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This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of Myrianthus arboreus and from Oenothera maritima Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy.
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Simulación del Acoplamiento Molecular , Proteómica , Humanos , Proteómica/métodos , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/química , Ácido Graso Sintasas/antagonistas & inhibidores , Triterpenos/farmacología , Triterpenos/química , Triterpenos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Espectrometría de Masas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Terpenos/química , Terpenos/farmacología , Terpenos/metabolismoRESUMEN
INTRODUCTION: Severe asthma patients often remain uncontrolled despite high-intensity therapies. Biological therapies targeting thymic stromal lymphopoietin (TSLP), a key player in asthma pathogenesis, have emerged as potential options. Currently, the only TSLP inhibitor approved for the treatment of severe asthma is the immunoglobulin G (IgG) 2λ anti-TSLP monoclonal antibody (mAb) tezepelumab. AREAS COVERED: This systematic review assesses the efficacy and safety of investigational TSLP inhibitors across different stages of development for asthma treatment. EXPERT OPINION: TSLP contributes to airway inflammation, making it a pivotal therapeutic target. Ecleralimab, an inhaled antibody fragment antigen binding, shows promising evidence in enhancing efficacy and reducing systemic adverse events. SAR443765, with its NANOBODY® formulation and bispecific inhibition of TSLP and IL-13, offers improved tissue penetration and efficacy. The mAB TQC2731 exhibits high in vitro bioactivity, and the strength of the mAb UPB-101 is to act against the TSLP receptor. Some studies include mild and moderate asthma patients, suggesting the potential for extending biological therapy to non-severe patients. This systematic review highlights the potential of TSLP inhibitors as valuable additions to asthma treatment, even in milder forms of the disease. Future research and cost-reduction efforts are needed to expanding access to these promising therapies.
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Asma , Linfopoyetina del Estroma Tímico , Humanos , Asma/tratamiento farmacológico , Citocinas , Inflamación , Anticuerpos Monoclonales/efectos adversosRESUMEN
Purpose: The aim of our study is to evaluate artificial intelligence (AI) support in pelvic fracture diagnosis on X-rays, focusing on performance, workflow integration and radiologists' feedback in a spoke emergency hospital. Materials and methods: Between August and November 2021, a total of 235 sites of fracture or suspected fracture were evaluated and enrolled in the prospective study. Radiologist's specificity, sensibility accuracy, positive and negative predictive values were compared to AI. Cohen's kappa was used to calculate the agreement between AI and radiologist. We also reviewed the AI workflow integration process, focusing on potential issues and assessed radiologists' opinion on AI via a survey. Results: The radiologist performance in accuracy, sensitivity and specificity was better than AI but McNemar test demonstrated no statistically significant difference between AI and radiologist's performance (p = 0.32). Calculated Cohen's K of 0.64. Conclusion: Contrary to expectations, our preliminary results did not prove a real improvement of patient outcome nor in reporting time but demonstrated AI high NPV (94,62%) and non-inferiority to radiologist performance. Moreover, the commercially available AI algorithm used in our study automatically learn from data and so we expect a progressive performance improvement. AI could be considered as a promising tool to rule-out fractures (especially when used as a "second reader") and to prioritize positive cases, especially in increasing workload scenarios (ED, nightshifts) but further research is needed to evaluate the real impact on the clinical practice.
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Two linear proline-rich peptides (1-2), bearing an N-terminal pyroglutamate, were isolated from the marine bacterium Microbacterium sp. V1, associated with the marine sponge Petrosia ficiformis, collected in the volcanic CO2 vents in Ischia Island (South Italy). Peptide production was triggered at low temperature following the one strain many compounds (OSMAC) method. Both peptides were detected together with other peptides (3-8) via an integrated, untargeted MS/MS-based molecular networking and cheminformatic approach. The planar structure of the peptides was determined by extensive 1D and 2D NMR and HR-MS analysis, and the stereochemistry of the aminoacyl residues was inferred by Marfey's analysis. Peptides 1-8 are likely to arise from Microbacterium V1 tailor-made proteolysis of tryptone. Peptides 1 and 2 were shown to display antioxidant properties in the ferric-reducing antioxidant power (FRAP) assay.
