Simulated Physiological Environment Research Articles

A CO-releasing coating based on carboxymethyl chitosan-functionalized graphene oxide for improving the anticorrosion and biocompatibility of magnesium alloy stent materials

Due to its biofunctions similar to NO, the CO gas signaling molecule has gradually shown great potential in cardiovascular biomaterials for regulating the in vivo performances after the implantation and has received increasing attention. To construct a bioactive surface with CO-releasing properties on the surface of magnesium-based alloy to augment the anticorrosion and biocompatibility, graphene oxide (GO) was firstly modified using carboxymethyl chitosan (CS), and then CO-releasing molecules (CORM401) were introduced to synthesize a novel biocompatible nanomaterial (GOCS-CO) that can release CO in the physiological environments. The GOCS-CO was further immobilized on the magnesium alloy surface modified by polydopamine coating with Zn2+ (PDA/Zn) to create a bioactive surface capable of releasing CO in the physiological environment. The outcomes showed that the CO-releasing coating can not only significantly enhance the anticorrosion and abate the corrosion degradation rate of the magnesium alloy in a simulated physiological environment, but also endow it with good hydrophilicity and a certain ability to adsorb albumin selectively. Owing to the significant enhancement of anticorrosion and hydrophilicity, coupled with the bioactivity of GOCS, the modified sample not only showed excellent ability to prevent platelet adhesion and activation and reduce hemolysis rate but also can promote endothelial cell (EC) adhesion, proliferation as well as the expression of nitric oxide (NO) and vascular endothelial growth factor (VEGF). In the case of CO release, the hemocompatibility and EC growth behaviors were further significantly improved, suggesting that CO molecules released from the surface can significantly improve the hemocompatibility and EC growth. Consequently, the present study provides a novel surface modification method that can simultaneously augment the anticorrosion and biocompatibility of magnesium-based alloys, which will strongly promote the research and application of CO-releasing bioactive coatings for surface functionalization of cardiovascular biomaterials and devices.

Discovery of Novel Aldose Reductase Inhibitors via the Integration of Ligand-Based and Structure-Based Virtual Screening with Experimental Validation.

Aldose reductase plays a central role in diabetes mellitus (DM) associated complications by converting glucose to sorbitol, resulting in a harmful increase of reactive oxygen species (ROS) in various tissues, such as the heart, vasculature, neurons, eyes, and kidneys. We employed a comprehensive approach, integrating both ligand- and structure-based virtual screening followed by experimental validation. Initially, candidate compounds were extracted from extensive drug and chemical libraries using the DeepChem's GraphConvMol algorithm, leveraging its capacity for robust molecular feature representation. Subsequent refinement employed molecular docking and molecular dynamics (MD) simulations, which are crucial for understanding compound-receptor interactions and dynamic behavior in a simulated physiological environment. Finally, the candidate compounds were subjected to experimental validation of their biological activity using an aldose reductase inhibitor screening kit. The comprehensive approach led to the identification of a promising compound, demonstrating significant potential as an aldose reductase inhibitor. This comprehensive approach not only yields a potential therapeutic intervention for DM-related complications but also establishes an integrated protocol for drug development, setting a new benchmark in the field.

Efficient and sensitive determination of storage time-temperature marker 5-hydroxy methyl furfural in bee honey based on Fluorescence quenching of human serum albumin

5-hydroxymethyl furfural (HMF) exhibits mutagenic and DNA strand-breaking activity. It is a useful tool to evaluate the effect of heat and time on foodstuffs processing. The fluorescence interaction of HMF with HSA has not been explored to date. Therefore, this work reports the interaction mechanism of HMF with HSA via fluorescence spectroscopy analysis in a simulated physiological environment. The experimental tries showed that HMF intensely quenched the native fluorescence of HSA via the dynamic quenching. According to fluorescence quenching calculations, the binding constants Kb are 1.26x10-4, 2.71x10-4 and 3.19x10-4 M-1 at 298, 303 and 308 K respectively, and the number of binding sites n is almost 1. Thermodynamic parameters values expose that both electrostatic and hydrophobic interactions are accountable for the interaction of HSA and HMF. The presented quenching method for the assay of HMF exhibited a good linearity in the range of 0.1 to 6.66 µg/mL with a detecting limit of 0.0184 µg/mL. These values made the developed method appropriate to be used in the estimation of HMF in samples of bee honey after its extraction using SupelcleanTM ENVI™ -18 SPE Tube. Five bee honey samples show a positive response of HMF after exposing these samples for inappropriate storage or extreme heating.

