Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.

Purpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SNAr/SN). Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5'-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS). Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The SNAr and vinyl sulfone fragments are either highly reactive or stable. DSF measurements with the different targets JNK3, USP7, and p53 identified reactive fragment hits causing a shift in the melting temperatures of the proteins. MS confirmed the covalent binding mode of all these fragments to USP7 and p53, while additionally identifying the SNAr-type electrophile SN002 as a mildly reactive covalent hit for p53. Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and -9.1 °C.

Determination and risk assessment of UV filters and benzotriazole UV stabilizers in wastewater from a wastewater treatment plant in Lüneburg, Germany.

UV filters and benzotriazole UV stabilizers are considered emerging contaminants in the environment. LC-MS/MS and GC-MS methods, involving a single solid phase extraction protocol, were developed and validated to determine eight UV filters and seven UV stabilizers, respectively in wastewater from a wastewater treatment plant (WWTP) in Lüneburg, Germany. The LC-MS/MS method exhibited extraction recoveries of ≥ 71% at six different fortification levels with limits of detection (LODs) range of 0.02 ng mL-1 - 0.09 ng mL-1. Extraction recoveries of 47 to 119% at six different fortification levels were obtained for the GC-MS method with LODs range of 0.01 - 0.09 ng mL-1. Among the UV filters, the highest mean concentration was determined for octocrylene (OCR) in influent (3.49 ng mL-1) while the highest mean concentration was measured for 2-hydroxy-4-octyloxybenzophenone (UV 531) in influent (0.44 ng mL-1) among the UV stabilizers. Potential risk to aquatic organisms was assessed by the risk quotient approach. Only OCR presented a high risk to aquatic invertebrates whereas 2-ethylhexyl 4-methoxycinnamate (EHMC) and 2-ethylhexyl salicylate (EHS) posed high risks to algae. Benzotriazole UV stabilizers presented negligible risks to aquatic invertebrates and fish. This work reports the detection of rarely studied 4-aminobenzoic acid (PABA) and UV 531 in WWTP influent and effluent. The occurrence and risk assessment of target benzotriazole UV stabilizers in wastewater from a German WWTP was demonstrated for the first time.

Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization,in vitroandin vivoassessment.

This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variablesX1: concentration of ethanol andX2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334 ± 2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through transmission electron microscopy analysis. X-ray diffraction analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6 h.In vivo,the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the Psoriasis Severity Index grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis.

Acrylate Reductase of an Anaerobic Electron Transport Chain of the Marine Bacterium Shewanella woodyi.

Many microorganisms are capable of anaerobic respiration in the absence of oxygen, by using different organic compounds as terminal acceptors in electron transport chain. We identify here an anaerobic respiratory chain protein responsible for acrylate reduction in the marine bacterium Shewanella woodyi. When the periplasmic proteins of S. woodyi were separated by ion exchange chromatography, acrylate reductase activity copurified with an ArdA protein (Swoo_0275). Heterologous expression of S. woodyi ardA gene (swoo_0275) in Shewanella oneidensis MR-1 cells did not result in the appearance in them of periplasmic acrylate reductase activity, but such activity was detected when the ardA gene was co-expressed with an ardB gene (swoo_0276). Together, these genes encode flavocytochrome c ArdAB, which is thus responsible for acrylate reduction in S. woodyi cells. ArdAB was highly specific for acrylate as substrate and reduced only methacrylate (at a 22-fold lower rate) among a series of other tested 2-enoates. In line with these findings, acrylate and methacrylate induced ardA gene expression in S. woodyi under anaerobic conditions, which was accompanied by the appearance of periplasmic acrylate reductase activity. ArdAB-linked acrylate reduction supports dimethylsulfoniopropionate-dependent anaerobic respiration in S. woodyi and, possibly, other marine bacteria.

A flexible, stretchable and wearable strain sensor based on physical eutectogels for deep learning-assisted motion identification.

