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1.
Cells ; 13(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38474364

RESUMO

Regenerative medicine aims to identify new research strategies for the repair and restoration of tissues damaged by pathological or accidental events. Mesenchymal stem cells (MSCs) play a key role in regenerative medicine approaches due to their specific properties, such as the high rate of proliferation, the ability to differentiate into several cell lineages, the immunomodulatory potential, and their easy isolation with minimal ethical issues. One of the main goals of regenerative medicine is to modulate, both in vitro and in vivo, the differentiation potential of MSCs to improve their use in the repair of damaged tissues. Over the years, much evidence has been collected about the ability of cytochalasins, a large family of 60 metabolites isolated mainly from fungi, to modulate multiple properties of stem cells (SCs), such as proliferation, migration, and differentiation, by altering the organization of the cyto- and the nucleo-skeleton. In this review, we discussed the ability of two different cytochalasins, cytochalasins D and B, to influence specific SC differentiation programs modulated by several agents (chemical or physical) or intra- and extra-cellular factors, with particular attention to human MSCs (hMSCs).


Assuntos
Adipogenia , Células-Tronco Mesenquimais , Humanos , Citocalasinas/metabolismo , Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Linhagem da Célula
2.
Fitoterapia ; 173: 105804, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38181894

RESUMO

Two new compounds eutyditerpenoid A (1) and seco-phenochalasin B (5), together with seven known compounds diaporthein A (2), aspergillon A (3), phenochalasin B (4), cytochalasins Z24 and Z25 (6 and 7), scoparasins A and B (8 and 9) were isolated from marine-derived Eutypella scoparia GZU-4-19Y. Among them, eutyditerpenoid A (1) with a rare 6/7/6 ring system possesing an anhydride moiety was the first example in the pimarane-type diterpenoids. Their structures were determined based on spectroscopic methods and the electronic circular dichroism (ECD) calculations. In the bioassays, all of the isolates were evaluated for their inhibitory activity against NO production induced by lipopolysaccharide in RAW 264.7 cells. Compounds 3 and 7 showed potent NO inhibition activity with IC50 values of 2.1 and 17.1 µM respectively, and the former also significantly suppressed the protein expression of iNOS and COX-2 at the concentration of 2.5 µM.


Assuntos
Ascomicetos , Diterpenos , Indóis , Lactonas , Estrutura Molecular , Ascomicetos/química , Diterpenos/farmacologia , Anti-Inflamatórios/farmacologia , Abietanos , Citocalasinas
3.
Phytochemistry ; 219: 113961, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38182030

RESUMO

Cocultivation of the high cytochalasan-producing fungi Aspergillus flavipes and Chaetomium globosum resulted in the isolation of 11 undescribed Chae-type cytochalasans. Their structures were determined by spectroscopic data and NMR data calculations. Asperchaetoglobin A (1) was the first Chae-type cytochalasan possessing an unprecedented nitrogen bridge between C-17 and C-20 to generate a surprising 5/6/12/5 multiple ring system; asperchaetoglobins B and C (2 and 3) displayed higher oxidation with an additional epoxide at the thirteen-member ring; asperchaetoglobin D (4) was the second Chae-type cytochalasin featuring a 5/6/12 tricyclic ring system. The cytotoxic activities against five human cancer cell lines and antibacterial activities against Staphylococcus aureus and Colon bacillus of selected compounds were evaluated in vitro.


