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Phytomedicine : International Journal... Aug 2024Leishmaniasis is a globally prevalent vector-borne disease caused by parasites of the genus Leishmania. The available chemotherapeutic drugs present problems related to...
BACKGROUND AND PURPOSE
Leishmaniasis is a globally prevalent vector-borne disease caused by parasites of the genus Leishmania. The available chemotherapeutic drugs present problems related to efficacy, emergence of parasite resistance, toxicity and high cost, justifying the search for new drugs. Several classes of compounds have demonstrated activity against Leishmania, including icetexane-type diterpenes, previously isolated from Salvia and other Lamiaceae genera. Thus, in this study, compounds of Salvia procurrens were investigated for their leishmanicidal and immunomodulatory activities.
METHODS
The exudate of S. procurrens was obtained by rapidly dipping the aerial parts in dichloromethane. The compounds were isolated by column and centrifugal planar chromatography over silica gel. The effects on L. amazonensis growth, survival, membrane integrity, reactive oxygen species (ROS) generation, mitochondrial membrane potential and cytotoxicity of the compounds towards human erythrocytes, peripheral blood mononuclear cells and macrophages were evaluated. The effects on intracellular amastigote forms, nitric oxide (NO) and TNF-α production were also investigated.
RESULTS
The exudate from the leaves afforded the novel icetexane 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2), fruticulin A (3) and demethylfruticulin A (4). The compounds (1-4) were tested against promastigotes of L. amazonensis and showed an effective inhibition of the parasite survival (IC = 4.08-16.26 μM). In addition, they also induced mitochondrial ROS production, plasma membrane permeability and mitochondrial dysfunction in treated parasites, and presented low cytotoxicity against macrophages. Furthermore, all diterpenes tested reduced the number of parasites inside macrophages, by mechanisms involving TNF-α, NO and ROS.
CONCLUSION
The results suggest the potential of 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2),fruticulin A (3) and demethylfruticulin A (4) as candidates for use in further studies on the design of anti-leishmanial drugs.
Topics: Salvia; Reactive Oxygen Species; Humans; Leishmania; Animals; Tumor Necrosis Factor-alpha; Nitric Oxide; Mice; Macrophages; Antiprotozoal Agents; Membrane Potential, Mitochondrial; Plant Leaves; Diterpenes; Leukocytes, Mononuclear; Erythrocytes; Plant Extracts; Mice, Inbred BALB C; RAW 264.7 Cells
PubMed: 38852475
DOI: 10.1016/j.phymed.2024.155796 -
Journal of Natural Products Oct 2023Eleven diterpenoids, wulfenioidins D-N (-), classified into five distinct carbon skeletons with one unreported framework, and four modified abietane diterpenoids were...
Eleven diterpenoids, wulfenioidins D-N (-), classified into five distinct carbon skeletons with one unreported framework, and four modified abietane diterpenoids were isolated from the whole plant of . The structures and absolute configurations were characterized by spectroscopic methods, single-crystal X-ray diffraction, and electronic circular dichroism analyses. Compounds and exhibited activity against Zika virus (ZIKV) with EC values of 8.07 and 8.50 μM, respectively, and showed no significant cytotoxicity toward Vero cells at 100 μM. Western blot and immunofluorescence experiments showed that compounds and interfered with the replication of the ZIKV by inhibiting the expression of the ZIKV envelope (E) protein.
Topics: Animals; Chlorocebus aethiops; Zika Virus; Orthosiphon; Vero Cells; Zika Virus Infection; Diterpenes; Molecular Structure
PubMed: 37737089
DOI: 10.1021/acs.jnatprod.3c00543 -
Acta Pharmacologica Sinica May 2024Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel...
Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis.
Topics: Epoxy Compounds; Humans; Phenanthrenes; Carcinoma, Non-Small-Cell Lung; Diterpenes; Paclitaxel; Drug Resistance, Neoplasm; Lung Neoplasms; Hedgehog Proteins; Hepatocyte Nuclear Factor 1-alpha; Animals; Cell Line, Tumor; Signal Transduction; Mice, Nude; ATP Binding Cassette Transporter, Subfamily B; Mice; Mice, Inbred BALB C; A549 Cells
PubMed: 38228910
DOI: 10.1038/s41401-023-01219-y -
The Journal of Nutrition Mar 2024
Topics: Vitamin K; Risk Factors; Vitamin K 1
PubMed: 38246356
DOI: 10.1016/j.tjnut.2024.01.014 -
Oncology Reports Nov 2023Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of , has been shown to exert strong antitumor properties. The aim of the present study was to...
Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of , has been shown to exert strong antitumor properties. The aim of the present study was to investigate the mechanisms underlying the proposed antitumor properties of PAB in the triple‑negative breast cancer cells, MDA‑MB‑231. The cell processes evaluated included cell proliferation by Cell Counting Kit‑8 assay, colony formation and EdU assay, apoptosis by Annexin V‑FITC/PI apoptosis assay, cell migration by Transwell migration assay and invasion by Transwell invasion assay. PAB significantly inhibited the proliferation of MDA‑MB‑231 cells through a mechanism that was considered to be associated with cell cycle arrest at the G/M phase. There was decreased protein expression levels of CDK1 and cyclin B1 and increased protein expression levels of p53 and p21. However, there were no well‑defined inhibitory effects on the normal breast cell line MCF10A. PAB also triggered apoptosis in a concentration‑dependent manner through the mitochondrial apoptosis pathway. It caused collapse of mitochondrial membrane potential, accumulation of reactive oxygen species and release of cytochrome c, as well as upregulation of cleaved caspase‑3, cleaved caspase‑9, cleaved PARP and Bax, and downregulation of Bcl‑2 and Bcl‑xl. The migration and invasion ability of MDA‑MB‑231 cells were inhibited by decreasing the expression levels of the epithelial‑mesenchymal transition‑related markers N‑cadherin and vimentin and increasing the expression of E‑cadherin. Moreover, the expression levels of PI3K (p110β), phosphorylated (p)‑AKT (ser) and p‑mTOR (ser) were downregulated and LY294002, a PI3K inhibitor, could interact additively with PAB to induce apoptosis of MDA‑MB‑231 cells. Overall, the present results demonstrated that PAB induced apoptosis via mitochondrial apoptosis and the PI3K/AKT/mTOR pathway in triple‑negative breast cancer. It also inhibited cellular proliferation, migration and invasion, suggesting that PAB may be a useful phytomedicine for the treatment of triple‑negative breast cancer.
Topics: Humans; Triple Negative Breast Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Apoptosis; Diterpenes
PubMed: 37711030
DOI: 10.3892/or.2023.8630 -
Bioorganic Chemistry Nov 2023A total of 17 structurally diverse clerodane diterpenoids, including ten undescribed clerodane diterpenoids (tinopanoids K-T, 1-10) and seven known compounds (11-17),...
A total of 17 structurally diverse clerodane diterpenoids, including ten undescribed clerodane diterpenoids (tinopanoids K-T, 1-10) and seven known compounds (11-17), were isolated from the vines and leaves of Tinospora crispa. Compound 3 has not only bear the dominant substituents of γ-hydroxy-α, β-unsaturated-γ-lactone with anti-inflammatory activity, but also a ternary epoxy structure at C-3/C-4. The planar structures and relative configurations of the clerodane diterpenoids were elucidated by spectroscopic data interpretation. The absolute configurations of compounds 1, 4, 8 and 13 were determined by single-crystal X-ray crystallographic, while that of compound 3 was determined using computed ECD data and single crystal X-ray diffraction of related p-bromobenzoate ester (3a). Subsequently, all compounds were evaluated for their inhibitory effect on nitric oxide (NO) production of LPS-activated BV-2 cells, and compounds 3 and 8 exhibited better NO inhibitory potency, with IC values of 5.6 and 13.8 μM than the positive control minocycline (Mino, IC = 22.9 μM). The corresponding results of western blot analysis and qRT-PCR revealed that compound 3 can significantly inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expressions, mRNA levels of pro-inflammatory cytokins of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). The underlying mechanism by which compound 3 exerted anti-neuroinflammatory effects was investigated by western blot and immunofluorescence assay, which suggested compound 3 inhibited LPS induced neuroinflammation via the suppression of toll-like receptor 4 (TLR4) dependent Signal Transducer and Activator of Transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways, and the activation of Heme Oxygenase-1 (HO-1) mediated signals.
Topics: Diterpenes, Clerodane; Tinospora; Lipopolysaccharides; Anti-Inflammatory Agents; Blotting, Western
PubMed: 37651894
DOI: 10.1016/j.bioorg.2023.106812 -
Molecules (Basel, Switzerland) Dec 2023(A.Rich.) Miers (Menispermaceae) has traditionally been used to alleviate headaches, rheumatism, mycetoma, and diabetes, among others. Despite its extensive use, the...
