Search Results (1,758)

Background/Objectives: Flavonoids are a diverse group of dietary polyphenolic compounds associated with a range of important biological activities. However, their low systemic bioavailability and extensive metabolism raise questions about how they exert their purported benefits. Methods: A comprehensive survey of literature published over the past 10 years was conducted, focusing on human, animal, and in vitro studies addressing the metabolic fate of major flavonoid subclasses. Results: Original research articles (n = 159) were selected following predetermined inclusion criteria. Data from diverse experimental models—including intestinal and hepatic systems—demonstrate that flavonoids undergo substantial transformation by Phase I and Phase II enzymes, alongside extensive biotransformation by the gut microbiota. In this critical narrative review we summarize dietary sources, bioavailability patterns, metabolic pathways, and analytical strategies, emphasizing advances enabled by high-resolution mass spectrometry. Recent findings indicate that enterohepatic recirculation and the biological activities of circulating and tissue-associated metabolites contribute significantly to the observed health effects, despite limited levels of parent compounds. Conclusions: Flavonoids exhibit limited oral bioavailability and undergo complex metabolic processing, yet growing evidence indicates that their metabolites play key roles in mediating beneficial effects. Understanding these metabolic pathways is essential for interpreting epidemiological associations and designing more effective intervention studies. Full article

The development of next-generation organotypic platforms and disease models has proven crucial for the progress toward personalized therapeutic solutions in cancer. Fetal bovine serum (FBS) is a nutrient-rich cell culture supplement that contains essential factors for cell growth. However, in addition to ethical and environmental concerns, the manufacturing of tumor models requires a more standardized and controlled environment. This has led to the commercialization of several alternatives for the substitution of FBS, in the form of both animal-based and synthetic products. We here test the use of two alternatives for the culture of glioblastoma cells in the fabrication of organotypic tumor models, in combination with an insightful review of the existing literature, which allows for the elucidation of the most relevant challenges and potential solutions. We assess metabolic activity and cell proliferation in both 2D and 3D culture systems to determine the influence of serum on cell attachment and growth. The 3D culture systems are fabricated by photopolymerization of gelatin methacrylamide to achieve hydrogels that closely mimic the native tissue’s extracellular environment. We aim to advance our understanding of the role of culture media in these models and provide practical guidance to optimize experimental design and enhance reproducibility, thereby facilitating their broader adoption by the research community. These studies are key for the biofabrication of next-generation organoids and other advanced in vitro tumor models. Full article

Biofabrication has significant potential to advance medicine and research by creating complex and anatomically accurate engineered tissues for implantation or in vitro modeling. However, a persisting challenge of the current biofabrication methods, such as hydrogel-based bioprinting, is to find an efficient, affordable, and reproducible method for the generation of hollow and branched geometries. This is critical for the recapitulation of anatomically realistic structures representative of cardiovascular, respiratory, and other organ systems. Existing bioprinting approaches require complex, multi-step processes and expensive specialized equipment, limiting accessibility and extending fabrication time. Here, we present an alternative ‘sacrificial’ method for the rapid and accessible creation of hollow and/or branched hydrogel constructs, which we term ‘soft templating’ (Sof-T). Sof-T utilizes ionic diffusion from a 3D-printed water-soluble polymer to crosslink surface-adsorbed hydrogels followed by the dissolution of the polymer, thus leaving behind the anatomically patterned hydrogels. Using this technique, we readily generated: (1) vascular-like bifurcated aortic conduits, with or without aneurysmal deformities; (2) upper and lower (branched) trachea models; and scale-reduced (3) human hearts and (4) bladders. Overall, Sof-T offers a simple, rapid, and cost-effective strategy for fabricating relatively complex, hollow hydrogel architectures, broadening the access to anatomically relevant constructs for biomedical research and translational and/or educational applications. Full article

