Co-metabolic degradation and metabolite detection of hexabromocyclododecane by Shewanella oneidensis MR-1.

Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant; however, it is a persistent organic pollutant as well as affects the human thyroid hormones and causes cancer. However, the degradation of HBCD has received little attention from researchers. Due to its bioaccumulative and hazardous properties, an appropriate strategy for its remediation is required. In this study, we investigated the biodegradation of HBCD using Shewanella oneidensis MR-1 under optimized conditions. The Box-Behnken design (BBD) was implemented for the optimization of the physical degradation parameters of HBCD. S. oneidensis MR-1 showed the best degradation performance at a temperature of 30 °C, pH 7, and agitation speed of 115 rpm, with an HBCD concentration of 1125 µg/L in mineral salt medium (MSM). The strain tolerated up to 2000 µg/L HBCD. Gas chromatography-mass spectrometry analysis identified three intermediates, including 2-bromo dodecane, 2,7,10-trimethyldodecane, and 4-methyl-1-decene. The results provide an insightful understanding of the biodegradation of HBCD by S. oneidensis MR-1 under optimized conditions and could pave the way for further eco-friendly applications. KEY POINTS: • HBCD biodegradation by Shewanella oneidensis • Optimization of HBCD biodegradation by the Box-Behnken analysis • Identification of useful metabolites from HBCD degradation.

Oxygen nanocarrier broke the hypoxia trap of solid tumors and rescued transfection efficiency for gene therapy.

BACKGROUND: Gene therapy shows great promise for a broad array of diseases. However, we found that hypoxic tumor microenvironment (TME) exerted significant inhibitory effects on transfection efficiency of a variety of gene vectors (such as Lipo 2000 and PEI) in an oxygen-dependent manner. Solid tumors inevitably resulted in acute hypoxic areas due to the rapid proliferation of tumor cells and the aberrant structure of blood vessels. Thus, the hypoxic TME severely limited the efficiency and application of gene therapy. METHODS: In our previous study, we constructed endoplasmic reticulum-targeted cationic liposomes, PAR-Lipo, which could effectively deliver genes and ensure high transfection efficiency under normoxia. Unsatisfactorily, the transfection efficiency of PAR-Lipo was rather poor under hypoxia. We believed that reoxygenation was the most direct and effective means to rescue the low transfection under hypoxia. Hence, we fabricated liposomes modified with perfluorooctyl bromide (PFOB@Lipo) to load oxygen and deliver it to tumor sites, which effectively alleviated the hypoxic nature of tumor. Then PAR-Lipo were applied to mediate high-efficiency delivery of tumor suppressor gene pTP53 to inhibit tumor progression. RESULTS: The results showed that such staged strategy augmented the expression of P53 protein in tumors and extremely suppressed tumor growth. CONCLUSION: This work was the first attempt to utilize an oxygen nanocarrier to assist the therapeutic effect of gene therapy under hypoxia, providing a new reference for gene therapy in malignant tumors. GRAPHICAL ABSTARCT.

Self-Assembly Nanoparticles of Natural Bioactive Abietane Diterpenes.