Physical eutectogels as a newly emerging type of conductive gel have gained extensive interest for the next generation multifunctional electronic devices. Nevertheless, some obstacles, including weak mechanical performance, low self-adhesive strength, lack of self-healing capacity, and low conductivity, hinder their practical use in wearable strain sensors. Herein, lignin as a green filler and a multifunctional hydrogen bond donor was directly dissolved in a deep eutectic solvent (DES) composed of acrylic acid (AA) and choline chloride, and lignin-reinforced physical eutectogels (DESL) were obtained by the polymerization of AA. Due to the unique features of lignin and DES, the prepared DESL eutectogels exhibit good transparency, UV shielding capacity, excellent mechanical performance, outstanding self-adhesiveness, superior self-healing properties, and high conductivity. Based on the aforementioned integrated functions, a wearable strain sensor displaying a wide working range (0-1500%), high sensitivity (GF = 18.15), rapid responsiveness, and excellent stability and durability (1000 cycles) and capable of detecting diverse human motions was fabricated. Additionally, by combining DESL sensors with a deep learning technique, a gesture recognition system with accuracy as high as 98.8% was achieved. Overall, this work provides an innovative idea for constructing multifunction-integrated physical eutectogels for application in wearable electronics.

Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. CONCLUSION: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.

Development and validation of LC-MS/MS method for trace analysis of acrylamide, acrylic acid and N, N-methylene bis acrylamide in sandy loam soil.

Acrylamide and N, N-methylene bis acrylamide are most commonly used monomer and crosslinker compounds employed in synthesis of super absorbent hydrogels. When applied as soil conditioners, there are apprehensions that these hydrogels degrade over time and thus may release the toxic monomers in the soil. A method was thus developed using Liquid Chromatography tandem mass spectrometry (LC-MS/MS) for the trace level quantification of acrylamide (AD), acrylic acid (AA) and N,N-methylene-bis-acrylamide (MBA) in sandy loam soil amended by two test hydrogels the Pusa Hydrogel and SPG 1118 hydrogel prepared using AD and MBA. The MRM (multiple reaction monitoring) transitions were optimized for both the compounds. Soil samples were extracted using dispersive solid-phase extraction (dSPE) with a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) technique, employing acetonitrile. All analytes were quantified at trace levels within a five-minute run using UHPLC equipped with a C-18 column. Single laboratory validation of the developed method in soil matrix was conducted based on specificity, linearity, sensitivity, accuracy, precision, matrix effect and measurement of uncertainty. LC-MS/MS exhibited a linear response in the concentration range of 0.001 to 1 µg mL-1, with correlation coefficient >+0.99. Acceptable recovery (within 70-120 %) with repeatability (%RSD ≤20 %) was obtained at 0.01 to 1 µg g-1 fortification levels. LOQ (Limit of quantification) of the method for AD, AA and MBA in soil matrix were 0.05, 1 and 0.01 µg g-1, respectively. Both intra-laboratory repeatability and intermediate precision at LOQ suggested well acceptable precise (HorRat≈ 0.3) method for quantification. Matrix enhancement effect was observed in the order: AA>AD>MBA. The Expanded Uncertainty (EU) in soil matrix at LOQ was 21.64 %, 28 % and 19 % for AD, AA and MBA respectively. Groundnut and wheat grown with application of the hydrogels showed no detectable residues of monomers in soil samples (total n = 60) near the root zone at the time of crop harvesting.

On the design of lignin reinforced acrylic acid/hyaluronic acid adhesive hydrogels with conductive PEDOT:HA nanoparticles.

