Release Mechanism Research Articles

Mitochondrial Dysfunction is a Crucial Immune Checkpoint for Neuroinflammation and Neurodegeneration: mtDAMPs in Focus.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damageadjacenthealthy neurons and recruit peripheral immune cells, furtheramplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating bothacute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

Characterizing seed dormancy in Epimedium brevicornu Maxim.: Development of novel chill models and determination of dormancy release mechanisms by transcriptomics

PurposeEpimedium brevicornu Maxim. is a perennial persistent C3 plant of the genus Epimedium Linn. in the family Berberaceae that exhibits severe physiological and morphological seed dormancy.We placed mature E. brevicornu seeds under nine stratification treatment conditions and explored the mechanisms of influence by combining seed embryo growth status assessment with related metabolic pathways and gene co-expression analysis.ResultsWe identified 3.9 °C as the optimum cold-stratification temperature of E. brevicornu seeds via a chilling unit (CU) model. The best treatment was variable-temperature stratification (10/20 °C, 12/12 h) for 4 months followed by low-temperature stratification (4 °C) for 3 months (4-3). A total of 63801 differentially expressed genes were annotated to 2587 transcription factors (TFs) in 17 clusters in nine treatments (0-0, 0-3, 1-3, 2-3, 3-3, 4-3, 4-2, 4-1, 4-0). Genes specifically highly expressed in the dormancy release treatment group were significantly enriched in embryo development ending in seed dormancy and fatty acid degradation, indicating the importance of these two processes. Coexpression analysis implied that the TF GRF had the most reciprocal relationships with genes, and multiple interactions centred on zf-HD and YABBY as well as on MYB, GRF, and TCP were observed.ConclusionIn this study, analyses of plant hormone signal pathways and fatty acid degradation pathways revealed changes in key genes during the dormancy release of E. brevicornu seeds, providing evidence for the filtering of E. brevicornu seed dormancy-related genes.

Seismic forecasting by gapped wavelet transform for the Río de la Plata craton and adjacent continental platform

Historical and instrumental seismicity from 1845 to the present was compiled for the Pampean regions of Argentina and Uruguay and the adjacent continental platform. These data were analyzed using the Gapped Wavelet Transform (GWT) with the aim of investigating recurrence patterns in the time series.The GWT analysis reveals the existence of periods of seismic activity and periods of seismic silence within the considered area. A 22-year period was determined as the main pattern of seismic activity, during which earthquakes are registered only in 11 years. Based on these results, a probabilistic earthquake forecasting model was created using the Bayesian Machine Learning method, which suggests that the current seismically active period spans from 2011 to 2023 ± 1, with a cessation until 2034 ± 1, while the next seismically active period would begin in 2034 ± 2 ending in 2046 ± 2.These periods or recurrence patterns are interpreted as intervals during which stress accumulates throughout intracrustal faults in the studied area, being then released through various events within the established temporal interval. The accumulation and release mechanisms are still a subject of debate. However, the earthquakes distribution suggests a sublatitudinal arrangement that tends to confirm some correspondence with the controlling faulting of the Quilmes Trough and others transtensional regional lineaments.

Aquasomes: A Promising Delivery Systems for Poorly Soluble Bioactives

Aquasomes are considered an excellent and efficient carrier system for the transport of drugs or biochemically active long chain macromolecules such as proteins and peptides, various hormones, antigens, enzymes, and genes in the recently burgeoning field of nanobiotechnology research. These are three-layer self-collecting structures composed of an oligomeric film covering a strong stage nanocrystalline centre to which biochemically dynamic particles adhere to, independent of changes in the environment and which self-assembles through non-covalent or ionic connections. Aquasomes are circular particles, 60–300 nm in size, that are used to deliver antigens and medications. The structural stability is provided by the solid core, while the active drug molecules are stabilized and protected from dehydration by the polyhydroxy oligomer covering. The most common way to distribute aquasome formulations is parenterally, however recent research indicates that there may be additional, oral, ways as well. A combination of targeted molecular shielding and prolonged release mechanism is used by aquasome to deliver their bioactive chemicals. The present paper offers an overview of the aquasome as a potentially useful medication delivery technique. It covers every facet of aquasome, such as their structure, the processes for preparing them, ways to characterize them, and medical uses as a drug delivery system.

