Search Results (3,646)

The retinal pigment epithelium (RPE) is a monolayer of cells located between retinal photoreceptors and the choroid, playing a critical role in maintaining visual function by protecting the retina and supporting photoreceptor metabolism. Damage to RPE cells can lead to visual disorders, including macular degeneration. Chronic exposure to high-energy blue light has been shown to elevate intracellular reactive oxygen species (ROS) in RPE cells, causing oxidative stress and cellular damage. In this study, a microfluidic platform incorporating a gradient-generating structure was developed to establish controllable and stable gradients of blue light intensity and chemical concentrations. This platform was used to investigate the effects of varying blue light intensities and antioxidant concentrations on oxidative stress in human RPE cells ARPE-19. Cells cultured within the microfluidic channels were exposed to different blue light intensities in combination with chemical treatments. Results demonstrated that ROS production increased with higher blue light intensity, whereas higher antioxidant concentrations effectively reduced ROS accumulation, supporting the ability of these antioxidants to attenuate blue-light-induced intracellular oxidative stress. The present microfluidic device enables simultaneous evaluation of multiple conditions within a single experiment, reducing reagent consumption and enhancing experimental efficiency. This in vitro microfluidic platform integrates chemical and light gradients to assess retinal oxidative damage and antioxidant effects, offering significant potential for ophthalmic drug screening and investigations of retinal protective mechanisms. Full article

Oxidative stress is a central and well-established driver of cardiovascular disease, contributing to mitochondrial dysfunction, endothelial injury, inflammatory activation, and progressive myocardial and vascular remodeling. Although the major endogenous sources of cardiovascular reactive oxygen species (ROS), including NADPH oxidases, mitochondrial electron transport chain leakage, and uncoupled nitric oxide synthase, are well characterized, an additional and underappreciated contributor has recently emerged: cytochrome P450 2D6 (CYP2D6), an enzyme classically regarded as a hepatic drug-metabolizing protein. Accumulating evidence indicates that CYP2D6 is expressed extrahepatically in cardiac, vascular, and neural tissue, where uncoupled catalytic cycling is proposed to generate ROS independently of its canonical xenobiotic-metabolizing role, although direct experimental evidence for this pathway in human cardiac and vascular tissue remains limited. CYP2D6-derived oxidative processes may interact with mitochondrial respiratory function, endothelial nitric oxide bioavailability, and redox-sensitive inflammatory pathways, potentially contributing to cardiovascular vulnerability under specific genetic or pathological conditions. Critically, the magnitude of this oxidative contribution is not fixed: it is dynamically shaped by inherited CYP2D6 genetic variation, with poor and ultra-rapid metabolizer phenotypes exhibiting divergent oxidative burden and pharmacokinetic vulnerability, and is further amplified by polypharmacy, multimorbidity, and inflammation-driven phenoconversion, whereby clinically expressed CYP2D6 activity diverges from inherited genotype in ways that intensify redox imbalance. These dynamics are particularly relevant in East Asian populations, where the decreased-function CYP2D6*10 allele is highly prevalent. In this narrative, hypothesis-generating review, we integrate evidence from pharmacogenomics, redox biology, and cardiovascular pharmacology to propose a conceptual framework that reframes CYP2D6 as a genetically and pharmacologically tunable node within cardiovascular redox biology. We further examine emerging redox biomarkers, multi-omics platforms, and AI-assisted modeling as translational strategies for capturing this dynamic oxidative risk in real time. This framework supports a shift from static genotype-guided prescribing toward oxidative-risk-informed, adaptive cardiovascular precision medicine. Importantly, our focus on CYP2D6 should not be interpreted as evidence that it is a major cardiovascular CYP isozyme or an established driver of cardiovascular pathology. Rather, CYP2D6 is examined here as a deliberately hypothesis-generating candidate whose unusually strong pharmacogenetic variability, clinically important cardiovascular drug substrates, dynamic susceptibility to phenoconversion, extrahepatic expression, and mechanistically plausible links to endogenous substrate metabolism and CYP-associated ROS generation provide a convergent rationale for focused investigation. The mechanistic framework proposed in this review has not yet been experimentally and prospectively validated and should not be applied directly to clinical decision-making without supporting clinical data. Full article

