also present in other vertebrates. To address this problem, the present study reports the immunolocalization of a MARCK-like protein in injured tissues of a lizard. Bioinformatics and immunofluorescence after 5BrdU administration, and detection of MARCK-like proteins, have been performed on regenerating tail and limb of the lizard Podarcis muralis. Transcriptome data indicate up-regulation of MARCKS and MARCK-like1 expression in the initial regenerating tail and limb blastemas, supporting their involvement in the activation of regeneration in both appendages. Immunofluorescence for 5BrdU shows numerous proliferating cells in the blastemas of both appendages. Immunolocalization of a MARCK-like protein, using an antibody generated against a homologous protein from the axolotl, shows that the wound epidermis, nerves, and myotubes accumulate most of the protein in the limb and tail. MARCK-like immunolabeling is also detected in the regenerating spinal cord of the tail. The study indicates that, although the limb later turns into a scar, the MARCK-like protein is also up-regulated in this appendage, like in the regenerating tail. These results indicate that the initial reaction to an injury in lizards, an amniote representative, includes some triggering processes observed in amphibians and fish (anamniotes), with the activation of MARCK-like genes and proteins. This suggests that a MARCK-like-dependant mechanism for tissue repair is likely activated during the initial phases of vertebrate wound healing. Full article

Caffeine is a nitrogenous base that naturally occurs in coffee (Cafea arabica), tea (Thea sinensis), and cocoa (Theobroma cacao). Chemically, caffeine is 1,3,5-trimethylxanthine, a purine analogue. Due to significant human consumption, caffeine effects have been widely studied. Being a natural xanthine derivative, the key degradative enzyme is xanthine oxidase, converting caffeine into 1-methyluric acid. Ecologically, caffeine is believed to act as a repellent molecule against insect feeding behavior. Caffeine’s chemical similarity to purines and plant hormones motivated this study, establishing the potential for cellular de-differentiation and re-differentiation. For this, a highly hormone-responsive plant species, Ornithogalum dubium, was used. As caffeine has been shown to induce endoreplication, the potential for new germlines in O. dubium is attractive. Using tissue culture, a range of caffeine concentrations were used (0.0125 mg/L to 2.0 mg/L) without additional hormones. A significant difference (p > 0.05) was observed for intermediate concentrations of 0.0125, 0.025, and 0.05 mg/L when compared to the control (no hormones). The highest rates of callus induction were obtained at a concentration of 0.025 mg/mL. Higher concentrations were phytotoxic (1.0 mg/L or greater). To conclude, caffeine-regenerated plants were not dissimilar to those obtained from canonical hormones. Full article

In thyroid cancer, the tumor immune microenvironment (TIME) plays a crucial role in cancer development, progression and response to treatment. Like many other cancers, thyroid cancer creates a complex network of interactions with immune cells directly (cell-to-cell) and via humoral mediators (i.e., cytokines). This dynamic microenvironment undergoes constant modification, which can lead to changes in the immunophenotype that might explain cancer progression, dedifferentiation and resistance to treatment. According to the cancer immunoediting hypothesis, cancerous tumors can shape their immune microenvironment to create an immunosuppressive milieu that allows them to evade classic immune surveillance. One mechanism by which this occurs is through the reprogramming of immune cells, often shifting their phenotypes from cytotoxic to regulatory. Recent research has shed light on cellular components and molecular interactions within the thyroid cancer TIME. Immune cells such as Tumor-Associated Lymphocytes (TALs), myeloid-derived suppressor cells (MDSCs), Tumor-Associated Macrophages (TAMs) and Double-Negative (DN) T cells seem to play key roles in shaping the immune response to thyroid cancer. Additionally, cytokines, chemokines and other signaling molecules contribute to the communication and regulation of immune cells within that microenvironment. By studying these interactions, researchers aim to uncover not just potential therapeutic targets but also biomarkers of thyroid cancer that could provide clues on severity and progression. Based on that knowledge, strategies such as the use of immune checkpoint inhibitors, antigen-specific targeted immunotherapies, and immunomodulatory agents are being explored to enhance the anti-tumor immune response and overcome cancer immunosuppressive mechanisms. In this review, we analyze the available literature and provide our own experience to unravel the complexity of the thyroid immune microenvironment. Continued research in this area holds promise for improving outcomes through the identification of immune markers of severity/progression of thyroid cancer and the development of innovative immunotherapeutic approaches. Full article