Mixing Order Asymmetry in Nanoparticle-Polymer Complexation and Precipitation Revealed by Isothermal Titration Calorimetry.

In recent years, there has been a renewed interest in complex coacervation, driven by concerted efforts to offer novel experimental and theoretical insights into electrostatic charge-induced association. While previous studies have primarily focused on polyelectrolytes, proteins, or surfactants, our work explores the potential of using cerium (CeO2) and iron (γ-Fe2O3) oxide nanoparticles (NPs) to develop innovative nanomaterials. By combining various charged species, such as polyelectrolytes, charged neutral block copolymers, and coated NPs, we study a wide variety of complexation patterns and compare them using isothermal titration calorimetry, light scattering, and microscopy. These techniques confirm that the titration of oppositely charged species occurs in two steps: the formation of polyelectrolyte complexes and subsequent phase (or microphase) separation, depending on the system studied. Across all examined cases, the entropic contribution to the total free energy surpasses the enthalpic contribution, in agreement with counterion release mechanisms. Furthermore, our investigation reveals a consistent asymmetry in the reaction enthalpy associated with the secondary process, with exothermic profiles observed upon the addition of cationic species to anionic ones and endothermic profiles in the reverse case.

Applications of Tissue Engineering

This article is written from a beginner's perspective to elucidate the concept of tissue engineering through its applications. It elaborates on the role of tissue engineering in burn skin treatment and drug delivery systems for cancer therapy. The first part of this article discusses the challenges and current issues related to burn injuries and the engineered techniques for their treatment. It highlights the need for scaffolds in skin tissue regeneration, along with the materials and methods used for treatment. The second part focuses on drug delivery mechanisms in tissue engineering, specifically in cancer treatments, explaining the carrier and release mechanisms of drugs targeting cancer cells. Most information was gathered from scientific articles, following the selection of focused applications. The basics of these applications were studied and explained in layman's terms, forming the foundation for an application-based learning experience. Personal reflections and comments are synthesized in the conclusion, making it accessible for those who want to learn about tissue engineering at a glance.

Development and Characterisation of deep Eutectic Mixture of the Atorvastatin Calcium for Oral Drug Delivery

The poor aqueous solubility and low oral bioavailability of atorvastatin calcium pose significant challenges in optimising its therapeutic efficacy. This study explores the formulation of deep eutectic solvents (DES) to enhance the solubility and bioavailability of atorvastatin calcium for oral delivery. Various DES formulations were prepared using choline chloride, choline bitartrate, and selected carboxylic acids. The formulations were characterised through physicochemical analysis, including pH, drug content, particle size, zeta potential, and Fourier-transform infrared spectroscopy. The most promising formulation, F12, exhibited a yellowish transparent appearance, a mean particle size of 74.21 nm, and a zeta potential of -22.3 mV, indicating good colloidal stability. In vitro drug release studies revealed a delayed release profile for F12 compared to the pure drug, potentially offering advantages in prolonged therapeutic effect and reduced dosing frequency. Kinetic modelling analysis suggested a diffusion-controlled release mechanism influenced by drug diffusion and polymer relaxation. Overall, this study demonstrates the potential of DES formulations in enhancing the solubility and bioavailability of atorvastatin calcium, paving the way for improved therapeutic outcomes and patient compliance.

Novel self-assembled micelles of dual-modified dextrin with pH responsiveness via grafted octenyl succinic anhydride and cysteamine for curcumin delivery

In this study, a novel dextrin-based micelle (OSAD-SH), dual-modified with octenyl succinic anhydride (OSA) and cysteamine, was developed to address the acid instability issues of micelle modified only by OSA and designed for curcumin delivery. Three amphiphilic OSAD-SH polymers with different free sulfhydryl content were first synthesized. The study demonstrated that OSAD-SH micelles exhibited strong self-assembly properties, appearing as spheres with diameters ranging from 92.41 to 194.20 nm. Blank micelles showed good dilution resistance, as well as stability against acid, thermal, and ionic strength. The curcumin encapsulated by the micelles was in an amorphous state. In vitro release experiment demonstrated that curcumin released from OSAD-SH micelles exhibited pH responsiveness. The Ritger-Peppas model effectively predicted the release behavior of curcumin, which followed a super case-II transport. The OSAD-SH micelle will be a promising nanocarrier for improving the physicochemical properties of curcumin in food fields.

