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1.
Proc Natl Acad Sci U S A ; 121(12): e2322453121, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38470919

RESUMO

The phlebotomine sandfly, Lutzomyia longipalpis, a major vector of the Leishmania parasite, uses terpene pheromones to attract conspecifics for mating. Examination of the L. longipalpis genome revealed a putative terpene synthase (TPS), which-upon heterologous expression in, and purification from, Escherichia coli-yielded a functional enzyme. The TPS, termed LlTPS, converted geranyl diphosphate (GPP) into a mixture of monoterpenes with low efficiency, of which ß-ocimene was the major product. (E,E)-farnesyl diphosphate (FPP) principally produced small amounts of (E)-ß-farnesene, while (Z,E)- and (Z,Z)-FPP yielded a mixture of bisabolene isomers. None of these mono- and sesquiterpenes are known volatiles of L. longipalpis. Notably, however, when provided with (E,E,E)-geranylgeranyl diphosphate (GGPP), LlTPS gave sobralene as its major product. This diterpene pheromone is released by certain chemotypes of L. longipalpis, in particular those found in the Ceará state of Brazil. Minor diterpene components were also seen as products of the enzyme that matched those seen in a sandfly pheromone extract.


Assuntos
Diterpenos , Psychodidae , Animais , Feromônios/metabolismo , Psychodidae/metabolismo , Diterpenos/metabolismo , Terpenos , Monoterpenos
2.
Proc Natl Acad Sci U S A ; 121(12): e2318996121, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38478688

RESUMO

Bestrhodopsins constitute a class of light-regulated pentameric ion channels that consist of one or two rhodopsins in tandem fused with bestrophin ion channel domains. Here, we report on the isomerization dynamics in the rhodopsin tandem domains of Phaeocystis antarctica bestrhodopsin, which binds all-trans retinal Schiff-base (RSB) absorbing at 661 nm and, upon illumination, converts to the meta-stable P540 state with an unusual 11-cis RSB. The primary photoproduct P682 corresponds to a mixture of highly distorted 11-cis and 13-cis RSB directly formed from the excited state in 1.4 ps. P673 evolves from P682 in 500 ps and contains highly distorted 13-cis RSB, indicating that the 11-cis fraction in P682 converts to 13-cis. Next, P673 establishes an equilibrium with P595 in 1.2 µs, during which RSB converts to 11-cis and then further proceeds to P560 in 48 µs and P540 in 1.0 ms while remaining 11-cis. Hence, extensive isomeric switching occurs on the early ground state potential energy surface (PES) on the hundreds of ps to µs timescale before finally settling on a metastable 11-cis photoproduct. We propose that P682 and P673 are trapped high up on the ground-state PES after passing through either of two closely located conical intersections that result in 11-cis and 13-cis RSB. Co-rotation of C11=C12 and C13=C14 bonds results in a constricted conformational landscape that allows thermal switching between 11-cis and 13-cis species of highly strained RSB chromophores. Protein relaxation may release RSB strain, allowing it to evolve to a stable 11-cis isomeric configuration in microseconds.


Assuntos
Diterpenos , Retinaldeído , Rodopsina , Isomerismo , Conformação Proteica , Rodopsina/metabolismo , Retinaldeído/química
3.
BMC Complement Med Ther ; 24(1): 113, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448925

