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1.
Pharm Biol ; 60(1): 1690-1700, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36073930

RESUMO

CONTEXT: Kirenol possesses anti-inflammatory, antifibrotic and anti-arthritic effects. However, its reno-protective effects against diabetic nephropathy (DN) have not been evaluated. OBJECTIVE: This study explores the reno-protective effects of kirenol against DN and clarifies the potential mechanisms. MATERIALS AND METHODS: The mesangial cells were treated with 20 µM kirenol and 10 ng/mL human recombinant TGF-ß1 or 30 mM glucose for 24 h. Then the cells were harvested to assay the expression of the target genes or proteins. Thirty C57BL/6J male mice were given high-fat diet with streptozotocin injection to induce diabetes and then were randomized into three groups (n = 10): vehicle administration (DM group), 2 mg/kg kirenol (DM + kirenol group) and 200 mg/kg metformin (Met group) for 3 months, orally. A healthy group (Con, n = 10) was included as the control. RESULTS: Compared to the DM group, kirenol treatment decreased the phosphorylation of Smad2/3 and NF-κB (0.64- and 0.43-fold) as well as the accumulation of FN and Col IV (0.58- and 0.35-fold); moreover, the expression of IκBα was restored to normal level by kirenol treatment both in vivo and in vitro. After kirenol treatment, IL-6 expression was decreased 0.35- and 0.57-fold, and TNF-α expression was decreased 0.34- and 0.46-fold, in vitro and in vivo, respectively. Furthermore, kirenol alleviated the glomerular basement membrane thickness and foot process fusion. DISCUSSION AND CONCLUSIONS: Kirenol could alleviate DN by downregulating the TGF-ß/Smads and the NF-κB signal pathway. Our study provides a potential mechanism for the treatment of DN with kirenol.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Diterpenos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
2.
Molecules ; 27(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36080468

RESUMO

Four new daphnane-type diterpenes named tianchaterpenes C-F (1-4) and six known ones were isolated from Stelleropsis tianschanica. Their structures were elucidated based on chemical and spectral analyses. The comparisons of calculated and experimental electronic circular dichroism (ECD) methods were used to determine the absolute configurations of new compounds. Additionally, compounds 1-10 were evaluated for their cytotoxic activities against HGC-27 cell lines; the results demonstrate that compound 2 had strong cytotoxic activities with IC50 values of 8.8 µM, for which activity was better than that of cisplatin (13.2 ± 0.67 µM).


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Diterpenos , Medicamentos de Ervas Chinesas , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/química , Estrutura Molecular
3.
Molecules ; 27(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36080472

RESUMO

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 µg/mL and 5.71 ± 0.14 µg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 µg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.


Assuntos
Antineoplásicos , Caesalpinia , Diterpenos , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Diterpenos/farmacologia , Humanos , Estrutura Molecular , Óxido Nítrico/metabolismo , Polienos/farmacologia
4.
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
5.
Zhongguo Zhong Yao Za Zhi ; 47(15): 4183-4189, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046909

RESUMO

This study aims to establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method for determining the concentrations of triptolide(TP) in plasma and liver, and to explore the toxicokinetics of TP and the relationship between TP exposure and liver injury in C57 BL/6 mice, so as to provide reference for dissecting the toxicity mechanism of TP. The liquid chromatography was conducted with ZORBAX SB-C_(18) column(3.0 mm×100 mm, 3.5 µm) and the mobile phase of methanol-0.05 mmol·L~(-1) ammonium acetate. Electrospray ionization(ESI) and multiple reaction monitoring(MRM) mode were employed for mass spectrometry. After oral administration of TP(toxic dose 600 µg·kg~(-1)), the blood and liver tissues of the C57 BL/6 mice were collected at different time points to measure the TP concentrations in plasma and liver tissues. Furthermore, the blood biochemical indexes, including alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), and total bile acid(TBA), were determined. After being processed by DAS 2.0, the experiment data showed that the TP in mice had the toxicokinetic parameters of T_(max)=5 min, C_(max)=14.38 ng·mL~(-1), t_(1/2)=0.76 h, AUC_(0-t)=5.63 h·ng·mL~(-1), MRT_(0-t)=0.56 h, and CL_(Z/F)=103.19 L·h~(-1)·kg~(-1). The trend of TP concentration in mouse liver tissue was consistent with that in plasma. The concentration of TP peaked at the time point of 5 min and then decreased until TP was completely metabolized. The plasma biochemical indexes(ALT, AST, ALP, and TBA) showed no significant changes within 3 h after TP administration. TP had high clearance rate and short residence time and did not significantly increase the blood biochemical indexes in mice. The results suggested that the exposure amount of free TP in vivo cannot directly cause liver injury, which might be caused by the binding of TP to some substances or the stimulation of inflammation and immune response.


