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1.
Molecules ; 29(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38893370

RESUMO

Kallopterolides A-I (1-9), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume Antillogorgia kallos. The structures and relative configurations of 1-9 were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.


Assuntos
Antozoários , Diterpenos , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Animais , Antozoários/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Antiprotozoários/isolamento & purificação , Região do Caribe , Estrutura Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Espectroscopia de Ressonância Magnética , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/isolamento & purificação
2.
Molecules ; 29(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38893484

RESUMO

To better assess the practical value and avoid potential risks of the traditionally medicinal and edible basidiomycete Schizophyllum commune, which may arise from undescribed metabolites, a combination of elicitors was introduced for the first time to discover products from cryptic and low-expressed gene clusters under laboratory cultivation. Treating S. commune NJFU21 with the combination of five elicitors led to the upregulated production of a class of unusual linear diterpene-derived variants, including eleven new ones (1-11), along with three known ones (12-14). The structures and stereochemistry were determined by 1D and 2D NMR, HRESIMS, ECD, OR and VCD calculations. Notably, the elongation terminus of all the diterpenes was decorated by an unusual butenedioic acid moiety. Compound 1 was a rare monocyclic diterpene, while 2-6 possessed a tetrahydrofuran moiety. The truncated metabolites 4, 5 and 13 belong to the trinorditerpenes. All the diterpenes displayed approximately 70% scavenging of hydroxyl radicals at 50 µM and null cytotoxic activity at 10 µM. In addition, compound 1 exhibited potent antifungal activity against the plant pathogenic fungi Colletotrichum camelliae, with MIC values of 8 µg/mL. Our findings indicated that this class of diterpenes could provide valuable protectants for cosmetic ingredients and the lead compounds for agricultural fungicide development.


Assuntos
Diterpenos , Schizophyllum , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/metabolismo , Schizophyllum/metabolismo , Schizophyllum/genética , Estrutura Molecular , Regulação para Cima/efeitos dos fármacos , Humanos
3.
Cells ; 13(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38891113

RESUMO

Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S985 phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y1003 and p-Y1234/5 MET species. PKC inhibition with BIM-1 blocked S985 phosphorylation of MET and led to MET cell surface accumulation. Treatment with metalloproteinase inhibitors prevented MET-ECD release into cell culture media, which was also blocked by PKC inhibitors. Furthermore, unbiased secretome analysis, performed using TMT-technology, identified additional targets of TT-dependent release of cell surface proteins from H357 head and neck cancer cells. We confirm that the MET co-signalling receptor syndecan-1 was cleaved from the cell surface in response to TT treatment. This was accompanied by rapid cleavage of the cellular junction adhesion protein Nectin-1 and the nerve growth factor receptor NGFRp75/TNFR16. These findings, that TT is a novel negative regulator of protumorigenic c-MET and NGFRp75/TNFR16 signalling, as well as regulating Nectin-1-mediated cell adhesion, further contribute to our understanding of the mode of action and efficacy of TT in the treatment of solid tumours.


Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Linhagem Celular Tumoral , Secretoma/metabolismo , Diterpenos/farmacologia , Proteínas de Membrana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sindecana-1/metabolismo , Nectinas/metabolismo , Proteína Quinase C/metabolismo
4.
Int J Mol Sci ; 25(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892285

RESUMO

The diterpene cafestol represents the most potent cholesterol-elevating compound known in the human diet, being responsible for more than 80% of the effect of coffee on serum lipids, with a mechanism still not fully clarified. In the present study, the interaction of cafestol and 16-O-methylcafestol with the stabilized ligand-binding domain (LBD) of the Farnesoid X Receptor was evaluated by fluorescence and circular dichroism. Fluorescence quenching was observed with both cafestol and 16-O-methylcafestol due to an interaction occurring in the close environment of the tryptophan W454 residue of the protein, as confirmed by docking and molecular dynamics. A conformational change of the protein was also observed by circular dichroism, particularly for cafestol. These results provide evidence at the molecular level of the interactions of FXR with the coffee diterpenes, confirming that cafestol can act as an agonist of FXR, causing an enhancement of the cholesterol level in blood serum.


