Search Results (1,589)

The tumor microenvironment (TME) has a substantial impact on the progression of gastric cancer. Collagen, the most abundant protein in the extracellular matrix (ECM), forms a dense physical barrier that regulates anti-tumor immunity in the TME. It is a significant regulator of the signaling pathways of cancer cells, which are responsible for migration, proliferation, and metabolism. ECM proteins, particularly remodeling enzymes and collagens, can be modified to increase stiffness and alter the mechanical properties of the stroma. This, in turn, increases the invasive potential of tumor cells and resistance to immunotherapy. Given the dynamic nature of collagen, novel therapeutic strategies have emerged that target both collagen biosynthesis and degradation, processes that are essential for addressing ECM stiffening. This review delineates the upregulation of the expression and deposition of collagen, as well as the biological functions, assembly, and reorganization that contribute to the dissemination of this aggressive malignancy. Furthermore, the review emphasizes the importance of creating 3D in vitro models that incorporate innovative biomaterials that avoid the difficulties of traditional 2D culture in accurately simulating real-world conditions that effectively replicate the distinctive collagen microenvironment. Ultimately, it investigates the use of decellularized ECM-derived biomaterials as tumor models that are designed to precisely replicate the mechanisms associated with the progression of stomach cancer. Full article

Spinal cord injury (SCI) remains a devastating neurological condition characterized by loss of sensory, motor and autonomic function. Despite decades of research, no FDA-approved regenerative therapies currently exist to restore lost function following SCI. Schwann cells (SCs) support axon regeneration, remyelination, and neuroprotection after SCI, with their therapeutic potential validated in clinical trials demonstrating safe and feasible transplantation in humans. Although SC transplantation has shown promising results, challenges remain, including modest graft survival, limited host integration, and restricted migration that collectively contribute to constrain efficacy. To address these limitations, biomaterial scaffolds have been explored as synergistic platforms to enhance SC delivery and function. When combined with natural or synthetic biomaterials such as hydrogels, nanofiber scaffolds, or ECM-mimetic matrices, SCs demonstrate improved survival, retention, spatial distribution, and regenerative activity. The intrinsic regenerative properties of SCs, first demonstrated in models of peripheral nerve injury, make them particularly well-suited for neural repair of the central nervous system (CNS) compared to other cell types and their effectiveness can be enhanced synergistically when combined with biomaterials. These constructs not only provide structural support but also modulate the lesion microenvironment, enhance axon growth and improve SC integration with host tissue. Combinatorial approaches incorporating biomaterials with SCs are emerging as next-generation strategies to optimize repair for clinical translation. This review focuses on current progress in SC-based therapies combined with biomaterials, highlighting key preclinical advances, clinical translation efforts, and the path forward toward effective regenerative interventions for SCI. Full article

Agro-photovoltaics (APV) or agrivoltaic systems integrate crop cultivation with solar energy production, offering a promising solution through the dual-use of land. This two-year study (2023 and 2024) examined the effects of an APV system on rice production. The results indicated that APV arrays created spatially variable light environments, with shadow lengths following predictable solar azimuth patterns and cloudy conditions mitigating shading effects through enhanced diffuse light. Compared with CK (non-shadow area), inter-panel plots (BP) maintained 77% photosynthetic efficiency and 85.4% plant height, whereas the areas beneath the panel showed a significant decrease in the relative chlorophyll content (SPAD values), photosynthesis rates, and yield. BP plots preserved a 78% fruiting rate through adaptive stomatal regulation, whereas LP zones (directly under the low eave) exhibited 35% higher intercellular CO₂ because of the limited assimilation in shading. Rice yield losses were correlated with shading intensity, driven by reduced panicles and grain filling. Moreover, the APV system achieved a high land equivalent ratio of 148–149% by combining 65–66% rice yield with 82.5% photovoltaics output. Based on the microenvironment created by the APV system, optimal crop types and fertilisation are essential for enhancing agricultural yields and improving land use efficiency. Full article