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Antioxidantes , Péptidos Cíclicos , Animales , Péptidos Cíclicos/química , Microbacterium , Prolina , Espectrometría de Masas en Tándem , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos , BacteriasRESUMEN
Cancer cell migration is a hallmark of the aggressiveness and progression of malignancies such as high-risk neuroblastoma. Given the lack of effective therapeutic solutions to counteract cancer progression, basic research aims to identify novel bioactive molecules with inhibitory potential on cancer cell migration. In this context, this work investigated the role of members of the salicylaldehyde secondary metabolite set from the sponge endophyte fungus Eurotium chevalieri MUT 2316 as potential inhibitors of human neuroblastoma SH-SY5Y cell migration. Since tetrahydroauroglaucin (TAG) and dihydroauroglaucin (DAG) were isolated in large amounts, both were evaluated for their anticancer properties towards SH-SY5Y cells. Both molecules were found to be non-cytotoxic by MTT assay and cytofluorimetric analysis. Moreover, DAG showed efficacy in inhibiting the highly migratory phenotype of SH-SY5Y cells by wound healing assay; whereas TAG, although structurally similar to DAG, showed no anti-migratory effect. Therefore, this work provides good reasons to conduct further in vitro and in vivo studies focusing on DAG as a potentially useful migrastatic natural marine molecule.
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Staphylococcusaureus is an important opportunistic pathogen that causes many infections in humans and animals. The inappropriate use of antibiotics has favored the diffusion of methicillin-resistant S. aureus (MRSA), nullifying the efforts undertaken in the discovery of antimicrobial agents. Oxadiazole heterocycles represent privileged scaffolds for the development of new drugs because of their unique bioisosteric properties, easy synthesis, and therapeutic potential. A vast number of oxadiazole-containing derivatives have been discovered as potent antibacterial agents against multidrug-resistant MRSA strains. Here, we investigate the ability of a new library of oxadiazoles to contrast the growth of Gram-positive and Gram-negative strains. The strongest antimicrobial activity was obtained with compounds 3 (4 µM) and 12 (2 µM). Compound 12, selected for further evaluation, was found to be noncytotoxic on the HaCaT cell line up to 25 µM, bactericidal, and was able to improve the activity of oxacillin against the MRSA. The highest synergistic interaction was obtained with the combination values of 0.78 µM for compound 12, and 0.06 µg/mL for oxacillin. The FIC index value of 0.396 confirms the synergistic effect of compound 12 and oxacillin. MRSA treatment with compound 12 reduced the expression of genes included in the mec operon. In conclusion, 12 inhibited the growth of the MRSA and restored the activity of oxacillin, thus resulting in a promising compound in the treatment of MRSA infection.
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The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC50 values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1ß and TNF-α. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis.
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Antiinflamatorios no Esteroideos/farmacología , Desarrollo de Medicamentos , Eicosanoides/biosíntesis , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Peritonitis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Araquidonato 5-Lipooxigenasa/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Masculino , Ratones , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Peritonitis/inducido químicamente , Prostaglandina-E Sintasas/antagonistas & inhibidores , Prostaglandina-E Sintasas/metabolismo , Relación Estructura-Actividad , ZimosanRESUMEN
The Gram-negative Pantoea eucrina D2 was isolated from the marine sponge Chondrosia reniformis. Sponges were collected in a shallow volcanic vents system in Ischia island (South Italy), influenced by CO2 emissions and lowered pH. The chemical diversity of the secondary metabolites produced by this strain, under different culture conditions, was explored by a combined approach including molecular networking, pure compound isolation and NMR spectroscopy. The metabolome of Pantoea cf. eucrina D2 yielded a very complex molecular network, allowing the annotation of several metabolites, among them two biosurfactant clusters: lipoamino acids and surfactins. The production of each class of metabolites was highly dependent on the culture conditions, in particular, the production of unusual surfactins derivatives was reported for the first time from this genus; interestingly the production of these metabolites only arises by utilizing inorganic nitrogen as a sole nitrogen source. Major components of the extract obtained under standard medium culture conditions were isolated and identified as N-lipoamino acids by a combination of 1D and 2D NMR spectroscopy and HRESI-MS analysis. Assessment of the antimicrobial activity of the pure compounds towards some human pathogens, indicated a moderate activity of leucine containing N-lipoamino acids towards Staphylococcus aureus, Staphylococcus epidermidis and a clinical isolate of the emerging food pathogen Listeria monocytogenes.
