RESUMEN
BACKGROUND AND PURPOSE: Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model. EXPERIMENTAL APPROACH: Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae. KEY RESULTS: PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction. CONCLUSION AND IMPLICATIONS: This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.
RESUMEN
Sortase A (SrtA) is a cysteine transpeptidase that binds to the periplasmic membrane and plays a crucial role in attaching surface proteins, including staphylococcal protein A (SpA), to the peptidoglycan cell wall. Six pentacyclic polyketides (1-6) were isolated from the marine sponge Xestospongia sp., and their structures were elucidated using spectroscopic techniques and by comparing them to previously reported data. Among them, halenaquinol (2) was found to be the most potent SrtA inhibitor, with an IC50 of 13.94 µM (4.66 µg/mL). Semi-quantitative reverse transcription PCR data suggest that halenaquinol does not inhibit the transcription of srtA and spA, while Western blot analysis and immunofluorescence microscopy images suggest that it blocks the cell wall surface anchoring of SpA by inhibiting the activity of SrtA. The onset and magnitude of the inhibition of SpA anchoring on the cell wall surface in S. aureus that has been treated with halenaquinol at a value 8× that of the IC50 of SrtA are comparable to those for an srtA-deletion mutant. These findings contribute to the understanding of the mechanism by which marine-derived pentacyclic polyketides inhibit SrtA, highlighting their potential as anti-infective agents targeting S. aureus virulence.
Asunto(s)
Aminoaciltransferasas , Antibacterianos , Proteínas Bacterianas , Pared Celular , Cisteína Endopeptidasas , Poríferos , Staphylococcus aureus , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Animales , Poríferos/microbiología , Antibacterianos/farmacología , Antibacterianos/química , Policétidos/farmacología , Policétidos/químicaRESUMEN
A chemical investigation of a methanol extract of Spongia sp., a marine sponge collected from the Philippines, identified 12 unreported scalarane-type alkaloids-scalimides A-L (1-12)-together with two previously described scalarin derivatives. The elucidation of the structure of the scalaranes based on the interpretation of their NMR and HRMS data revealed that 1-12 featured a ß-alanine-substituted E-ring but differed from each other through variations in their oxidation states and substitutions occurring at C16, C24, and C25. Evaluation of the antimicrobial activity of 1-12 against several Gram-positive and Gram-negative bacteria showed that 10 and 11 were active against Micrococcus luteus and Bacillus subtilis, respectively, with MIC values ranging from 4 to 16 µg/mL.
Asunto(s)
Antibacterianos , Poríferos , Animales , Antibacterianos/farmacología , Bacterias Gramnegativas , Bacillus subtilis , MetanolRESUMEN
The new polyketides lopouzanones A and B, as well as the new 1-O-acetyl and 2-O-acetyl derivatives of dendrodochol B, were isolated from the sponge-derived marine fungus Lopadostoma pouzarii strain 168CLC-57.3. Moreover, six known polyketides, gliorosein, balticolid, dendrodolide G, dihydroisocoumarine, (-)-5-methylmellein, and dendrodochol B, were identified. The structures of the isolated compounds were determined by a combination of NMR and ESIMS techniques. The absolute configurations of the lopouzanones A and B were determined using the Mosher's method. The cytotoxicity of the isolated compounds against human prostate cancer cells PC-3 and normal rat cardiomyocytes H9c2 was investigated. Gliorosein showed weak DPPH radical-scavenging activity and in vitro cardioprotective effects toward rotenone toxicity and CoCl2-mimic hypoxia.
Asunto(s)
Ascomicetos , Policétidos , Humanos , Ratas , Animales , Policétidos/química , Ascomicetos/química , Espectroscopía de Resonancia Magnética/métodos , Estructura MolecularRESUMEN
Saxitoxin (STX) is a highly toxic marine neurotoxin produced by phytoplankton and a growing threat to ecosystems worldwide due to the spread of toxic algae. Although STX is an established sodium channel blocker, the overall profile of transcriptional levels in STX-exposed organisms has yet to be described. Here, we describe a toxicity assay and transcriptome analysis of the copepod Tigriopus japonicus exposed to STX. The half-maximal lethal concentration of STX was 12.35 µM, and a rapid mortality slope was evident at concentrations between 12 and 13 µM. STX induced changes in swimming behavior among the copepods after 10 min of exposure. In transcriptome analysis, gene ontology revealed that the genes involved in nervous system and gene expression were highly enriched. In addition, the congenital neurological disorder and nuclear factor erythroid 2-related factor 2-mediated oxidative stress pathways were identified to be the most significant in network analysis and toxicity pathway analysis, respectively. This study provides valuable information about the effects of STX and related transcriptional responses in T. japonicus.
