Search Results (4,144)

Pluripotent stem cell (PSC) differentiation is orchestrated by intricate autocrine and paracrine signaling networks. Among these, exosomes, key components of the cellular secretome, are implicated as crucial mediators of intercellular communication via delivery of bioactive molecules, including microRNAs (miRNAs). This study investigated the role of exosomal miRNAs in stem cell differentiation using Dgcr8-deficient mouse embryonic stem cells (mESCs), which are incapable of producing mature miRNAs. Although the differentiation capacity was markedly impaired in these cells, partial restoration was observed following treatment with exosomes derived from differentiating wild-type mESCs. Exosomal miRNA uptake was confirmed, and gene ontology analysis revealed significant enrichment of pathways associated with cell fate determination, morphogenesis, and apoptosis regulation. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that exosomal miRNAs modulated multiple osteoinductive signaling cascades, notably the MAPK and TGF-β pathways, in Dgcr8-deficient cells. Apoptotic markers were also downregulated, suggesting a protective effect conferred by the exosomal cargo. Collectively, our results suggest that exosome-mediated delivery of miRNAs may represent a fundamental mechanism by which pluripotent stem cells coordinate stress responses and differentiation trajectories, providing novel insights into the regulation of embryogenesis. Full article

The apple (Malus domestica Borkh.) is one of the most widely consumed fruits worldwide due to its pleasant sensory properties and rich phytochemical composition. Therefore, the present study aimed to comprehensively investigate the chemical composition, antioxidant activity, anticancer effects, and molecular interactions of peel and pulp extracts of the Hünkar apple cultivar collected from different locations, using a combined experimental and computational strategy. These factors had a big effect on the extracts’ phenolic composition and biological activity. Moreover, the anticancer results were corroborated by molecular docking analyses, which offered further understanding of the interactions between bioactive compounds and cancer-associated target proteins. This integrative approach underscores the impact of both biological and methodological variables on the antioxidant and anticancer properties of apple-derived extracts, reinforcing their potential as natural sources of bioactive compounds. Cytotoxic activity against HT-22 and C6 cell lines was evaluated using the MTT assay, showing dose- and time-dependent antiproliferative effects. Apple extracts exhibited anticancer effects that were dependent on dosage and duration. The activities of chemicals found in extracts of Hünkar apple samples collected from four different locations against brain cancer proteins (PDB ID: 2DME, 6YPE, 1RV1) were examined. ADME/T analysis was then performed on the three molecules with the highest activity. The quantum chemical properties of these three molecules were also examined using the Gaussian package program with B3LYP, HF, M062X level in 6–31g, 6–31++g, and 6–31++g(d,p) basis sets. Full article

Nanoemulsions are pivotal carriers which are increasingly adopted as carriers for poorly soluble active molecules. This review provides a critical overview of ‘green’ nanoemulsions, which are systems based on renewable, biodegradable, and non-toxic components and/or using sustainable production techniques. We here focus on the role of food-grade oils (including poly-unsaturated fatty acid-rich sources) and green excipients, with special attention on the interfacial properties of biosurfactants such as proteins, polysaccharides, and small-molecule surfactants. This review provides a critical overview of the formulation principles, interfacial phenomena, and physicochemical stability of green nanoemulsions, with reference to topical and pharmaceutical applications. The performance of nanoemulsions as delivery systems for bioactive lipids, essential oils, vitamins, carotenoids, phenolic compounds, and conventional drugs is examined through representative case studies. Known limitations, including oxidative instability, compositional variability, and difficulties in large scale production, are analyzed along with future opportunities in multifunctional formulations and sustainable processing. Overall, green nanoemulsions emerge as promising next-generation platforms for safe, effective, and environmentally friendly drug delivery. Full article

(1) Background: Gastric cancer (GC) remains a major global health challenge due to its high heterogeneity and aggressive progression. The discovery of novel bioactive molecules with anticancer properties has, therefore, become a critical research focus. In this study, we synthesized and characterized 4,4′-(5,8-dioxa-2,11-diazadodecane-1,11-diene-1,12-diyl)diphenol (DODP) and evaluated its anticancer potential using molecular docking, bioinformatics, and experimental analyses. (2) Methods: The chemical structure of DODP was confirmed through ¹H and ¹³C NMR spectroscopy. Molecular docking was conducted to examine the interaction of DODP with apoptosis and cell cycle-related proteins (TP53, MDM2, and MYC) and the immune checkpoint marker CD274 (PD-L1). Cytotoxicity against AGS GC cells was determined using the MTT assay at concentrations ranging from 0.01 to 50 µM, and gene expression alterations were analyzed by quantitative polymerase chain reaction (qPCR) and bioinformatics evaluation. (3) Results: NMR data verified the successful synthesis of DODP. The docking results indicated strong binding affinity, especially with TP53 and CD274. DODP showed notable cytotoxicity after 72 h of exposure and induced upregulation of TP53, MYC, and CD274 and downregulation of MDM2 in AGS cells. Although the patterns were consistent with cell-based and bioinformatic analyses, significant discriminatory ability in blood samples was observed only for MYC (AUC = 0.651; p = 0.044). (4) Conclusions: DODP influenced apoptosis-associated transcriptional responses in GC, offering early mechanistic evidence that should be evaluated in more comprehensive biological models. Full article