Development and characterization of liposomal formulations containing sesquiterpene lactones for the treatment of chronic gout

Gout and hyperuricemia are characterized by high uric acid levels, and their treatment involves medications that have adverse effects. In this study, we evaluated oral liposomal formulations with eremantholide C and goyazensolide as a novel approach to reduce the toxicity associated with these substances while maintaining their anti-hyperuricemic activity. We characterized the formulations and evaluated them based on encapsulation efficiency and stability over 12 months and under simulated physiological environments. We determined the toxicity of the liposomal formulations in Caco-2 cells and the anti-hyperuricemic activity in rats. The formulations exhibited nanometric size, a narrow size distribution, and a negative zeta potential, indicating their stability and uniformity. The efficient encapsulation of the sesquiterpene lactones within the liposomes emphasizes their potential for sustained release and therapeutic efficacy. Stability evaluation revealed a small decrease in the eremantholide C concentration and a remarkable stability in the goyazensolide concentration. In Caco-2 cells, the liposomes did not exert toxicity, but did exhibit an antiproliferative effect. In vivo assays demonstrated that the liposomes reduced serum uric acid levels. Our study represents an advancement in gout and hyperuricemia treatment. The liposomal formulations effectively reduced the toxicity associated with the sesquiterpene lactones while maintaining their therapeutic effects.

New insights on the high-corrosion resistance of UHP Mg-Ge alloys tested in a simulated physiological environment

UHP Mg-Ge alloys was recently found to provide excellent corrosion resistance. This paper provides new insights on the mechanism of improved corrosion resistance of UHP Mg-Ge alloys in Hanks' solution. The studied UHP Mg-0.5Ge and UHP Mg-1Ge alloys showed superior corrosion resistance compared to UHP Mg and WE43, with the Mg-1Ge exhibiting the best corrosion performance. The exceptional corrosion resistance of the UHP alloy is attributed to (i) Mg2Ge's ability to suppress cathodic kinetics, (ii) Ge's capability to accelerate the formation of a highly passive layer, and the (iii) low amounts of corrosion-accelerating impurities.

Ce-doped MgO films on AZ31 alloy substrate for biomedical applications: preparation, characterization and testing

Magnesium ions, MgO nanoparticles and thin films, magnesium alloys and cerium compounds are materials intensively studied due to their corrosion protection, antibacterial and pharmacological properties. In this work, we have designed, prepared and investigated, novel thin films of MgO doped with cerium, deposited on Mg alloy (AZ31) for temporary implants, in order to enhance their life time. More precisely, we report on microstructure and corrosion behavior of MgO pure and doped with 0.1 at % Ce films, fabricated by sol–gel route coupled with spin-coating technique, on AZ31 alloy substrate. A modified sol–gel method that start from magnesium acetylacetonate, cerium nitrate and 2–methoxyethanol (as a stabilizer for the sol) was been used successfully for cerium doped MgO sol precursor preparation. The structure and morphology of the surface of the coatings, before and after immersion for 7–30 d in Hank’s solution at 37 °C, were characterized by x-ray diffraction (XRD), scanning electron microscopy, high-resolution transmission electron microscope, x-ray photoelectron spectroscopy and Fourier infrared transmittance spectrum (FT–IR). A comparison between the corrosion protection of undoped MgO and MgO doped with 0.1 at % Ce coatings on the AZ31 alloy substrate is performed by electrochemical tests and immersion tests using open circuit potential and electrochemical impedance spectroscopy in Hank’s solution, at 37 °C. The electrochemical results showed that the protection of the AZ31 alloy substrate against corrosion was better with the doped with 0.1 at % Ce MgO film deposited than with pure MgO coting. The investigations of the films after immersion in Hank’s solution, at 37 °C, for 7, 21 and 30 d indicated that the grown layer on the film is bone like apatite that suggests a good bioactivity of 0.1 at % Ce–doped MgO coating. Our work demonstrates that the performance corrosion protection of the biodegradable magnesium alloys used for orthopedic applications, in simulated physiological environments (Hank and Ringer) can be enhanced through coating with Ce3+ doped MgO sol–gel thin film.

