RESUMEN
BACKGROUND: The role of periodontal ligament stem cells (PDLSCs) in repairing periodontal destruction is crucial, but their functions can be impaired by excessive oxidative stress (OS). Nocardamine (NOCA), a cyclic siderophore, has been shown to possess anti-cancer and anti-bacterial properties. This study aimed to investigate the protective mechanisms of NOCA against OS-induced cellular dysfunction in PDLSCs. METHODS: The cytotoxicity of NOCA on PDLSCs was assessed using a CCK-8 assay. PDLSCs were then treated with hydrogen peroxide (H2O2) to induce OS. ROS levels, cell viability, and antioxidant factor expression were analyzed using relevant kits after treatment. Small molecule inhibitors U0126 and XAV-939 were employed to block ERK signaling and Wnt pathways respectively. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining of mineralized nodules. Expression levels of osteogenic gene markers and ERK pathway were determined via real-time quantitative polymerase chain reaction (RT-qPCR) or western blot (WB) analysis. ß-catenin nuclear localization was examined by western blotting and confocal microscopy. RESULTS: NOCA exhibited no significant cytotoxicity at concentrations below 20 µM and effectively inhibited H2O2-induced OS in PDLSCs. NOCA also restored ALP activity, mineralized nodule formation, and the expression of osteogenic markers in H2O2-stimulated PDLSCs. Mechanistically, NOCA increased p-ERK level and promoted ß-catenin translocation into the nucleus; however, blocking ERK pathway disrupted the osteogenic protection provided by NOCA and impaired its ability to induce ß-catenin nuclear translocation under OS conditions in PDLSCs. CONCLUSIONS: NOCA protected PDLSCs against H2O2-induced OS and effectively restored impaired osteogenic differentiation in PDLSCs by modulating the ERK/Wnt signaling pathway.
Asunto(s)
Diferenciación Celular , Peróxido de Hidrógeno , Osteogénesis , Estrés Oxidativo , Ligamento Periodontal , Células Madre , Ligamento Periodontal/citología , Ligamento Periodontal/metabolismo , Ligamento Periodontal/efectos de los fármacos , Humanos , Estrés Oxidativo/efectos de los fármacos , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/toxicidad , Osteogénesis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , beta Catenina/metabolismo , Supervivencia Celular/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Cultivadas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25â µg/mL.
Asunto(s)
Antibacterianos , Chaetomium , Pruebas de Sensibilidad Microbiana , Poríferos , Chaetomium/química , Animales , Poríferos/microbiología , Poríferos/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Citocalasinas/farmacología , Citocalasinas/química , Citocalasinas/aislamiento & purificación , Conformación MolecularRESUMEN
Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.
Asunto(s)
Dysidea , Poríferos , Sesquiterpenos , Animales , Dysidea/química , Poríferos/química , Sesquiterpenos/farmacología , Sesquiterpenos/química , Antiinflamatorios/farmacología , FN-kappa B , Estructura MolecularRESUMEN
An unusual secomeroterpenoid, dysambiol (1), was isolated from a Dysidea sp. marine sponge collected from the South China Sea. Dysambiol features an unprecedented secomeroterpene scaffold with a rare lactone bridge. The structure of 1 was determined by extensive spectroscopic analysis, Mosher's method, and electronic circular dichroism calculation. Dysambiol displayed potent anti-inflammatory activity in LPS-induced Raw 264.7 macrophages by regulating the NF-κB/MPAK signaling pathway.
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Dysidea , Poríferos , Animales , Antiinflamatorios/farmacología , China , Dicroismo CircularRESUMEN
Aspergetherins A-D (1-4), four new chlorinated biphenyls, were isolated from the rice fermentation of a marine sponge symbiotic fungus Aspergillus terreus 164018, along with seven known biphenyl derivatives (5-11). The structures of four new compounds were determined by a comprehensive analysis of the spectroscopic data, including HR-ESI-MS and 2D NMR data. All 11 isolates were evaluated for their anti-bacterial activity against two strains of methicillin-resistant Staphylococcus aureus (MRSA). Among them, compounds 1, 3, 8 and 10 showed anti-MRSA activity with MIC values of 1.0-128â µg/mL. Preliminary structure-activity relationship analysis unveiled that both chlorinated substitution and esterification of 2-carboxylic acid could impact the antibacterial activity of biphenyls.