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Antibacterianos/farmacología , Medios de Cultivo/farmacología , Redes y Vías Metabólicas , Metaboloma/efectos de los fármacos , Pantoea/fisiología , Poríferos/microbiología , Staphylococcus aureus/efectos de los fármacos , Ácidos/química , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Medios de Cultivo/química , Humanos , Filogenia , Poríferos/fisiologíaRESUMEN
Rhamnolipids (RLs) are surface-active molecules mainly produced by Pseudomonas spp. Antarctica is one of the less explored places on Earth and bioprospecting for novel RL producer strains represents a promising strategy for the discovery of novel structures. In the present study, 34 cultivable bacteria isolated from Edmonson Point Lake, Ross Sea, Antarctica were subjected to preliminary screening for the biosurfactant activity. The positive strains were identified by 16S rRNA gene sequencing and the produced RLs were characterized by liquid chromatography coupled to high resolution mass spectrometry (LC-HRESIMS) and liquid chromatography coupled with tandem spectrometry (LC-MS/MS), resulting in a new mixture of 17 different RL congeners, with six previously undescribed RLs. We explored the influence of the carbon source on the RL composition using 12 different raw materials, such as monosaccharides, polysaccharides and petroleum industry derivatives, reporting for the first time the production of RLs using, as sole carbon source, anthracene and benzene. Moreover, we investigated the antimicrobial potential of the RL mixture, towards a panel of both Gram-positive and Gram-negative pathogens, reporting very interesting results towards Listeria monocytogenes with a minimum inhibitory concentration (MIC) value of 3.13 µg/mL. Finally, we report for the first time the antimicrobial activity of RLs towards three strains of the emerging multidrug resistant Stenotrophomonas maltophilia with MIC values of 12.5 µg/ml.
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Antibacterianos/farmacología , Decanoatos/farmacología , Pseudomonas , Ramnosa/análogos & derivados , Tensoactivos/química , Animales , Regiones Antárticas , Decanoatos/química , Humanos , Listeria monocytogenes/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Ramnosa/química , Ramnosa/farmacología , Stenotrophomonas maltophilia/efectos de los fármacosRESUMEN
A wide range of prescreening tests for antimicrobial activity of 59 bacterial isolates from sediments of Ria Formosa Lagoon (Algarve, Portugal) disclosed Vibrio spartinae 3.6 as the most active antibacterial producing strain. This bacterial strain, which has not previously been submitted for chemical profiling, was subjected to de novo whole genome sequencing, which aided in the discovery and elucidation of a prodigiosin biosynthetic gene cluster that was predicted by the bioinformatic tool KEGG BlastKoala. Comparative genomics led to the identification of a new membrane di-iron oxygenase-like enzyme, annotated as Vspart_02107, which is likely to be involved in the biosynthesis of cycloprodigiosin and analogues. The combined genomics-metabolomics profiling of the strain led to the isolation and identification of one new branched-chain prodigiosin (5) and to the detection of two new cyclic forms. Furthermore, the evaluation of the minimum inhibitory concentrations disclosed the major prodigiosin as very effective against multi-drug-resistant pathogens including Stenotrophomonas maltophilia, a clinical isolate of Listeria monocytogenes, as well as some human pathogens reported by the World Health Organization as prioritized targets.
