Active Transport Mechanism Research Articles

Studies on absorption mechanism and pharmacokinetic properties of albendazole-bile acid conjugate: In vivo and in vitro

PurposeTo improve the oral bioavailability of albendazole (ABZ), a series of albendazole-bile acid conjugates (ABCs) were synthesized. ABC's transmembrane transport mechanism and in vivo pharmacokinetic properties were preliminarily studied. MethodsThe transmembrane transport mechanism of ABCs was studied using the Caco-2 monolayer cell model and intestinal perfusion model. The concentration of ABCs and ABZ were evaluated using High-Performance Liquid Chromatography (HPLC) and HPLC-Mass Spectrometry (HPLC-MS/MS). ResultsCompared to ABZ, better permeability was observed for different types and concentrations of ABCs using the Caco-2 monolayer cell model, with ABC-C8 showing the highest permeability. The transmembrane transport of ABCs was affected by ASBT inhibitors, indicating an ASBT-mediated active transport mechanism. Additionally, introducing cholic acid resulted in ABZ no longer being a substrate for P-gp, MRP2, and BCRP, effectively reversing ABZ efflux. In vivo unidirectional intestinal perfusion results in rats showed that ABCs altered the absorption site of ABZ from the jejunum to the ileum. The absorption efficiency of ABCs in each intestinal segment was higher than that of ABZ, and the transmembrane transport efficiency decreased with increasing concentrations of ASBT inhibitors. This further confirmed the presence of both passive diffusion and ASBT-mediated active transport mechanisms in the transport of ABCs. The solubility of ABCs in gastric juice and pharmacokinetics in rats showed that ABZ-C4 exhibited enhanced solubility. Moreover, ABCs significantly increased oral bioavailability compared to ABZ, with ABC-C4 showing an approximately 31-fold increase in bioavailability. ConclusionThe transmembrane transport mechanism of ABCs involves a combination of ASBT-mediated active transport and passive diffusion. Moreover, the incorporation of BAs successfully reverses the efflux of ABZ by efflux proteins. Among the synthesized conjugates, ABC-C4 demonstrated superior dissolution behavior both in vitro and in vivo.

Membrane transport of rare earth metal ions N, N’-bisdioctylphosphorylmethyl-1,4-diaminobutane by the active transport mechanism

The method of membrane extraction for rare earth elements (REE) using the carrier N, N’-bisdioctylphosphorylmethyl-1,4-diaminobutane (DPDA-8) ions, leveraging an active transport mechanism, has been optimized. The distribution of DPDA-8 within the membrane pores was confirmed using scanning electron microscopy (SEM). Both light and heavy REE extractions from a simulated solution using DPDA-8 and trioctylphosphine oxide (TOPO) in 1,2-dichlorobenzene were explored. The influence of feed solution pH, carrier and anion concentration, supported liquid membrane (SLM) type and stability, and cell temperature, among other parameters, were meticulously examined. The results indicate a decrease in permeability with a decrease in feed solution pH attributed to competitive acid transport through the membrane. Additionally, the formation of H-complexes between carriers and perchloric or phosphoric acids was investigated using Fourier Transform Infrared (FTIR) spectroscopy and X-ray diffraction (XRD) techniques. Changes in the stretching bands of amino and phosphine oxide groups in DPDA-8 were monitored and characterized. XRD analysis of the crystal structures of salts DPDA-6·ClO4 and DPDA-12·H2PO4 revealed a two-dimensional layered supramolecular organization with varying anion positions relative to hydrophobic fragments. The DPDA-8 carrier demonstrated significantly higher permeability values compared to TOPO, with differences in permeability exceeding twofold for certain metals. FTIR spectroscopy identified the main coordination centers of DPDA-8 during the liquid–liquid extraction of specific REEs.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Anticancer Effect of PtIIPHENSS, PtII5MESS, PtII56MESS and Their Platinum(IV)-Dihydroxy Derivatives against Triple-Negative Breast Cancer and Cisplatin-Resistant Colorectal Cancer.

