ABSTRACT
Application of oil toxicity modelling for assessing the risk of spills to coral reefs remains uncertain due to a lack of data for key tropical species and environmental conditions. In this study, larvae of the coral Acropora millepora were exposed to six aromatic hydrocarbons individually to generate critical target lipid body burdens (CTLBBs). Larval metamorphosis was inhibited by all six aromatic hydrocarbons, while larval survival was only affected at concentrations >2000 µg L-1. The derived metamorphosis CTLBB of 9.7 µmol g-1 octanol indicates larvae are more sensitive than adult corals, and places A. millepora larvae among the most sensitive organisms in the target lipid model (TLM) databases. Larvae were also more sensitive to anthracene and pyrene when co-exposed to ecologically relevant levels of ultraviolet radiation. The results suggest that the application of the phototoxic TLM would be protective of A. millepora larvae, provided adequate chemical and light data are available.
Subject(s)
Anthozoa , Hydrocarbons, Aromatic , Hydrozoa , Animals , Larva , Ultraviolet Rays , Coral Reefs , Hydrocarbons, Aromatic/pharmacology , Lipids/pharmacologyABSTRACT
A pH-triggering supramolecular antibacterial photosensitizer was constructed by host-guest interaction between a water-soluble porphyrin photosensitizer and carboxylatopillar[5]arene (P[5]). The formation of the supramolecular complex not only improves the biocompatibility of the photosensitizer, but also enhances antibacterial efficacy by pH-triggering dissociation under the low pH bacterial microenvironment.
Subject(s)
Anti-Bacterial Agents/pharmacology , Hydrocarbons, Aromatic/pharmacology , Photosensitizing Agents/pharmacology , Anti-Bacterial Agents/chemistry , Escherichia coli/drug effects , Hydrocarbons, Aromatic/chemistry , Microbial Sensitivity Tests , Photosensitizing Agents/chemistry , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Staphylococcus aureus/drug effectsABSTRACT
To meet the demand for alternatives to commonly used antibiotics, this paper evaluates the antimicrobial potential of arene-ruthenium(II) complexes and their salts, which may be of value in antibacterial treatment. Their antimicrobial activity (MIC, MBC/MFC) was examined in vitro against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris and Candida albicans and compared with classic antibiotics used as therapeutics. Selected arene-ruthenium(II) complexes were found to have synergistic effects with oxacillin and vancomycin against staphylococci. Their bactericidal effect was found to be associated with cell lysis and the ability to cut microbial DNA. To confirm the safety of the tested arene-ruthenium(II) complexes in vivo, their cytotoxicity was also investigated against normal human foreskin fibroblasts (HFF-1). In addition, the antioxidant and thus pro-health potential of the compounds, i.e., their nonenzymatic antioxidant capacity (NEAC), was determined by two different methods: ferric-TPTZ complex and DPPH assay.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Microbial/drug effects , Hydrocarbons, Aromatic/pharmacology , Pyrazoles/pharmacology , Ruthenium Compounds/pharmacology , Anti-Bacterial Agents/chemistry , Antioxidants/pharmacology , Cell Survival/drug effects , Cells, Cultured , Drug Synergism , Fibroblasts/drug effects , Foreskin/cytology , Foreskin/drug effects , Free Radical Scavengers/pharmacology , Humans , Hydrocarbons, Aromatic/chemistry , Male , Oxacillin/pharmacology , Pyrazoles/chemistry , Ruthenium Compounds/chemistry , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Vancomycin/pharmacologyABSTRACT
Here we report the first small-molecule inhibitors of human sulfide:quinone oxidoreductase (SQOR) that decrease the rate of breakdown of hydrogen sulfide (H2S), a potent cardioprotective signaling molecule. SQOR is a mitochondrial membrane-bound protein that catalyzes a two-electron oxidation of H2S to sulfane sulfur (S0), using glutathione (or sulfite) and coenzyme Q (CoQ) as S0 and electron acceptor, respectively. Inhibition of SQOR may constitute a new approach for the treatment of heart failure with reduced ejection fraction. Starting from top hits identified in a high-throughput screen, we conducted SAR development guided by docking of lead candidates into our crystal structure of SQOR. We identified potent SQOR inhibitors such as 19 which has an IC50 of 29 nM for SQOR inhibition and favorable pharmacokinetic and ADME properties required for in vivo efficacy testing.