Hydrogels are of great importance in biomedical engineering. They possess the ability to mimic bodily soft tissues, and this allows exciting possibilities for applications such as tissue engineering, drug delivery and wound healing, however much work remains on stability and mechanical robustness to allow for translation to clinical applications. The work herein describes the synthesis and analysis of a biocompatible, versatile hydrogel that has tailorable swelling, high stability when swollen and thermal stability. The synthesis methods used produce a hydrogel with high elasticity, good mechanical properties and rapid crosslinking whilst displaying biocompatibility, adhesion, and conductivity. It has been shown that cell viability in the samples is above 80 % in all cases, a Young's Modulus of up to 85 kPa and high swelling degrees were achieved. These materials show potential for use in numerous applications such as adhesive sensors, skin grafts and drug delivery systems.

Biodegradation by Cancer Cells of Magnetite Nanoflowers with and without Encapsulation in PS-b-PAA Block Copolymer Micelles.

Magnetomicelles were produced by the self-assembly of magnetite iron oxide nanoflowers and the amphiphilic poly(styrene)-b-poly(acrylic acid) block copolymer to deliver a multifunctional theranostic agent. Their bioprocessing by cancer cells was investigated in a three-dimensional spheroid model over a 13-day period and compared with nonencapsulated magnetic nanoflowers. A degradation process was identified and monitored at various scales, exploiting different physicochemical fingerprints. At a collective level, measurements were conducted using magnetic, photothermal, and magnetic resonance imaging techniques. At the nanoscale, transmission electron microscopy was employed to identify the morphological integrity of the structures, and X-ray absorption spectroscopy was used to analyze the degradation at the crystalline phase and chemical levels. All of these measurements converge to demonstrate that the encapsulation of magnetic nanoparticles in micelles effectively mitigates their degradation compared to individual nonencapsulated magnetic nanoflowers. This protective effect consequently resulted in better maintenance of their therapeutic photothermal potential. The structural degradation of magnetomicelles occurred through the formation of an oxidized iron phase in ferritin from the magnetic nanoparticles, leaving behind empty spherical polymeric ghost shells. These results underscore the significance of encapsulation of iron oxides in micelles in preserving nanomaterial integrity and regulating degradation, even under challenging physicochemical conditions within cancer cells.

Tailorable acrylate-endcapped urethane-based polymers for precision in digital light processing: Versatile solutions for biomedical applications.

Bioengineering seeks to replicate biological tissues exploiting scaffolds often based on polymeric biomaterials. Digital light processing (DLP) has emerged as a potent technique to fabricate tissue engineering (TE) scaffolds. However, the scarcity of suitable biomaterials with desired physico-chemical properties along with processing capabilities limits DLP's potential. Herein, we introduce acrylate-endcapped urethane-based polymers (AUPs) for precise physico-chemical tuning while ensuring optimal computer-aided design/computer-aided manufacturing (CAD/CAM) mimicry. Varying the polymer backbone (i.e. poly(ethylene glycol) (PEG) versus poly(propylene glycol) (PPG)) and photo-crosslinkable endcap (i.e. di-acrylate versus hexa-acrylate), we synthesized a series of photo-crosslinkable materials labeled as UPEG2, UPEG6, UPPG2 and UPPG6. Comprehensive material characterization including physico-chemical and biological evaluations, was followed by a DLP processing parametric study for each material. The impact of the number of acrylate groups per polymer (2 to 6) on the physico-chemical properties was pronounced, as reflected by a reduced swelling, lower water contact angles, accelerated crosslinking kinetics, and increased Young's moduli upon increasing the acrylate content. Furthermore, the different polymer backbones also exerted a substantial effect on the properties, including the absence of crystallinity, remarkably reduced swelling behaviors, a slight reduction in Young's modulus, and slower crosslinking kinetics for UPPG vs UPEG. The mechanical characteristics of DLP-printed samples showcased the ability to tailor the materials' stiffness (ranging from 0.4 to 5.3 MPa) by varying endcap chemistry and/or backbone. The in vitro cell assays confirmed biocompatibility of the material as such and the DLP-printed discs. Furthermore, the structural integrity of 3D scaffolds was preserved both in dry and swollen state. By adjusting the backbone chemistry or acrylate content, the post-swelling dimensions could be customized towards the targeted application. This study showcases the potential of these materials offering tailorable properties to serve many biomedical applications such as cartilage TE.