Assuntos
Aspergillus , Chaetomium , Citocalasinas , Humanos , Estrutura Molecular , Técnicas de Cocultura , Citocalasinas/química
4.
Phytochemistry ; 215: 113861, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37726084

RESUMO

Seven previously undescribed cytochalasans, namely, boerechalasins A-G, together with one analogue, were characterized from the solid culture of the fungus Boeremia exigua. Their structures and absolute configurations were elucidated on the basis of extensive spectroscopic analysis as well as electronic circular dichroism calculations. Remarkably, boerechalasin F possessed an unusual sulfoxide moiety that might be derived from methionine, while boerechalasin G had an unusual 5-methylcyclohexane-1,2,3-triol substituent at N-2 position. Boerechalasins A and E exhibited inhibitory activities against nitric oxide production in LPS-induced RAW264.7 macrophages with IC50 values of 21.9 and 5.7 µM, respectively. Boerechalasin F displayed cytotoxicity against human MCF‒7 cells with an IC50 value of 22.8 µM.


Assuntos
Ascomicetos , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Macrófagos , Citocalasinas/farmacologia , Citocalasinas/química , Estrutura Molecular
5.
Biomolecules ; 13(8)2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37627312

RESUMO

The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. To interfere with the complex inter- and intracellular interactions the actin cytoskeleton confers, small molecular inhibitors have been used, foremost of all to study the relevance of actin filaments and their turnover for various cellular processes. The most prominent inhibitors act by, e.g., sequestering monomers or by interfering with the polymerization of new filaments and the elongation of existing filaments. Among these inhibitors used as tool compounds are the cytochalasans, fungal secondary metabolites known for decades and exploited for their F-actin polymerization inhibitory capabilities. In spite of their application as tool compounds for decades, comprehensive data are lacking that explain (i) how the structural deviances of the more than 400 cytochalasans described to date influence their bioactivity mechanistically and (ii) how the intricate network of ABPs reacts (or adapts) to cytochalasan binding. This review thus aims to summarize the information available concerning the structural features of cytochalasans and their influence on the described activities on cell morphology and actin cytoskeleton organization in eukaryotic cells.


Assuntos
Citoesqueleto de Actina , Actinas , Fenômenos Fisiológicos Celulares , Citoesqueleto , Citocalasinas/farmacologia
6.
Sci Rep ; 13(1): 9724, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37322086

RESUMO

Biofilm-mediated drug resistance is a key virulence factor of pathogenic microbes that cause a serious global health threat especially in immunocompromised individuals. Here, we investigated the antihyphal and antibiofilm activity of 19,20­epoxycytochalasin Q (ECQ), a cytochalasin actin inhibitor isolated from medicinal mushroom Xylaria sp. BCC1067 against Candida albicans. Remarkably, 256 µg/ml of ECQ inhibited over 95% of C. albicans hyphal formation after 24 h-treatment. Combined ECQ and lipid-based biosurfactant effectively enhanced the antihyphal activity, lowering required ECQ concentrations. Hyphal fragmentation and reduction of biofilm biomass, shown by SEM and AFM visualization of ECQ-treated biofilms, were well corelated to the reduced metabolic activities of young and 24 h-preformed C. albicans biofilms. Induced intracellular accumulation of reactive oxygen species (ROS) also occurred in accompany with the leakage of shrunken cell membrane and defective cell wall at increasing ECQ concentrations. Transcriptomic analyses via RNA-sequencing revealed a massive change (> 1300 genes) in various biological pathways, following ECQ-treatment. Coordinated expression of genes, associated with cellular response to drugs, filamentous growth, cell adhesion, biofilm formation, cytoskeleton organization, cell division cycle, lipid and cell wall metabolisms was confirmed via qRT-PCR. Protein-protein association tool identified coupled expression between key regulators of cell division cyclin-dependent kinases (Cdc19/28) and a gamma-tubulin (Tub4). They coordinated ECQ-dependent hyphal specific gene targets of Ume6 and Tec1 during different phases of cell division. Thus, we first highlight the antihyphal and antibiofilm property of the novel antifungal agent ECQ against one of the most important life-threatening fungal pathogens by providing its key mechanistic detail in biofilm-related fungal infection.


