Barrier Transport Research Articles

A synthesized view of the CSF-blood barrier and its surgical implications for aging disorders

In this review, we explore the mechanisms of the blood-cerebrospinal fluid (CSF) barrier and CSF transport. We briefly review the mathematical framework for CSF transport as described by a set of well-studied partial differential equations. Moreover, we describe the major contributors of CSF flow through both diffusive and convective forces beginning at the molecular level and extending into macroscopic clinical observations. In addition, we review neurosurgical perspectives in understanding CSF outflow pathways. Finally, we discuss the implications of flow dysregulation in the context of neurodegenerative diseases and discuss the rising role of perivascular drainage pathways including glymphatics.

Improvements in Exercise for Alzheimer's Disease: Highlighting FGF21-Induced Cerebrovascular Protection.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Currently, it has shown a trend of earlier onset, with most patients experiencing a progressive decline in cognitive function following the disease's onset, which places a heavy burden on society and family. Since no drug cure for AD exists, exploring new ways for its treatment and prevention has become critical. Early vascular damage is an initial trigger for neuronal injury in AD, underscoring the importance of vascular health in the early stages of the disease. Patients with early AD experience abnormal blood-brain barrier transport of amyloid-β (Aβ) peptides, with excess Aβ being deposited in the cerebral vasculature. The toxic effects of Aβ lead to abnormalities in cerebrovascular structure and function. Fibroblast growth factor21 (FGF21) is an endocrine factor that positively regulates energy homeostasis and glucose-lipid metabolism. Notably, it is one of the effective targets for metabolic disease prevention and treatment. Recent studies have found that FGF21 has anti-aging and vasoprotective effects, with receptors for FGF21 present in the brain. Exercise stimulates the liver to produce large amounts of FGF21, which enters the blood-brain barrier with the blood to exert neurovascular protection. Therefore, we review the biological properties of FGF21, its role in the cerebrovascular structure and function in AD, and the mechanism of exercise-regulated FGF21 action on AD-related cerebrovascular changes, aiming to provide a new theoretical basis for using exercise to ameliorate degenerative neurological diseases.

Strategies to Enhance Nanocrystal Formulations for Overcoming Physiological Barriers Across Diverse Routes of Administration.

Poor aqueous solubility and bioavailability limit the translation of new drug candidates into clinical applications. Nanocrystal formulations offer a promising approach for improving the dissolution rate and saturation solubility. These formulations are applicable for various routes of administration, with each presenting unique opportunities and challenges posed by the physiological barriers. The development of nanocrystal formulation requires comprehensive understanding of these barriers and the biological environment, along with strategic modulation of particle size, surface properties, and charge to facilitate improved bioavailability to the target site. This review focuses on applications of nanocrystals for diverse administration routes and strategies in overcoming anatomical and physiological delivery barriers. The orally administered nanocrystals benefit from increased solubility, prolonged gastrointestinal retention, and enhanced permeation. However, the nanocrystals, due to their small size and high surface area, are susceptible to aggregation in the presence of gastric fluids and are more prone to enzymatic degradation compared to the macrocrystalline form. Although nanocrystal formulations are composed of pure API, the application of excipients like stabilizers reduces the aggregation and improves formulation stability, solubility, and bioavailability. Some excipients can facilitate sustained drug release. Emerging research in nanocrystals include their application in blood-brain barrier transport, intranasal delivery, stimuli responsiveness, multifunctionality, and diagnostic purposes. However, the challenges related to toxicity, scale-up, and clinical translation still need further attention. Overall, nanocrystal engineering serves as a versatile platform for expanding the therapeutic potential of insoluble drugs and enabling dose reduction for existing drugs, which can minimize toxicity and improve bioavailability at lower dosages.

Memantine/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-β1/Smad Signaling Pathway and Amyloid-β Clearance

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-signaling as well. Combined memantine/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-β1/p-Smad2/p21 pathway and regulating Aβ-clearance.Graphical

Enhanced brain delivery and antiproliferative activity of resveratrol using milk-derived exosomes

