Search Results (2,776)

Lactoferrin is a naturally occurring bioactive glycoprotein that is part of the body’s innate immune system and has essential roles in iron metabolism, microbial defense, inflammation regulation, and tissue repair. It supports the natural regulation of iron bioavailability in skin and hair follicles, helping to reduce excess free-iron-driven oxidative stress while preserving levels of necessary iron for cellular functions. Lactoferrin promotes cell regeneration by increasing proliferation across in vitro systems, stimulating wound healing in scratch assays, and boosting matrix production in fibroblast models. Lactoferrin can also modulate inflammatory signaling involved in skin and hair physiology by providing balanced cytokine suppression, suggesting potential value in cosmetic or dermatological applications. Here, we present the first focused summary of lactoferrin’s role specifically in skin and hair biology, distinguished from prior reviews in systemic or multi-system broad health contexts. We link mechanistic insights with clinical and preclinical evidence and uniquely map molecular functions to dermatologic and trichologic outcomes. We also provide an overview of clinical skin studies that have explored lactoferrin as a supportive agent in conditions such as acne, and highlight that, despite mechanistic plausibility, there are no existing available reports of well-controlled human clinical trials leveraging lactoferrin for hair-focused outcomes. In summary, we propose lactoferrin as not just an anti-inflammatory molecule, but also as a microenvironment stabilizer, and particularly relevant for hair and skin support as an alternative to pharmacological interventions. By addressing both established and underexplored applications, this review provides a translational framework for clinical development and provides a comprehensive rationale behind leveraging lactoferrin for hair and skin epithelial health. Full article

Astrocytes play a crucial role in maintaining neuronal microenvironment homeostasis and regulating synaptic plasticity within the hippocampus. Magnoflorine (MGN), a naturally occurring isoquinoline alkaloid, has demonstrated biological activity in the central nervous system. However, its effects on astroglial cells remain poorly understood. The present study aimed to evaluate the impact of acute and chronic administration of MGN (10 and 20 mg/kg body weight) on the morphology and morphometric parameters of GFAP-positive astrocytes in the CA1 field of the mouse hippocampus. Immunohistochemical and morphometric analyses were performed in the oriens layer (SO), pyramidal layer (SP), radiate layer (SR), and lacunose-molecular layer (SLM). MGN significantly modulated astrocyte density, cell size, and the number of processes in a dose-, time-, and layer-dependent manner. A heterogeneous and layer-specific astroglial response was particularly evident following chronic administration of the tested compound. Together with the observed lack of significant differences in analysed parameters, decreases were mainly detected after administration of the low MGN dose, whereas the 20 mg/kg dose induced primarily increased structural complexity. Thus, the direction of changes was not uniform across all layers. The most prominent changes were detected in the SLM layer. Overall, MGN modulated astrocyte morphology and reactivity in a context-dependent manner. These findings indicate a modulatory influence of MGN on astroglial structural plasticity rather than a uniform directional effect. Although the observed changes may be associated with alterations in astroglia-mediated mechanisms involved in maintaining neuronal homeostasis and responses to stress, their functional significance requires further investigation. Full article

Compounds of plant origin have increasingly emerged as anticancer agents through direct cytotoxicity and sensitizing mechanisms. Melanoma remains the most aggressive form of skin cancer that exhibits a steadily increasing number of new cases globally each year, thus urgently requiring more effective therapeutic strategies. Therefore, phytochemicals can be considered promising candidates, particularly when used in combination with immune checkpoint inhibitors. Their ability to optimize therapeutic efficacy and strengthen antitumor immune responses is mediated through various mechanisms that include the stimulation of T cell activity, the regulation of the TME, the activation of intrinsic immune responses and cytokine signaling, and the regulation of immune checkpoints such as PD-1/PD-L1, CTLA-4, and LAG-3. Additionally, these compounds can alter key signaling pathways that control immune regulation. Nevertheless, the extrapolation of preclinical studies to clinical applications remains limited by insufficient clinical evidence, the lack of standardized therapeutic protocols, and poor pharmacokinetic behavior. Consequently, further studies are required in order to clarify their actual efficacy and to better define their role in modern oncology. This article aims to review the mechanisms that underlie the anticancer sensitizing activity of major classes of plant-derived compounds such as polyphenols, flavonoids, terpenoids, alkaloids, and isothiocyanates. The available preclinical and clinical evidence were reported together with their potential synergistic effects when combined with immune checkpoint inhibitors. An important aspect related to the anticancer effects of these compounds lies in their ability to simultaneously target multiple signaling pathways. Furthermore, advanced formulations such as nanoparticulated delivery systems are discussed as strategies to optimize their clinical application and therapeutic outcomes. Full article