Assuntos
Colesterol , Café , Diterpenos , Receptores Citoplasmáticos e Nucleares , Diterpenos/farmacologia , Diterpenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Colesterol/metabolismo , Humanos , Café/química , Simulação de Acoplamento Molecular , Ligação Proteica , Simulação de Dinâmica Molecular , Dicroísmo Circular
5.
Exp Biol Med (Maywood) ; 249: 10051, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38881848

RESUMO

Podocyte injury or dysfunction can lead to proteinuria and glomerulosclerosis. Zonula occludens 1 (ZO-1) is a tight junction protein which connects slit diaphragm (SD) proteins to the actin cytoskeleton. Previous studies have shown that the expression of ZO-1 is decreased in chronic kidney disease (CKD). Thus, elucidation of the regulation mechanism of ZO-1 has considerable clinical importance. Triptolide (TP) has been reported to exert a strong antiproteinuric effect by inhibiting podocyte epithelial mesenchymal transition (EMT) and inflammatory response. However, the underlying mechanisms are still unclear. We found that TP upregulates ZO-1 expression and increases the fluorescence intensity of ZO-1 in a puromycin aminonucleoside (PAN)-induced podocyte injury model. Permeablity assay showed TP decreases podocyte permeability in PAN-treated podocyte. TP also upregulates the DNA demethylase TET2. Our results showed that treatment with the DNA methyltransferase inhibitors 5-azacytidine (5-AzaC) and RG108 significantly increased ZO-1 expression in PAN-treated podocytes. Methylated DNA immunoprecipitation (MeDIP) and hydroxymethylated DNA immunoprecipitation (hMeDIP) results showed that TP regulates the methylation status of the ZO-1 promoter. Knockdown of TET2 decreased ZO-1 expression and increased methylation of its promoter, resulting in the increase of podocyte permeability. Altogether, these results indicate that TP upregulates the expression of ZO-1 and decreases podocyte permeability through TET2-mediated 5 mC demethylation. These findings suggest that TP may alleviate podocyte permeability through TET2-mediated hydroxymethylation of ZO-1.


Assuntos
Dioxigenases , Diterpenos , Compostos de Epóxi , Fenantrenos , Podócitos , Proteína da Zônula de Oclusão-1 , Podócitos/metabolismo , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteína da Zônula de Oclusão-1/metabolismo , Fenantrenos/farmacologia , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Dioxigenases/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Permeabilidade/efeitos dos fármacos , Humanos , Metilação de DNA/efeitos dos fármacos
6.
Sci Rep ; 14(1): 13967, 2024 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886585

RESUMO

Twelve polyoxygenated cyclohex(a/e)ne diterpene esters, named albiflorenes A-L (1-12), were isolated from the whole plants of Kaempferia albiflora, known as "Prao Mang Mum." Their structures and relative stereochemistry were determined by extensive spectroscopic analysis. Furthermore, the comparison of experimental electronic circular dichroism (ECD) curves with the curves predicted by TDDFT was used to determine the absolute configurations. Albiflorenes contain polyoxygenated cyclohexane (or cyclohexene) derivatives, which are linked to either isopimarane or abietane diterpene acid units. The discovery marks the first occurrence of a conjugate between polyoxygenated cyclohexane (or cyclohexene) rings and diterpenoids. Among the isolates, albiflorene C specifically exhibited antibacterial activity against Bacillus cereus with MIC and MBC values of 3.13 and 6.25 µg/mL, respectively.


Assuntos
Antibacterianos , Diterpenos , Ésteres , Testes de Sensibilidade Microbiana , Zingiberaceae , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Ésteres/química , Ésteres/farmacologia , Zingiberaceae/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bacillus cereus/efeitos dos fármacos , Estrutura Molecular , Dicroísmo Circular
7.
Immun Inflamm Dis ; 12(6): e1322, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38888462

