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1.
Int J Mol Sci ; 22(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638551

RESUMO

Different approaches have been reported to enhance penetration of small drugs through physiological barriers; among them is the self-assembly drug conjugates preparation that shows to be a promising approach to improve activity and penetration, as well as to reduce side effects. In recent years, the use of drug-conjugates, usually obtained by covalent coupling of a drug with biocompatible lipid moieties to form nanoparticles, has gained considerable attention. Natural products isolated from plants have been a successful source of potential drug leads with unique structural diversity. In the present work three molecules derived from natural products were employed as lead molecules for the synthesis of self-assembled nanoparticles. The first molecule is the cytotoxic royleanone 7α-acetoxy-6ß-hydroxyroyleanone (Roy, 1) that has been isolated from hairy coleus (Plectranthus hadiensis (Forssk.) Schweinf). ex Sprenger leaves in a large amount. This royleanone, its hemisynthetic derivative 7α-acetoxy-6ß-hydroxy-12-benzoyloxyroyleanone (12BzRoy, 2) and 6,7-dehydroroyleanone (DHR, 3), isolated from the essential oil of thicket coleus (P. madagascariensis (Pers.) Benth.) were employed in this study. The royleanones were conjugated with squalene (sq), oleic acid (OA), and/or 1-bromododecane (BD) self-assembly inducers. Roy-OA, DHR-sq, and 12BzRoy-sq conjugates were successfully synthesized and characterized. The cytotoxic effect of DHR-sq was previously assessed on three human cell lines: NCI-H460 (IC50 74.0 ± 2.2 µM), NCI-H460/R (IC50 147.3 ± 3.7 µM), and MRC-5 (IC50 127.3 ± 7.3 µM), and in this work Roy-OA NPs was assayed against Vero-E6 cells at different concentrations (0.05, 0.1, and 0.2 mg/mL). The cytotoxicity of DHR-sq NPs was lower when compared with DHR alone in these cell lines: NCI-H460 (IC50 10.3 ± 0.5 µM), NCI-H460/R (IC50 10.6 ± 0.4 µM), and MRC-5 (IC5016.9 ± 0.5 µM). The same results were observed with Roy-OA NPs against Vero-E6 cells as was found to be less cytotoxic than Roy alone in all the concentrations tested. From the obtained DLS results, 12BzRoy-sq assemblies were not in the nano range, although Roy-OA NP assemblies show a promising size (509.33 nm), Pdl (0.249), zeta potential (-46.2 mV), and spherical morphology from SEM. In addition, these NPs had a low release of Roy at physiological pH 7.4 after 24 h. These results suggest the nano assemblies can act as prodrugs for the release of cytotoxic lead molecules.


Assuntos
Abietanos/química , Abietanos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Animais , Linhagem Celular , Chlorocebus aethiops , Humanos , Hidrocarbonetos Bromados/química , Ácido Oleico/química , Extratos Vegetais/química , Plectranthus/química , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacologia , Esqualeno/química , Testes de Toxicidade Aguda/métodos , Células Vero
2.
Molecules ; 26(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34577074

RESUMO

Nepeta bracteata Benth. is used clinically to treat tracheal inflammation, coughs, asthma, colds, fevers, adverse urination, and other symptoms, along with functions in clearing heat and removing dampness. However, there have been few studies characterizing the material basis of its efficacy. Therefore, the aim of this study was to screen for compounds with anti-inflammatory activities in N. bracteata Benth. Using silica gel, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, 10 compounds were separated from N. bracteata Benth. extract, including four new diterpenoids (1-4), one amide alkaloid (5), and five known diterpenoids (6-10). The structures of all the isolates were elucidated by HR-ESI-MS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, we investigated the anti-inflammatory activities of compounds 1-10. It is worth noting that all were able to inhibit nitric oxide (NO) production with IC50 values < 50 µM and little effect on RAW 264.7 macrophage viability. Compounds 2 and 4 displayed remarkable inhibition with IC50 values of 19.2 and 18.8 µM, respectively. Meanwhile, screening on HCT-8 cells demonstrated that compounds 2 and 4 also had moderate cytotoxic activities with IC50 values of 36.3 and 41.4 µM, respectively, which is related to their anti-inflammatory effects.