The polyphenol resveratrol (RSV) undergoes extensive phase II metabolism, which limits its bioavailability and bioactivity, including anticancer effects. Growing preclinical evidence reinforces milk-derived exosomes (EXOs) as promising nanocarrier drugs and bioactives delivery systems. Herein, to overcome the mentioned RSV’s drawbacks, EXOs were loaded with RSV (EXO-RSV) to evaluate its brain delivery in Sprague-Dawley rats and its in vitro antiproliferative effects against human neuroblastoma SH-SY5Y and glioblastoma U-87MG cancer cells compared with non-encapsulated RSV. Pharmacokinetic analyses in perfused brains showed RSV detection only after EXO-RSV administration, not after non-encapsulated RSV administration. Encapsulation also resulted in lower concentrations of phase II-derived RSV metabolites in circulation. Additionally, blood-brain barrier (BBB) transport assays using human brain microvascular endothelial cells (HBMECs) corroborated that encapsulation enhanced RSV transport efficiency and protected it from cellular metabolism. In vitro and in silico analyses of phase-II conjugates, primarily RSV 3-glucuronide, showed lower capacity than RSV to cross the BBB. Finally, EXO-RSV (47−750 nM) showed an increased dose-dependent antiproliferative efficacy on both cancer cell lines compared with the non-encapsulated RSV (10 μM), which was ineffective after 72 h of treatment. Our findings suggest that EXOs protect RSV from phase II metabolism and enhance its brain delivery and antiproliferative activity.

A detailed evaluation of the advantages among extracellular vesicles from three cell origins for targeting delivery of celastrol and treatment of glioblastoma

As one of the most common brain tumors, glioblastoma (GBM) lacks efficient therapeutic treatment and remains lethal. Extracellular vesicles (EVs) have emerged as a promising platform for GBM therapies. Nevertheless, the properties of EVs are significantly influenced by their cell origins. This study aimed to evaluate the advantages of EVs derived from bone marrow mesenchymal stem cells (BMSCs), human glioblastoma cells (U-87 MG) and macrophage cells (RAW264.7) to develop a more effective strategy for the delivery of anti-GBM drug celastrol (Cel). Three kinds of EVs exhibited spherical- or oval-shapes with an average size ranging from 90 to 140 nm. Western blot analysis confirmed the presence of specific EV markers (ALIX, CD63 or TSG101). Notably, the yield of BMSCs-derived EVs (BMSC-EVs) significantly surpassed that of U-87 MG and RAW264.7 cells. Furthermore, BMSC-EVs demonstrated the highest entrapment efficiency for Cel (72 %) and enhanced internalization into the target cells U-87 MG. The increased cytotoxicity and cell apoptosis further confirmed that Cel-loaded BMSC-EVs (BMSC-EVs-Cel) were more potent for killing U-87 MG cells compared with free Cel. In vivo studies utilizing both orthotopic and subcutaneous GBM models revealed facilitated blood–brain barrier penetration and transportation of cargo into tumor tissue by BMSC-EVs. Importantly, BMSC-EVs-Cel could effectively inhibit GBM growth, induce tumor tissue apoptosis and suppress intratumoral microvessel density in comparison with free Cel and temozolomide, while successfully decrease systemic toxicity. Overall, this study elucidates the properties of EVs derived from distinct cell origins and highlights the great potential of BMSC-EVs for brain tumor treatment.

Probing marine macroalgal phlorotannins as an antibacterial candidate against Salmonella typhi: Molecular docking and dynamics simulation approach

The increasing prevalence of drug-resistant bacterial strains, including multidrug-resistant Salmonella typhi, has raised significant concerns about the effectiveness of traditional antimicrobial treatments. To address this issue, the study employed computational techniques to evaluate the potential of natural phlorotannins derived from marine algae as alternative antibacterial agents against S. typhi. A total of 104 phlorotannins were retrieved from PubChem and subjected to molecular docking with three specific target proteins of S. typhi. Among the compounds tested, Compound-10 a derivative of dieckol exhibited the highest affinity for the Omptin family outer membrane protease [pgtE] protein and for the cell invasion protein sipB protein. The docking results revealed strong interactions between the phlorotannins and the target proteins, indicating their potential as antimicrobial agents. Additionally, pharmacokinetic studies using the QikProp module demonstrated that the top-ranked compounds showed favourable drug-like properties with good druggable efficiency, moderate gut-blood barrier transport, and high human oral absorption. Most compounds passed the rule of three and five drug-likeness criteria, indicating their potential as drug candidates. Furthermore, MM-GBSA analysis provided relative binding affinity estimations, ranking the compounds based on their calculated binding energies. These results align reasonably well with experimental binding affinities, reinforcing the potential of the identified compounds as potent binders to their target proteins. This study highlights the promising antibacterial potential of marine phlorotannins against S. typhi. Further in vitro studies are warranted to validate these compounds' efficacy and anti-microbial activity, ultimately paving the way for developing new therapeutic strategies to combat drug-resistant Salmonella infections.

Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood–Brain Barrier Transport of Mesoridazine and Metoclopramide

Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with Km values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H+-coupled organic cation (H+/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H+/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.

PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators.

Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of the Sertoli cell actin cytoskeleton is vital for spermatogenesis, but the underlying mechanism remains largely unclear. Here, we report that the RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Particularly, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics are controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins, and PTBP1 is a critical regulatory factor in generating such isoforms.

Simultaneous Regulation of Organic and Inorganic Components in Interphase by Fiber Separator for High-Stable Sodium Metal Batteries.

Uncontrollable side reactions at the metal interface have been identified as the root cause of the formation of a fragile solid electrolyte interphase, leading to irreversible sodium loss in sodium metal batteries. Here, we proposed an interface engineering strategy that employed a carboxyl functionalized cellulose separator to provide strong dipole moments and induce the cleavage of P-F bond to construct a solid electrolyte interphase (SEI) rich in NaF. In addition, we employed nuclear magnetic resonance technology confirmed that the separator with strong dipole moments prevented the reduction of organic solvents by attracting electrons, thereby inhibiting the formation of organic oligomers. SEI with high NaF content and few oligomers is smooth and robust, obviously decreasing the interface impedance of the Na anode. The symmetric Na||Na cells, equipped with the functionalized separator, efficiently operated for 1400 hours with a stable 72 mV overpotential at 0.25 mA cm-2, exhibiting low energy barrier and fast ion transport kinetics. The Na||Na3V2(PO4)3 cell also showed stable cycling performance, with the capacity remaining at 94.83 % of the initial capacity after 1000 cycles at 1C. The proposed separator could control the formation and composition of SEI, paving the way for the development of long-life sodium metal batteries.

Placental extracellular vesicles: their unique characteristics of the blood-brain barrier transport

Placental extracellular vesicles: their unique characteristics of the blood-brain barrier transport

Exploring Kp,uu,BBB values smaller than unity in remoxipride: A physiologically-based CNS model approach highlighting brain metabolism in drugs with passive blood-brain barrier transport

(Aim)Kp,uu,BBB values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). Kp,uu,BBB values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism. (Methods)The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg kg-1) and external (IV 4 and 8 mg kg-1) rat microdialysis studies plasma and brainECF data were analysed. (Results)The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5. (Conclusion)For drugs with Kp,uu,BBB values < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

Angiopep-2 conjugated biomimetic nano-delivery system loaded with resveratrol for the treatment of methamphetamine addiction

Methamphetamine (METH) addiction can damage the central nervous system, resulting in cognitive impairment and memory deficits. Low target effects have limited the utility of anti-addiction drugs because the presence of the blood–brain barrier hinders the effective delivery of drugs to the brain. Angiopep-2 can recognize and target low-density lipoprotein receptor-associated protein 1 (LRP-1) on the surface of cerebral capillary endothelial cells, causing cross-cell phagocytosis, and thus has high blood–brain barrier transport capacity. Resveratrol (RSV) has been found to be a neuroprotective agent in many nervous system diseases. In our study, we modified Angiopep-2 on the surface of the erythrocyte membrane to obtain a modified erythrocyte membrane (Ang-RBCm) and coated RSV-loaded poly(ε-caprolactone)–poly(ethylene glycol) (PCL-PEG) nanoparticles with Ang-RBCm (Ang-RBCm@RSVNPs) to treat METH addiction. Our results showed that Ang-RBCm@RSVNPs can penetrate the blood–brain barrier and accumulate in the brain better than free RSV. Besides, mice treatetd with Ang-RBCm@RSVNPs showed less preference to METH-paired chamber and no noticeable tissue toxicity or abnormality was found in H&E staining images. Electrophysiological experiments demonstrated Ang-RBCm@RSVNPs could elevate synaptic plasticity impaired by METH. These indicated that Ang-RBCm@RSVNPs has better anti-addiction and neuroprotective effects. Therefore, Ang-RBCm@RSVNPs has great potential in the treatment of METH addiction.

Circulating low-molecular-weight (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport.

