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1.
Toxicol Lett ; 375: 21-28, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36563867

RESUMO

Danshen Si Wu is a Traditional Chinese Medicine used for menopausal complains. Beside tanshinone IIA (Tan IIA), Danshen also contains tanshinone I (Tan I), cryptotanshinone (CT) and dihydrotanshinone (DT). The aim of this study was to compare the biological activity of these tanshinones and to determine their cytotoxicity and genotoxicity. Purities and stabilities of the substances were analyzed by LC-DAD and LC-MS analyses. DT and CT concentrations decreased rapidly in dimethylsulfoxide and were converted to Tan I and Tan IIA, respectively. In aqueous solution concentration of all tanshinones decreased after 24 h. Tan I and Tan IIA showed dose-dependent bioactivity mediated by ERα and ERß. No cytotoxic and genotoxic effects for Tan I and Tan IIA were detected. In a yeast transactivation assay Tan I and Tan IIA showed antiandrogenic activity. A significant anabolic activity in C2C12 cells could be detected for Tan I and Tan IIA. In conclusion our data provide evidence that Tan I and Tan IIA are the most relevant bioactive tanshinones in Danshen. Our finding that all tanshinones display a certain instability in aqueous solutions is relevant when discussing their potential therapeutic benefits in humans.


Assuntos
Abietanos , Fenantrenos , Humanos , Abietanos/toxicidade , Abietanos/química , Fenantrenos/toxicidade , Cromatografia Líquida
2.
J Org Chem ; 88(1): 455-461, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36516399

RESUMO

Baccaramiones A-D (1-4), four highly oxygenated and rearranged trinorditerpenoids, were isolated from Baccaurea ramiflora. Compound 1 is a 1(10 → 5)-abeo-15,16,17-trinor-ent-abietane featuring a unique 5/6/6 spirocyclic scaffold, and 2-4 are the first example of a novel 20(10 → 5)-abeo-15,16,17-trinor-ent-abietane skeleton. Their structures were established by spectroscopic analysis, X-ray crystallography, and electronic circular dichroism calculations. A plausible biosynthetic pathway for 1-4 was proposed. Interestingly, compounds 3 and 4 exhibited significant immunosuppressive activities against concanavalin A-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation in vitro.


Assuntos
Abietanos , Imunossupressores , Abietanos/química , Dicroísmo Circular , Estrutura Molecular
3.
Biomed Pharmacother ; 158: 114154, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36584429

RESUMO

BACKGROUND: Bladder cancer (BC) is a common urological malignancy that still lacks effective treatments. Abietic acid (AA) is an abietane diterpene that possesses various biological activities, including antitumor activity. This study aimed at evaluating the effects of AA on BC cells. MATERIALS AND METHODS: The 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess the effects of AA on the viability of BC cells. Annexin-V and FITC staining was used to assess cellular death. The type of cell death was determined by the administration of various specific cell death inhibitors. Commercial kits were used to measure the levels of reactive oxygen species (ROS), intracellular iron, malondialdehyde (MDA), and glutathione (GSH). Real-time polymerase chain reaction (RT-PCR) and western blot analysis were used to assay mRNA and protein levels, respectively. The role of glutathione peroxidase 4 (GPX4) in the antitumor effects of AA was evaluated using the forced expression of GPX4 in BC cells. The impact of HO-1 on the antitumor effects of AA was examined by gene silencing and pharmacological inhibition of the protein. Finally, the antitumor effects of AA were evaluated in xenograft models. RESULTS: AA selectively inhibited the viability of BC cells but not normal cells. AA-induced ferroptosis in BC cells was evidenced by the upregulation of ROS, intracellular iron, and MDA. AA treatment led to the downregulation of GPX4 and the upregulation of HO-1 in BC cells. Forced expression of GPX4 or inhibition of HO-1 resulted in decreased ferroptosis triggered by AA in BC cells. AA also showed synergistic effects with various chemotherapeutic agents against BC and inhibited the growth of BC cells in vivo. CONCLUSION: This study revealed AA-induced ferroptosis in BC cells both in vitro and in vivo. AA might be applied as a promising agent for the treatment of BC.