Different approaches have been reported to enhance penetration of small drugs through physiological barriers; among them is the self-assembly drug conjugates preparation that shows to be a promising approach to improve activity and penetration, as well as to reduce side effects. In recent years, the use of drug-conjugates, usually obtained by covalent coupling of a drug with biocompatible lipid moieties to form nanoparticles, has gained considerable attention. Natural products isolated from plants have been a successful source of potential drug leads with unique structural diversity. In the present work three molecules derived from natural products were employed as lead molecules for the synthesis of self-assembled nanoparticles. The first molecule is the cytotoxic royleanone 7α-acetoxy-6ß-hydroxyroyleanone (Roy, 1) that has been isolated from hairy coleus (Plectranthus hadiensis (Forssk.) Schweinf). ex Sprenger leaves in a large amount. This royleanone, its hemisynthetic derivative 7α-acetoxy-6ß-hydroxy-12-benzoyloxyroyleanone (12BzRoy, 2) and 6,7-dehydroroyleanone (DHR, 3), isolated from the essential oil of thicket coleus (P. madagascariensis (Pers.) Benth.) were employed in this study. The royleanones were conjugated with squalene (sq), oleic acid (OA), and/or 1-bromododecane (BD) self-assembly inducers. Roy-OA, DHR-sq, and 12BzRoy-sq conjugates were successfully synthesized and characterized. The cytotoxic effect of DHR-sq was previously assessed on three human cell lines: NCI-H460 (IC50 74.0 ± 2.2 µM), NCI-H460/R (IC50 147.3 ± 3.7 µM), and MRC-5 (IC50 127.3 ± 7.3 µM), and in this work Roy-OA NPs was assayed against Vero-E6 cells at different concentrations (0.05, 0.1, and 0.2 mg/mL). The cytotoxicity of DHR-sq NPs was lower when compared with DHR alone in these cell lines: NCI-H460 (IC50 10.3 ± 0.5 µM), NCI-H460/R (IC50 10.6 ± 0.4 µM), and MRC-5 (IC5016.9 ± 0.5 µM). The same results were observed with Roy-OA NPs against Vero-E6 cells as was found to be less cytotoxic than Roy alone in all the concentrations tested. From the obtained DLS results, 12BzRoy-sq assemblies were not in the nano range, although Roy-OA NP assemblies show a promising size (509.33 nm), Pdl (0.249), zeta potential (-46.2 mV), and spherical morphology from SEM. In addition, these NPs had a low release of Roy at physiological pH 7.4 after 24 h. These results suggest the nano assemblies can act as prodrugs for the release of cytotoxic lead molecules.

Total Synthesis and Anti-Inflammatory Bioactivity of (-)-Majusculoic Acid and Its Derivatives.

The first total synthesis of marine natural product, (-)-majusculoic acid (1) and its seven analogs (9-15), was accomplished in three to ten steps with a yield of 3% to 28%. The strategy featured the application of the conformational controlled establishment of the trans-cyclopropane and stereochemical controlled bromo-olefination or olefination by Horner-Wadsworth-Emmons (HWE) reaction. The potential anti-inflammatory activity of the eight compounds (1 and 9-15) was evaluated by determining the nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7. (-)-Majusculoic acid (1), methyl majusculoate (9), and (1R,2R)-2-((3E,5Z)-6-bromonona-3,5-dien-1-yl)cyclopropane-1-carboxylic acid (12) showed significant effect with inhibition rates of 33.68%, 35.75%, and 43.01%, respectively. Moreover, they did not show cytotoxicity against RAW264.7 cells, indicating that they might be potential anti-inflammatory agents.

Asialoglycoprotein Receptor-Targeted Superparamagnetic Perfluorooctylbromide Nanoparticles.

Background: The decrease in asialoglycoprotein receptor (ASGPR) levels is observed in patients with chronic liver disease and liver tumor. The aim of our study was to develop ASGPR-targeted superparamagnetic perfluorooctylbromide nanoparticles (M-PFONP) and wonder whether this composite agent could target buffalo rat liver (BRL) cells in vitro and could improve R2 ∗ value of the rat liver parenchyma after its injection in vivo. Methods: GalPLL, a ligand of ASGPR, was synthesized by reductive amination. ASGPR-targeted M-PFOBNP was prepared by a film hydration method coupled with sonication. Several analytical methods were used to investigate the characterization and safety of the contrast agent in vitro. The in vivo MR T2 ∗ mapping was performed to evaluate the enhancement effect in rat liver. Results: The optimum concentration of Fe3O4 nanoparticles inclusion in GalPLL/M-PFOBNP was about 52.79 µg/mL, and the mean size was 285.6 ± 4.6 nm. The specificity of GalPLL/M-PFOBNP for ASGPR was confirmed by incubation experiment with fluorescence microscopy. The methyl thiazolyl tetrazolium (MTT) test showed that there was no significant difference in the optical density (OD) of cells incubated with all GalPLL/M-PFOBNP concentrations. Compared with M-PFOBNP, the increase in R2 ∗ value of the rat liver parenchyma after GalPLL/M-PFOBNP injection was higher. Conclusions: GalPLL/M-PFOBNP may potentially serve as a liver-targeted contrast agent for MR receptor imaging.

Synthesis, Structural Characterization, and Optical Properties of Benzene-Fused Tetracyclic and Pentacyclic Stiboles.