Subject(s)
Enzyme Inhibitors/pharmacology , Hydrocarbons, Aromatic/pharmacology , Oxidoreductases Acting on Sulfur Group Donors/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hydrocarbons, Aromatic/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Molecular Structure , Oxidoreductases Acting on Sulfur Group Donors/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.
Subject(s)
Breast Neoplasms/pathology , ErbB Receptors/metabolism , NF-kappa B/metabolism , Plakophilins/metabolism , Protein Processing, Post-Translational , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , ErbB Receptors/genetics , Female , Humans , Hydrocarbons, Aromatic/pharmacology , Mice , Mice, Nude , NF-kappa B/genetics , Phosphorylation , Plakophilins/genetics , Signal Transduction , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/geneticsABSTRACT
Diabetes mellitus (DM) is a significant common metabolic disorder seen all over the world. In 2020, according to the International Diabetes Federation (IDF), out of 463 million people who have diabetes all over the world, 77 million belong to India. As per the statistical prediction, the affected numbers are probably expected to rise to 642 million by 2040. The commercially available anti-diabetic drugs in the market include metformin, sulphonyl urea, meglitinides, miglitol, acarbose, biguanides, and thiazolidinediones cause side effects like hypoglycaemia, dizziness, liver cell injury, digestive discomfort, neurological defects, etc. Hence, bioactive organosulphur based functional ligands are chosen in this study to arrive at a newer drug for DM. In this work, in silico analysis of organosulphur molecular descriptors like physicochemical properties, solubility, drug score, and toxicity predictions are evaluated using OSIRIS and Toxtree freeware. The essential parameters for discovering drugs for biopharmaceutical formulations viz the solubility of drugs and toxicity have been calculated. The protein target Dipeptidyl peptidase DPP4 (PID: 2RIP) was docked against energy minimised sulphur compounds using Hex 6.3. The results indicate that the drug likeliness of the molecule 4, that is, N-[(3,3-dimethyl piperidin-2-yl) methyl]-4-ethyl sulphonyl aniline is active with decreasing binding energy score (-212.24 Kcal mol-1 ) with no toxicity and also few sulphur compounds are active against diabetes compared to standard drug metformin (-158.33 Kcal mol-1 ). The best drug-like ligand N-[(3,3-dimethyl piperidin-2-yl) methyl]-4-ethyl sulphonyl aniline, was docked using commercial Maestro Schrodinger software to predict the results.
Subject(s)
Computer Simulation , Diabetes Mellitus/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Hydrocarbons, Aromatic/pharmacology , Sulfhydryl Compounds/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Drug Discovery , Humans , Hydrocarbons, Aromatic/chemistry , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Pharmaceutical Preparations , Sulfhydryl Compounds/chemistry , Toxicity TestsABSTRACT
Rice is a source of bioactive compounds related to human health and has been used for both consumption and traditional medicine. The authors investigated the synergistic and additive effect of rice extract (RE) combined with five aromatic compounds against three enzymes: α-glucosidase, α-amylase and tyrosinase. RE was purified by thin-layer chromatography (TLC) and preparative TLC (PTLC) with different solvent systems. RE had higher α-glucosidase and α-amylase inhibitory activity than the five aromatic compounds, while the five aromatic compounds had higher tyrosinase inhibitory activity than RE. The combination of RE/acarbose produced synergic inhibition of α-glucosidase and α-amylase, whereas RE showed additive inhibition of both enzymes when combined with aromatic compounds. The five aromatic compounds showed additive inhibition of tyrosinase when combined with RE. The combination of 2-methoxy-4-vinylphenol/vanillin/guaiacol produced synergistic inhibition of α-amylase while showing antagonism of α-glucosidase and tyrosinase. Interestingly, the RE produced additive inhibition of α-glucosidase, α-amylase and tyrosinase when combined with the 2-methoxy-4-vinylphenol/vanillin/guaiacol combination. RE had rich bioactive compounds related to α-glucosidase, α-amylase and tyrosinase inhibitory activity. Volatile compounds, including 2-methoxy-4-vinylphenol, vanillin and guaiacol, enhanced the inhibitory activity of RE against α-glucosidase, α-amylase and tyrosinase activities.