Biocompatible Co-P Metallic Glasses with Superior Degradation Tolerance in Physiological Environments.

Metallic glasses represent a class of metallic alloys with a fully amorphous structure and attractive properties, making them promising in bioimplant applications. Here, the degradation tolerance of biocompatible cobalt-phosphorus (Co-P) metallic glasses was studied in a simulated physiological environment. The metallic glasses were synthesized in the form of coatings through a facile electrodeposition approach. This method utilizes their outstanding surface characteristics and bypasses the size limitations usually associated with their bulk counterparts. The Co-P alloys showed exceptional tribological response with ∼14% lower coefficient of friction and 2 orders of magnitude lesser wear rate compared to SS316 stainless steel. In addition, the Co-P alloys showed a 3 times higher hardness and 4 times higher hardness/modulus ratio compared to SS316, indicating better elastic recovery under dynamic shear stresses that are common in load-bearing bioimplants. The Co-P metallic glasses exhibited excellent hemocompatibility and cytocompatibility in terms of lower platelet adhesion, spreading, and aggregation, a hemolysis ratio lower than 1%, and enhanced surface wettability, suggesting a superlative performance in bioimplant applications.

Synthesis of hydroxyethyl starch 200/0.5-loaded albumin nanoparticles: biocompatibility and interaction mechanism.

We aimed to synthesize hydroxyethyl starch (HES) 200/0.5-loaded bovine serum albumin nanoparticles (HBNs) and investigate the compatibility and binding mechanism in simulated physiological environments. Here, to elucidate the morphology, biocompatibility, and formation mechanism of HBNs, techniques such as scanning electron microscopy, haemolysis test, fluorescence, and circular dichroism spectroscopy were applied. The thermodynamic parameters at body temperature (ΔS° = -26.7J·mol-1 ·K-1 , ΔH° = -3.20 × 104 J·mol-1 , and ΔG = -2.35 × 104 J·mol-1 ) showed a 1:1 binding stoichiometry, which was formed by hydrogen bonds and van der Waals interactions. In addition, the conformational analysis showed that the microenvironment of fluorophores was altered with the adaptational protein secondary structural changes. Energy transfer occurred from the fluorophores to HES with a high possibility. All these results provided accurate and complete primary data for demonstrating the interaction mechanisms of HES with BSA, which helps to understand its pharmaceutical effects in blood.

Dextran-Based Injectable Hydrogel Composites for Bone Regeneration.

Currently, bone infections caused by diseases or injuries are a major health issue. In addition, the conventional therapeutic approaches used to treat bone diseases or injuries present several drawbacks. In the area of tissue engineering, researchers have been developing new alternative therapeutic approaches, such as scaffolds, to promote the regeneration of injured tissues. Despite the advantages of these materials, most of them require an invasive surgical procedure. To overcome these problems, the main focus of this work was to develop scaffolds for bone regeneration, which can be applied using injectable hydrogels that circumvent the use of invasive procedures, while allowing for bone regeneration. Throughout this work, injectable hydrogels were developed based on a natural polymer, dextran, along with the use of two inorganic compounds, calcium β-triphosphate and nanohydroxyapatite, that aimed to reinforce the mechanical properties of the 3D mesh. The materials were chemically characterized considering the requirements for the intended application: the swelling capacity was evaluated, the degradation rate in a simulated physiological environment was assessed, and compression tests were performed. Furthermore, vancomycin was incorporated into the polymeric matrices to obtain scaffolds with antibacterial performance, and their drug release profile was assessed. The cytotoxic profile of the hydrogels was assessed by an MTS assay, using osteoblasts as model cells. The data obtained demonstrated that dextran-based hydrogels were successfully synthesized, with a drug release profile with an initial burst between 50 and 80% of the drug. The hydrogels possess fair biocompatibility. The swelling capacity showed that the stability of the samples and their degradation profile is compatible with the average time period required for bone regeneration (usually about one month) and have a favorable Young's modulus (200-300 kPa). The obtained hydrogels are well-suited for bone regeneration applications such as infections that occur during implantation or bone graft substitutes with antibiotics.

