Impact of renal hypoxia on OAT1 expression and adefovir-induced cytotoxicity in human 3D-RPTEC spheroids.

Transcorneal permeation is the main entry route into the eye for topically applied drugs, but the impact of active transport on corneal permeability is still poorly understood. We aimed to identify the influence of transporters for rabbit corneal permeability by utilizing the PermeaSys microfluidic system, which requires <20 times smaller tissue pieces and 10 times smaller exposure volumes of the study compound, than the commonly used Ussing chamber. The rabbit corneal permeability was first validated with three model compounds, rhodamine 123, benzoic acid, and paracellular marker compound lucifer yellow, before studying the permeability with three clinically used drugs, ciprofloxacin, diclofenac, and methotrexate. Both bidirectional and inhibition studies were performed. Rhodamine 123 did not show directionality nor altered permeability in the presence of an inhibitor, but the permeability of benzoic acid was affected by a monocarboxylate transporter inhibitor, valproic acid. Clinically used compounds ciprofloxacin, diclofenac, and methotrexate did not show directionality in the corneal permeability studies. However, methotrexate permeability was altered when administered together with sulfasalazine and MK-571, which can inhibit several known drug transporters. The data generated here with the PermeaSys instrument is comparable to studies conducted with the Ussing chamber, indicating that it can be reliably used for the study of permeability and active transport in the cornea. However, active transport does not appear to have a great impact on the corneal permeability of the studied drug compounds.

Methodological innovations in perfusable vascular networks: Advancing high-density tissue models.

Chrono-neuro-nanocarriers: Synchronizing circadian rhythms and glymphatic flow for targeted brain drug delivery

Plant-derived natural compounds targeting drug resistance in ovarian cancer: Molecular mechanisms and therapeutic perspectives.

Numerical Simulation of Caputo Fractional Model for Temperature-Influenced Drug Transport

L-type amino acid transporter 1 targeting self-assembly polyelectrolyte nanocomplex with enhanced nose to brain delivery of oxytocin.

Inhibition of activated hepatic stellate cells (HSCs) is essential for treating fibrotic liver disease, while the capillarized hepatic sinusoidal barrier extremely hinders HSC-targeted drug delivery and early intervention. Herein, we developed a dual-phase barrier-penetrating nanomedicine (SFR-RA@lip) based on the coassembly of silibinin (SIL) and riociguat (RIO), with retinoic acid (RA) for HSCs targeting and a lipid shell to facilitate multipathway transcellular transport. In the initial phase, SFR-RA@lip exploits caveolin-mediated endocytosis and endoplasmic reticulum-Golgi apparatus trafficking to rapidly traverse liver sinusoidal endothelial cells (LSECs) and reach HSCs for an early intervention. Meanwhile, clathrin-mediated endocytosis facilitates the normalization of LSECs, restoring fenestrae through the NO-sGC-cGMP pathway activation. This fenestrae restoration facilitates a second-phase delivery, further enhancing the drug transport and accumulation in HSCs. In a thioacetamide-induced fibrotic liver model, SFR-RA@lip demonstrated significantly improved hepatic distribution and antifibrotic efficacy. This dual-phase nanosystem enhances trans-sinusoidal drug delivery and improves antifibrotic efficacy, offering a promising strategy for the treatment of liver fibrosis.

Artemether, a potent lipophilic antimalarial drug, suffers from poor aqueous solubility and low, variable oral bioavailability, which can compromise its therapeutic efficacy and contribute to the emergence of drug-resistant malaria strains. The present study aimed to develop and evaluate a Self-Emulsifying Drug Delivery System (SMEDDS) to enhance the solubility, dissolution, and intestinal permeability of artemether. Solubility studies were conducted to identify suitable excipients, and Capryol 90 (oil), Cremophor EL (surfactant), and Transcutol P (co-surfactant) were selected based on their superior drug solubilizing capacity. The optimized SMEDDS formulation was subjected to in vitro dissolution and ex vivo permeability studies using the Caco-2 cell model. The in vitro dissolution study demonstrated a significant improvement in drug release from the SMEDDS formulation, with more than 95% of artemether released within 30 minutes, compared to less than 20% release from the conventional suspension. This enhancement is attributed to the spontaneous formation of a fine oil-inwater nanoemulsion, providing a large surface area and maintaining the drug in a solubilized state. Furthermore, ex vivo permeability studies revealed a marked increase in drug transport across intestinal cell monolayers, with the SMEDDS formulation showing approximately 3.8-fold higher apparent permeability compared to the suspension. These findings confirm that the SMEDDS formulation effectively overcomes the dissolution and permeability limitations of artemether. The developed system offers a promising strategy to enhance oral bioavailability and therapeutic performance of lipophilic drugs. This approach may significantly contribute to improving malaria treatment outcomes and reducing variability in drug absorption.