Improving the quality of Glycyrrhiza stems and leaves through solid-state fermentation: flavonoid content, antioxidant activity, metabolic profile, and release mechanism

Glycyrrhiza stems and leaves (GSL) are waste products of Glycyrrhiza; however, it has been considered a potential source of flavonoid compounds. In this study, GSL was processed by solid-state fermentation (SSF) to improve the flavonoid content and antioxidant activity. Firstly, a near-infrared (NIR) prediction model for flavonoid content in fermented Glycyrrhiza stems and leaves (FGSL) was established. Next, the effects of SSF on the antioxidant activity and metabolite profile of GSL were investigated. Finally, the possible mechanism of ferment release of flavonoids was explored based on enzyme activity, thermogravimetric analysis, and FTIR spectroscopy. The results revealed that NIR spectroscopy can efficiently analyze flavonoid contents in GSL, with predicted determination coefficient (Rp2) and root mean square error (RMSEP) of 0.9874 and 0.125, respectively. SSF significantly increased the levels of flavonoids, and enhanced the scavenging activities of DPPH radical and hydroxyl radical and reducing power of FGSL. Widely targeted metabolomic analysis showed the detection of 461 differential metabolites were identified after SSF, with 141 metabolites remarkably up-regulated and 320 metabolites of FGSL down-regulated during fermentation. The main types of differential metabolites were phenolic acids and flavonoids, and the destruction of cellulose by SFF was crucial to the release of flavonoids. In conclusion, our study revealed that SSF remarkably improved the phytochemical components of FGSL by increasing enzyme activity and destroying cellulose structure, thereby contributing to the enhancement of antioxidant activity. This study provided a scientific basis for the production of high-value flavonoids from plant materials and offered a novel approach to elucidate the release and conversion of flavonoids.Graphical

A new intracellularly regulated release pattern controlled by coordinated carrier cracking and drug release

To further develop intracellular delivery systems of macromolecular drugs, understanding the cracking mechanisms and drug release behaviors of environment-responsive carriers, as well as their intrinsic linkages, is essential for achieving personalized or diversified delivery of macromolecular drugs. Herein, we designed a class of degradable dendritic mesoporous nanoparticles (DDMSNs), utilizing very large cavities and tetrasulfide bonds in the skeleton to achieve high drug loading and release within tumor cells. To comprehensively understand and develop intracellular drug delivery systems, this study delved deeper into the delivery of tetrasulfide-bonded DDMSNs, including chemical reactions, cracking kinetics, and release kinetics. First, the drug release of the DDMSNs within the cytoplasm was closely related to the chemical reaction of tetrasulfide bonds. Thus, based on experiments, the oxidation–reduction mechanism of tetrasulfide-bonded DDMSNs was explained, and the relationship was elaborated between cracking and drug release of the DDMSNs with different sulfur contents. To further explore this relationship, the cracking behavior, drug-loading capacity and release capacity of the DDMSNs was investigated with the different sulfur contents in different simulated environments, and in MDA-MB-231 cancer cells. Inspired by the reaction kinetic calculations, we analyzed the cracking and drug release behavior of the DDMSNs, and ultimately achieved dual cracking secondary drug release of the carriers by controlling the content of sulfur elements. Here, we report improved biomedical materials for advanced, customized, and intentional intracellular delivery of therapeutic macromolecules, in which theoretical calculations and experimental components were combined to study the mechanism of drug release influenced by carrier cracking, providing essential guidance for designing advanced drug delivery systems through a chemical engineering method.

Antibody-Calixarene Drug Conjugate: A General Drug Delivery Platform for Tumor-Targeted Therapy.

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.

Extracellular vesicle-derived miR-146a as a novel crosstalk mechanism for high-fat induced atherosclerosis by targeting SMAD4