Development of resistance to cisplatin, oxaliplatin and carboplatin remains a challenge for their use as chemotherapies, particularly in breast and colorectal cancer. Here, we compare the anticancer effect of novel complexes [Pt(1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtIIPHENSS), [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII5MESS) and [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)](NO3)2 (PtII56MESS) and their platinum(IV)-dihydroxy derivatives with cisplatin. Complexes are greater than 11-fold more potent than cisplatin in both 2D and 3D cell line cultures with increased selectivity for cancer cells over genetically stable cells. ICP-MS studies showed cellular uptake occurred through an active transport mechanism with considerably altered platinum concentrations found in the cytoskeleton across all complexes after 24 h. Significant reactive oxygen species generation was observed, with reduced mitochondrial membrane potential at 72 h of treatment. Late apoptosis/necrosis was shown by Annexin V-FITC/PI flow cytometry assay, accompanied by increased sub-G0/G1 cells compared with untreated cells. An increase in S and G2+M cells was seen with all complexes. Treatment resulted in significant changes in actin and tubulin staining. Intrinsic and extrinsic apoptosis markers, MAPK/ERK and PI3K/AKT activation markers, together with autophagy markers showed significant activation of these pathways by Western blot. The proteomic profile investigated post-72 h of treatment identified 1597 MDA-MB-231 and 1859 HT29 proteins quantified by mass spectroscopy, with several differentially expressed proteins relative to no treatment. GO enrichment analysis revealed a statistically significant enrichment of RNA/DNA-associated proteins in both the cell lines and specific additional processes for individual drugs. This study shows that these novel agents function as multi-mechanistic chemotherapeutics, offering promising anticancer potential, and thereby supporting further research into their application as cancer therapeutics.

Endocytosis at the maternal-fetal interface: balancing nutrient transport and pathogen defense.

Endocytosis represents a category of regulated active transport mechanisms. These encompass clathrin-dependent and -independent mechanisms, as well as fluid phase micropinocytosis and macropinocytosis, each demonstrating varying degrees of specificity and capacity. Collectively, these mechanisms facilitate the internalization of cargo into cellular vesicles. Pregnancy is one such physiological state during which endocytosis may play critical roles. A successful pregnancy necessitates ongoing communication between maternal and fetal cells at the maternal-fetal interface to ensure immunologic tolerance for the semi-allogenic fetus whilst providing adequate protection against infection from pathogens, such as viruses and bacteria. It also requires transport of nutrients across the maternal-fetal interface, but restriction of potentially harmful chemicals and drugs to allow fetal development. In this context, trogocytosis, a specific form of endocytosis, plays a crucial role in immunological tolerance and infection prevention. Endocytosis is also thought to play a significant role in nutrient and toxin handling at the maternal-fetal interface, though its mechanisms remain less understood. A comprehensive understanding of endocytosis and its mechanisms not only enhances our knowledge of maternal-fetal interactions but is also essential for identifying the pathogenesis of pregnancy pathologies and providing new avenues for therapeutic intervention.

Phase-separated droplets swim to their dissolution

Biological macromolecules can condense into liquid domains. In cells, these condensates form membraneless organelles that can organize chemical reactions. However, little is known about the physical consequences of chemical activity in and around condensates. Working with model bovine serum albumin (BSA) condensates, we show that droplets swim along chemical gradients. Active BSA droplets loaded with urease swim toward each other. Passive BSA droplets show diverse responses to externally applied gradients of the enzyme’s substrate and products. In all these cases, droplets swim toward solvent conditions that favor their dissolution. We call this behavior “dialytaxis”, and expect it to be generic, as conditions which favor dissolution typically reduce interfacial tension, whose gradients are well-known to drive droplet motion through the Marangoni effect. These results could potentially suggest alternative physical mechanisms for active transport in living cells, and may enable the design of fluid micro-robots.