Solid drug-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes are used to enhance drug solubility and microneedle (MN)-mediated delivery efficiency. However, mechanistic understanding of HPβCD effects in solution on drug transport across pathways in MN-pretreated skin remains limited. This study investigated the in vitro permeation of rhein (RN) across MN-pretreated neonatal porcine skin from saturated RN solutions containing 0-200mM HPβCD. Phase solubility, total flux (Jtotal), and permeability coefficient through the microchannel pathway (PMCP) were determined, along with dermal transport at varying HPβCD concentrations. Permeation experiments under asymmetric and symmetric donor-receiver HPβCD conditions were conducted to elucidate potential interactions between HPβCD and skin transport pathways. RN solubility increased from 241.9 ± 16.4µg/mL (0mM HPβCD) to 1,092.5 ± 54.9µg/mL (200mM HPβCD), showing a linear trend up to 50mM. MN permeation studies confirmed that RN transport occurred predominantly through microchannels. The highest Jtotal (3.87 ± 0.40μg/cm2/h) was achieved at 25mM HPβCD, with no further enhancement at higher concentration. Although increasing HPβCD concentration improved RN solubility, PMCP and dermal transport decreased. Identical permeation profiles under symmetric and asymmetric conditions at 50mM HPβCD indicated no direct interaction between HPβCD and MN-pretreated skin. In summary, HPβCD-mediated solubility enhancement increased RN flux across MN-pretreated skin, but not microchannel permeability or dermal diffusion.

Introduction: Colorectal cancer remains a leading cause of cancer mortality worldwide, characterized by significant heterogeneity in therapeutic response. Essential trace elements, serve as critical cofactors in DNA repair mechanisms, apoptotic signaling, and drug transport. This study aimed to evaluate the predictive value of baseline serum levels of these elements regarding the clinical response to first-line chemotherapy in patients with colon cancer. Material and Methods: This descriptive-analytical cross-sectional study was conducted at Imam Khomeini Hospital, Urmia University of Medical Sciences, Iran. A total of 30 patients with histologically confirmed colon cancer receiving standard platinum-based chemotherapy were enrolled. Pre-treatment serum concentrations of Zn, Cu, and Mg were quantified using colorimetric assays. Treatment response was evaluated upon completion of the regimen according to RECIST criteria. Associations between trace element levels and chemotherapy response (Complete Response vs. Non-Response) were analyzed using independent t-tests and multivariate logistic regression. Results: The cohort exhibited a mean age of 60.31 ±10.61 years and a distinct female predominance (63.3 %). A high rate of therapeutic resistance was observed, with 56.7 % of patients classified as non-responders. Patients achieving a Complete Response demonstrated significantly higher baseline serum Magnesium levels (2.07 ± 0.22 mg/dL) compared to non-responders (1.83 ± 0.36 mg/dL; P=0.047). Multivariate logistic regression identified serum Magnesium as a significant independent predictor, where higher levels reduced the likelihood of non-response (P=0.048). Serum Zinc and Copper levels did not show statistically significant associations with treatment outcomes in this cohort (P&gt;0.05). Conclusion: Baseline serum Magnesium levels are significantly associated with chemotherapy efficacy in colon cancer patients. These findings suggest that adequate magnesium status may facilitate optimal pharmacodynamic activity, potentially by modulating the cellular uptake of platinum-based agents. Routine assessment of serum Magnesium could serve as an accessible biomarker for stratifying patients at risk of chemoresistance.

Gut microbiome-related tryptophan metabolites modulate drug transporters, with prominent effects on OAT1 and OAT3.

Model-guided design of lymphatic drug delivery systems using osmotic pressure, viscosity and lymph node size.