The effect of slow strain rate tension and cyclic loading on biodegradable Zn–2%Fe–0.8%Mn alloy in a simulated physiological environment

Zinc-based alloys have gained increased interest as biodegradable structural materials for medical applications due to their adequate biocompatibility, crucial roles in many physiological functions and attractive antibacterial properties. However, the major drawbacks of zinc alloys relate to their inadequate mechanical properties and tendency to provoke fibrous encapsulation due to relatively high standard potential. Based on the promising effect of Mn on properties of Zn-based alloys, the present study aimed at evaluating the suitability of Zn–2%Fe–0.8%Mn alloy as a potential biodegradable implant under in-vitro conditions. This evaluation focused on the passivation characteristics as determined by cyclic potentiodynamic polarization analysis, immersion test, stress corrosion behavior by slow strain rate testing (SSRT), corrosion fatigue and direct cell viability in terms of cell adherence and proliferation after 24 and 48 h post incubation. The results showed that the addition of 0.8%Mn to the base Zn–2%Fe alloy improves the specific strength and direct cell viability characteristics while decreasing the effectiveness of natural passivation processes. The main overall effect of adding 0.8%Mn to Zn–2%Fe alloy were (i) reduced stress corrosion resistance in terms of time to failure at a low strain rate (2.5 × 10−7 s−1) from 285 h to 205 h (ii) reduced corrosion fatigue endurance from 4,997,285 cycles to only 377,552 cycles to failure at the lowest load of 30 MPa.

Chitosan-Collagen Electrospun Nanofibers Loaded with Curcumin as Wound-Healing Patches.

Composite chitosan-collagen nanofibrous mats embedded with curcumin were prepared via a single-step electrospinning procedure and explored as wound-healing patches with superior biological activity. A mild crosslinking protocol consisting of a short exposure to ammonia vapor and UV radiation was developed to ensure proper stability in physiological-like conditions without affecting the intrinsic biocompatibility of chitosan and collagen. The fabricated composite patches displayed a highly porous, homogeneous nanostructure consisting of fibers with an average diameter of 200 nm, thermal stability up to 200 °C, mechanical features able to ensure protection and support to the new tissues, and water-related properties in the ideal range to allow exudate removal and gas exchange. The release kinetic studies carried out in a simulated physiological environment demonstrated that curcumin release was sustained for 72 h when the mats are crosslinked hence providing prolonged bioactivity reflected by the displayed antioxidant properties. Remarkably, combining chitosan and collagen not only ensures prolonged stability and optimal physical-chemical properties but also allows for better-promoting cell adhesion and proliferation and enhanced anti-bacteriostatic capabilities with the addition of curcumin, owing to its beneficial anti-inflammatory effect, ameliorating the attachment and survival/proliferation rates of keratinocytes and fibroblasts to the fabricated patches.

Benchtop proof of concept and comparison of iron- and magnesium-based bioresorbable flow diverters.

Bioresorbable flow diverters (BRFDs) could significantly improve the performance of next-generation flow diverter technology. In the current work, magnesium and iron alloy BRFDs were prototyped and compared in terms of porosity/pore density, radial strength, flow diversion functionality, and resorption kinetics to offer insights into selecting the best available bioresorbable metal candidate for the BRFD application. BRFDs were constructed with braided wires made from alloys of magnesium (MgBRFD) or iron (FeBRFD). Pore density and crush resistance force were measured using established methods. BRFDs were deployed in silicone aneurysm models attached to flow loops to investigate flow diversion functionality and resorption kinetics in a simulated physiological environment. The FeBRFD exhibited higher pore density (9.9 vs 4.3 pores/mm2) and crush resistance force (0.69 ± 0.05 vs 0.53 ± 0.05 N/cm, p = 0.0765, n = 3 per group) than the MgBRFD, although both crush resistances were within the range previously reported for FDA-approved flow diverters. The FeBRFD demonstrated greater flow diversion functionality than the MgBRFD, with significantly higher values of established flow diversion metrics (mean transit time 159.6 ± 11.9 vs 110.9 ± 1.6, p = 0.015; inverse washout slope 192.5 ± 9.0 vs 116.5 ± 1.5, p = 0.001; n = 3 per group; both metrics expressed as a percentage of the control condition). Last, the FeBRFD was able to maintain its braided structure for > 12 weeks, whereas the MgBRFD was almost completely resorbed after 5 weeks. The results of this study demonstrated the ability to manufacture BRFDs with magnesium and iron alloys. The data suggest that the iron alloy is the superior material candidate for the BRFD application due to its higher mechanical strength and lower resorption rate relative to the magnesium alloy.