The rise of antimicrobial resistance and the global burden of cancer demand innovative therapeutic strategies. Frog skin secretions offer a rich source of bioactive peptides, some of which exhibit remarkable dual functionality—potent antimicrobial activity coupled with selective anticancer effects. This review highlights frog skin-derived peptides that bridge the gap between antimicrobial and anticancer therapeutics, emphasizing their structural diversity, mechanisms of action, and translational potential. A comprehensive literature search was conducted to identify peptides isolated from diverse anuran species, with emphasis on studies reporting structural features, activity against Gram-positive and Gram-negative bacteria, including multidrug resistant clinical isolates, anticancer effects, and underlying molecular mechanisms of cytotoxicity. Peptides such as dermaseptins, temporins, and brevinins disrupt microbial membranes while triggering apoptosis or necrosis in cancer cells. Key physicochemical characteristics, including net positive charge, amphipathicity, and α-helical conformation, contribute to their dual functionality. Recent advances in peptide engineering and delivery have improved stability, selectivity, and therapeutic efficacy, enhancing the clinical prospects of these naturally occurring bioactive molecules. Frog skin peptides represent promising candidates for the development of next-generation antimicrobial and anticancer therapeutics. Full article

Terpenoids represent a large class of bioactive natural compounds with promising pharmacological properties, including anti-inflammatory, antimicrobial, and anticancer activities. However, their clinical application is often limited by poor aqueous solubility, low membrane permeability, and suboptimal bioavailability. Phytosomal delivery systems have emerged as a promising strategy to enhance the pharmacokinetic performance of plant-derived compounds by forming molecular complexes between bioactive molecules and phospholipids. This review critically examines the structural principles, preparation methods, physicochemical characterization, and biological performance of terpenoid phytosomes. Particular attention is given to the molecular interactions between terpenoids and phospholipids that govern complex formation and vesicular assembly. The review also summarizes current analytical techniques used to confirm phytosome formation and discusses the influence of formulation parameters, including phospholipid composition and molar ratios, on stability and biological activity. In addition, emerging insights from molecular modeling and membrane interaction studies are considered to better understand the mechanisms underlying improved drug delivery. Finally, challenges related to safety assessment, manufacturing scalability, and clinical translation of phytosomal systems are discussed. Overall, terpenoid phytosomes represent a promising nanodelivery platform capable of improving the pharmacokinetic profile and therapeutic potential of terpenoid compounds. Full article

Dysregulated angiogenesis is involved in cancer and numerous ischemic, autoimmune and inflammatory diseases, prompting extensive research that has yielded a growing array of angiogenesis-modulating molecules used in clinical practice. The dietary phytocomplex of Cruciferous vegetables exhibits multiple biological activities in both in vitro and in vivo models. However, the impact of a myrosinase-activated broccoli extract (MaBE) on angiogenesis, as well as on stromal–endothelial interactions governing endothelial cell behavior, has not yet been explored. We investigated the effects of MaBE on endothelial–stromal crosstalk using endothelial cells (HUVECs) and fibroblasts (HFF1) both individually and in a fibroblast-conditioned medium model. MaBE dose-dependently inhibited endothelial viability, migration and tube formation, key steps of angiogenesis, through interference with the VEGF–VEGFR2 axis. Notably, MaBE also markedly suppressed HFF1-driven HUVEC migration and capillary-like structure formation, likely through the inhibition of fibroblast motility and the downregulation of VEGF and angiogenin signaling in HFF1 cells. Overall, these findings provide new insight into MaBE regulation of pro-angiogenic behaviors in both endothelial cells and fibroblasts while disrupting their functional interplay. By targeting multiple cellular compartments and key mediators involved in angiogenesis, MaBE emerges as a promising bioactive extract with potential relevance for the management of pathological angiogenesis-related disorders. Full article

