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Liver cancer refers primarily to hepatocellular carcinoma (HCC) accounting for over 90% of cases and is the highest incidence in men in Thailand. Over the past decades, the incidence of HCC dramatically increased with a strong rise of mortality rates. Garcinia mangostana, "Queen of Fruit" of Thailand, is known as a rich source of xanthones with potent cytotoxic properties against various cancer cells. Study on xanthones is provoking not only due to the structural diversity but also a wide variety of pharmacological activities. Hence the aim of the current study is to determine the effects of metabolites from G. mangostana root on cell proliferation and migration of hepatocellular carcinoma cells. Twenty-two metabolites, including two new benzophenones and one new biphenyl, were isolated and characterized. Five xanthones with a prenyl moiety showed significant cytotoxicity against both HCC cells tested; however, only dulxanthone D displayed the most promising activity on the migration of Huh7 HCC cells, comparable to sorafenib, a standard drug. Moreover, the compound dose-dependently induced apoptosis in Huh7 cells via mitochondrial pathway. Accordingly, dulxanthone D held a great potential for development as a novel migration inhibitor for effective HCC treatment., (© 2022. The Author(s).)

Polyetherketoneketone (PEKK) is considered to be a potential substitute material for metal bone implants because of its advantageous biocompatibility, chemical stability, and mechanical properties, but clinical application has been severely restricted due to PEKK's lack of antibacterial ability and biological activity. In this study, LL-37, a natural human antimicrobial peptide, was successfully modified on the PEKK surface with polydopamine as the intermediate layer and released continuously for more than 6 days. The results of the MTT assay, colony counts, and Live/Dead staining demonstrated that compared to unmodified PEKK, the LL-37-modified PEKK significantly inhibited the adhesion, vitality, and bacterial biofilm growth of Staphylococcus aureus and Escherichia coli in a concentration-dependent way. Furthermore, the LL-37-modified PEKK enhanced biocompatibility (cell adhesion and viability) and promoted osteogenic differentiation of human umbilical cord Wharton's jelly-derived mesenchymal stem cells. Our data suggested that LL-37-modified PEKK might be a promising material for use in orthopedic implants.

Four new pestalone-type benzophenones, pestalotinones A-D (1-4), along with six known congeners, pestalone, pestalone E-F, SB87-Cl, SB87-H, and pestalachloride B, were isolated from the endophytic fungus Pestalotiopsis trachicarpicola SC-J551 cultivated on rice grains. Their structures were established by extensive spectroscopic analysis. Compounds 1-3 exhibited potent activity against Staphylococcus aureus and MRSA (MIC: 1.25-2.5 μg ml -1 ) while no cytotoxicity against Vero cells (IC 50  > 50 μM). The activity profile of this group of compounds suggested that replacement of the C-14 aldehyde with an oxymethyl greatly increases their activity and selectivity towards the bacteria and chlorine substitutions result in the increase of antibacterial activity and slight decrease of cytotoxicity against the mammalian cells., (© 2022. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

A new benzophenone huanglongmycin (HLM) D ( 1 ) and two new monomeric xanthones huanglongmycin E ( 2 ) and F ( 3 ), together with four known aromatic polyketides aloesaponarin II ( 4 ) and the previously isolated huanglongmycin A-C ( 5-7 ) were obtained from cave-derived Streptomyces sp. CB09001. The structures of 1-3 were established based on 1D, 2D NMR and HRMS data. Compounds 1-7 may be biosynthesized by a type II huanglongmycin polyketide synthase based on gene inactivation of hlmG encoding KSɑ in hlm gene cluster and their plausible biosynthetic mechanism was proposed.

One new xanthone, griseophenexanthone A (1), one new benzophenone, digriseophene A (2), and 14 previously reported compounds were isolated from the culture of Penicillium sp. ct-28, an endophytic fungus of Corydlis tomentella. The structures of the isolated compounds were identified by an extensive analysis of HRESIMS, 1D and 2D NMR. MTT assay showed that six xanthones (1 and 3-7) significantly inhibited cell proliferation in four cancer cell lines, with IC 50 values ranging from 18.12 ± 2.42 to 85.55 ± 7.66 μM. Our results showed that slight structural changes led to obvious activity differences among these compounds. We also investigated the effects of the six xanthones on cell cycle and apoptosis in human hepatoma HepG2 cells. Compound 7 caused cell cycle arrest at G1 phase, compounds 5 and 6 caused cell cycle arrest at S phase, whereas compounds 1, 3 and 4 had no effects on cell cycle distribution. All six xanthones induced apoptosis in dose-dependent manners in HepG2 cells accompanied by degradation of PARP and activation of caspase 3. The structure-activity relationship analysis revealed that the effects of these xanthones on cell cycle and apoptosis in HepG2 cells were closely related to the substituent groups on their skeleton. Our studies provide novel insights for the structural optimization of xanthones in the development of new anticancer drugs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Two benzophenone glucosides ( 1 and 2 ), five flavan-3-ol dimers ( 5 - 9 ), and 17 known compounds ( 3 , 4 , and 10 - 24 ) were identified from the bark extract of Cassia abbreviata . The chemical structures display two points of interest. First, as an unusual characteristic feature of the 1 H NMR spectra of 1 and 2 , the signals for the protons on glucosidic carbons C-2 are shielded as compared to those generally observed for glucosyl moieties. The geometrically optimized 3D structures derived from conformational analysis and density functional theory (DFT) calculations revealed that this shielding effect originates from intramolecular hydrogen bonds in 1 and 2 . Additionally, 3 - 15 were identified as dimeric B-type proanthocyanidins, which have 2 R ,3 S -absolute-configured C-rings and C-4-C-8″ linkages, as evidenced by X-ray crystallography and by NMR and ECD spectroscopy. These results suggest the structure-determining procedures for some reported dimers need to be reconsidered. The trypanocidal activities of the isolated compounds against Trypanosoma brucei brucei , T. b. gambiense , T. b. rhodesiense , T. congolense , and T. evansi were evaluated, and the active compounds were identified.

Michler's ethylketone (MEK, 4,4'-bis(diethylamino)benzophenone), commonly-known as an intermediate in the synthesis of dyes and pigments, was successfully screened and optimized as a novel matrix for the enhancement of lipid in situ detection and imaging in tissues by MALDI-MSI. The results show several properties of MEK as a powerful MALDI matrix, including strong UV absorption, µm-sized crystals and uniform matrix-coating, super high vacuum chemical stability, low matrix-related ion interference, super soft ionization, and high lipid ionization efficiency.

