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1.
Molecules ; 27(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36364182

RESUMO

Lung cancer, especially adenocarcinoma, is the second most occurring and highest fatality-causing cancer worldwide. Many natural anticancer compounds, such as sesquiterpene lactones (SLs), show promising anticancer properties. Herein, we examined Lactucin, an SL from the plant Cichorium intybus, for its cytotoxicity, apoptotic-inducing, cell cycle inhibiting capacity, and associated protein expression. We also constructed a biotinylated Lactucin probe to isolate interacting proteins and identified them. We found that Lactucin stops the proliferation of A549 and H2347 lung adenocarcinoma cell lines while not affecting normal lung cell MRC5. It also significantly inhibits the cell cycle at G0/G1 stage and induces apoptosis. The western blot analysis shows that Lactucin downregulates the MAPK pathway, cyclin, and cyclin-dependent kinases, inhibiting DNA repair while upregulating p53, p21, Bax, PTEN, and downregulation of Bcl-2. An increased p53 in response to DNA damage upregulates p21, Bax, and PTEN. In an activity-based protein profiling (ABPP) analysis of A549 cell's protein lysate using a biotinylated Lactucin probe, we found that Lactucin binds PGM, PKM, and LDHA PDH, four critical enzymes in central carbon metabolism in cancer cells, limiting cancer cells in its growth; thus, Lactucin inhibits cancer cell proliferation by downregulating the MAPK and the Central Carbon Metabolism pathway.


Assuntos
Chicória , Neoplasias Pulmonares , Sesquiterpenos , Humanos , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Carbono/metabolismo , Sesquiterpenos/farmacologia , Lactonas/farmacologia , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Apoptose , Ciclinas/metabolismo , Linhagem Celular Tumoral
2.
Chem Senses ; 472022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36374622

RESUMO

Flavor compounds provide aroma and sensations in the oral cavity. They are not present alone in the oral cavity, but rather in combination with several other food ingredients. This study aimed to clarify the relationship between the mixing of pungent flavor compounds and the response of pungent receptors, TRPV1 and TRPA1 channels. We focused on lactones that activate TRPV1 despite their presence in bland foods, such as dairy products and fruits, and analyzed their interaction with receptors using TRPV1- and TRPA1-expressing HEK293 cells. We found that γ-octalactone, γ-nonalactone, and δ-nonalactone activated TRPA1. When mixed with pungent components, some γ- and δ-lactones inhibited capsaicin-mediated TRPV1 responses, and δ-dodecalactone inhibited allyl isothiocyanate-mediated TRPA1 responses. Furthermore, the dose-response relationship of capsaicin and γ-nonalactone to TRPV1 suggests that γ-nonalactone acts as an agonist or antagonist of TRPV1, depending on its concentration. Conversely, γ-nonalactone and δ-dodecalactone were found to act only as agonists and antagonists, respectively, against TRPA1. These results suggest that lactones in foods may not only endow food with aroma, but also play a role in modulating food pungency by acting on TRPV1 and TRPA1. The dose-response relationships of a mixture of flavor compounds with TRPV1 and TRPA1 provide insights into the molecular physiological basis of pungency that may be the cornerstone for developing new spice mix recipes.


Assuntos
Capsaicina , Canal de Cátion TRPA1 , Canais de Cátion TRPV , Paladar , Canais de Potencial de Receptor Transitório , Humanos , Capsaicina/farmacologia , Células HEK293 , Lactonas/farmacologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo
3.
Molecules ; 27(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36364247