IntroductionExosome-miR-146a is significantly increased in patients with Atherosclerosis (AS), but its mechanism and effect on AS have not been fully elucidated. ObjectivesTo explore the change rule and mechanism of exosomes release, and the role and molecular mechanism of exosome-miR-146a in AS. MethodsWe isolated and identified exosomes from THP-1 macrophages after treating them with ox-LDL. Then used co-immunoprecipitation and silver staining to identify the proteins involved in regulating exosome release. PKH67 was used to label exosomes to confirm that cells can absorb them, and then co-culture with HVSMCs for cell proliferation and migration detection. The target genes of miR-146a were screened and identified through bioinformatics and luciferase activity assay, and the expression of miR-146a and related proteins was detected through qRT-PCR and Western blot in HUVECs. An AS model in LDLR-/- mice induced by a high-fat diet was developed to investigate the impact of exosome-miR-146a on AS. ResultsThe results showed that experimental foam cells from AS showed higher expression of miR-146a. It was observed that NMMHC IIA and HSP70 interacted to regulate the release of exosomes. And HUVECs can absorb exosomes derived from macrophages. In addition, we also found that miR-146a directly targeted the SMAD4 gene to modulate the p38 MAPK signaling pathway, thereby mediating HUVECs damage. Furthermore, exosome-miR-146a induced abnormal proliferation and migration of HVSMCs. The expression of miR-146a was significantly reduced in miR-146a-mimics mice and increased in miR-146a inhibitor mice whereas the inhibition of miR-146a effectively reduced while increasing miR-146a worsened AS in mice. ConclusionOur findings expressed the potential of miR-146a as a favorable therapeutic target for AS, however, further exploration is suggestive for deep understanding of the mechanisms regulating exosome-miR-146a release in vivo and to develop effective therapeutic strategies involving miR-146a.

Nanofabrication of Losartan Potassium Sustained Release Floating Microspheres using Different Grades of Ethyl Cellulose and its Insight on Release Profiles.

A sustained release system for losartan potassium designed to delay its residence time in the stomach through the preparation of solvent evaporation technique-based floating microspheres. The influence of the different grades of Ethocel™ such as 4 cps, 10 cps, and 22 cps as well as the drug: polymer ratio on various properties of microspheres were tested. Thermal and functional analysis revealed no interaction between the encapsulated drug and polymer. The results indicated that the mean diameter of microspheres increased with a change in grades of ethyl cellulose relating to viscosity. However, the drug incorporation efficiency within ethyl cellulose microspheres decreased with increasing viscosity of ethyl cellulose. The bulk density of the formulations was proportionally dependent on concentration and the viscosity of the polymer, which resulted in a decrease in floating capacity from 90.02% to 73.58%. Moreover, the drug release was indirectly proportional to the viscosity of ethyl cellulose tested. The in vitro release profile exhibited a burst effect with a biphasic release pattern following Fickian diffusion, indicating a diffusioncontrolled release mechanism. The results demonstrated that the viscosity of ethyl cellulose significantly affects the floating capacity and drug release pattern from microspheres.

FORMULATION OF POLYHERBAL NANOPARTICLES FROM GLOCHIDION ZEYLANICUM PLANT A. JUSS. OF LEAVES EXTRACT

The drug was evaluated by using different in UV, Solubility, pH determination were used for the characterization of leaf extract. Polymeric nanoparticles have demonstrated significant promise in the targeted delivery of pharmaceuticals for many medical conditions. In concluded we go over the most popular techniques for creating and describing polymeric nanoparticles (NPs), the effectiveness of the active compounds binding to the polymeric core, and the in vitro release mechanisms. We also go over the toxicity and ecotoxicology of nanoparticles to humans and the environment because nanoparticle safety is very important.

How caged motion in the contact layer enhances thermal tunneling across a liquid/solid interface

Ever more powerful and densely packed chips for applications like cryptocurrency mining and artificial intelligence generate such enormous heat fluxes that designers are pivoting from gas to liquid cooling to forestall damage from thermal runaway. Even with optimal flow patterns, however, the intrinsic thermal boundary resistance at the liquid/solid (L/S) interface poses an additional source of thermal impedance. There is a lingering misconception in the field that the higher the liquid contact density, the more frequent the L/S collision rate and the smaller the thermal slip length. Here we present an insightful counterexample based on nonequilibrium molecular dynamics simulations of a simple liquid confined between two face centered cubic crystals at different temperatures aligned with the [001], [011] or [111] facet plane. Measurements of various static and dynamic quantities of the contact layer reveal the ways in which long-range order, anisotropy of the L/S potential, and correlated motion act to reduce thermal boundary resistance. Systems with the smallest thermal slip length exhibit two distinct features: 2D caged motion with stringlike alignment of liquid particles, unlike that observed in glassy systems, and larger nonergodicity parameter with shorter, not longer, caging times. This trapping and release mechanism suggests a paradigm for the design of L/S interfaces to maximize thermal exchange across a classical L/S interface. Published by the American Physical Society 2024