Organic near-infrared room temperature phosphorescence materials have unparalleled advantages in bioimaging due to their excellent penetrability. However, limited by the energy gap law, the near-infrared phosphorescence materials (>650 nm) are very rare, moreover, the phosphorescence lifetimes of these materials are very short. In this work, we have obtained organic room temperature phosphorescence materials with long wavelengths (600/657-681/732 nm) and long lifetimes (102-324 ms) for the first time through the guest-host doped strategy. The guest molecule has sufficient conjugation to reduce the lowest triplet energy level and the host assists the guest in exciton transfer and inhibits the non-radiative transition of guest excitons. These materials exhibit good tissue penetration in bioimaging. Thanks to the characteristic of long lifetime and long wavelength emissive phosphorescence materials, the tumor imaging in living mice with a signal to background ratio value as high as 43 is successfully realized. This work provides a practical solution for the construction of organic phosphorescence materials with both long wavelengths and long lifetimes., (© 2022. The Author(s).)

In the present work, the antimicrobial peptide (AMP) of GL13K was successfully coated onto a polyetheretherketone (PEEK) substrate to investigate its antibacterial activities against Staphylococcus aureus ( S. aureus ) bacteria. To improve the coating efficiency, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was mixed with a GL13K solution and coated on the PEEK surface for comparison. Both energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS) data confirmed 30% greater peptide coating on PEEK/GL13K-EDC than PEEK without EDC treatment. The GL13K graft levels are depicted in the micrograms per square centimeter range. The PEEK/GL13K-EDC sample showed a smoother and lower roughness (Rq of 0.530 µm) than the PEEK/GL13K (0.634 µm) and PEEK (0.697 µm) samples. The surface of the PEEK/GL13K-EDC was more hydrophilic (with a water contact angle of 24°) than the PEEK/GL13K (40°) and pure PEEK (89°) samples. The pure PEEK disc did not exhibit any inhibition zone against S. aureus . After peptide coating, the samples demonstrated significant zones of inhibition: 28 mm and 25 mm for the PEEK/GL13K-EDC and PEEK/GL13K samples, respectively. The bacteria-challenged PEEK sample showed numerous bacteria clusters, whereas PEEK/GL13K contained a little bacteria and PEEK/GL13K-EDC had no bacterial attachment. The results confirm that the GL13K peptide coating was able to induce antibacterial and biofilm-inhibitory effects. To the best of our knowledge, this is the first report of successful GL13K peptide grafting on a PEEK substrate via EDC coupling. The present work illustrates a facile and promising coating technique for a polymeric surface to provide bactericidal activity and biofilm resistance to medical implantable devices.

Implant-associated infections and inadequate osseointegration are two challenges of implant materials in orthopedics. In this study, a lithium-ion-loaded (Li+)/mussel-inspired antimicrobial peptide (AMP) designed to improve the osseointegration and inhibit bacterial infections effectively is prepared on a polyetheretherketone (PEEK) biomaterial surface through the combination of hydrothermal treatment and mussel-inspired chemistry. The results illustrate that the multifunctional PEEK material demonstrated a great inhibitory effect on Escherichia coli and Staphylococcus aureus , which was attributed to irreversible bacterial membrane damage. In addition, the multifunctional PEEK can simultaneously upregulate the expression of osteogenesis-associated genes/proteins via the Wnt/β-catenin signaling pathway. Furthermore, an in vivo assay of an infection model revealed that the multifunctional PEEK implants killed bacteria with an efficiency of 95.03%. More importantly, the multifunctional PEEK implants accelerated the implant-bone interface osseointegration compared with pure PEEK implants in the noninfection model. Overall, this work provides a promising strategy for improving orthopedic implant materials with ideal osseointegration and infection prevention simultaneously, which may have broad application clinical prospects.

Benzophenones (BPs) are extensively used in a wide variety of cosmetic products and other materials (e.g., textiles or plastics) to avoid damaging effects of UV radiation. In the present work, we compared two extraction methods for the determination of BPs, namely, 2,4-dihydroxybenzophenone (BP-1), 2-hydroxy-4-methoxybenzophenone (BP-3) and 2,2-dihydroxy-4-methoxybenzophenone (BP-8), in water and cosmetics samples. The following extraction methods were used for the research: solid-phase extraction (SPE) and microextraction by packed sorbent (MEPS), whereas analysis was performed by gas chromatography with mass spectrometric detection. A comparison between the methods indicates that the MEPS technique(s) can be reliably used for analysis of BPs (sunscreen residue) in water samples and cosmetic samples with satisfactory results. This microextraction technique is cheap, easy, quick to implement, and consumes small amounts of solvents. On the other hand, the main advantage of the SPE method are low detection limits for the determination of BPs in water samples, i.e., from 0.034 to 0.067 µg L -1 , while, for the MEPS method, LODs were at the level of 1.8-3.2 µg L -1 . For both methods, the recoveries of BPs were 96-107% and 44-70% for water and cosmetics samples, respectively. The presented methods are suitable for use in cosmetics quality control and environmental pollution assessment.

Polyetheretherketone (PEEK) is a biocompatible polymer, but its clinical application is largely limited due to its inert surface. To solve this problem, a multifunctional PEEK implant is urgently fabricated. In this work, a dual-metal-organic framework (Zn-Mg-MOF74) coating is bonded to PEEK using a mussel-inspired polydopamine interlayer to prepare the coating, and then, dexamethasone (DEX) is loaded on the coating surface. The PEEK surface with the multifunctional coating provides superior hydrophilicity and favorable stability and forms an alkaline microenvironment when Mg 2+ , Zn 2+ , 2,5-dihydroxyterephthalic acid, and DEX are released due to the coating degradation. In vitro results showed that the multifunctional coating has strong antibacterial ability against both Escherichia coli and Staphylococcus aureus ; it also improves human umbilical vein endothelial cell angiogenic ability and enhances rat bone marrow mesenchymal stem cell osteogenic differentiation activity. Furthermore, the in vivo rat subcutaneous infection model, chicken chorioallantoic membrane model, and rat femoral drilling model verify that the PEEK implant coated with the multifunctional coating has strong antibacterial and angiogenic ability and promotes the formation of new bone around the implant with a stronger bone-implant interface. Our findings indicate that DEX loaded on the Zn-Mg-MOF74 coating-modified PEEK implant with bacteriostasis, angiogenesis, and osteogenesis properties has great clinical application potential as bone graft materials.

Cyclooxygenases 2 (COX2) is a therapeutic target for many inflammation and oxidative stress associated diseases. A high-throughput technique, biolayer interferometry, was performed to primarily screen the potential COX2 binding activities of twelve newly synthesized double hydroxide-based benzophenone derivatives. Binding confirmation was achieved by molecular docking and multi-spectroscopy studies. Such a combined method provided a comprehensive understanding of binding mechanism and conformational changes. Compounds DB2, SC2 and YB2 showed effective COX2 binding activity and underlined the benefits of three phenolic hydroxyl groups adjacent to each other on the B ring. The twelve tested derivatives were further evaluated for antioxidant activity, wherein compound SC2 showed the highest activity. Its concentration for the 50% of maximal effect (EC 50 ) value was approximately 1000 times greater than that of the positive controls. SC2 treatment effectively improved biochemical indicators caused by oxidative stress. Overall, compound SC2 could serve as a promising candidate for further development of a new potent COX2 inhibitor.

