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1.
Phytochemistry ; 225: 114171, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38844058

RESUMO

Seven undescribed abietane diterpenoids [abietamethinols A-G (1-7)] were isolated from the twigs and leaves of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic methods including 2D NMR, and they were further confirmed by X-ray crystallographic data. Lophanic acid was considered as the precursor of 1-7 in the biosynthesis pathway hypothesis. These compounds were evaluated for their cytotoxic, anti-bacterial and anti-AIV (avian influenza virus) activities. Compound 5 showed 42.9% inhibitory activity against the cancer cell line SMMC-7721 at the concentration of 40 µM, 3 and 4 could inhibit the bacterial growth of Streptococcus sobrinus by 55.3% and 63.2% at the concentrations of 148.6 and 141.9 µM, respectively, and 4 was demonstrated with antiviral activity against AIV with the inhibitory effect of 68.4% at 25 µM.


Assuntos
Abietanos , Antibacterianos , Antineoplásicos Fitogênicos , Antivirais , Isodon , Testes de Sensibilidade Microbiana , Abietanos/farmacologia , Abietanos/química , Abietanos/isolamento & purificação , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Isodon/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Folhas de Planta/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Conformação Molecular , Vírus da Influenza A/efeitos dos fármacos
2.
Molecules ; 29(12)2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38930799

RESUMO

Four new diterpenoids, isodosins A-D (1-4), together with nine known compounds (5-13) were isolated and identified from the aerial parts of Isodon serra (Maxim.) Hara. The structures of the new diterpenoids were elucidated based on the analysis of HR-ESI-MS data, 1D/2D-NMR-spectroscopic data, and electronic circular dichroism (ECD) calculations. Cytotoxicities of compounds 2, 3, 5, 6, and 9 against the HepG2 and H1975 cell lines were evaluated with the MTT assay. As a result, compounds 2, 3, and 6 revealed higher levels of cytotoxicity against HepG2 cells than against H1975 cells. Moreover, compund 6 demonstrated the most efficacy in inhibiting the proliferation of HepG2 cells, with an IC50 value of 41.13 ± 3.49 µM. This effect was achieved by inducing apoptosis in a dose-dependent manner. Furthermore, the relationships between the structures and activities of these compounds are briefly discussed.


Assuntos
Antineoplásicos Fitogênicos , Apoptose , Diterpenos , Isodon , Componentes Aéreos da Planta , Humanos , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Isodon/química , Componentes Aéreos da Planta/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Células Hep G2 , Estrutura Molecular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais
3.
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
4.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2478-2488, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812147

RESUMO

In order to analyze the similarities and differences of chemical compositions between the roots and stems and leaves of Isodon japonicus(IJ), this study utilized UPLC-Q-TOF-MS technology to systematically characterize its chemical compositions, analyzed and identified the structure of its main compounds, and established a method for simultaneous determination of its content by refe-rence substance. A total of 34 major compounds in IJ, including 14 reference compounds, were identified or predicted online. Moreover, an UPLC-UV content determination method was developed for 11 compounds [danshensu, caffeic acid, vicenin-2,(1S,2S)-globoidnan B, rutin,(+)-rabdosiin,(-)-rabdosiin,(1S,2S)-rabdosiin, shimobashiric acid C, rosmarinic acid, and pedalitin]. The method exhibited excellent separation, stability, and repeatability, with a wide linear range(0.10-520.00 µg·mL~(-1)) and high linearity(R~2>0.999). The average recovery rates ranged from 94.72% to 104.2%. The principal component analysis(PCA) demonstrated a clear difference between the roots and stems and leaves of IJ, indicating good separation by cluster. Furthermore, the orthogonal partial least squares discriminant analysis(OPLS-DA) model was employed, and six main differentially identified compounds were identified: rosmarinic acid, shimobashiric acid C, epinodosin, pedalitin, rutin, and(1S,2S)-rabdosiin. In summary, this study established a strategy and method for distinguishing different parts of IJ, providing a valuable tool for quality control of IJ and a basis for the ratio-nal utilization and sustainable development of IJ.