To overcome the poor oral bioavailability of Panax Notoginseng Saponins (PNS) caused by low permeability and acid instability, this study designed bioadhesive microspheres co-loaded with PNS and N-acetyl-L-cysteine (PNS-NAC-BMS). This system aims to protect PNS from gastric degradation and enhance its intestinal permeability and oral bioavailability. PNS-NAC-BMS were fabricated via solvent evaporation and characterized for morphology, particle size, drug loading, encapsulation efficiency, mucoadhesion, and in vitro release. Permeability was assessed using Purified Mucin Intestinal Mucus (PIM), Artificial Intestinal Mucus (AIM), and Rat Native Intestinal Mucus (RIM). Oral bioavailability was assessed through rat pharmacokinetic studies. PNS-NAC-BMS exhibited spherical morphology with uniform particle sizes. They achieved high encapsulation efficiency (91.55%) and intestinal adhesion (94.83%), with sustained release. The system showed high apparent permeability coefficients across three models (PIM, AIM, RIM). Pharmacokinetic studies revealed prolonged release and a 2.6-fold increase in oral bioavailability versus PNS Active Pharmaceutical Ingredients (PNS APIs). Recently, patents (US 20230338448, CN 118873498) describe PNS delivery using nanocomposites and liposomes. However, none exist for NAC-modified adhesive microspheres, underscoring the novelty of this study. The BMS system significantly improves the oral bioavailability through combined mucoadhesion and NAC-mediated penetration. NAC promotes drug transport across the mucus barrier by cleaving mucin disulfide bonds and increasing lipid solubility. However, promising long-term stability, scalable production, and mucosal safety of NAC require further study. PNS-NAC-BMS significantly enhanced intestinal adhesion and sustained drug release, thereby synergistically improving intestinal mucus permeability and oral bioavailability, demonstrating potential as an effective oral drug delivery system.

Relating plaque psoriasis barrier function changes with the underlying skin morphology and physiology.

Targeting brain tumors remains a formidable challenge due to the presence of complex physiological barriers, notably the blood-brain barrier (BBB), the blood-brain tumor barrier (BBTB), and the nose- tobrain barrier. These barriers hinder effective drug delivery, limiting therapeutic efficacy. This review provides a comprehensive analysis of the anatomical and molecular characteristics of these barriers, with particular emphasis on the heterogeneity of the BBTB and its implications for targeted drug transport. A detailed overview of various brain tumor types-including glioblastoma, pediatric brain tumors, and brain metastases-is presented alongside a critical evaluation of existing therapeutic modalities. The review highlights the advancement of ultramolecular pharmaceuticals specifically engineered to circumvent the BBTB, focusing on both transvascular and cell-mediated delivery mechanisms. The role of nanomedicine in modulating the immune response and altering the tumor microenvironment is explored as a promising avenue for enhancing therapeutic outcomes. Particular emphasis is placed on nanogels as a versatile and efficient drug delivery platform. Key fabrication techniques such as precipitation polymerization, emulsion polymerization, self-assembly, and micro-templating methods are thoroughly discussed, alongside strategies for polymer crosslinking to enhance stability and functionality. In addition, the review addresses preclinical evaluation strategies, including in vitro models (e.g., BBB-mimicking systems, tumor spheroids) and in vivo studies in animal models, to assess the safety, biodistribution, and therapeutic efficacy of nanogel-based systems. Finally, current clinical progress, challenges, and future perspectives are presented, underscoring the urgent need for innovative, targeted, and personalized drug delivery approaches. This review aims to guide future research in overcoming delivery obstacles and improving outcomes for patients with brain tumors through the strategic integration of advanced nanotechnology and molecular targeting.

Alterations in the pharmacokinetics or pharmacodynamics of a drug could be the result of interaction with nutritional elements or due to the nutritional status of patients. This review summarizes the findings of previous studies on the interaction between the most prescribed drugs and food variables. From the commencement of databases related to the topic of interest to January 2024, all relevant articles were searched in PubMed, Scopus, and Web of Science. Milk, grapefruit juice, or alcohol could lead to specific food-drug interactions. Patients who require surgery should refrain from using ginseng for at least a week prior to the operation. The interaction of drugs, such as carbamazepine with capsaicin, saquinavir with garlic, and warfarin with ginkgo biloba, needs vigilant attention. Among epileptic patients, in those taking phenobarbital and phenytoin, due to an increase in the metabolism of vitamin D, supplementation of vital minerals might be optional. The curcumin's effect in patients with doxorubicin, due to the modulation of cellular pathways (P-glycoproteins, other ABC transporters), could be complex. Interactions between drug and food variables could cause an alteration in drug efficiency or toxicity due to changes in drug transporters. Attention to the induction or inhibition of cytochrome P450 by food content could help mitigate the risk of unwanted side effects. The population of elderly, patients on drugs with patients on drugs with a narrow therapeutic window, pregnant women, and children needs more attention. To better assess the benefit-risk relationship, a full and comprehensive dietary recall, including simultaneous intake of drugs and food, is recommended.