Assuntos
Fígado , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão/métodos , Diterpenos , Compostos de Epóxi , Camundongos , Fenantrenos , Espectrometria de Massas em Tandem/métodos , Toxicocinética
6.
Biomed Pharmacother ; 149: 112906, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-36068772

RESUMO

Delphinium trichophorum Franch (DTF), a species endemic to China, has been widely used for centuries in Tibet as an indigenous medicine for treating cough, pneumonia, and pulmonary fibrosis. Hetisine-type C20-diterpenoid alkaloids have been reported to be characteristic and active ingredients. Herein, five ones with relatively high contents in D. trichophorum, including 2α,11α,13ß-triacetylhetisine (DTF1), trichodelphinine A (DTF2), trichodelphinine D (DTF3), 2α-acetyl-11α,13ß-dihydroxyhetisine (DTF4), and trichodelphinine C (DTF5), were investigated for anti-fibrosis effects using fibroblasts induced by TGF-ß1 or LPS for the first time. The results showed that all five tested compounds decreased hydroxyproline (HYP) levels and inhibited the abnormal proliferation of 3T6 and HFL-1 cells induced by either TGF-ß1 or LPS. Moreover, DTF1 and DTF2 attenuated the production of collagen (Col-1 and Col-3) at relatively low doses, suggesting their higher efficiency among the five alkaloids. Based on large-scale ligand-based pharmacophore modeling, TGFBR1 was screened as a potential target for these tested alkaloids. The molecular docking results also exhibited high-affinity interactions between TGFBR1 and five alkaloids, especially DTF1 and DTF2. Further experiments revealed that DTF1 and DTF2 could inhibit the expression of TGF-ß1 and α-SMA and the phosphorylation of Smad3 and Smad4 while restoring the expression of Smad7 protein. Overall, DTF1 and DTF2 may reduce collagen generation and delay the development of pulmonary fibrosis by inhibiting the activation of the TGF-ß/Smad signaling pathway. Our results provide experimental and theoretical evidence for DTF1 and DTF2 as superior candidates for further development of anti-fibrotic drugs.


Assuntos
Alcaloides , Delphinium , Diterpenos , Fibrose Pulmonar , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Delphinium/metabolismo , Diterpenos/uso terapêutico , Fibrose , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
7.
Thromb Res ; 218: 177-185, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36057168