Study on the mechanism and degradation behavior of Encifer adhaerens DNM-S1 capturing dimethyl phthalate

The global concern surrounding pollution caused by phthalates is escalating, with dimethyl phthalate (DMP) emerging as one of the most prevalent contaminants within the phthalates (PAEs) category. Although the biodegradation of DMP is considered both safe and efficient, its underlying degradation mechanism is not yet fully elucidated, and the degradation performance can be somewhat inconsistent. To address this issue, our study isolated a DMP-degrading bacterium (DNM-S1) from a vegetable greenhouse. The resulting data revealed that DNM-S1 exhibited a remarkable degradation performance, successfully degrading 84.98% of a 2000 mg L−1 DMP solution within 72 h. Remarkably, it achieved complete degradation of a 50 mg L−1 DMP solution within just 3 h. DMP degradation by DNM-S1 was also found to be efficient even under low-temperature conditions (10 °C). Our research further indicates that DNM-S1 is capable of capturing DMP through the ester bond in the bacterium's cell wall fatty acids, forming hydrogen bonds through hydrophobic interactions. The DMP was then transported into the DNM-S1 protoplasm using an active transport mechanism. Interestingly, the secondary metabolites of DNM-S1 contained natural carotenoids, which could potentially counteract the damaging effects of PAEs on cell membrane permeability. In summary, these findings highlight the potential of DNM-S1 in addressing PAEs pollution and provide new insights into the metabolic mechanism of PAEs degradation.

Vitamin C in dermatology and cosmetology: a review

Vitamin C is a very powerful water-soluble antioxidant with various potential benefits for patients with skin diseases. The chemically active form of vitamin C is L-ascorbic acid (LAA) and thus is used extensively in medical practices. Due to an active transport mechanism, the absorption of vitamin C in the gut is limited, thereby reducing the amount of drug absorbed orally despite a high dosage, which in turn reduces the bioavailability of vitamin C in the skin. Therefore, topical use of vitamin C is usually preferred in dermatology practice. The function of vitamin C is mostly linked to its electron-donating property. Several processes such as reduction of iron in the gastrointestinal tract, synthesis of carnitine, gene transcription, protection against reactive oxygen species (ROS), demethylation of DNA, Hydroxylation of transcription factors, tRNA, and ribosomal proteins, collagen, and hormonal synthesis are carried out due to the active participation of vitamin C in the body. Scurvy usually occurs due to inadequate consumption of vitamin C through a regular diet or inability to absorb the vitamin C in the body. 90% of ascorbic acid comes from fresh fruits and vegetable consumption, failure of which can lead to scurvy.

Nanomaterials in Medicine: Understanding Cellular Uptake, Localization, and Retention for Enhanced Disease Diagnosis and Therapy.

Nanomaterials (NMs) have emerged as promising tools for disease diagnosis and therapy due to their unique physicochemical properties. To maximize the effectiveness and design of NMs-based medical applications, it is essential to comprehend the complex mechanisms of cellular uptake, subcellular localization, and cellular retention. This review illuminates the various pathways that NMs take to get from the extracellular environment to certain intracellular compartments by investigating the various mechanisms that underlie their interaction with cells. The cellular uptake of NMs involves complex interactions with cell membranes, encompassing endocytosis, phagocytosis, and other active transport mechanisms. Unique uptake patterns across cell types highlight the necessity for customized NMs designs. After internalization, NMs move through a variety of intracellular routes that affect where they are located subcellularly. Understanding these pathways is pivotal for enhancing the targeted delivery of therapeutic agents and imaging probes. Furthermore, the cellular retention of NMs plays a critical role in sustained therapeutic efficacy and long-term imaging capabilities. Factors influencing cellular retention include nanoparticle size, surface chemistry, and the cellular microenvironment. Strategies for prolonging cellular retention are discussed, including surface modifications and encapsulation techniques. In conclusion, a comprehensive understanding of the mechanisms governing cellular uptake, subcellular localization, and cellular retention of NMs is essential for advancing their application in disease diagnosis and therapy. This review provides insights into the intricate interplay between NMs and biological systems, offering a foundation for the rational design of next-generation nanomedicines.

Investigations Towards Tryptophan Uptake and Transport Across an In Vitro Model of the Oral Mucosa Epithelium.

Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.

Unveiling the role of linear alkyl organic cations in 2D layered tin halide perovskite field-effect transistors.