RESUMO

The study of allelopathic activity of plants and the isolation and characterization of the responsible allelochemicals can lead to the development of environment friendly alternative approaches to weed control. Conyza species are invasive weeds that use allelopathic activity as part of a successful strategy to outcompete neighboring plants. Broomrape weeds are parasitic plants that use host-induced germination and the formation of a haustorium as strategies to infect host plants. The control of broomrape infection in most affected crops is limited or non-existing. In the current study, we investigated the allelopathic activity of Conyza bonariensis organic extracts in suicidal germination and radicle growth of four broomrape species (Orobanche crenata, Orobanche cumana, Orobanche minor and Phelipanche ramosa). A bioactivity-driven fractionation of Conyza bonariensis extracts led to the identification of two germination-inducing molecules and two growth-inhibitory compounds. The germination-inducing metabolites had species-specific activity being hispidulin active on seeds of O. cumana and methyl 4-hydroxybenzoate active in P. ramosa. The growth-inhibitory metabolites (4Z)-lachnophyllum lactone and (4Z,8Z)-matricaria lactone strongly inhibited the radicle growth of all parasitic weed species studied. Some structure-activity relationships were found as result of the study herein presented.


Assuntos
Conyza , Orobanche , Humanos , Plantas Daninhas , Feromônios/farmacologia , Germinação , Sementes , Lactonas/farmacologia
4.
J Nat Prod ; 85(11): 2557-2569, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36351173

RESUMO

A library of more than 2500 plant extracts was screened for activity on oncogenic signaling in melanoma cells. The ethyl acetate extract from the aerial parts of Artemisia argyi displayed pronounced inhibition of the PI3K/AKT pathway. Active compounds were tracked with the aid of HPLC-based activity profiling, and altogether 21 active compounds were isolated, including one novel dimerosequiterpenoid (1), one new disesquiterpenoid (2), three new guaianolides (3-5), 12 known sesquiterpenoids (6-17), and four known flavonoids (19-22). A new eudesmanolide derivative (13b) was isolated as an artifact formed by methanolysis. Compound 1 is the first adduct comprising a sesquiterpene lactone and a methyl jasmonate moiety. The absolute configurations of compounds 1 and 3-18 were established by comparison of their experimental and calculated ECD spectra. The absolute configuration for 2 was determined by X-ray diffraction analysis. Guaianolide 8 was the most potent sesquiterpene lactone, inhibiting the PI3K/AKT pathway with an IC50 value of 8.9 ± 0.9 µM.


Assuntos
Artemisia , Melanoma , Sesquiterpenos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Compostos Fitoquímicos , Melanoma/tratamento farmacológico , Estrutura Molecular
5.
Molecules ; 27(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36234934

RESUMO

Seven new sesquiterpenes, named croargoid A-G (1-7), were isolated from the bark of Croton argyratus. Compounds 1-4 were the first examples of eudesmane sesquiterpene lactones containing C5-OH group. Compound 7 was a highly degraded eudesmane sesquiterpene possessing a rare eleven-carbon skeleton. Their structures with stereochemistry were mainly elucidated by NMR analyses in combination with MS and ECD data. Cytotoxicities and NO inhibitions of all isolates were evaluated and only compound 5 showed moderate NO inhibitory activity.


Assuntos
Croton , Sesquiterpenos de Eudesmano , Sesquiterpenos , Carbono , Lactonas/farmacologia , Estrutura Molecular , Casca de Planta , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/farmacologia
6.
Molecules ; 27(19)2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36235222