Assuntos
Ferroptose , Neoplasias da Bexiga Urinária , Humanos , Abietanos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ferro/metabolismo
4.
Nat Prod Res ; 36(24): 6207-6214, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36463507

RESUMO

As a part of natural defense, plants initiate the secretion of gum containing numerous pharmacologically active essential metabolites. A fraction of such gum-resin from Araucaria cunninghamii Mudie, when screened against human cancer cell lines, was found to be active. Further, it was subjected to an LCMS-DNP (Dictionary of Natural Products) based dereplication study followed by a detailed phytochemical investigation to obtain pure metabolites. Also, the gum resin of A. cunninghamii was found to be a rich source of abietanes and labdanes. The LCMS-DNP-based dereplication study identified many known metabolites, which were isolated for the first time from this plant as well as a new labdane diterpenoid (9). The compounds were characterized via spectroscopic techniques, which were subsequently compared with the already existing literature data. The metabolites were screened against seven human cancer cell lines. The anticancer activity was further supported by molecular docking studies.


Assuntos
Antineoplásicos , Araucaria , Diterpenos , Humanos , Simulação de Acoplamento Molecular , Diterpenos/farmacologia , Antineoplásicos/farmacologia , Abietanos
5.
Molecules ; 27(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364087

RESUMO

The roots of Euphorbia fischeriana have been used as a traditional Chinese medicine for the treatment of tuberculosis and ringworm. In the current study, diterpenoids from the ethyl acetate extract of the roots E. fischeriana and their cytotoxic effects against five cancer lines were investigated. Two new ent-abietane diterpenoids, euphonoids H and I (1-2), as well as their two analogues (3-4) were first isolated from this source. The structures of the two new compounds were elucidated on the basis of spectroscopic data and quantum chemical calculation. Their absolute configurations were assigned via ECD spectrum calculation. The isolated compounds were evaluated for their antiproliferative activities against five cancer cell lines. Compounds 1 and 2 exhibited significant inhibitory effects against human prostate cancers C4-2B and C4-2B/ENZR cell lines with IC50 values ranging from 4.16 ± 0.42 to 5.74 ± 0.45 µM.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Diterpenos , Euphorbia , Neoplasias , Humanos , Euphorbia/química , Abietanos/farmacologia , Abietanos/análise , Diterpenos/química , Antineoplásicos/análise , Raízes de Plantas/química , Estrutura Molecular , Antineoplásicos Fitogênicos/química
6.
Int J Mol Sci ; 23(21)2022 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-36362395

RESUMO

Tanshinones are the bioactive constituents of Danshen (Salvia miltiorrhiza Bunge), which is used in Traditional Chinese Medicine to treat cardiovascular and other diseases, and they synthesize and accumulate in the root periderm of S. miltiorrhiza. However, there is no relevant report on the initial stage of tanshinone synthesis, as well as the root structure and gene expression characteristics. The present study aims to provide new insights into how these bioactive principles begin to synthesize by characterizing possible differences in their biosynthesis and accumulation during early root development from both spatial and temporal aspects. The morphological characteristics and the content of tanshinones in roots of S. miltiorrhiza were investigated in detail by monitoring the seedlings within 65 days after germination (DAGs). The ONT transcriptome sequencing was applied to investigate gene expression patterns. The periderm of the S. miltiorrhiza storage taproot initially synthesized tanshinone on about 30 DAGs. Three critical stages of tanshinone synthesis were preliminarily determined: preparation, the initial synthesis, and the continuous rapid synthesis. The difference of taproots in the first two stages was the smallest, and the differentially expressed genes (DEGs) were mainly enriched in terpene synthesis. Most genes involved in tanshinone synthesis were up regulated during the gradual formation of the red taproot. Plant hormone signal transduction and ABC transport pathways were widely involved in S. miltiorrhiza taproot development. Five candidate genes that may participate in or regulate tanshinone synthesis were screened according to the co-expression pattern. Moreover, photosynthetic ferredoxin (FD), cytochrome P450 reductase (CPR), and CCAAT binding transcription factor (CBF) were predicted to interact with the known downstream essential enzyme genes directly. The above results provide a necessary basis for analyzing the initial synthesis and regulation mechanism of Tanshinones.