RESUMO

INTRODUCTION: Triptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms underlying its effects in rheumatoid arthritis remain incompletely understood. METHODS: Collagen-induced arthritis (CIA) model was induced in Sprague-Dawley rats by immunization with bovine type II collagen, and TP was administrated as treatment. The therapeutic effect of TP was evaluated based on paw swelling, histopathology, and serum levels of inflammatory factors. Exosomes isolated from rat serum were characterized by transmission electron microscopy, dynamic light scattering, and western blot analysis. Proteomic profiling of exosomes was analyzed by direct DIA quantitative proteomics analysis. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes databases were employed for enrichment analysis related to molecular function, biological processes, and signaling pathways. Western blot analysis was used to analyze differentially expressed proteins. RESULTS: TP treatment ameliorated arthritic phenotypes in CIA rats as evidenced by reduced arthritis score, paw swelling, pathological injury severity scores, and serum levels of inflammatory cytokines. The proteomic analysis revealed that TP treatment significantly inhibited complement and coagulation cascades, interleukin-17 signaling pathway, and cholesterol metabolism, which were reactivated in CIA rats. Importantly, lipocalin 2 (LCN2) and myeloperoxidase (MPO) levels were markedly upregulated in the CIA group but suppressed upon TP administration. Furthermore, in synovial tissues, LCN2 and MPO expression levels were also elevated in the CIA group but decreased following TP treatment. CONCLUSION: Our findings demonstrate that TP alleviates CIA, possibly through modulation of exosomal LCN2 and MPO proteins.


Assuntos
Artrite Experimental , Diterpenos , Compostos de Epóxi , Exossomos , Fenantrenos , Proteômica , Ratos Sprague-Dawley , Animais , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/imunologia , Ratos , Proteômica/métodos , Exossomos/metabolismo , Masculino , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças
8.
Biomed Pharmacother ; 176: 116939, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38870629

RESUMO

BACKGROUND: Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis. METHODS: The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5. CONCLUSIONS: Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.


Assuntos
Diazepam , Hipnóticos e Sedativos , Simulação de Acoplamento Molecular , Sono , Tiopental , Animais , Masculino , Hipnóticos e Sedativos/farmacologia , Camundongos , Diazepam/farmacologia , Sono/efeitos dos fármacos , Tiopental/farmacologia , Diterpenos/farmacologia , Cafeína/farmacologia , Simulação por Computador , Receptores de GABA-A/metabolismo , Humanos , Relação Dose-Resposta a Droga , Latência do Sono/efeitos dos fármacos
9.
Antivir Ther ; 29(3): 13596535241259952, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38873947

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is the receptor that enables SARS-CoV-2 to invade host cells. Previous studies have reported that reducing ACE2 expression may have an anti-SARS-CoV-2 effect. In this study, we constructed a pGL4.10-F2-ACE2 vector with double luciferase genes (firefly and Renilla luciferase) under the control of the ACE2 promoter and used it to screen compounds from Chinese traditional medicinal herbs (CTMHs) that can inhibit ACE2 transcription in human cells. We transfected HEK293T cells with pGL4.10-F2-ACE2 and treated them with CTMH compounds and then measured fluorescence to evaluate the indirect inhibition of ACE2 transcription. Out of 37 compounds tested, andrographolide demonstrated a dose-dependent inhibition of ACE2 transcription. We further confirmed by RT-qPCR and Western blot assays that andrographolide also reduced ACE2 expression in BEAS-2B cells in a dose-dependent manner. Moreover, pseudovirus infection assays in BEAS-2B cells demonstrated that andrographolide can inhibit SARS-CoV-2 infection in a dose-dependent manner. These results suggest that andrographolide has potential anti-SARS-CoV-2 activity and could be a candidate drug for COVID-19 prevention and treatment.


Assuntos
Enzima de Conversão de Angiotensina 2 , Tratamento Farmacológico da COVID-19 , Diterpenos , Regulação para Baixo , SARS-CoV-2 , Humanos , Diterpenos/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Células HEK293 , Regulação para Baixo/efeitos dos fármacos , COVID-19/virologia , Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia
10.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 192-198, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836662

RESUMO

Intervertebral disc degeneration (IDD) is characterized by the decreased function and number of nucleus pulposus cells (NPCs) caused by excessive intervertebral disc (IVD) pressure. This research aims to provide novel insights into IDD prevention and treatment by clarifying the effect of andrographolide (ANDR) on IDD cell autophagy and oxidative stress under mechanical stress. Human primary NPCs were extracted from the nucleus pulposus tissue of non-IDD trauma patients. An IDD cell model was established by posing mechanical traction on NPCs. Through the construction of an IDD rat model, the influence of ANDR on IDD pathological changes was explored in vivo. The proliferation and autophagy of NPCs were decreased while the apoptosis rate and oxidative stress reaction were increased by mechanical traction. ANDR intervention obviously alleviated this situation. MiR-9 showed upregulated expression in IDD cell model, while FoxO3 and PINK1/Parkin were downregulated. Decreased proliferation and autophagy as well as enhanced apoptosis and oxidative stress response of NPCs were observed following miR-9 mimics and H89 intervention, while the opposite trend was observed after FoxO3 overexpression. FoxO3 is a direct target downstream miR-9. The in vivo experiments revealed that after ANDR intervention, the number of apoptotic cells in rat IVD tissue decreased and the autophagy increased. In conclusion, ANDR improves NPC proliferation, and autophagy, inhibits apoptosis and oxidative stress, and alleviates the pathological changes of IDD via the miR-9/FoxO3/PINK1/Parkin axis, which may be a new and effective treatment for IDD in the future.