RESUMO

Human glioblastoma multiforme (GBM) is one of the most malignant brain tumors, with a high mortality rate worldwide. Conventional GBM treatment is now challenged by the presence of the blood-brain barrier (BBB), drug resistance, and post-treatment adverse effects. Hence, developing bioactive compounds isolated from plant species and identifying molecular pathways in facilitating effective treatment has become crucial in GBM. Based on pharmacodynamic studies, andrographolide has sparked the interest of cancer researchers, who believe it may alleviate difficulties in GBM therapy; however, it still requires further study. Andrographolide is a bicyclic diterpene lactone derived from Andrographis paniculata (Burm.f.) Wallich ex Nees that has anticancer properties in various cancer cell lines. The present study aimed to evaluate andrographolide's anticancer effectiveness and potential molecular pathways using a DBTRG-05MG cell line. The antiproliferative activity of andrographolide was determined using the WST-1 assay, while scratch assay and clonogenic assay were used to evaluate andrographolide's effectiveness against the cancer cell line by examining cell migration and colony formation. Flowcytometry was also used to examine the apoptosis and cell cycle arrest induced by andrographolide. The mRNA and protein expression level involved in the ERK1/2/c-Myc/p53 signaling pathway was then assessed using qRT-PCR and Western blot. The protein-protein interaction between c-Myc and p53 was determined by a reciprocal experiment of the co-immunoprecipitation (co-IP) using DBTRG-05MG total cell lysate. Andrographolide significantly reduced the viability of DBTRG-05MG cell lines in a concentration- and time-dependent manner. In addition, scratch and clonogenic assays confirmed the effectiveness of andrographolide in reducing cell migration and colony formation of DBTRG-05MG, respectively. Andrographolide also promoted cell cycle arrest in the G2/M phase, followed by apoptosis in the DBTRG-05MG cell line, by inducing ERK1/2, c-Myc, and p53 expression at the mRNA level. Western blot results demonstrated that c-Myc overexpression also increased the production of the anti-apoptotic protein p53. Our findings revealed that c-Myc and p53 positively interact in triggering the apoptotic signaling pathway. This study successfully discovered the involvement of ERK1/2/c-Myc/p53 in the suppression of the DBTRG-05MG cell line via cell cycle arrest followed by the apoptosis signaling pathway following andrographolide treatment.


Assuntos
Diterpenos , Glioblastoma , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Pontos de Checagem da Fase G2 do Ciclo Celular , Glioblastoma/metabolismo , Humanos , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Drug Des Devel Ther ; 16: 3493-3555, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248243

RESUMO

The secondary metabolites isolated from soil fungi have received more and more attention, especially new compounds that exhibited good biological activities. In this review, a total of 546 new compounds are included in the relevant literature since 2011. The new compounds are isolated from soil fungi, We divided these compounds into seven categories, including alkaloids, terpenoids, steroids, ketones, phenylpropanoids, quinones, esters, lactones, etc. In addition, the biological activities and structure-activity relationships of these compounds have also been fully discussed. The activities of these compounds are roughly divided into eight categories, including anticancer activity, antimicrobial activity, anti-inflammatory activity, antioxidant activity, antiviral activity, antimalarial activity, immunosuppressive activity and other activities. Since natural products are an important source of new drugs, this review may have a positive guiding effect on drug screening.


Assuntos
Alcaloides , Antimaláricos , Produtos Biológicos , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Fungos , Cetonas , Lactonas/farmacologia , Quinonas/farmacologia , Solo , Terpenos/farmacologia
8.
Bioorg Chem ; 129: 106183, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36209565

RESUMO

Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the IC50 values were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.


Assuntos
Antineoplásicos , Asteraceae , Neoplasias , Sesquiterpenos , Humanos , Lactonas/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Compostos Fitoquímicos , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Glutationa S-Transferase pi
9.
Org Lett ; 24(40): 7328-7333, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36200745

RESUMO

Molecular network analysis of Streptomyces sp. CMB-MW079 detected rare phosphorylated natural products. Miniaturized cultivation profiling (MATRIX) established optimal conditions for the production, isolation, and identification of the polyketide δ-lactone phoslactomycin E (1) and new ester homologues, phoslactomycins J and K (2 and 3), as well as unprecedented heterocyclic analogues, the tetrahydrofuran cyclolactomycins A-D (4-7) and γ-lactone isocyclolactomycins A-C (8-10). We propose a biogenetic relationship linking these cometabolites with the known lactomycins A-C which were tentatively identified as minor cometabolites.