Subject(s)
Glycoside Hydrolase Inhibitors/pharmacology , Hydrocarbons, Aromatic/pharmacology , Monophenol Monooxygenase/antagonists & inhibitors , Oryza/chemistry , Plant Extracts/pharmacology , alpha-Amylases/antagonists & inhibitors , alpha-Glucosidases/metabolism , Drug Interactions , HumansABSTRACT
We reported an efficient multicomponent polyannulation for in situ generation of heteroaromatic hyperbranched polyelectrolytes by using readily accessible internal diynes and low-cost, commercially available arylnitriles, NaSbF6 , and H2 O/AcOH. The polymers were obtained in excellent yields (up to 99 %) with extraordinary high molecular weights (Mw up to 1.011×106 ) and low polydispersity indices. The resulting polymers showed good processibility and high quantum yields with tunable emission in the solid state, making them ideal materials for highly ordered fluorescent photopatterning. These hyperbranched polyelectrolytes also possessed strong ability to generate reactive oxygen species, which allowed their applications in efficient bacterial killing and customizable photodynamic patterning of living organisms in a simple and cost-effective way.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Heterocyclic Compounds/pharmacology , Hydrocarbons, Aromatic/pharmacology , Polyelectrolytes/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacteria/metabolism , Heterocyclic Compounds/chemistry , Hydrocarbons, Aromatic/chemistry , Molecular Structure , Molecular Weight , Polyelectrolytes/chemical synthesis , Polyelectrolytes/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Nuclear dot protein 52 kDa (NDP52, also known as CALCOCO2) functions as a selective autophagy receptor. The linear ubiquitin chain assembly complex (LUBAC) specifically generates the N-terminal Met1-linked linear ubiquitin chain, and regulates innate immune responses, such as nuclear factor-κB (NF-κB), interferon (IFN) antiviral, and apoptotic pathways. Although NDP52 and LUBAC cooperatively regulate bacterial invasion-induced xenophagy, their functional crosstalk remains enigmatic. Here we show that NDP52 suppresses canonical NF-κB signaling through the broad specificity of ubiquitin-binding at the C-terminal UBZ domain. Upon TNF-α-stimulation, NDP52 associates with LUBAC through the HOIP subunit, but does not disturb its ubiquitin ligase activity, and has a modest suppressive effect on NF-κB activation by functioning as a component of TNF-α receptor signaling complex I. NDP52 also regulates the TNF-α-induced apoptotic pathway, but not doxorubicin-induced intrinsic apoptosis. A chemical inhibitor of LUBAC (HOIPIN-8) cancelled the increased activation of the NF-κB and IFN antiviral pathways, and enhanced apoptosis in NDP52-knockout and -knockdown HeLa cells. Upon Salmonella-infection, colocalization of Salmonella, LC3, and linear ubiquitin was detected in parental HeLa cells to induce xenophagy. Treatment with HOIPIN-8 disturbed the colocalization and facilitated Salmonella expansion. In contrast, HOIPIN-8 showed little effect on the colocalization of LC3 and Salmonella in NDP52-knockout cells, suggesting that NDP52 is a weak regulator in LUBAC-mediated xenophagy. These results indicate that the crosstalk between NDP52 and LUBAC regulates innate immune responses, apoptosis, and xenophagy.