RESUMO

BACKGROUND: Triptolide is a widely utilized natural anti-inflammatory drug in clinical practice. Aim of this study was to evaluate effects of triptolide on hPDLSCs osteogenesis in an inflammatory setting and to investigate underlying mechanisms. METHODS: Using the tissue block method to obtain hPDLSCs from extracted premolar or third molar. Flow cytometry, osteogenic and adipogenic induction were carried out in order to characterise the features of the cells acquired. hPDLSC proliferative activity was assessed by CCK-8 assay to determine the effect of TNF-α and/or triptolide. The impact of triptolide on the osteogenic differentiation of hPDLSCs was investigated by ALP staining and quantification. Osteogenesis-associated genes and proteins expression level were assessed through PCR and Western blotting assay. Finally, BAY-117,082 was used to study the NF-κB pathway. RESULTS: In the group treated with TNF-α, there was an elevation in inflammation levels while osteogenic ability and the expression of both osteogenesis-associated genes and proteins decreased. In the group co-treated with TNF-α and triptolide, inflammation levels were reduced and osteogenic ability as well as the expression of both osteogenesis-associated genes and proteins were enhanced. At the end of the experiment, both triptolide and BAY-117,082 exerted similar inhibitory effects on the NF-κB pathway. CONCLUSION: The osteogenic inhibition of hPDLSCs by TNF-α can be alleviated through triptolide, with the involvement of the p-IκBα/NF-κB pathway in this mechanism.


Assuntos
Diterpenos , NF-kappa B , Fenantrenos , Fator de Necrose Tumoral alfa , Humanos , Osteogênese , Inibidor de NF-kappaB alfa , Ligamento Periodontal , Transdução de Sinais , Células-Tronco , Inflamação , Compostos de Epóxi
4.
Planta ; 259(4): 87, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38460012

RESUMO

MAIN CONCLUSION: Protein modeling, carbocation docking, and molecular dynamics along with structure-based mutability landscapes provided insight into taxadiene synthase catalysis (first step of the anticancer Taxol biosynthesis), protein structure-function correlations, and promiscuity. Plant terpenes belong to one of the largest and most diverse classes of natural products. This diversity is driven by the terpene synthase enzyme family which comprises numerous different synthases, several of which are promiscuous. Taxadiene synthase (TXS) is a class I diterpene synthase that catalyzes the first step in the biosynthesis pathway of the diterpene Taxol, an anticancer natural product produced by the Taxus plant. Exploring the molecular basis of TXS catalysis and its promiscuous potential garnered interest as a necessary means for understanding enzyme evolution and engineering possibilities to improve Taxol biosynthesis. A catalytically active closed conformation TXS model was designed using the artificial intelligence system, AlphaFold, accompanied by docking and molecular dynamics simulations. In addition, a mutability landscape of TXS including 14 residues was created to probe for structure-function relations. The mutability landscape revealed no mutants with improved catalytic activity compared to wild-type TXS. However, mutations of residues V584, Q609, V610, and Y688 showed high degree of promiscuity producing cembranoid-type and/or verticillene-type major products instead of taxanes. Mechanistic insights into V610F, V584M, Q609A, and Y688C mutants compared to the wild type revealed the trigger(s) for product profile change. Several mutants spanning residues V584, Q609, Y688, Y762, Q770, and F834 increased production of taxa-4(20),11(12)-diene which is a more favorable substrate for Taxol production compared to taxa-4(5),11(12)-diene. Finally, molecular dynamics simulations of the TXS reaction cascade revealed residues involved in ionization, carbocation stabilization, and cyclization ushering deeper understanding of the enzyme catalysis mechanism.


Assuntos
Diterpenos , Isomerases , Simulação de Dinâmica Molecular , Inteligência Artificial , Paclitaxel , Diterpenos/metabolismo , Catálise
5.
Bioorg Chem ; 145: 107253, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452588

RESUMO

Phytochemical study on Euphorbia milii, a common ornamental plant, resulted in the identification of thirteen new ent-rosane diterpenoids (1-13), three new ent-atisane diterpenoids (14-16), and a known ent-rosane (17). Their structures were delineated using spectroscopic data, quantum chemical calculations, and X-ray diffraction experiments. Euphomilone F (1) represented a rare ent-rosane-type diterpenoid with a 5/7/6 skeleton. Euphoainoid G (8) was a rare rosane diterpenic acid. Compounds 9 and 10 carried infrequent tetrahydrofuran rings, and compounds 11-13 was 18-nor-ent-rosane diterpenoids. All isolates were evaluated for their inhibitory effects on RANKL-induced osteoclasts. Notably, compounds with aromatic ester groups (2-7) showed promising activities (IC50 < 10 µM), underscoring the significance of acylated A-ring moieties in the ent-rosane skeleton for anti-osteoclastogenesis. Thirteen synthetic derivatives were obtained through esterification of 17. Of these, compound 27 exhibited remarkable improvement, with an IC50 of 0.8 µM, more than a 12-fold increase in potency compared to the parent compound 17 (IC50 > 10 µM). This work presents a series of new ent-rosane diterpenoids with potential antiosteoporosis agents.