The Tumour Microenvironment (TME) is pivotal for melanoma progression and contributes to therapy resistance. While dermal cell involvement is well established, the role of epidermal cells remains less defined. To explore the contribution of Normal Human Keratinocytes (NHKs) to melanoma biology, we investigated the modification of gene and protein expression of NHKs exposed to melanoma-conditioned medium or maintained in a co-culture system. The analysis focused on pathways related to proliferation, inflammation, Extracellular Matrix (ECM) remodelling, and cell adhesion. Due to the well-documented melanoma–fibroblast crosstalk, Normal Human Fibroblasts (NHFs) and Cancer-Associated Fibroblasts (CAFs) were used as comparative references. Keratinocyte gene expression changes under the influence of melanoma secretome only partially overlapped with those of NHFs and CAFs, indicating cell-type-specific responses. Exposure to melanoma-conditioned medium induced the upregulation of bFGF, CXCL-16, TIMP-2, and E-cadherin in NHKs, alongside downregulating TGF-β and MMP-9. Although bFGF is a recognized pro-tumorigenic factor, the modulation of CXCL-16, TIMP-2, and TGF-β may reflect a protective response. Notably, under co-culture conditions, NHKs exhibited a pronounced pro-inflammatory and ECM-remodelling phenotype, characterized by elevated production of cytokines (IL-1α, IL-1β, and IL-8) and ECM-degrading enzymes (MMP-7, 9, 12, and 13), indicative of a pro-tumoral feature. Collectively, these findings underscore an active role for NHKs in melanoma initiation and progression. Full article

One of the main limitations of photodynamic therapy (PDT) is hypoxia, which is caused by increased tumour proliferation creating a hypoxic tumour microenvironment (TME), as well as oxygen consumption by PDT. Hypoxia-activated prodrugs (HAPs), such as molecules containing aliphatic or aromatic N-oxide functionalities, are non-toxic prodrugs that are activated in hypoxic regions, where they are reduced into their cytotoxic form. The (oxido)pyridylporphyrins tested in this work were synthesised as potential HAPs from their AB₃ pyridylporphyrin precursors, using m-chloroperbenzoic acid (m-CPBA) as an oxidising reagent. Their ground-state and excited-state spectroscopic properties, singlet oxygen (¹O₂) production by the photodegradation of 1,3-diphenylisobenzofurane (DPBF) and theoretical lipophilicity were determined. In vitro analyses included cellular uptake, localisation and (photo)cytotoxicity under normoxia and CoCl₂-induced hypoxia. The CoCl₂ hypoxia model was used to reveal their properties, as related to HIF-1 activation and HIF-1α accumulation. (Oxido)pyridylporphyrins showed promising properties, such as the long lifetime of the excited triplet state, a high quantum yield of intersystem crossing, and high production of ROS/¹O₂. Lower cellular uptake resulted in an overall lower phototoxicity of these N-oxide porphyrins in comparison to their N-methylated analogues, and both porphyrin series were less active on CoCl₂-treated cells. (Oxido)pyridylporphyrins showed higher selectivity for pigmented melanoma cells, and the antioxidant activity of melanin pigment seemed to have a lower impact on their PDT activity compared to their N-methylated analogues in both CoCl₂-induced hypoxia and normoxia. Their potential HAP activity will be evaluated under conditions of reduced oxygen concentration in our future studies. Full article

Uncontrolled and excessive inflammation could negatively impact embryo implantation, potentially leading to implantation failure or miscarriage. Small extracellular vesicles (sEVs) secreted by extravillous trophoblasts (EVTs) play a significant role in mediating the homeostasis at the maternal–fetal interface. In the present work we assessed the role of EVT-derived sEVs in the protection of the human blastocyst’s integrity and function in a microenvironment with excessive Th1-induced inflammation using the Sw71 blastocyst-like surrogate (Sw71 BLS) as a model of implanting a human embryo. Conditioned media from primary trophoblast-derived EVT cells were used as the source for sEVs’ isolation by precipitation. sEVs were characterized by TEM, IEM, and protein content. To simulate Th1-induced inflammation, we performed TCR stimulation and polyclonal activation of isolated T cells, which preferentially led to Th1 cytokine production. The use of the Sw71 spheroid model allowed us to monitor directly the damaging effect of high levels of Th1 cytokines on the ability of trophoblast cells to self-organize and migrate. The addition of EVT-sEVs unlocked the absolute migration capacity of the trophoblast cells in a healthy microenvironment. However, EVT-sEV treatment could not counteract the adverse effects of excessive Th1-mediated inflammation. This study provides a platform for further elucidation of the EVT-sEV dosage and potency for trophoblast functional recovery. Full article