Subject(s)
Apoptosis , Immunity, Innate , Macroautophagy , Nuclear Proteins/metabolism , Ubiquitin-Protein Ligase Complexes/metabolism , Ubiquitin/metabolism , A549 Cells , Apoptosis/drug effects , Enzyme Inhibitors/pharmacology , HEK293 Cells , HeLa Cells , Humans , Hydrocarbons, Aromatic/pharmacology , Immunity, Innate/drug effects , Macroautophagy/drug effects , NF-kappa B/genetics , NF-kappa B/metabolism , Nuclear Proteins/genetics , Protein Binding , Salmonella enterica , Signal Transduction , Tumor Necrosis Factor-alpha/pharmacology , Ubiquitin-Protein Ligase Complexes/antagonists & inhibitors , Ubiquitin-Protein Ligase Complexes/genetics , UbiquitinationABSTRACT
The development of activatable photosensitizers to allow for the reversible control of singlet oxygen (1O2) production for photodynamic therapy (PDT) faces great challenges. Fortunately, the flourishing field of supramolecular biotechnology provides more effective strategies for activatable PDT systems. Here, we developed a new reversible PDT on a switch that controls the 1O2 generation of self-assembled albumin nanotheranostics in vitro and in vivo. A new molecular design principle of aggregation-induced self-quenching photochromism and albumin on-photoswitching was demonstrated using a new asymmetric, synthetic diarylethene moiety DIA. The photosensitizer porphyrin and DIA were incorporated as building blocks in a glutaraldehyde-induced covalent albumin cross-linking nanoplatform, HSA-DIA-porphyrin nanoparticles (NPs). More importantly, the excellent photoswitching property of DIA enables the resultant nanoplatform to act as a facile, switchable strategy for photodynamic-immunotherapy.
Subject(s)
Albumins/metabolism , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Immunotherapy/methods , Photochemotherapy/methods , Singlet Oxygen/metabolism , Cell Line, Tumor , Humans , Hydrocarbons, Aromatic/metabolismABSTRACT
Astacin metalloproteinases, in particular meprins α and ß, as well as ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. Moreover, some compounds already exhibited higher activity against individual astacin proteinases compared to recently reported inhibitors and also a favorable off-target selectivity profile, thus qualifying them as very suitable chemical probes for target validation.
Subject(s)
Amines/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery , Hydrocarbons, Aromatic/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Metalloproteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Amines/chemical synthesis , Amines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrocarbons, Aromatic/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Metalloendopeptidases/metabolism , Metalloproteases/metabolism , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Recombinant Proteins/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Aroma compounds are diverse low molecular weight organic molecules responsible for the flavour of food, medicines or cosmetics. Natural and artificial aroma compounds are manufactured and used by the industry to enhance the flavour and fragrance of products. While the low concentrations of aroma compounds present in food may leave no effect on the structural integrity of the mucosa, the effect of concentrated aroma volatiles is not well understood. At high concentrations, like those found in some flavoured products such as e-cigarettes, some aroma compounds are suggested to elicit a certain degree of change in the mucin glycoprotein network, depending on their functional group. These effects are particularly associated with carbonyl compounds such as aldehydes and ketones, but also phenols which may interact with mucin and other glycoproteins through other interaction mechanisms. This study demonstrates the formation of such interactions in vitro through the use of molecular hydrodynamics. Sedimentation velocity studies reveal that the strength of the carbonyl compound interaction is influenced by compound hydrophobicity, in which the more reactive short chain compounds show the largest increase in mucin-aroma sedimentation coefficients. By contrast, the presence of groups that increases the steric hindrance of the carbonyl group, such as ketones, produced a milder effect. The interaction effects were further demonstrated for hexanal using size exclusion chromatography light scattering (SEC-MALS) and intrinsic viscosity. In addition, phenolic aroma compounds were identified to reduce the sedimentation coefficient of mucin, which is consistent with interactions in the non-glycosylated mucin region.
Subject(s)
Hydrocarbons, Aromatic/pharmacology , Hydrodynamics , Mucins/metabolism , Hydrophobic and Hydrophilic Interactions/drug effects , Mucins/chemistry , Phenols/pharmacologyABSTRACT
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Hydrocarbons, Aromatic/pharmacology , Small Molecule Libraries/pharmacology , Animals , Free Radicals/antagonists & inhibitors , Hydrocarbons, Aromatic/chemistry , Mice , Mice, Transgenic , Molecular Structure , Oxidation-Reduction , Protein Aggregates/drug effects , Small Molecule Libraries/chemistryABSTRACT
There is strong interest in the valorization of lignin to produce valuable products; however, its structural complexity has been a conversion bottleneck. Chemical pretreatment liberates lignin-derived soluble fractions that may be upgraded by bioconversion. Cholinium ionic liquid pretreatment of sorghum produced soluble, aromatic-rich fractions that were converted by Pseudomonas putida (P.â putida), a promising host for aromatic bioconversion. Growth studies and mutational analysis demonstrated that P.â putida growth on these fractions was dependent on aromatic monomers but unknown factors also contributed. Proteomic and metabolomic analyses indicated that these unknown factors were amino acids and residual ionic liquid; the oligomeric aromatic fraction derived from lignin was not converted. A cholinium catabolic pathway was identified, and the deletion of the pathway stopped the ability of P.â putida to grow on cholinium ionic liquid. This work demonstrates that aromatic-rich fractions obtained through pretreatment contain multiple substrates; conversion strategies should account for this complexity.