Assuntos
Diterpenos , Euphorbia , Osteogênese , Euphorbia/química , Extratos Vegetais/química , Osteoclastos , Diterpenos/farmacologia , Diterpenos/química , Estrutura Molecular
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(3): 222-228, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38512032

RESUMO

Objective To investigate the effects of triptolide (TP) on microglial M1/M2 polarization after cerebral ischemia-reperfusion (I/R) injury in rats and the underlying molecular mechanism. Methods A rat model of middle cerebral artery occlusion (MCAO) was established. TP was administered to rats at doses of 0.1 and 0.2 mg/kg, with a sham surgery group as the control group. Longa scoring was performed to grade neurological deficits in rats; HE staining was used to observe the morphology of neurons in ischemic brain tissues; neuron-specific nuclear protein (NeuN) immunofluorescence staining was used to measure the number of neurons; and Western blot analysis was used to measure the expression levels of ionised calcium-binding adaptor molecule-1 (Iba1), inducible nitric oxide synthase (iNOS), arginase 1 (Arg1), Toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), NeuN and caspase-3 in ischemic-brain tissues. The protein levels of interleukin 1ß (IL-1ß) and IL-10 were measured by ELISA. Immunofluorescence double labelling was performed to detect the expression of Arg1 and TLR4 in microglia. Results Compared with the model group, the neurological score of the TP treatment group was significantly reduced and the neuronal damage was significantly alleviated. IL-1ß levels decreased while IL-10 levels increased. The expression levels of iNOS, TLR4, NF-κB and caspase-3 decreased, while the expression levels of Arg1 and NeuN increased. Conclusion TP treatment ameliorates cerebral I/R injury in rats, which may be attributed to the promotion of microglial M2 polarization, thereby reducing the release of inflammatory factors and inhibiting apoptosis.


Assuntos
Isquemia Encefálica , Diterpenos , Fenantrenos , Traumatismo por Reperfusão , Animais , Ratos , Caspase 3 , Interleucina-10 , Microglia , Receptor 4 Toll-Like , NF-kappa B , Reperfusão , Traumatismo por Reperfusão/tratamento farmacológico , Interleucina-1beta , Isquemia Encefálica/tratamento farmacológico , Compostos de Epóxi
7.
J Agric Food Chem ; 72(11): 5574-5584, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38468388

RESUMO

To explore the use of nonfood plant-derived secondary metabolites for plant protection, a series of ester derivatives for controlling the major migratory agricultural pests were obtained by structural modification of andrographolide, a labdane diterpenoid isolated from Andrographis paniculata. Compound Id showed good insecticidal activity against the fall armyworm Spodoptera frugiperda Smith. Compounds IIa (LC50: 0.382 mg/mL) and IIIc (LC50: 0.563 mg/mL), the acaricidal activities of which were, respectively, 13.1 and 8.9 times that of andrographolide (LC50: 4.996 mg/mL), exhibited strong acaricidal and control effects against Tetranychus cinnabarinus Boisduval. Against Aphis citricola Van der Goot, compounds IIIc and IVb displayed 3.9- and 3.7-fold pronounced aphicidal activity of andrographolide. Effects of compound Id on three protective enzymes (superoxide dismutase, peroxidase, and catalase) of S. frugiperda were also observed. The obvious differences of epidermal cuticle structures of mites treated with compound IIa were determined by scanning electron microscopy. Structure-activity relationships indicated that 14-ester derivatives of andrographolide showed potential insecticidal/acaricidal activities and can be further utilized as lead compounds.


