Search Results (3,248)

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

The application of personalized medicine to lung adenocarcinoma has resulted in new therapies based on specific oncogenic drivers that have improved patient outcomes. However, oncogene-defined subsets of patients exhibit a significant heterogeneity of response to these agents. Defining the factors that mediate the varied depth and duration of response are critical to developing new therapeutic strategies. While the examination of patient samples can provide important correlations, definitive mechanistic studies require the use of relevant preclinical models. Based on a large body of data, interactions between cancer cells and the surrounding tumor microenvironment, comprised of inflammatory, immune, and vascular cells, represent a critical determinant of therapeutic response. In this review, we focus on preclinical models that can be used to explore these interactions, identify new therapeutic targets, and test combination therapies. In particular, we will describe the use of implantable orthotopic immunocompetent models employing a panel of murine lung adenocarcinoma cell lines with oncogenic drivers common to human lung adenocarcinoma as a powerful system to develop new treatment approaches. Full article

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

Background/Objectives: Medulloblastoma (MB) is the second leading cause of cancer-related death in children. Its tumor microenvironment (TME) includes endothelial, glial, and immune cells that influence tumor architecture and progression. Neuropilin-1 (NRP1), a co-receptor for semaphorins and vascular endothelial growth factor (VEGF), is expressed in various cell types during oncogenesis, yet its role in MB progression remains unclear. This study aimed to evaluate the expression and localization of NRP1 and glial fibrillary acidic protein (GFAP) in MB tissue. Methods: We analyzed MB tissue samples using immunohistochemistry, immunofluorescence, and quantitative PCR. Samples were stratified by molecular subgroup (WNT, SHH, non-WNT/non-SHH). We assessed NRP1 expression in tumor-associated microglia/macrophages (TAMs) and endothelial cells, as well as GFAP expression in astrocytes and tumor cells. Histopathological correlations and survival analyses were also conducted. Results: NRP1 was consistently expressed by TAMs across all MB molecular subgroups. Tumor vasculature showed strong endothelial NRP1 expression, while perivascular astrocytic coverage was frequently absent. Astrocytic processes exhibited spatial differences according to tumor histology. In SHH-MBs, a subset of tumor cells showed aberrant GFAP expression, which correlated with tumor recurrence or progression. Conclusions: NRP1 and GFAP display distinct expression patterns within the MB microenvironment, reflecting subgroup-specific biological behavior. Endothelial NRP1 positivity combined with limited vascular-astrocytic interaction and aberrant GFAP expression in SHH-MB may contribute to dysregulated angiogenesis and tumor progression. These findings warrant further investigation to explore their prognostic and therapeutic implications. Full article

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy. Full article

(1) Background: The escalating issue of soil degradation caused by excessive chemical fertilizer application poses significant threats to the sustainable development of Chinese flowering cabbage (Brassica campestris L. ssp. chinensis (L.) var. utilis Tsen et Lee) production. This research aimed to identify the impacts of reduced chemical fertilizer application integrated with organic amendments on cabbage yield and rhizosphere soil microenvironment characteristics. (2) Methods: A biennial field experiment was conducted during the 2022–2023 growing seasons at Lijun Town, Yinchuan City, Ningxia Hui Autonomous Region. Five treatments were tested: (i) Control (CK, no fertilizer); (ii) Conventional chemical fertilization (CF1, chemical fertilizer only); (iii) Reduced chemical fertilization (CF2, 30% less chemical fertilizer); (iv) CF2 + Well-decomposed chicken manure (FCM, 30% less chemical fertilizer + rotted chicken manure); and (v) CF2 + Vermicompost (FEM, 30% less chemical fertilizer + vermicompost). (3) Results: In 2023, the FCM treatment reduced electrical conductivity (EC) by 24.80% and pH by 2.16%, while the FEM treatment decreased EC by 31.13% and pH by 3.84% compared to controls. The FEM treatment significantly enhanced total nitrogen content by 12.71% and 8.85% relative to CF1 and FCM treatments, respectively. Compared to CF1, FEM increased soil organic matter content by 10.49% in 2022 and 11.24% in 2023. Organic fertilizer amendments elevated available nitrogen, phosphorus, and potassium levels while enhancing sucrase activity: FCM and FEM treatments increased sucrase activity by 23.62% and 32.00%, respectively, in 2022. Organic fertilization improved bacterial diversity and richness, optimized microbial community structure, and increased the relative abundance of Bacillus. It also upregulated microbial metabolic pathways related to carbohydrate and amino acid metabolism. Soil nutrients and bacterial community structure showed positive correlations with yield, whereas soil enzyme activities exhibited negative correlations. Key factors influencing yield were identified as Proteobacteria, Chloroflexi, available potassium, organic matter, available nitrogen, Actinobacteria, Firmicutes, total nitrogen, pH, and sucrase activity. (4) Conclusions: Integrated analysis of yield and soil microenvironmental parameters demonstrates that the fertilization regimen combining 30% chemical fertilizer reduction with vermicompost amendment (FEM) constitutes a more efficient fertilization strategy for Chinese flowering cabbage, making it suitable for regional promotion in the Ningxia area. Full article