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Antibacterianos/biosíntesis , Indoles/química , Pirroles/química , Vibrio/genética , Vibrio/metabolismo , Antibacterianos/química , Bacterias/efectos de los fármacos , Biología Computacional , Ciclización , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Genómica , Listeria monocytogenes/efectos de los fármacos , Metabolómica , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Ionización de Electrospray , Stenotrophomonas maltophilia/efectos de los fármacosRESUMEN
The n-butanolic extract, from an Iranian specimen of Nepeta asterotricha Rech. f. (NABE), displayed anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated J774A.1 macrophages, which reduced nitrites and cytokines production. Bioassay guided fractionation of the extract led to the isolation of four iridoid glycosides, including a new one known as nepetamoside (1), one hexenyl-diglycoside, and some polyphenol and flavonoid components. None of the isolated iridoid components displayed significant effects on nitrites formation in an in vitro LPS-induced model of inflammation, thus suggesting that the plant anti-inflammatory effect is probably due to a synergistic action among its constituents.
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Nepeta/química , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Fraccionamiento Químico , Citocinas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Análisis EspectralRESUMEN
The exploration of poorly studied areas of Earth can highly increase the possibility to discover novel bioactive compounds. In this study, the cultivable fraction of fungi and bacteria from Barents Sea sediments has been studied to mine new bioactive molecules with antibacterial activity against a panel of human pathogens. We isolated diverse strains of psychrophilic and halophilic bacteria and fungi from a collection of nine samples from sea sediment. Following a full bioassay-guided approach, we isolated a new promising polyextremophilic marine fungus strain 8Na, identified as Aspergillus protuberus MUT 3638, possessing the potential to produce antimicrobial agents. This fungus, isolated from cold seawater, was able to grow in a wide range of salinity, pH and temperatures. The growth conditions were optimised and scaled to fermentation, and its produced extract was subjected to chemical analysis. The active component was identified as bisvertinolone, a member of sorbicillonoid family that was found to display significant activity against Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 30 µg/mL.
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Alquenos/farmacología , Antibacterianos/metabolismo , Aspergillus/química , Aspergillus/aislamiento & purificación , Ciclohexanonas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/farmacología , Bacterias/química , Bacterias/aislamiento & purificación , Hongos/química , Hongos/aislamiento & purificación , Sedimentos Geológicos/microbiología , Pruebas de Sensibilidad Microbiana , Océanos y Mares , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
Marine fungi represent an important but still largely unexplored source of novel and potentially bioactive secondary metabolites. The antimicrobial activity of nine sterile mycelia isolated from the green alga Flabellia petiolata collected from the Mediterranean Sea was tested on four antibiotic-resistant bacterial strains using extracellular and intracellular extracts obtained from each fungal strain. The isolated fungi were identified at the molecular level and assigned to one of the Dothideomycetes, Sordariomycetes or Eurotiomycetes classes. Following assessment of inhibition of bacterial growth (IC50), all crude extracts were subjected to preliminary (1)H NMR and TLC analysis. According to preliminary pharmacologic and spectroscopic/chromatographic results, extracts of fungal strains MUT 4865, classified as Beauveria bassiana, and MUT 4861, classified as Microascacea sp.2, were selected for LC-HRMS analysis. Chemical profiling of antibacterial extracts from MUT 4861 and MUT 4865 by LC HRMS allowed identification of the main components of the crude extracts. Several sphingosine bases were identified, including a compound previously unreported from natural sources, which gave a rationale to the broad spectrum of antibacterial activity exhibited.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Productos Biológicos/farmacología , Hongos/química , Hongos/clasificación , Antibacterianos/aislamiento & purificación , Productos Biológicos/aislamiento & purificación , Chlorophyta/microbiología , Cromatografía en Capa Delgada , Hongos/aislamiento & purificación , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Mar MediterráneoRESUMEN
OBJECTIVE: To explore anti-inflammatory activities of organic extract and its semi-purified fractions (ethanol, acetone, methanol/dichloromethane) from the Mediterranean gorgonian Eunicella singularis. METHODS: The anti-inflammatory and analgesic activities were evaluated, using the carrageenan-induced rat paw edema model and the acetic acid writhing test in mice. The gastroprotective activity was determined using HCl/EtOH induced gastric ulcers in rats. The purification and structure elucidation of compound(s) from the more effective fraction were determined by chromatographic and spectroscopic methods and in comparison with data reported in the literature. RESULTS: The fraction F-EtOH showed an important anti-inflammatory activity associated with significant analgesic and gastroprotective properties. The purification and structure elucidation of compound(s) from this fraction lead to the identification of one diterpenoid and four sterols. CONCLUSIONS: These results suggested that components from the active fraction can be used to treat various anti-inflammatory diseases.
