Search Results (12,782)

Lipophenols, combining phenolic and lipid moieties in a single molecule, are valuable candidates for providing enhanced bioactive properties with therapeutic potential, including anti-inflammatory functions associated with immune-mediated diseases such as intestinal bowel disease (IBD). Thus, palmitoyl–epigallocatechin gallate (PEGCG), a lipophilic derivative of epigallocatechin gallate (EGCG), has been highlighted for its enhanced stability in lipid-rich environments and bioavailability due to improved cellular uptake. However, the contribution of lipophilic esterification to PEGCG’s capacity to inhibit inflammation and the development of harmful autoimmune responses remains underexplored. This work uncovered the differential efficiency of EGCG and its palmitoyl derivative in modulating, in vitro, the interleukin profile generated by intestinal epithelium under inflammatory conditions. Therefore, both could attenuate the immune response by lowering macrophage migration and polarisation towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. While the fatty acid moiety gave PEGCG a functional advantage over EGCG in adjusting the interleukin-based response of intestinal epithelium to inflammation—since both of them decreased, to a similar extent, the expression of pro-inflammatory interleukins, namely IL-6, IL-17, IL-18, IL-23, and TNF-α (which lowered by 11.2%, on average)—the former was significantly more efficient in cushioning the increase in IL-1β and IL-12p70 (by 9.2% and 10.4%, respectively). This immune modulation capacity did not significantly impact the migration and expression of costimulatory molecules featuring M1 (CD86⁺) or M2 (CD206⁺) phenotypes by THP-1-derived macrophages, for which both bioactive compounds exhibited equivalent efficiency. Nonetheless, the analysis of the pro- and anti-inflammatory interleukins secreted by differentiated macrophages allowed the identification of an advantage for PEGCG, which decreased the expression of the pro-inflammatory immune mediators IL-1β and IL-12p70, IL-23, and TNF-α more efficiently. These results suggest that lipophilisation of phenolic compounds presents exciting potential for extending their application as functional molecules by combining the effects of their polar head with their ability to interfere with membranes, conveyed by their lipophilic tail. In addition, the enhanced reactivity would confer a higher capacity to interact with cellular signalling molecules and thus inhibit or attenuate the immune response, which is of special interest for preventing the onset and severity of immune-mediated pathologies such as IBD. Full article

Monocytes/macrophages promote the repair of acutely injured muscle while contributing to dystrophic changes in chronically injured muscle in Duchenne muscular dystrophy (DMD) patients and animal models including mdx and mdx^5cv mice. To elucidate the molecular mechanisms underlying this functional difference, we compared the transcriptomes of intramuscular monocytes/macrophages from wild-typed (WT) uninjured muscles, WT acutely injured muscles, and mdx^5cv dystrophic muscles, using single cell-based RNA sequencing (scRNA-seq) analysis. Our study identified multiple transcriptomically diverse monocyte/macrophage subclusters, which appear to be induced by the intramuscular microenvironment. They expressed feature genes differentially involved in muscle inflammation, regeneration, and extracellular matrix (ECM) remodeling, but none of them conform to strict M1 or M2 activation. The Gpnmb⁺Spp1⁺ macrophage subcluster, an injury-associated subcluster that features the signature genes of reported scar-associated macrophages (SAMs) involved in ECM remodeling and fibrosis, is present transiently in acutely injured muscle and persistently in chronically injured dystrophic muscle, along with the persistence of monocytes. Our findings suggest that the persistent monocyte/macrophage infiltration and activation induced by continuous injury may underlie the pathogenic roles of macrophages in mdx^5cv muscles. Controlling muscle injury and subsequent macrophage infiltration and activation may be important to the treatment of DMD. Full article

