Search Results (1,603)

Adipogenesis is one way by which adipose tissue expands in our body. It is a complex tightly regulated process involving differentiation of mesenchymal stem cells (MSCs) into mature, lipid-containing adipocytes. One of the byproducts of this mechanism is leptin, an adipokine that plays a pivotal role in regulating food intake and energy homeostasis. While the increase in leptin secretion in proportion to fat mass expansion shows that leptin functions as a downstream marker of adipogenesis, emerging studies suggest that leptin itself may influence the adipogenesis process and act as a regulator. However, despite much research done to explore this, its role remains incompletely understood and often contradictory, with studies reporting pro-adipogenic, anti-adipogenic, or neutral effects depending on experimental context. These discrepancies highlight the influence of factors such as leptin concentration, timing of exposure, cell type, adipose depot, and species differences. This review gathers current evidence on leptin’s role in adipogenesis, integrating findings from diverse experimental models and biological systems. We further examine the underlying molecular mechanisms and signaling pathways involved, aiming to clarify the context-dependent effects of leptin and identify key knowledge gaps to guide future research in adipose tissue biology and metabolic disease. Full article

Interferons (IFNs) play fundamental roles in cancer immunity. We have previously shown that conditional ablation of Notch pathway genes in a mouse model of glioma results in impaired IFNγ signaling and immunosuppressive tumors. However, it remained unclear whether the interaction between the Notch and IFN signaling pathways could be leveraged to counteract immune evasion in glioma. Here, we investigated whether expression of the intrinsically active Notch intracellular domain (NICD) could enhance IFN responses in glioma cells. Using a doxycycline (Dox)-inducible system, we overexpressed (OE) NICD in U-251MG human glioma cells. NICD-OE dramatically potentiated STAT1 phosphorylation in response to stimulation with either IFNγ or IFNα. Moreover, NICD-OE induced the expression of the transcription factor IRF1, a regulator of IFN signaling responses. Notably, NICD-OE in U-251MG human glioma cells boosted the IFNγ-dependent transcription of the CXCL9 and CXCL10 genes, which encode cytokines that regulate T cell function. Accordingly, NICD-OE in vivo promoted cytotoxic T lymphocyte recruitment to the tumor and reduced tumor cell proliferation in a murine glioma model. Hence, we have identified a signaling network that could be exploited to enhance anti-tumor immunity in glioma subtypes. Full article

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes—PTPN11, NRAS, KRAS, NF1, or CBL—establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention. Full article

Morphological disciplines, namely Human Anatomy, Histology, and Embryology, have traditionally provided the foundational knowledge for medical education, offering spatial, cellular, and temporal coordinates of the human body. However, reducing these disciplines to static and purely descriptive learning undermines their deeper purpose: interpreting morphology as the dynamic outcome of biological processes. This review emphasizes three interrelated pillars of morphological sciences—cell differentiation, tissue homeostasis, and organ remodeling—as essential frameworks for understanding both normal physiology and disease pathogenesis. Cell differentiation establishes functional identity, tissue homeostasis ensures structural stability, and organ remodeling enables adaptation to both physiological and pathological stimuli. Dysregulation of these programs underlies a wide range of conditions, from degenerative diseases and chronic inflammation to neoplasms. Integrating classical morphological knowledge with modern approaches—including stem cell biology, organoids, tissue engineering, and computational modeling—enables predictive and regenerative strategies in personalized medicine. Furthermore, recent advances in artificial intelligence applied to histopathology have enhanced our capacity to detect early deviations from homeostasis and guide targeted interventions. By combining spatial, cellular, and molecular perspectives, the morphological sciences can provide clinicians with tools to interpret disease as the result of altered biological programs, anticipate pathology, and design precise therapeutic strategies. This integrated approach highlights the renewed centrality of morphology in contemporary medicine, bridging foundational knowledge with predictive, regenerative, and personalized healthcare. Full article