Subject(s)
Hydrocarbons, Aromatic/chemistry , Lignin/chemistry , Pseudomonas putida/drug effects , Pseudomonas putida/metabolism , Amino Acids/chemistry , Biomass , Fatty Acids/chemistry , Gas Chromatography-Mass Spectrometry , Hydrocarbons, Aromatic/pharmacology , Ionic Liquids/chemistry , Proteomics , Signal Transduction , Tandem Mass SpectrometryABSTRACT
AIM: The present investigation was aimed at isolating and identifying bacterial strains from cured vanilla beans. Additionally, the study focused on evaluating bacterial processes pertaining to the aromatic compounds production (ACP). METHODS AND RESULTS: Three bacteria were isolated from Vanilla planifolia beans, previously subjected to the curing process. According to morphological, biochemical and 16S rRNA analysis, the strains were identified as Citrobacter sp., Enterobacter sp. and Pseudomonas sp. The polygalacturonase activity (PGA) was determined using the drop, cup-plate and DNS methods. Aromatic compounds production was analysed by cup-plate method using FA as substrate and quantified by high performance liquid chromatography (ppm), the functional groups of vanillic acid (VA) were identified by FT-IR and the aromatic compounds (AC) resistance was determined and reported as minimum inhibitory concentration. Citrobacter sp., Enterobacter sp. and Pseudomonas showed PGA (70·31 ± 364, 76·07 ± 12·47 and 51 ± 10·92 U ml-1 respectively), were producers of VA (3·23 ± 0·49, 324 ± 41 and 265·99 ± 11·61 ppm respectively) and were resistant to AC. CONCLUSIONS: The Gram-negative bacteria isolated from V. planifolia beans were responsible for ACP. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first evidence for the role of Gram-negative bacterial isolates from cured Mexican V. planifolia beans in the process related to ACP.
Subject(s)
Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacteria/metabolism , Hydrocarbons, Aromatic/metabolism , Vanilla/microbiology , Bacterial Proteins/metabolism , Drug Resistance, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/genetics , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Microbial Sensitivity Tests , Polygalacturonase/metabolism , RNA, Ribosomal, 16S/genetics , Vanillic Acid/chemistry , Vanillic Acid/metabolismABSTRACT
Heterologous production of fungal ligninolytic cocktails is challenging due to the low yields of catalytically active lignin modifying peroxidases. Production using a natural system, such as a wood-rotting fungus, is a promising alternative if specific or preferential induction of the ligninolytic activities could be achieved. Using transcriptomics, gene expression of the white-rot Dichomitus squalens during growth on mixtures of aromatic compounds, with ring structures representing the two major lignin sub-units, was compared to a wood substrate. Most of the genes encoding lignin modifying enzymes (laccases and peroxidases) categorised as highly or moderately expressed on wood were expressed similarly on aromatic compounds. Higher expression levels of a subset of manganese and versatile peroxidases was observed on di- compared to mono-methoxylated aromatics. The expression of polysaccharide degrading enzymes was lower on aromatic compounds compared to wood, demonstrating that the induction of lignin modifying enzymes became more specific. This study suggests potential for aromatic waste streams, e.g. from lignocellulose pretreatment, to produce a lignin-specific enzyme cocktail from D. squalens or other white-rot fungi.
Subject(s)
Fungal Proteins/genetics , Gene Expression Profiling/methods , Hydrocarbons, Aromatic/pharmacology , Polyporaceae/growth & development , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Fungal/drug effects , Hydrocarbons, Aromatic/chemistry , Laccase/genetics , Lignin/metabolism , Peroxidases/genetics , Polyporaceae/metabolism , Wood/chemistry , Wood/microbiologyABSTRACT
The review discusses the theory of interceptor-protector action (the IPA theory) as the new self-consistent biophysical theory establishing a quantitative interrelation between parameters measured in independent physico-chemical experiment and in vitro biological experiment for the class of DNA binding drugs. The elements of the theory provide complete algorithm of analysis, which may potentially be applied to any system of DNA targeting aromatic drugs. Such analytical schemes, apart from extension of current scientific knowledge, are important in the context of rational drug design for managing drug's response by changing the physico-chemical parameters of molecular complexation.