Assuntos
Quimiometria , Medicamentos de Ervas Chinesas , Isodon , Espectrometria de Massas , Folhas de Planta , Cromatografia Líquida de Alta Pressão/métodos , Isodon/química , Espectrometria de Massas/métodos , Quimiometria/métodos , Folhas de Planta/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Raízes de Plantas/química , Caules de Planta/química
5.
Fitoterapia ; 174: 105840, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38296167

RESUMO

The phytochemical investigation of the aerial parts of Isodon japonica var. glaucocalyx afforded four undescribed (glaucocalyxin O-R, 1-4) and six known ent-kauranoids (5-10). Their structures were established using NMR and MS measurements. Compounds 1 and 2 are dimeric ent-kaurane-type diterpenoids. Moreover, the plausible biogenetic pathways for compounds 1 and 2 were proposed as Michael addition between two monomers. Eight compounds were assayed for their anti-inflammatory activity by evaluating NO production in LPS-induced RAW 267.4 cells, and compounds 7, 8 and 9 exhibited relatively remarkable anti-inflammatory activities at 10 µM.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Isodon/química , Estrutura Molecular , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos/química , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais
6.
Int J Biol Macromol ; 258(Pt 2): 129123, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38163496

RESUMO

Isodon rubescens has garnered much attention due to its anti-tumor or anti-cancer properties. However, little is known about the molecular mechanism of oridonin biosynthesis leveraging the regulatory network between small RNAs and mRNAs. In this study, the regulatory networks of miRNAs and targets were examined by combining mRNA, miRNA, and degradome. A total of 348 miRNAs, including 287 known miRNAs and 61 novel miRNAs, were identified. Among them, 51 miRNAs were significantly expressed, and 36 miRNAs responded to MeJA. A total of 3066 target genes were associated with 228 miRNAs via degradome sequencing. Multi-omics analysis demonstrated that 27 miRNA-mRNA pairs were speculated to be involved in MeJA regulation, and 36 miRNA-mRNA pairs were hypothesized to be involved in the genotype-dependence of I. rubescens. Furthermore, 151 and 7 miRNA-mRNA modules were likely engaged in oridonin biosynthesis as identified by psRNATarget and degradome sequencing, respectively. Some miRNA-mRNA modules were confirmed via RT-qPCR. Moreover, miRNAs targeting plant hormone signal transduction pathway genes were identified, such as miR156, miR167, miR393, and PC-3p-19822_242. Collectively, our results demonstrate for the first time that miRNAs are identified in I. rubescens, and laid a solid foundation for further research on the molecular mechanism of oridonin biosynthesis mediated by miRNA.


Assuntos
Diterpenos do Tipo Caurano , Isodon , MicroRNAs , MicroRNAs/genética , Isodon/genética , Isodon/metabolismo , Multiômica , Transcriptoma , RNA Mensageiro/genética , Regulação da Expressão Gênica de Plantas
7.
Fitoterapia ; 173: 105788, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38141880

RESUMO

As our ongoing searching for the bioactive natural terpenoids, nine ent-kauranoids (1-9), including three previously undescribed ones (1, 2, and 9), were isolated from the aerial parts of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic data analysis, including NMR, MS, and ECD. Compounds 1 and 2 were a pair of tautomeric compounds, which was confirmed by the HPLC analysis and low temperature NMR testing. The underlying mechanism of the tautomer was proposed as an intramolecular SN2 reaction, which was explained by quantum chemical calculation. The HOMO-LUMO gap and the free energy revealed the spontaneous of the tautomeric of the 1 and 2. Additionally, the similar phenomena were also found in the two groups of known compounds 3 and 4 and 6 and 7, respectively. Apart from the tautomer, compounds 3 and 4 can be hydrolyzed into 5 through ester hydrolysis in CDCl3, while compounds 6, 7 can be hydrolyzed into 8 through ester hydrolysis. These phenomena were also confirmed through HPLC analysis and low temperature nuclear magnetic resonance tests and the mechanism was studied using quantum chemical calculation.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Isodon , Estrutura Molecular , Isodon/química , Componentes Aéreos da Planta/química , Ésteres , Ensaios de Seleção de Medicamentos Antitumorais
8.
Int J Mol Sci ; 24(17)2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37686256

RESUMO

Two undescribed ent-kaurene diterpenes, named guidongnins I (1) and J (2), were isolated from the medicinal plant Isodon rubescens. Compound 1 was determined to contain an unprecedented 23 carbons in the skeleton by bearing an extra isopropyl group at C-17 out of the diterpenoid parent structure, and compound 2 was the first example of 6,7-seco-7,20-olide-ent-kaurenes with two fused-tetrahydrofuran rings formed between C-6 and C-19/C-20 through oxygen bridges. Their structures, including their absolute configurations, were determined using the analyses of the spectroscopic and X-ray diffraction data. Guidongnins I (1) and J (2) were assessed for their anti-cancer activities against the growth of various cancer cell lines, and 2 displayed cytotoxic potency against HepG2 at IC50 27.14 ± 3.43 µM.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Isodon , Diterpenos do Tipo Caurano/farmacologia , Diterpenos/farmacologia , Carbono , Linhagem Celular
9.
Drug Des Devel Ther ; 17: 2335-2351, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37576085