Assuntos
Antifúngicos , Candida albicans , Humanos , Antifúngicos/farmacologia , Citocalasinas/farmacologia , Divisão Celular , Ciclo Celular , Hifas , Biofilmes , Lipídeos/farmacologia
7.
Fitoterapia ; 168: 105523, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37146734

RESUMO

Fungi are important resources of novel bioactive compounds which have a high potential to be drug leads or candidates for further pharmacological applications. Phomopsis, a genus widely distributed in the environment, can produce various types of compounds including polyketides, alkaloids, terpenoids, cytochalasins, steroids and flavonoids. The metabolites of Phomopsis sp. showed diverse bioactivities such as antibacterial, anti-inflammatory, antimalarial, and so on, many of which may influence the physiological behaviour of the host plants. In this review, we focus on the chemical structures and biological activities of 183 specialized metabolites isolated from Phomopsis sp. in the decade (2013-2022). Moreover, the biosynthetic pathways of some typical components are summarized.


Assuntos
Alcaloides , Phomopsis , Estrutura Molecular , Antibacterianos , Citocalasinas/farmacologia , Fungos
8.
Mycologia ; 115(3): 277-287, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37017575

RESUMO

The recent description of the putative fungal pathogen of greenheart trees, Xylaria karyophthora (Xylariaceae, Ascomycota), prompted a study of its secondary metabolism to access its ability to produce cytochalasans in culture. Solid-state fermentation of the ex-type strain on rice medium resulted in the isolation of a series of 19,20-epoxidated cytochalasins by means of preparative high-performance liquid chromatography (HPLC). Nine out of 10 compounds could be assigned to previously described structures, with one compound being new to science after structural assignment via nuclear magnetic resonance (NMR) assisted by high-resolution mass spectrometry (HRMS). We propose the trivial name "karyochalasin" for the unprecedented metabolite. The compounds were used in our ongoing screening campaign to study the structure-activity relationship of this family of compounds. This was done by examining their cytotoxicity against eukaryotic cells and impact on the organization of networks built by their main target, actin-a protein indispensable for processes mediating cellular shape changes and movement. Moreover, the cytochalasins' ability to inhibit the biofilm formation of Candida albicans and Staphylococcus aureus was examined.


Assuntos
Xylariales , Cromatografia Líquida de Alta Pressão , Actinas/metabolismo , Citocalasinas/química , Citocalasinas/farmacologia
9.
J Org Chem ; 88(5): 3185-3192, 2023 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-36812072

RESUMO

Mass spectrometry (MS)-based metabolic profiling of the endophytic fungus Chaetomium nigricolor F5 guided the isolation of five novel cytochalasans, chamisides B-F (1-5), and two known ones, chaetoconvosins C and D (6 and 7). Their structures including stereochemistry were unambiguously determined by MS, nuclear magnetic resonance, and single-crystal X-ray diffraction analyses. Compounds 1-3 share a new 5/6/5/5/7-fused pentacyclic skeleton in cytochalasans and are appropriately proposed to be the key biosynthetic precursors of co-isolated cytochalasans with a 6/6/5/7/5, 6/6/5/5/7, or 6/6/5 ring system. Remarkably, compound 5 with a relatively flexible side chain showed promising inhibition activity against the cholesterol transporter protein Niemann-Pick C1-like 1 (NPC1L1), expanding the function of cytochalasans.


Assuntos
Sordariales , Estrutura Molecular , Fungos , Citocalasinas/farmacologia , Citocalasinas/química
10.
Fitoterapia ; 166: 105434, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36681097