RESUMO

BACKGROUND: Postoperative myocardial injury (PMI) after major vascular surgery, detected by elevated cardiac troponin (cTn), has been associated with morbidity and mortality. It is unclear whether the pathophysiology of PMI is determined by increased platelet activity. OBJECTIVE: To examine the relationship between platelet activation (P-selectin expression) and PMI in patients undergoing elective open abdominal aortic surgery. METHODS: This prospective, single-centre, observational, cohort study included 33 patients undergoing elective open abdominal aortic surgery between March 2018 and April 2021. Patients were routinely treated with aspirin. Unstimulated platelet activation was measured by platelet bound P-selectin expression (range 0-100 %). Explorative coagulation measurements were: stimulated platelet aggregation measured with the VerifyNow® assay (aspirin cartridge), with the Multiplate® analyzer (ASPI, ADP and TRAP) and stimulated coagulation status evaluated by the TEG® Hemostasis Analyzer System (global hemostasis cartridge). The primary outcome was cTn release assessed by the fifth generation high-sensitive cTn assay. Multivariable generalized linear mixed models were used to evaluate the association between platelet function and cTn concentrations over time. RESULTS: Ten patients (30.3 %) developed PMI. Increased P-selectin expression directly after surgery was associated with the cTn concentrations over 48 h (ß = 1.39 (1.1-1.75), P = 0.0064). No association was found between P-selectin measured later after surgery (at 24 h or 48 h) and cTn concentrations. Furthermore, there was no association between the explorative coagulation parameters and cTn release. CONCLUSION: Platelet reactivity, assessed by P-selectin expression measured directly after surgery is associated with PMI, assessed by elevated cTn concentrations in the early postoperative period in patients undergoing elective open abdominal aortic surgery.


Assuntos
Aspirina , Selectina-P , Difosfato de Adenosina , Estudos de Coortes , Diterpenos , Humanos , Período Pós-Operatório , Estudos Prospectivos , Troponina , Procedimentos Cirúrgicos Vasculares/efeitos adversos
8.
Microb Cell Fact ; 21(1): 197, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123694

RESUMO

BACKGROUND: CYP725A4 catalyses the conversion of the first Taxol® precursor, taxadiene, to taxadiene-5α-ol (T5α-ol) and a range of other mono- and di-hydroxylated side products (oxygenated taxanes). Initially known to undergo a radical rebound mechanism, the recent studies have revealed that an intermediate epoxide mediates the formation of the main characterised products of the enzyme, being T5α-ol, 5(12)-oxa-3(11)-cyclotaxane (OCT) and its isomer, 5(11)-oxa-3(11)-cyclotaxane (iso-OCT) as well as taxadienediols. Besides the high side product: main product ratio and the low main product titre, CYP725A4 is also known for its slow enzymatic activity, massively hindering further progress in heterologous production of Taxol® precursors. Therefore, this study aimed to systematically explore the key parameters for improving the regioselectivity and activity of eukaryotic CYP725A4 enzyme in a whole-cell eukaryotic biocatalyst, Saccharomyces cerevisiae. RESULTS: Investigating the impact of CYP725A4 and reductase gene dosages along with construction of self-sufficient proteins with strong prokaryotic reductases showed that a potential uncoupling event accelerates the formation of oxygenated taxane products of this enzyme, particularly the side products OCT and iso-OCT. Due to the harmful effect of uncoupling products and the reactive metabolites on the enzyme, the impact of flavins and irons, existing as prosthetic groups in CYP725A4 and reductase, were examined in both their precursor and ready forms, and to investigate the changes in product distribution. We observed that the flavin adenine dinucleotide improved the diterpenoids titres and biomass accumulation. Hemin was found to decrease the titre of iso-OCT and T5α-ol, without impacting the side product OCT, suggesting the latter being the major product of CYP725A4. The interaction between this iron and the iron precursor, δ-Aminolevulinic acid, seemed to improve the production of these diterpenoids, further denoting that iso-OCT and T5α-ol were the later products. While no direct correlation between cellular-level oxidative stress and oxygenated taxanes was observed, investigating the impact of salt and antioxidant on CYP725A4 further showed the significant drop in OCT titre, highlighting the possibility of enzymatic-level uncoupling event and reactivity as the major mechanism behind the enzyme activity. To characterise the product spectrum and production capacity of CYP725A4 in the absence of cell growth, resting cell assays with optimal neutral pH revealed an array of novel diterpenoids along with higher quantities of characterised diterpenoids and independence of the oxygenated product spectra from the acidity effect. Besides reporting on the full product ranges of CYP725A4 in yeast for the first time, the highest total taxanes of around 361.4 ± 52.4 mg/L including 38.1 ± 8.4 mg/L of T5α-ol was produced herein at a small, 10-mL scale by resting cell assay, where the formation of some novel diterpenoids relied on the prior existence of other diterpenes/diterpenoids as shown by statistical analyses. CONCLUSIONS: This study shows how rational strain engineering combined with an efficient design of experiment approach systematically uncovered the promoting effect of uncoupling for optimising the formation of the early oxygenated taxane precursors of Taxol®. The provided strategies can effectively accelerate the design of more efficient Taxol®-producing yeast strains.