The main purpose of regenerative medicine for degenerative eye diseases is to create cells to replace lost or damaged ones. Due to their anatomical, genetic, and epigenetic features, characteristics of origin, evolutionary inheritance, capacity for dedifferentiation, proliferation, and plasticity, mammalian and human RPE cells are of great interest as endogenous sources of new photoreceptors and other neurons for the degrading retina. Promising methods for the reprogramming of RPE cells into retinal cells include genetic methods and chemical methods under the influence of certain low-molecular-weight compounds, so-called small molecules. Depending on the goal, which can be the preservation or the replacement of lost RPE cells and cellular structures, various small molecules are used to influence certain biological processes at different levels of cellular regulation. This review discusses the potential of the chemical reprogramming of RPE cells in comparison with other somatic cells and induced pluripotent stem cells (iPSCs) into neural cells of the brain and retina. Possible mechanisms of the chemically induced reprogramming of somatic cells under the influence of small molecules are explored and compared. This review also considers other possibilities in using them in the treatment of retinal degenerative diseases based on the protection, preservation, and support of survived RPE and retinal cells. Full article

Hyaluronic acid (HA) is a key component of synovial fluid as it plays a crucial role in joint physiology. Its biological activity is influenced by molecular weight, local concentration, and persistence in joints. High-molecular-weight HA has a consolidated history of clinical use, whereas little is known about the metabolic effect of low-molecular-weight hyaluronate on cartilage differentiation. This study explores the potential of HA-based nanoparticles (NPs) on chondrocytes differentiation in vitro. Starting from 25 kDa and 250 kDa sodium hyaluronate solutions, two types of NPs were prepared by antisolvent precipitation in ethanol. The resulting NPs were dried in the presence of dipalmitoyl phosphatidylcholine, a natural synovial fluid component, then applied on an in vitro model of horse articular chondrocytes: no toxicity was observed and NPs prepared from 250 kDa HA promoted chondrocyte differentiation to a larger extent with respect to corresponding HA solutions, as evidenced by increased gene expression of chondrogenic markers (Col2a1 and Sox9) and reduced expression of dedifferentiation markers (Col1a1 and Runx2). These findings suggest that HA-based NPs are more effective at promoting the cellular internalization of the molecule and the differentiation of chondrocytes in vitro and could be a promising platform for drug delivery and cartilage repair. Full article

Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in theranostic power of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in “differentiated thyroid cancers” remains a clinical problem despite optimized RAI administration protocols. Functional mis-differentiation and associated RAI-indifference are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory mis-differentiated thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols. Full article

Urodelean amphibians can regenerate the tail and the spinal cord (SC) and maintain this ability throughout their life. This clearly distinguishes these animals from mammals. The phenomenon of tail and SC regeneration is based on the capability of cells involved in regeneration to dedifferentiate, enter the cell cycle, and change their (or return to the pre-existing) phenotype during de novo organ formation. The second critical aspect of the successful tail and SC regeneration is the mutual molecular regulation by tissues, of which the SC and the apical wound epidermis are the leaders. Molecular regulatory systems include signaling pathways components, inflammatory factors, ECM molecules, ROS, hormones, neurotransmitters, HSPs, transcriptional and epigenetic factors, etc. The control, carried out by regulatory networks on the feedback principle, recruits the mechanisms used in embryogenesis and accompanies all stages of organ regeneration, from the moment of damage to the completion of morphogenesis and patterning of all its structures. The late regeneration stages and the effects of external factors on them have been poorly studied. A new model for addressing this issue is herein proposed. The data summarized in the review contribute to understanding a wide range of fundamentally important issues in the regenerative biology of tissues and organs in vertebrates including humans. Full article