Two-dimensional cell culture systems lack the ability to replicate the complex, three-dimensional (3D) architecture and cellular microenvironments found in vivo. Multicellular spheroids (MCSs) present a promising alternative, with the ability to mimic native cell–cell and cell–matrix interactions and provide 3D architectures similar to in vivo conditions. These factors are critical for various biomedical applications, including cancer research, tissue engineering, and drug discovery and development. Polymeric materials such as hydrogels, solid scaffolds, and ultra-low attachment surfaces serve as versatile platforms for 3D cell culture, offering tailored biochemical and mechanical cues to support cellular organization. This review article focuses on the structure–property relationships of polymeric biomaterials that influence MCS formation, growth, and functionality. Specifically, we highlight their physicochemical properties and their influence on spheroid formation using key natural polymers, including collagen, hyaluronic acid, chitosan, and synthetic polymers like poly(lactic-co-glycolic acid) and poly(N-isopropylacrylamide) as examples. Despite recent advances, several challenges persist, including spheroid loss during media changes, limited viability or function in long-term cultures, and difficulties in scaling for high-throughput applications. Importantly, the development of MCS platforms also supports the 3R principle (Replacement, Reduction, and Refinement) by offering ethical and physiologically relevant alternatives to animal testing. This review emphasizes the need for innovative biomaterials and methodologies to overcome these limitations, ultimately advancing the utility of MCSs in biomedical research. Full article

We investigated the role of the intermediate-conductance, Ca²⁺-activated K⁺ channel K_Ca3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M₂ macrophages (M₂-MACs), which serve as a useful model for studying tumor-associated macrophages (TAMs). CCL2 is a potent chemoattractant involved in the recruitment of immunosuppressive cells and its expression is regulated through intracellular signaling pathways such as ERK, JNK, and Nrf2 in various types of cells including macrophages. The transcriptional expression of CCL2 was suppressed in M₂-MACs following treatment with a K_Ca3.1 activator or an LRRC8A inhibitor via distinct signaling pathways: ERK–CREB2 and JNK–c-Jun pathways for K_Ca3.1, and the NOX2–Nrf2–CEBPB pathway for LRRC8A. Under in vitro conditions mimicking the elevated extracellular K⁺ concentration ([K⁺]_e) characteristic of the tumor microenvironment (TME), CCL2 expression was markedly upregulated, and this increase was reversed by treatment with them in M₂-MACs. Additionally, the WNK1–AMPK pathway was, at least in part, involved in the high [K⁺]_e-induced upregulation of CCL2. Collectively, modulating K_Ca3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, T_regs, and MDSCs) in the TME. Full article

This review aims to discuss how heat stress affects ovarian follicles and oocytes, steroidogenesis, and embryo development in ruminants. The literature shows that quiescent primordial follicles appear to be less susceptible to heat stress, but from the primary follicle stage onwards, they begin to suffer the consequences of heat stress. These adverse effects are exacerbated when the follicles are cultured in vitro. In antral follicles, heat stress reduces granulosa cell viability and proliferation in both in vivo and in vitro models. Oocyte maturation, both nuclear and cytoplasmic, is also compromised, and embryo quality declines under elevated thermal conditions. These effects are linked to intracellular disturbances, including oxidative imbalance, mitochondrial dysfunction, and altered hormonal signaling. The differences between in vivo and in vitro responses reflect the complexity of the biological impact of heat stress and emphasize the protective role of the physiological microenvironment. A better understanding of how heat stress alters the function of ovarian follicles, oocytes, and embryos is crucial. This knowledge is critical to devise effective strategies that mitigate damage, support fertility, and improve outcomes in assisted reproduction for livestock exposed to high environmental temperatures. Full article