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Antibacterianos , Aspergillus , Compuestos de Bifenilo , Poríferos , Animales , Antibacterianos/química , Aspergillus/química , Staphylococcus aureus Resistente a Meticilina/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Poríferos/microbiología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacologíaRESUMEN
Covering: 2010 to 2021Sesquiterpene quinone/quinols (SQs) are characterized by a C15-sesquiterpenoid unit incorporating a C6-benzoquinone/quinol moiety. Numerous unprecedented carbon skeletons have been constructed with various connection patterns between the two parts. The potent anti-cancer, anti-inflammatory, anti-microbial, anti-viral, and fibrinolytic activities of SQs are associated with their diverse structures. The representative avarol has even entered the stage of clinical phase II research as an anti-HIV agent, and was developed as paramedic medicine against psoriasis. This review provides an overall summary of 558 new natural SQs discovered between 2010 and 2021, including seven groups and sixteen structure-type subgroups, which comprehensively recapitulates their chemical structures, spectral characteristics, source organisms, biological activities, synthesis, and biosynthesis, aiming to expand the application scope of this unique natural product resource.
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Hidroquinonas , Sesquiterpenos , Sesquiterpenos/farmacología , Quinonas/farmacología , BenzoquinonasRESUMEN
Four new sesquiterpene quinone meroterpenoids, dysideanones F-G (1-2) and dysiherbols D-E (3-4), were isolated from the marine sponge Dysidea avara collected from the South China Sea. The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra, and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations. Anti-inflammatory evaluation showed that dysiherbols D-E (3-4) exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC50 values of 10.2 and 8.6 µmol·L-1, respectively.
Asunto(s)
Dysidea , Poríferos , Sesquiterpenos , Animales , Dysidea/química , Quinonas/química , Quinonas/farmacología , Sesquiterpenos/química , Sesquiterpenos/farmacología , EsqueletoRESUMEN
The precursor ion scanning-supercritical fluid chromatography (PI-SFC) method was applied to explore new methionine sulfoxide-containing cycloheptapeptides, axinellasins A-D (1-4), from the marine sponge Axinella sp. Their structures, including absolute configurations, were elucidated by detailed spectroscopic analyses and X-ray crystallography. The total synthesis of 4 was completed via an Fmoc solid/solution-phase synthesis. Compounds 1-4 exhibited immunosuppressive effects via inhibition of T and B cell proliferation, and 1 and 4 showed better inhibitory activities than their corresponding diastereomers.
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Axinella , AnimalesRESUMEN
Chemical investigation of the marine sponge Dysidea avara, collected from the South China Sea, yielded 13 steroids, including nine new (1-9) and four known (10-13) ones. The new structures were elucidated as (3S,14R)-3,14-dihydroxycholesta-5,8-dien-7-one (1), (22E,24R)-7α-ethoxy-5α,6α-epoxyergosta-8(14),22-dien-3ß-ol (2), 3ß-hydroxy-7α-ethoxy-5α,6α-epoxy-8(14)-cholestene (3), 3ß,5α-dihydroxy-6α-ethoxychofesta-7,9(11)-diene (4), 3ß,5α-dihydroxy-6ß-ethoxycholest-7-ene (5), (22E,24R)-24-ethoxy-3ß,5α-dihydroxy-6ß-ethoxyergosta-7,22-diene (6), (22E)-3ß,5α-dihydroxy-6ß-ethoxycholesta-7,22-diene (7), 24-ethoxy-3ß,5α-dihydroxy-6ß-ethoxycholest-7-ene (8 and 9), by extensive spectroscopic analyses, such as HR-ESI-MS, 1D and 2D NMR data. The absolute configuration of 1 was assigned by comparison the experimental ECD spectra with the calculated ones. Among the 13 metabolites, compounds 1, 4, 11, 12, and 13 showed NF-κB inhibitory activities in human HER-293 cells with IC50 values of 6.4, 18.7, 8.1, 9.6, and 7.5â µM, respectively. Preliminary structure-activity relationship analysis unveiled that the conjugated ketones or unsaturated double bonds might be the functional groups for the five active steroids.