Colon cancer is one of the leading causes of death, requiring advanced therapies that need models for developing new drugs. Conventional cell culture models do not accurately and precisely reproduce the complexity of the tumor microenvironment, limiting their usefulness in research and therapy development. To address this weakness, patient-derived organoids have emerged as promising in vitro models. The implementation of these organoid-based models into more physiologically relevant systems is expected to improve their clinical relevance. Thus, integrating these organoids into microfluidic chips acting as bioreactors will likely improve the predictive response of therapies in personalized medicine. In this article, we report the development of a new colon cancer organoid-on-a-chip model that enables the in vitro culture of patient-derived colon cancer organoids under continuous culture media flow. We demonstrate how the developed organoids were derived from tumor biopsies of patients with colorectal cancer, expanded in standard three-dimensional (3D) culture, and cultured inside the microfluidic chips. The microfluidic chip chambers are designed to house organoids in a controlled environment, allowing the injection of therapies and monitoring by optical microscopy in real time. The in vitro therapies tested were a combination of drugs based on 5-fluorouracil and oxaliplatin at different concentrations. As a result, we demonstrate for the first time that this model proves the capability of this technology for in vitro testing colon cancer therapies. Full article

Background: SYHA1805 is a potent farnesoid X receptor (FXR) agonist currently in development for Metabolic Dysfunction-Associated Steatohepatitis (MASH). Methods: To determine the first-in-human (FIH) dose and guide its clinical development, an integrated approach combining in vitro and in vivo ADME and toxicological characterizations, cross-species allometric scaling (AS), and physiologically based pharmacokinetic (PBPK) modeling was employed. Results: Using monkeys and rats as extrapolation species, AS predicted a human intravenous clearance of 20.7 L/h and a steady-state volume of distribution of 15.1 L. Based on body surface area and exposure-based modeling, an FIH dosing regimen for single-dose administration was proposed, ranging from a 30 mg starting dose to a 3000 mg maximum, with an effective dose of 1150 mg. These dosing strategies were further supported by PBPK models, which accurately estimated human systemic exposure. The model simulations were subsequently validated by clinical trial data from a single ascending dose (SAD) study (CTR20202354). Conclusions: These findings establish a robust pharmacokinetic foundation for the continued clinical advancement of SYHA1805. Full article

Natural products have long contributed to oncology by providing structurally diverse metabolites and pharmacologically relevant scaffolds. Despite advances in precision oncology, immunotherapy, and targeted therapies, cancer remains a leading cause of morbidity and mortality worldwide. Plant-derived metabolites continue to attract attention due to their ability to modulate key processes such as apoptosis, metabolic adaptation, epigenetic regulation, oxidative stress, inflammation, and tumor microenvironment signaling. However, current evidence is heterogeneous and often based on simplified in vitro models or insufficiently characterized extracts. This review critically distinguishes pharmacologically validated findings from preliminary claims with limited translational relevance. A narrative synthesis of global advances was conducted, focusing on mechanistic pathways, major phytochemical classes, and emerging technologies shaping compound discovery and preclinical validation. The potential contribution of Chilean biodiversity was also examined. Although several Chilean plant species demonstrate cytotoxic, anti-inflammatory, and antioxidant activities relevant to oncology, most findings remain preclinical, limited by inadequate taxonomic identification, lack of phytochemical standardization, scarce in vivo validation, and insufficient pharmacological characterization. The future impact of natural products on oncology will depend on stricter standards for chemical characterization, biological validation, and translational relevance. Chilean biodiversity represents a promising yet largely prospective source for cancer-related drug discovery. Full article