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The individual chemical components of commercial extract of Gymnema sylvestre, a medicinal plant used in the traditional systems of the Indian medicine for its antidiabetic and hypolipidemic properties, were isolated and evaluated for their capability to act as modulators of nuclear and membrane receptors involved in glucose and lipid homeostasis. The study disclosed for the first time that individual gymnemic acids are potent and selective antagonists for the ß isoform of LXR. Indeed the above activity was shared by the most abundant aglycone gymnemagenin (10) whereas gymnestrogenin (11) was endowed with a dual LXRα/ß antagonistic profile. Deep pharmacological investigation demonstrated that gymnestrogenin, reducing the expression of SREBP1c and ABCA1 in vitro, is able to decrease lipid accumulation in HepG2 cells. The results of this study substantiate the use of G. sylvestre extract in LXR mediated dislypidemic diseases.
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Descubrimiento de Drogas , Gymnema sylvestre/química , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Saponinas/química , Saponinas/farmacología , Triterpenos/química , Triterpenos/farmacología , Células Hep G2 , Humanos , Receptores X del Hígado , Modelos Moleculares , Receptores Nucleares Huérfanos/química , Receptores Nucleares Huérfanos/genética , Conformación Proteica , Activación Transcripcional/efectos de los fármacosRESUMEN
The analysis of two Thorectidae sponge samples, Hyrtios sp. and Petrosaspongia sp., collected at Fiji Islands, led to the isolation of five new scalarane derivatives along with fifteen known compounds. Their structures were elucidated on the basis of NMR and MS spectroscopic data. The small library of natural scalarane derivatives was investigated for their ability to modulate the activity of trans-activation response DNA-binding protein of 43 kDa (TDP-43), a key factor in several neurodegenerative conditions and the study resulted in the identification of potent inhibitors of TDP-43 protein.
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ADN de Cadena Simple/química , Proteínas de Unión al ADN/antagonistas & inhibidores , Fármacos Neuroprotectores/química , Poríferos/química , Sesterterpenos/química , Animales , Proteínas de Unión al ADN/química , Cinética , Estructura Molecular , Fármacos Neuroprotectores/aislamiento & purificación , Fármacos Neuroprotectores/farmacología , Unión Proteica/efectos de los fármacos , Sesterterpenos/aislamiento & purificación , Sesterterpenos/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Gorgonians of the genus Eunicella are known for possessing a wide range of pharmacological activities such as antiproliferative and antibacterial effect. The aim of this study was to evaluate the anti-inflammatory and gastroprotective effect of the organic extract and its semi-purified fractions from the white gorgonian Eunicella singularis and the isolation and identification of pure compound(s) from the more effective fraction. METHODS: Anti-inflammatory activity was evaluated, using the carrageenan-induced rat paw edema test and in comparison to the reference drug Acetylsalicylate of Lysine. The gastroprotective activity was determined using HCl/EtOH induced gastric ulcers in rats. The purification of compound(s) from the more effective fraction was done by two chromatographic methods (HPLC and MPLC). The structure elucidation was determined by extensive spectroscopic analysis (1H and 13C NMR, COSY, HMBC, HMQC and NOESY) and by comparison with data reported in the literature. RESULTS: The evaluation of the anti-inflammatory activity of different fractions from Eunicella singularis showed in a dependent dose manner an important anti-inflammatory activity of the ethanol fraction, the percentage of inhibition of edema, 3 h after carrageenan injection was 66.12%, more effective than the reference drug (56.32%). In addition, this ethanolic fraction showed an interesting gastroprotective effect compared to the reference drugs, ranitidine and omeprazol. The percentage of inhibition of gastric ulcer induced by HCl/ethanol in rats was 70.27%. The percentage of the reference drugs (ranitidine and omeprazol) were 65 and 87.53%, respectively. The purification and structure elucidation of compound(s) from this ethanolic fraction were leading to the isolation of five sterols: cholesterol (5α-cholest-5-en-3ß-ol) (1); ergosterol (ergosta-5,22-dien-3ß-ol) (2); stigmasterol (24-ethylcholesta-5,22-dien-3b-ol) (3); 5α,8α-epidioxyergosta 6,22-dien-3ß-ol (4) and 3ß-hydroxy-5α,8α-epidioxyergosta-6-ene (5); and one diterpenoid: palmonine D (6). CONCLUSION: Based on data presented here, we concluded that diterpenoids and sterols detected in the ethanolic fraction can be responsible for its pharmacological activity.