Subject(s)
DNA/chemistry , Hydrocarbons, Aromatic/chemistry , Receptors, Drug/chemistry , Binding Sites , Binding, Competitive , Biophysical Phenomena , Drug Evaluation, Preclinical , Humans , Hydrocarbons, Aromatic/pharmacology , Ligands , Models, ChemicalABSTRACT
Amphiphilic molecules linked by an aromatic nucleus were developed that showed high selectivity toward bacteria over mammalian cells, and low drug resistance. A promising compound 4g exhibited strong bactericidal activity against a panel of sensitive and resistant bacteria, low toxicity, the ability to reduce cell viability in biofilms, stability in mammalian fluids, rapid killing of pathogens, and high in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA).
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Hydrophobic and Hydrophilic Interactions , Biofilms/drug effects , Biofilms/growth & development , Cell Survival/drug effects , Methicillin-Resistant Staphylococcus aureus/cytology , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/physiology , Microbial Sensitivity TestsABSTRACT
In our screening program on marine-derived actinomycetes, Nonomuraea sp. AKA32 isolated from deep-sea water collected from a depth of 800 m in Sagami Bay, Japan was found to produce compounds cytotoxic to cancer cells. Activity-guided purification led to the isolation of a new aromatic polyketide, akazamicin (1), along with two known compounds, actinofuranone C (2) and N-formylanthranilic acid (3). Structures of these compounds were elucidated through the interpretation of NMR and MS spectroscopic data. Compounds 1, 2, and 3 displayed cytotoxicity against murine B16 melanoma cell line with the IC50 value of 1.7, 1.2, and 25 µM, respectively.
Subject(s)
Actinobacteria/metabolism , Antineoplastic Agents/isolation & purification , Aquatic Organisms/metabolism , Biological Products/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/isolation & purification , Hydrocarbons, Aromatic/pharmacology , Inhibitory Concentration 50 , Japan , Magnetic Resonance Spectroscopy , Mass Spectrometry , Melanocytes/drug effects , Mice , Molecular Structure , Polyketides/chemistry , Polyketides/isolation & purification , Polyketides/pharmacology , Seawater/microbiologyABSTRACT
A representative group of multicyclic aromatic hydrocarbons (MAHC) which can be further classified as bridged-ring (bridged-MAHC) or fused-ring (fused-MAHC) were examined for their ability to interact with the estrogen receptor of rainbow trout (rtER) in a hepatic cytosolic estrogen receptor competitive binding assay (cyto rtERαß) and the vitellogenin (Vtg) mRNA gene activation liver slice assay. All five fused-MAHCs; naphthalene (NAFT), fluorene (FE), Fluoranthene (FAT), pyrene (PY), and 9,10-dihydroanthracene (DAC) had no estrogenic activity in the in vitro assays used. Five of the eight bridged-MAHCs; triphenylethylene (3PE), o-terphenyl (OTP), triphenylmethane (TPM), 1,1-diphenylethylene (DPE), and cis-stilbene (CSB) were positive in the rtER-binding assay. The additional three bridged-MAHC's; trans-stilbene (TSB), tetraphenylethylene (4PE), and 4,4-di-tertbutylphenyl (DtBB) were determined to be non-binders due to isomeric configuration, solubility limitation, and possible steric hinderance. It is possible that the bridged-MAHCs bind to the rtER through a proposed aromatic-aromatic stacking (π-π interaction) facilitated by perpendicular ring orientation achieved through free rotation of the bridged rings. The fused-ring structures are locked in a planar configuration which doesn't allow for rotation of rings perpendicular to one another. This first report of the rtER-binding of bridged-MAHCs in fish demonstrates binding for a class of chemicals normally not thought of as having an affinity for the estrogen receptor and further supports the versatility or promiscuity of ER ligand selectivity.