Two-dimensional (2D) tin halide perovskites are promising semiconductors for field-effect transistors (FETs) owing to their fascinating electronic properties. However, the correlation between the chemical nature of organic cations and charge carrier transport is still far from understanding. In this study, the influence of chain length of linear alkyl ammonium cations on film morphology, crystallinity, and charge transport in 2D tin halide perovskites is investigated. The carbon chain lengths of the organic spacers vary from propylammonium to heptanammonium. The increase of alkyl chain length leads to enhanced local charge carrier transport in the perovskite film with mobilities of up to 8 cm2 V-1 s-1, as confirmed by optical-pump terahertz spectroscopy. A similar improved macroscopic charge transport is also observed in FETs, only to the chain length of HA, due to the synergistic enhancement of film morphology and molecular organization. While the mobility increases with the temperature rise from 100 K to 200 K due to the thermally activated transport mechanism, the device performance decreases in the temperature range of 200 K to 295 K because of ion migration. These results provide guidelines on rational design principles of organic spacer cations for 2D tin halide perovskites and contribute to other optoelectronic applications.

Local Anesthetics: Review of Pharmacological Considerations

Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is not so regular, and the negative effects are so low, that providers can overlook a lot of their pharmacotherapeutic principles understandable. The purpose of this continuing education article is important for various local anesthesia formulas in current use. Local anesthetics inhibit nerve conduction by inhibiting the passage of sodium ions through channels or ionophores within neural membranes. Usually these channels are present at rest, during which access to sodium ions is prohibited. When the neuron is excited, the channel adopts an activated or open state, in which sodium ions spread to the cell and begin depolarization. After a sharp change in membrane voltage, the sodium channel adopts an inactive state, at which point the active transport mechanisms return sodium ions outward. After this repolarization, the canal receives a normal state of rest. Valuing these sodium channel States helps explain the privileged sensitivity of local anesthetics for different classes of neuronal fibers

CSF‐plasma albumin ratio differs by sex in community dwelling older adults

AbstractBackgroundBlood‐brain barrier (BBB) permeability is associated with Alzheimer’s disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlb interaction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume.ResultFemale sex was associated with lower QAlb (p<0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values>0.7) or neuroimaging outcomes (p‐values>0.2). Models stratified by sex were also null for neuropsychological (p‐values>0.93) and neuroimaging outcomes (p‐values>0.11).ConclusionElevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings. Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082

Dielectric Relaxation Behavior and Electrical Conduction Mechanism of PVA/ZnO Nanocomposites for Flexible Electronic Device Application

Transport properties of polyvinyl alcohol/ZnO nanocomposites (PVA/ZnO) of varying ZnO nanofiller are studied focussing on their potential application in electronic device application. The structural, morphological, and elemental composition studies of the prepared samples are done by X‐ray diffraction (XRD), scanning electron microscope (SEM), and energy‐dispersive X‐ray analysis (EDX). XRD confirms the formation of nanocomposites. SEM image shows the dispersion of ZnO nanoparticles on the surface of PVA matrix. EDX verifies that no external impurities are present in the nanocomposite samples. Frequency‐ and temperature‐dependent dielectric measurement of the samples reveals maximum dielectric constant at PVA/15 wt% ZnO nanocomposite. Dielectric loss results show a lossless behavior at higher frequencies (<0.2), indicating their suitability for high‐frequency applications. The AC conductivity studies reveal that electrical conduction mechanism in the nanocomposites is governed by the correlated barrier hopping mechanism. Activation energy of the samples reveals the presence of two thermally activated transport mechanism above and below 353 K. The imaginary part of electric modulus with frequency shows a single relaxation peak indicating the transition from long‐range to short‐range mobility with increasing frequency and temperature above 353 K. The contribution of grain and grain boundary in the electrical conduction process is confirmed from the Nyquist plot.

4-Ethylphenol-fluxes, metabolism and excretion of a gut microbiome derived neuromodulator implicated in autism.