Severe mental disorders, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), are leading causes of global disability, yet current treatments remain largely symptomatic and fail to alter disease trajectories. Converging evidence from genetics, longitudinal studies, and systems neuroscience supports a dimensional and transdiagnostic architecture of psychopathology, involving shared polygenic risk and overlapping neurodevelopmental and circuit-level alterations. Traditional approaches—such as post-mortem brain analysis, neuroimaging, and animal models—have delineated core molecular perturbations (e.g., dopaminergic, glutamatergic, and GABAergic dysfunction), as well as informed translational frameworks for mechanistic investigation, but remain constrained by restricted access to dynamic processes and incomplete recapitulation of human-specific biology. The advent of human-derived cellular models, particularly human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), has partially addressed these limitations, enabling the study of patient-specific neurodevelopment and synaptic function in vitro. Within this evolving landscape, the olfactory neuroepithelium (ONE) has emerged as an accessible source of neural progenitors, obtainable through minimally invasive procedures, providing a window into living human neurobiology. ONE-derived cells retain donor-specific genetic and epigenetic signatures while recapitulating disease-relevant phenotypes across major psychiatric disorders, including altered neurodevelopmental dynamics, synaptic gene expression, and inflammatory profiles. Here, we present a narrative review of the principal cellular and tissue models used in biological psychiatry, examining their respective strengths, limitations, and translational relevance across experimental contexts. By situating these approaches within a unified framework, we aim to clarify their complementarity, identify current gaps, and outline future directions, highlighting the emerging potential of ONE-based models to bridge genetic risk, cellular dysfunction, and clinical phenotype, thereby advancing precision psychiatry. Full article

Drug resistance represents one of the most critical challenges in modern medicine, undermining the efficacy of therapies across both bacterial infections and cancer. Although these conditions arise in fundamentally distinct biological systems, they are governed by shared evolutionary pressures that drive the emergence and selection of resistant populations. This narrative review provides an integrative, cross-disciplinary perspective on drug resistance, focusing on bacteria and cancer and emphasizing the shared evolutionary and molecular mechanisms underlying treatment failure in both domains. Key resistance strategies include efflux-mediated drug export, target modification, enzymatic drug inactivation, metabolic reprogramming, epigenetic and transcriptional plasticity, and protection conferred by specialized microenvironments. These processes are further reinforced by phenotypic heterogeneity, including bacterial persister cells and cancer stem-like cells, which contribute to recurrence and multidrug resistance. Collectively, these parallels define drug resistance as a convergent evolutionary phenomenon driven by adaptability under selective pressure. Recognizing these shared mechanisms reveals important translational opportunities for therapeutic intervention. Strategies such as combination therapy, drug repurposing, nanotechnology-enabled delivery systems, and host-directed approaches offer promising avenues to prevent, delay, or overcome resistance. By integrating insights from microbiology and oncology, this review proposes a unified framework for resistance biology and highlights the potential of cross-disciplinary strategies to improve treatment durability and clinical outcomes. Full article

Soft tissue sarcomas (STS) comprise a rare and highly heterogeneous group of mesenchymal-derived malignancies, accounting for less than 1% of all cancers and characterized by diverse histologic and molecular subtypes. Despite their low incidence, STS account for a disproportionate burden of cancer-related morbidity and mortality, largely driven by their risk of metastatic dissemination. Early detection of metastatic spread is a cornerstone of preoperative staging, treatment planning, and postoperative monitoring in patients with STS. Although conventional imaging modalities remain fundamental for surveillance of metastatic disease, they may fail to accurately detect metastatic sites and provide limited insight into tumor biology. Advances in precision medicine have positioned liquid biopsy as a minimally invasive approach for the analysis of tumor-derived material, facilitating characterization of tumor biology and identification of prognostic biomarkers. Circulating tumor cells (CTCs) represent intact and viable tumor cells that provide unique genomic and phenotypic traits that could not be assessed using acellular tumor-derived material. They have emerged as promising biomarkers for monitoring disease progression, assessing treatment response, and stratifying prognosis. Particularly, their clinical value as prognostic biomarkers has been established in epithelial-derived malignancies. Despite these advances, the role of CTCs in STS remains largely investigational, mainly due to STS heterogeneity and the lack of standardized protocols for detection across platforms. Therefore, this narrative review summarizes the biomolecular mechanisms underlying CTCs in STS, including the role of phenotypic plasticity in tumor intravasation, anoikis resistance and its interaction with the tumor microenvironment, and stem cell-like phenotypes in tumor initiation at distant sites. Furthermore, we discuss current methodologies for CTC detection, highlighting emerging approaches developed to address the limitations of conventional methods. Finally, we provide a critical overview of subtype-specific detection strategies, as well as their clinical implications in treatment response monitoring and prognostic assessment. Full article