Assuntos
Autofagia , Diterpenos , Proteína Forkhead Box O3 , Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Estresse Oxidativo , Proteínas Quinases , Ratos Sprague-Dawley , Estresse Mecânico , Ubiquitina-Proteína Ligases , MicroRNAs/metabolismo , MicroRNAs/genética , Autofagia/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Humanos , Diterpenos/farmacologia , Núcleo Pulposo/metabolismo , Núcleo Pulposo/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Ratos , Masculino , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Feminino , Adulto , Modelos Animais de Doenças
11.
Drug Deliv ; 31(1): 2354687, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38823413

RESUMO

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Beside early detection, early diagnosis, and early surgery, it is urgent to try new strategies for the treatment of HCC. Triptolide (TPL) has been employed to treat HCC. However, its clinical applications were restricted by the narrow therapeutic window, severe toxicity, and poor water-solubility. In this study, we developed cancer cell membrane-camouflaged biomimetic PLGA nanoparticles loading TPL (TPL@mPLGA) with the homologous targeting property for the treatment of HCC. The TPL@mPLGA was successfully prepared with particle size of 195.5 ± 7.5 nm and zeta potential at -21.5 ± 0.2 mV with good stability. The drug loading (DL) of TPL@mPLGA was 2.94%. After Huh-7 cell membrane coating, the natural Huh-7 cell membrane proteins were found to be retained on TPL@mPLGA, thus endowing the TPL@mPLGA with enhanced accumulation at tumor site, and better anti-tumor activity in vitro and in vivo when compared with TPL or TPL@PLGA. The TPL@mPLGA showed enhanced anti-tumor effects and reduced toxicity of TPL, which could be adopted for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Compostos de Epóxi , Neoplasias Hepáticas , Nanopartículas , Fenantrenos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Compostos de Epóxi/química , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Fenantrenos/administração & dosagem , Fenantrenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Camundongos , Membrana Celular/efeitos dos fármacos , Tamanho da Partícula , Portadores de Fármacos/química , Camundongos Nus , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Camundongos Endogâmicos BALB C
12.
Fitoterapia ; 176: 105987, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38703916

RESUMO

In Brazil, latex from Euphorbia umbellata (African milk tree) has been increasingly used in folk medicine to treat several types of cancer, including melanoma. The effect of lyophilized latex (LL), its hydroethanolic extract (E80), triterpene (F-TRI)- and diterpene (F-DIT)-enriched fractions, along with six isolated phorbol esters from LL and phorbol 12-myristate 13-acetate (PMA) on J774A.1, THP-1, SK-MEL-28, and B16-F10 cell line viability were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The compounds were identified by 2D-NMR and HRESIMS. The effect of the LL, extract and fractions on cell viability was also assessed through a resazurin reduction assay. At 100 µg/ml, LL, and its fractions moderately inhibited J774A.1 (37.5-59.5%) and THP-1 (12.6-43.6%) metabolism. LL (IC50 70 µg/ml) and F-TRI (IC50 68 µg/ml) were barely more effective against B16-F10 cells, and only F-TRI exerted an inhibitory effect on SK-MEL-28 cells (IC50 66-75 µg/ml). The samples did not effectively inhibit THP-1 growth (IC50 69-87 µg/ml, assessed by MTT). B16-F10 was susceptible to PMA (IC50 53 µM) and two 12-phenylacetate esters (IC50 56-60 µM), while SK-MEL-28 growth was inhibited (IC50 58 µM) by one of these kinds of esters with an additional 4ß-deoxy structure. Synagrantol A (IC50 39 µM) was as effective as PMA (IC50 47 µM) in inhibiting J774A.1 growth in a dose-dependent manner. Furthermore, an in silico study with target receptors indicated a high interaction of the compounds with the PKC proteins. These results provide useful knowledge on the effect of tigliane-type diterpenes on tumor cell from the perspective of medicinal chemistry.