RESUMO

Chemical investigation of an endophytic fungus herein identified as Diaporthe cf. ueckeri yielded four known compounds, named cytochalasins H and J and dicerandrols A and B. Reports of acid sensitivity within the cytochalasan family inspired an attempt of acid-mediated conversion of cytochalasins H and J, resulting in the acquisition of five polycyclic cytochalasins featuring 5/6/5/8-fused tetracyclic and 5/6/6/7/5-fused pentacyclic skeletons. Two of the obtained polycyclic cytochalasins constituted unprecedented analogues, for which the trivial names cytochalasins J4 and J5 were proposed, whereas the others were identified as the known phomopchalasin A, phomopchalasin D and 21-acetoxycytochalasin J3. The structures of the compounds were determined by extensive spectral analysis, namely HR-ESIMS, ESIMS and 1D/2D NMR. The stereochemistry of cytochalasins J4 and J5 was proposed using their ROESY data, biosynthetic and mechanistic considerations and by comparison of their ECD spectra with those of related congeners. All compounds except for cytochalasins H and J were tested for antimicrobial and cytotoxic activity. Cytochalasins J4 and J5 showed neither antimicrobial nor cytotoxic activity in the tested concentrations, with only weak antiproliferative activity observable against KB3.1 cells. The actin disruptive properties of all cytochalasins obtained in this study and of the previously reported cytochalasins RKS-1778 and phomopchalasin N were examined, and monitored by fluorescence microscopy using human osteo-sarcoma (U2-OS) cells. Compared to their precursor molecules (cytochalasins H and J), phomopchalasins A and D, 21-acetoxycytochalasin J3, cytochalasins J4 and J5 revealed a strongly reduced activity on the F-actin network, highlighting that the macrocyclic ring is crucial for bioactivity.


Assuntos
Antineoplásicos , Citocalasinas , Humanos , Estrutura Molecular , Fungos
11.
Nat Prod Res ; 37(1): 85-92, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34311632

RESUMO

Four new leucine-derived cytochalasans, possessing a 5,6,5,8-ring (1) and a 5,6,11-ring core (2-4), were isolated from a cultivated endophytic fungus Xylaria sp. strain WH2D4 (Xylariaceae). This fungus was isolated from leaves of the neotropical tree species Palicourea elata (Sw.) Borhidi (Rubiaceae) collected in Costa Rica. The chemical structures were determined by employing IR, MS as well as 1D- and 2D-NMR experiments. The stereochemistry at C-15 of compound 4 was determined by quantum calculations. The isolated compounds did not affect germination and growth of Trichoderma reesei and the opportunistic human fungal pathogen T. longibrachiatum.


Assuntos
Rubiaceae , Xylariales , Humanos , Costa Rica , Rubiaceae/química , Xylariales/química , Espectroscopia de Ressonância Magnética , Citocalasinas/química
12.
Mar Drugs ; 20(10)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36286441

RESUMO

A mangrove endophytic fungus Phomopsis asparagi DHS-48 was found to be particularly productive with regard to the accumulation of substantial new compounds in our previous study. In order to explore its potential to produce more unobserved secondary metabolites, epigenetic manipulation was used on this fungus to activate cryptic or silent genes by using the histone deacetylase (HDAC) inhibitor sodium butyrate and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-Aza). Based on colony growth, dry biomass, HPLC, and 1H NMR analyses, the fungal chemical diversity profile was significantly changed compared with the control. Two new compounds, named phaseolorin J (1) and phomoparagin D (5), along with three known chromones (2-4) and six known cytochalasins (6-11), were isolated from the culture treated with sodium butyrate. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD and 13C NMR calculations. The immunosuppressive and cytotoxic activities of all isolated compounds were evaluated. Compounds 1 and 8 moderately inhibited the proliferation of ConA (concanavalin A)-induced T and LPS (lipopolysaccharide)-induced B murine spleen lymphocytes. Compound 5 exhibited significant in vitro cytotoxicity against the tested human cancer cell lines Hela and HepG2, which was comparative to the positive control adriamycin and fluorouracil. Our finding demonstrated that epigenetic manipulation should be an efficient strategy for the induction of new metabolites from mangrove endophytic fungi.