Poly-ether-ether-ketone (PEEK) has attracted increasing attention as a promising orthopaedic implant material owing to its excellent mechanical properties and biocompatibility. However, its antibacterial properties must be improved as an implant material. In this study, PEEK was sulfonated to obtain a porous surface, and graphene oxide (GO) was deposited to form a coating with antibacterial activity and biocompatibility. After PEEK was sulfonated for different durations, GO was deposited on the surface to prepare the coating (SPEEK-GO), which was then characterised using scanning electron microscopy (SEM), Raman spectroscopy, and contact angle measurements. The in vitro study included antimicrobial and cellular tests. The results showed that the PEEK sulfonated using a 10-min treatment exhibited a uniform porous structure and provided a better basal surface for the deposition of GO. The SPEEK-GO coating displayed strong antibacterial activity against two common dental pathogens. It exhibited good adhesion and proliferation of MC3T3-E1. Moreover, it showed osteogenic differentiation as bone implant material., (© 2021. The Author(s).)

In this work, we developed the first 3D-printed polyetheretherketone (PEEK)-based bone scaffold with multi-functions targeting challenging bone diseases such as osteosarcoma and osteomyelitis. A 3D-printed PEEK/graphene nanocomposite scaffold was deposited with a drug-laden (antibiotics and/or anti-cancer drugs) hydroxyapatite coating. The graphene nanosheets within the scaffold served as effective photothermal agents that endowed the scaffold with on-demand photothermal conversion function under near-infrared laser irradiation. The bioactive hydroxyapatite coating significantly boosted the stem cell proliferation in vitro and promoted new bone growth in vivo . The presence of antibiotics and anti-cancer drugs enabled eradication of drug-resistant bacteria and ablation of osteosarcoma cancer cells, the treatment efficacy of which can be further enhanced by on-demand laser-induced heating. The promising results demonstrate the strong potential of our multi-functional scaffold in applications such as bone defect repair and multimodal treatment of osteosarcoma and osteomyelitis.

Polyetheretherketone (PEEK) is widely considered as a promising material for joint implants but it still has limitations involving high friction and wear. To mimic the cartilage-subchondral bone structure in natural joints, a polyvinyl alcohol (PVA) hydrogel layer was fabricated on the PEEK substrate to provide a lubrication mechanism. In addition, tannic acid was applied to form dynamic hydrogen bonds with PVA molecules, for the purpose of strengthening the hydrogel layer and endowing it with self-healing ability. Our experimental results demonstrated that the prepared PEEK-hydrogel composite exhibited good biotribological performance with a low average friction coefficient around 0.06 and little wear after the friction test. It also could repair the scratch made by a blade spontaneously at room temperature taking advantage of the reversibility of the hydrogen bonds. The influence of the properties of the PVA hydrogel and the concentration of tannic acid on the frictional and self-healing behavior of the composite structure was investigated and the internal mechanism was discussed. This work presents a facile method to fabricate a PEEK-hydrogel composite possessing outstanding tribological properties and self-healing capacity simultaneously, hopefully promoting its potential in producing artificial joints.

As a chronic metabolic disease, diabetes mellitus (DM) creates a hyperglycemic micromilieu around implants, resulting inthe high complication and failure rate of implantation because of mitochondrial dysfunction in hyperglycemia. To address the daunting issue, the authors innovatively devised and developed mitochondria-targeted orthopedic implants consisted of nutrient element coatings and polyetheretherketone (PEEK). Dual nutrient elements, in the modality of ZnO and Sr(OH) 2 , are assembled onto the sulfonated PEEK surface (Zn&Sr-SPEEK). The results indicate the synergistic liberation of Zn 2+ and Sr 2+ from coating massacres pathogenic bacteria and dramatically facilitates cyto-activity of osteoblasts upon the hyperglycemic niche. Intriguingly, Zn&Sr-SPEEK implants are demonstrated to have a robust ability to recuperate hyperglycemia-induced mitochondrial dynamic disequilibrium and dysfunction by means of Dynamin-related protein 1 (Drp1) gene down-regulation, mitochondrial membrane potential (MMP) resurgence, and reactive oxygen species (ROS) elimination, ultimately enhancing osteogenicity of osteoblasts. In vivo evaluations utilizing diabetic rat femoral/tibia defect model at 4 and 8 weeks further confirm that nutrient element coatings substantially augment bone remodeling and osseointegration. Altogether, this study not only reveals the importance of Zn 2+ and Sr 2+ modulation on mitochondrial dynamics that contributes to bone formation and osseointegration, but also provides a novel orthopedic implant for diabetic patients with mitochondrial modulation capability., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524-536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein-ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein-ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.

Phytochemical investigation of clove resulted in the isolation of two new natural compounds, a ferulic acid derivative, sabrinic acid ( 1 ) and a benzophenone derivative ( 2 ) together with two known compounds kaempferol-3,5-dimethyl ether ( 3 ) and 4-methyl benzoic acid ( 4 ). Compounds 3 and 4 were isolated for the first time from the genus Syzygium. The structures of compounds were elucidated through modern spectroscopic techniques including 1D and 2D NMR spectroscopy.

Polyetheretherketone (PEEK) has been widely used in the fields of orthopedics and trauma, but weak osteointegration and bacterial infection affect its long-term stability and repair effects. Surface modification is an effective way to improve the osteogenic and antibacterial activity of PEEK implants. In the present study, a layer of acrylic acid (AA) polymer coating loaded with zinc ions (Zn 2+ ) was constructed on the surface of PEEK (PEEK-AA-Zn) using a strategy of combining plasma-induced graft polymerization with a chemical immersion technique. Successful construction of the AA coating remarkably enhanced the hydrophilicity of PEEK, and effectively loaded and released Zn 2+ . In vitro cell culture using MC3T3-E1 preosteoblasts showed that the Zn 2+ released from PEEK-AA-Zn promoted cell proliferation and elevated gene expression levels of alkaline phosphatase (ALP), osteocalcin (OCN) and bone sialoprotein (BSP). Antibacterial tests revealed that PEEK-AA-Zn efficiently inhibited the proliferation of Staphylococcus aureus ( S. aureus ). These results suggest that the combined method of graft polymerization and ion incorporation endows PEEK with excellent osteogenic and antibacterial activity, which provides a wide range of possibilities for developing PEEK implants with multifunctional properties for bone tissue repair.