Corrosion Performance of Ti6Al7Nb Alloy in Simulated Body Fluid for Implant Application Characterized Using Macro- and Microelectrochemical Techniques

In this paper, the applicability of Ti6Al7Nb as a more biocompatible alternative for bone and dental implants than Ti6Al4V and pure titanium in terms of corrosion resistance and electrochemical inertness is investigated. The chemical inertness and corrosion resistance of the Ti6Al7Nb biomaterial were characterized by a multi-scale electrochemical approach during immersion in simulated physiological environments at 37 °C comparing its behavior to that of c.p. Ti, Ti6Al4V, and stainless steel. The establishment of a passive regime for Ti6Al7Nb results from the formation of a thin layer of metal oxide on the surface of the material which prevents the action of aggressive species in the physiological medium from direct reaction with the bulk of the alloy. Conventional electrochemical methods such as potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) provide quantified information on the surface film resistance and its stability domain that encompasses the potential range experienced in the human body; unfortunately, these methods only provide an average estimate of the exposed surface because they lack spatial resolution. Although local physiological environments of the human body are usually simulated using different artificial physiological solutions, and changes in the electrochemical response of a metallic material are observed in each case, similar corrosion resistances have been obtained for Ti6Al7Nb in Hank’s and Ringer’s solutions after one week of immersion (with a corrosion resistance of the order of MΩ cm2). Additionally, scanning electrochemical microscopy (SECM) provides in situ chemical images of reactive metal and passive dielectric surfaces to assess localized corrosion phenomena. In this way, it was observed that Ti6Al7Nb exhibits a high corrosion resistance consistent with a fairly stable passive regime that prevents the electron transfer reactions necessary to sustain the metal dissolution of the bulk biomaterial. Our results support the proposition of this alloy as an efficient alternative to Ti6Al4V for biomaterial applications.

Acid-Responsive Macroporous Silica Nanoparticles for Bcl-2-Functional-Converting Peptide Release and Synergism with Celastrol for Enhanced Therapy against Resistant Cancer.

Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.

The controlled degradation of bacterial cellulose in simulated physiological environment by immobilization and release of cellulase

Bacterial cellulose (BC) has good network structure, biocompatibility, and excellent mechanical properties, and is widely used in the field of biomaterials. The controllable degradation of BC can further broaden its application. Oxidative modification and cellulases may endow BC with degradability, but these methods inevitably lead to the obvious reduction of its initial mechanical properties and uncontrolled degradation. In this paper, the controllable degradation of BC was realized for the first time by using a new controlled release structure that combines the immobilization and release of cellulase. The immobilized enzyme has higher stability and is gradually released in the simulated physiological environment, and its load can control the hydrolysis rate of BC well. Furthermore, the BC-based membrane prepared by this method retains the favorable physicochemical performance of the original BC, including flexibility and great biocompatibility, and holds good application prospects in drug control release or tissue repair.

Surface engineered mesoporous silica carriers for the controlled delivery of anticancer drug 5-fluorouracil: Computational approach for the drug-carrier interactions using density functional theory.