Asunto(s)
Dysidea/química , FN-kappa B/antagonistas & inhibidores , Esteroides/farmacología , Animales , China , Células HEK293 , Humanos , Conformación Molecular , FN-kappa B/metabolismo , Estereoisomerismo , Esteroides/química , Esteroides/aislamiento & purificaciónRESUMEN
Six new bisabolane-type phenolic sesquiterpenoids, including plakordiols A-D (1-4), (7R, 10R)-hydroxycurcudiol (5) and (7R, 10S)-hydroxycurcudiol (6) were isolated from the marine sponge Plakortis simplex collected from the South China Sea. Their structures were determined based on extensive analysis of spectroscopic data. Their configurations were assigned by coupling constant analysis, NOESY correlations, and the modified Mosher's method. Furthermore, their cytotoxic and antibacterial activities were evaluated.
Asunto(s)
Sesquiterpenos Monocíclicos , Plakortis , Animales , Antibacterianos/farmacología , China , Estructura Molecular , Sesquiterpenos Monocíclicos/farmacología , Océano Pacífico , Plakortis/químicaRESUMEN
Dysiscalarones A-E (1-5), five new scalarane-type bishomoscalarane sesterterpenoids, were isolated from marine sponge Dysidea granulosa collected from the South China Sea, together with two known ones, honulactone A (6) and phyllofolactone I (7). The new structures were determined by extensive spectroscopic analysis including HR-ESI-MS and 1D and 2D NMR data, and their absolute configurations were assigned by single crystal X-ray diffraction analyses. The inhibitory activity of all the seven isolates on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of these metabolites, dysiscalarones A-B (1-2), honulactone A (6), and phyllofolactone I (7) showed inhibitory activities with respective IC50 values of 16.4, 18.5, 2.6, and 3.7 µM, which suggested that the γ-methylated α,ß-unsaturated γ-lactone might be the functional group. In addition, all the seven metabolites showed no significant cytotoxicity against lung cancer PC9 cell line at the concentration of 20 µM.
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Dysidea/química , Óxido Nítrico/antagonistas & inhibidores , Sesterterpenos/farmacología , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Células RAW 264.7 , Sesterterpenos/química , Sesterterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
BACKGROUND: Marine natural products harbor a variety of pharmacological activities, and the sea species have been becoming a main source of new drug candidate. In pursuit of safer and more effective anti-inflammation drug, the anti-inflammatory activities, anti-oxygenation effects and underlying molecular mechanisms of compound dysiarenone from Dysidea arenaria were investigated via LPS-induced RAW 264.7 cell model. METHODS: Firstly, RAW 264.7 cells have been stimulated with LPS and treated with dysiarenone, and the cell viability of the LPS-treated RAW 264.7 cells was examined. One-step method, DCFH-DA fluorescence probe method was used to detect reactive oxygen species (ROS). The modulation of dysiarenone on anti-inflammation was detected by enzyme-linked immunosorbent assay by measuring the release of inflammatory cytokines (TNF-α and IL-6), and inflammatory mediators (LTB4). Further, the underlying anti-inflammatory mechanism of dysiarenone was explored by determining the expression of inducible 5-LOX, MAPKs, p-Akt, and p-NF-κB p65. Oxidative stress is tightly connected with inflammation, which was also evaluated through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (OH-1) signaling pathway. RESULTS: Our study unraveled that dysiarenone between 2 and 8 µM reduces the inflammation responses via suppressing the production of inflammatory cytokines (TNF-α and IL-6) and inflammatory mediators (LTB4). Dysiarenone down-regulated the protein levels of inducible 5-LOX via the inhibition of phosphorylation of MAPKs (including p38, ERK), Akt and NF-κB p65. Additionally, dysiarenone decreases ROS accumulation by upregulating HO-1 expression via nuclear translocation of Nrf2. CONCLUSION: In conclusion, we demonstrated that dysiarenone possesses anti-inflammation and anti-oxidation activity via inhibiting 5-LOX/NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Dysiarenone might be a promising lead compound for inflammatory diseases.