Epithelial Mesenchymal Transition (EMT) is a dedifferentiation process implicated in many physio-pathological conditions including tumor transformation. EMT is regulated by several extracellular mediators and under certain conditions it can be reversible. Autophagy is a conserved catabolic process in which intracellular components such as protein/DNA aggregates and abnormal organelles are degraded in specific lysosomes. In cancer, autophagy plays a controversial role, acting in different conditions as both a tumor suppressor and a tumor-promoting mechanism. Experimental evidence shows that deep interrelations exist between EMT and autophagy-related pathways. Although this interplay has already been analyzed in previous studies, understanding mechanisms and the translational implications of autophagy/EMT need further study. The role of autophagy in EMT is not limited to morphological changes, but activation of autophagy could be important to DNA repair/damage system, cell adhesion molecules, and cell proliferation and differentiation processes. Based on this, both autophagy and EMT and related pathways are now considered as targets for cancer therapy. In this review article, the contribution of autophagy to EMT and progression of cancer is discussed. This article also describes the multiple connections between EMT and autophagy and their implication in cancer treatment. Full article

In response to injury, vascular smooth muscle cells (VSMCs) of the arterial wall dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The ERK1/2 pathway participates in cellular proliferation and migration, while dual-specificity phosphatase 6 (DUSP6, also named MKP3) can dephosphorylate activated ERK1/2. We showed that DUSP6 was expressed in low baseline levels in normal arteries; however, arterial injury significantly increased DUSP6 levels in the vessel wall. Compared with wild-type mice, Dusp6-deficient mice had smaller neointima. In vitro, IL-1β induced DUSP6 expression and increased VSMC proliferation and migration. Lack of DUSP6 reduced IL-1β-induced VSMC proliferation and migration. DUSP6 deficiency did not affect IL-1β-stimulated ERK1/2 activation. Instead, ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1β, indicating that ERK1/2 functions upstream of DUSP6 to regulate DUSP6 expression in VSMCs rather than downstream as a DUSP6 substrate. IL-1β decreased the levels of cell cycle inhibitor p27 and cell–cell adhesion molecule N-cadherin in VSMCs, whereas lack of DUSP6 maintained their high levels, revealing novel functions of DUSP6 in regulating these two molecules. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining p27 and N-cadherin levels. Full article

MicroRNAs (MiRNAs) are small, non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. We analyzed the differential expression of miRNAs in 119 endometrial carcinomas, measuring their expression in histological subtypes, molecular subtypes, and tumors with CTNNB1 mutations. Tumors were subdivided into histological and molecular subtypes as defined by The Cancer Genome Atlas. The expression levels of 352 miRNAs were quantified using the PanoramiR panel. Mir-449a, mir-449b-5p, and mir-449c-5p were the top three miRNAs showing increased expression in both endometrioid and de-differentiated carcinomas but were not significantly increased in serous and clear cell carcinomas. The miRNAs with the most increased expression in serous and clear cell carcinomas were miR-9-3p and miR-375, respectively. We also identified 62 differentially expressed miRNAs among different molecular subtypes. Using sequential forward selection, we built subtype classification models for some molecular subtypes of endometrial carcinoma, comprising 5 miRNAs for MMR-deficient tumors, 10 miRNAs for p53-mutated tumors, and 3 miRNAs for CTNNB1-mutated tumors, with areas under curves of 0.75, 0.85, and 0.78, respectively. Our findings confirm the differential expression of miRNAs between various endometrial carcinoma subtypes and may have implications for the development of diagnostic and prognostic tools. Full article