RESUMO

Aim: Many studies have demonstrated the hepatoprotective or anti-fibrotic effects of Isodon ternifolius, but its pharmacological basis and mechanism remain unclear. In this study, we used in vitro models to validate the predicted results and revealed the potential mechanism of action and active ingredients through network pharmacology methods and molecular docking. Methods: The chemical components of Isodon ternifolius were identified by literatures. Potential targets of Isodon ternifolius were predicted by Swiss Target Prediction. The disease targets were collected through the databases of Gene Card. Common targets of Isodon ternifolius and liver fibrosis were obtained by online tool Venny 2.1. PPI protein interaction network was obtained using String database, and target protein interaction network was drawn using Cytoscape software. Signaling pathway enrichment analysis was performed on drug-disease targets with of DAVID database. Results: Twenty-one potential active ingredients and 298 potential targets were predicted by Swiss Target Prediction platform. Ninety pathways related to liver fibrosis were obtained by KEGG enrichment. The TLR4, MAPK and PI3K-Akt signaling pathways are mostly associated with liver fibrosis. Molecular docking techniques were used to validate the core target proteins TNF, Akt1, MAPK1, EGFR and TLR4 binding to the ingredients of Isodon ternifolius, which showed that a multitude of ingredients of Isodon ternifolius were able to bind to the above target proteins, especially 2α-hydroxy oleanolic acid and (-)-Lambertic acid. Our experimental validation results showed that Isodon ternifolius inhibited the activation of PI3K-Akt and ERK1/2 signaling pathways. Conclusion: Through a network pharmacology approach and in vitro cell assay, we predicted and validated the active compounds of Isodon ternifolius and its potential targets for LF treatment. The results suggest that the mechanism of Isodon ternifolius treating LF by inhibiting angiogenesis may be related to the ERK1/2 and PI3K/Akt signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas , Isodon , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Receptor 4 Toll-Like , Cirrose Hepática/tratamento farmacológico
10.
Zhongguo Zhong Yao Za Zhi ; 48(14): 3913-3921, 2023 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-37475083

RESUMO

The present study aimed to investigate the inhibitory effect and mechanism of Isodon terricolous-medicated serum on lipopolysaccharide(LPS)-induced hepatic stellate cell(HSC) activation. LPS-induced HSCs were divided into a blank control group, an LPS model group, a colchicine-medicated serum group, an LPS + blank serum group, an I. terricolous-medicated serum group, a Toll-like receptor 4(TLR4) blocker group, and a TLR4 blocker + I. terricolous-medicated serum group. HSC proliferation was detected by methyl thiazolyl tetrazolium(MTT) assay. Enzyme-linked immunosorbent assay(ELISA) was used to measure type Ⅰ collagen(COL Ⅰ), COL Ⅲ, transforming growth factor-ß1(TGF-ß1), intercellular adhesion molecule-1(ICAM-1), α-smooth muscle actin(α-SMA), vascular cell adhesion molecule-1(VCAM-1), cysteinyl aspartate-specific proteinase-1(caspase-1), and monocyte chemotactic protein-1(MCP-1). Real-time PCR(RT-PCR) was used to detect mRNA expression of TLR4, IκBα, and NOD-like receptor thermal protein domain associated protein 3(NLRP3), nuclear factor-κB(NF-κB) p65, gasdermin D(GSDMD), and apoptosis-associated speck-like protein containing a CARD(ASC) in HSCs. Western blot(WB) was used to detect the protein levels of TLR4, p-IκBα, NF-κB p65, NLRP3, ASC, and GSDMD in HSCs. The results showed that I. terricolous-medicated serum could inhibit the proliferation activity of HSCs and inhibit the secretion of COL Ⅰ, COL Ⅲ, α-SMA, TGF-ß1, caspase-1, MCP-1, VCAM-1, and ICAM-1 in HSCs. Compared with the LPS model group, the I. terricolous-medicated serum group, the colchicine-medicated serum group, and the TLR4 blocker group showed down-regulated expression of p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and up-regulated expression of IκBα. Compared with the TLR4 blocker group, the TLR4 blocker + I. terricolous-medicated serum group showed decreased expression of TLR4, p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and increased expression of IκBα. In conclusion, I. terricolous-medicated serum down-regulates HSC activation by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway.