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Antozoos/química , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antiulcerosos/química , Antiulcerosos/aislamiento & purificación , Descubrimiento de Drogas , Animales , Antiinflamatorios/administración & dosificación , Antiulcerosos/administración & dosificación , Carragenina/administración & dosificación , Modelos Animales de Enfermedad , Diterpenos/administración & dosificación , Diterpenos/química , Edema/inducido químicamente , Edema/tratamiento farmacológico , Etanol , Femenino , Ácido Clorhídrico , Masculino , Fitosteroles/administración & dosificación , Fitosteroles/química , Ratas , Ratas Wistar , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológicoRESUMEN
Marine organisms and their metabolites represent a unique source of potential pharmaceutical substances. In this study, we examined marine-derived substances for their bioactive properties in a cell-based Chikungunya virus (CHIKV) replicon model and for in vitro anti-inflammatory activity. In the screening of a marine sample library, crude extracts from the Indian soft coral, Sinularia kavarattiensis, showed promising activity against the CHIKV replicon. Bioassay-guided chemical fractionation of S. kavarattiensis resulted in the isolation of six known norcembranoids (1-6) and one new compound, named kavaranolide (7). The structures were elucidated on the basis of NMR and MS spectroscopic data. Compounds 1-3 and 5-7 were evaluated for their replicon-inhibiting potential in the CHIKV model by using a luminescence-based detection technique and live cell imaging. Compounds 1 and 2 showed moderate inhibition of the CHIKV replicon, but imaging studies also revealed cytotoxic properties. Moreover, the effects of the isolated compounds on primary microglial cells, an experimental model for neuroinflammation, were evaluated. Compound 2 was shown to modulate the immune response in microglial cells and to possess potential anti-inflammatory properties by dose-dependently reducing the release of pro- and anti-inflammatory cytokines.
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Antozoos/metabolismo , Antiinflamatorios/aislamiento & purificación , Antivirales/aislamiento & purificación , Diterpenos/aislamiento & purificación , Animales , Virus Chikungunya/efectos de los fármacos , Diterpenos/química , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Relación Estructura-ActividadRESUMEN
In recent years many sterols with unusual structures and promising biological profiles have been identified from marine sources. Here we report the isolation of a series of 24-alkylated-hydroxysteroids from the soft coral Sinularia kavarattiensis, acting as pregnane X receptor (PXR) modulators. Starting from this scaffold a number of derivatives were prepared and evaluated for their ability to activate the PXR by assessing transactivation and quantifying gene expression. Our study reveals that ergost-5-en-3ß-ol (4) induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target gene CYP3A4. To shed light on the molecular basis of the interaction between these ligands and PXR, we investigated, through docking simulations, the binding mechanism of the most potent compound of the series, 4, to the PXR. Our findings provide useful functional and structural information to guide further investigations and drug design.
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Antozoos/química , Hidroxiesteroides/farmacología , Receptores de Esteroides/efectos de los fármacos , Animales , Citocromo P-450 CYP3A/genética , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Hidroxiesteroides/química , Hidroxiesteroides/aislamiento & purificación , Ligandos , Simulación del Acoplamiento Molecular , Receptor X de Pregnano , Receptores de Esteroides/metabolismoRESUMEN
Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.