Background/Objectives: Programmed cell death protein 1 (PD-1) is a key immune checkpoint that suppresses anti-tumor T-cell responses and is an established target for cancer immunotherapy. UDIZ-007 is a fully human anti-PD-1 antibody that blocks PD-1/PD-L1 and PD-1/PD-L2 interactions and eradicates MC38-hPD-L1 colon tumors in B-hPD-1 transgenic mice. This study further characterized the pharmacokinetics (PK), immunogenicity, and safety of UDIZ-007 to support its clinical development. Methods: UDIZ-007 was produced in a stable Chinese hamster ovary (CHO) cell line, and its biophysical and in vitro functional profiles were assessed. PK, immunogenicity, and safety were evaluated in mice and cynomolgus macaques. Results: UDIZ-007 showed biophysical and in vitro functional properties consistent with therapeutic antibodies and demonstrated potent, dose-dependent anti-tumor activity against MC38-hPD-L1 colon tumors engrafted in B-hPD-1 transgenic mice. Single-dose PK studies in mice at 10 and 100 mg/kg and in cynomolgus macaques at 10, 50, and 101.2 mg/kg showed a trend toward dose-proportional exposure. In cynomolgus macaques, UDIZ-007 had a prolonged half-life of approximately 12 days. Repeated intravenous administration at 10, 50, or 101.2 mg/kg in cynomolgus macaques was generally well tolerated, with no major treatment-related toxicities. Accordingly, the no-observed-adverse-effect level (NOAEL) was established at the highest tested dose, 101.2 mg/kg. Anti-drug antibodies (ADAs) were detected in some animals and were associated with expected PK variability but not with adverse effects. Tissue cross-reactivity studies across 32 human and cynomolgus macaque tissues showed binding primarily restricted to lymphoid tissues known to express PD-1. Conclusions: UDIZ-007 demonstrated robust anti-tumor activity, favorable PK and safety profiles, as well as selective binding to PD-1-expressing tissues, supporting its clinical development as a potential cancer immunotherapy. Full article

The rise of multidrug-resistant (MDR) pathogens in the pediatric population represents a significant global health challenge, compounded by a historically stagnant antibiotic pipeline for children. While several novel antibiotics have been approved for adults in recent decades, pediatric labeling is often deferred due to the complexities of developmental pharmacology and due to a certain precautionary prudence in introducing new drugs onto the market for this population. This review explores the landscape of the most recent antibiotics, including advanced cephalosporins (ceftaroline, cefiderocol, and ceftobiprole), novel beta-lactam/beta-lactamase inhibitor combinations (e.g., ceftazidime/avibactam, meropenem/vaborbactam), and long-acting lipoglycopeptides. We analyze their approval trials, pediatric-specific PK/PD profiles, and the balance between on-label use and evidence-based off-label prescriptions. Furthermore, we emphasize the role of antimicrobial stewardship through the “3 D’s” rule and the evolution of Therapeutic Drug Monitoring (TDM) from reactive safety controls to proactive, model-informed precision dosing (MIPD). Finally, we advocate for a multidisciplinary synergy between pediatricians and pharmacologists as the cornerstone for optimizing outcomes and preserving the efficacy of the future antibiotic pipeline. Full article

Two immunocompromised patients with relapsing babesiosis were cured using a well-tolerated course of tafenoquine (171 and 212 days, respectively), with negative polymerase chain reactivity intentionally exceeding the 120-day lifespan of erythrocytes before discontinuing the tafenoquine. During the first 10 days of tafenoquine both patients also received an atovaquone-containing drug regimen. This was prescribed based on the demonstrated benefit of atovaquone on the efficacy of tafenoquine for completely eradicating B. microti in an animal study. Full article

Conjunctival lymphoma classically appears as a painless salmon-pink subepithelial infiltrate, but its indolent forms can closely imitate inflammatory ocular surface disease and delay diagnosis, particularly when an uncommon subtype such as small lymphocytic lymphoma presents bilaterally and in isolation. A woman in her early fifties presented with one month of left ocular discomfort and sectoral redness, and slit-lamp examination revealed two multilobulated hyperaemic bulbar conjunctival nodules, clinically indistinguishable from nodular episcleritis. Topical corticosteroids and a topical non-steroidal anti-inflammatory drug relieved the ocular discomfort and hyperaemia, but the nodules regressed only partially and at no point resolved. This dissociation between symptomatic relief and persistence of the lesions was, in retrospect, the earliest argument against a purely inflammatory process. The initial work-up pointed toward inflammatory and granulomatous causes: elevated serum angiotensin-converting enzyme and lysozyme raised the possibility of sarcoidosis, although thoracic computed tomography, bronchoscopy and a first conjunctival biopsy performed without a lymphoma-directed panel were unrevealing, showing only reactive lymphoid hyperplasia. Approximately one year later, recurrent and now bilateral disease prompted a repeat biopsy with directed immunohistochemistry, which demonstrated a CD20-positive small B-cell infiltrate co-expressing CD5 and CD23 with negative cyclin D1 and CD10, consistent with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Systemic staging with ¹⁸F-FDG PET/CT and bone marrow biopsy revealed no definite extra-conjunctival disease. After multidisciplinary review of observation, local radiotherapy and surgical excision, systemic therapy was preferred given the bilateral, recurrent and symptomatic course, and oral ibrutinib 420 mg once daily achieved complete clinical regression at three months and a sustained ocular response at two years, with indefinite haematological and ophthalmological surveillance planned. Full article