Soluble Fluorinated Cardo Copolyimide as an Effective Additive to Photopolymerizable Compositions Based on Di(meth)acrylates: Application for Highly Thermostable Primary Protective Coating of Silica Optical Fiber.

The development of photocurable compositions is in high demand for the manufacture of functional materials for electronics, optics, medicine, energy, etc. The properties of the final photo-cured material are primarily determined by the initial mixture, which needs to be tuned for each application. In this study we propose to use simple systems based on di(meth)acrylate, polyimide and photoinitiator for the preparation of new photo-curable compositions. It was established that a fluorinated cardo copolyimide (FCPI) based on 2,2-bis-(3,4-dicarboxydiphenyl)hexafluoropropane dianhydride, 9,9-bis-(4-aminophenyl)fluorene and 2,2-bis-(4-aminophenyl)hexafluoropropane (1.00:0.75:0.25 mol) has excellent solubility in di(met)acrylates. This made it possible to prepare solutions of FCPI in such monomers, to study the effect of FCPI on the kinetics of their photopolymerization in situ and the properties of the resulting polymers. According to the obtained data, the solutions of FCPI (23 wt.%) in 1,4-butanediol diacrylate (BDDA) and FCPI (15 wt.%) in tetraethylene glycol diacrylate were tested for the formation of the primary protective coatings of the silica optical fibers. It was found that the new coating of poly(BDDA-FCPI23%) can withstand prolonged annealing at 200 °C (72 h), which is comparable or superior to the known most thermally stable photo-curable coatings. The proposed approach can be applied to obtain other functional materials.

Environmental implications and nanotechnological advances in octocrylene-enriched sunscreen formulations: A comprehensive review.

Ultraviolet (UV) radiation is a major contributor to skin aging, cancer, and other detrimental health effects. Sunscreens containing FDA-approved UV filters, like avobenzone, offer protection but suffer from photodegradation and potential phototoxicity. Encapsulation, antioxidants, and photostabilizers are strategies employed to combat these drawbacks. Octocrylene, an organic UV filter, utilizes nanotechnology to enhance sun protection factor (SPF). This review examines recent literature on octocrylene-enriched sunscreens, exploring the interplay between environmental impact, nanotechnological advancements, and clinical trial insights. A critical focus is placed on the environmental consequences of sunscreen use, particularly the potential hazards UV filters pose to marine ecosystems. Research in the Mediterranean Sea suggests bacterial sensitivity to these filters, raising concerns about their integration into the food chain. This review aims to guide researchers in developing effective strategies for photostabilization of UV filters. By combining encapsulation, photostabilizers, and antioxidants, researchers can potentially reduce phototoxic effects and contribute to developing more environmentally friendly sunscreens.

Development and in vitro/in vivo evaluation of famotidine hydrochloride bioadhesive sustained release suspension.

To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.

A superabsorbent and pH-responsive copolymer-hydrogel based on acemannan from Aloe vera (Aloe barbadensis M.): A smart material for drug delivery.