The expectation that antimony (Sb) compounds should display phosphorescence emissions based on the "heavy element effect" prompted our interest in the introduction of antimony to a biaryl as the bridging atom in a fused heterole system. Herein, the synthesis, molecular structures, and optical properties of novel benzene-fused heteroacenes containing antimony or arsenic atoms are described. The stiboles and arsole were prepared by the condensation of dibromo(phenyl)stibane or dichloro(phenyl)arsine with dilithium intermediates derived from the corresponding dibromo compounds. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal analysis revealed that the linear pentacyclic stibole was highly symmetric in both the solution and crystal states. In contrast, the curved pentacyclic stibole adopted a helical structure in solution, and surprisingly, only M helical molecules were crystallized from the racemate. All synthesized compounds produced very weak or no emissions at room temperature or in the solid state. In contrast, the linear penta- and tetracyclic stiboles exhibited clear phosphorescence emissions in the CHCl3 frozen matrix at 77 K under aerobic conditions.

Progress of Bromophenols in Marine Algae from 2011 to 2020: Structure, Bioactivities, and Applications.

Marine algae contain various bromophenols that have been shown to possess a variety of biological activities, including antiradical, antimicrobial, anticancer, antidiabetic, anti-inflammatory effects, and so on. Here, we briefly review the recent progress of these marine algae biomaterials and their derivatives from 2011 to 2020, with respect to structure, bioactivities, and their potential application as pharmaceuticals.

Targeted gold nanoshelled hybrid nanocapsules encapsulating doxorubicin for bimodal imaging and near-infrared triggered synergistic therapy of Her2-positve breast cancer.

A multifunctional targeted nanoplatform combining photothermal therapy and chemotherapy has emerged as a promising strategy for comprehensive therapies of breast cancer. In this study, we constructed human epidermal growth factor receptor 2 (Her2)-targeted gold nanoshelled poly(lactic-co-glycolic acid) hybrid nanocapsules encapsulating perfluorooctyl bromide, superparamagnetic iron oxide nanoparticles, and doxorubicin (Her2-GPDH nanocapsules) as theranostic agent for bimodal ultrasound/magnetic resonance imaging and synergistic photothermal-chemotherapy of Her2-postive breast cancer cells. Her2-GPDH nanocomposites possessed well-defined spherical morphology, and the average diameter was about 296 nm with good dispersion. Targeting assays demonstrated that Her2-GPDH nanocapsules exhibited higher targeting binding to Her2-positive SKBR3 cells than Her2-negative MDA-MB-231cells. The encapsulation efficiency and the loading content of doxorubicin in Her2-GPDH nanocapsules were 39 ± 1.45% and 3.8 ± 0.52%, respectively, and the agent exhibited pH-responsive and near-infrared light-triggered stepwise release behavior of doxorubicin. In vitro, the agent had potential to serve as feasible candidate for ultrasound imaging and T2-weighted magnetic resonance imaging with a relatively high relaxivity. Cell experiments confirmed that the agent had significant photothermal cytotoxicity on SKBR3 cells, and the combined photothermal-chemotherapy could significantly enhance the anti-tumor effect. In summary, the present Her2-GPDH nanocapsules, a novel multifunctional nanoplatform, will offer a new way for early bimodal molecular-level diagnosis and synergistic treatment of Her2-positve breast cancer.

Silica nanoparticle coated perfluorooctyl bromide for ultrasensitive MRI.

MRI with hyperpolarized 129Xe can achieve low-concentration detection. Herein, nanoparticle-coated perfluorooctyl bromide (PFOB) was developed as a 129Xe MRI contrast agent with a moderate exchange rate, sufficient stability and feasible surface modification. The αvß3 integrin overexpressed by non-small-cell lung cancer A549 cells was successfully detected by 129Xe MRI with high specificity through adequate surface modifications.

Stereoisomer specific reaction of hexabromocyclododecane with Fe(ii) associated with iron oxides.