Assuntos
Acaricidas , Produtos Biológicos , Diterpenos , Inseticidas , Praguicidas , Animais , Praguicidas/química , Estrutura Molecular , Produtos Biológicos/química , Ésteres/química , Inseticidas/química , Relação Estrutura-Atividade , Acaricidas/química , Diterpenos/farmacologia , Diterpenos/química
8.
Acta Cir Bras ; 39: e391424, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38511762

RESUMO

PURPOSE: XinJiaCongRongTuSiZiWan (XJCRTSZW) is a traditional Chinese medicine compound for invigorating the kidney, nourishing blood, and promoting blood circulation. This study aimed to explore the effect of XJCRTSZW on triptolide (TP)-induced oxidative stress injury. METHODS: Adult female Sprague-Dawley rats and human ovarian granulosa cell lines were treated with TP and XJCRTSZW. Hematoxylin and eosin staining, enzyme-linked immunosorbent assay, flow cytometry, CCK-8, JC-1 staining, transmission electron microscopy, reverse transcription-quantitative polymerase chain reaction, and Western blotting were performed in this study. RESULTS: XJCRTSZW treatment observably ameliorated the TP-induced pathological symptoms. Furthermore, XJCRTSZW treatment observably enhanced the TP-induced reduction of estradiol, anti-Mullerian hormone, progesterone, superoxide dismutase, ATP content, mitochondrial membrane potential, p62, and Hsp60 mRNA, and protein levels in vivo and in vitro (p < 0.05). However, TP-induced elevation of follicle stimulating hormone and luteinizing hormone concentrations, malondialdehyde levels, reactive oxygen species levels, apoptosis rate, mitophagy, and the mRNA and protein expressions of LC3-II/LC3-I, PTEN-induced kinase 1 (PINK1), and Parkin were decreased (p < 0.05). In addition, XJCRTSZW treatment markedly increased cell viability in vitro (p < 0.05). CONCLUSIONS: XJCRTSZW protects TP-induced rats from oxidative stress injury via the mitophagy-mediated PINK1/Parkin pathway.


Assuntos
Diterpenos , Mitocôndrias , Mitofagia , Fenantrenos , Adulto , Ratos , Feminino , Humanos , Animais , Ratos Sprague-Dawley , Estresse Oxidativo , Ubiquitina-Proteína Ligases , Transdução de Sinais , Proteínas Quinases/metabolismo , Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Compostos de Epóxi
9.
Ren Fail ; 46(1): 2320834, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38482580

RESUMO

BACKGROUND: This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. METHODS: A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. RESULTS: The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study's duration. CONCLUSIONS: This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.


Assuntos
Diterpenos , Medicamentos de Ervas Chinesas , Glomerulonefrite Membranosa , Síndrome Nefrótica , Humanos , Pessoa de Meia-Idade , Diterpenos/efeitos adversos , Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/efeitos adversos , Síndrome Nefrótica/tratamento farmacológico , Estudos Prospectivos
10.
Molecules ; 29(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474596

RESUMO

Euphorbia is a large genus of the Euphorbiaceae family. Around 250 species of the Euphorbia genus have been studied chemically and pharmacologically; different compounds have been isolated from these species, especially diterpenes and triterpenes. Several reports show that several species have anti-inflammatory activity, which can be attributed to the presence of diterpenes, such as abietanes, ingenanes, and lathyranes. In addition, it was found that some diterpenes isolated from different Euphorbia species have anti-cancer activity. In this review, we included compounds isolated from species of the Euphorbia genus with anti-inflammatory or cytotoxic effects published from 2018 to September 2023. The databases used for this review were Science Direct, Scopus, PubMed, Springer, and Google Scholar, using the keywords Euphorbia with anti-inflammatory or cytotoxic activity. In this review, 68 studies were collected and analyzed regarding the anti-inflammatory and anti-cancer activities of 264 compounds obtained from 36 species of the Euphorbia genus. The compounds included in this review are terpenes (95%), of which 68% are diterpenes, especially of the types ingenanes, abietanes, and triterpenes (approximately 15%).