Type 2 diabetes is a serious public health problem in the 21st century. To find new substances supporting diabetes therapy, researchers are increasingly paying attention to the biological potential of edible flowers. This study assessed the antidiabetic potential of ethanol, 50% ethanol, and water extracts from Paeonia officinalis L., Forsythia × intermedia, Gomphrena globosa L., and Clitoria ternatea L. flowers. Extracts were tested for antioxidant activity (DPPH, ABTS, FRAP, CUPRAC, and Fe²⁺ chelation), enzyme inhibition (α-glucosidase, α-amylase, hyaluronidase, and cholinesterases), and anti-inflammatory effects (NO inhibition in LPS-stimulated RAW264.7 macrophages). Phytochemical composition was also analysed. Extracts of P. officinalis stood out with the highest total phenolic content (50% ethanol extract of P. officinalis 178.49 mg GAE/g) and total flavonoid content (aqueous extracts of P. officinalis 4.27 mg QE/g), high gallic acid level, and the effective inhibition of α-glucosidase and α-amylase (α-glucosidase inhibition 98–99% for all P. officinalis extracts, and α-amylase inhibition ~ 100% for ethanolic extract). Strong hyaluronidase (76.9–95.5%) and cholinesterase inhibition was also observed. F. × intermedia extracts were rich in rutin and chlorogenic acid and showed potent inhibitory effects on α-glucosidase (50% ethanol extract 91.59%), α-amylase (aqueous extract 89.35%), and hyaluronidase (aqueous extract 73.8%). Ethanol extracts of G. globosa exhibited a high α-amylase inhibition (93–95%). Although C. ternatea showed moderate antioxidant activity, it showed an apparent anti-inflammatory effect, effectively reducing NO production in activated macrophages for 50% ethanol extract. In summary, P. officinalis and F. × intermedia flowers are promising sources of extracts with antioxidant, antidiabetic, and anti-inflammatory effects supporting their use in further research on type 2 diabetes therapy. Full article

Background: Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic drugs is important. Natural products are the source of secondary metabolites with different biological activities, such as antibacterial, anticancer, anti-inflammatory, and antiparasitic. Objectives: In this work, secondary metabolites (phenols and terpenes) from natural products were selected to be evaluated against the epimastigotes of NINOA and A1 strains of Trypanosoma cruzi and the promastigotes of M379 strain and FCQEPS native isolate of Leishmania mexicana. Additionally, their cytotoxicity and selectivity index were determined. Methods: Eighteen secondary metabolites were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes; additionally, their cytotoxicity on the J774.2 macrophage cell line was determined. Results: The compounds l-(-)-menthol (14, IC₅₀ = 24.52 µM) and β-citronellol (11, IC₅₀ = 21.54 µM) had higher trypanocidal activity than the reference drug (benznidazole) against NINOA and A1 strains of T. cruzi, respectively. On the other hand, para-anisyl alcohol (4, IC₅₀ = 34.89 µM) had higher leishmanicidal activity than the reference drug (glucantime^®) against M379 and the FCQEPS native isolate of L. mexicana. Finally, in silico, the determination of their pharmacokinetic and toxicological properties showed that they are promising candidates for oral and topical uses. Conclusions: This study opens the possibility of using secondary metabolites as scaffolds for access to the development of new molecules for the treatment of parasite diseases. Full article

Extracellular vesicles (EVs) are nanoscale, membrane-bound particles secreted by diverse cell types and act as pivotal mediators of intercellular communication during bone regeneration. These vesicles transport bioactive cargo including proteins, lipids, mRNAs, and microRNAs that modulate osteogenesis, angiogenesis, and immune responses within the bone microenvironment. EVs originating from mesenchymal stem cells, osteoblasts, endothelial cells, and macrophages have demonstrated substantial potential to promote bone formation, inhibit bone resorption, and enhance vascularization. This review examines the biogenesis, classification, and cellular uptake mechanisms of EVs, focusing on their roles in osteogenesis and their therapeutic applications in fracture healing, osteoporosis, and bone tissue engineering. Despite their promise, significant challenges remain, including the need for standardization, scalable production, and assessment of long-term safety to enable clinical translation of EV-based therapies. Here, we provide a comprehensive overview of EV biology, elucidate the molecular mechanisms of EVs in bone regeneration, and discuss innovative strategies to optimize their therapeutic efficacy, highlighting their potential as next-generation orthobiologics. Full article