Bee pollen is an extraordinary nutritional product of honeybees. Its valuable profile depends on the concentration of bioactive compounds, influenced by multiple factors, such as geographical origin and botanical species. Pollen samples produced by a single farm and collected during four different seasonal periods were first subjected to palynological analysis and then evaluated for their volatile profile and the content of selected nutraceutical compounds. The June sample, characterized by a high percentage of Castanea pollen, exhibited the higher concentration of soluble sugars, proteins, antioxidant molecules and minerals. The heatmap and hierarchical clustering confirmed a pronounced seasonal variability in bee pollen volatile composition, strongly linked to changes in floral availability. The greatest dissimilar volatilomic fingerprints are represented by samples collected in November (monofloral pollen of Hedera helix) and April (polyfloral pollen). The seasonal variability on the bioactive compounds, as well as in aromatic composition, seem to be linked to the different compositions of plant pollen, related to its botanical origin. This study expands current knowledge on the chemical characterization of bee pollen and supports the use of volatilome analysis as a complementary tool to palynological investigation for assessing botanical origin, quality, and the ecological and sensory value of this bee product. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds—sesquiterpene lactones (achillin and polymatin A) and naphthoquinones (α, β-lapachone and lapachol)—in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC₅₀ values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. The naphtoquinones α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC₅₀ of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure–activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research. Full article

Bacterial membrane vesicles (BMVs) are non-replicative, bilayered nanostructures secreted by both Gram-negative and Gram-positive bacteria. Rather than being passive byproducts of cell envelope turnover, BMVs are increasingly recognized as regulated particles that selectively package proteins, lipids, nucleic acids, and other bioactive molecules. Through these cargos, BMVs mediate a wide range of biological processes, including bacterial stress adaption, intercellular communication, virulence delivery, and host immune modulation. In this review, we integrate recent advancements in understanding the molecular mechanisms underlying BMV biogenesis and composition and discuss how their heterogeneity contributes to their functional diversity. Beyond their biological roles, we critically examine the translational potential of BMVs in vaccine development, targeted drug delivery, cancer therapy, diagnostic tools, and biotechnological applications. However, significant challenges related to their safety, efficacy, and large-scale production must be addressed to realize their full clinical potential. We review recent progress and ongoing obstacles in the use of BMVs across various biomedical applications and propose strategies for their clinical translation. Full article

Sphingolipids, first discovered in 1874 by Johann Thudicum, are among the eight recognized classes of lipids and are present in essentially all plants, animals, and fungi, as well as some viruses and prokaryotes. In mammals, sphingolipids are enriched in the central nervous system (CNS), where they play vital roles in tissue development; membrane structure; cell adhesion and recognition; and, importantly, signaling. A subset of sphingolipids including ceramide, glucosylceramide, and sphingosine has been shown to have bioactive properties, but two sphingolipids in particular (ceramide-1-phosphate and sphingosine-1-phosphate) have been shown to exert their effects at least in part due to the activation of cell surface-expressed G protein-coupled receptors. In the CNS, sphingosine-1-phosphate signaling has specifically emerged as a productive therapeutic target for the treatment of neurodegenerative disease, with the first small molecule targeting sphingosine-1-phosphate receptors approved roughly 15 years ago for the treatment of multiple sclerosis. As more specific activators and inhibitors of these receptors have been developed and entered the clinical trial pipeline, now is an appropriate time to examine the current state of our knowledge of the role that these receptors play in the CNS and highlight the current landscape of available modulators targeting these pathways. Full article

Background: Antimicrobial resistance (AMR) is a global healthcare threat. Traditional largely non-selective antibiotics produce side effects due to the natural host microbiome being modified creating a loss in homeostasis. In women, AMR is a cause of acute generational impact. For example, bacterial vaginosis (BV), the most common gynecological infection in reproductive-age women, is a serious public health concern due to its high rates of recurrence, secondary infections, and reproductive issues; and two currently prescribed antibiotics for BV do not fully resolve the symptoms. Objective: The strong need for innovative, potent, safe, and selective therapeutics has prompted a search for such bioactive molecules in milk. Resulting from 200 million years of evolutionary pressure, mammalian lactation not only nourishes infants, but it has also been under relentless Darwinian selective pressure to provide protection from a variety of infections. Methods: Computationally designed human-milk-inspired peptides (AMPs) were tested in standard microbicidal assays for activity against BV pathogens, and evaluated for stability and safety. Results: Several AMPs are bactericidal towards Gardnerella vaginalis, a major BV-associated pathogen, and other BV-associated pathogens. Some novel AMPs do not impact the viability of key lactobacilli linked to a healthy vaginal microbiome. These stable, membrane-acting cationic AMPs reduce inflammation during an infection assay and are safe in EpiVag organoid tissues. Conclusions: AMPs can address concerns like non-selectivity and antibiotic resistance—thereby addressing AMR. Lead AMPs from this study offer a promising solution for the development of novel therapeutics for the treatment of BV, which may reduce the burden of AMR. Full article