Assuntos
Isodon , NF-kappa B , NF-kappa B/genética , NF-kappa B/metabolismo , Células Estreladas do Fígado , Fator de Crescimento Transformador beta1/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Colchicina/metabolismo , Colchicina/farmacologia , Caspases
11.
Chem Pharm Bull (Tokyo) ; 71(7): 502-507, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37394598

RESUMO

Two new diterpenes named trichoterpene I (1) and trichoterpene II (2) were isolated from the extract from the leaves of Isodon trichocarpus together with 19 known diterpenes. Their chemical structures were elucidated on the basis of chemical and physicochemical properties. Among them, oridonin (3), effusanin A (4), and lasiokaurin (9) with the α,ß-unsaturated carbonyl moiety showed antiproliferative activities against breast cancer MDA-MB-231 and human astrocytoma U-251 MG cells [i.e., non-cancer stem cells (non-CSCs)] and their cancer stem cells (CSCs) isolated by sphere formation. In particular, compound 4 (IC50 = 0.51 µM) showed a higher antiproliferative activity against MDA-MB-231 CSCs than against MDA-MB-231 non-CSCs. The antiproliferative activity toward CSCs of compound 4 was equal to adriamycin (positive control, IC50 = 0.60 µM).


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Neoplasias , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Diterpenos/farmacologia , Diterpenos/química , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Doxorrubicina , Isodon/química , Folhas de Planta/química , Células-Tronco
12.
J Nat Prod ; 86(5): 1230-1239, 2023 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-37146221

RESUMO

Amethystoidesic acid (1), a triterpenoid with an unprecedented 5/6/6/6 tetracyclic skeleton, and six undescribed diterpenoids, amethystoidins A-F (2-7), were isolated from the rhizomes of Isodon amethystoides along with 31 known di- and triterpenoids (8-38). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of a triterpenoid possessing a rare ring system (5/6/6/6) derived from a contracted A-ring and the 18,19-seco-E-ring of ursolic acid. Compounds 6, 16, 21, 22, 24, and 27 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which could be partly mediated by the downregulation of LPS-induced inducible nitric oxide synthase (iNOS) protein expression.


Assuntos
Isodon , Triterpenos , Isodon/química , Rizoma/metabolismo , Triterpenos/farmacologia , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Óxido Nítrico , Estrutura Molecular
13.
Bioorg Chem ; 135: 106512, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37027948

RESUMO

Twenty new ent-kaurane diterpenoids, wardiisins A-T (1-20), along with two previously undescribed artefactual compounds (21 and 22) and twelve known analogues (23-34), were isolated from the aerial part of Isodon wardii. Their structures were elucidated by comprehensive analysis of spectroscopic data and single-crystal X-ray diffraction, and most of them were found to bear unusual C-12 oxygenation. Compounds 4, 7, 8, 19, 20, 21 exhibited remarkable cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MDA-MB-231, and SW480, with IC50 values ranging from 0.3 to 5.2 µM. Moreover, 7 was found to induce G2/M cell cycle arrest and promote apoptosis in SW480 cell lines.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Humanos , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Isodon/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Componentes Aéreos da Planta/química , Antineoplásicos/farmacologia , Antineoplásicos/análise , Estrutura Molecular
14.
Org Lett ; 25(17): 2981-2985, 2023 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-37083455

RESUMO

(+)-Isoscopariusins B (1) and C (2), two meroditerpenoids containing a 6/6/4 tricyclic carbon skeleton and seven continuous stereocenters, were identified from Isodon scoparius. The structures were determined by nuclear magnetic resonance analysis and concise biomimetic syntheses from readily available alkene 5 in seven and six steps, respectively. An intermolecular [2+2] photocycloaddition with cooperative catalysis of a Lewis acid and an Ir photocatalyst was used to construct a cyclobutane core with four stereogenic centers.