The reactions of hexabromocyclododecane (HBCD) isomers with Fe(ii) associated with iron oxides were performed in a pH range from 6.15 to 7.50 at room temperature. It was observed that Fe(ii) associated with iron oxides (i.e., goethite, magnetite, hematite) is a better reductant than just an aqueous solution of Fe(ii) to potentially reduce HBCD in subsurface environments. The reaction of HBCD with Fe(ii) associated with iron oxides is also stereoisomer specific with α-HBCD reacting much slower than ß-HBCD and γ-HBCD. The reaction is pH dependent and it is faster with increased pH. The initial concentration of Fe(ii) and HBCD can also affect the reaction rate. The reaction is negligible when all the Fe(ii) is sorbed to magnetite and no Fe(ii) remains dissolved. It was also observed that the reaction of 100 nM HBCD is slower than the reaction of 1.0 µM HBCD with Fe(ii) associated with magnetite. In addition, natural organic matter (NOM) was found to inhibit the degradation of HBCD by Fe(ii) associated with iron oxides.

Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.

Degradation of hexabromocyclododecane (HBCD) by nanoscale zero-valent aluminum (nZVAl).

Hexabromocyclododecane (HBCD) has been listed in Annex A of the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2013, but till now there is a lack of efficient methods for its degradation. In this study, nanoscale zero-valent aluminum (nZVAl), an excellent reductant with a very low redox potential of E0(Al3+/Al0) = -1.662 V and strong electron transfer ability, was used to reductively degrade HBCD. Nearly 100% HBCD was degraded within 8 h reaction at 25 °C in ethanol/water (v/v, 50/50) solution without pH adjustment. And about 67% cyclododecatriene (CDT) was obtained, which is the complete debromination product. What's more, the yield of Br- could achieve nearly 100% after optimizing conditions. The reaction was strongly promoted by increasing the dosages of nZVAl or decreasing the initial concentration of HBCD. The temperature had the most significant influence and the degradation was completed in 40 min with elevating the reaction temperature to 45 °C. The reaction mechanism was further revealed through the characterization of nZVAl particles before and after the reaction by SEM-EDS, TEM, HRTEM, XRD, and XPS. It was found that, after corrosion of the oxide film on the surface of nZVAl, metallic aluminum inside was exposed. The reactive sites were provided and electrons released were transferred from nZVAl to HBCD, causing HBCD degraded to dibromocyclododecadiene (DBCD) and then CDT by reductive debromination. These findings imply that nZVAl can degrade HBCD efficiently with no extra energy input and this offers a new idea for better treatment of HBCD.

Naturally Drug-Loaded Chitin: Isolation and Applications.

Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are typical examples of demosponges with well-developed chitinous skeletons. In particular, species belonging to the family Ianthellidae possess chitinous, flat, fan-like fibrous skeletons with a unique, microporous 3D architecture that makes them particularly interesting for applications. In this work, we focus our attention on the demosponge Ianthella flabelliformis (Linnaeus, 1759) for simultaneous extraction of both naturally occurring ("ready-to-use") chitin scaffolds, and biologically active bromotyrosines which are recognized as potential antibiotic, antitumor, and marine antifouling substances. We show that selected bromotyrosines are located within pigmental cells which, however, are localized within chitinous skeletal fibers of I. flabelliformis. A two-step reaction provides two products: treatment with methanol extracts the bromotyrosine compounds bastadin 25 and araplysillin-I N20 sulfamate, and a subsequent treatment with acetic acid and sodium hydroxide exposes the 3D chitinous scaffold. This scaffold is a mesh-like structure, which retains its capillary network, and its use as a potential drug delivery biomaterial was examined for the first time. The results demonstrate that sponge-derived chitin scaffolds, impregnated with decamethoxine, effectively inhibit growth of the human pathogen Staphylococcus aureus in an agar diffusion assay.

Kinase Chemodiversity from the Arctic: The Breitfussins.

In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C-H (3 - 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

Advances in Treatment of Brominated Hydrocarbons by Heterogeneous Catalytic Ozonation and Bromate Minimization.

The formation of carcinogenic bromate ions is a constraint when ozone is used for the remediation of water containing brominated organic materials. With its strong oxidizing ability, ozone rapidly transforms bromide in aqueous media to bromate, through a series of reactions involving hydroxyl radicals. Several strategies, such as limiting the ozone concentration, maintaining pH < 6, or the use of ammonia or hydrogen peroxide were explored to minimize bromate generation. However, most of the above strategies had a negative effect on the ozonation efficiency. The advanced oxidation processes, using catalysts together with ozone, have proven to be a promising technology for the degradation of pollutants in wastewater, but very few studies have been conducted to find ways to minimize bromate formation during this approach. The proposed article, therefore, presents a comprehensive review on recent advances in bromate reduction in water by catalytic ozonation and proposes reaction mechanisms associated with the catalytic process. The main aim is to highlight any gaps in the reported studies, thus creating a platform for future research and a quest to find environment friendly and efficacious catalysts for minimizing bromate formation in aqueous media during ozonation of brominated organic compounds.