Vascularization remains a fundamental bottleneck in tissue engineering, as the absence of functional vascular networks limits oxygen and nutrient delivery, resulting in necrotic cores and poor host integration. While structural scaffold design and cell sourcing have advanced considerably, emerging evidence indicates that paracrine signaling, rather than direct cell contact or scaffold architecture alone, is the primary driver of angiogenesis and vasculogenesis within engineered constructs. Key cell types, including endothelial cells (ECs) and mesenchymal stem cells (MSCs), engage in bidirectional paracrine crosstalk through the secretion of vascular endothelial growth factor (VEGF), angiopoietins, hepatocyte growth factor, and platelet-derived growth factor, among other mediators. While researchers have long focused on improving scaffold structure and cell selection, growing evidence shows that the chemical messages cells send to one another play a far more important role in driving blood vessel formation than previously appreciated. This review explores how cells embedded within engineered scaffolds communicate through secreted signals to coordinate the growth of new blood vessels. Two cell types, MSCs and ECs, are central to this process: cells that line blood vessels and bone marrow-derived stem cells. These cells exchange a variety of chemical messages that instruct neighboring cells to multiply, move, and organize into vessel-like structures. Importantly, the material properties of the scaffold itself, including its stiffness, surface texture, and degradation over time, influence the signals cells produce and how those signals spread through the tissue. Strategies to amplify paracrine signaling include growth factor-loaded delivery systems, hypoxic and genetic preconditioning of MSCs, and perfusion bioreactor culture. In vitro and in vivo evidence consistently demonstrates that coculture systems leveraging paracrine interactions produce superior vascular outcomes compared to single-cell or acellular constructs. Despite this progress, challenges related to signaling complexity, reproducibility, and clinical translation persist. Integration of transcriptomic and proteomic profiling, computational modeling, and machine learning approaches offers a path toward rationally designed scaffolds that recapitulate the spatiotemporal dynamics of native vascular signaling and ultimately support functional tissue regeneration. Full article

Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer’s disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure–activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood–brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer’s disease. Full article

The rise of antimicrobial resistance and the persistence of difficult-to-treat infections have stimulated interest in new strategies to overcome these problems. Among these strategies, dendrimers, which are highly branched monodisperse macromolecules, have emerged as innovative antimicrobial and anti-infective platforms. Dendrimers can act as intrinsic antimicrobial agents through multivalent interactions or membrane disruption or serve as nanocarriers for antibiotics, antiviral agents, antibiofilm compounds, gas-releasing active molecules, or photosensitizers. This review analyzes dendrimer-based anti-infective systems for which in vivo or clinical evaluation has been reported. The literature covers diverse platforms, including PAMAM, poly(L-lysine), peptide, carbosilane, phosphorhydrazone, polyglycerol, polyester, and other dendritic architectures. The available evidence includes infected animal models, pharmacokinetic and biodistribution studies, local tolerance studies, and clinical trials. PAMAM systems are the most extensively explored preclinically, whereas poly(L-lysine) dendrimer astodrimer/SPL7013 remains the most clinically advanced example. Overall, dendrimers provide a chemically tunable and biologically versatile approach to anti-infective research, but the current evidence remains heterogeneous. Direct comparison across studies is limited by differences in dendrimer scaffold, generation, surface chemistry, formulation, pathogen, infection model, administration route, dosing regimen, and biological endpoint. Future development will require better-defined in vivo models, more systematic safety and biodistribution studies, clearer structure–activity relationships, and stronger links between in vitro activity and clinically relevant efficacy. Full article