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

Nosocomial infections caused by ESKAPE pathogens represent a significant burden to global health. These pathogens may exhibit multidrug resistance (MDR) mechanisms, of which mechanisms such as efflux pumps and biofilm formation are gaining significant importance. Multidrug resistance mechanisms in ESKAPE pathogens have led to an increase in the effective costs in health care and a higher risk of mortality in hospitalized patients. These pathogens utilize antimicrobial efflux pump mechanisms and bacterial biofilm-forming capabilities to escape the bactericidal action of antimicrobials. ESKAPE bacteria forming colonies demonstrate increased expression of efflux pump-encoding genes. Efflux pumps not only expel antimicrobial agents but also contribute to biofilm formation by bacteria through (1) transport of molecules and transcription factors involved in biofilm quorum sensing, (2) bacterial fimbriae structure transport for biofilm adhesion to surfaces, and (3) regulation of a transmembrane gradient to survive the difficult conditions of biofilm microenvironments. The synergistic role of these mechanisms complicates treatment outcomes. Given the mechanistic link between biofilms and efflux pumps, therapeutic strategies should focus on targeting anti-biofilm mechanisms alongside efflux pump inactivation with efflux pump inhibitors. This review explores the molecular interplay between efflux pumps and biofilm formation, emphasizing potential therapeutic strategies such as efflux pump inhibitors (EPIs) and biofilm-targeting agents. Full article

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors, largely due to its profound intratumoral heterogeneity and immunosuppressive microenvironment. Various classifications of GBM subtypes were created based on transcriptional and methylation profiles. This effort, followed by the development of new technology such as single-nuclei sequencing (snRNAseq) and spatial transcriptomics, led to a better understanding of the glioma cells’ plasticity and their ability to transition between diverse cellular states. GBM cells can mimic neurodevelopmental programs to resemble oligodendrocyte or neural progenitor behavior and hitchhike the local neuronal network to support their growth. The tumor microenvironment, especially under hypoxic conditions, drives the tumor cell clonal selection, which then reshapes the immune cells’ functions. These adaptations contribute to immune evasion by progressively disabling T cell and myeloid cell functions, ultimately establishing a highly immunosuppressive tumor milieu. This complex and metabolically constrained environment poses a major barrier to effective antitumor immunity and limits the success of conventional therapies. Understanding the dynamic interactions between glioma cells and their microenvironment is essential for the development of more effective immunotherapies and rational combination strategies aimed at overcoming resistance and improving patient outcomes. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

The human skin microbiota, a complex community of bacterial, fungal, and viral organisms, plays a crucial role in maintaining skin homeostasis and regulating host-pathogen interactions. Dysbiosis within this microbial ecosystem has been implicated in various dermatological conditions, including acne vulgaris, psoriasis, seborrheic dermatitis, and atopic dermatitis. This review, for the first time, provides recent advancements in all four layers of omic technologies—metagenomics, metatranscriptomics, metaproteomics, and metabolomics—offering comprehensive insights into microbial diversity, in the context of functional skin modeling. Thus, this review explores the application of these omic tools to in vitro skin models, providing an integrated framework for understanding the molecular mechanisms underlying skin–microbiota interactions in both healthy and pathological contexts. We highlight the importance of developing advanced in vitro skin models, including the integration of immune components and endothelial cells, to accurately replicate the cutaneous microenvironment. Moreover, we discuss the potential of these models to identify novel therapeutic targets, enabling the design of personalized treatments aimed at restoring microbial balance, reinforcing the skin barrier, and modulating inflammation. As the field progresses, the incorporation of multi-omic approaches into skin-microbiome research will be pivotal in unraveling the complex interactions between host and microbiota, ultimately advancing therapeutic strategies for skin-related diseases. Full article