Assuntos
Diterpenos , Paclitaxel , Alcenos , Ácido Aminolevulínico , Antioxidantes , Hidrocarbonetos Aromáticos com Pontes , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/metabolismo , Compostos de Epóxi , Flavina-Adenina Dinucleotídeo , Hemina , Ferro , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Taxoides/metabolismo
9.
Biomed Pharmacother ; 153: 113443, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076558

RESUMO

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.


Assuntos
Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Diterpenos , Neoplasias Pulmonares , Animais , Apoptose , Autofagia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Receptores ErbB , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Fosfatidilinositol 3-Quinases , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR/metabolismo
10.
J Am Chem Soc ; 144(36): 16332-16337, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36043948

RESUMO

From both structural and functional perspectives, the large family of daphnane diterpene orthoesters (DDOs) represent a truly remarkable class of natural products. As potent lead compounds for the treatment of pain, neurodegeneration, HIV/AIDS, and cancer, their medicinal potential continues to be heavily investigated, yet synthetic routes to DDO natural products remain rare. Herein we report a distinct approach to this class of complex diterpenes, highlighted by a 15-step total synthesis of the flagship DDO, resiniferatoxin.


Assuntos
Produtos Biológicos , Diterpenos
11.
Chem Biodivers ; 19(9): e202200473, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35931661

RESUMO

An undescribed tigliane diterpenoid, 13-acetyl-12,17-di-O-tiglylphorbol (1), along with thirty-three known components, were isolated from the stems of Croton tiglium L. var. xiaopadou (Euphorbiaceae). Their structures were established based on spectroscopic data and ECD spectra. Their anti-neuroinflammatory effects were evaluated in LPS-induced BV-2 microglia. Thirteen tested compounds showed significant inhibitory activities, especially compounds 10, 16, 18 and 21 exhibited an inhibitory effect with IC50 values in the range of 12.39 to 17.80 µM, which are comparable with that of the positive control (minocycline, IC50 13.92 µM).


Assuntos
Croton , Diterpenos , Forbóis , Croton/química , Diterpenos/química , Diterpenos/farmacologia , Lipopolissacarídeos/farmacologia , Minociclina , Estrutura Molecular , Doenças Neuroinflamatórias
12.
Bioorg Chem ; 128: 106067, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35921787

RESUMO

Thirteen undescribed diterpenoids, including an ent-isopimarane (1), ten ent-atisanes (2-8 and 15-17), and two ingenanes (20 and 21) and ten known compounds, were separated from the whole plant of E. wallichii. The structures and absolute stereochemistry of these compounds were delineated by 1D and 2D NMR, mass spectrometry, pyridine-induced solvent shifts, and X-ray diffraction analyses. Euphwanoid A (1) is elucidated as an ent-16­norisopimarane type diterpenoid featuring a C-8-O-C-15 lactone fragment. And euphwanoid B (2) represents a rare ent-atisane type tetranorditerpene possessing a tetrahydrofuran moiety. In addition, all these isolated compounds were assayed for their protective effects on H2O2-induced BV-2 microglial cells damage. And representative compound 1 could protect BV-2 cells against oxidative damage via the NRF2/HO-1 signaling pathway.