Date palm (Phoenix dactylifera L.) by-products from bioethanol production represent an underutilized resource rich in bioactive molecules. This study aims to their valorization through characterization of polysaccharides and phenolic compounds from the Medjool variety, both before and after yeast fermentation for bioethanol production. Three sequential types of by-products were analyzed—Ext1 (post hot-extraction), Ext2 (post fermentation), and Ext3 (post distillation)—and compared with Dat-Me. High Performance Liquid Chromatograp-Diode Array Detector-Mass Spectrometry (HPLC-DAD-MS) analysis allowed identifying 22 phenolic compounds, primarily cinnamic acid derivatives and glycosylated flavones such as luteolin and chrysoeriol. Fermentation increased total phenolic content from dry weight, while leading to an improved polysaccharide recovery (i.e., from 14.2% to 42.1% dry weight). Two polysaccharide fractions (F1 and F2) were isolated and characterized by ¹H-NMR and Dynamic Light Scattering (DLS). F1 is a pectic polysaccharide, with a galacturonic acid content ranging from 24.2% (Ext3) to 52.2% (Dat-Me), a degree of methylation (DM) between 34.4 and 50.6%, and a degree of acetylation (DA) of 23.6–42.2%. F2 consists of a non-pectic polysaccharide, characterized by a low galacturonic acid content (5.6–6.8%) and a DM of 12.6–47.1%, but it is highly acetylated, with a DA ranging from 90.1 to 93.3%. DLS analysis confirmed fermentation-induced depolymerization, with molecular weights ranging from 6.6 × 10⁴ to 8.5 × 10⁵ KDa for both the fractions. Overall, Medjool date by-products obtained after bioethanol production represent a sustainable source of high-value phenolic antioxidants and polysaccharides with different structures suitable for future applications in food, pharmaceutical, and cosmetic formulations. Full article

Antimicrobial resistance (AMR) is one of the most pressing global public health challenges, compromising the effectiveness of standard antibiotic therapies and increasing morbidity, mortality, and healthcare costs. The scarcity of new antibiotics has driven research into alternative strategies to restore or enhance the effectiveness of existing drugs. Natural compounds, including polyphenols, alkaloids, terpenes and terpenoids, antimicrobial peptides, and microbial secondary metabolites, exhibit multitarget activities such as membrane disruption, efflux pump inhibition, biofilm suppression, and quorum sensing interference. In parallel, synthetic and semi-synthetic small-molecule inhibitors have been rationally designed to target specific resistance determinants, including β-lactamases, efflux systems, quorum sensing pathways, and stress-induced mutagenesis mechanisms such as the SOS response and DNA repair processes. These agents act as adjuvants, restoring susceptibility or reducing bacterial virulence without exerting strong selective pressure. The integration of natural bioactive compounds and targeted small-molecule inhibitors represents a promising complementary strategy for conventional antibiotics. Further pharmacological and clinical investigations are required to translate these approaches into effective tools within antimicrobial stewardship programs and broader public health strategies aimed at mitigating the global burden of AMR. This narrative review analyses the recent literature on natural compounds and synthetic or semi-synthetic small-molecule inhibitors with documented activity against antimicrobial resistance mechanisms. Full article

The increasing interest in valorizing agricultural by-products has positioned grape pomace as a rich source of bioactive compounds. This study developed an effect-directed extraction (EDE) approach guided by bioactivity quantification on thin layer chromatography (TLC). Twelve grape pomaces were screened based on antioxidant and tyrosinase inhibitory properties. Using hydroalcoholic solvent (ethanol:water, 1:1), the two most promising sources (Malbec from San Rafael) were subjected to response surface methodology (RSM) to optimize extraction of anti-browning and antioxidant compounds visualized as TLC spots. Temperature and time were optimized (76 °C, 45 min), and samples were analyzed using TLC coupled with DPPH and laccase inhibition bioautography. Antioxidant compounds showed retention factor values on TLC plates of 0.37 and 0.75 (DPPH/ABTS-active), while laccase inhibition occurred at Rf 0.35, coinciding with the primary tyrosinase inhibition zone. However, subsequent bioassay-guided HPLC fractionation and HRMS/MS analysis revealed that tyrosinase and laccase inhibitions are mediated by distinct compounds within this bioactive zone, highlighting a synergistic multi-target effect in the optimized extract that is retained throughout the process. The primary tyrosinase inhibitor at Rf ~0.35 was tentatively elucidated as an acylated anthocyanin, consistent with malvidin-3-O-(p-coumaroyl)glucoside. Optimized extracts were evaluated on Pink Lady apple slices at different timepoints. The browning index was reduced by 25% versus the control at 15 h, confirmed by significantly lower ΔE values (p < 0.05). The process requires only food-grade solvents and conventional equipment, facilitating scale-up for grape pomace generated worldwide. Validating the EDE strategy, this TLC-guided approach successfully tracked and preserved the primary anti-tyrosinase activity from the crude waste matrix down to the tentatively identified molecule, contributing to circular economy objectives in the wine industry. Full article