Assuntos
Cromonas , Citocalasinas , Humanos , Camundongos , Animais , Citocalasinas/farmacologia , Cromonas/farmacologia , Lipopolissacarídeos , Ácido Butírico , Concanavalina A , Estrutura Molecular , Imunossupressores , Fungos , Epigênese Genética , Azacitidina , Fluoruracila , Doxorrubicina , Histona Desacetilases , Metiltransferases , DNA
13.
PLoS One ; 17(10): e0275002, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36190979

RESUMO

Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 µM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs.


Assuntos
Antiprotozoários , Produtos Biológicos , Trypanosoma cruzi , Actinas , Antiprotozoários/química , Produtos Biológicos/farmacologia , Citocalasinas , Descoberta de Drogas , Humanos , Doenças Negligenciadas/tratamento farmacológico
14.
Toxins (Basel) ; 14(9)2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-36136526

RESUMO

The genus Pyrenophora includes two important cereal crop foliar pathogens and a large number of less well-known species, many of which are also grass pathogens. Only a few of these have been examined in terms of secondary metabolite production, yet even these few species have yielded a remarkable array of bioactive metabolites that include compounds produced through each of the major biosynthetic pathways. There is little overlap among species in the compounds identified. Pyrenophora tritici-repentis produces protein toxin effectors that mediate host-specific responses as well as spirocyclic lactams and at least one anthraquinone. Pyrenophora teres produces marasmine amino acid and isoquinoline derivatives involved in pathogenesis on barley as well as nonenolides with antifungal activity, while P. semeniperda produces cytochalasans and sesquiterpenoids implicated in pathogenesis on seeds as well as spirocyclic lactams with phytotoxic and antibacterial activity. Less well-known species have produced some unusual macrocyclic compounds in addition to a diverse array of anthraquinones. For the three best-studied species, in silico genome mining has predicted the existence of biosynthetic pathways for a much larger array of potentially toxic secondary metabolites than has yet been produced in culture. Most compounds identified to date have potentially useful biological activity.


Assuntos
Doenças das Plantas , Sesquiterpenos , Aminoácidos , Antraquinonas/farmacologia , Antibacterianos , Antifúngicos , Citocalasinas , Isoquinolinas , Lactamas , Doenças das Plantas/microbiologia
15.
J Integr Neurosci ; 21(5): 147, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36137973

RESUMO

OBJECTIVE: This study aimed to conduct proteomic analysis of the sphincter in a neurogenic bladder caused by T10 spinal cord injury. The differentially expressed proteins (DEPs) of the sphincters (internal urethral sphincter) in the neurogenic bladders (NBs) of rats after complete transection of the T10 spinal cord segment were screened using tandem mass tag (TMT)-based quantitative labeling, and their biological information was analyzed. METHODS: Twelve adult Sprague Dawley rats out of 40 were randomly assigned to the blank group (n = 12), while the remaining 28 were placed in the T10 spinal cord injury model via modified Hassan Shaker spinal cord transection; 12 of these rats were then randomly selected as the model group. The rats in both groups underwent urodynamics detection and hematoxylin and eosin (H&E) staining. The proteins expressed in the bladder sphincter were detected using TMT-based quantitative proteomics. DEPs were defined as proteins with fold change >1.5 or <1/1.5, p < 0.05, and unique peptide ≥2. The DEPs were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using KOBAS 3.0., and gene ontology functional annotation analysis was performed using the Cytoscape 3.7.1. BiNGO plug-in. The protein-protein interaction network was then constructed using the interactive gene-retrieval tool STRING and Cytoscape software. RESULTS: The leak-point pressure and maximum cystometric volume in the model group were significantly higher than those in the blank group (p < 0.01), and H&E staining showed continuous interruption of the bladder sphincter fibers in the model group. A total of 250 DEPs were screened in the bladder sphincter, 83 of which were up-regulated and 167 of which were down-regulated. KEGG analysis of the DEPs was used to screen 15 pathways, including metabolic pathways, extracellular matrix (ECM)-receptor interaction, adhesion spots, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, the cytochalasin signaling pathway, and the advanced glycation end-products (AGE)/receptor for AGEs (RAGE) signaling pathway in diabetic complications and vascular smooth muscle contraction. CONCLUSIONS: It is of great significance to explore the pathological mechanism of non-inhibitory contraction of the bladder sphincter caused by spinal cord injury above the T10 segment from the perspective of ECM-receptor interaction, focal adhesion-activated PI3K/Akt signaling pathway, and cell relaxation signaling pathways. Synaptic vesicle glycoprotein (Sv2A) involved in the release of neurotransmitters from synaptic vesicles, arrestin ß2 inhibitory proteins involved in α-adrenergic receptors and G-protein-coupled receptor internalization, and calmodulin and calmodulin binding protein involved in calcium-sensitive signaling pathways may be potential targets for developing new ways to treat bladder sphincter overactivity caused by T10 spinal cord injury.