Asunto(s)
Copépodos , Saxitoxina , Animales , Saxitoxina/toxicidad , Copépodos/genética , Ecosistema , Neurotoxinas/farmacología , Bloqueadores de los Canales de Sodio/farmacologíaRESUMEN
Phytochemicals from the genus, Fagonia, have been attracting increasing attention due to their potential beneficial effects on human health. Fagonia species contain various types of phytochemicals such as flavonoids, alkaloids, saponins, terpenoids, coumarins and tannins. In this study, we investigated the phytochemical composition of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica and their bioactivity toward breast cancer MCF-7 cells in vitro. The results revealed that F. indica contains phytochemicals consistent with the reported phytochemical composition of this Fagonia species, with greater amounts of aglycones detected in the hydrolyzed extract. The crude extract of F. indica without acid hydrolysis was found to be ineffective in inhibiting the growth of MCF-7 cells at doses below 1000 µg/mL. However, after acid hydrolysis (to mimic gastro-intestinal hydrolysis), the F. indica extract became growth-inhibitory to MCF-7 cells as low as 10 µg/mL and the cytotoxicity increased with increasing dose and time of treatment. The results suggest that F. indica extracts contain phytochemicals in glycosidic forms whose aglycones are active as anti-proliferative agents toward breast cancer cells in vitro.
RESUMEN
Two nitrogenous metabolites, bacillimide (1) and bacillapyrrole (2), were isolated from the culture broth of the marine-derived actinomycete Streptomyces bacillaris. Based on the results of combined spectroscopic and chemical analyses, the structure of bacillimide (1) was determined to be a new cyclopenta[c]pyrrole-1,3-dione bearing a methylsulfide group, while the previously reported bacillapyrrole (2) was fully characterized for the first time as a pyrrole-carboxamide bearing an alkyl sulfoxide side chain. Bacillimide (1) and bacillapyrrole (2) exerted moderate (IC50 = 44.24 µM) and weak (IC50 = 190.45 µM) inhibitory effects on Candida albicans isocitrate lyase, respectively. Based on the growth phenotype using icl-deletion mutants and icl expression analyses, we determined that bacillimide (1) inhibits the transcriptional level of icl in C. albicans under C2-carbon-utilizing conditions.
Asunto(s)
Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Isocitratoliasa/efectos de los fármacos , Streptomyces/metabolismo , Antifúngicos/aislamiento & purificación , Candida albicans/enzimología , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Nitrógeno/metabolismoRESUMEN
AmpC BER is an extended-spectrum (ES) class C ß-lactamase with a two-amino-acid insertion in the H10 helix region located at the boundary of the active site compared with its narrow spectrum progenitor. The crystal structure of the wild-type AmpC BER revealed that the insertion widens the active site by restructuring the flexible H10 helix region, which is the structural basis for its ES activity. Besides, two sulfates originated from the crystallization solution were observed in the active site. The presence of sulfate-binding subsites, together with the recognition of ring-structured chemical scaffolds by AmpC BER, led us to perform in silico molecular docking experiments with halisulfates, natural products isolated from marine sponge. Inspired by the snug fit of halisulfates within the active site, we demonstrated that halisulfate 3 and 5 significantly inhibit ES class C ß-lactamases. Especially, halisulfate 5 is comparable to avibactam in terms of inhibition efficiency; it inhibits the nitrocefin-hydrolyzing activity of AmpC BER with a Ki value of 5.87 µM in a competitive manner. Furthermore, halisulfate 5 displayed moderate and weak inhibition activities against class A and class B/D enzymes, respectively. The treatment of ß-lactamase inhibitors (BLIs) in combination with ß-lactam antibiotics is a working strategy to cope with infections by pathogens producing ES ß-lactamases. Considering the emergence and dissemination of enzymes insensitive to clinically-used BLIs, the broad inhibition spectrum and structural difference of halisulfates would be used to develop novel BLIs that can escape the bacterial resistance mechanism mediated by ß-lactamases.