Assuntos
Abietanos/farmacologia , Anti-Inflamatórios/farmacologia , Nepeta/química , Extratos Vegetais/farmacologia , Abietanos/química , Abietanos/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Camundongos , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Células RAW 264.7
3.
Phytochemistry ; 192: 112950, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34530282

RESUMO

Carnosic acid (CA), a phenolic diterpene and abietane-type compound, is a potent natural antioxidant with medical benefits. The present paper elucidates, for the first time, the kinetics and the exact mechanism of the peroxyl radical scavenging activity of CA in the gas phase and under physiological conditions. According to the obtained results, the reaction of CA with HOO• is significantly faster in aqueous solution than in the gas phase and nonpolar environments. The abstraction of the hydrogen atom from 2-OH is the decisive mechanism in the gas phase and nonpolar media, while both hydrogen abstraction (15%) and electron transfer (85%) mechanisms can take place in aqueous solution. The overall rate coefficient in water (4.73 × 106 M-1 s-1) is about 36 times higher than that of the reference antioxidant Trolox (1.30 × 105 M-1 s-1), suggesting that CA is a potent scavenger of peroxyl radicals in polar media.


Assuntos
Abietanos , Sequestradores de Radicais Livres , Abietanos/farmacologia , Antioxidantes/farmacologia , Sequestradores de Radicais Livres/farmacologia , Cinética , Peróxidos
4.
Biomolecules ; 11(7)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356625

RESUMO

Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson's disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC50 less than 10 µM. They also suppressed hMAO-B activity, with an IC50 below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M4 antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD.


Assuntos
Abietanos , Inibidores da Monoaminoxidase , Monoaminoxidase , Fenantrenos , Receptor Muscarínico M4 , Salvia miltiorrhiza/química , Abietanos/química , Abietanos/farmacologia , Animais , Células CHO , Cricetulus , Humanos , Monoaminoxidase/química , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Receptor Muscarínico M4/química , Receptor Muscarínico M4/genética , Receptor Muscarínico M4/metabolismo
5.
Phytochemistry ; 191: 112926, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34425461

RESUMO

Two seco-norabietane diterpenes with unique structures, namely abrotafuran and abrotacid, were isolated from the roots of Salvia abrotanoides (Kar.) Sytsma. The compounds were characterized by 1D and 2D NMR spectroscopic techniques, ECD, and HR-ESIMS experiments. Plausible biosynthetic pathways of abrotafuran and abrotacid were proposed. These compounds did not exhibit antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa. However, the rearranged seco-norabietane abrotafuran showed antiproliferative activity on HeLa (cervical carcinoma) and Jurkat (T-cell leukemia) cell lines.


Assuntos
Diterpenos , Salvia , Abietanos/farmacologia , Diterpenos/farmacologia , Estrutura Molecular , Raízes de Plantas , Esqueleto
6.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443454

RESUMO

Two new abietane diterpenoids (1,2), along with five known diterpenoids (3-7), were first isolated and purified from the stems of Clerodendrum bracteatum. The structures of the new compounds were established by extensive analysis of mass spectrometric and 1-D, 2-D NMR spectroscopic data. Their antioxidant activities were determined on DPPH radical scavenging and ABTS. The in vitro cytotoxic activities of the compounds were evaluated against the HL-60 and A549 cell lines by the MTT method.