Assuntos
Traumatismos da Medula Espinal , Bexiga Urinaria Neurogênica , Animais , Arrestinas , Cálcio , Calmodulina , Proteínas de Ligação a Calmodulina , Citocalasinas , Amarelo de Eosina-(YS) , Hematoxilina , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Proteômica , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa , Receptores Acoplados a Proteínas G , Medula Espinal , Traumatismos da Medula Espinal/complicações , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinaria Neurogênica/terapia
16.
Colloids Surf B Biointerfaces ; 218: 112784, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36030725

RESUMO

Mechanical properties play key roles in the immune system, especially the activation, transformation and subsequent effector responses of immune cells. As transmembrane adhesion receptors, integrins mediate the adhesion events of both cells and cell-extracellular matrix (ECM). Integrin affinity would influence the crosslinking of cytoskeleton, leading to the change of elastic properties of cells. In this study, the cells were treated with F-actin destabilizing agent Cytochalasin-D (Cyt-D), fixed by Glutaraldehyde, and cultivated in hypotonic solution respectively. We used Atomic force microscopy (AFM) to quantitatively measure the elasticity of Jurkat cells and adhesion properties between integrins and vascular cell adhesion molecule-1 (VCAM-1), and immunofluorescence to study the alteration of cytoskeleton. Glutaraldehyde had a positive effect on the adhesion force and Young's modulus. However, these mechanical properties decreased in a hypotonic environment, confirming the findings of cellular physiological structure. There was no significant difference in the bond strength and elasticity of Jurkat cells treated with Cytochalasin-D, probably because of lower importance of actin in suspension cells. All the treatments in this study pose a negative effect on the adhesion probability between integrins and VCAM-1, which demonstrates the effect of structural alteration of the cytoskeleton on the conformation of integrin. Clear consistency between adhesion force of integrin/VCAM-1 bond and Young's modulus of Jurkat cells was shown. Our results further demonstrated the relationship between cytoskeleton and integrin-ligand by mechanical characteristics.


Assuntos
Integrinas , Molécula 1 de Adesão de Célula Vascular , Actinas , Adesão Celular , Citocalasinas/farmacologia , Glutaral , Humanos , Soluções Hipotônicas/farmacologia , Integrinas/metabolismo , Células Jurkat , Ligantes , Microscopia de Força Atômica/métodos , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/farmacologia
17.
Mar Drugs ; 20(8)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36005528

RESUMO

Three new cytochalasins, phomoparagins A-C (1-3), along with five known analogs (4-8), were isolated from Phomopsis asparagi DHS-48, a mangrove-derived endophytic fungus. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD techniques. Notably, 1 possessed an unprecedented 5/6/5/8/5-fused pentacyclic skeleton. These compounds were tested for their inhibitory activity against concanavalin A (ConA)/lipopolysaccharide (LPS)-induced spleen lymphocyte proliferation and calcineurin (CN) enzyme. Several metabolites (2 and 4-6) exhibited fascinating inhibitory activities with a relatively low toxicity. Furthermore, 2 was demonstrated to inhibit ConA-stimulated activation of NFAT1 dephosphorylation and block NFAT1 translocation in vitro, subsequently inhibiting the transcription of interleukin-2 (IL-2). Our results provide evidence that 2 may, at least partially, suppress the activation of spleen lymphocytes via the CN/NFAT signaling pathway, highlighting that it could serve as an effective immunosuppressant that is noncytotoxic and natural.