Gut-microbiome-derived metabolites, such as 4-Ethylphenol [4EP], have been shown to modulate neurological health and function. Although the source of such metabolites is becoming better understood, knowledge gaps remain as to the mechanisms by which they enter host circulation, how they are transported in the body, how they are metabolised and excreted, and the way they exert their effects. High blood concentrations of host-modified 4EP, 4-ethylphenol sulfate [4EPS], are associated with an anxiety phenotype in autistic individuals. We have reviewed the existing literature and discuss mechanisms that are proposed to contribute influx from the gut microbiome, metabolism, and excretion of 4EP. We note that increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of 4EP and/or 4EPS across the gut epithelium and the Blood Brain Barrier [BBB]. Similarly, kidney dysfunction, another complication observed in autistic individuals, impacts clearance of 4EP and its derivatives from circulation. Evidence indicates that accumulation of 4EPS in the brain of mice affects connectivity between subregions, particularly those linked to anxiety. However, we found no data on the presence or quantity of 4EP and/or 4EPS in human brains, irrespective of neurological status, likely due to challenges sampling this organ. We argue that the penetrative ability of 4EP is dependent on its form at the BBB and its physicochemical similarity to endogenous metabolites with dedicated active transport mechanisms across the BBB. We conclude that future research should focus on physical (e.g., ingestion of sorbents) or metabolic mechanisms (e.g., conversion to 4EP-glucuronide) that are capable of being used as interventions to reduce the flux of 4EP from the gut into the body, increase the efflux of 4EP and/or 4EPS from the brain, or increase excretion from the kidneys as a means of addressing the neurological impacts of 4EP.

Active Transport and Ocular Distribution of Intravitreally Injected Liposomes.

Drug delivery to the retina remains a challenge due to ocular barriers and fast clearing mechanisms. Nanocarrier drug delivery systems (NDDSs) hold the promise of prolonging intraocular retention times and increasing drug concentrations in the retina. Anionic and cationic PEGylated liposomes, loaded with oxaliplatin (OxPt) to be used as trace element, were prepared from dry lipid powders. The differently charged liposomes were intravitreally injected in C57BL/6JrJ mice; eyes were harvested 2hours and 24hours post-injection. To investigate active transport mechanisms in the eye, a subset of mice were pre-injected with chloroquine before injection with cationic liposomes. Eyes were dissected and the distribution of OxPt in different tissues were quantified by inductively coupled plasma mass spectrometry (ICP-MS). Both liposome formulations enhanced the retention time of OxPt in the vitreous over free OxPt. Surprisingly, when formulated in cationic liposomes, OxPt translocated through the retina and accumulated in the RPE-sclera. Pre-injection with chloroquine inhibited the transport of liposomal OxPt from the vitreous to the RPE-sclera. We show that liposomes can enhance the retention time of small molecular drugs in the vitreous and that active transport mechanisms are involved in the trans retinal transport of NDDS after intravitreal injections. These results highlight the need for understanding the dynamics of ocular transport mechanisms in living eyes when designing NDDS with the back of the eye as the target. Active transport of nanocarriers through the retina will limit the drug concentration in the neuronal retina but might be exploited for targeting the RPE.

Light-Driven Chloride and Sulfate Pump with Two Different Transport Modes.

Ion pumps are membrane proteins that actively translocate ions by using energy. All known pumps bind ions in the resting state, and external energy allows ion transport through protein structural changes. The light-driven sodium-ion pump Krokinobacter eikastus rhodopsin 2 (KR2) is an exceptional case in which ion binding follows the energy input. In this study, we report another case of this unusual transport mode. The NTQ rhodopsin from Alteribacter aurantiacus (AaClR) is a natural light-driven chloride pump, in which the chloride ion binds to the resting state. AaClR is also able to pump sulfate ions, though the pump efficiency is much lower for sulfate ions than for chloride ions. Detailed spectroscopic analysis revealed no binding of the sulfate ion to the resting state of AaClR, indicating that binding of the substrate (sulfate ion) to the resting state is not necessary for active transport. This property of the AaClR sulfate pump is similar to that of the KR2 sodium pump. Photocycle dynamics of the AaClR sulfate pump resemble a non-functional cycle in the absence of anions. Despite this, flash photolysis and difference Fourier transform infrared spectroscopy suggest transient binding of the sulfate ion to AaClR. The molecular mechanism of this unusual active transport by AaClR is discussed.