Assuntos
Produtos Biológicos , Lactonas , Compostos Organofosforados , Policetídeos , Streptomyces , Vespas , Animais , Austrália , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Ésteres/química , Furanos/química , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/isolamento & purificação , Compostos Organofosforados/farmacologia , Policetídeos/química , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Streptomyces/química , Streptomyces/metabolismo , Vespas/microbiologia
10.
Steroids ; 188: 109118, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36183814

RESUMO

New steroidal D-homo androstane derivative, 5α,6ß-dibromo-3ß-hydroxy-17-oxa-17a-homoandrostan-16-one was synthesized and its structure was confirmed by NMR spectroscopy. In silico ADME properties of this compound were assessed using the SwissADME online prediction tool. Six human cancer cell lines (MDA-MB-231, MCF-7, PC3, HT-29, HeLa, and A549) and one human noncancerous cell line (MRC-5) were used for in vitro cytotoxicity testing. Novel steroidal dibromide was also tested for relative binding affinity for the ligand binding domain of estrogen receptor α and ß or the androgen receptor using a published assay in yeast cells. Ligand binding domains of each steroid receptor were expressed in-frame with yellow fluorescent protein in yeast and the fluorescence intensity changes upon addition of test compound was measured. The new compound showed selective cytotoxic activity against HT-29 (colon adenocarcinoma) and A549 (lung adenocarcinoma) cell lines, as well as the potential to induce apoptosis in HT-29 cells, while results obtained from ligand binding assay in yeast suggested a lack of significant estrogenic or androgenic properties.


Assuntos
Adenocarcinoma , Antineoplásicos , Neoplasias do Colo , Humanos , Lactonas/farmacologia , Linhagem Celular Tumoral , Saccharomyces cerevisiae , Ligantes , Esteroides/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células
11.
J Toxicol Environ Health A ; 85(23): 972-987, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36208226

RESUMO

Cancer and infectious diseases are among the leading causes of death in the world. Despite the diverse array of treatments available, challenges posed by resistance, side effects, high costs, and inaccessibility persist. In the Solanaceae plant family, few studies with Vassobia breviflora species relating to biological activity are known, but promising results have emerged. The phytochemicals present in the ethyl acetate fraction were obtained using ESI-MS-QTOF, and the antioxidants assays 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical capture (ABTS), plasma ferric reduction capacity (FRAP), and total antioxidant capacity (TAC). Cytotoxic activity was evaluated by MTT, Neutral Red, and lactate dehydrogenase (LDH) released. The production of reactive oxygen species, nitric oxide, and purinergic enzymes was also investigated. Antibacterial activity was measured through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antibiofilm activity, in addition to genotoxicity in plasmid DNA. Five major masses were identified D-glucopyranose II, allyl disulfide, γ-lactones, pharbilignoside, and one mass was not identified. V. breviflora exhibited relevant antioxidant and cytotoxic activity against the HeLa cell line and enhanced expression effect in modulation of purinergic signaling. Antibacterial activities in the assays in 7 ATCC strains and 8 multidrug-resistant clinical isolates were found. V. breviflora blocked biofilm formation in producing bacteria at the highest concentrations tested. However, there was no plasmid DNA cleavage at the concentrations tested. Data demonstrated that V. breviflora exhibited an antioxidant effect through several methods and proved to be a promising therapeutic alternative for use against tumor cells via purinergic signaling and multidrug-resistant microorganisms, presenting an anti-biofilm effect.


Assuntos
Antioxidantes , Solanaceae , Acetatos , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias , DNA/farmacologia , Células HeLa , Humanos , Lactato Desidrogenases , Lactonas/farmacologia , Testes de Sensibilidade Microbiana , Vermelho Neutro/farmacologia , Óxido Nítrico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio , Ácidos Sulfônicos
12.
Plant Physiol Biochem ; 190: 1-10, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36084353