Mesenchymal stem cells (MSCs) are central effectors in regenerative medicine, yet their clinical translation is hindered by inconsistent therapeutic outcomes and a lack of standardized light-delivery protocols. This review addresses an underexplored dimension of photobiomodulation (PBM): the divergent, wavelength-dependent signaling programs triggered in MSCs by red/near-infrared (NIR) versus blue light. By integrating biophysical principles of light delivery with a systems biology analysis of protein–protein interaction networks (STRING/GO), we delineate a “Dual Photonic Programming” framework. Red/NIR light (600–1100 nm) targets mitochondrial cytochrome c oxidase, activating a bioenergetic-anabolic program centered on PI3K/Akt/mTOR and Wnt/β-catenin—pathways essential for structural tissue repair. Blue light (400–500 nm) engages cytosolic flavins to drive a secretory-paracrine program that modulates vesicle trafficking and immunomodulatory cargo release. We further examine the dosimetric paradox, demonstrating how culture-environment optics and the Arndt–Schultz biphasic law govern the transition from regenerative stimulation to inhibitory oxidative stress. By tailoring photonic parameters to the MSC’s anatomical origin and metabolic baseline, PBM can serve as a high-fidelity bio-switch for orchestrated tissue repair, providing a mechanistic roadmap for standardized regenerative therapies. Full article

Extramedullary relapse (EMR) of acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) represents a clinically and biologically distinct entity compared with medullary relapse, characterized by marked heterogeneity, compartmental immune escape mechanisms, and generally poor prognosis. EMR arises at the intersection of clonal resistance, evolutionary disease adaptation, and heterogeneous distribution of the graft-versus-leukemia effect, resulting in evolutionary trajectories that are often dissociated between medullary and extramedullary compartments. In the absence of prospectively validated therapeutic algorithms, EMR management requires a structured and adaptive approach based on multidimensional assessment integrating leukemia biology, disease burden and anatomical distribution, bone marrow minimal residual disease (MRD) status, and immune reconstitution. Therapeutic strategies include local treatments, targeted agents, immunotherapies, and immunomodulatory interventions, applied within a dynamic sequence tailored to treatment response. Follow-up plays a central role as an active tool for prognostic stratification and clinical decision-making, enabling early detection of systemic progression and optimization of the timing of consolidative strategies, including second Allo-HSCT in selected patients. An integrated and biologically driven management of post-Allo-HSCT EMR is essential to improve outcomes in this high-risk clinical setting. Full article

Deposition of fibrous connective tissue within the extracellular matrix is initially an adaptive and reversible wound-healing process. However, persistent dysregulation of fibrotic signaling pathways induces irreversible cellular dysfunction, tissue degeneration and organ failure. Despite the high mortality rate associated with fibrotic diseases, there are very limited approved anti-fibrotic treatments and there is no therapeutic drug effective enough to completely invert the fibrotic process. Accordingly, new therapeutic agents that will attenuate ongoing fibrosis and, at the same time, promote regeneration of injured tissue are urgently needed. The search for new therapies has been revolutionized by recent advances in stem cell biology. Mesenchymal stem cells (MSCs) are promising candidates for the therapy of organ fibrosis because of their differentiation capabilities and immunomodulatory properties. The capacity of MSCs to suppress chronic inflammation and promote tissue repair and regeneration underlies their therapeutic effects in diseases such as liver cirrhosis, idiopathic pulmonary fibrosis, cardiac fibrosis, systemic sclerosis, and renal fibrosis. In this review, we summarize the present understanding of fibrotic disease, highlight promising research avenues, including MSC-based treatment options, and discuss the challenges involved with the clinical application of MSCs. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer. Full article

Background and Clinical Significance: Dyskeratosis congenita (DC) is a rare inherited disorder classified as a telomere biology disorder and characterized by multisystem involvement, including bone marrow failure and mucocutaneous abnormalities. Oral manifestations such as leukoplakia, increased susceptibility to infection, and abnormal dental development have been reported; however, detailed descriptions of long-term oral functional management in pediatric patients remain limited. This report aims to describe the longitudinal oral management and imaging-based assessment of dental development in a child with DC and to discuss the clinical implications in the context of existing literature. Case Presentation: A female patient diagnosed with dyskeratosis congenita due to a heterozygous TINF2 mutation was followed from early childhood. She underwent hematopoietic stem-cell transplantation at five years of age and later required lung and liver transplantation. Long-term oral management included regular professional oral care, preventive strategies, and periodic imaging evaluation. Panoramic radiographs obtained over several years demonstrated generalized delayed eruption and incomplete root formation relative to chronological age, with apparent early arrest of root elongation. Discussion: This case highlights the potential association between telomere dysfunction, intensive systemic therapy in early childhood, and arrested odontogenesis. These findings suggest a possible association between telomere dysfunction, early intensive systemic therapy, and impaired root formation. Despite severe systemic disease, continuous preventive oral care and imaging-based monitoring were effective in maintaining oral health and detecting mucosal changes. Conclusions: Long-term preventive oral management combined with noninvasive imaging assessment may play an important role in preserving oral function and monitoring dental development in pediatric patients with dyskeratosis congenita. This case adds to the limited literature on longitudinal oral outcomes in this rare disorder. Full article

Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted—namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC. Full article

Hematologic malignancies arise and progress within a systemic ecosystem in which the gut microbiota is an increasingly recognized, partially modifiable component. Across acute leukemias, chronic lymphocytic leukemia, plasma cell disorders, lymphomas, and clonal myeloid neoplasms, human studies consistently report reduced microbial diversity, depletion of barrier-supportive, short-chain fatty acid-producing commensals, and enrichment of Gram-negative, pro-inflammatory, or hospital-adapted taxa. These alterations are associated with pre-leukemic clonal expansion, adverse genetic and immunological features, progression from precursor conditions, and inferior outcomes after chemotherapy, immunochemotherapy, chimeric antigen receptor T-cell therapy, and allogeneic hematopoietic stem cell transplantation. Mechanistic work in animal models and ex vivo systems demonstrates that microbiota-derived signals and metabolites—including Th17/IL-17-skewing consortia and the lipopolysaccharide intermediate ADP heptose sensed by the cytosolic receptor ALPK1—can actively modulate hematopoietic stem and progenitor cell fitness, inflammatory circuits, and malignant cell survival, supporting a causal role in disease biology. At the same time, major knowledge gaps remain because most human cohorts are small, single-center, and cross-sectional, frequently rely on 16S rRNA profiling, and are vulnerable to dietary, geographic, and treatment-related confounding. Within this context, three translational domains appear particularly promising: pharmaco-microbiomics, microbiome-informed risk stratification, and rational microbiota-targeted interventions, particularly diet-based strategies and antimicrobial stewardship. Here, we provide an integrated, disease-spanning synthesis of these data, emphasizing clonal hematopoiesis and myeloid neoplasms as emerging examples of microbiota–marrow crosstalk and outlining practical priorities for embedding microbiome science into future hematologic trials. Routine microbiome profiling or empiric microbiota-directed therapies cannot yet be recommended in everyday hematology practice, but integrating microbiome science into prospective therapeutic and transplant trials offers a realistic path to improved disease modeling, biomarker development, and rational adjunctive strategies to enhance outcomes for patients with hematologic malignancies. Full article

Piperine (PIP), a plant alkaloid with anti-inflammatory and antioxidant effects, has poor solubility and bioavailability, limiting its therapeutic potential in macrophage-mediated inflammatory and oxidative stress conditions. Despite various nanocarrier systems being explored for bioactive compounds, the specific combination of mannose-functionalized chitosan with dual stabilizers (TPGS and Tween 80) for enhanced macrophage targeting and piperine delivery has not been investigated. We hypothesized that this novel formulation would significantly enhance piperine solubility, macrophage uptake, and anti-inflammatory/antioxidant effects compared to conventional systems, while modulating apoptosis-related pathways. This study evaluated targeted and non-targeted nanoparticles synthesized by ionic gelation and emulsification using RAW 264.7 and THP-1 macrophages. FTIR, UV–Vis, XRD, and CHNS confirmed mannose conjugation, while SEM, TEM, and AFM revealed morphology. Physicochemical properties were assessed by DLS, encapsulation efficiency (EE%), drug loading (DL%), and stability. Biological evaluations included drug release, cytotoxicity (MTT), apoptosis analysis (Annexin V–FITC/PI staining), cellular uptake (fluorescence microscopy with coumarin-6), anti-inflammatory assays (extracellular and intracellular NO inhibition, cytokine suppression), antioxidant activity (DPPH, ABTS, FRAP, TAC), intracellular ROS/RNS, and apoptosis-related markers. Targeted nanoparticles showed larger mean size (162 nm) versus non-targeted ones (78 nm). EE% was 82% (targeted) and 92% (non-targeted). Both demonstrated sustained 72 h release. Cellular uptake was significantly greater for targeted nanoparticles. Both formulations reduced NO and pro-inflammatory cytokines, regulated apoptosis-associated markers, and induced controlled apoptosis at higher concentrations, with stronger effects observed for targeted particles. Antioxidant activity increased dose-dependently, with targeted nanoparticles showing superior intracellular ROS/RNS suppression. This novel multi-functional platform efficiently encapsulates PIP, enhances macrophage targeting, modulates apoptosis pathways, and demonstrates superior therapeutic promise for inflammation-related disorders. Full article