Venetoclax pharmacokinetics in participants with end-stage renal disease undergoing haemodialysis.

Aims: Renal insufficiency is a common comorbidity in patients with haematological malignancies. This study aimed to assess how end-stage renal disease (ESRD) might affect the pharmacokinetics of venetoclax, a Bcl-2 inhibitor, in participants with ESRD undergoing haemodialysis.

Methods: Venetoclax was administered as a single 100-mg dose to 6 female participants with ESRD (estimated glomerular filtration rate <15 mL/min) both prior to haemodialysis and between haemodialysis days and 7 healthy female participants with normal renal function (estimated glomerular filtration rate >90 mL/min).

Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes.

The purpose of this study was to investigate the effects of the volatile anesthetic agents isoflurane and sevoflurane, at clinically relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability), monolayers of brain microvascular endothelial cells ([C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-minute exposure of mice to isoflurane on the brain tight junction proteins.

Advanced Microfluidic Vascularized Tissues as Platform for the Study of Human Diseases and Drug Development.

The vascular system plays a critical role in human physiology and diseases. It is a complex subject to study using in vitro models due to its dynamic and three-dimensional microenvironment. Microfluidic technology has recently become a popular technology in various biological fields for its advantages in mimicking complex microenvironments to an extent not achievable by more conventional platforms.

In Vitro Models of the Blood-Brain Barrier.

Traditional in vitro models can replicate many essential features of drug transport/permeability across the blood-brain barrier (BBB) but are not entirely projecting in vivo central nervous system (CNS) uptake. Species differences fail to translate experimental therapeutics from the research laboratory to the clinic. Improved in vitro modeling of human BBB is vital for both CNS drug discovery and delivery.

In-Vivo and Ex-Vivo Brain Uptake Studies of Peptidomimetic Neurolysin Activators in Healthy and Stroke Animals.

Purpose: Neurolysin (Nln) is a peptidase that functions to preserve the brain following ischemic stroke by hydrolyzing various neuropeptides. Nln activation has emerged as an attractive drug discovery target for treatment of ischemic stroke. Among first-in-class peptidomimetic Nln activators, we selected three lead compounds (9d, 10c, 11a) for quantitative pharmacokinetic analysis to provide valuable information for subsequent preclinical development.

A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance and Efflux of Sucrose and Mannitol after IV Injection in Awake Mice.

Purpose: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake.

Methods: Stable isotope-labeled [C]sucrose and [C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h.

Molecular Mechanisms of Multi-Organ Failure in COVID-19 and Potential of Stem Cell Therapy.

As the number of confirmed cases and deaths occurring from Coronavirus disease 2019 (COVID-19) surges worldwide, health experts are striving hard to fully comprehend the extent of damage caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 primarily manifests itself in the form of severe respiratory distress, it is also known to cause systemic damage to almost all major organs and organ systems within the body. In this review, we discuss the molecular mechanisms leading to multi-organ failure seen in COVID-19 patients.

A Quasi-Physiological Microfluidic Blood-Brain Barrier Model for Brain Permeability Studies.

Microfluidics-based organ-on-a-chip technology allows for developing a new class of in-vitro blood-brain barrier (BBB) models that recapitulate many hemodynamic and architectural features of the brain microvasculature not attainable with conventional two-dimensional platforms. Herein, we describe and validate a novel microfluidic BBB model that closely mimics the one in situ. Induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) were juxtaposed with primary human pericytes and astrocytes in a co-culture to enable BBB-specific characteristics, such as low paracellular permeability, efflux activity, and osmotic responses.

pH-Responsive Nanocomposite Based Hydrogels for the Controlled Delivery of Ticagrelor; In Vitro and In Vivo Approaches.

Background: Ticagrelor (TG), an antiplatelet drug is employed to treat patients with acute coronary syndrome, but its inadequate oral bioavailability due to poor solubility and low permeability restricts its effectiveness.

Purpose: This contemporary work was aimed to design a novel pH-sensitive nanocomposite hydrogel (NCH) formulation incorporating thiolated chitosan (TCH) based nanoparticles (NPs) of Ticagrelor (TG), to enhance its oral bioavailability for effectively inhibiting platelet aggregation.

Methods: NCHs were prepared by free radical polymerization technique, using variable concentrations of chitosan (CH) as biodegradable polymer, acrylic acid (AA) as a monomer, N,N-methylene bisacrylamide (MBAA) as cross-linker, and potassium persulphate (KPS) as initiator.