The persistence of an immunosuppressive microenvironment remains a formidable challenge for cancer immunotherapy, particularly in tumors with immune-excluded or immune-desert phenotypes. Increasing evidence indicates that chronic inflammation and tumor progression are intrinsically linked through shared signaling hubs, including NF-κB and PI3K/Akt. Osthole, a natural coumarin compound, has been reported to exhibit both potent anti-inflammatory and antitumor activities; however, whether these effects reflect a coordinated regulation of the inflammation–cancer axis remains unclear. In this study, we deployed an integrative framework founded on network pharmacology, molecular docking, and rigorous molecular dynamics simulations, complemented by literature-based evidence synthesis, to computationally explore the potential mechanisms underlying Osthole’s dual activities. Our analysis revealed that Osthole’s predicted targets are significantly enriched in signaling pathways bridging inflammatory and oncogenic processes, most notably the PI3K/Akt, NF-κB, and TGF-β/Smad pathways. Crucially, MD simulations provided supportive computational evidence, suggesting that Osthole forms stable, energetically favorable complexes with core protein hubs (AKT1, RELA, and TGFB1) under the simulated conditions. Evidence from representative inflammatory and tumor models supports the biological plausibility of these predictions, including suppression of pro-inflammatory signaling, mitigation of maladaptive tissue remodeling, and induction of apoptosis. Furthermore, in hepatocellular carcinoma models, Osthole-mediated apoptosis appeared linked to HMGB1-related inflammatory signaling, highlighting its potential to modulate the local immune niche. Collectively, this convergence of systems-level predictions and dynamic structural evidence identifies Osthole as a promising multi-target candidate for the coordinated regulation of inflammation-associated tumor progression, providing a robust rationale for further experimental validation. Full article

Acute kidney injury (AKI) lacks targeted pharmacological interventions. While the DanShen–DaHuang (DS-DH) herb pair shows clinical potential for AKI treatment, and our prior study has validated its nephroprotective efficacy in a cisplatin-induced murine model, its specific molecular targets within the renal microenvironment remain undefined. In this study, we integrated network pharmacology and weighted gene co-expression network analysis (WGCNA) to screen AKI-related targets of the DS-DH pair. A multi-algorithmic machine learning pipeline (including LASSO, Boruta, Random Forest, GBM, XGBoost, and Decision Trees) was utilized to calculate feature importance scores and rank core genes. Subsequently, single-cell RNA sequencing (scRNA-seq) data (GSE197266) were analyzed for transcriptomic mapping, pseudotime trajectory, and cell–cell communication. Finally, molecular docking evaluated theoretical binding affinities. After database screening, a total of 603 drug–disease intersecting targets were obtained. Subsequently, 917 module genes significantly associated with AKI were identified by WGCNA, and 62 core candidate genes were determined after intersecting with the above targets. Multi-algorithm machine learning ranked the importance of the 62 targets, with transketolase (TKT) ranking the highest. To elucidate the mechanism of TKT in AKI, scRNA-seq analysis was performed on 77,593 high-quality cells. The results showed that Tkt was specifically enriched in renal macrophages, with the highest expression in the M2-polarized subset. Pseudotime analysis further revealed that Tkt expression dynamics were highly synchronized with the differentiation trajectory of M2 macrophages and positively correlated with the repair markers Arg1 and Mrc1. Cell–cell communication analysis predicted that Tkt⁺ M2 macrophages act as active communication hubs via the Spp1 and Mif signaling axes. Molecular docking validated the favorable binding affinity between core DS-DH compounds and the TKT active pocket. This computational framework predicts that the DS-DH herb pair might mitigate AKI by potentially targeting TKT, a metabolic enzyme closely associated with macrophage M2 polarization. By prioritizing targets via multi-algorithmic scoring, we provide a data-driven rationale and candidate targets for future experimental validation. Full article

Cancer stem cells (CSCs) are a distinct subpopulation within a tumor that play an important role in tumor initiation, metastasis, therapeutic resistance, and cancer relapse. Their persistence is strongly influenced by the tumor microenvironment (TME), which provides a range of biological signals that maintain stemness, promote immune evasion, and resistance to cancer treatment. Therefore, effective targeting of CSCs is essential to improve therapeutic efficacy. In this review, we summarize the key characteristics of CSCs and their niche within the TME, emphasizing their interactions with immune cells, stromal components, and secreted factors. We also discuss the major challenges in targeting CSCs, including immune evasion, metabolic constraints, and intratumoral heterogeneity. We further highlight current and emerging immunotherapeutic strategies targeting CSCs, including immune checkpoint inhibitors, cancer vaccines, monoclonal antibodies, nanobodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T and CAR-NK cell therapies, oncolytic viruses, as well as innovative approaches such as targeted protein degradation. Finally, we emphasize the importance of a combinatorial approach that integrates CSCs targeting with modulation of the TME. Together, these strategies may lead to more durable responses, enhance therapy efficacy and reduce the risk of tumor recurrence. Full article

TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway. While TRAF3 has a well-established role in immune function, mainly via B- and T-lymphocyte regulation, its roles in cancer remain unclear. Breast cancer is the most common malignancy in women and a neoplasm displaying high levels of intratumoral heterogeneity. Identifying and understanding key molecules at the interface of breast cancer cells and the immune system is crucial for advancing therapeutic strategies for breast cancer patients. Here, by employing publicly available breast cancer datasets, breast cancer cell lines stably expressing TRAF3, mass spectrometry analysis in combination with functional assays, co-culture systems, and signal pathway characterization, we sought to assess the specific role of TRAF3 in breast cancer cells and how TRAF3-expressing breast cancer cells affect their immune microenvironment. Our results indicate that TRAF3 protein overexpression inhibits colony formation through apoptosis regulation. Proteome analysis for TRAF3 interactors and over-representation analysis identified multiple protein complexes related to cell cycle, apoptosis, and immune responses. Furthermore, TRAF3-expressing breast cancer cells displayed reduced levels of PD-L1 and when co-cultured with PBMCs induced a pro-inflammatory profile with increased CD16-NK cells and higher levels of IFN-γ and TNF-α and lower IL-10 and Tregs in the culture. These findings further expand the role of TRAF3 in breast cancer, not only as a regulator of EMT and survival of cancer cells, but also as a modulator of the tumor-immune microenvironment. Full article

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1α, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC–immune synapses, identifying “metabolic hotspots” associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC–immune interactions in metastatic cancer. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Mitochondria have emerged as critical regulators of cancer biology, transcending their classical role as cellular powerhouses to orchestrate complex metabolic, signaling, and survival pathways essential for tumorigenesis. This review examines the multifaceted role of mitochondria in cancer, integrating initial discoveries with recent advances from recent studies. We explore how mitochondrial DNA mutations, metabolic reprogramming, and alterations in mitochondrial dynamics contribute to malignant transformation, tumor progression, and therapeutic resistance. Mitochondrial dysfunction, long considered a consequence of the Warburg effect, is now recognized as an active driver of oncogenesis through retrograde signaling, oxidative stress modulation, and tumor microenvironment remodeling. The review highlights emerging therapeutic strategies targeting mitochondrial metabolism, including inhibitors of oxidative phosphorylation, mitochondrial-targeted drugs, and approaches exploiting metabolic vulnerabilities. Understanding the complex interplay between mitochondrial function and cancer biology provides a foundation for developing novel diagnostic biomarkers and precision oncology approaches. Full article

Mitochondrial stress has emerged as a key regulator of tumor–immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor–immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy, characterized by rapid progression, early metastasis, and resistance to conventional therapies. Increasing evidence indicates that the behavior of residual tumor cells is strongly influenced by physicochemical properties of their microenvironment. Surface engineering strategies using nanostructured materials may therefore represent a complementary approach to modulating cancer cell activity. In this study, we investigated whether a graphene oxide (GO) aerosol nanofilm modifies the biological behavior of PDAC cells in vitro. The GO aerosol (4.5 g/L) was characterized using STEM, DLS, zeta potential measurements, LIBS, EDX, and FTIR spectroscopy. Ultrastructural analysis revealed thin, wrinkled GO sheets forming partially overlapping lamellar structures, while physicochemical characterization confirmed a highly oxidized stable nanomaterial. Human PDAC cell lines (BxPC-3 and AsPC-1) were cultured on GO-modified substrates to assess morphology (SEM), metabolic activity (XTT assay), migratory capacity (wound healing assay over 72 h), and expression of genes related to proliferation and epithelial–mesenchymal transition (EMT) by RT-qPCR. GO nanofilm significantly reduced cell viability and inhibited migration in both cell lines. SEM analysis demonstrated shortened cytoplasmic projections and altered membrane integrity. Gene expression profiling revealed cell line-dependent transcriptional responses, including modulation of components of the PI3K/AKT/mTOR pathway and EMT-associated markers. Collectively, our findings demonstrate that GO aerosol nanofilm alters PDAC cell morphology, viability, and migratory behavior in vitro. Surface-mediated modulation of tumor cell activity may represent a promising adjunct strategy for limiting residual cancer cell survival and metastatic potential. Full article