Polyetheretherketone (PEEK) is an important material applied in orthopedic applications, as it posses favorable properties for orthopedic implants, e.g., radiolucency and suitable elastic modulus. However, PEEK exhibits insufficient osteogenesis and osteointegration that limits its clinical applications. In this study, we aimed to enhance the osteogenisis of PEEK by using a surface coating approach. Nanocomposite coating composed of albumin/lithium containing bioactive glass nanospheres was fabricated on PEEK through dip-coating method. The presence of nanocomposite coating on PEEK was confirmed by SEM, FTIR, and XRD techniques. Nanocomposite coatings significantly enhanced hydrophilicity and roughness of PEEK. The nanocomposite coatings also enhanced adhesion, proliferation, and osteogenic differentiation of bone mesenchymal stem cells due to the presence of bioactive glass nanospheres and the BSA substrate film. The results indicate the great potential of the nanocomposite coating in enhancing osteogenesis and osteointegration of PEEK implants., (© 2021. The Author(s).)

Reported here is the design of an electrochemical sensor for dopamine (DA) based on a screen print carbon electrode modified with a sulphonated polyether ether ketone-iron (III) oxide composite (SPCE-Fe 3 O 4 /SPEEK). L. serica leaf extract was used in the synthesis of iron (III) oxide nanoparticles (Fe 3 O 4 NPs). Successful synthesis of Fe 3 O 4 NP was confirmed through characterization using Fourier transform infrared (FTIR), ultraviolet-visible light (UV-VIS), X-ray diffractometer (XRD), and scanning electron microscopy (SEM). Cyclic voltammetry (CV) was used to investigate the electrochemical behaviour of Fe 3 O 4 /SPEEK in 0.1 M of phosphate buffer solution (PBS) containing 5 mM of potassium ferricyanide (III) solution (K 3 [Fe(CN) 6 ]). An increase in peak current was observed at the nanocomposite modified electrode SPCE-Fe 3 O 4 /SPEEK) but not SPCE and SPCE-Fe 3 O 4 , which could be ascribed to the presence of SPEEK. CV and square wave voltammetry (SWV) were employed in the electroxidation of dopamine (0.1 mM DA). The detection limit (LoD) of 7.1 μM and 0.005 μA/μM sensitivity was obtained for DA at the SPCE-Fe 3 O 4 /SPEEK electrode with concentrations ranging from 5-50 μM. LOD competes well with other electrodes reported in the literature. The developed sensor demonstrated good practical applicability for DA in a DA injection with good resultant recovery percentages and RSDs values.

We developed a photoreactive molecular glue, BP Glue-N 3 , which can provide a universal strategy to enhance the efficacy of DNA aptamers by temporary-to-permanent stepwise stabilization of their conjugates with target proteins. As a proof-of-concept study, we applied BP Glue-N 3 to the SL1 (DNA aptamer)/c-Met (target protein) conjugate system. BP Glue-N 3 can adhere to and temporarily stabilize this aptamer/protein conjugate multivalently using its guanidinium ion (Gu + ) pendants that form a salt bridge with oxyanionic moieties (e.g., carboxylate and phosphate) and benzophenone (BP) group that is highly affinitive to DNA duplexes. BP Glue-N 3 is designed to carry a dual-mode photoreactivity; upon exposure to UV light, the temporarily stabilized aptamer/protein conjugate reacts with the photoexcited BP unit of adhering BP Glue-N 3 and also a nitrene species, possibly generated by the BP-to-N 3 energy transfer in BP Glue-N 3 . We confirmed that SL1, covalently conjugated with c-Met, hampered the binding of hepatocyte growth factor (HGF) onto c-Met, even when the SL1/c-Met conjugate was rinsed prior to the treatment with HGF, and suppressed cell migration caused by HGF-induced c-Met phosphorylation.

The aim of this study was to promote bioactivity of the PEEK surface using sulfuric acid and piranha solution. PEEK was functionalized by a sulfuric acid treatment for 90 s and by piranha solution for 60 and 90 s. Chemical modification of the PEEK surface was evaluated by infrared spectroscopy, contact angle analysis, cytotoxicity, cell adhesion and proliferation. The spectroscopy characteristic band associated with sulfonation was observed in all treated samples. PEEK with piranha solution 60 s showed an increase in the intensity of the bands, which was even more significant for the longer treatment (90 s). The introduction of the sulfonic acid functional group reduced the contact angle. In cytotoxicity assays, for all treatments, the number of viable cells was higher when compared to those of untreated PEEK. PEEK treated with sulfuric acid and piranha solution for 60 s were the treatments that showed the highest percentage of cell viability with no statistically significant differences between them. The modified surfaces had a greater capacity for inducing cell growth, indicative of effective cell adhesion and proliferation. The proposed chemical modifications are promising for the functionalization of PEEK-based implants, as they were effective in promoting bioactivation of the PEEK surface and in stimulating cell growth and proliferation.

Polyetheretherketone (PEEK), due to its excellent mechanical and physico-chemical parameters, is an attractive substitute for hard tissues in orthopedic applications. However, PEEK is hydrophobic and lacks surface-active functional groups promoting cell adhesion. Therefore, the PEEK surface must be modified in order to improve its cytocompatibility. In this work, extreme ultraviolet (EUV) radiation and two low-temperature, EUV induced, oxygen and nitrogen plasmas were used for surface modification of polyetheretherketone. Polymer samples were irradiated with 100, 150, and 200 pulses at a 10 Hz repetition rate. The physical and chemical properties of EUV and plasma modified PEEK surfaces, such as changes of the surface topography, chemical composition, and wettability, were examined using atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and goniometry. The human osteoblast-like MG63 cells were used for the analysis of cell viability and cell adhesion on all modified PEEK surfaces. EUV radiation and two types of plasma treatment led to significant changes in surface topography of PEEK, increasing surface roughness and formation of conical structures. Additionally, significant changes in the chemical composition were found and were manifested with the appearance of new functional groups, incorporation of nitrogen atoms up to ~12.3 at.% (when modified in the presence of nitrogen), and doubling the oxygen content up to ~25.7 at.% (when modified in the presence of oxygen), compared to non-modified PEEK. All chemically and physically changed surfaces demonstrated cyto-compatible and non-cytotoxic properties, an enhancement of MG63 cell adhesion was also observed.