Cancer is a leading cause of death worldwide, causing about 10 million deaths annually. Obesity contributes to cancer progression by inducing chronic inflammation, immunosuppressive microenvironment, metabolic dysfunction, and therapeutic resistance. Accumulating evidence shows that obesity can advance the infiltration of immunosuppressive cells and ameliorate the function and cytotoxicity of tumor-killing cells such as natural killer cells, natural killer T cells, macrophages, and CD8 T cells in cancer patients, resulting in cancer progression. Understanding the molecular signaling pathways involved in obesity-induced immunosuppression and cancer cell proliferation enables us to screen new biomarkers for cancer early diagnosis and improve anti-tumor therapeutic efficacy in obese patients with cancer. In this review, we first review the molecular mechanisms by which obesity induces the immunosuppressive landscape in the tumor microenvironment and some key obesity-associated factors causing immunotherapeutic suppression and metabolic dysfunction. Then, the application of natural products in the treatment of obesity and obesity-associated cancers is summarized. In addition, we discuss the contradictory functions of obesity in cancer risk and treatment outcome. The potent roles of precision medicine and artificial intelligence in the management of obesity-related cancers are highlighted. Full article

Osteoarthritis (OA) is an inflammatory joint disease and the leading cause of musculoskeletal disability affecting human and veterinary patients. New therapeutics halting inflammation while preserving joint homeostasis remain a critical need. Voltage-gated sodium (NaV) channels regulate the pro-inflammatory response of macrophages in the synovium, the central driver of joint homeostasis. Neosaxitoxin (NeoSTX) is a phycotoxin that blocks NaV channels, conferring a unique potential to regulate joint inflammation. This study evaluated the safety of intra-articular administration of NeoSTX in horses. Sixteen horses were allocated into two groups (n = 8/each). One group received one intraarticular dose (20 µg/2 mL of saline) of NeoSTX into one tarsocrural joint, while the control group received 2 mL of saline (0.9% NaCl). No differences were observed between groups for systemic or local signs of inflammation, including objective measures of surface temperature and joint effusion. Concentrations of synovial fluid total nucleated and differential cell counts, total protein, glucose, calcium, and 23 cytokines/chemokines measured throughout this study did not differ between treatment groups. In this short-term study, intra-articular NeoSTX injection was shown to be well tolerated and likely safe. Ongoing studies should elucidate the role of NeoSTX in modulating synovial mechanisms of inflammation and its endogenous resolution. Full article

Chronic inflammation is closely associated with various diseases, underscoring the need for natural, biocompatible anti-inflammatory candidates. For this purpose, mussel foot protein could be an excellent candidate due to its diverse biological activities. Hence, this study systematically evaluates the anti-inflammatory effects of a highly soluble mussel foot protein (HMFP) and HMFP-PEG using LPS-stimulated RAW264.7 cells as an in vitro inflammation model. The results reveal that both HMFP and HMFP-PEG markedly reduced intracellular reactive oxygen species (ROS) levels and suppressed the secretion of pro-inflammatory mediators, including IL-1β, TNF-α, and NO, while promoting the production of anti-inflammatory cytokines such as IL-10 and TGF-β. Mechanistically, both agents markedly inhibited the LPS-induced phosphorylation of PI3K, Akt, NF-κB, and IκB, indicating that their anti-inflammatory effects are mediated via suppression of the PI3K/Akt and NF-κB signaling pathways. Furthermore, HMFP and HMFP-PEG downregulated the expression of the inflammatory marker iNOS and markedly upregulated the M2 macrophage marker CD206, suggesting a role in promoting macrophage polarization toward an anti-inflammatory M2 phenotype. Notably, NF-κB signaling was identified as a key mediator in the anti-inflammatory mechanisms of both HMFP and its PEG-modified form. Collectively, these findings demonstrate that HMFP and HMFP-PEG exert significant anti-inflammatory effects through dual inhibition of NF-κB and PI3K/Akt signaling and by promoting M2 macrophage polarization, indicating their potential as promising candidates for the treatment of inflammation-related diseases. Full article