Introduction: Drug delivery systems are the topmost priority to increase drug safety and efficacy. In this study, hybrid porous silicates SBA-15 and its derivatives SBA@N and SBA@3N were synthesized and loaded with an anticancer drug, 5-fluorouracil. The drug release was studied in a simulated physiological environment. Method: These materials were characterized for their textural and physio-chemical properties by scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), small-angle X-ray diffraction (SAX), and nitrogen adsorption/desorption techniques. The surface electrostatics of the materials was measured by zeta potential. Results: The drug loading efficiency of the prepared hybrid materials was about 10%. In vitro drug release profiles were obtained in simulated fluids. Slow drug release kinetics was observed for SBA@3N, which released 7.5% of the entrapped drug in simulated intestinal fluid (SIF, pH 7.2) and 33% in simulated body fluid (SBF, pH 7.2) for 72h. The material SBA@N presented an initial burst release of 13% in simulated intestinal fluid and 32.6% in simulated gastric fluid (SGF, pH 1.2), while about 70% of the drug was released within the next 72h. Density functional theory (DFT) calculations have also supported the slow drug release from the SBA@3N material. The release mechanism of the drug from the prepared carriers was studied by first-order, second-order, Korsmeyer-Peppas, Hixson-Crowell, and Higuchi kinetic models. The drug release from these carriers follows Fickian diffusion and zero-order kinetics in SGF and SBF, whereas first-order, non-Fickian diffusion, and case-II transport were observed in SIF. Discussion: Based on these findings, the proposed synthesized hybrid materials may be suggested as a potential drug delivery system for anti-cancer drugs such as 5-fluorouracil.

Incorporating Tantalum Oxide Nanoparticles into Implantable Polymeric Biomedical Devices for Radiological Monitoring.

Longitudinal radiological monitoring of biomedical devices is increasingly important, driven by the risk of device failure following implantation. Polymeric devices are poorly visualized with clinical imaging, hampering efforts to use diagnostic imaging to predict failure and enable intervention. Introducing nanoparticle contrast agents into polymers is a potential method for creating radiopaque materials that can be monitored via computed tomography. However, the properties of composites may be altered with nanoparticle addition, jeopardizing device functionality. Thus, the material and biomechanical responses of model nanoparticle-doped biomedical devices (phantoms), created from 0-40 wt% tantalum oxide (TaOx ) nanoparticles in polycaprolactone and poly(lactide-co-glycolide) 85:15 and 50:50, representing non, slow, and fast degrading systems, respectively, are investigated. Phantoms degrade over 20 weeks in vitro in simulated physiological environments: healthy tissue (pH 7.4), inflammation (pH 6.5), and lysosomal conditions (pH 5.5), while radiopacity, structural stability, mechanical strength, and mass loss are monitored. The polymer matrix determines overall degradation kinetics, which increases with lower pH and higher TaOx content. Importantly, all radiopaque phantoms could be monitored for a full 20 weeks. Phantoms implanted in vivo and serially imaged demonstrate similar results. An optimal range of 5-20 wt% TaOx nanoparticles balances radiopacity requirements with implant properties, facilitating next-generation biomedical devices.

Abstract P2-24-08: Altersolanol B, a fungal metabolite, induces proteasome-dependent degradation of estrogen receptor α (ERα) and inhibits downstream signaling targets in ER+ breast adenocarcinoma cells

Abstract We recently reported the cellular signal-modulating properties of altersolanol B (AB), a minor fungal tetrahydroanthraquinone (THAQ) metabolite, in the estrogen receptor positive (ER+) human breast adenocarcinoma cell lines, MCF-7 and T47D. MCF-7 (IC50 5.5 µM) and T47D (IC50 8.8 µM) were observed to be 4- and 2.4-fold more sensitive to the antiproliferative effects of AB, respectively, compared to MDA-MB-231 (triple-negative, IC50 21.3 µM). AB disrupted both AKT and ERK1/2 signaling leading to intrinsic apoptosis in MCF-7. The clinical limitations of multi-agent combination therapy that targets multiple pathways in cancer may potentially be circumvented by using a single molecule, such as AB, that inhibits both AKT and ERK1/2 signaling. The THAQ pharmacophore, with its disrupted conjugated ring system and relative redox inactivity, may possess greater mechanistic advantage against ER+ breast cancer when compared to the fully conjugated ring systems of the anthracyclines (doxorubicin) and anthraquinone (mitoxantrone) that are associated with nonselective mechanisms. The present phase of our study provides evidence that AB downregulated ERα expression at the post-translational level through the induction of proteasome-dependent degradation similar to a classical selective estrogen receptor degrader (SERD). AB dose-dependently downregulated both wild-type (WT)- and 17β-estradiol (E2)-stimulated ERα protein expression without altering mRNA expression in ER+ cells. This was corroborated by the marked reduction in the expression of downstream ERα target genes (cathepsin D and pS2). AB also dose-dependently downregulated cyclin D1, the estrogen-independent activator of ER. Antiproliferative effects were enhanced when ER+ cells were exposed to a combination of AB and the ERα-selective antagonist, MPP dihydrochloride. The AKT activator, SC79, showed that the AB-induced ERα protein downregulation was independent of the inhibition of AKT-FOXO1 signaling. The expression of Hsp90 was not affected. Co-treatment with the protein synthesis inhibitor, cycloheximide, revealed that AB downregulated ERα expression at the post-translational level. The proteosome inhibitor, MG-132, effectively suppressed AB-induced ERα degradation and restored cellular proliferation. In silico approaches were adopted to probe the direct binding of AB to ERα. AB demonstrated significant binding affinity with human ERα (PDB ID - 3ert) compared to the binding of the standard SERD, fulvestrant. Non-covalent bonding interaction analysis further revealed that, much like fulvestrant, AB successfully interacted with 5 major amino acid residues (i.e., Ala350, Asp351, Leu525, Leu536 and Trp383) at the ligand-binding domain of ERα which is stabilized by 7 non-bonding interactions. Principal component analysis indicated that binding with AB improved the compactness of 3ert folding. Molecular dynamics simulation indicated that the 3ert-AB interaction was stable even in the 100 ns simulated physiological environment. Citation Format: Md Afjalus Siraj, Md Sajjadur Rahman, Aaron T. Jacobs, Ghee T. Tan. Altersolanol B, a fungal metabolite, induces proteasome-dependent degradation of estrogen receptor α (ERα) and inhibits downstream signaling targets in ER+ breast adenocarcinoma cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-08.