Brazilian green and red propolis stand out as commercial products for different medical applications. In this article, we report the antimicrobial activities of the hydroalcoholic extracts of green (EGP) and red (ERP) propolis, as well as guttiferone E plus xanthochymol (8) and oblongifolin B (9) from red propolis, against multidrug-resistant bacteria (MDRB). We undertook the minimal inhibitory (MIC) and bactericidal (MBC) concentrations, inhibition of biofilm formation (MICB 50 ), catalase, coagulase, DNase, lipase, and hemolysin assays, along with molecular docking simulations. ERP was more effective by displaying MIC and MBC values <100 μg mL -1 . Compounds 8 and 9 displayed the lowest MIC values (0.98 to 31.25 μg mL -1 ) against all tested Gram-positive MDRB. They also inhibited the biofilm formation of S. aureus (ATCC 43300 and clinical isolate) and S. epidermidis (ATCC 14990 and clinical isolate), with MICB 50 values between 1.56 and 6.25 μg mL -1 . The molecular docking results indicated that 8 and 9 might interact with the catalase's amino acids. Compounds 8 and 9 have great antimicrobial potential., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: To examine the effect of static versus expandable polyether ether ketone (PEEK) cages on both clinical and radiographic outcomes., Methods: A retrospective cohort study was conducted on patients who underwent one-level transforaminal lumbar interbody fusion with either a static or expandable PEEK cage. Patient outcomes were obtained from chart review and radiographic outcomes were measured using standing, lateral radiographs. Recovery ratios and the proportion of patients achieving the minimally clinically important difference were calculated for Oswestry Disability Index (ODI), Physical Component Score-12, Mental Component Score-12, visual analogue scale for back, and visual analogue scale for leg at 1 year and compared between groups. Multivariate linear regression analysis was performed to determine the effect of cage type on the change in patient-reported outcome measures, controlling for demographic factors., Results: A total of 240 patients (137 static, 103 expandable) were included in the final analysis. ΔPhysical Component Score-12 scores at 3 months were significantly greater for the static group (16.0 vs. 10.0, P = 0.043) compared with the expandable group. Multivariate regression demonstrated that use of an expandable cage was associated with greater improvements in ΔODI (β: -7.82, P = 0.048) at 1 year. No differences were found in the perioperative change in sagittal spinal alignment within or between groups at 1 year. Subsidence rates failed to show any statistically significant difference between the 2 groups., Conclusions: Transforaminal lumbar interbody fusion with an expandable PEEK cage is an independent predictor of improved ODI scores at 1 year. Our study showed no significant differences in subsidence rates or changes in sagittal spinal alignment between static and expandable PEEK cages., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ten new polyisoprenylated benzophenone derivatives, 4,8-epi-uralione F (1), 4,8-epi-uralione G (2), uralione S (3), coccinone J (4), 6-epi-coccinone C (5), coccinone I (6), 36-hydroxy-guttiferone J (7), multiflorone I (8), garciniagifolone F (9) and 36-hydroxy-garciniagifolone F (10), were isolated from the fruits of Garcinia cambogia, along with seven known analogues. The structures of the new compounds were established based on the detailed analysis of 1D and 2D nuclear magnetic resonance (NMR) spectra and high resolution electrospray ionization mass spectrometra (HRESIMS), and their absolute configurations were determined from the electronic circular dichroism (ECD) spectra. All the isolates were tested for their inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The results indicated that compound 1 displayed a potent NO inhibitory effect with an IC50 value of 41.60 ± 0.17 μM. Furthermore, compound 1 suppressed inducible NO synthase (iNOS) expression in a dose-dependent manner through inhibiting the activation of nuclear factor-κB (NF-κB).

Chitosan (Cs) was cross-linked with four various quantities of 4,4'-(5,5'‑carbonylbis(1,3-dioxoisoindoline-5,2-diyl))dibenzoyl isothiocyanate. Elemental analysis, FTIR and 1 H NMR spectroscopy assured that the amino groups of chitosan reacted with the isothiocyanate groups of the cross-linker producing four new hydrogels namely as BBTU-Cs-1, BBTU-Cs-2, BBTU-Cs-3, and BBTU-Cs-4 according to the increment of their cross-linking content, respectively. SEM showed their porous structures and XRD indicated their amorphous nature. Their swell ability increased with decreasing the medium pH value and with increasing cross-linking density. In comparison with the popular COX inhibitor Celecoxib, these hydrogels showed an inhibition activity towards COX enzymes with selective inhibition towards COX-2. Their inhibition activity could be arranged as follows: Celecoxib > BBTU-Cs-4 > BBTU-Cs-3 > BBTU-Cs-2 > BBTU-Cs-1. BBTU-CS-4 hydrogel exhibited a potent inhibition against COX-2 (IC 50 0.42 μg/ml) compared with that observed for the standard Celecoxib (IC 50 0.26 μg/ml). BBTU-Cs-4 is more potent against H. pylori compared to the other hydrogels. BBTU-Cs-4 at a concentration of 7.81 μg/ml is able to kill 100% of the H. pylori and exhibits a preferential ability to inhibit 89.35% of COX-2 than COX-1 (0%). These findings make BBTU-Cs-4 a promising anti-H. pylori and selective anti-inflammatory agent., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A robust and sensitive analytical method was developed and validated for the simultaneous analysis of the levels of 10 benzophenone derivatives (BPs; BP, BP-1, BP-2, BP-3, BP-8, 2-hydroxybenzophenone [2-OHBP], 4-hydroxybenzophenone [4-OHBP], 4-methylbenzophenone [4-MBP], methyl-2-benzoylbenzoate [M2BB], and 4-benzoylbiphenyl [PBZ]) in 54 breakfast cereal samples. A fast pesticide extraction (FaPEx) technique coupled with isotope-labeled internal standards ultra-high-performance liquid chromatography-tandem mass spectrometry was employed. The developed method exhibited satisfactory linearity (R 2 > 0.998), high precision (intraday and interday relative standard deviations in the ranges of 1.4%-20.8% and 3.2%-23.9%, respectively), and a limit of detection ranging from 0.001 to 0.122 ng/g. BP and 4-MBP were detected in all samples, BP-3 was detected in >59% of the samples, M2BB was detected in 14% of the samples, and 4-OHBP was detected in 7% of the samples. The mean level (range) of BP was significantly higher in corn flakes [146.9 (25.3-1083.8) ng/g] than in oatmeal [22.8 (14.2-67.5) ng/g], and it contributed the most to the overall levels of the BPs, followed by 4-MBP. When the samples were stratified according to their packaging material, the mean level of BP was significantly higher in corn flake samples with plastic packaging (251.9 ng/g) than in corn flake and oatmeal samples with laminated aluminum foil packaging. Two samples of six-grain muesli contained remarkably high levels of BP (1084 and 1055 ng/g); both were nonorganic samples packaged in a polylactide bag. Future studies must examine the possible risks that these contaminants pose to human health.

Due to its excellent mechanical and low-friction properties, polyetheretherketone (PEEK) has been widely investigated for use in orthopedic applications over the past decade. However, the bioinertness and poor osteogenic properties of PEEK have hampered its clinical application. In this study, the surface of PEEK was modified by co-treatment with hydrofluoric acid and nitric acid (AFN). The microstructures of the modified PEEK surfaces were investigated using scanning electron microscopy. The water contact angles of the surfaces were also measured. To evaluate their cytocompatibility, PEEK samples were used as substrates to culture rat bone mesenchymal stem cells, and cell adhesion, viability, and expression of specific marker genes were measured. Treatment of PEEK with AFN (PEEK-AFN) was found to enable better osteoblast adhesion, spreading, and proliferation; the activity of alkaline phosphatase (an early osteogenic differentiation marker) was also found to be enhanced post-treatment. Furthermore, PEEK-AFN was able to modulate macrophage polarization and down regulated the expression of proinflammatory factors via inhibiting the NF-κB pathway. Thus, treatment of PEEK with AFN could promote M2 polarization of the macrophages and stimulate the differentiation of osteoblasts. These results provide valuable information that could facilitate the use of PEEK-based composites as bone implant materials., (© 2020 Wiley Periodicals LLC.)