Assuntos
Ciclobutanos , Isodon , Estrutura Molecular , Biomimética , Espectroscopia de Ressonância Magnética , Isodon/química , Catálise , Estereoisomerismo
15.
Planta ; 257(5): 90, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36991182

RESUMO

MAIN CONCLUSION: We identify two ferruginol synthases and a 11-hydroxyferruginol synthase from a traditional Chinese medicinal herb Isodon lophanthoides and propose their involvement in two independent abietane diterpenoids biosynthetic pathways. Isodon lophanthoides is a traditional Chinese medicinal herb rich in highly oxidized abietane-type diterpenoids. These compounds exhibit a wide range of pharmaceutical activities, yet the biosynthesis is barely known. Here, we describe the screening and functional characterization of P450s that oxidize the abietane skeleton abietatriene. We mainly focused on CYP76 family and identified 12 CYP76AHs by mining the RNA-seq data of I. lophanthoides. Among the 12 CYP76AHs, 6 exhibited similar transcriptional expression features as upstream diterpene synthases, including root or leaf-preferential expression pattern and highly MeJA inducibility. These six P450s were considered as first-tier candidates and functionally characterized in yeast and plant cells. In yeast assays showed that both CYP76AH42 and CYP76AH43 were ferruginol synthases hydroxylating the C12 position of abietatriene, whereas CYP76AH46 was characterized as a 11-hydroxyferruginol synthase which catalyzes two successive oxidations at C12 and C11 of abietatriene. Heterologous expression of three CYP76AHs in Nicotiana benthamiana resulted in the formation of ferruginol. qPCR analysis showed CYP76AH42 and CYP76AH43 were mainly expressed in the root, which was consistent with the distribution of ferruginol in the root periderms. CYP76AH46 was primarily expressed in the leaves where barely ferruginol or 11-hydroxyferruginol was detected. In addition to distinct organ-specific expression pattern, three CYP76AHs exhibited different genomic structures (w or w/o introns), low protein sequence identities (51-63%) and were placed in separate subclades in the phylogenetic tree. These results suggest that the identified CYP76AHs may be involved in at least two independent abietane biosynthetic pathways in the aerial and underground parts of I. lophanthoides.


Assuntos
Diterpenos , Isodon , Abietanos , Isodon/química , Isodon/genética , Isodon/metabolismo , Saccharomyces cerevisiae/metabolismo , Filogenia , Diterpenos/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo
16.
Phytochemistry ; 209: 113621, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36893826

RESUMO

The phytochemical investigation of the EtOAc extract from the aerial parts of Isodon eriocalyx afforded seventeen diterpenoids, including eight undescribed compounds. Eriocalyxins H-L have unique structural characteristics featuring a 5-epi-ent-kaurane diterpenoid scaffold with eriocalyxins H-K also possess an unusual 6,11-epoxyspiro-lactone ring while eriocalyxin L, a 1,7:3,20-diepoxy-ent kaurene, features an 1,7-oxygen linkage. The structures of these compounds were elucidated by spectroscopic data interpretation, and the absolute configurations of eriocalyxins H, I, L, and M were confirmed by single-crystal X-ray diffraction. The isolates were screened for their inhibitory activities against VCAM-1 and ICAM-1 at 5 µM. While eriocalyxin O, coetsoidin A and laxiflorin P were found to significantly inhibit both VCAM-1 and ICAM-1, 8 (17),13-ent-labdadien-15 â†’ 16-lactone-19-oic acid displayed evidently inhibitory effect against ICAM-1.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos , Isodon , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Isodon/química , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão de Célula Vascular/análise , Antineoplásicos Fitogênicos/química , Diterpenos/química , Componentes Aéreos da Planta/química , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais
17.
Bioorg Med Chem Lett ; 82: 129149, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36690039

RESUMO

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.


Assuntos
Antineoplásicos , Isodon , Humanos , Antineoplásicos/farmacologia , Relação Estrutura-Atividade , Células HL-60 , Células HCT116
18.
Nat Prod Res ; 37(1): 68-76, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34498960

RESUMO

A new icetexane diterpenoid, 11, 12, 20α-trihydroxyl-7ß-methoxyicetexa-8, 11, 13-triene-19, 10-lactone [Phyllane A (1)], and a new abietane diterpenoid, 7ß, 20-epoxy-3ß, 17-acetoxy-abieta-8, 11, 13-teriene-11, 12-diol [phyllane B (2)], along with two known compounds (3 and 4) were isolated from the methanol (MeOH) extract of twigs and leaves of the folk medicinal Isodon phyllopodus. Their structures were determined by spectroscopic analyses including 2 D NMR spectral data, and further confirmed by X-ray single crystal diffraction. Moreover, the compounds were evaluated for their cytotoxicity and anti-HIV activities, and phyllane A showed anti-HIV activity with an IC50 value of 15.7 µM, but phyllane B was found to be cytotoxic to the A549 host cells with a CC50 value of 108.5 µM.