RESUMO

Strigolactones (SLs) play prominent roles in regulating shoot branching and root architecture in model plants. However, their roles in non-model (particularly woody) plants remain unclear. Liriodendron chinense is a timber tree species widely planted in southern China. The outturn percentage and wood quality of L. chinense are greatly affected by the branching characteristics of its shoot, and the rooting ability of the cuttings is key for its vegetative propagation. Here, we isolated and analyzed the function of the MORE AXILLARY GROWTH 1 (LcMAX1) gene, which is involved in L. chinense SL biosynthesis. RT-qPCR showed that LcMAX1 was highly expressed in the roots and axillary buds. LcMAX1 was located in the endoplasmic reticulum (ER) and nucleus. LcMAX1 ectopic expression promoted primary root growth, whereas there were no phenotypic differences in shoot branching between transgenic and wild-type (WT) A. thaliana plants. LcMAX1 overexpression in the max1 mutant restored them to the WT A. thaliana phenotypes. Additionally, AtPIN1, AtPIN2, and AtBRC1 expressions were significantly upregulated in transgenic A. thaliana and the max1 mutant. It was therefore speculated that LcMAX1 promotes primary root growth by regulating expression of auxin transport-related genes in A. thaliana, and LcMAX1 inhibits shoot branching by upregulating expression of AtBRC1 in the max1 mutant. Altogether, these results demonstrated that the root development and shoot branching functions of LcMAX1 were similar to those of AtMAX1. Our findings provide a foundation for obtaining further insights into root and branch development in L. chinense.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Liriodendron , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/metabolismo , Lactonas/farmacologia , Liriodendron/metabolismo , Brotos de Planta/metabolismo
13.
Nutrients ; 14(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36079888

RESUMO

The aim of the study was to explain the effects of sesquiterpene lactones (SLs) from chicory (Cichorium intybus L.) root extracts as inhibitors of acetylcholinesterase (AChE) at the molecular level and to determine the inhibition of AChE activity by specific SLs (lactucin and lactucopicrin) and different chicory extracts. The obtained SLs-rich extracts were purified by the countercurrent partition chromatography (CPC) technique. AChE inhibitors were analyzed using two models: isothermal titration calorimetry (ITC) and docking simulation. The results of ITC analysis of the enzyme and the ligands' complexation showed strong interactions of SLs as well as extracts from chicory with AChE. In a test of enzyme activity inhibition after introducing acetylcholine into the model system with SL, a stronger ability to inhibit the hydrolysis of the neurotransmitter was observed for lactucopicrin, which is one of the dominant SLs in chicory. The inhibition of enzyme activity was more efficient in the case of extracts, containing different enzyme ligands, exhibiting complementary patterns of binding the AChE active site. The study showed the high potential of using chicory to decrease the symptoms of Alzheimer's disease.


Assuntos
Chicória , Sesquiterpenos , Acetilcolinesterase/metabolismo , Calorimetria , Chicória/química , Inibidores da Colinesterase/farmacologia , Lactonas/química , Lactonas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Compostos Fitoquímicos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia
14.
J Tradit Chin Med ; 42(5): 749-757, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36083482

RESUMO

OBJECTIVE: To systematically evaluate the anti-inflammatory potential of diterpene lactones from Chuanxinlian () (AP). METHODS: We firstly adopted zebrafish, a novel and ideal animal model for high-throughput drug screening, to investigate the anti-inflammatory activities of 17 diterpene lactones isolated from AP. RESULTS: The results showed that most of diterpene lactones displayed significant anti-inflammatory effects in lipopolysaccharide microinjection-, copper sulfate exposure- or tail transection-induced zebrafish inflammation models. Moreover, diterpene lactone 3-deoxy-andrographoside (AP-5) was firstly found to attenuate inflammatory responses, which was closely associated with the myeloid differentiation primary response 88/nuclear factor-kappa B and signal transducer and activator of transcription 3 pathways. CONCLUSION: Our research sheds light on the inestimable roles of zebrafish in high-throughput drug screening, elucidates the potent inhibitory effects of diterpene lactones against inflammation and indicates that AP-5 may serve as a potential alternative agent for the treatment of inflammatory diseases.


Assuntos
Diterpenos , Peixe-Zebra , Andrographis paniculata , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Inflamação/tratamento farmacológico , Lactonas/farmacologia , Lactonas/uso terapêutico , Lipopolissacarídeos/farmacologia , NF-kappa B/genética , NF-kappa B/metabolismo , Extratos Vegetais
15.
Int Immunopharmacol ; 112: 109201, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36067652

RESUMO

Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-ß1 (TGF-ß1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3ß/ß-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs.