RESUMEN
The Federated States of Micronesia (FSM) is an island country in the western Pacific and is a known biodiversity hotspot. However, a relatively small number of fungi (236 species) have been reported till July 2021. Since fungi play major ecological roles in ecosystems, we investigated the fungal diversity of FSM from various sources over 2016 and 2017 and constructed a local fungal inventory, which also included the previously reported species. Fruiting bodies were collected from various host trees and fungal strains were isolated from marine and terrestrial environments. A total of 99 species, of which 78 were newly reported in the FSM, were identified at the species level using a combination of molecular and morphological approaches. Many fungal species were specific to the environment, host, or source. Upon construction of the fungal inventory, 314 species were confirmed to reside in the FSM. This inventory will serve as an important basis for monitoring fungal diversity and identifying novel biological resources in FSM.
RESUMEN
A total of eight new oxygenated 4-exo-methylene sterols, 1-8, together with one artifact 9 and six known sterols 11-16, were isolated from the marine sponge Theonella swinhoei collected from the Bohol province in Philippines. Structures of sterols 1-8 were determined from 1D and 2D NMR data. Among the sterols, 8α-hydroxytheonellasterol (4) spontaneously underwent an allylic 1,3-hydroxyl shift to produce 15α-hydroxytheonellasterol (9) as an artifact; this was rationalized by quantum mechanical calculations of the transition state. In addition, the 1,2-epoxy alcohol subunit of 8α-hydroxy-14,15-ß-epoxytheonellasterol (5) was assigned using the Gauge-Independent Atomic Orbital (GIAO) NMR chemical shift calculations and subsequent DP4+ analysis. Finally, comparison of the 13C chemical shifts of isolated 7α-hydroxytheonellasterol (6) with the reported values revealed significant discrepancies at C-6, C-7, C-8, and C-14, leading to reassignment of the C-7 stereochemistry in the known structure.
Asunto(s)
Antiinflamatorios/química , Esteroles/química , Theonella/metabolismo , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Oxidación-Reducción , Teoría Cuántica , Células RAW 264.7 , Estereoisomerismo , Esteroles/aislamiento & purificación , Esteroles/farmacología , Relación Estructura-ActividadRESUMEN
We describe a divergent and enantioselective total synthesis of (+)-ieodomycin A and (+)-ieodomycin B with three stereoisomers. The main advantage of the present synthesis is the late-stage elaboration of the side chain, which would afford a wide range of structurally diverse analogs with interesting bioactivities.
RESUMEN
Transient receptor potential ankyrin 1 (TRPA1) is a cation channel that plays a critical role in the occurrence and transmission of pain. By screening 393 marine invertebrate extracts for their antagonistic activity against TRPA1, it was found that the extract of the edible sea cucumber Bohadschia vitiensis had a remarkable potency. Bioassay-guided separation of the extract resulted in the isolation of six triterpene glycosides, including a novel analog. All six isolated compounds exhibited high inhibitory potency against TRPA1 (IC50 values ranging from 0.60 to 3.26 µM), which is comparable to that of a previously developed synthetic antagonist (A-967079). The discovery of TRPA1 antagonists, originated from this edible sea cucumber, opens the door for the elaboration of the valuable triterpene scaffold for the development of novel safe analgesics.
Asunto(s)
Glicósidos/farmacología , Pepinos de Mar/química , Canal Catiónico TRPA1/antagonistas & inhibidores , Triterpenos/farmacología , Animales , Glicósidos/química , Glicósidos/aislamiento & purificación , Células HEK293 , Humanos , Estructura Molecular , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/metabolismo , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
Three new phenazine derivatives (1-3), along with known compounds (4-7) of saphenic acid derivatives, were isolated from a deep-sea sediment-derived yeast-like fungus Cystobasidium larynigs collected from the Indian Ocean. The structures of the new compounds (1-3) were determined by analysis of spectroscopic data, semi-synthesis and comparison of optical rotation values. All the isolated compounds (1-7), except for 2, showed nitric oxide (NO) production inhibitory effect against lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells without cytotoxicity at concentrations up to 30 µg/mL. This is the first report on the yeast-like fungus Cystobasidium laryngis producing phenazines and anti-inflammatory activity of 1-7 including saphenic acid (4).