Circulating metabolites resulting from colonic metabolism of dietary (poly)phenols are highly abundant in the bloodstream, though still marginally explored, particularly concerning their brain accessibility. Our goal is to disclose (poly)phenol metabolites' blood-brain barrier (BBB) transport, in vivo and in vitro, as well as their role at BBB level. For three selected metabolites, benzene-1,2-diol-3-sulfate/benzene-1,3-diol-2-sulfate (pyrogallol-sulfate - Pyr-sulf), benzene-1,3-diol-6-sulfate (phloroglucinol-sulfate - Phlo-sulf), and phenol-3-sulfate (resorcinol-sulfate - Res-sulf), BBB transport was assessed in human brain microvascular endothelial cells (HBMEC). Their potential in modulating in vitro BBB properties at circulating concentrations was also studied. Metabolites' fate towards the brain, liver, kidney, urine, and blood was disclosed in Wistar rats upon injection. Transport kinetics in HBMEC highlighted different BBB permeability rates, where Pyr-sulf emerged as the most in vitro BBB permeable metabolite. Pyr-sulf was also the most potent regarding BBB properties improvement, namely increased beta(β)-catenin membrane expression and reduction of zonula occludens-1 membrane gaps. Whereas no differences were observed for transferrin, increased expression of caveolin-1 upon Pyr-sulf and Res-sulf treatments was found. Pyr-sulf was also capable of modulating gene and protein expression of some solute carrier transporters. Notably, each of the injected metabolites exhibited a unique tissue distribution in vivo, with the remarkable ability to almost immediately reach the brain.

PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators.

Spermatogenesis is a biological process within the testis that produces haploid spermatozoa for the continuity of species. Sertoli cells are somatic cells in the seminiferous epithelium that orchestrate spermatogenesis. Cyclic reorganization of Sertoli cell actin cytoskeleton is vital for spermatogenesis, but the underlying mechanism remains largely unclear. Here, we report that RNA-binding protein PTBP1 controls Sertoli cell actin cytoskeleton reorganization by programming alternative splicing of actin cytoskeleton regulators. This splicing control enables ectoplasmic specializations, the actin-based adhesion junctions, to maintain the blood-testis barrier and support spermatid transport and transformation. Particularly, we show that PTBP1 promotes actin bundle formation by repressing the inclusion of exon 14 of Tnik, a kinase present at the ectoplasmic specialization. Our results thus reveal a novel mechanism wherein Sertoli cell actin cytoskeleton dynamics is controlled post-transcriptionally by utilizing functionally distinct isoforms of actin regulatory proteins, and PTBP1 is a critical regulatory factor in generating such isoforms.

Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine, and chloroquine in Rhesus macaques.

Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding Anopheles, resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of Plasmodium vivax and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.

Neuroinflammation-on-a-chip for multiple sclerosis research: a narrative review.

Multiple sclerosis (MS) is a chronic inflammatory condition that impacts the central nervous system. It is distinguished by processes like demyelination, gliosis, neuro-axonal harm, and inflammation. The prevailing theory suggests that MS originates from an immune response directed against the body's own antigens within the central nervous system. The main aim of this research paper "Neuroinflammation-on-a-Chip" for studying multiple sclerosis is to enhance our comprehension of MS development, demonstrate the application of cutting-edge technology, and potentially provide valuable insights for therapeutic approaches. The available literature for this Narrative Review was searched on various bibliographic databases, PubMed, NCBI, and many other medical references using an individually verified, prespecified approach. Studies regarding the significance of MS and its neuroinflammatory pathogenesis in addition to the development and optimization of neuroinflammatory-on-a-chip and the advancement in innovations in this field have been reviewed in this research for a better understanding of "Neuroinflammation-on-a-chip for multiple sclerosis". The level of evidence of the included studies was considered as per the Centre for Evidence-Based Medicine recommendations. Several studies have indicated that the brain-chip model closely mimics cortical brain tissue compared to commonly used conventional cell culture methods like the Transwell culture system. Additionally, these studies have clearly demonstrated that further research using brain chips has the potential to enhance our understanding of the molecular mechanisms and roles of blood-brain barrier (BBB) transporters in both normal and disease conditions. Understanding neuroinflammation processes remains essential to establish new MS treatments approaches. The utilization of brain chips promises to advance our understanding of the molecular processes involving BBB transporters, both in normal and diseased states. Further research needs to be addressed in order to enhance the performance and understanding of neuroinflammation on a chip, hence aiming to provide more effective treatments for all CNS diseases.