Assuntos
Antineoplásicos , Diterpenos , Euphorbia , Triterpenos , Euphorbia/química , Abietanos , Estrutura Molecular , Diterpenos/química , Triterpenos/química , Anti-Inflamatórios
11.
Biomed Pharmacother ; 172: 116269, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38367549

RESUMO

AGS-30, a new andrographolide derivative, showed significant anticancer and anti-angiogenic characteristics. However, its role in controlling macrophage polarization and tumor immune response is unknown. Thus, the main goals of this study are to investigate how AGS-30 regulates macrophage polarization and how it suppresses breast cancer metastasis. AGS-30 inhibited IL-4 and IL-13-induced RAW 264.7 and THP-1 macrophages into M2-like phenotype. However, AGS-30 did not affect the LPS and IFN-γ-induced polarization of M1-like macrophages. AGS-30 reduced the mRNA expressions of CD206, Arg-1, Fizz-1, Ym-1, VEGF, IL-10, MMP2, and MMP9 in M2-like macrophages in a concentration-dependent manner. In contrast, andrographolide treatment at 5 µM did not affect M1-like and M2-like macrophage polarization. The conditioned medium from M2-like macrophages increased 4T1 breast cancer cell migration and invasion, whereas AGS-30 inhibited these effects. In the 4T1 breast tumor xenograft mice, the tumor volume and weight were reduced without affecting body weight after receiving AGS-30. AGS-30 treatment also reduced lung and liver metastasis, with reduced STAT6, CD31, VEGF, and Ki67 protein expressions. Moreover, the tumors had considerably fewer M2-like macrophages and Arg-1 expression, but the proportion of M1-like macrophages and iNOS expression increased after AGS-30 treatment. Same results were found in the tail vein metastasis model. In conclusion, this study shows that AGS-30 inhibits breast cancer growth and metastasis, probably through inhibiting M2-like macrophage polarization. Our findings suggest that AGS-30 may be a potential immunotherapeutic alternative for metastatic breast cancer.


Assuntos
Neoplasias da Mama , Diterpenos , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/tratamento farmacológico , Meios de Cultivo Condicionados , Diterpenos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
12.
J Am Soc Mass Spectrom ; 35(3): 603-612, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38391322

RESUMO

Plant diterpene glycosides are essential for diverse physiological processes. Comprehensive structural characterization proved to be a challenge due to variations in glycosylation patterns, diverse aglycone structures, and the absence of comprehensive reference databases. In this study, a method for fine-scale characterization was proposed based on energy-resolved (ER) untargeted LC-MS/MS metabolomics analysis using steviol glycosides as a demonstration. Energy-dependent fragmentation patterns were unveiled by a series of model compounds. Distinct glycosylation sites were discerned by leveraging varying fragmentation energies for the precursor ions. The sugar moiety linkage at C19OOH (R1) exhibited facile and intact cleavage at low collision energies, while the sugar moiety at C13-OH (R2) demonstrated consecutive cleavage with increasing energy. Aglycone ions exhibited a higher relative intensity at NCE 50, with relative intensities ranging from 95% to 100%. Subsequently, aglycone candidates, R1 sugar composition, and R2 sugar sequence were deduced through ER-MS/MS analysis. The developed method was applied to Stevia rebaudiana leaves. A total of 91 diterpene glycosides were unambiguously identified, including 16 steviol glycosides with novel acetylglycosylation patterns. This method offers a rapid alternative for glycan analysis and the structural differentiation of isomers. The developed method enhances the understanding of diterpene glycosides in plants, providing a reliable tool for the in-depth characterization of complex metabolite profiles.