Assuntos
Citocalasinas , Fungos , Citocalasinas/farmacologia , Imunossupressores/farmacologia , Estrutura Molecular , Phomopsis
18.
Drug Discov Ther ; 16(4): 148-153, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36002309

RESUMO

Phenochalasin A, a unique phenol-containing cytochalasin produced by the marine-derived fungus Phomopsis sp. FT-0211, was originally discovered in a cell morphological assay of observing the inhibition of lipid droplet formation in mouse peritoneal macrophages. To investigate the mode of action and binding proteins, phenochalasin A was radio-labeled by 125I. Iodinated phenochalasin A exhibited the same biological activity as phenochalasin A. [125I]Phenochalasin A was found to be associated with an approximately 40 kDa protein, which was identified as G-actin. Furthermore, detail analyses of F-actin formation in Chinese hamster ovary cells (CHO-K1 cells) indicated that phenochalasin A (2 µM) caused elimination of F-actin formation on the apical site of the cells, suggesting that actin-oriented specific function(s) in cytoskeletal processes are affected by phenochalasin A.


Assuntos
Actinas , Gotículas Lipídicas , Actinas/análise , Actinas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Citocalasinas/metabolismo , Citocalasinas/farmacologia , Indóis , Radioisótopos do Iodo , Lactonas , Gotículas Lipídicas/química , Gotículas Lipídicas/metabolismo , Macrófagos Peritoneais/química , Macrófagos Peritoneais/metabolismo , Camundongos , Fenóis
19.
Phytochemistry ; 202: 113295, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35787352

RESUMO

Six previously undescribed cytochalasans, ueckerchalasins A-E and 4'-hydroxycytochalasin J3, together with eight known congeners, were isolated from solid cultures of the endophytic fungus Diaporthe ueckerae SC-J0123 which was originally isolated from the leaves of Pteris vittata L. Their structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction, and theoretical simulations of ECD spectra and 13C NMR shifts. Ueckerchalasins A-C have a carbon-carbon bridge between C-14 and C-20, forming a rare 5/6/6/7-fused heterocyclic core. Ueckerchalasins C and D displayed selective activity against human carcinoma HeLa and HepG2 cells. Ueckerchalasins C was also active against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA).


Assuntos
Ascomicetos , Gleiquênias , Staphylococcus aureus Resistente à Meticilina , Pteris , Poluentes do Solo , Ascomicetos/química , Carbono , Citocalasinas/química , Humanos , Pteris/microbiologia
20.
Chem Biodivers ; 19(8): e202200550, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35727302

RESUMO

Two new antimicrobial cytochalasin derivatives, 6ß,7ß-epoxydeoxaphomin C (1) and 12-hydroxydeoxaphomin C (2), a new natural occurring product 24-nor-cytochalasin B (3), together with two related known analogs (4-5) were isolated and identified from an endozoic fungus Curvularia verruculosa CS-129, isolated from the deep-sea squat lobster Shinkaia crosnieri which was collected in cold seep region of south China sea. The structures of new compounds were elucidated on the basis of detailed spectroscopic analysis and ECD calculation. The spectroscopic data of 24-nor-cytochalasin B (3) were reported for the first time. All compounds were tested for their antibacterial activities against human and aquatic pathogenic bacteria.


Assuntos
Curvularia , Citocalasinas , Antibacterianos/química , Citocalasina B , Citocalasinas/química , Citocalasinas/farmacologia , Fungos , Humanos , Estrutura Molecular
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