Small biomolecules provide important information on cellular metabolism, signaling and disease-associated molecular changes. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) enables rapid, high-throughput and spatially resolved molecular analysis, but its application to small biomolecules is often limited by poor ionization, low-mass background interference, ion suppression and insufficient structural information. To address these analytical challenges, this review summarizes chemical derivatization strategies that improve MALDI-MS analysis of small biomolecules. The representative strategies are discussed according to reaction mode and target functional group, including solution-phase, on-target, on-tissue, reactive-matrix-assisted and photo-/in-source approaches, with emphasis on amine-, carbonyl-, carboxyl- and double-bond-containing biomolecules. Chemical derivatization improves MALDI-MS performance by selectively modifying target functional groups, introducing charged or ionizable tags, enhancing molecular discrimination and providing additional structural information. These strategies have expanded the detection and annotation of neuroactive amines, carbonyl compounds, glycans, carboxylic acid metabolites and lipid double-bond isomers, while also extending MALDI-MS analysis to other specific functional groups, natural products and drug-related molecules. Overall, chemical derivatization is an important approach for improving the sensitivity, selectivity, structural annotation and analytical coverage of MALDI-MS-based small biomolecule analysis. Future developments should further address reaction selectivity, spatial fidelity, quantitative reliability and confident identification of derivatization products. Full article

Background/Objectives: Bacterial wound infections remain a significant clinical burden because of prolonged healing and the increasing prevalence of multidrug-resistant bacteria. This study aimed to develop a curcumin-loaded liposomal nanosystem (Lipo-Cur) for light-triggered photodynamic antibacterial therapy and enhanced wound repair. Methods: Lipo -Cur was prepared and characterized in terms of morphology, particle size, dispersibility, drug en-capsulation, curcumin solubility, and photostability. Reactive oxygen species generation under 430 nm blue-light irradiation was evaluated. The antibacterial activity of Lipo-Cur against Staphylococcus aureus and Escherichia coli was assessed in vitro. Its effects on the proliferation, migration, and colony formation of L929 and HaCaT cells were also examined. Therapeutic efficacy and biosafety were further evaluated in a murine S. aureus-infected wound model. Results: Lipo-Cur exhibited a near-spherical morphology with an average diameter of 134.8 nm, excellent dispersibility, high drug encapsulation, and improved curcumin solubility and photostability. Under 430 nm blue-light irradiation, Lipo-Cur efficiently generated reactive oxygen species. It exhibited minimum inhibitory concentrations of 100 and 125 μg/mL against S. aureus and E. coli, respectively, and achieved bactericidal rates exceeding 95%, outperforming free curcumin. Lipo-Cur also significantly enhanced L929 and HaCaT cell proliferation, migration, and colony formation, indicating favorable biocompatibility. In the murine infect-ed-wound model, Lipo-Cur combined with blue-light irradiation (Lipo-Cur-BL⁺) achieved 93.76 ± 1.56% wound closure by day 12, accelerated tissue regeneration, reduced inflammation, and caused no evident systemic toxicity or hemolysis. Conclusions: These findings demonstrate that Lipo-Cur is a safe and effective photodynamic antibacterial platform with considerable potential for treating bacterially infected wounds and promoting wound healing. Full article

Background: Therapeutic drug monitoring (TDM) has emerged as an important strategy for optimizing anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). However, data regarding anti-TNF pharmacokinetics and immunogenicity from Middle Eastern populations remain limited. This study evaluated the associations between serum anti-TNF trough concentrations, anti-drug antibody (ADAb) levels, and therapeutic response among Iraqi patients with IBD receiving infliximab or adalimumab therapy. Methods: This cross-sectional observational study included 80 patients with Crohn’s disease or ulcerative colitis receiving maintenance infliximab or adalimumab therapy at a tertiary Gastroenterology Center in Iraq. Patients were categorized as responders or non-responders according to clinical disease activity indices and biochemical assessment. Serum trough levels of infliximab and adalimumab, as well as ADAb concentrations, were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Responders had significantly higher serum trough concentrations than non-responders for both infliximab [3.75 µg/mL (IQR: 3.40–4.15) vs. 1.05 µg/mL (IQR: 0.92–1.12), p < 0.001] and adalimumab [6.32 µg/mL (IQR: 5.67–7.15) vs. 3.30 µg/mL (IQR: 2.70–4.26), p < 0.001]. Adalimumab-treated non-responders had significantly higher ADAb levels compared with responders (p = 0.047). Conclusions: Favorable therapeutic outcomes in Iraqi IBD patients treated with anti-TNF agents were associated with adequate serum trough levels and low ADAb levels. Reactive therapeutic drug monitoring may provide clinically valuable pharmacokinetic information capable of guiding individualized treatment optimization and identifying mechanisms of treatment failure in patients receiving infliximab or adalimumab therapy. Full article

Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators. Full article

Starch, a natural source of energy in the form of glucose chains, is widely utilized in various industrial and scientific fields. In its native state, starch is thermally unstable and undergoes gelatinization. Physicochemical modifications of starch aim to increase its thermal and structural stability while simultaneously enhancing its reactivity by introducing new functional groups. The primary objective of this study was to develop thermally stable and economically viable starch-based drug carriers capable of the controlled release of a negatively charged component sourced from aronia extract. Potato starch underwent a series of chemical modifications, specifically quaternary amine etherification, citric acid esterification, and/or hydrothermal modification. The characterization involved determining several parameters: the degree of amino substitution groups; starch particle size using a laser particle size analyzer; viscosity and pH; gelation temperature and heat capacity measured by scanning calorimetry (DSC); mass degradation analyzed via thermogravimetric analysis (TG); crystallinity determined by X-ray diffraction (XRD); potential intermolecular interactions studied by Fourier-Transform Infrared Spectroscopy with Attenuated Total Reflectance (FTIR-ATR); and the rate of chlorogenic acid release from aronia extract tablets quantified by spectrophotometry. The highest cationization results were achieved using citrate starches, reaching up to 86%. The combined application of citric acid esterification and cationization, coupled with an annealing process, resulted in increased viscosity, amorphousness, and enzyme resistance of the starch. Citric acid esterification significantly improved the thermal stability of the starch. Furthermore, FTIR studies revealed the formation of electrostatic interactions between the functional groups of the starch and the components of aronia extract. The amount of chlorogenic acid released showed significant variation (70–100%) depending on the type of starch modification. Collectively, these studies confirmed that both hydrothermal and chemical modifications influence the thermal and structural stability of the starch. Utilizing all combination modification strategies ensured the production of highly promising carriers for active substances. Full article

Policosanol (sugarcane wax alcohol), phosphatidylserine, and Ginkgo biloba leaf extract are Ministry of Food and Drug Safety (MFDS), Republic of Korea-listed functional foods for health-promoting effects. Herein, a combination of policosanol, phosphatidylserine, and G. biloba leaf extract (hereafter PPG) was investigated against metabolic stress induced by a high-cholesterol, high-galactose (HCHG) diet in hyperlipidemic and hyperglycemic zebrafish. After 9 weeks of feeding, the zebrafish following the HCHG diet co-supplemented with PPG exhibited a significant 14.1% (p < 0.02) reduction in body weight and higher zebrafish survivability compared to the HCHG-supplemented group. Significantly reduced total cholesterol (TC, 1.2-fold), triglycerides (TG, 1.4-fold), low-density lipoprotein cholesterol (LDL-C, 1.3-fold), and glucose levels (1.2-fold), along with a 1.5-fold (p = 0.003) elevated high-density lipoprotein cholesterol (HDL-C), were observed in the PPG co-supplemented group relative to the HCHG group. In addition, the HCHG-elevated plasma malondialdehyde (MDA), diminished ferric ion reduction activity (FRA), and paraoxonase (PON)-like activity significantly (p < 0.001) reverted by 1.6-fold, 1.4-fold, and 1.6-fold, respectively, by co-supplementation with PPG. Consistently, the plasma from the PPG-supplemented group showed greater ability to prevent carboxymethyllysine (CML)-induced apoptotic death, altered heart rate, and developmental deformities in zebrafish embryos. Moreover, PPG exerted significant protective effects against HCHG-induced hepatomegaly and fatty liver, accompanied by marked inhibition of hepatic interleukin (IL)-6 and reactive oxygen species (ROS) generation. Consistently, PPG supplementation inhibits ROS generation and senescence in the liver, intestine, brain, kidney, testis and ovary and protects the organ damage caused by exposure to HCHG. Similarly, in intestinal tissue, HCHG-induced fibrosis and oxidative stress were mitigated by the co-supplementation of PPG. The findings indicate that PPG is an effective combination for preventing dyslipidemia, oxidative stress, inflammation, and multi-organ damage associated with HCHG-mediated metabolic stress in zebrafish. Full article