Assuntos
Abietanos/isolamento & purificação , Abietanos/farmacologia , Antioxidantes/farmacologia , Clerodendrum/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Células A549 , Abietanos/química , Morte Celular/efeitos dos fármacos , Diterpenos/química , Células HL-60 , Humanos , Espectroscopia de Ressonância Magnética
7.
Dermatol Ther ; 34(5): e15086, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34350676

RESUMO

Tanshinone IIA has been reported to exhibit anti-inflammatory effects, while it is not clear whether Tanshinone IIA has protective role in vitiligo. Premelanosome (PMEL) CD8+ T cells were adoptive transferred into Krt14- Kitl* mice with Kit ligand (KITL) over-expressed, to construct the vitiligo model. Pdk1fl/fl and Stat3fl/fl mice were crossed with Cd8cre mice to establish Pdk1TKO and Stat3TKO mice. Tanshinone IIA (200 µg) was intravenous injected to treat vitiligo in mice every 3 days. The accumulation of macrophages and CD8+ T cells in the ear skin was assayed by flow cytometry. Bone marrow-derived macrophages (BMDMs) were induced and stimulated with lipopolysaccharides (LPS) and IL-4. It was found that Tanshinone IIA alleviated the development of vitiligo, impaired PMEL CD8+ T cells accumulation in the ear skin, and inhibited LPS-induced TNF-α, IL-6, and IL-1ß expression and secretion in BMDMs, which could also inhibit IL-4-induced Arg-1 and Mrc-1 expression in BMDMs. In addition, Tanshinone IIA could inhibit the proliferation and cytotoxic function of CD8+ T cells indicated by the expression of Perforin, Granzymeb, and IFN-γ. Furthermore, Tanshinone IIA treated Pdk1TKO mice, not Stat3TKO mice, showed impaired PMEL CD8+ T cells accumulation in the ear skin. In summary, Tanshinone IIA alleviates vitiligo development with impaired CD8+ T cells accumulation and activation of Pdk1-Akt pathway.


Assuntos
Vitiligo , Abietanos/farmacologia , Animais , Linfócitos T CD8-Positivos , Camundongos , Proteínas Proto-Oncogênicas c-akt , Vitiligo/tratamento farmacológico
8.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202760

RESUMO

A phytochemical investigation of the leaves of the medicinal plant Isodon rubescens led to the isolation of the two new degraded abietane lactone diterpenoids rubesanolides F (1) and G (2). Their structures were elucidated based on the analyses of the HRESIMS and 1D/2D NMR spectral data, and their absolute configurations were determined by ECD spectrum calculations and X-ray single crystal diffraction methods. Compounds 1 and 2, with a unique γ-lactone subgroup between C-8 and C-20, were found to form a carbonyl carbon at C-13 by removal of the isopropyl group in an abietane diterpene skeleton. Rubesanolide G (2) is a rare case of abietane that possesses a cis-fused configuration between rings B and C. The two isolates were evaluated for their biological activities against two cancer cell lines (A549 and HL60), three fungal strains (Candida alba, Aspergillus niger and Rhizopus nigricans) and three bacterial strains (Escherichia coli, Staphylococcus aureus and Bacillus subtilis).


Assuntos
Abietanos , Anti-Infecciosos , Antineoplásicos Fitogênicos , Bactérias/crescimento & desenvolvimento , Fungos/crescimento & desenvolvimento , Isodon/química , Lactonas , Neoplasias/tratamento farmacológico , Folhas de Planta/química , Células A549 , Abietanos/química , Abietanos/isolamento & purificação , Abietanos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Células HL-60 , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia
9.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198827