Assuntos
Diterpenos do Tipo Caurano , Diterpenos , Glucosídeos , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Diterpenos/análise , Glicosídeos , Extratos Vegetais/química , Açúcares/análise , Íons/análise , Folhas de Planta/química
13.
Phytomedicine ; 126: 155462, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38394734

RESUMO

BACKGROUND: Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism. PURPOSE: This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT. METHODS: The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRß were used to evaluate the role of andrographolide on PDGFRß. The western blotting was used to investigate Wnt/ß-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo. RESULTS: Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRß and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/ß-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo. CONCLUSIONS: Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRß /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.


Assuntos
Neoplasias Colorretais , Diterpenos , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Cetuximab/farmacologia , Cetuximab/genética , Cetuximab/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores ErbB/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Via de Sinalização Wnt , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação
14.
J Nat Prod ; 87(2): 304-314, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38320172

RESUMO

Pleosmaranes A-R (1-18), 18 new isopimarane-type diterpenoids, together with four known analogs (19-22), were isolated from the mangrove endophytic fungus Pleosporales sp. HNQQJ-1. Their structures and absolute configurations were established by analysis of their spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1-9 possess an unusual aromatic B ring and a 20-nor-isopimarane skeleton. Compounds 15-17 contain a unique 2-oxabicyclo[2.2.2]octane moiety. Compound 18 features an unexpected 2-oxabicyclo[3.2.1]octane moiety. Compounds 8 and 12 exhibited a moderate inhibitory effect against LPS-induced NO production, with IC50 values of 19 and 25 µM, respectively.


Assuntos
Ascomicetos , Diterpenos , Abietanos/farmacologia , Octanos , Ascomicetos/química , Diterpenos/farmacologia , Estrutura Molecular
15.
J Nat Prod ; 87(2): 358-364, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38320400

RESUMO

Bioassay-guided isolation of the extract from the marine sponge Diacarnus spinipoculum showing inhibitory activity against human transient receptor potential ankyrin 1 (hTRPA1) resulted in the isolation of 12 norditerpene cyclic peroxides (1-12) and eight norsesterterpene cyclic peroxides (13-20). Among these, 10 (5-7, 11, 12, 16-20) are unprecedented analogs. Compounds with either a hydroxy (5, 11) or a methoxy (6, 12) group attached to the cyclohexanone moiety were obtained as epimeric mixtures at C-11, while compounds 4, 6, 10, and 12 are likely the artifacts of isolation. The absolute configurations of the new compounds were established based on an NMR-based empirical method and comparison of specific rotation values. Mosher ester analysis revealed the absolute configurations of compounds 17-20. The inhibitory activity of the isolated compounds against hTRPA1 varied significantly depending on their structures, with the norsesterterpenoid 19 displaying the most potent activity (IC50 2.0 µM).


Assuntos
Diterpenos , Poríferos , Animais , Humanos , Anquirinas/antagonistas & inibidores , Estrutura Molecular , Peróxidos/farmacologia , Peróxidos/química , Poríferos/química , Terpenos/farmacologia , Terpenos/química
16.
Clin Orthop Surg ; 16(1): 125-133, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38304216