Bixin, an apocarotenoid from Bixa orellana seeds, is a valuable natural pigment with industrial and pharmacological applications. Traditional extraction methods rely on organic solvents, but eco-friendly alternatives like silk fibroin solution (SFS) are emerging. This study evaluated SFS for bixin extraction from annatto seeds, optimizing conditions using Box-Behnken Design (BBD). The optimal parameters 1.5% SFS, 60 °C, and 60 min yielded 10.87 mg/mL (liquid extract of annatto seeds, LEAS + SFS) and 150.72 mg/g (solid extract of annatto seeds, SEAS + SFS). Cell viability was assessed in human dermal fibroblasts (HDFn) and RAW 264.7 murine macrophages via MTT assay. After 24 and 72 h, LEAS + SFS, SEAS + SFS, purified bixin (PB), and SFS maintained >70% viability in HDFn cells. Similarly, RAW 264.7 cells showed >70% viability after 24 h, indicating low cytotoxicity. These results highlight the biocompatibility of SFS-extracted bixin, supporting its potential in food, cosmetics, and biomedicine. The study demonstrates that SFS is an effective, sustainable alternative to traditional solvents, offering high extraction efficiency and minimal toxicity. This method aligns with green chemistry principles, providing a promising solution for bixin production. Full article

Mistletoe (Viscum album L.) has been used in complementary cancer therapy for decades, but its mechanisms remained poorly understood until recently. This review synthesizes transformative advances in mistletoe cancer research from 2020 to 2025, focusing on newly discovered molecular mechanisms, immunomodulatory properties, and clinical applications. We conducted a comprehensive analysis of controlled studies, mechanistic investigations, and real-world evidence published between 2020 and 2025. The discovery of mistletoe-induced immunogenic cell death (ICD) represents a paradigm shift in understanding its anticancer effects. Mistletoe extracts trigger endoplasmic reticulum stress, leading to calreticulin exposure in 18–51% of cancer cells and a 7-fold increase in adenosine triphosphate (ATP) release. Three-dimensional culture models revealed enhanced macrophage reprogramming effects, with a 15.8% increase in pro-inflammatory interleukin (IL)-6 and a 26.4% reduction in immunosuppressive IL-10. Real-world evidence from over 400 non-small-cell lung cancer patients shows that combining mistletoe with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors doubles median overall survival (6.8 to 13.8 months), with biomarker-selected populations experiencing up to a 91.2% reduction in death risk. The Johns Hopkins Phase I trial established intravenous administration safety at 600 mg three times weekly. Advanced analytical approaches including metabolomics, chronobiology, and machine learning are enabling precision medicine applications. These findings position mistletoe as a scientifically validated component of integrative oncology, bridging traditional medicine with evidence-based cancer care. Future research should focus on ferroptosis mechanisms, single-cell immune profiling, and standardized clinical protocols. Full article

Toxoplasma gondii is a globally distributed protozoan parasite and a major cause of congenital infections, particularly in South America. Current therapies for congenital toxoplasmosis are limited by toxicity, long treatment regimens, and suboptimal efficacy, highlighting the urgent need for safer and more effective alternatives. In this study, we evaluated the antiparasitic effects of crude ethanolic extract of Brazilian Red Propolis (BRP) and its isolated compounds, focusing on 7-O-methylvestitol, in human trophoblast (BeWo) cells and third-trimester placental explants. Both BRP and 7-O-methylvestitol significantly reduced T. gondii adhesion, invasion, and intracellular replication, without compromising host cell viability. Ultrastructural analyses revealed irreversible parasite damage, and cytokine profiling demonstrated immunomodulatory effects, with enhanced production of interleukin (IL)-6, IL-8, and macrophage migration inhibitory factor (MIF) in BeWo cells and downregulation of IL-6, MIF, and tumor Necrosis Factor (TNF) in infected placental villi. Notably, 7-O-methylvestitol reproduced and, in some assays, surpassed the antiparasitic activity of BRP, suggesting it as a key bioactive constituent responsible for the therapeutic potential of the extract. These findings support the identification of 7-O-methylvestitol as a promising lead compound for structure-based drug design and repositioning strategies, advancing the development of novel, safe, and targeted therapies against congenital toxoplasmosis. Full article