Background: The fibrous tumor extracellular matrix (ECM), driven by cancer-associated fibroblasts (CAFs), forms a physical barrier against drugs and immune cells, yet direct CAF elimination risks promoting metastasis. Methods: In this study, we developed a locally injectable hydrogel based on synergistic dynamic covalent crosslinking (imine and boronate ester bonds), enabling instant gelation, shear thinning, and dual-pH/ROS-responsive degradation. Two types of drug-loaded nanoparticles (NPs), coated with homotypic cell membranes, were incorporated into this hydrogel. In the acidic, reactive oxygen species (ROS)-rich tumor microenvironment (TME), the system responsively releases the antifibrotic drug SIS3 to reprogram CAFs while simultaneously delivering doxorubicin (DOX) specifically to tumor cells. Biological effects were evaluated in vitro using cell cultures and in vivo in mouse models. Results: This dynamic hydrogel-based co-delivery system effectively reprograms CAFs, reduces tumor mechanical stress, breaks the fibrotic barrier, and promotes the deep infiltration of chemotherapeutics and immune cells, thereby enhancing the efficacy of chemotherapy. Conclusions: This injectable pH/ROS-responsive dynamic covalent hydrogel, loaded with CAF- and cancer cell-targeting NPs, remodels the TME, enhances drug and immune cell penetration, and offers a promising biomaterial-based strategy for cervical cancer treatment. Full article

Background: Effective topical management of sensitive skin remains challenging because inadequate cutaneous delivery limits the therapeutic performance of many anti-inflammatory agents. Glycyrrhetinic acid (GA) possesses well-recognized anti-inflammatory and barrier-protective activities, yet its clinical potential is constrained by poor aqueous solubility and inefficient skin delivery. This study aimed to develop a hyaluronic acid (HA)-engineered ethosomal system to enhance the local delivery and therapeutic efficacy of GA for sensitive skin. Methods: HA-coated GA-loaded ethosomes (HAGA-ETs) were prepared by electrostatic adsorption of HA onto a cationic ethosomal template. The physicochemical properties, release behavior, storage stability, skin retention, cellular uptake, and biological activities of HAGA-ETs were systematically evaluated using TNF-α/IFN-γ-stimulated HaCaT cells and an SLS-induced 3D reconstructed skin model. Results: HAGA-ETs exhibited a mean particle size of 140.1 nm, encapsulation efficiency exceeding 95%, sustained drug release, and good storage stability. Compared with Free-GA and unmodified ethosomes, HAGA-ETs showed improved cytocompatibility, enhanced skin retention, greater keratinocyte uptake, and stronger anti-inflammatory activity. HA pre-saturation attenuated the enhanced cellular uptake of HAGA-ETs, supporting the involvement of HA receptor-mediated cellular interaction. HAGA-ETs also more effectively restored barrier-related markers, suppressed hyper-reactivity- and allergy-associated mediators, and inhibited the activation of MAPK/NF-κB, JAK1/STAT1, and TRPV1-related signaling pathways in both cellular and 3D skin models. Conclusions: HA surface engineering effectively improved the topical delivery and local therapeutic efficacy of GA by enhancing skin retention and keratinocyte interaction. HAGA-ETs represent a promising nanoplatform for the local management of sensitive skin. Full article

Innovative antibacterial agents, which need to be urgently developed, should provide a new path that avoids pathogenic bacteria drug resistance. A promising strategy to treat bacterial infections consists of implementing nanoparticles (NPs). Several nanomaterials, including metal NPs, induce oxidative stress in living cells by producing reactive radicals at their surface. The oxidative stress thus raised is a potent mechanism of antibacterial action. Owing to their reactive oxygen species (ROS)-related ability, metal NPs could contribute to the targeted bioactivity of preparations designed on their basis. However, totally inorganic nanomaterials frequently suffer from relatively low selectivity with respect to bacterial targets, limited dispersibility, and undesirable side effects linked to ambiguous toxicity. For the development of bacteria drug resistance, the incorporation of specific ligands responsible for bacterial eradication into NPs seems to be necessary. The synergistic action of NPs with natural materials demonstrates complementary effects and improved antibacterial capacity. The modification of NPs by natural organic supporting agents extracted from plants could potentially resolve some of the existing issues related to bacterial drug resistance. The purpose of the current work is to review the ROS-mediated antibacterial manifestation strategy of metal NPs conjugated with botanical bactericidal substances. Different aspects of the metal toxicity of NPs and the compromised selectivity of ROS for bacterial pathogens are also considered. Full article