RESUMEN
A neutral-loss scanning mass method was used to explore new kynurenine-containing cycloheptapeptides, phakefustatins A-C (1-3), from the marine sponge Phakellia fusca. Their structures were elucidated by spectroscopic analysis and the advanced Marfey's method. 1 was total synthesized via a final-stage ozonolysis strategy by the combination of solid/solution-phase synthesis. Phakefustatin A (1) was identified as a RXRα modulator to inhibit cancer cell growth, and its pharmacophores could be Kyn and guanidine groups.
Asunto(s)
Quinurenina/química , Péptidos Cíclicos/química , Poríferos/química , Animales , Estructura Molecular , Análisis EspectralRESUMEN
Three new cadinane sesquiterpenes, trichodermaloids A (1), B (2), and C (5) were isolated from a symbiotic fungus Trichoderma sp. SM16 derived from the marine sponge Dysidea sp., together with three known ones, aspergilloid G (3), rhinomilisin E (4), and rhinomilisin G (6). The complete structures of three new compounds were determined by HR-MS and NMR spectroscopic analyses coupled with ECD calculations. The absolute configurations of two known compounds (4 and 6) were determined for the first time. The six isolates were inactive as antibacterial agents. However, trichodermaloids A and B have shown cytotoxicity on human NCIH-460 lung, NCIC-H929 myeloma, and SW620 colorectal cancer cell lines with IC50 values at the range of 6.8-12.7â µm.
Asunto(s)
Poríferos/microbiología , Sesquiterpenos/química , Trichoderma/química , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación Molecular , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Staphylococcus aureus/efectos de los fármacos , Simbiosis , Trichoderma/metabolismoRESUMEN
Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B-E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B-E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS-PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.
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Antibióticos Antineoplásicos/biosíntesis , Proteínas Bacterianas/metabolismo , Depsipéptidos/biosíntesis , Hidroxibenzoatos/química , Sintasas Poliquetidas/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular , Depsipéptidos/química , Depsipéptidos/toxicidad , Humanos , Compuestos Orgánicos/química , Compuestos Orgánicos/metabolismo , Compuestos Orgánicos/toxicidad , Streptomyces/enzimología , Streptomyces/metabolismoRESUMEN
Three unusual chlorinated PKS-NRPS hybrid metabolites, flavipesides A-C (1-3), were isolated from a strain of marine sponge symbiotic fungus Aspergillus flavipes 164013. Their structures were determined by spectroscopic data analysis, and absolute configurations were assigned by single-crystal X-ray diffraction with ECD spectral analysis. Flavipesides A-C showed potent pancreatic lipase (PL) inhibitory activity with IC50 values of 0.07-0.23 µM.