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Organismos Acuáticos/química , Hongos/química , Fenazinas/química , Fenazinas/farmacología , Levaduras/química , Animales , Línea Celular , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7RESUMEN
Three furan-containing scalarane sesterterpenoids (1â»3) and a novel pyrrole-containing analog (4) were isolated from the sponge Scalarispongia species. Compound 3, reported in the literature as a synthetic derivative of furoscalarol 2, was for the first time isolated from a natural source. During the separation performed using a silica column in the presence of methanol, 16-methoxy derivatives (5, 6) were obtained from the unintended reaction of 2. The isolated natural products 3 and 4 and the artifact 5 showed moderate to high cytotoxicity against six human cancer cell lines, whereas compound 6, the C-16 epimer of 5, showed no cytotoxicity at a concentration of 60 µΜ.
Asunto(s)
Antineoplásicos/farmacología , Furanos/química , Neoplasias/patología , Poríferos/química , Sesterterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Sesterterpenos/química , Sesterterpenos/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
We describe a synthetic approach for a set of fluorescent thieno[3,2- b]pyridine-5(4 H)-one derivatives and their photophysical properties. These fluorophores are prepared by a series of reactions employing the Suzuki-Miyaura cross-coupling reaction and a regioselective aza-[3 + 3] cycloaddition of 3-aminothiophenes with α,ß-unsaturated carboxylic acids. Our findings revealed that the photophysical properties are chemically tunable by an appropriate choice of functional group on the thieno[3,2- b]pyridine-5(4 H)-one scaffold.
RESUMEN
Two new sceptrin derivatives (1,2) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge Agelas kosrae. By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin (1) and ageleste C (2), were determined to be structural analogs of each other that differ at the imidazole moiety. Dioxysceptrin was also found to exist as a mixture of α-amido epimers. The sceptrin alkaloids exhibited weak cytotoxicity against cancer cells. Compounds 1 and 2 also moderately exhibited anti-angiogenic and isocitrate lyase-inhibitory activities, respectively.
Asunto(s)
Agelas/química , Alcaloides/farmacología , Productos Biológicos/farmacología , Pirroles/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/aislamiento & purificación , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Productos Biológicos/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Enzimas , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isocitratoliasa/antagonistas & inhibidores , Pirroles/química , Pirroles/aislamiento & purificación , EstereoisomerismoRESUMEN
Four novel secondary metabolites possessing a unique 6/5/5 tricyclic ring system, streptoglycerides A-D (1-4), were isolated from a marine actinomycete Streptomyces sp. derived from a mangrove sample collected on Kosrae Island. Their structures and absolute configurations were elucidated by spectroscopic data and electronic circular dichroism data. Streptoglyceride C (3) showed a weak inhibitory effect on the production of nitric oxide in BV-2 microglia cells.
Asunto(s)
Glicéridos/química , Streptomyces/química , Ciclización , Modelos Moleculares , Conformación MolecularRESUMEN
Three new cyclopeptides, phakellistatins 20-22 (1-3), as well as 10 known cyclopeptides of the same structural class were isolated from the tropical sponge Stylissa flabelliformis. By a combination of chemical and spectroscopic methods, the structures of the new compounds were determined to be an epimeric mixture of cycloheptapeptides (1) and two epimeric cyclodecapeptides (2 and 3) related to the phakellistatins. The cyclopeptides were evaluated for in vitro cytotoxicity against a variety of cancer cell lines, and compounds 2 and 3 exhibited significant activity.
Asunto(s)
Péptidos Cíclicos/química , Poríferos/química , Células A549 , Animales , Línea Celular Tumoral , Células HCT116 , Humanos , Células K562 , Péptidos Cíclicos/farmacologíaRESUMEN
Although radiation therapy is an effective treatment modality in many cancers, there is an urgent need to develop therapeutic drugs capable of overcoming radioresistance or minimizing normal tissue toxicity. A wide variety of marine-derived bioactive compounds have been screened for anti-cancer drug discovery, but little is known regarding radiation therapy applications. In this study, six different extracts of marine sponges collected from the Micronesian sea were screened for anti-cancer and radiosensitizing activity. Two extracts derived from Agelas sponges collected off the coast of Kosrae and Chuuk, the Federated States of Micronesia significantly decreased clonogenic survival of hepatocellular carcinoma (HCC) cells after exposure to ionizing radiation (IR). The Agelas extracts augmented IR-induced apoptosis and accumulation of reactive oxygen species (ROS). Endoplasmic reticulum (ER) stress was increased via unfolded protein response stimulation, which induced autophagy. N-acetylcysteine, a ROS scavenger, diminished ER stress and autophagy induction effects. This result indicated that Agelas extracts may sensitize HCC cells to IR via ROS overproduction in vitro. Our findings suggest that the Agelas sp. may have potential utility in radiosensitizer development.