(A.Rich.) Miers (Menispermaceae) has traditionally been used to alleviate headaches, rheumatism, mycetoma, and diabetes, among others. Despite its extensive use, the active components of the plant have never been investigated. In this work, a series of furanoditerpenoids (-) and five compounds from other classes (-) were isolated from . Notably, two new compounds were discovered and named: tinobakisin () and tinobakiside (). Their molecular structures were elucidated with NMR, MS, UV, IR, and ECD spectra. Additionally, known compounds (- and -) were corroboratively identified through spectral comparisons with previously reported data, while highlighting and addressing some inaccuracies in the prior literature. Remarkably, compounds , , , and exhibited a superior anti-glycation effect, outperforming established agents like rutin and quercetin in a lab model of protein glycation with glucose. The overall findings suggest that furanoditerpenoids play a crucial role in the antidiabetic properties of This research marks the first comprehensive phytochemical investigation of , opening the door for further investigation into furanoditerpenoids and their biological mechanisms.
Topics: Animals; Tinospora; Menispermaceae; Diterpenes, Clerodane; Coleoptera; Glucose
PubMed: 38202737
DOI: 10.3390/molecules29010154 -
Planta Medica Aug 2023The emergence and re-emergence of viruses has highlighted the need to develop new broad-spectrum antivirals to mitigate human infections. Pursuing our search for new...
The emergence and re-emergence of viruses has highlighted the need to develop new broad-spectrum antivirals to mitigate human infections. Pursuing our search for new bioactive plant-derived molecules, we study several diterpene derivatives synthesized from jatropholones A and B and carnosic acid isolated from and , respectively. Here, we investigate the antiviral effect of the diterpenes against human adenovirus (HAdV-5) that causes several infections for which there is no approved antiviral therapy yet. Ten compounds are evaluated and none of them present cytotoxicity in A549 cells. Only compounds 2, 5 and 9 inhibit HAdV-5 replication in a concentration-dependent manner, without virucidal activity, whereas the antiviral action takes place after virus internalization. The expression of viral proteins E1A and Hexon is strongly inhibited by compounds 2 and 5 and, in a lesser degree, by compound 9. Since compounds 2, 5 and 9 prevent ERK activation, they might exert their antiviral action by interfering in the host cell functions required for virus replication. Besides, the compounds have an anti-inflammatory profile since they significantly inhibit the levels of IL-6 and IL-8 produced by THP-1 cells infected with HAdV-5 or with an adenoviral vector. In conclusion, diterpenes 2, 5 and 9 not only exert antiviral activity against adenovirus but also are able to restrain pro-inflammatory cytokines induced by the virus.
Topics: Humans; Antiviral Agents; Adenoviridae Infections; Adenoviridae; Adenoviruses, Human; Diterpenes; Virus Replication
PubMed: 36940926
DOI: 10.1055/a-2058-3635 -
Journal of Enzyme Inhibition and... Dec 2024is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids...
is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids (-), including a new one with a rarely occurring α,β-unsaturated diketone C-ring, were isolated from . Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives (). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1β, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.
Topics: Humans; Orthosiphon; Abietanes; Arthritis, Rheumatoid; Tumor Necrosis Factor-alpha; Diterpenes; NF-kappa B
PubMed: 38234133
DOI: 10.1080/14756366.2023.2296355 -
Journal of Natural Products Apr 2024A detailed chemical study of the extract from the soft coral resulted in the isolation and identification of seven new sesquiterpenoids, bellissinanes A-G (-), along...
A detailed chemical study of the extract from the soft coral resulted in the isolation and identification of seven new sesquiterpenoids, bellissinanes A-G (-), along with four new diterpenes (-). Bellissinane A () is the third reported nardosinane-type sesquiterpene bearing a 6/5/6 tricyclic system. Bellissinanes C and D (, ) contain a phenylethylamine fragment, which is relatively unusual in marine organisms. Bellissinanes E-G (-) belong to the rare class of nornardosinane sesquiterpenoids. Structurally uncommon octahydro-1-indenyl-type and prenyleudesmane-type skeletons were characterized for herpetopanone B () and bellissimain A (), respectively. Bellissinane E () exhibited in vivo angiogenesis-promoting activity.
Topics: Animals; Molecular Structure; Anthozoa; Sesquiterpenes; Diterpenes; Nuclear Magnetic Resonance, Biomolecular; Marine Biology; Terpenes
PubMed: 38548686
DOI: 10.1021/acs.jnatprod.4c00112