A l-lysine-coated graphene oxide/magnetic hydroxyapatite/cubic metal-organic frameworks for targeted and pH-controlled release of doxorubicin to cancer cells

Research on biocompatible metal-organic frameworks (MOFs) has recently attracted much attention from researchers as drug delivery systems. In this study, for the first time, Cu MOFs grown on graphene oxide capped with magnetic hydroxyapatite (MOF Cu@GO/HAp-SiO2-Fe3O4), and then the surface of the resulting nanocomposites was modified with the l-lysine amino acid (Lys-MOF Cu@GO/HAp-SiO2-Fe3O4) to prepare a controlled and pH-sensitive nanocomposite for targeted delivery of doxorubicin (DOX) to MDA-MB-231 breast cancer cells and MCF-10A normal cells. Different techniques confirmed the successful preparation of the designed nanocomposites. The values of encapsulation efficiencies (EE%) for MOF Cu@GO/HAp-SiO2-Fe3O4 and Lys-MOF Cu@GO/HAp-SiO2-Fe3O4 was found to be 79.3 % and 96.5 %, respectively. The in vitro DOX release results showed that the Lys-MOF Cu@GO/HAp-SiO2-Fe3O4 has a more controlled release than that of MOF Cu@GO/HAp-SiO2-Fe3O4 due to the slow diffusion of the drug through the Lys shell. In addition, both nanocomposites showed a pH-response release behavior. The release mechanism of DOX by the designed nanocomposites also revealed that the Korsmeyer-Peppas model is the best model to describe the release of the drug. Furthermore, in vitro cytotoxicity investigation confirmed that the prepared MOF Cu@GO/HAp-SiO2-Fe3O4 and Lys-MOF Cu@GO/HAp-SiO2-Fe3O4 nanocomposite had good biocompatibility against MDA-MB-231 and MCF-10A cells. Whereas, DOX-MOF Cu@GO/HAp-SiO2-Fe3O4 and DOX-Lys-MOF Cu@GO/HAp-SiO2-Fe3O4 against MDA-MB-231 cells increased the cytotoxicity as a result of the targeting and controlled delivery of the DOX to the cancer cells. The in vitro antioxidant activity and hemolysis experiments revealed that the designed Lys-MOF Cu@GO/HAp-SiO2-Fe3O4 have excellent antioxidant activity and good haemocompatibility, respectively, as a suitable nanocomposites for drug applications. Therefore, it is suggested that the prepared nanocomposites can be good for biological applications.

Preparation and Characterization of Sodium Alginate‐Based Hydrogel for Delivery of Hydrophilic Drug Metformin Hydrochloride

AbstractThis research delves into the development of a hydrogel based on sodium alginate (Na‐Alg), CMTKG and PSA for the controlled release of Metformin Hydrochloride (Metformin HCl), a commonly used drug for the treatment of type 2 diabetes. The hydrogel was synthesized via a free radical mechanism using N, N′‐methylene‐bis(acrylamide) (MBA) as a crosslinker and potassium persulphate (KPS) as an initiator. The hydrogels were analyzed using techniques such as ATR‐FTIR, and SEM. The research also investigated swelling behaviour, drug loading, drug encapsulation efficiency, and release kinetics of Metformin HCl. The finding revealed that the hydrogel exhibited pH‐responsive metformin HCl release, with higher drug release perceived at pH 7.4 compared to pH 1.2. Mathematical models were employed to study the drug release mechanism, indicating diffusion as a mechanism liable for the drug release from the hydrogel. Moreover, the synthesized metformin HCl‐loaded Na‐Alg/PSA/CMTKG hydrogel shows excellent anti‐diabetic activity on α‐amylase and α‐glucosidase enzyme. Henceforth, the formulated hydrogel reveals potential for facilitating the targeted release of Metformin HCl, offering opportunities for improving patient amenability and lessening side effects related to frequent dosing.