RESUMO

The objective of this study was to investigate molecular mechanisms underlying the ability of carnosic acid to attenuate an early increase in reactive oxygen species (ROS) levels during MDI-induced adipocyte differentiation. The levels of superoxide anion and ROS were determined using dihydroethidium (DHE) and 2'-7'-dichlorofluorescin diacetate (DCFH-DA), respectively. Both superoxide anion and ROS levels peaked on the second day of differentiation. They were suppressed by carnosic acid. Carnosic acid attenuates the translation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 (Nox4), p47phox, and p22phox, and the phosphorylation of nuclear factor-kappa B (NF-κB) and NF-κB inhibitor (IkBa). The translocation of NF-κB into the nucleus was also decreased by carnosic acid. In addition, carnosic acid increased the translation of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCSc), and glutathione S-transferase (GST) and both the translation and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, these results indicate that carnosic acid could down-regulate ROS level in an early stage of MPI-induced adipocyte differentiation by attenuating ROS generation through suppression of NF-κB-mediated translation of Nox4 enzyme and increasing ROS neutralization through induction of Nrf2-mediated translation of phase II antioxidant enzymes such as HO-1, γ-GCS, and GST, leading to its anti-adipogenetic effect.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Abietanos/farmacologia , DNA Helicases/genética , Heme Oxigenase-1/genética , Proteínas de Membrana/genética , NADPH Oxidase 4/genética , Inibidor de NF-kappaB alfa/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Antioxidantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Grupo dos Citocromos b/genética , Etídio/análogos & derivados , Etídio/farmacologia , Fluoresceínas/farmacologia , Glutationa Transferase/genética , Camundongos , NADPH Oxidases/genética , Biossíntese de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
10.
Phytother Res ; 35(8): 4309-4323, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34169595

RESUMO

Myocardial apoptosis contributes to acute ethanol-induced cardiac injury. Improving immoderate apoptosis has become the potential therapeutic strategy for acute ethanol-induced heart damage. Previous studies reported that Tanshinone IIA (Tan IIA), a key ingredient extracted from Salvia miltiorrhiza Bunge, performed an anti-apoptotic role against acute ethanol-related cell damage. In this study, we investigated whether Tan IIA protected the acute ethanol-induced cardiac damage in vivo and in vitro. C57BL/6 mice were treated with acute ethanol and then treated with Tan IIA. The results showed that Tan IIA significantly improved heart function and blocked myocardial apoptosis. Acute ethanol exposure induced H9C2 cells apoptosis. Treatment with Tan IIA abrogated acute ethanol-induced H9C2 cells apoptosis. Mechanistically, Tan IIA inhibited apoptosis by downregulating the programmed cell death protein 4 (PDCD4) expression and activating the phosphoinositide 3-kinase (PI3K)/Akt pathway. Furthermore, PDCD4 overexpression abrogated Tan IIA-mediated anti-apoptotic role and activation on the PI3K/Akt pathway. Interestingly, the PI3K inhibitor (LY294002) application significantly attenuated the main protective effects of Tan IIA. In conclusion, Tan IIA improves acute ethanol-induced myocardial apoptosis mainly through regulating the PDCD4 expression and activating the PI3K/Akt signaling pathway. We provide evidence that Tan IIA is a new treatment approach for acute ethanol-induced heart damage.


Assuntos
Abietanos/farmacologia , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Etanol , Miocárdio/patologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Etanol/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
11.
Sci Rep ; 11(1): 12217, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108553

RESUMO

The liposoluble tanshinones are bioactive components in Salvia miltiorrhiza and are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydrolase activity of FHIT through competing for the substrate-binding site with an IC50 value of 2.2 ± 0.05 µM. Notably, near 100 times lower binding affinities were determined between STS and other HIT proteins, including GALT, DCPS, and phosphodiesterase ENPP1, while no direct binding was detected with HINT1. Moreover, TSA, Tanshinone I (TanI), and Cryptotanshinone (CST) exhibited similar inhibitory activity as STS. Finally, we demonstrated that depletion of FHIT significantly blocked TSA's pro-apoptotic function in colorectal cancer HCT116 cells. Taken together, our study sheds new light on the molecular basis of the anti-cancer effects of the tanshinone compounds.