Nickel-Catalyzed Hydroarylation of Alkynes under Reductive Conditions with Aryl Bromides and Water.

An operationally simple nickel-catalyzed hydroarylation reaction for alkynes is described. This three-component coupling reaction utilizes commercially available alkynes and aryl bromides, along with water and Zn. An air-stable and easily synthesized Ni(II) precatalyst is the only entity used in the reaction that is not commercially available. This reductive cross-coupling reaction displays a fairly unusual anti selectivity when aryl bromides with ortho substituents are used. In addition to optimization data and a preliminary substrate scope, complementary experiments including deuterium labeling studies are used to provide a tentative catalytic mechanism. We believe this report should inspire and inform other Ni-catalyzed carbofunctionalization reactions.

A new strategy for the in vitro selection of stapled peptide inhibitors by mRNA display.

Hydrocarbon stapled peptides are promising therapeutics for inhibition of intracellular protein-protein interactions. Here we develop a new high-throughput strategy for hydrocarbon stapled peptide discovery based on mRNA display of peptides containing α-methyl cysteine and cyclized with m-dibromoxylene. We focus on development of a peptide binder to the HPV16 E2 protein.

Nickel-Catalyzed Addition of Aryl Bromides to Aldehydes To Form Hindered Secondary Alcohols.

Transition-metal-catalyzed addition of aryl halides across carbonyls remains poorly developed, especially for aliphatic aldehydes and hindered substrate combinations. We report here that simple nickel complexes of bipyridine and PyBox can catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield (33 examples, 70% average yield). Mechanistic studies show that an arylnickel, and not an arylzinc, adds efficiently to cyclohexanecarboxaldehyde, but only in the presence of a Lewis acid co-catalyst (ZnBr2).

Decoding the antineoplastic efficacy of Aplysin targeting Bcl-2: A de novo perspective.

The B-cell lymphoma-2 (Bcl-2) family proteins have been attributed to be the key regulators in programmed cell death and apoptosis with a prominent role in human cancer. Understanding the fundamental principles of cell survival and death have been the main cornerstone in cancer drug discovery for identification of novel anticancer agents. In this context the Bcl-2 family of anti-and pro-apoptotic proteins provide an excellent opportunity for development of anticancer agents, as blocking the Bcl-2 or Bcl-XL functionally promotes apoptosis in tumor cells and also sensitize them to chemo- and radiotherapies. The present study reports the identification of novel Aplysin analogs as BCL-2 inhibitors from a sequential virtual screening approach using drug-like, ADMET, docking, pharmacophore filters and molecular dynamics simulation. We identified promising Aplysin analogs that have a potential to be Bcl-2 inhibitors just like the standard drug Obatoclax. One of the compound analog 11 was identified to be a promising inhibitor of Bcl-2 in the docking, pharmacophore and simulation based models.The molecular modeling information provided here can be vital in designing of the novel Bcl-2 inhibitors.

Sorption behaviors of tris-(2,3-dibromopropyl) isocyanurate and hexabromocyclododecanes on polypropylene microplastics.

In recent years, microplastics in oceans have become a serious environmental problem and the focus of attention. In the present study, the sorption of TBC and HBCDs by microplastics in simulated seawater is examined. The effects of particle size, temperature, salinity, and concentration on the adsorption of TBC and HBCDs by microplastics are studied. Results indicate that the first-order adsorption kinetic model is more suitable than the pseudo-second-order kinetic model to describe adsorption. The equilibrium adsorption times are 15 h and 10 h for TBC and HBCDs, respectively. The adsorption capacity increases with the decrease in particle size. The adsorption capacity gradually increases at first and then decreases with the increase in salinity and temperature. The maximum adsorption capacity is at 15 °C and 14% salinity. Compared with the linear and Freundlich models, the Langmuir model is more suitable; this indicates that the main adsorption mechanism might be chemical adsorption.