Assuntos
Antineoplásicos Fitogênicos , Diterpenos , Isodon , Abietanos/farmacologia , Abietanos/química , Isodon/química , Antineoplásicos Fitogênicos/química , Diterpenos/química , Folhas de Planta/química , Estrutura Molecular
19.
Mol Plant ; 16(3): 517-532, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36518072

RESUMO

The ent-kaurenoids (e.g., oridonin and enmein) from the Isodon genus (Lamiaceae) are one class of diterpenoids with rich structural diversity and intriguing pharmaceutical activity. In contrast to the well-established gibberellin pathway, oxidative modifications diversifying the ent-kaurene skeleton in Isodon have remained undetermined for half a century. Here we report a chromosome-level genome assembly of I. rubescens, a well-recognized oridonin producer long favored by Asian people as a traditional herb with antitumor effects. The shoot apex was confirmed to be the actual region actively producing ent-kaurene diterpenoids. Through comparative genomics and phylogenetic analyses, we discovered a cluster of tandem-duplicated CYP706V oxygenase-encoding genes located on an ancient genomic block widely distributed in eudicots, whereas almost exclusively emerged in Isodon plants. In the shoot apex, IrCYP706V2 and IrCYP706V7 oxidized the ent-kaurene core in the initial stage of oridonin biosynthesis. Loss of CYP706Vs in other Lamiaceae plants offered an explanation for the specific kaurenoid production in Isodon plants. Moreover, we found that the Isodon genomes encode multiple diterpenoid synthases that are potentially involved in generating diterpenoid diversity. These findings provided new insights into the evolution of the lineage-specific diterpenoid pathway and laid a foundation for improving production of bioactive ent-kaurene-type diterpenoids by molecular breeding and synthetic biology approaches.


Assuntos
Diterpenos do Tipo Caurano , Isodon , Lamiaceae , Isodon/genética , Oxirredutases , Filogenia
20.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-981524

RESUMO

The present study aimed to investigate the inhibitory effect and mechanism of Isodon terricolous-medicated serum on lipopolysaccharide(LPS)-induced hepatic stellate cell(HSC) activation. LPS-induced HSCs were divided into a blank control group, an LPS model group, a colchicine-medicated serum group, an LPS + blank serum group, an I. terricolous-medicated serum group, a Toll-like receptor 4(TLR4) blocker group, and a TLR4 blocker + I. terricolous-medicated serum group. HSC proliferation was detected by methyl thiazolyl tetrazolium(MTT) assay. Enzyme-linked immunosorbent assay(ELISA) was used to measure type Ⅰ collagen(COL Ⅰ), COL Ⅲ, transforming growth factor-β1(TGF-β1), intercellular adhesion molecule-1(ICAM-1), α-smooth muscle actin(α-SMA), vascular cell adhesion molecule-1(VCAM-1), cysteinyl aspartate-specific proteinase-1(caspase-1), and monocyte chemotactic protein-1(MCP-1). Real-time PCR(RT-PCR) was used to detect mRNA expression of TLR4, IκBα, and NOD-like receptor thermal protein domain associated protein 3(NLRP3), nuclear factor-κB(NF-κB) p65, gasdermin D(GSDMD), and apoptosis-associated speck-like protein containing a CARD(ASC) in HSCs. Western blot(WB) was used to detect the protein levels of TLR4, p-IκBα, NF-κB p65, NLRP3, ASC, and GSDMD in HSCs. The results showed that I. terricolous-medicated serum could inhibit the proliferation activity of HSCs and inhibit the secretion of COL Ⅰ, COL Ⅲ, α-SMA, TGF-β1, caspase-1, MCP-1, VCAM-1, and ICAM-1 in HSCs. Compared with the LPS model group, the I. terricolous-medicated serum group, the colchicine-medicated serum group, and the TLR4 blocker group showed down-regulated expression of p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and up-regulated expression of IκBα. Compared with the TLR4 blocker group, the TLR4 blocker + I. terricolous-medicated serum group showed decreased expression of TLR4, p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and increased expression of IκBα. In conclusion, I. terricolous-medicated serum down-regulates HSC activation by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway.


Assuntos
NF-kappa B/metabolismo , Células Estreladas do Fígado , Fator de Crescimento Transformador beta1/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Isodon , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 4 Toll-Like/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Colchicina/farmacologia , Caspases
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