Assuntos
Abietanos/farmacologia , Hidrolases Anidrido Ácido/antagonistas & inibidores , Apoptose , Neoplasias Colorretais/tratamento farmacológico , Hidrolases/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Salvia miltiorrhiza/química , Abietanos/química , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Células Tumorais Cultivadas
12.
Theranostics ; 11(14): 6891-6904, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093860

RESUMO

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Hematopoese/efeitos dos fármacos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Imunoprecipitação da Cromatina , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Hematopoese/genética , Histonas/metabolismo , Humanos , Leucemia/enzimologia , Leucemia/genética , Metaloproteinase 9 da Matriz/genética , Proteínas de Neoplasias/genética , Complexo Repressor Polycomb 2/metabolismo , Ligação Proteica , RNA-Seq , Salvia miltiorrhiza/química , Ressonância de Plasmônio de Superfície , Transcriptoma/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
13.
Drug Deliv ; 28(1): 1132-1140, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34121558

RESUMO

Prostate cancer is the second most frequently diagnosed cancer in the men population. Combination anticancer therapy using doxorubicin (DOX) and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, maximize the treatment effect, and overcome multi-drug resistance. The purpose of this study is to construct a drug delivery system for the co-delivery of DOX and tanshinones (TAN). Lipid nanoparticles loaded with DOX and TAN (N-DOX/TAN) were prepared by emulsification and solvent-diffusion method. PSMA targeted nanoparticles loaded with DOX and TAN (P-N-DOX/TAN) were synthesized by conjugating a PSMA targeted ligand to N-DOX/TAN. We evaluate the performance of this system in vitro and in vivo. P-N-DOX/TAN has a size of 139.7 ± 4.1 nm and a zeta potential of 11.2 ± 1.6 mV. The drug release of DOX and TAN from P-N-DOX/TAN was much faster than that of N-DOX/TAN. N-DOX/TAN presented more inhibition effect on tumor growth than N-DOX and N-TAN, which is consistent with the synergistic results and successfully highlighting the advantages of combing the DOX and TAN in one system. P-N-DOX/TAN achieved higher uptake by LNCaP cells (58.9 ± 1.9%), highest tumor tissue distribution, and the most significant tumor inhibition efficiency. The novel nanomedicine offers great promise for the dual drug delivery to prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.


Assuntos
Abietanos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Nanopartículas/química , Neoplasias da Próstata/tratamento farmacológico , Abietanos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular , Química Farmacêutica , Doxorrubicina/administração & dosagem , Portadores de Fármacos , Combinação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Distribuição Aleatória , Propriedades de Superfície , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Free Radic Biol Med ; 175: 56-64, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058321

RESUMO

PB125® is a phytochemical composition providing potent Nrf2 activation as well as a number of direct actions that do not involve Nrf2. Nrf2 is a transcription actor that helps maintain metabolic balance by providing redox-sensitive expression of numerous genes controlling normal day-to-day metabolic pathways. When ordinary metabolism is upset by extraordinary events such as injury, pathogenic infection, air or water pollution, ingestion of toxins, or simply by the slow but incessant changes brought about by aging and genetic variations, Nrf2 may also be called into action by the redox changes resulting from these events, whether acute or chronic. A complicating factor in all of this is that Nrf2 levels decline with aging, leaving the elderly less able to maintain proper redox balance. The dysregulated gene expression that results can cause or exacerbate a wide variety of pathological conditions, including susceptibility to viral infections. This review examines the characteristics desirable in Nrf2 activators that have therapeutic potential, as well as some of the patterns of dysregulated gene expression commonly observed during pulmonary infections and the normalizing effects possible by judicious use of phytochemicals to increase the activation level of available Nrf2.