Assuntos
Diterpenos , Euphorbia , Diterpenos/química , Diterpenos/farmacologia , Euphorbia/química , Peróxido de Hidrogênio/farmacologia , Microglia , Estrutura Molecular
13.
Bioorg Chem ; 128: 106059, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35933895

RESUMO

Ten new icetexane diterpenoids, salpratins E-N (1-10) and a known analogue (11) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 â†’ 3)-abeo-icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Cav3.2 T-type Ca2+ channel (TTCC) inhibitors with IC50 values of 2.9, 5.1, 2.3, and 3.2 µM, respectively. Five icetexane related derivatives (13-17) were synthesized from an abietane type precursor, (+)-carnosic acid (12), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Cav3.2, having IC50 values of 6.7 and 2.4 µM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Cav3.2 analgesics.


Assuntos
Canais de Cálcio Tipo T , Diterpenos , Salvia , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Camundongos , Estrutura Molecular , Salvia/química
14.
J Nanobiotechnology ; 20(1): 384, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35999612

RESUMO

BACKGROUND: Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. RESULTS: We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. CONCLUSION: The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.


Assuntos
Exossomos , Integrina alfaVbeta3/metabolismo , Melanoma , Neoplasias Cutâneas , Animais , Linhagem Celular Tumoral , Diterpenos , Compostos de Epóxi , Exossomos/metabolismo , Humanos , Integrinas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Peptídeos Cíclicos/metabolismo , Fenantrenos , Neoplasias Cutâneas/tratamento farmacológico , Distribuição Tecidual
15.
Drug Deliv ; 29(1): 2751-2758, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35999774

RESUMO

Triptolide (TP) has its unique curative effect in the treatment of rheumatoid arthritis (RA), but its application is limited by the poor water solubility and multi-organ toxicity. We herein developed a novel nanoparticle platform composed of L-ascorbate palmitate (VP, vitamin C derivative) that can deliver TP to synergistically treat arthritis and inhibit the occurrence of oxidative stress. The TP-loaded nanoparticles (termed TP-VP NPs) showed the suitable particle size (about 145 nm) and good physical stability. TP-VP NPs effectively down-regulated IL-1ß, IL-6 and TNF-α levels to inhibit the erosion of synovitis and bone tissue, and alleviate the swelling and deformation of CIA mice's feet. Compared to the TP, TP-VP NPs could inhibit effectively the oxidative stress in liver, and alleviate significantly the triptolide-induced toxicity injury in liver, kidney and testicle. The results demonstrated that TP-VP NPs is a promising triptolide delivery system for the treatment of RA, which enhances the water solubility of TP and reduces the toxicity of TP in vivo.


Assuntos
Artrite Reumatoide , Diterpenos , Fenantrenos , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Ácido Ascórbico , Diterpenos/farmacologia , Compostos de Epóxi , Camundongos , Micelas , Palmitatos/uso terapêutico , Fenantrenos/farmacologia , Água
16.
PLoS One ; 17(8): e0272520, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35925998

RESUMO

Agricultural practice in adjusting planting density and harvest date are important factors for plant development and crop improvement, reaching maximum yields and enhancing the production of secondary metabolites. However, it is unclear as to the optimal planting densities during mass production that encourage consistent, high yield secondary metabolite content. For this, controlled environment, crop production facilities such as plant factories with artificial lighting (PFAL) offer opportunity to enhance quality and stabilize production of herbal plants. This study assessed the effect of plant density and harvest date on physiological responses, yield and andrographolide (AP1) content in Andrographis paniculata (Andrographis) using hydroponic conditions in a PFAL system. Andrographis, harvested at vegetative stage (30 days after transplanting; 30 DAT) and initial stage of flowering (60 DAT) exhibited no significant differences in growth parameters or andrographolide accumulation according to planting densities. Harvest time at flowering stage (90 DAT) showed the highest photosynthetic rates at a planting density of 15 plants m-2. Highest yield, number of leaves, and Andrographolide (AP1) content (mg per gram of DW in m2) were achieved at a more moderate planting density (30 plants m-2). Finally, five out of seventeen indices of leaf reflectance reveal high correlation (r = 0.8 to 1.0 and r = -0.8 to -1.0, P<0.01) with AP1 content. These results suggest that a planting density of 30 plants m-2 and harvest time of 90 DAT provide optimal growing condition under the hydroponic PFAL system.