Background: Laminectomy is a traditional method for treating lumbar diseases; however, the destruction of the posterior structures may cause postoperative symptoms. An individualized poly-ether-ether-ketone (PEEK) artificial lamina was designed to reconstruct the posterior structures after laminectomy. This study aimed to explore the biomechanical effects of reconstruction of the posterior structures with an individualized PEEK artificial lamina using validated finite element models., Objective: To examine the biomechanical effects of individualized PEEK artificial lamina on postlaminectomy lumbar., Methods: A finite element (FE) model of L3-5 was developed based on computed tomography images. Four surgical models (laminectomy, artificial lamina alone, ligament reconstruction, and osseointegration) were constructed, representing different stages of L4 artificial lamina implantation. The range of motion (ROM), intradiscal pressure (IDP), stresses in the annulus fibrosus at the surgical level and cephalad adjacent level, and stresses in the artificial lamina and screws were measured., Results: The ROM, IDP, and stresses in the annulus fibrosus of the different artificial lamina models decreased compared to those of the laminectomy model at both surgical and adjacent levels for all motion patterns, most notably in the osseointegration model. In addition, the results of the stresses in the implants showed that the artificial lamina could enhance the lumbar isthmus and disperse the abnormally concentrated stresses after laminectomy., Conclusion: The application of a PEEK artificial lamina has the potential to stabilize the postlaminectomy lumbar spine and prevent adjacent segment disease (ASD) and iatrogenic lumbar deformities, resulting in a reduction in the incidence of post-lumbar surgery syndrome.

Polyether ether ketone (PEEK) has shown great promise for implant and biomedical applications because of its excellent chemical, mechanical, and biocompatible properties. However, PEEK is bioinert, which causes weak cell adhesion and limits its use for biomedical applications such as bone implants. Therefore, the activation of the PEEK's surface for cell attachment is desirable. In this study, oxygen plasma and gelatin were used to modify PEEK's surface and the effects of surface roughness, wettability, and cell adhesion to the surface were studied. Surface roughness was measured using a laser scanning confocal microscope, and wettability was measured using the sessile drop method. There was no significant difference in the roughness of the three samples. The gelatin-coated surface showed higher wettability than the plasma-modified or control samples. The cell attachment and proliferation rate were assessed by scanning electron microscopy and the XTT assay, respectively. The XTT assay results indicated that a greater number of cells grew on the gelatin-coated PEEK surface than on the control or plasma-treated surfaces. These results confirmed that the plasma and gelatin treatments enhanced the biocompatibility of the PEEK samples. The increase in biocompatibility could make PEEK a better material candidate for treating bone related injuries and defects., (© 2020 Wiley Periodicals LLC.)

Guttiferone F, a natural polyprenylated polycyclic acylphloroglucinol, was originally assigned as the 30-epimer of garcinol by NMR data analyses. Conversion of guttiferone F in the presence of acid afforded its cyclized form ( 2a ), which was previously assigned as 30- epi -cambogin. However, the absolute configurations of guttiferone F and 2a have not been determined. Reinvestigation of the structures of those two compounds, using X-ray and NMR data analyses and chemical transformation, revealed that the original assignment of the C-30 absolute configuration in guttiferone F and 2a should be inverted. Guttiferone F is indeed garcinol, and 2a , which was previously identified as 30- epi -cambogin, is cambogin.

Benzophenone is a mutagen, carcinogen, and endocrine disruptor. Its presence in food products or food packaging is banned in the United States. Under California Proposition 65, there is no safe harbor for benzophenone in any personal care products, including sunscreens, anti-aging creams, and moisturizers. The purpose of this study was to determine (1) if benzophenone was present in a wide variety of commercial sun protection factor (SPF)/sunscreen products, (2) whether benzophenone concentration in the product increased over time, and (3) if the degradation of octocrylene was the likely source for benzophenone contamination. Benzophenone concentration was assayed in nine commercial sunscreen products from the European Union and eight from the United States (in triplicate), including two single ingredient sources of octocrylene. These same SPF items were subjected to the United States Food and Drug Administration (U.S. FDA)-accelerated stability aging protocol for 6 weeks. Benzophenone was measured in the accelerated-aged products. Sixteen octocrylene-containing product lines that were recently purchased had an average concentration of 39 mg/kg benzophenone, ranging from 6 mg/kg to 186 mg/kg. Benzophenone was not detectable in the product that did not contain octocrylene. After subjecting the 17 products to the U.S. FDA-accelerated stability method, the 16 octocrylene-containing products had an average concentration of 75 mg/kg, ranging from 9.8 mg/kg to 435 mg/kg. Benzophenone was not detectable in the product that did not contain octocrylene. Benzophenone was detected in the pure octocrylene manufactured ingredient. Octocrylene generates benzophenone through a retro-aldol condensation. In vivo , up to 70% of the benzophenone in these sunscreen products may be absorbed through the skin. U.S. FDA has established a zero tolerance for benzophenone as a food additive. In the United States, there were 2999 SPF products containing octocrylene in 2019. The safety of octocrylene as a benzophenone generator in SPF or any consumer products should be expeditiously reviewed by regulatory agencies.

Benzophenone-1 (BP-1), one of the commonly used ultraviolet filters, has caused increasing public concern due to frequently detected residues in environmental and recreational waters. Its susceptibility to residual chlorine and the potential to subsequently trigger endocrine disruption remain unknown. We herein investigated the chlorination of BP-1 in swimming pool water and evaluated the endocrine disruption toward the human androgen receptor (AR). The structures of monochlorinated (P1) and dichlorinated (P2) products were separated and characterized by mass spectrometry and 1 H- 1 H NMR correlation spectroscopy. P1 and P2 exhibited significantly higher antiandrogenic activity in yeast two-hybrid assays (EC 50 , 6.13 μM and 9.30 μM) than did BP-1 (12.89 μM). Our 350 ns Gaussian accelerated molecular dynamics simulations showed the protein dynamics in a long-time scale equilibrium, and further energy calculations revealed that although increased hydrophobic interactions are primarily responsible for enhanced binding affinities between chlorinated products and the AR ligand binding domain, the second chloride in P2 still hinders the complex motion because of the solvation penalty. The mixture of BP-1-P1-P2 elicited additive antiandrogenic activity, well fitted by the concentration addition model. P1 and P2 at 1 μM consequently downregulated the mRNA expression of AR-regulated genes, NKX3.1 and KLK3 , by 1.7-9.1-fold in androgen-activated LNCaP cells. Because chlorination of BP-1 occurs naturally by residual chlorine in aquatic environments, our results regarding enhanced antiandrogenic activity and disturbed AR signaling provided evidence linking the use of personal care products with potential health risks.