Lactobacillus species play a fundamental role in maintaining a healthy vaginal microbiota and have been increasingly recognized for their protective effects against high-risk human papillomavirus (HR-HPV) infection and the progression of cervical intraepithelial neoplasia (CIN). These beneficial bacteria contribute to host defense through multiple mechanisms, including the production of lactic acid that sustains a low vaginal pH, enhancement of epithelial barrier integrity via E-cadherin regulation, and modulation of immune signaling pathways such as interferon responses and NF-κB activity. Lactobacillus strains exert anti-inflammatory effects by downregulating pro-inflammatory cytokines and interfering with oncogenic pathways including Wnt/β-catenin and the expression of HPV E6 and E7 proteins. Additionally, they may regulate tumor-suppressor microRNAs and modulate dendritic cell and macrophage activity, supporting antiviral immunity. Recent studies have explored their potential influence on CIN regression and HR-HPV clearance, particularly the strains Lactobacillus crispatus and L. gasseri, which are associated with favorable microbial community states. This review explores the potential mechanisms through which Lactobacillus species contribute to HR-HPV clearance and the regression of cervical dysplasia, integrating evidence from molecular studies, in vivo models, and clinical trials. The emerging role of probiotic interventions as adjunctive strategies in HPV management is also discussed, highlighting their possible synergy with conventional treatments and prophylactic vaccination. Full article

Background/Objectives: Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. Methods: We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer types, uncovering diverse expression, mutation, and epigenetic patterns. Results: Key regulators such as IGF2BP3, CFI, and ELF3 showed cancer-specific prognostic significance. We developed an RNA Modification Score (RMS) with strong prognostic performance (AUC up to 0.92), correlating with the tumor stage, immune infiltration, and immunotherapy response. High-risk groups exhibited immune checkpoint dysregulation and enriched M1 macrophages in glioblastoma. Drug screening highlighted oncrasin-72 as a potential therapy. Validation via single-cell/spatial transcriptomics and immunohistochemistry confirmed the spatial localization of critical genes like CFI and ELF3. Conclusions: Our study reveals the multifaceted role of RNA modifications in cancer, providing a translational framework for personalized prognosis and therapy in precision oncology. Full article

Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Methods: Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC). Results: Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses. Conclusions: Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape. Full article

Osteochondral regeneration remains a major clinical challenge due to the complex architecture and biomechanical demands of the osteochondral unit. Bioactive hydrogels have emerged as promising materials capable of supporting repair through their capacity to mimic the extracellular matrix (ECM), enable cell encapsulation, and deliver bioactive cues. However, recent insights reveal that simply engineering hydrogels for structural and cellular support is insufficient. A new paradigm is emerging—one that embraces the complexity of the osteochondral niche by integrating immunomodulatory and mechanobiological cues into biomaterial design. In particular, the hydrogel’s capacity to modulate macrophage polarization and support the immunoregulatory function of mesenchymal stem cells (MSCs) is critical to orchestrate regenerative outcomes. Simultaneously, the mechanical properties of hydrogels—such as stiffness, porosity, and viscoelasticity—can profoundly influence stem cell fate and local tissue morphogenesis. This review discusses recent advances in hydrogel-based strategies for osteochondral repair, highlighting the interplay between immunological signals and the mechanical microenvironment, and calls for a shift from reductionist tissue-engineering approaches to systems-level design of tunable, immuno-mechanobiological microenvironments. Full article