RESUMO

Background: Foot deformities can cause abnormal biomechanics of the ankle joint and the development of osteoarthritis. It was hypothesized that foot deformities would be related to medial ankle osteoarthritis, and this study investigated this relationship using radiographic measurements. Methods: Seventy-six ankles of 76 patients (32 men and 44 women; mean age, 69.0 years) with medial ankle osteoarthritis were included. Eleven radiographic measurements evaluated ankle joint orientation (tibial plafond inclination [TPI], medial distal tibial angle [MDTA], and anterior distal tibial angle [ADTA]), ankle joint incongruency (tibiotalar tilt [TT]), foot deformities (lateral talo-first metatarsal angle [Lat talo-1MT], anteroposterior talo-first metatarsal angle [AP talo-1MT], and talonavicular coverage), talar body migration (medial talar center migration [MTCM] and anterior talar center migration [ATCM]), internal rotation (IR) of the talus, and mechanical tibiofemoral angle. All were statistically analyzed using Pearson's correlation coefficients and regression analyses. Results: Ankle joint orientation to the ground (TPI, p = 0.002), increased foot arch (Lat talo-1MT, p < 0.001), and IR of the talus (p = 0.001) were significantly associated with ankle joint incongruency (TT) in linear regression analysis. Ankle joint incongruency (TT, p = 0.003), medial talar body migration (MTCM, p = 0.042), and increased foot arch (Lat talo-1MT, p = 0.022) were significantly associated with IR of the talus in the binary logistic regression analysis. MTCM was significantly correlated with TPI (r = 0.251, p = 0.029), TT (r = 0.269, p = 0.019), MDTA (r = 0.359, p = 0.001), ATCM (r = -0.522, p < 0.001), and AP talo-1MT (r = 0.296, p = 0.015). ATCM was significantly correlated with TPI (r = -0.253, p = 0.027), ADTA (r = 0.349, p = 0.002), and Lat talo-1MT (r = -0.344, p = 0.002). Conclusions: Ankle joint orientation, foot deformities, and talar rotation were associated with ankle joint incongruency in medial ankle osteoarthritis when evaluated radiographically. These findings need to be considered during surgical treatment for medial ankle osteoarthritis. However, the biomechanical significance of these radiographic measurements requires further investigation.


Assuntos
Diterpenos , Deformidades do Pé , Osteoartrite do Joelho , Masculino , Humanos , Feminino , Idoso , Tornozelo , Estudos Retrospectivos , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia
17.
J Ethnopharmacol ; 324: 117791, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38301987

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. AIM OF THE STUDY: This study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. MATERIALS AND METHODS: This experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. RESULTS: The findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. CONCLUSIONS: Results suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.


Assuntos
Abietanos , Diterpenos , Salvia miltiorrhiza , Neoplasias Gástricas , Animais , Camundongos , Humanos , Neoplasias Gástricas/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Camundongos Nus , Serina-Treonina Quinases TOR , Transdução de Sinais , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Salvia miltiorrhiza/química
18.
Pharm Biol ; 62(1): 183-194, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38351624

RESUMO

CONTEXT: The therapeutic potential of andrographolide is hindered by its poor oral bioavailability and unpredictable pharmacokinetics, primarily due to its limited water solubility. OBJECTIVE: This work aimed to enhance the solubility and pharmacokinetics of andrographolide, a bioactive compound in Andrographis paniculata (Burm. f.) Nees (Acanthaceae), using solubilizing agents and a bioenhancer. MATERIALS AND METHODS: Four groups of beagles were compared: (1) A. paniculata powder alone (control), (2) A. paniculata powder with 50% weight/weight (w/w) ß-cyclodextrin solubilizer, (3) A. paniculata powder with 1% w/w sodium dodecyl sulfate (SDS) solubilizer, and (4) A. paniculata powder co-administered with 1% w/w SDS solubilizer and 10% piperine bioenhancer. All groups received a consistent oral dose of 3 mg/kg of andrographolide, administered both as a single dose and multiple doses over seven consecutive days. RESULTS: Thirteen chemical compounds were identified in A. paniculata powder, including 7 diterpenoids, 5 flavonoids, and 1 phenolic compound. A. paniculata co-administration with either 50% w/w ß-cyclodextrin or 1% w/w SDS, alone or in combination with 10% w/w piperine, significantly increased systemic andrographolide exposure by enhancing bioavailability (131.01% to 196.05%) following single and multiple oral co-administration. Glucuronidation is one possible biotransformation pathway for andrographolide, as evidenced by the excretion of glucuronide conjugates in urine and feces. CONCLUSION: The combination of solubilizing agents and a bioenhancer improved the oral bioavailability and pharmacokinetics of andrographolide, indicating potential implications for A. paniculata formulations and clinical therapeutic benefits. Further investigation in clinical studies is warranted.