Selenium nanoparticles (SeNPs), which are nanoscale particles of elemental selenium (Se⁰), combine the biological activity of selenium with the distinctive properties inherent in nanomaterials, thereby making SeNPs a more promising candidate for advancing selenium-based resources. In this work, several strains of Bacillus with sodium selenite-reducing ability were isolated from selenium-rich soils. Bacillus subtilis ESNS-2 with high selenium tolerance was selected as the target strain. Under culture conditions supplemented with 5 mmol/L sodium selenite, this strain exhibited a reduction efficiency of 75.4 ± 0.6% over 24 h. The produced bioSeNPs were purified, decorated using polysaccharides from the seeds of Plantago asiatica L. (PLP), and subsequently systematically characterized using various means. The results revealed that the prepared PLP-bioSeNPs were regularly spherical elemental selenium particles, with an average particle size of 96.9 ± 1.1 nm, a PDI of 0.108 ± 0.003, and a zeta potential of −19.7 ± 0.4 mV. Characterization confirmed that they exhibited excellent dispersibility and stability. In vitro antioxidant assays, both bioSeNPs and the PLP-bioSeNP complex demonstrated pronounced dose-dependent scavenging activity against DPPH• and ABTS⁺• radicals. In a D-galactose-induced aging mouse model, both bioSeNPs and PLP-bioSeNPs alleviated D-galactose-induced hepatic and cerebral damage, as well as associated behavioral deficits, through the modulation of oxidative stress balance and suppression of inflammation. This study successfully accomplished the efficient production of SeNPs utilizing Bacillus subtilis ESNS-2. The modification of PLP provided innovative strategies for the development of macromolecular drugs, with a specific emphasis on enhancing stability. Full article

Background: The cosmetic industry is a rapidly expanding, high-value sector that drives continuous research into biologically active compounds and advanced delivery technologies aimed at improving skin health. Objective: To investigate the biological activity of apple-derived extracellular vesicles (ADEVs) and to evaluate strategies to enhance the transcutaneous penetration of ADEV-based formulations. Methods: In vitro, purified ADEVs were characterized in terms of size distribution and concentration. Their internalization was assessed in different cell types, and gene expression analysis was performed in treated cellular models. Ex vivo, PKH26-labeled ADEVs were applied to human surgical skin samples, either alone or in combination with microneedling (MN) using different procedural protocols. Fluorescence distribution was quantified in both epidermal and dermal compartments. Results: ADEV characterization showed a size range of 102–160 nm and a particle concentration of 9.48 × 10¹¹ particles/mL, together with morphological features consistent with EVs. ADEVs demonstrated efficient cellular internalization in vitro and modulated the expression of selected target genes (CDH5, NOS3, KLF2, and KLF4). In the ex vivo model, fluorescence signal associated with PKH26-labeled ADEV-based formulations was detected within human skin layers. A significant treatment effect was observed in both epidermal (F = 33.57, p < 0.001) and dermal compartments (F = 7.57, p = 0.018), with the highest fluorescence signal consistently detected when EV application was preceded by MN (MN + EVs). Notably, ADEV-based formulation alone also induced a significant increase in the epidermis compared with untreated controls, although of lower magnitude than that observed following MN pre-treatment. Conclusions: These findings support a controlled evaluation of microneedling as a strategy to enhance the distribution of ADEV-based formulations within human skin, highlighting the importance of application sequence. More broadly, this work contributes to the development of standardized and reproducible delivery approaches, while underscoring the need for further methodological refinement to achieve vesicle-specific tracking in complex tissues. Full article

The spread of multidrug-resistant (MDR) bacteria has renewed interest in combining the targeted killing of bacteriophages with immunomodulatory antimicrobial peptides (AMPs). AMPs offer broad antimicrobial, antibiofilm, and immunomodulatory effects, although their efficacy is limited by stability, delivery, and toxicity. Phage-based systems may help address some of these limitations by localizing antimicrobial activity and improving bacterial targeting. In this perspective, we treat engineered phages as programmable “Trojan horses” that deliver AMPs into their bacterial targets, framing this concept alongside the rapid growth of AI-guided AMP design as well as phage–host matching. The evidence thus far is largely preclinical. AMP-armed phages have shown activity in vitro and in animal models, while engineered phages have only recently entered early-phase clinical trials. Reasons why phage-delivered AMPs remain largely in the preclinical and early translational stages are delineated. We argue that the primary hurdle lies in the gap between the separate advancement of AMP design on one end and phage–host matching on the other. The alignment of these interests, along with manufacturing and regulatory efforts, will likely be what allows this therapy to reach the bedside. Full article