Chemoresistance remains a major barrier to durable disease control in gastric cancer, limiting the effectiveness of perioperative and palliative systemic therapies. Increasing evidence indicates that resistance is driven by a complex interplay between tumor-intrinsic adaptations and tumor microenvironment-mediated survival pathways. Although chemoresistance can be innate or acquired, a variety of mechanisms could coexist within the tumor, with various processes acting synergistically. MicroRNAs, as key post-transcriptional regulators, have emerged as central modulators of these resistance networks. This review summarizes the principal mechanisms of chemoresistance in gastric cancer and synthesizes current evidence on how microRNAs-derived from tumor cells and the tumor microenvironment-promote or reverse resistance to commonly used chemotherapeutic agents and targeted therapy/immunotherapies, highlighting therapeutic opportunities. Evidence was organized by mechanism (drug transport and metabolism, DNA damage response, apoptosis and survival signaling, autophagy, epithelial-to-mesenchymal transition/cancer stem cell plasticity, and immune escape) and by drug class.

Women of African ancestry develop more aggressive breast cancer (BCa) with poorer survival outcomes, yet only 8% of available cell lines represent this population, impeding targeted treatment development. Here, we aimed to establish and characterize new cell lines from an Afro-Caribbean patient to better understand population-specific BCa biology. We developed three lines (ACRJ-BC24 parent, α, and β) from a patient with 100% African ancestry. Karyotype analysis revealed progressive chromosomal instability, with the β-clone showing X-11 translocations correlating with higher Ki-67 expression and enhanced tumorigenic capacity. Immunohistochemistry and immunoblotting demonstrated their transition from hormone-positive to triple-negative phenotypes. Transcriptional profiling identified significant enrichment in extracellular matrix organization pathways mechanistically linked to chromosomal instability, explaining their distinct drug responses. The parent line demonstrated notable sensitivity to PARP inhibitors and microtubule-targeting agents, while the β-clone showed enhanced platinum sensitivity correlating with its chromosomal abnormalities. The parent line exhibited atypical dose-response patterns to gemcitabine and docetaxel, possibly relating to ECM-mediated drug transport mechanisms. This resource provides valuable tools for studying BCa disparities in African ancestry populations, offering the first cell line models from this underrepresented population for hypothesis-driven mechanistic studies.

Abstract This review is based on a systematic search and qualitative synthesis of studies from PubMed, Scopus, Web of Science, and Google Scholar, examining pharmacogenomic, genetic, and epigenetic factors influencing metformin's effects on aging and longevity. Additional references were identified from bibliographies and clinical trial registries. Metformin, a widely used antidiabetic drug, has gained attention in longevity research for its biological effects beyond glycemic control. However, responses to metformin vary considerably, especially in aging populations. This review examines the pharmacogenomic, genetic, and epigenetic factors that shape its efficacy and tolerability, emphasizing their relevance to personalized longevity medicine. We discuss key pharmacogenomic variants in drug transporter genes such as SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC47A1/SLC47A2 (MATE1/2-K), which affect metformin absorption, distribution, and clearance. Additionally, polymorphisms in metabolic regulators like ataxia telangiectasia mutated (ATM), LKB1, PRKAB2, and TCF7L2 modulate downstream signaling pathways, most notably adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) that are central to metformin's anti-aging effects. Beyond genetic influences, metformin may exert epigenetic modifications, such as alterations in DNA methylation, histone acetylation, and non-coding RNA expression. These changes have been reported to impact aging-related pathways such as oxidative stress response, mitochondrial function, inflammation, and autophagy. Notably, metformin has been shown in preclinical and translational studies to downregulate aging-associated microRNAs (such as miR-34a) and modulate epigenetic enzymes and antioxidant responses, thereby supporting cellular homeostasis. Preclinical evidence and select human studies suggest that metformin may influence risk trajectories of age-related conditions (e.g., cardiometabolic disease, cancer, neurodegeneration), although direct effects on human longevity remain unproven. Ongoing trials like Targeting Aging with Metformin (TAME) aim to reposition metformin as a first-in-class therapy targeting the biology of aging itself. However, recent findings from trials like MET-PREVENT underscore the need for precision in patient selection, dose optimization, and biomarker integration. By integrating pharmacogenomic and epigenetic profiling, personalized metformin therapy could become a cornerstone in geroscience. This review supports a personalized approach to optimize metformin's benefits in diverse aging populations and outlines future steps for clinical translation.