Combining natural polysaccharides with synthetic materials improves their functional properties which are essential for designing sustained-release drug delivery systems. In this context, the Aloe vera leaf mucilage/hydrogel (ALH) was reacted with acrylic acid (AA) to synthesize a copolymerized hydrogel, i.e., ALH-grafted-Polyacrylic acid (ALH-g-PAA) through free radical copolymerization. Concentrations of the crosslinker N,N'-methylene-bis-acrylamide (MBA), and the initiator potassium persulfate (KPS) were optimized to study their effects on ALH-g-PAA swelling. The FTIR and solid-state NMR (CP/MAS 13C NMR) spectra witnessed the formation of ALH-g-PAA. Scanning electron microscopy (SEM) analysis revealed superporous nature of ALH-g-PAA. The gel fraction (%) of ALH-g-PAA was directly related to the concentrations of AA and MBA whereas the sol fraction was inversely related to the concentrations of AA and MBA. The porosity (%) of ALH-g-PAA directly depends on the concentration of AA and MBA. The ALH-g-PAA swelled admirably at pH 7.4 and insignificantly at pH 1.2. The ALH-g-PAA offered on/off switching properties at pH 7.4/1.2. The metoprolol tartrate was loaded on different formulations of ALH-g-PAA. The ALH-g-PAA showed pH, time, and swelling-dependent release of metoprolol tartrate (MT) for 24 h following the first-order kinetic and Korsmeyer-Peppas model. Haemocompatibility studies ascertained the non-thrombogenic and non-hemolytic behavior of ALH-g-PAA.

Design and preparation of reticular superabsorbent hydrogel material with nutrient slow-release and high shear strength for ecological remediation of abandoned mines with steep slopes.

In order to solve ecological remediation issues for abandoned mines with steep slopes, a kind of hydrogels with high cohesion and water-retaining were designed by inorganic mineral skeleton combining with polymeric organic network cavities. This eco-friendly hydrogel (MFA/HA-g-p(AA-co-AM)) was prepared with acrylic acid (AA)-acrylamide (AM) as network, which was grafted with humic acids (HA) as network binding point reinforcement skeleton and polar functional group donors, KOH-modified fly ash (MFA) as internal supporter. The maximum water absorption capacities were 1960 g/g for distilled water, which followed the pseudo-second-order model. This super water absorption was attributed to the first stage of 62 % fast absorption due to the high specific surface area, pore volume and low osmotic pressure, moreover, the multiple hydrophilic functional groups and network structure swell contributed to 36 % of the second stage slow adsorption. In addition, the pore filling of water in mesoporous channels contributed the additional 2 % water retention on the third stage. The high saline-alkali resistance correlated with the electrostatic attraction with MFA and multiple interactions with oxygen-containing functional groups in organic components. MFA and HA also enhanced the shear strength and fertility retention properties. After 5 cycles of natural dehydration and reabsorption process, these excellent characteristics of reusability and water absorption capacity kept above 97 %. The application of 0.6 wt% MFA/HA-g-p(AA-co-AM) at 15° slope could improve the growth of ryegrass by approximately 45 %. This study provides an efficient and economic superabsorbent material for ecological restoration of abandoned mines with steep slopes.

Acrylated adhesive proteinic microneedle patch for local drug delivery and stable device implantation.

Microneedle patches have been developed as favorable platforms for delivery systems, such as the locoregional application of therapeutic drugs, and implantation systems, such as electronic devices on visceral tissue surfaces. However, the challenge lies in finding materials that can achieve both biocompatibility and stable fixation on the target tissue. To address this issue, utilizing a biocompatible adhesive biomaterial allows the flat part of the patch to adhere as well, enabling double-sided adhesion for greater versatility. In this work, we propose an adhesive microneedle patch based on mussel adhesive protein (MAP) with enhanced mechanical strength via ultraviolet-induced polyacrylate crosslinking and Coomassie brilliant blue molecules. The strong wet tissue adhesive and biocompatible nature of engineered acrylated-MAP resulted in the development of a versatile wet adhesive microneedle patch system for in vivo usage. In a mouse tumor model, this microneedle patch effectively delivered anticancer drugs while simultaneously sealing the skin wound. Additionally, in an application of rat subcutaneous implantation, an electronic circuit was stably anchored using a double-sided wet adhesive microneedle patch, and its signal location underneath the skin did not change over time. Thus, the proposed acrylated-MAP-based wet adhesive microneedle patch system holds great promise for biomedical applications, paving the way for advancements in drug delivery therapeutics, tissue engineering, and implantable electronic medical devices.