The increasing demand for tissue and organ replacement has positioned biofabrication as a transformative field within regenerative medicine. Biofabrication is an interdisciplinary approach that combines cells, biomaterials, and bioactive molecules to generate biologically functioning structures and tissue models. However, the size of biofabricated constructs often remains limited due to the lack of vascular structures. Cells located in the inner regions of larger constructs suffer from a lack of oxygen and nutrients, which results in hypoxia and reduced cell viability. Furthermore, integration into the host vasculature is crucial for the long-term survival of constructs intended for in vivo implantation. Consequently, strategies to improve the vascularization of biofabricated constructs have gained significant attention. In this review, we focus on approaches for the in vitro and in vivo vascularization of biofabricated constructs. We summarize the types and sources of vascular cells used in biofabrication, as well as the signaling molecules and biomaterials that can be incorporated into biofabricated scaffolds. A special focus is placed on advanced vascularization strategies such as the in ovo chorioallantoic membrane (CAM) and in vivo arteriovenous (AV) loop models. Furthermore, we describe the role of vascularization in advanced tissue models used for disease modeling and drug screening. Although the clinical translation of biofabricated constructs is still limited by a lack of vasculature and size constraints, biofabrication offers great potential for tissue replacement, personalized medicine, and the reduction of animal experiments. Full article

Chronic obstructive pulmonary disease (COPD) represents a major global health issue, characterized by persistent airflow limitation, chronic inflammation, and progressive tissue remodeling. Its clinical and molecular heterogeneity, combined with the lack of resolutive therapies, underscores the urgent need for advanced experimental tools to improve understanding and therapeutic development. Traditional 2D cell culture systems, though historically useful, fail to replicate the complexity of the human lung. In this review, we analyze the remarkable relevance of advanced 3D models for studying COPD pathophysiology, including epithelial injury and regeneration, extracellular matrix remodeling, and interactions with environmental triggers such as cigarette smoke and airborne pollutants. Three-dimensional in vitro models, such as ALI cultures, lung organoids, and lung-on-a-chip platforms, PCLS, and lung ECM-derived hydrogels offer more physiologically relevant environments to investigate epithelial dysfunction, immune responses, and host-pathogen interactions. We discuss the contribution of viral and bacterial infections to COPD exacerbations, and explore how 3D models have become essential tools for modeling these events. We also highlight recent advances in personalized medicine that use patient-derived organoids and ALI cultures for drug screening and biomarker discovery. Furthermore, we examine the therapeutic potential of probiotics and extracellular vesicle-associated microRNAs to modulate inflammation and epithelial repair. Collectively, these innovative systems represent powerful platforms to promote precision medicine in COPD. Full article

Cancer accounts for approximately ten million deaths annually. The majority of these are attributable to resistance-driven tumor progression and metastasis. Although increasingly effective, precise, and selective therapeutic strategies are being developed, cancer cells retain the capacity to dynamically alter their phenotype and evade treatment. Traditional in vitro approaches rely heavily on cell line monocultures; however, their limited clinical translatability has driven the development of more advanced model systems. Three-dimensional in vitro models, including spheroids, organoids, and bioprinted tissues, provide more physiologically relevant and rapid insights, but fail to capture systemic pharmacodynamics and anatomical complexity. Emerging in vivo models, such as genetically engineered mouse models (GEMMs) of carcinogenesis and patient-derived xenografts (PDXs), as well as their derived organoids, provide a more comprehensive understanding of tumor biology. The preservation of tumor heterogeneity, microenvironment, and drug sensitivity profiles has positioned PDX models as widely used platforms in both drug development and therapy response prediction. Despite limitations—including variable engraftment rates, genetic drift, lack of fully functional immune systems, ethical concerns, and high costs—PDX models, when integrated with complementary techniques, contribute significantly to identifying novel therapeutic targets and combinations. Moreover, they support clinical decision-making by enabling drug response prediction based on genetic landscapes and co-clinical response data. Full article