Ultraviolet (UV) filters are used in cosmetics, personal care products and packaging materials to provide sun protection for human skin and other substances. Little is known about these substances, but they continue to be released into the environment. The acute toxicity of 4,4'-dihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC to Chlorella vulgaris and Daphnia magna were analyzed in this study. The 96 h-EC50 values of 4,4'-dihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC on C. vulgaris were 183.60, 3.50 and 0.16874 mg/L, respectively. The 48 h-LC50 of 4,4'-dihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC on D. magna were 12.50, 3.74 and 0.54445 mg/L, respectively. The toxicity of a mixture of 4,4'-dihydroxybenzophenone and 4-MBC showed addictive effect on C. vulgaris, while the toxicity of mixtures of 4,4'-dihydroxybenzophenone and 2,4,4'-trihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC as well as 4,4'-dihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC all showed antagonistic effect on C. vulgaris. The induced no-effect concentrations of 4,4'-dihydroxybenzophenone, 2,4,4'-trihydroxybenzophenone and 4-MBC by the assessment factor (AF) method were 0.0125, 0.00350 and 0.000169 mg/L, respectively., Competing Interests: The authors have declared that no competing interests exist.

Moisture penetration into active biomedical implants such as the bionic ear and eye is a major problem in healthcare since surgery is required to replace devices affected by corrosion. Existing methods for measuring moisture leak rates such as the commercially available dynamic relative humidity method are not sufficiently sensitive to guarantee security against moisture penetration. Helium leak detection is highly sensitive but is challenged by the unknown relation to the moisture leak rate because of mixed flow modes involving liquid water. A standard moisture leak traceable to fundamental units is not currently available, preventing direct comparison of moisture and helium leak rates in the same device. Here, we demonstrate a practical calibrated moisture leak based on the stable polymer poly(ether-ether-ketone), for calibrating heavy water mass spectrometry. Using biomedical test structures from manufactured encapsulations, we show that in the majority of cases, calibrated measurements of molar moisture leak rates exceed the helium leak rate, especially for very small and large leaks. Comparison with theory shows that LaPlace pressure is the driving force for the enhanced moisture flows. We recommend that the compliance limit for helium testing in biomedical devices be reduced by one order of magnitude.

Microglia are the principle cell type driving sustained neuroinflammation in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis. Interestingly, microglia locked into a chronic M1 pro-inflammatory phenotype significantly up-regulate the cannabinoid receptor 2 (CB2) expression. Our approach to exploiting CB2 as a therapeutic target in neuroinflammatory diseases focuses on the development of selective CB2 inverse agonists to shift microglia bias to a M2 pro-wound healing phenotype. Herein we report work designed to refine the structure activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone CB2 inverse agonist scaffold. A series of analogs of our lead compound SMM-189 were synthesized and measured for affinity/selectivity, potency, and efficacy in regulating cAMP production and β-arrestin recruitment. In this series compound 40 demonstrated a significant increase in potency and efficacy for cAMP stimulation compared to SMM-189. Akin to our lead SMM-189, this compound was highly efficacious in biasing microglia to an M2 pro-wound healing phenotype in LPS stimulated cell lines. These results advance our understanding of the structure-activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold and provide further support for regulating microglia activation using CB2 inverse agonists., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Three new caged polyprenylated benzophenone derivatives named burlemarxiones D-F (1-3) were isolated from the hexane extract of Clusia burle-marxii trunks. Burlemarxione D (1) contains the tetracyclo[8.3.1.0 3,11 .0 5,10 ]tetradecane core skeleton also observed for burlemarxione A, its probable immediate precursor. However, two additional rings are formed to produce an unprecedented complex-caged core skeleton. These additional rings could be formed by a radical cyclization reaction of one prenyl group at C-5 with C-1 and C-33, followed by oxidative dehydrogenation (rearomatization) or by an intramolecular [4 + 2] radical cycloaddition (Diels-Alder reaction), followed by an enolization reaction (rearomatization). Burlemarxiones E and F were isolated after methylation with diazomethane that was necessary to avoid the interconversion of the pair of β-diketones in tautomeric equilibrium. The proposed biosynthetic pathway for burlemarxiones D-F involves the condensation of either lavandulyl pyrophosphate or 2-(1-methylvinyl)-hexa-5-enyl pyrophosphate with the acylphloroglucinol derivative 6-benzoyl-5-hydroxy-5-cyclohexen-1,3-dione, followed by consecutive prenylation reactions. Therefore, Clusia burle-marxii reinforces the claim that the genus Clusia is an important source of sophisticated caged polyprenylated benzophenone derivatives., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The novel coronavirus SARS-CoV-2 has prompted a worldwide pandemic and poses a great threat to public safety and global economies. Most present personal protective equipment (PPE) used to intercept pathogenic microorganisms is deficient in biocidal properties. Herein, we present green nanofibers with effective antibacterial and antiviral activities that can provide sustainable bioprotection by continuously producing reactive oxygen species (ROS). The superiority of the design is that the nanofibers can absorb and store visible light energy and maintain the activity under light or dark environment. Moreover, the nanofibers can uninterruptedly release ROS in the absence of an external hydrogen donor, acting as a biocide under all weather conditions. A facile spraying method is proposed to rapidly deploy the functional nanofibers to existing PPE, such as protective suits and masks. The modified PPE exhibit stable ROS production, excellent capacity for storing activity potential, long-term durability, and high bactericidal (>99.9%) and viricidal (>99.999%) efficacies., (© 2021 Wiley-VCH GmbH.)

To prevent infections associated with medical implants, various antimicrobial silver-coated implant materials have been developed. However, these materials do not always provide consistent antibacterial effects in vivo despite having dramatic antibacterial effects in vitro, probably because the antibacterial effects involve silver-ion-mediated reactive oxygen species generation. Additionally, the silver application process often requires extremely high temperatures, which damage non-metal implant materials. We recently developed a bacteria-resistant coating consisting of hydroxyapatite film on which ionic silver is immobilized via inositol hexaphosphate chelation, using a series of immersion and drying steps performed at low heat. Here we applied this coating to a polymer, polyetheretherketone (PEEK), and analyzed the properties and antibacterial activity of the coated polymer in vitro and in vivo. The ionic silver coating demonstrated significant bactericidal activity and prevented bacterial biofilm formation in vitro. Bio-imaging of a soft tissue infection mouse model in which a silver-coated PEEK plate was implanted revealed a dramatic absence of bacterial signals 10 days after inoculation. These animals also showed a strong reduction in histological features of infection, compared to the control animals. This innovative coating can be applied to complex structures for clinical use, and could prevent infections associated with a variety of plastic implants.