Removal, fate, and bioavailability of fluoroquinolone antibiotics in a phytoremediation system with four wetland plants: Combing dynamic DGT and traditional methods

Phytoremediation is considered an effective technology for remediating antibiotic-contaminated water; however, its underlying mechanisms remain poorly understood. Therefore, this study investigated the phytoremediation potential of fluoroquinolone antibiotics (FQs) by different wetland plant species. The phytoremediation rates of ΣFQs were 46–69 %, and rhizosphere microorganism degradation (accounting for 90–93 %) dominated the FQ removal over that of plant uptake and hydrolysis. Dissipation of the FQs in the hydroponic system followed a first-order kinetic model. The joint action of the more powerful absorptive capacity of plants and stronger microbial degradation ability in the rhizosphere was the reason that Cyperus papyrus showed significantly higher FQ phytoremediation rates than the other three plant species, which implied that the plant species is a critical factor affecting phytoremediation efficiency. The FQ distribution in plant tissues decreased from root > stem > leaf, suggesting that FQs were more concentrated in the roots than in the aboveground tissues. Negative correlations between the diffusive gradient in thin films and root concentrations implied that these wetland plant species took up FQs mainly via active transport mechanism (requiring some vectors, perhaps via exudates); whereas, the process of root-to-stem transfer and upward transport represented passive transport, which mainly depended on transpiration. These results facilitate an improved understanding of phytoremediation processes and improve their future applications.

PBTK modeled perfluoroalkyl acid kinetics in zebrafish eleutheroembryos suggests impacts on bioconcentrations by chorion porosity dynamics

The zebrafish eleutheroembryo (zfe) is widely used as a model to characterize the toxicity of chemicals. However, analytical methods are still missing to measure organ concentrations. Therefore, physiologically-based toxicokinetic (PBTK) modeling may overcome current limitations to help understand the relationship between toxic effects and internal exposure in various organs.A previous PBTK model has been updated to include the chorionic transport barrier and its permeabilization, hatching dynamics within a zfe population over development, and active mediated transport mechanisms. The zfe PBTK model has been calibrated using measured time-dependent internal concentrations of PFBA, PFHxS, PFOA, and PFOS in a zfe population and evaluated using external datasets from the literature.Calibration was successful with 96% of the predictions falling within a 2-fold range of the observed concentrations. The external dataset was correctly estimated with about 50% of the predictions falling within a factor of 3 of the observed data and 10% of the predictions are out of the 10-fold error. The calibrated model suggested that active mediated transport differs between PFAS with a sulfonic and carboxylic acid functional end groups.This PBTK model predicts well the fate of PFAS with various physicochemical properties in zfe. Therefore, this model may improve the use of zfe as an alternative model in toxicokinetic-toxicodynamic studies and help to refine and reduce zfe-based experiments, while giving insights into the internal kinetics of chemicals.

Towards a multiscale model of P-glycoprotein efflux.

The blood-brain barrier (BBB) remains a major roadblock to the delivery of drugs to the brain. While in vitro and in vivo measurements of permeability are widely used to predict brain penetration, very little is known about the mechanisms of passive and active transport. Detailed insight into interactions between solutes and cell membranes could provide new insight into drug design and screening. Multidrug resistance (MDR) is a problem that affects treatment of many diseases, and is often associated with P-glycoprotein (P-gp, ABCB1 or MDR1), one of the ABC family of transporters. These efflux pumps transport substrates that have crossed the blood-brain barrier back out into circulation, thereby limiting bioavailability in the local tissue. The mechanism of how P-gp is inhibited is not well understood, in particular how the ligand reaches its binding site. Here, we build a multiscale model of transport across the BBB. Firstly, we demonstrate our BBB membrane model of the brain microvascular endothelial cell (hBMEC) membrane. We perform simulate unbiased atomistic MD simulations to visualize translocation of a library of 23 solutes across a lipid bilayer representative of brain microvascular endothelial cells (hBMEC). Secondly, we perform simulations of the active transport of P-glycoprotein (P-gp) efflux out of the cell for a substrate and a potential third-generation inhibitor. Then, we demonstrate results using a novel coarse-grain model of P-gp with MARTINI 3.0, which enables us to access much longer timescales.