Bovine Serum Albumin Nanoparticles as a Proposed Drug Formulation for the Delivery of 10H-2,7-diazaphenothiazine

The synthesis of new compounds and nanoparticles is one of many attempts to circumvent the drug resistance. Albumin nanoparticles are biocompatible drug carriers with an ability to incorporate drugs without modifications. 10H-2,7-diazphenothiazine (2,7-DAPT) is a newly phenothiazine derivative with an anticancer, immunomodulatory and anti-inflammatory activity with a low cytotoxicity toward normal splenocytes at the same time. Up to now, no administration route for 2,7-DAPT has been proposed, so the novelty of the study is synthesis of nanoparticles containing an active ingredient not yet used in the clinic. The aim of the study was to encapsulate 2,7-DAPT into bovine serum albumin (BSA) nanoparticles by desolvation method. This study was supplemented with spectroscopic studies of 2,7-DAPT, size and morphology measurements as well as release analysis at pH 7.4 and 5.6. 2,7-DAPT is a compound with high stability in solution and an ability to absorb at UV-Vis range. Based on the results of scanning electron microscopy, nanoparticles size oscillates around the value of 204 nm. The release of 2,7- DAPT from the nanoparticles was characterized by different mechanisms of release, which were dependent on the pH of the release buffer. The above results indicate the potential usefulness of the obtained nanoparticles. Due to the lack of studies of nanoparticles containing this substance, more detailed future analyses are required.

Early activation of hepatic stellate cells induces rapid initiation of retinyl ester breakdown while maintaining lecithin:retinol acyltransferase (LRAT) activity

Lecithin:retinol acyltransferase (LRAT) is the main enzyme producing retinyl esters (REs) in quiescent hepatic stellate cells (HSCs). When cultured on stiff plastic culture plates, quiescent HSCs activate and lose their RE stores in a process similar to that in the liver following tissue damage, leading to fibrosis. Here we validated HSC cultures in soft gels to study RE metabolism in stable quiescent HSCs and investigated RE synthesis and breakdown in activating HSCs.HSCs cultured in a soft gel maintained characteristics of quiescent HSCs, including the size, amount and composition of their characteristic large lipid droplets. Quiescent gel-cultured HSCs maintained high expression levels of Lrat and a RE storing phenotype with low levels of RE breakdown. Newly formed REs are highly enriched in retinyl palmitate (RP), similar to freshly isolated quiescent HSCs, which is associated with high LRAT activity. Comparison of these quiescent gel-cultured HSCs with activated plastic-cultured HSCs showed that although during early activation the total RE levels and RP-enrichment are reduced, levels of RE formation are maintained and mediated by LRAT. Loss of REs was caused by enhanced RE breakdown in activating HSCs. Upon prolonged culturing, activated HSCs have lost their LRAT activity and produce small amounts of REs by DGAT1. This study reveals unexpected dynamics in RE metabolism during early HSC activation, which might be important in liver disease as early stages are reversible. Soft gel cultures provide a promising model to study RE metabolism in quiescent HSCs, allowing detailed molecular investigations on the mechanisms for storage and release.

A pH and near-infrared light dual-responsive drug delivery system based on TiO2 nanotube arrays modified with polydopamine and Fe3+

This paper reports a novel drug delivery system based on TiO2 nanotube arrays (TNTs) modified with polydopamine (PDA) and Fe3+, which can load and release alendronate (NaAL), a drug for osteoporosis treatment, in a pH-responsive and near-infrared light-triggered manner. The samples were characterized by electron scanning microscopy(SEM/EDS), Fourier Transform infrared spectroscopy(FTIR), X-ray diffraction(XRD), X-ray Photoelectron Spectroscopy(XPS) and Thermogravimetry(TG). The drug release behavior of the samples was investigated under different pH and light conditions. The results showed that the TNTs-PDA-Fe3+ had improved drug loading capacity compared with the TNTs and TNTs-PDA. The drug release was pH-responsive and near-infrared light-triggered, the drug release from the sample with a pH of 4.6 was much greater than the pH of 11 and 7.4, and the photothermal conversion effificiency of TNTs-PDA-Fe3+-NaAL was 32.9 %. The drug release mechanism was attributed to the coordination bond between Fe3+ and NaAL, and the photothermal effect of the PDA. The cytotoxicity and biocompatibility of the samples were evaluated by MTT assay using mouse embryonic osteoblasts cells. The results indicated that the samples had no obvious cytotoxicity and could promote the cell proliferation and differentiation. The paper concludes that the TNTs-PDA-Fe3+-NaAL system is a potential implantable drug delivery platform for bone-related diseases.