Assuntos
Andrographis , Diterpenos , Andrographis/metabolismo , Andrographis paniculata , Diterpenos/metabolismo , Extratos Vegetais/metabolismo , Folhas de Planta/metabolismo
17.
Mar Drugs ; 20(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36005501

RESUMO

Three new 5,5,6,6,5-pentacyclic spongian diterpenes, spongenolactones A-C (1-3), were isolated from a Red Sea sponge Spongia sp. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and the absolute configurations of 1-3 were determined on the basis of comparison of the experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. Compounds 1-3 are the first 5,5,6,6,5-pentacyclic spongian diterpenes bearing an ß-hydroxy group at C-1. These metabolites were assayed for their cytotoxic, antibacterial, and anti-inflammatory activities. All three compounds were found to exert inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils. Furthermore, 1 showed a higher activity against the growth of Staphylococcus aureus in comparison to 2.


Assuntos
Diterpenos , Poríferos , Animais , Diterpenos/química , Humanos , Oceano Índico , Estrutura Molecular , Staphylococcus aureus
18.
Mar Drugs ; 20(8)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36005518

RESUMO

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.


Assuntos
Diterpenos , Hipertensão , Sítios de Ligação , Canais de Cálcio Tipo L/metabolismo , Diterpenos/farmacologia , Humanos , Lactonas , Vasodilatadores/farmacologia
19.
Molecules ; 27(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36014466

RESUMO

Euphorbia resinifera latex has been extensively utilized in traditional medicine due to its range of bioactivities. Chromatographic separations on silica gel of ethanol extract of E. resinifera latex led to the development of a new procedure for isolating resiniferatoxin (4) via dried E. resinifera latex and the identification of nine compounds. Among these, catechol (7), protocatechuic acid (8) and 3,4-dihydroxyphenylacetic acid (9), known phenolic compounds, were identified for the first time in E. resinifera latex. Herein we investigated the effects of major compounds of the latex of E. resinifera on the yeast Saccharomyces cerevisiae, on the growth of Aspergillus carbonarius, a widespread fungal contaminant, and on the breast cancer cell line MCF7 as well as on MCF10A normal breast cells. 12-deoxyphorbol-13-isobutyrate-20-acetate (2) had an inhibiting effect on the growth of A. carbonarius, and 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) showed a negative effect on yeast cell growth and also a cytotoxic effect on breast cancer cell line MCF7, but not on MCF10A cells. Deglucosyl euphorbioside A (5) and euphorbioside A (6) showed a discoloration effect that was possibly related to mitochondrial functionality in yeast, and also cytotoxicity only on the cancer cell line that was tested. Interestingly, treatment of MCF7 cells with 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) and deglucosyl euphorbioside A (5) not only led to a specific cytotoxic effect but also to the increase in the level of intracellular ROS.


Assuntos
Antineoplásicos , Neoplasias da Mama , Diterpenos , Euphorbia , Antifúngicos , Antineoplásicos/farmacologia , Diterpenos/química , Euphorbia/química , Feminino , Humanos , Látex/química , Saccharomyces cerevisiae
20.
J Am Chem Soc ; 144(33): 15033-15037, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35948064

RESUMO

Mollanol A is the first isolated member of the mollane-type grayanoids which possesses an unprecedented C-nor-D-homograyanane carbon skeleton and an 5,8-epoxide. Due to its transcriptional activation effects on the Xbp1 upstream promoters in different cell types, it has a potential therapeutic effect on inflammatory bowel disease. Here we report the first total synthesis of mollanol A, which constitutes a 15-step synthesis from commercially available materials via a convergent strategy. The synthesis involves an InCl3-catalyzed Conia-ene cyclization reaction to construct the bicyclo[3.2.1]octane moiety and a vinylogous aldol reaction/intramolecular oxa-Michael addition sequence to rapidly assemble the oxa-bicyclo[3.2.1] core.


Assuntos
Diterpenos , Ciclização
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