Assuntos
Euphorbia , Látex , Ésteres de Forbol , Euphorbia/química , Látex/química , Ésteres de Forbol/farmacologia , Humanos , Camundongos , Animais , Linhagem Celular Tumoral , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Brasil , Monócitos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Terpenos/farmacologia , Terpenos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Acetato de Tetradecanoilforbol , Melanoma/tratamento farmacológico
13.
Fitoterapia ; 176: 106019, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744380

RESUMO

Diterpenoids occupy an important slot of the natural products diversity space with wide ranges of bioactivities and complex structures, providing potential applications for the development of therapeutics. In this study, we reported four new abietane-type diterpenoids viroxocin B-E (1-4), a new totarane-type diterpenoid viroxocin F (5), and a new sempervirane-type diterpenoid viroxocin G (6) along with four known compounds (7-10), isolated and identified from a widely used Traditional Chinese Medicine, Isodon serra (I. serra). Their structures were established by spectroscopic data analysis, experimental and calculated electronic circular dichroism (ECD) data, as well as X-ray diffraction analysis. Compounds 2, 5, 7, 8 and 10 exhibited promising anti-inflammatory activities in lipopolysaccharide (LPS)-induced RAW 267.4 cells, and their inhibition rates on NO production were more than 60% at 10 µM. Compound 7 showed cytotoxicity against human renal cell carcinoma 769P at 20 µM, the inhibition rate was 52.66%.


Assuntos
Anti-Inflamatórios , Antineoplásicos Fitogênicos , Diterpenos , Isodon , Compostos Fitoquímicos , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/química , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Estrutura Molecular , Camundongos , Isodon/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , China , Células RAW 264.7 , Óxido Nítrico/metabolismo
14.
Fitoterapia ; 176: 106007, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38744384

RESUMO

Three p-terphenyl metabolites (1-3), three indole-diterpenoids (4-6), an herbicide sesquiterpene (7), a flavonoid (8), and five other small molecules containing nitrogen (9-13) were isolated from the medicinal insect (Periplaneta americana)-derived endophytic Aspergillus taichungensis SMU01. Their chemical structures were elucidated on the basis of spectroscopic data and quantum chemical computational methods. Biological activity of these isolates in the differentiation of mouse CD4+ T cell subsets was evaluated. Importantly, metabolites 2 targeting JAK-STAT signaling pathway could hold potential benefits in maintaining peripheral immune homeostasis and alleviating the progression of autoimmune diseases.


Assuntos
Aspergillus , Imunossupressores , Periplaneta , Animais , Camundongos , Estrutura Molecular , Aspergillus/química , Imunossupressores/farmacologia , Imunossupressores/isolamento & purificação , Periplaneta/microbiologia , Linfócitos T CD4-Positivos , Endófitos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Transdução de Sinais , Camundongos Endogâmicos C57BL , Feminino
15.
Fitoterapia ; 176: 106021, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762074

RESUMO

Acanthopanacis Cortex (A.-C) with a long history of more than1000 years, has been used to treat rheumatism effectively. Nineteen diterpenoids have been isolated from A.-C, including six new compounds (1-6). Among them, compounds 7, 9-11, 13, and 17 were discovered from A.-C for the first time. The structures of 1-6 were determined by analyzing their NMR data and comparing their experimental and calculated electronic circular dichroism spectra. Moreover, the single-crystal X-ray diffraction data of 1, 2, 8, and 14 were provided. The anti-inflammatory activity of 1-5 and 7-18 on neutrophil elastase, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) has been studied in vitro, and the results showed that 15 had almost no inhibitory effects on COX-1 at 200 µM but a significant activity against COX-2 with an IC50 of 0.73 ± 0.006 µΜ. It indicated that compound 15 can provide valuable information for the design of selective COX-2 inhibitors.