Effect of polarization on tunnelling electroresistance in ferroelectric tunnel junctions

High-quality epitaxial BiFeO3 (BFO) films were grown on (001)-, (110)- and (111)-oriented Nb:SrTiO3 (NSTO) substrates by pulsed laser deposition. The type of domain structure can be modulated using BFO ferroelectric films with different crystalline orientations. The ON/OFF ratios obtained in (001)-, (110)- and (111)-oriented Au/BFO/NSTO ferroelectric tunnel junctions (FTJs) are 6 × 103, 3 × 104 and 2 × 105, respectively. Analysis of the I–V curves of tunnelling current and average BFO ferroelectric barrier height proves that the polarization intensity of the BFO films modulates both the ferroelectric barrier and the Schottky barrier profile, which further influences the electronic tunnelling probability in BFO FTJs. This work will be useful for further study on achieving a giant ON/OFF ratio and developing insights into the barrier profile and transport mechanism of metal/ferroelectric/semiconductor-type FTJs.

Non-linear blood-brain barrier transport and dosing strategies influence receptor occupancy ratios of morphine and its metabolites in pain matrix.

Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose-effect relationships of morphine, we investigated the effects of its non-linear blood-brain barrier (BBB) transport on μ-receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate- and extended-release formulations were generated using a physiology-based pharmacokinetic model of the CNS, with non-linear BBB transport of morphine. The simulated CNS exposure profiles were then used to derive corresponding μ-receptor occupancies at multiple CNS pain matrix locations. Simulated CNS exposure profiles for morphine, M3G and M6G, associated with non-linear BBB transport of morphine resulted in varying μ-receptor occupancies between different dose regimens, formulations and CNS locations. At lower doses, the μ-receptor occupancy of morphine was relatively higher than at higher doses of morphine, due to the relative contribution of M3G and M6G. At such higher doses, M6G showed higher occupancy than morphine, whereas M3G occupancy was low throughout the dose ranges. Non-linear BBB transport of morphine affects the μ-receptor occupancy ratios of morphine with its metabolites, depending on dose and route of administration, and CNS location. These predictions need validation in animal or clinical experiments, to understand the clinical implications.

Comparative Analysis of the Physiological and Transport Functions of Various Sources of Renal Proximal Tubule Cells Under Static and Fluidic Conditions in PhysioMimix{trade mark, serif} T12 Platform.

In vitro models that can faithfully replicate critical aspects of kidney tubule function such as directional drug transport are in high demand in pharmacology and toxicology. Accordingly, development and validation of new models is underway. The objective of this study was to characterize physiological and transport functions of various sources of human renal proximal tubule epithelial cells (RPTECs). We tested TERT1-immortalized RPTEC, including OAT1-, OCT2- or OAT3-overexpressing variants, and primary RPTECs. Cells were cultured on transwell membranes in static (24-well transwells) and fluidic (transwells in PhysioMimix{trade mark, serif} T12 organ-on-chip with 2 mL/s flow) conditions. Barrier formation, transport, and gene expression were evaluated. We show that two commercially available primary RPTECs were not suitable for studies of directional transport on transwells because they formed a substandard barrier even though they exhibited higher expression of transporters, especially under flow. TERT1-parent, -OAT1 and -OAT3 cells formed robust barriers, but were unaffected by flow. TERT1-OAT1 cells exhibited inhibitable para-aminohippurate transport, it was enhanced by flow. However, efficient tenofovir secretion and perfluorooctanoic acid reabsorption by TERT1-OAT1 cells were not modulated by flow. Gene expression showed that TERT1 and TERT1-OAT1 cells were most correlated with human kidney than other cell lines, but that flow did not have noticeable effects. Overall, our data show that addition of flow to in vitro studies of the renal proximal tubule may afford benefits in some aspects of modeling kidney function, but that careful consideration of the impact such adaptations would have on the cost and throughput of the experiments is needed. Significance Statement The topic of reproducibility and robustness of the complex microphysiological systems is looming large in the field of biomedical research; therefore, the uptake of these new models by the end-users is slow. This study systematically compared various RPTEC sources and experimental conditions, aiming to identify the level of model complexity needed for testing renal tubule transport. We demonstrate that while tissue chips may afford some benefits, their throughput and complexity need careful consideration in each context of use.