Asunto(s)
4-Butirolactona/análogos & derivados , Aspergillus/química , Inhibidores Enzimáticos/farmacología , Hongos/química , Lipasa/metabolismo , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Hongos/metabolismo , Lipasa/química , Estructura Molecular , Poríferos/química , Análisis EspectralRESUMEN
Two unique nitrogenous sesquiterpene quinone meroterpenoids, dysidinoid B (1) and dysicigyhone A (2), together with eight known analogues (3-10) were isolated and characterized from the marine sponge Dysidea septosa. Their structures with absolute configurations were established by a combination of extensive spectroscopic, electron circular dichroism (ECD) and single-crystal X-ray diffraction data analysis. Structurally, dysicigyhone A (2) possessed a unique benzo[d]oxazolidine-2-one unit. Additionally, dysidinoid B (1) exhibited significant anti-inflammatory effect by inhibiting TNF-α and IL-6 generation with IC50 values of 9.15 µM and 17.62 µM, respectively. Further in vivo anti-inflammatory assay verified that the dysidinoid B (1) alleviated the CuSO4-induced robust acute inflammatory response in zebrafish model.
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Antiinflamatorios/farmacología , Benzoquinonas/farmacología , Inflamación/tratamiento farmacológico , Nitrógeno/farmacología , Poríferos/química , Sesquiterpenos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Benzoquinonas/química , Células Cultivadas , Sulfato de Cobre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Inflamación/inducido químicamente , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Ratones , Modelos Moleculares , Estructura Molecular , Nitrógeno/química , Células RAW 264.7 , Sesquiterpenos/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Pez CebraRESUMEN
The termite nest-derived fungus Trichoderma virens CMB-TN16 cultivated on rice-based media produced seven new first-in-class trimeric sesquiterpenes, trivirensols A-G (11-17). Structures inclusive of absolute configurations were assigned by detailed spectroscopic analysis and biosynthetic considerations. Although trivirensols exhibit no cytotoxicity to mammalian carcinoma cells, selected examples are bacteriostatic against vancomycin-resistant Enterococcus faecalis (VRE). Structure-activity relationship (SAR) investigations combined with in situ chemical stability studies documented bacteriostatic activity for trivirensols A (11) and B (12) and the co-metabolite divirensols A (4), B (5), and G (10), all of which share a common terminal butenolide. Significantly, SAR studies also revealed bacteriostatic activity for trivirensols C (13) and G (17) and the co-metabolite divirensol C (6), all of which share a common hydrated butenolide terminal. Of note, when exposed to VRE cell cultures, the hydrated butenolides 6, 13, and 17 undergo rapid in situ dehydration to corresponding butenolides, suggesting hydrated butenolides are a pro-drug form of the butenolide VRE bacteriostatic pharmacophore.
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Antibacterianos/química , Antibacterianos/farmacología , Isópteros/microbiología , Sesquiterpenos/química , Sesquiterpenos/farmacología , Trichoderma/química , Animales , Australia , Biotransformación , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Trichoderma/aislamiento & purificaciónRESUMEN
Eleven new nitrogenous meroterpenoids, cinerols A-K (1-11), were isolated from the marine sponge Dysidea cinerea collected in the South China Sea, and their structures were determined by detailed spectroscopic analysis. Cinerols A (1) and B (2) feature a rare 5H-pyrrolo[1,2a]benzimidazole moiety, while cinerols C-G (3-7) are examples of rare meroterpene benzoxazoles. The cinerols are noncytotoxic to human melanoma A375 cells at the concentration of 32 µM; however, selected cinerols exhibit moderate inhibitory activity against one or more of protein-tyrosine phosphatase 1B, ATP-citrate lyase, and SH2 domain-containing phosphatase-1 with IC50 values of 2.8-27 µM.
Asunto(s)
Monoterpenos/aislamiento & purificación , Nitrógeno/química , Poríferos/química , Animales , Biología Marina , Monoterpenos/química , Monoterpenos/farmacologíaRESUMEN
The chemical investigation of the marine sponge Dysidea frondosa discovered a pair of unprecedented bioconjugates that are composed of a meroterpene and an unusual psammaplysin alkaloid. The structures of frondoplysins A (1) and B (2) were characterized by analysis of HRMS and NMR data coupled with single-crystal X-ray diffraction. Frondoplysin A was found to be a potent inhibitor targeting protein-tyrosine phosphatase 1B (PTP1B) with an IC50 value of 0.39 µM.