Assuntos
Anti-Inflamatórios , Ciclo-Oxigenase 2 , Diterpenos , Elastase de Leucócito , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/química , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Elastase de Leucócito/antagonistas & inibidores , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Ciclo-Oxigenase 1/metabolismo , Acanthaceae/química , Humanos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , China
16.
Fitoterapia ; 176: 106034, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38795853

RESUMO

Ten diterpenoids including six unreported abietane-type diterpenoids Glecholmenes A-F (1-6) and an undescribed labdane-type diterpenoid Glecholmene G (9), together with three known diterpenoids (7,8,10), were firstly isolated from the aerial part of G. longituba. Their structures were established mainly by nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) methods. Electronic circular dichroism (ECD) calculations and X-ray crystallographic analyses were used for the determination of their absolute configurations. The anti-inflammatory activity of all compounds was evaluated using the classical LPS-induced NO release model in RAW264.7 cells. Compound 2 displayed significant anti-inflammatory activities with IC50 values of 29.08 ± 1.40 µM (Aminoguanidine hydrochloride as the positive control, IC50 = 21.84 ± 0.48 µM).


Assuntos
Anti-Inflamatórios , Diterpenos , Compostos Fitoquímicos , Componentes Aéreos da Planta , Animais , Camundongos , Componentes Aéreos da Planta/química , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Células RAW 264.7 , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Óxido Nítrico/metabolismo , Abietanos/farmacologia , Abietanos/isolamento & purificação , Lamiaceae/química , China
17.
Fitoterapia ; 176: 106046, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38821322

RESUMO

14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.


Assuntos
Antibacterianos , Diterpenos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pleuromutilinas , Compostos Policíclicos , Compostos Policíclicos/farmacologia , Compostos Policíclicos/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Diterpenos/farmacologia , Diterpenos/química , Camundongos , Animais , Estrutura Molecular , Células RAW 264.7 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico
18.
Cells ; 13(10)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38786033

RESUMO

Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Ácido Palmítico , Piroptose , Tretinoína , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Diterpenos/farmacologia , Ácido Palmítico/farmacologia , Piroptose/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Tretinoína/farmacologia , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos
19.
ACS Infect Dis ; 10(6): 1980-1989, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38703116

RESUMO

In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.


Assuntos
Antibacterianos , Diterpenos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pleuromutilinas , Compostos Policíclicos , Infecções Estafilocócicas , Tiazóis , Compostos Policíclicos/farmacologia , Compostos Policíclicos/química , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Infecções Estafilocócicas/tratamento farmacológico , Desenho de Fármacos , Células RAW 264.7
20.
Exp Parasitol ; 262: 108773, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38723845

RESUMO

Giardiasis is a prevalent parasitic diarrheal disease caused by Giardia lamblia, affecting people worldwide. Recently, the availability of several drugs for its treatment has highlighted issues such as multidrug resistance, limited effectiveness and undesirable side effects. Therefore, it is necessary to develop alternative new drugs and treatment strategies that can enhance therapeutic outcomes and effectively treat giardiasis. Natural compounds show promise in the search for more potent anti-giardial agents. Our investigation focused on the effect of Andrographolide (ADG), an active compound of the Andrographis paniculata plant, on Giardia lamblia, assessing trophozoite growth, morphological changes, cell cycle arrest, DNA damage and inhibition of gene expression associated with pathogenic factors. ADG demonstrated anti-Giardia activity almost equivalent to the reference drug metronidazole, with an IC50 value of 4.99 µM after 24 h of incubation. In cytotoxicity assessments and morphological examinations, it showed significant alterations in trophozoite shape and size and effectively hindered the adhesion of trophozoites. It also caused excessive ROS generation, DNA damage, cell cycle arrest and inhibited the gene expression related to pathogenesis. Our findings have revealed the anti-giardial efficacy of ADG, suggesting its potential as an agent against Giardia infections. This could offer a natural and low-risk treatment option for giardiasis, reducing the risk of side effects and drug resistance.


Assuntos
Antiprotozoários , Pontos de Checagem do Ciclo Celular , Dano ao DNA , Diterpenos , Giardia lamblia , Concentração Inibidora 50 , Espécies Reativas de Oxigênio , Trofozoítos , Diterpenos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/crescimento & desenvolvimento , Giardia lamblia/genética , Trofozoítos/efeitos dos fármacos , Trofozoítos/crescimento & desenvolvimento , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Dano ao DNA/efeitos dos fármacos , Antiprotozoários/farmacologia , Humanos , Animais , Expressão Gênica/efeitos dos fármacos , Metronidazol/farmacologia
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