Comparative assessment of in vitro BBB tight junction integrity following exposure to cigarette smoke and e-cigarette vapor: a quantitative evaluation of the protective effects of metformin using small-molecular-weight paracellular markers.

Background: The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from blood-borne agents and potentially harmful xenobiotics. Our group's previous data has shown that tobacco smoke (TS) and electronic cigarettes (EC) affect the BBB integrity, increase stroke incidence, and are considered a risk factor for multiple CNS disorders. Metformin was also found to abrogate the adverse effects of TS and EC.

Enrichment of the erythrocyte miR-451a in brain extracellular vesicles following impairment of the blood-brain barrier.

Extracellular RNAs (exRNAs) are present in all biofluids and incorporate many types of RNAs including miRNA. To enhance their stability outside of the cell, exRNAs are bound within ribonucleoprotein complexes or packaged into extracellular vesicles (EVs). The blood-brain barrier (BBB) is a dynamic interface between the systemic circulation and the CNS and is responsible for maintaining a stable extracellular environment for CNS cells.

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview.

The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain.

A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity.

The blood-brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain's metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain-blood interface.

LC-MS/MS-based in vitro and in vivo investigation of blood-brain barrier integrity by simultaneous quantitation of mannitol and sucrose.

Background: Understanding the pathophysiology of the blood brain-barrier (BBB) plays a critical role in diagnosis and treatment of disease conditions. Applying a sensitive and specific LC-MS/MS technique for the measurement of BBB integrity with high precision, we have recently introduced non-radioactive [C]sucrose as a superior marker substance. Comparison of permeability markers with different molecular weight, but otherwise similar physicochemical properties, can provide insights into the uptake mechanism at the BBB.

Estimating Brain Permeability Using In Vitro Blood-Brain Barrier Models.

The blood-brain barrier (BBB) is a vital biological interface that regulates transfer of different molecules between blood and brain and, therefore, maintains the homeostatic environment of the CNS. In order to perform high-throughput screening of therapeutics in drug discovery, specific properties of the BBB are investigated within in vitro BBB platforms. In this chapter, we detail the process and steps for the iPSC to BMEC and astrocyte differentiation as well as TEER and permeability measurement in Transwell platform of in vitro BBB model.

In vitro modeling of the neurovascular unit: advances in the field.

The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS).

Isoflurane increases cell membrane fluidity significantly at clinical concentrations.

There is an on-going debate whether anesthetic drugs, such as isoflurane, can cause meaningful structural changes in cell membranes at clinical concentrations. In this study, the effects of isoflurane on lipid membrane fluidity were investigated using fluorescence anisotropy and spectroscopy. In order to get a complete picture, four very different membrane systems (erythrocyte ghosts, a 5-lipid mixture that mimics brain endothelial cell membrane, POPC/Chol, and pure DPPC) were selected for the study.

Effects of Encapsulated Cells on the Physical-Mechanical Properties and Microstructure of Gelatin Methacrylate Hydrogels.

Gelatin methacrylate (GelMA) has been gaining popularity in recent years as a photo-crosslinkable biomaterial widely used in a variety of bioprinting and tissue engineering applications. Several studies have established the effects of process-based and material-based parameters on the physical-mechanical properties and microstructure of GelMA hydrogels. However, the effect of encapsulated cells on the physical-mechanical properties and microstructure of GelMA hydrogels has not been fully understood.

Brain Uptake of [C] and [C]Sucrose Quantified by Microdialysis and Whole Tissue Analysis in Mice.

Among small, hydrophilic drug-like molecules, [C]sucrose has long been considered the gold standard for determination of blood-brain barrier permeability. However, we have recently shown in rats that, compared with liquid chromatography-tandem mass spectrometry analysis of stable isotope (C) of sucrose, [C]sucrose significantly overestimates the brain tissue concentration and uptake of sucrose by a factor of 6 to 7. This discrepancy is due to the presence of small quantities of lipophilic impurities in [C]sucrose tracer solutions.

Production of nanocellulose in miniature-bioreactor: Optimization and characterization.

Bacterial cellulose (BC) is a very fascinating microbial biopolymer which is mainly produced by Gluconacetobacter xylinum. Optimization of BC production by G. xylinum was performed based on scale-down studies in miniature-bioreactor and response surface methodology in which the optimum pH value (6.