Assuntos
Nefropatias Diabéticas , Diterpenos , Obstrução Ureteral , Animais , Humanos , Camundongos , Andrographis paniculata , beta Catenina/metabolismo , Nefropatias Diabéticas/metabolismo , Diterpenos/uso terapêutico , Diterpenos/farmacologia , Transição Epitelial-Mesenquimal , Fibrose , Glicogênio Sintase Quinase 3 beta/metabolismo , Lactonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Dióxido de Silício , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/complicações
16.
Phytomedicine ; 106: 154397, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36084403

RESUMO

BACKGROUND: Centipeda minima (L.) A. Braun & Asch (C. minima) has been used as a traditional Chinese herbal medicine to treat multiple diseases, including sinusitis, rhinitis, headache, and allergy. To date, the anticancer properties of C. minima have drawn considerable attention owing to the anticancer potential of C. minima extracts, the identification of active components, and the elucidation of underlying molecular mechanisms. However, the anticancer properties and significance of active components in C. minima have rarely been summarized. PURPOSE: This review presents a comprehensive summary of the anticancer properties exhibited by active components of C. minima. METHODS: An extensive search for published articles on the anticancer activities and active components of C. minima was performed using Web of Science, PubMed, Science Direct, and Google Scholar. RESULTS: C. minima extracts exhibited both anticancer and chemosensitizing effects. Phytochemical studies have identified the active anticancer components of C. minima extracts. Sesquiterpene lactones, such as 6-O-angeloylplenolin (6-OAP, or brevilin A) and arnicolide D, have similar structures and anticancer mechanisms. As the most abundant sesquiterpene lactone in C. minima, 6-OAP exhibits anticancer activities mainly by targeting Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase and signal transducers and activators of transcription 3 (STAT3). Clinical trials have assessed the potential of 6-OAP in patients with vertex balding and alopecia areata, given its effect on JAK-STATs signaling. Chlorogenic acid, a representative organic acid in C. minima, reportedly possesses anticancer potential and inhibits tumor growth by affecting tumor microenvironment and has been approved for phase II clinical trials in patients with glioma in China. CONCLUSION: In the present review, we highlight intriguing anticancer properties mediated by active compounds isolated from C. minima extracts, particularly sesquiterpene lactones, which might provide clues for developing novel anticancer drugs. Relevant clinical trials on chlorogenic acid and 6-OAP can promote anticancer clinical applications. Therefore, it is worth comprehensively elucidating underlying anticancer mechanisms and conducting clinical trials on C. minima and its active components.


Assuntos
Asteraceae , Medicamentos de Ervas Chinesas , Proteínas F-Box , Plantas Medicinais , Sesquiterpenos , Asteraceae/química , Ácido Clorogênico , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Ubiquitina-Proteína Ligases
17.
Biochem J ; 479(19): 2013-2034, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36094147

RESUMO

The opportunistic bacterium Pseudomonas aeruginosa secretes the quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (C12) to co-ordinate gene expression profiles favorable for infection. Recent studies have demonstrated that high concentrations of C12 impair many aspects of host cell physiology, including mitochondrial function and cell viability. The cytotoxic effects of C12 are mediated by the lactonase enzyme, Paraoxonase 2 (PON2), which hydrolyzes C12 to a reactive metabolite. However, the influence of C12 on host cell physiology at concentrations observed in patients infected with P. aeruginosa is largely unknown. Since the primary site of P. aeruginosa infections is the mammalian airway, we sought to investigate how PON2 modulates the effects of C12 at subtoxic concentrations using immortalized murine tracheal epithelial cells (TECs) isolated from wild-type (WT) or PON2-knockout (PON2-KO) mice. Our data reveal that C12 at subtoxic concentrations disrupts mitochondrial bioenergetics to hinder cellular proliferation in TECs expressing PON2. Subtoxic concentrations of C12 disrupt normal mitochondrial network morphology in a PON2-dependent manner without affecting mitochondrial membrane potential. In contrast, higher concentrations of C12 depolarize mitochondrial membrane potential and subsequently trigger caspase signaling and apoptotic cell death. These findings demonstrate that different concentrations of C12 impact distinct aspects of host airway epithelial cell physiology through PON2 activity in mitochondria.