Assuntos
COVID-19 , Fator 2 Relacionado a NF-E2 , Abietanos/farmacologia , Idoso , Humanos , Fator 2 Relacionado a NF-E2/genética , SARS-CoV-2
15.
Phytomedicine ; 87: 153574, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34006448

RESUMO

BACKGROUND: Leelamine (LEE) is a lipophilic diterpene amine phytochemical, which can be naturally extracted from pine's bark trees. It has been extensively studied recently for its promising chemopreventive and anti-cancer effects against various cancers such as that of prostate and breast. HYPOTHESIS: We examined the potential impact of LEE in affecting the activation of signal transducer and activator of transcription 3 (STAT3) and promoting apoptosis in human multiple myeloma (MM) cells. METHODS: We evaluated the effect of LEE on STAT3 signaling pathway in MM cells by using Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR). Thereafter, apoptosis was evaluated using cell cycle analysis and Annexin V assay. RESULTS: We noted that LEE could attenuate the phosphorylation of STAT3 and other up-stream signaling molecules such as JAK1, JAK2, and Src activation in U266 and MM.1S cells. It also diminished STAT3 translocation into the nucleus and enhanced the expression of protein-tyrosine phosphatase epsilon (PTPε). Additionally, LEE caused cell cycle arrest and synergistically augmented the apoptotic actions of bortezomib against MM cells. CONCLUSIONS: Our data indicates that LEE could block STAT3 signaling cascade linked to tumorigenesis and can be used in combination with approved anti-cancer agents in attenuating MM growth and survival.


Assuntos
Abietanos/farmacologia , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Mieloma Múltiplo/metabolismo , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 1/genética , Janus Quinase 2/genética , Mieloma Múltiplo/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Braz J Med Biol Res ; 54(8): e10685, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34037092

RESUMO

Tanshinone I (Tan I) is one of the main bioactive ingredients derived from Salvia miltiorrhiza Bunge, which has exhibited antitumor activities toward various human cancer cells. However, its effects and underlying mechanisms on human chronic myeloid leukemia (CML) cells still require further investigation. This study determined the effects and mechanisms of anti-proliferative and apoptosis induction activity induced by Tan I against K562 cells. The cytotoxic effect of Tan I at varying concentrations on K562 cells was evaluated via MTT assay. Cell apoptosis was further investigated through DAPI staining and flow cytometry analysis. The expression levels of apoptosis-related proteins and activities of JNK/ATF2 and ERK signaling pathways were analyzed by western blot. Quantitative PCR was performed to further determine mRNA expression levels of JNK1/2 and ERK1/2 after Tan I treatment. The results indicated that Tan I significantly inhibited K562 cell growth and induced apoptosis in a concentration- and time-dependent manner. It induced significant cellular morphological changes and increased apoptosis rates in CML cells. Tan I promoted the cleavages of caspase-related proteins, as well as increased the expression levels of PUMA. Furthermore, Tan I significantly activated JNK and inhibited ATF-2 and ERK signaling pathways. The mRNA expression levels of JNK1/2 and ERK1/2 were up-regulated by Tan I, further confirming its regulatory effects on JNK/ERK signaling pathways. Overall, our results indicated that Tan I suppressed cell viability via JNK- and ERK-mediated apoptotic pathways in K562 cells, suggesting that it might be a promising candidate as a novel anti-leukemia drug.


Assuntos
Abietanos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Abietanos/farmacologia , Apoptose , Linhagem Celular Tumoral , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
17.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846794

RESUMO

Following the publication of the above paper, a concerned reader drew to the Editor's attention that Fig. 5 contained apparent anomalies, including unexpectedly similar-looking cells and repeated patternings of the cells in terms of their layout/arrangement within the data panels. After having conducted an independent investigation in the Editorial Office, the Editor of Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence regarding the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Molecular Medicine Reports 11: 931­939, 2015; DOI: 10.3892/mmr.2014.2819].