Antimalarial 9-methoxystrobilurin derivatives from cultures of the basidiomycete Favolaschia minutissima.

Investigation of cultures of the basidiomycete Favolaschia minutissima TBRC-BCC 19434 led to the isolation of two undescribed ß-methoxyacrylate metabolites, 9-methoxystrobilurins R (1) and S (2), and a degraded aldehyde derivative, favodehyde E (3). 9-Methoxystrobilurin derivatives 1 and 2 exhibited significant antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with IC50 values of 0.12 and 0.21 µM, respectively.

Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology.

The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards. Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher ScientificTM twin screw extruder. All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.

Deriving a point of departure for assessing the skin sensitization risk of wearable device constituents with in vitro methods.

Wearable devices are in contact with the skin for extended periods. As such, the device constituents should be evaluated for their skin sensitization potential, and a Point of Departure (PoD) should be derived to conduct a proper risk assessment. Without historical in vivo data, the PoD must be derived with New Approach Methods (NAMs). To accomplish this, regression models trained on LLNA data that use data inputs from OECD-validated in vitro tests were used to derive a predicted EC3 value, the LLNA value used to classify skin sensitization potency, for three adhesive monomers (Isobornyl acrylate (IBOA), N, N- Dimethylacrylamide (NNDMA), and Acryloylmorpholine (ACMO) and one dye (Solvent Orange 60 (SO60)). These chemicals can be used as constituents of wearable devices and have been associated with causing allergic contact dermatitis (ACD). Using kinetic DPRA and KeratinoSens™ data, the PoDs obtained with the regression model were 180, 215, 1535, and 8325 µg/cm2 for IBOA, SO60, ACMO, and NNDMA, respectively. The PoDs derived with the regression model using NAMs data will enable a proper skin sensitization risk assessment without using animals.

Activation of SIRT1/Nrf2/HO-1 and Beclin-1/AMPK/mTOR autophagy pathways by eprosartan ameliorates testicular dysfunction induced by testicular torsion in rats.

Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical intervention to reinstate vital testicular perfusion, notwithstanding the paradoxical detrimental impact of reperfusion. Although no drugs have secured approval for this urgent circumstance, antioxidants emerge as promising candidates. This study aspires to illustrate the influence of eprosartan, an AT1R antagonist, on testicular torsion in rats. Wistar albino rats were meticulously separated into five groups, (n = 6): sham group, eprosartan group, testicular torsion-detorsion (T/D) group, and two groups of T/D treated with two oral doses of eprosartan (30 or 60 mg/kg). Serum testosterone, sperm analysis and histopathological examination were done to evaluate spermatogenesis. Oxidative stress markers were assessed. Bax, BCL-2, SIRT1, Nrf2, HO-1 besides cleaved caspase-3 testicular contents were estimated using ELISA or qRT-PCR. As autophagy markers, SQSTM-1/p62, Beclin-1, mTOR and AMPK were investigated. Our findings highlight that eprosartan effectively improved serum testosterone levels, testicular weight, and sperm count/motility/viability, while mitigating histological irregularities and sperm abnormalities induced by T/D. This recovery in testicular function was underpinned by the activation of the cytoprotective SIRT1/Nrf2/HO-1 axis, which curtailed testicular oxidative stress, indicated by lowering the MDA content and increasing GSH content. In terms of apoptosis, eprosartan effectively countered apoptotic processes by decreasing cleaved caspase-3 content, suppressing Bax and stimulating Bcl-2 gene expression. Simultaneously, it reactivated impaired autophagy by increasing Beclin-1 expression, decreasing the expression of SQSTM-1/p62 and modulate the phosphorylation of AMPK and mTOR proteins. Eprosartan hold promise for managing testicular dysfunction arising from testicular torsion exerting antioxidant, pro-autophagic and anti-apoptotic effect via the activation of SIRT1/Nrf2/HO-1 as well as Beclin-1/AMPK/mTOR pathways.