Assuntos
Salvia miltiorrhiza , Salvia miltiorrhiza/genética , Salvia miltiorrhiza/metabolismo , Regulação da Expressão Gênica de Plantas , Raízes de Plantas , Abietanos , Proteínas de Plantas/metabolismo
7.
Org Lett ; 24(44): 8104-8108, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36286341

RESUMO

Rugosiformisin A, a skeleton-rearranged abietane-type diterpenoid with a spiro[4.5]decane motif, was isolated from Isodon rugosiformis. Its structure was unambiguously established via NMR spectroscopic analysis and single-crystal X-ray diffraction. A bioinspired asymmetric synthesis of rugosiformisin A was achieved in 15 steps with 2.7% overall yield. The synthesis features an iridium-catalyzed asymmetric polyene cyclization and a semipinacol rearrangement.


Assuntos
Diterpenos , Isodon , Isodon/química , Abietanos/química , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Esqueleto , Estrutura Molecular , Diterpenos/química
8.
Molecules ; 27(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36234983

RESUMO

Abietic acid, a naturally occurring fir resin compound, that exhibits anti-inflammatory and wound-healing properties, was formulated into biocompatible emulgels based on stable microemulsions with the addition of a carbamate-containing surfactant and Carbopol® 940 gel. Various microemulsion and emulgel formulations were tested for antioxidant and wound-healing properties. The chemiluminescence method has shown that all compositions containing abietic acid have a high antioxidant activity. Using Strat-M® skin-modelling membrane, it was found out that emulgels significantly prolong the release of abietic acid. On Wistar rats, it was shown that microemulsions and emulgels containing 0.5% wt. of abietic acid promote the rapid healing of an incised wound and twofold tissue reinforcement compared to the untreated group, as documented by tensiometric wound suture-rupture assay. The high healing-efficiency is associated with a combination of antibacterial activity of the formulation components and the anti-inflammatory action of abietic acid.


Assuntos
Antioxidantes , Cicatrização , Abietanos , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Carbamatos , Emulsões , Géis , Ratos , Ratos Wistar , Tensoativos
9.
Molecules ; 27(19)2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36235219

RESUMO

Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in the immune system. Dendritic cells (DCs) are a key type of leukocyte involved in the initiation and regulation of the immune/inflammatory response and natural or synthetic compounds that modulate DC functions could be potential anti-inflammatory/immunomodulatory agents. Herein, we report the screening of 23 known semisynthetic AA and DHA derivatives, and TQs, synthesized previously by us, in a multi-analyte DC-based assay that detects inhibition of pro-inflammatory cytokine production. Based on the magnitude of the inhibitory effect observed and the number of cytokines inhibited, a variety of activities among compounds were observed, ranging from inactive/weak to very potent inhibitors. Structurally, either alcohol or methyl ester substituents on ring A along with the introduction of aromaticity and oxidation in ring C in the abietane skeleton were found in compounds with higher inhibitory properties. Two DHA derivatives and two TQs exhibited a significant inhibition in all pro-inflammatory cytokines tested and were further investigated. The results confirmed their ability to inhibit, dose dependently, LPS-stimulated expression of the co-stimulatory molecules CD40 and/or CD86 and the production of the pro-inflammatory cytokines IL-1ß, IL-6, IL-12 and TNFα. Our results demonstrate that DC maturation process can be targeted by semisynthetic DHA derivatives and TQ epimers and indicate the potential of these compounds as optimizable anti-inflammatory/immunomodulatory agents.


Assuntos
Abietanos , Fator de Necrose Tumoral alfa , Abietanos/metabolismo , Abietanos/farmacologia , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Células Dendríticas , Ésteres/farmacologia , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
10.
Molecules ; 27(19)2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36235255

RESUMO

Secondary metabolites from the sawmill waste Picea abies bark were extracted using an innovative two-step extraction that includes a first step with supercritical CO2 (SCO2) and a second step using green solvents, namely ethanol, water, and water ethanol mixture. Maceration (M), ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE) techniques were applied in the second step. A total of nineteen extract were obtained and yield were compared. Bark extracts were characterized by LC-DAD-MSn and classes of compounds were quantified as abietane derivatives, piceasides, flavonoids, and phenolics to compare different extractions. Obtained extracts were studied by in vitro assay to evaluate potential pharmaceutical, nutraceutical and cosmetic uses assessing the antioxidant activity as well as the inhibitory activity on target enzymes. Results show that the "smart extraction chain" is advantageous in term of yield of extraction and phytoconstituent concentration. SCO2 extract, presenting a unique composition with a large amount of abietane derivatives, exerted the best activity for amylase inhibition compared to the other extracts.