Assuntos
Alcaloides , Andrographis , Benzodioxóis , Diterpenos , Piperidinas , Alcamidas Poli-Insaturadas , beta-Ciclodextrinas , Animais , Cães , Andrographis paniculata , Disponibilidade Biológica , Pós , Andrographis/química , Extratos Vegetais , Excipientes
19.
Vet Microbiol ; 290: 109992, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38306769

RESUMO

Brachyspira species are Gram negative, anaerobic bacteria that colonise the gut of many animals, including poultry. In poultry, Brachyspira species can be commensal (B. innocens, B. murdochii, 'B. pulli') or pathogenic (B. pilosicoli, B. intermedia, B. alvinipulli or rarely B. hyodysenteriae), the latter causing avian intestinal spirochaetosis (AIS). Antimicrobial therapy options for treatment is limited, frequently involving administration of the pleuromutilin, tiamulin, in water. In this study 38 Brachyspira isolates from chickens in the UK, representing both commensal and pathogenic species, were whole genome sequenced to identify antimicrobial resistance (AMR) mechanisms and the minimum inhibitory concentration (MIC) to a number of antimicrobials was also determined. We identified several new variants of blaOXA in B. pilosicoli and B. pulli isolates, and variations in tva which led to two new tva variants in B.murdochii and B.pulli. A number of isolates also harboured mutations known to encode AMR in the 16S and 23S rRNA genes. The percentage of isolates that were genotypically multi-drug resistance (MDR) was 16%, with the most common resistance profile being: tetracycline, pleuromutilin and beta-lactam, which were found in three 'B. pulli' and one B. pilosicoli. There was good correlation with the genotype and the corresponding antibiotic MIC phenotypes: pleuromutilins (tiamulin and valnemulin), macrolides (tylosin and tylvalosin), lincomycin and doxycycline. The occurrence of resistance determinants identified in this study in pathogenic Brachyspira, especially those which were MDR, is likely to impact treatment of AIS and clearance of infections on farm.


Assuntos
Brachyspira , Infecções por Bactérias Gram-Negativas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Galinhas/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Farmacorresistência Bacteriana/genética , Resistência beta-Lactâmica , Reino Unido , Diterpenos
20.
Molecules ; 29(4)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38398604

RESUMO

Andrographis paniculata is a medicinal plant traditionally used to produce diterpene lactones and flavonoids, which possess various biological activities. Widely distributed in China, India, and other Southeast Asia countries, A. paniculata has become an important economic crop, significantly treating SARS-CoV-2, and is being cultivated on a large scale in southern China. The biosynthesis of active ingredients in A. paniculata are regulated and controlled by genes, but their specific roles are still not fully understood. To further explore the growth regulation factors and utilization of its medicinal parts of this industrial crop, chemical and transcriptome analyses were conducted on the roots, stems, and leaves of A. paniculata to identify the biosynthesis pathways and related candidate genes of the active ingredients. The chemical analysis revealed that the main components of A. paniculata were diterpene lactones and flavonoids, which displayed potential ability to treat SARS-CoV-2 through molecular docking. Moreover, the transcriptome sequencing annotated a total of 40,850 unigenes, including 7962 differentially expressed genes. Among these, 120 genes were involved in diterpene lactone biosynthesis and 60 genes were involved in flavonoid biosynthesis. The expression of diterpene lactone-related genes was the highest in leaves and the lowest in roots, consistent with our content determination results. It is speculated that these highly expressed genes in leaves may be involved in the biosynthesis pathway of diterpenes. Furthermore, two class Ⅰ terpene synthases in A. paniculata transcriptome were also annotated, providing reference for the downstream pathway of the diterpene lactone biosynthesis. With their excellent market value, our experiments will promote the study of the biosynthetic genes for active ingredients in A. paniculata and provide insights for subsequent in vitro biosynthesis.


Assuntos
Andrographis , Diterpenos , Terpenos/metabolismo , Transcriptoma , Andrographis/genética , Andrographis/química , Flavonoides/metabolismo , Simulação de Acoplamento Molecular , Diterpenos/química , Lactonas/metabolismo , Antivirais/metabolismo
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