Ultrasound-assisted synthesis of MIL-88(Fe) conjugated starch-Fe3O4 nanocomposite: A safe antibacterial carrier for controlled release of tetracycline

A constructing antibiotic carrier with a sustained release profile is a promising method to stop long-term bacterial infection, which is of ideal interest in different biomedical fields. To end this, the present study aims to design a novel carrier based on the modification of biopolymeric starch for the rising possible interaction between carrier and antibiotic agent. We established an in-situ ultrasound-assisted method was applied to grow and create MIL-88(Fe) framework in the structure of magnetic polysaccharide (i.e., St/Fe3O4) synthesized by precipitation method resulting in St/Fe3O4/MIL-88(Fe) nanocomposite. It was loaded with a high amount of Tetracycline (TC) through its immersion into the TC aqueous solution. The release profile of TC-loaded St/Fe3O4/MIL-88(Fe) displays a lower initial burst release (about 26 % after 12 h) and followed by a controlled and sustained release (about 73 % up to 168 h) in the simulated physiological environment at pH 7.4. The in vitro cytotoxicity showed good cytocompatibility against Human skin fibroblast (HFF-1) cells. TC-loaded St/Fe3O4/MIL-88(Fe) showed higher antibacterial activity against both S. aureus and E. coli with the MIC value of 64 and 128 μg·mL−1, respectively.

The effects of electrodeposition temperature on morphology and corrosion resistance of calcium phosphorus coatings on magnesium alloy: comparative experimental and molecular dynamics simulation studies.

In this study, CaP coatings were prepared on the surface of an AZ31B magnesium alloy using electroplating in order to slow down the degradation rate of magnesium alloy in the simulated physiological environment. The effect of plating temperature on the properties of CaP coatings was investigated by combining experimental techniques with molecular dynamics (MD) simulation. The surface morphology of CaP coatings changed from dendritic lamellar to granular structure with the increase of plating temperature, but the main structure of CaP coatings prepared at all temperatures was CaHPO4·2H2O. The CaP coatings prepared at 60 °C have higher corrosion resistance compared to coatings prepared at other temperatures. The MD simulation revealed the DCPD/Mg interfacial binding mechanism, and DCPD/Mg could form a stable interfacial layer at different temperatures because the binding energy was negative. HPO42- and H2O groups in the DCPD structure acted as riveting groups in the interfacial layer and formed Mg-HPO42- and Mg-H2O dipole pairs with Mg respectively through electrostatic interaction and van der Waals forces. The interfacial bonding energy between DCPD/Mg reached its lowest at 60 °C and the relative contents of HPO42- and H2O in the interface layer were the highest at this temperature, which may explain the high corrosion resistance and high bonding force of CaP coatings prepared at this temperature.