Assuntos
Homosserina , Percepção de Quorum , 4-Butirolactona/análogos & derivados , Animais , Arildialquilfosfatase/genética , Arildialquilfosfatase/metabolismo , Arildialquilfosfatase/farmacologia , Caspases/metabolismo , Células Epiteliais/metabolismo , Homosserina/metabolismo , Homosserina/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia , Mamíferos/metabolismo , Camundongos , Mitocôndrias/metabolismo , Pseudomonas aeruginosa/metabolismo
18.
Phytomedicine ; 106: 154417, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36063584

RESUMO

BACKGROUND: Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed. PURPOSE: This study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug. METHODS: The research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines. RESULTS: Securinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation. CONCLUSION: Although there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.


Assuntos
Alcaloides , Leucemia , Azepinas , Linhagem Celular Tumoral , Compostos Heterocíclicos de Anel em Ponte , Humanos , Janus Quinases , Lactonas/farmacologia , Leucemia/tratamento farmacológico , Lisina , Masculino , Fosfatidilinositóis , Piperidinas , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Tirosina
19.
ACS Chem Biol ; 17(11): 3110-3120, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36173746

RESUMO

ß-Lactam antibiotics comprise one of the most widely used therapeutic classes to combat bacterial infections. This general scaffold has long been known to inhibit bacterial cell wall biosynthesis by inactivating penicillin-binding proteins (PBPs); however, bacterial resistance to ß-lactams is now widespread, and new strategies are urgently needed to target PBPs and other proteins involved in bacterial cell wall formation. A key requirement in the identification of strategies to overcome resistance is a deeper understanding of the roles of the PBPs and their associated proteins during cell growth and division, such as can be obtained with the use of selective chemical probes. Probe development has typically depended upon known PBP inhibitors, which have historically been thought to require a negatively charged moiety that mimics the C-terminus of the PBP natural peptidoglycan substrate, d-Ala-d-Ala. However, we have identified a new class of ß-lactone-containing molecules that interact with PBPs, often in an isoform-specific manner, and do not incorporate this C-terminal mimetic. Here, we report a series of structural biology experiments and molecular dynamics simulations that we utilized to evaluate specific binding modes of this novel PBP inhibitor class. In this work, we obtained <2 Å resolution X-ray structures of four ß-lactone probes bound to PBP1b from Streptococcus pneumoniae. Despite their diverging recognition modes beyond the site of covalent modification, these four probes all efficiently labeled PBP1b, as well as other PBPs from S. pneumoniae. From these structures, we analyzed protein-ligand interactions and characterized the ß-lactone-bound active sites using in silico mutagenesis and molecular dynamics. Our approach has clarified the dynamic interaction profile in this series of ligands, expanding the understanding of PBP inhibitor binding.


Assuntos
Lactonas , Simulação de Dinâmica Molecular , Proteínas de Ligação às Penicilinas/metabolismo , Lactonas/farmacologia , beta-Lactamas/metabolismo , Streptococcus pneumoniae/química , Ligantes , Proteínas de Bactérias/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química
20.
Biomed Pharmacother ; 155: 113699, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36116253

RESUMO

Drugs that exhibit a high degree of tumor cell selectivity while minimizing normal cell toxicity are an area of active research interest as a means of designing novel antitumor agents. The pharmacological benefits of Chinese herbal medicine-based treatments have been the focus of growing research interest in recent years. Sesquiterpenoids derived from the Atractylodes macrocephala volatile oil preparations exhibit in vitro and in vivo antitumor activity. Atracylenolides exhibit anti-proliferative, anti-metastatic, and immunomodulatory activity in a range of tumor cell lines in addition to being capable of regulating metabolic activity such that it is a promising candidate drug for the treatment of diverse cancers. The present review provides a summary of recent advances in Atractylenolide-focused antitumor research efforts.


Assuntos
Medicamentos de Ervas Chinesas , Óleos Voláteis , Sesquiterpenos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Transdução de Sinais
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