Introduction: Accumulating evidence indicates that neutrophils undergo reprogramming of their effector functions as they migrate from the bloodstream into an inflamed tissue. Here, we examined the role of the small ubiquitin-like modifier (SUMO) conjugation in modulating neutrophil functional changes in the inflammatory microenvironment. Methods: Primary human and murine neutrophils were used to assess SUMOylation levels in vitro by Western blotting and results were validated in clinical samples from patients undergoing surgery involving hypothermic circulatory arrest. SUMOylation was inhibited with TAK-981, and its impact on neutrophil migration, NETosis, and phagocytosis was assessed in vitro. The in vivo effect of TAK-981 on neutrophil tissue infiltration was further evaluated using a sterile sponge assay in mice. Results: Our results demonstrated that neutrophil SUMOylation was induced by factors of the inflammatory microenvironment (temperature and oxidative stress) and inflammatory stimulants in vitro, and under conditions of general inflammatory activation in patients. Further, we found that blocking SUMOylation with TAK-981 in vitro blunted neutrophil migration and phagocytosis but did not affect NETosis. Notably, TAK-981 treatment reduced neutrophil accumulation in sterile sponges in mice. Conclusions: Our work identifies SUMOylation as a novel mechanism of neutrophil tissue reprogramming. Blocking SUMOylation may provide a therapeutic option to limit the contribution of neutrophils to inflammation-associated tissue damage. Full article

Fusobacterium nucleatum and activating mutations in the Kirsten rat sarcoma virus oncogene homolog (KRAS) are increasingly recognized as cooperative drivers of colorectal cancer (CRC). F. nucleatum promotes tumorigenesis via adhesion to epithelial cells, modulation of the immune microenvironment, and delivery of virulence factors, while KRAS mutations—present in 60% of CRC cases—amplify proliferative signaling and inflammatory pathways. Here, we review the molecular interplay by which F. nucleatum enhances KRAS-driven oncogenic cascades and, conversely, how KRAS mutations reshape the tumor niche to favor bacterial colonization. We further discuss the use of KRAS as a prognostic biomarker and explore promising non-antibiotic interventions—such as phage therapy, antimicrobial peptides, and targeted small-molecule inhibitors—aimed at selectively disrupting F. nucleatum colonization and virulence. This integrated perspective on microbial–genetic crosstalk offers novel insights for precision prevention and therapy in CRC. Full article

Fibrotic disorders pose a significant global health burden due to limited treatment options, creating an urgent need for novel therapeutic strategies. Amphiregulin (AREG), a low-affinity ligand for the epidermal growth factor receptor (EGFR), has emerged as a key mediator of fibrogenesis through dual signaling pathways. Unlike high-affinity EGFR ligands, AREG induces sustained signaling that activates downstream effectors and promotes the integrin-mediated activation of transforming growth factor (TGF)-β. This enables both canonical and non-canonical EGFR signaling pathways that contribute to fibrosis. Elevated AREG expression correlates with disease severity across multiple organs, including the lungs, kidneys, liver, and heart. The therapeutic targeting of AREG has shown promising antifibrotic and anticancer effects, suggesting a dual-benefit strategy. The increasing recognition of the shared mechanisms between fibrosis and cancer further supports the development of unified treatment approaches. The inhibition of AREG has been shown to sensitize fibrotic tumor microenvironments to chemotherapy, enhancing combination therapy efficacy. Targeted therapies, such as Self-Assembled-Micelle inhibitory RNA (SAMiRNA)-AREG, have demonstrated enhanced specificity and favorable safety profiles in preclinical studies and early clinical trials. Personalized treatment based on AREG expression may improve clinical outcomes, establishing AREG as a promising precision medicine target for both fibrotic and malignant diseases. This review aims to provide a comprehensive understanding of AREG biology and evaluate its therapeutic potential in fibrosis and cancer. Full article