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, with limited survival benefit from the current standard of care consisting of maximal safe resection, radiotherapy, and temozolomide-based chemotherapy. The highly infiltrative growth pattern, profound intratumoral heterogeneity, and strongly immunosuppressive tumor microenvironment together contribute to therapeutic resistance and frequent recurrence. In this context, oncolytic herpes simplex virus (oHSV) has emerged as a promising therapeutic platform for glioblastoma because of its dual capacity to directly lyse tumor cells and stimulate antitumor immune responses. In addition, the large viral genome and well-characterized biology of herpes simplex virus enable extensive genetic engineering to improve tumor selectivity, safety, and immunomodulatory function. In this review, we summarize the molecular design strategies that have driven the development of oHSV for glioblastoma, including attenuation of neurovirulence, enhancement of tumor-selective replication, and arming with immune-stimulatory transgenes. We further discuss the major biological barriers within the GBM tumor microenvironment that continue to limit therapeutic efficacy, with particular attention given to representative engineered oHSV platforms and the lessons learned from preclinical and early-phase clinical studies. A dedicated section examines these barriers in detail, including restricted intratumoral viral spread, antiviral innate immunity, and immunosuppressive myeloid cell dominance. We also review current efforts to improve outcomes through rational combination strategies with radiotherapy, immune checkpoint blockade, cytokine modulation, and other multimodal approaches. Although encouraging advances have been achieved, the clinical translation of oHSV therapy for glioblastoma still faces substantial challenges in patient selection, delivery optimization, response assessment, and treatment integration. A deeper understanding of virus–host–tumor interactions and more precise engineering of viral platforms may help unlock the full potential of oHSV-based therapy. Overall, oHSV represents one of the most compelling translational approaches in glioblastoma and provides a valuable framework for the development of mechanism-driven viro-immunotherapy in neuro-oncology. Full article

Background: Impaired angiogenesis and persistent inflammation are hallmarks of chronic diabetic wounds. Extracellular vesicles derived from dental pulp stem cells (DPSC-EVs) represent a promising cell-free therapy for tissue repair; however, their clinical translation is hindered by suboptimal yields and attenuated bioactivity associated with conventional two-dimensional (2D) culture. This study investigated whether a biomimetic three-dimensional (3D) fibrin/gelatin hydrogel system could optimize the therapeutic potency of DPSC-EVs for diabetic wound healing. Methods: DPSCs were encapsulated within 3D fibrin/gelatin scaffolds, followed by comprehensive characterization of cell viability and morphology. 3D-EVs and 2D-EVs were isolated via ultracentrifugation and validated by transmission electron microscopy and nanoparticle tracking analysis. The pro-angiogenic capacity of 3D-EVs was evaluated using human umbilical vein endothelial cells (HUVECs) under high-glucose (HG) stress. Additionally, the immunomodulatory effects were assessed by monitoring macrophage polarization in lipopolysaccharide-stimulated RAW 264.7 cells. The therapeutic efficacy was further validated in vivo using a streptozotocin (STZ)-induced diabetic mouse model with full-thickness cutaneous wounds. Results: The 3D fibrin/gelatin hydrogel provided a supportive microenvironment that significantly augmented the secretory productivity of DPSCs. Compared to 2D-EVs, 3D-EVs exhibited superior functional resilience in restoring HUVEC migration and tube formation under HG-induced oxidative stress. Furthermore, 3D-EVs effectively orchestrated the macrophage transition from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype, thereby modulating the immune microenvironment. In vivo, topical administration of 3D-EVs markedly accelerated wound closure, promoted re-epithelialization, and enhanced microvascular density and collagen maturation in diabetic mice. Conclusions: Our findings demonstrate that the 3D fibrin/gelatin culture system effectively primes the therapeutic profile of DPSC-EVs. These engineered vesicles accelerate diabetic wound healing by synergistically promoting angiogenesis and resolving chronic inflammation, offering a robust and potent cell-free strategy for the management of chronic diabetic ulcers. Full article

GJB2-associated hearing loss is the most common form of non-syndromic hereditary deafness worldwide. However, it exhibits significant heterogeneity in terms of both clinical presentation and biological basis. This review focuses on mechanism-oriented therapeutic strategies for GJB2-associated hearing loss, investigating how different types of GJB2 variants correspond to distinct clinical phenotypes and underlying pathogenic mechanisms, and aims to determine appropriate treatments. Current evidence suggests that GJB2-associated hearing loss is not solely caused by channel dysfunction resulting from gap junction defects, but rather the result of multiple pathological processes, including impaired GJB2 transcriptional regulation, cochlear developmental abnormalities, sensory epithelial degeneration and secondary damage pathways such as inflammation. Consequently, emerging therapeutic approaches can be viewed as interventions targeting specific mechanisms, including gene therapy, restoration of protein transport and pharmacological modulation of damage to the cochlear microenvironment. Overall, this review highlights the importance of aligning therapeutic strategies with specific GJB2 variants, underlying pathogenic mechanisms, and the developmental window during which cochlear injury remains biologically reversible. Full article