Assuntos
Abietanos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Mama/metabolismo , Humanos
18.
J Leukoc Biol ; 110(2): 315-325, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33909909

RESUMO

Natural killer (NK) cells have a great potential in cancer immunotherapy. However, their therapeutic efficacy is clinically limited owing to cancer cell immune escape. Therefore, it is urgently necessary to develop novel method to improve the antitumor immunity of NK cells. In the present study, it was found that the natural product tanshinone IIA (TIIA) enhanced NK cell-mediated killing of non-small cell lung cancer (NSCLC) cells. TIIA in combination with adoptive transfer of NK cells synergistically suppressed the tumor growth of NSCLC cells in an immune-incompetent mouse model. Furthermore, TIIA significantly inhibited the tumor growth of Lewis lung cancer (LLC) in an immune-competent syngeneic mouse model, and such inhibitory effect was reversed by the depletion of NK cells. Moreover, TIIA increased expressions of ULBP1 and DR5 in NSCLC cells, and inhibition of DR5 and ULBP1 reduced the enhancement of NK cell-mediated lysis by TIIA. Besides, TIIA increased the levels of p-PERK, ATF4 and CHOP. Knockdown of ATF4 completely reversed the up-regulation of ULBP1 and DR5 by TIIA in all detected NSCLC cells, while knockdown of CHOP only partly reduced these enhanced expressions in small parts of NSCLC cells. These results demonstrated that TIIA could increase the susceptibility of NSCLC cells to NK cell-mediated lysis by up-regulating ULBP1 and DR5, suggesting that TIIA had a promising potential in cancer immunotherapy, especially in NK cell-based cancer immunotherapy.


Assuntos
Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Animais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas Ligadas por GPI/genética , Humanos , Neoplasias Pulmonares , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Molecules ; 26(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923673

RESUMO

BACKGROUND: Osteoporosis results from excessive bone resorption and reduced bone formation, triggered by sex hormone deficiency, oxidative stress and inflammation. Tanshinones are a class of lipophilic phenanthrene compounds found in the roots of Salvia miltiorrhiza with antioxidant and anti-inflammatory activities, which contribute to its anti-osteoporosis effects. This systematic review aims to provide an overview of the skeletal beneficial effects of tanshinones. METHODS: A systematic literature search was conducted in January 2021 using Pubmed, Scopus and Web of Science from the inception of these databases. Original studies reporting the effects of tanshinones on bone through cell cultures, animal models and human clinical trials were considered. RESULTS: The literature search found 158 unique articles on this topic, but only 20 articles met the inclusion criteria and were included in this review. The available evidence showed that tanshinones promoted osteoblastogenesis and bone formation while reducing osteoclastogenesis and bone resorption. CONCLUSIONS: Tanshinones modulates bone remodelling by inhibiting osteoclastogenesis and osteoblast apoptosis and stimulating osteoblastogenesis. Therefore, it might complement existing strategies to prevent bone loss.


Assuntos
Abietanos/farmacologia , Animais , Antioxidantes/farmacologia , Humanos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos
20.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919842

RESUMO

Carnosic acid (CA), carnosol (CL) and rosmarinic acid (RA), components of the herb rosemary, reportedly exert favorable metabolic actions. This study showed that both CA and CL, but not RA, induce significant phosphorylation of AMP-dependent kinase (AMPK) and its downstream acetyl-CoA carboxylase 1 (ACC1) in HepG2 hepatoma cells. Glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), rate-limiting enzymes of hepatic gluconeogenesis, are upregulated by forskolin stimulation, and this upregulation was suppressed when incubated with CA or CL. Similarly, a forskolin-induced increase in CRE transcriptional activity involved in G6PC and PCK1 regulations was also stymied when incubated with CA or CL. In addition, mRNA levels of ACC1, fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) were significantly reduced when incubated with CA or CL. Finally, it was shown that CA and CL suppressed cell proliferation and reduced cell viability, possibly as a result of AMPK activation. These findings raise the possibility that CA and CL exert a protective effect against diabetes and fatty liver disease, as well as subsequent cases of hepatoma.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Abietanos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/genética , Lipogênese/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Ácidos Graxos/biossíntese , Gluconeogênese/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Camundongos , Oxirredução , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rosmarinus/química , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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