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. It also functions as a potent non-enzymatic antioxidant, protecting tissues from oxidative stress. REG3A expression is tightly regulated by inflammatory stimuli and is robustly induced during immune activation, where it limits microbial invasion, dampens tissue injury, and promotes epithelial repair. Beyond its antimicrobial and immunomodulatory properties, REG3A contributes to the resolution of inflammation and the maintenance of tissue homeostasis. However, its role in cancer is highly context-dependent. In some tumor types, REG3A fosters malignant progression by enhancing cell survival, proliferation, and invasiveness. In others, it acts as a tumor suppressor, inhibiting growth and metastatic potential. These opposing effects are likely dictated by a combination of factors, including the tissue of origin, the composition and dynamics of the tumor microenvironment, and the stage of disease progression. Additionally, the secreted nature of REG3A implies both local and systemic effects, further modulated by organ-specific physiology. Experimental variability may also reflect differences in methodologies, analytical tools, and model systems used. This review synthesizes current knowledge on the pleiotropic functions of REG3A, emphasizing its roles in epithelial defense, immune regulation, redox homeostasis, and oncogenesis. A deeper understanding of REG3A’s pleiotropic effects could open up new therapeutic avenues in both inflammatory disorders and cancer. Full article

Hepatocellular carcinoma (HCC) is a malignancy with a complex pathogenesis, course, and prognosis with increasing incidence. The most significant contributing factor to the development of HCC is the chronic process of inflammation and remodeling of the cirrhotic liver, in which the interaction between the tumor microenvironment (TME) and cancer cells plays a pivotal role. In recent years, increasing focus has been directed toward the role of platelets (PLTs) in mediating interactions between tumor cells and the TME and in the progression and spread of HCC, as well as other cancers. Due to their abundance in the bloodstream and intracellular granules rich in mediators facilitating their ability to modulate the immune system, PLTs play a significant role in carcinogenesis. In the context of HCC, the role of PLTs in the healing and regeneration processes of the liver has been recognized for some time. In recent years, there has been an increasing utilization of PLTs in prognostic models for patients with HCC. Given their role and the availability of clinical options that block PLTs’ action, clinical trials of platelet blockers in the adjunctive treatment of HCC are becoming increasingly common. However, further research, both preclinical and clinical, is necessary to fully elucidate the role of PLTs in HCC and their potential use as a therapeutic target. In this literature review, we summarize the current knowledge on PLTs in HCC and focus on their potential use in everyday clinical practice. Full article

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized ¹³C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized ¹³C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) ¹H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response. Full article

Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article

Background: Bone marrow mesenchymal stem cells (BM-MSCs) are significant in chemo- and radiotherapy resistance. Previous research has focused on BM-MSCs, demonstrating their functional involvement in cancer progression as mediators in the tumor microenvironment. They play multiple roles in tumorigenesis, angiogenesis, and metastasis. BM-MSC-derived exosomes (BM-MSCs-exo) are small vesicles, typically 50–300 nm in diameter, isolated from BM-MSCs. Some studies have demonstrated the tumor-suppressive effects of BM-MSCs-exo. Objective: This study aimed to investigate their role in modulating the impact of chemoradiotherapy (CRT) in different types of cervical cancer spheroid cells. Methods: The spheroids after treatment were subject to size measurement, cell viability, and caspase activity. Then, the molecular mechanism was elucidated by Western blot analysis. Results: We observed a reduction in spheroid size and an increase in cell death in HeLa spheroids, while no significant changes in size or cell viability were found in SiHa spheroids. At the molecular level, CRT treatment combined with BM-MSCs-exo in HeLa spheroids induced apoptosis through the activation of the NF-κB pathway, specifically via the NF-κB1 (P50) transcription factor, leading to the upregulation of apoptosis-related molecules. In contrast, CRT combined with BM-MSCs-exo in SiHa spheroids exhibited an opposing effect: although cellular viability decreased, caspase activity also decreased, which correlated with increased HSP27 expression and the subsequent downregulation of apoptotic molecules. Conclusion: Our study provides deeper insight into the potential of BM-MSCs-exo in cervical cancer treatment, supporting the development of more effective and safer therapeutic strategies for clinical application. Full article

Masting, or the synchronous and intermittent production of seeds, can have profound consequences for Tropical Montane Cloud Forest (TMCF) tree populations and the trophic webs that depend on their mass flowering and seeds. Over the past 80 years, the importance of Fagus mexicana Martínez (Mexican beech) masting has become apparent in terms of conservation and management, promoting regeneration, and conserving endangered tree species, as well as the conscientious development of edible beechnuts as a non-timber forest product. The establishment of the relict-endemic Mexican beech is unknown, and several microenvironmental factors could influence natural regeneration. Thus, this study was conducted in two well-preserved Mexican beech forests to assess the influence of light incidence and soil moisture on the natural germination and seedling establishment of beeches. During two masting years (2017 and 2024), we assessed in situ beechnut germination and establishment. We tested the effect of the microenvironment of the oldest beeches on beechnut germination and seedling establishment. Our study highlights the complexity of the microenvironment of old beeches influencing the early stages of establishment and provides insights into possible conservation actions aimed at mitigating the impact of environmental change and humans. Full article