Purpose: Diazepam is utilized as a convulsion antidote following nerve gas attacks. As an emergency medicine, it requires storage at ambient temperatures which often doesn't meet manufacturers' requirements, leading to an early invalidation of the product. Current work investigated this issue., Methods: Long-term stability of diazepam ampoules for injection stored in an ambient temperature of the Mediterranean climate for ~10 years vs storage at room temperature was studied., Results: Diazepam assay and pH remained within pharmacopeial specifications irrespective of storage conditions. A major degradation product 2-methylamino-5-chlorobenzophenone (MACB) showed a clear trend of accumulation as a function of storage time, exceeding the permitted limit at ~2 years, irrespective of storage conditions. A strong correlation between the discoloration of the solutions and the concentration of MACB was obtained. Intravenous administration of MACB to rats at doses ~2200-fold higher than permissible specification levels caused neither mortality nor any toxicological nor post-mortem findings., Conclusions: Regarding the parameters tested: diazepam assay, MACB assay, and pH, storing ampoules of diazepam solution for injection in field conditions of high temperatures of the Mediterranean climate did not cause accelerated degradation as compared to room temperature. These findings open an option for the usage of expired ampoules in special scenarios.

Background: The current approach to reducing bacterial contamination in blood transfusion products is through detection or pathogen reduction methods, some of which utilize ultraviolet (UV) light photosensitizers. A small number of photosensitizers are being used as single agents in combination with UV light, but their efficacy can be limited against some pathogens. Benzophenone (BP) and vitamins B1, B6, and K3 have been identified as effective UVA photosensitizers for inactivation of bacteria. We evaluated whether combining pairs of photosensitizers in this group would have synergistic bactericidal effects on Gram-negative and Gram-positive bacteria., Study Design and Methods: Bacteria species of Escherichia coli, Bacillus cereus, Staphylococcus aureus, and Klebsiella pneumoniae were mixed with 0 to 100 mM concentrations of photosensitizers and exposed to UVA irradiation at 18 J/cm 2 to assess their bactericidal effects., Results: Single photosensitizers irradiated with UVA produced a range of bactericidal activity. When combined in pairs, all demonstrated some synergistic bactericidal effects with up to 4-log reduction above the sum of activities of individual molecules in the pair against bacteria in plasma. Photosensitizer pairs with BP had the highest synergism across all bacteria. With vitamin K3 in the pair, synergism was evident for Gram-positive but not for Gram-negative bacteria. Vitamin B1 and vitamin B6 had the least synergism. These results indicate that a combination approach with multiple photosensitizers may extend effectiveness of pathogen reduction in plasma., Conclusions: Combining photosensitizers in pathogen reduction methods could improve bactericidal efficacy and lead to use of lower concentrations of photosensitizers to reduce toxicities and unwanted side effects., (© 2020 AABB.)

The degradation behavior of eight benzodiazepines (BZPs): alprazolam, etizolam, diazepam, triazolam, nitrazepam (NZP), flunitrazepam (FNZ), bromazepam, and lorazepam, in artificial gastric juice was monitored by a LC/photodiode array detector (PDA) to estimate their pharmacokinetics in the stomach. For drugs that were degradable, such physicochemical parameters as reaction rate constant were measured to evaluate the effect of storage conditions on drug degradability, such as whether the degradation proceeds faster by increasing storage temperature, or whether the degradation reaction is reversible by adjusting pH. As a result, it was confirmed that although the eight BZPs degraded in artificial gastric juice, most of them could be restored when pH was increased, and the restoration rates differed depending on the pH and the type of BZP. As for NZP, an Arrhenius plot was drawn to obtain the physicochemical parameters, such as activation energy and activation entropy involved in the degradation reaction, and the reaction kinetics was discussed. In addition, two substances were confirmed as the degradation products of NZP in artificial gastric juice: one was a reversible degradation product (A) (intermediate) and the other was an irreversible degradation product (B) (final degradation product). The intermediate was identified as 2-amino-N-(2-benzoyl-4-nitrophenyl)-acetamide, and the final degradation product was 2-amino-5-nitrobenzophenone. Therefore, when detecting NZP in human stomach contents, such as during judicial dissection, it would be prudent to target NZP as well as the intermediate (A) and the final degradation product (B).

Surface roughness, bioactivity, and antibacterial properties are desirable in skeletal implants. We hot-pressed a mix of particulate sodium chloride (NaCl) salt and silicon nitride (β-Si 3 N 4 ) onto the surface of bulk PEEK. NaCl grains were removed by leaching in water, resulting in a porous PEEK surface embedded with sim15 vol% β-Si 3 N 4 particles. This functionalized surface showed the osteogenic and antibacterial properties previously reported in bulk silicon nitride implants. Surface enhancement of PEEK with β-Si 3 N 4 could improve the performance of spinal fusion cages, by facilitating arthrodesis and resisting bacteria., (© 2020 IOP Publishing Ltd.)

Garcinia morella (Gaertn.) Desr. is an evergreen tree that yields edible fruits, oil, and resin. It is a source of "gamboge", a gum/resin that has a wide range of uses. The fruits, leaves, and seeds of this tree are rich in bioactive compounds, including xanthones, flavonoids, phenolic acids, organic acids, and terpenoids. Evidence from different studies has demonstrated the antioxidant, antifungal, antiviral, hepatoprotective, anticancer, anti-inflammatory, antibacterial, and larvicidal activities of the fruit, leaf, and seed extracts of G. morella . This review summarizes the information on the phytochemicals of G. morella and the biological activities of its active constituents.

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mangifera indica Linn popularly known as mango is used in folk medicine to treat gastrointestinal disorders. The aim of this study was to identify the metabolomic composition of lyophilized extract of mango leaf (MIE), to evaluate the antioxidant activity on several oxidative stress systems (DPPH, FRAP, TBARS, and ABTS), the spasmolytic and antispasmodic activity, and intestinal protective effect on oxidative stress induced by H 2 O 2 in rat ileum. Twenty-nine metabolites were identified and characterized based on their ultra-high-performance liquid chromatography (UHPLC) high-resolution orbitrap mass spectrometry, these include: benzophenone derivatives, xanthones, phenolic acids, fatty acids, flavonoids and procyanidins. Extract demonstrated a high antioxidant activity in in-vitro assays. MIE relaxed ( p < 0.001) intestinal segments of rat pre-contracted with acetylcholine (ACh) (10 -5 M). Pre-incubation of intestinal segments with 100 µg/mL MIE significantly reduced ( p < 0.001) the contraction to H 2 O 2 . Similar effects were observed with mangiferin and quercetin (10 -5 M; p < 0.05) but not for gallic acid. Chronic treatment of rats with MIE (50 mg/kg) for 28 days significantly reduced ( p < 0.001) the H 2 O 2 -induced contractions. MIE exhibited a strong antioxidant activity, spasmolytic and antispasmodic activity, which could contribute to its use as an alternative for the management of several intestinal diseases related to oxidative stress.

Guttiferone A (GA) 1 , a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5 , embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum . Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1 , dose-response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum -infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.