Assuntos
Abies , Picea , Pinus , Abietanos , Amilases , Antioxidantes/farmacologia , Dióxido de Carbono , Suplementos Nutricionais , Etanol , Flavonoides , Casca de Planta , Extratos Vegetais/farmacologia , Solventes , Água
11.
Phytomedicine ; 107: 154464, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36215789

RESUMO

BACKGROUND: Abietic acid (AA) has been reported to exhibit anti-inflammatory activity, however its protective effect against inflammation and its trigger factor i.e., oxidative stress and the related sequelae i.e., apoptosis and fibrosis in the kidney in diabetes mellitus (DM) is unknown. PURPOSE: To identify the ability of AA to mitigate the inflammatory and inflammation-related insults to the kidney in DM. METHODS & STUDY DESIGN: Adult male rats were induced type-2 DM by feeding with a high-fat diet for twelve weeks followed by injection with a single dose of streptozotocin (STZ) (30 mg/kg/bw) intraperitoneally at twelve weeks. Following DM confirmation, AA (10 and 20 mg/kg/day) was given orally for another four weeks. Then the fasting blood glucose (FBG) and renal profile were determined and oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) tests were performed. A day after the last treatment, rats were sacrificed and kidneys were harvested and subjected for histopathological and molecular biological analysis. RESULTS: AA treatment was found to reduce the FBG, serum urea and creatinine levels (p < 0.05) while improving the OGTT and ITT (p < 0.05) in diabetic rats. Besides, AA treatment also mitigated kidney histopathological changes, reduces kidney oxidative stress as reflected by reduced levels of RAGE and Keap1 but increased levels of kidney antioxidants Nrf2, SOD, CAT, GPX, HO-1 & NQO-1 (p < 0.05). Additionally, AA treatment also decreases kidney inflammation (NF-kB p65, IL-1ß, IL-6, TNF-α and iNOS) and fibrosis (TGF-ß1 and GSK-3ß) (p < 0/05). Kidney apoptosis decreased as reflected by decreased levels of Bax, caspase-3 and caspase-9 while its anti-apoptosis Bcl-2 protein levels increased (p < 0.05). CONCLUSION: AA helps to mitigate nephropathy development in DM via counteracting oxidative stress, inflammation and apoptosis.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Insulinas , Abietanos , Animais , Anti-Inflamatórios/farmacologia , Glicemia/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Creatinina , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrinogênio/metabolismo , Fibrose , Glicogênio Sintase Quinase 3 beta/metabolismo , Inflamação/metabolismo , Insulinas/efeitos adversos , Insulinas/metabolismo , Interleucina-6/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Estreptozocina/efeitos adversos , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
12.
Anal Cell Pathol (Amst) ; 2022: 9358583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36204303

RESUMO

Tanshinone IIA (TanIIA) is the main active ingredient in the fat-soluble components isolated from Salvia miltiorrhiza Bunge. Our previous studies have convincingly proved that TanIIA is an effective drug against human colorectal carcinoma cells. In order to further demonstrate the effect of TanIIA on CRC, we carried out exploratory research about it in vivo and in vitro. The results demonstrated that TanIIA were observably more effective than control group in preventing tumor growth, and it has increased the survival time. Cancer cells viability and proliferation were accompanied by concentration and time dependent decline reached with TanIIA. We found that TanIIA altered the morphology of cytoskeleton and it could obviously induce apoptosis of colorectal cancer cells and block the cells in the G0/G1 phase. TanIIA also increased phosphorylation of p38MAPK, upregulated ATF-2 expression and downregulated Transgelin-2 expression, which could be reversed by SB203580, a p38MAPK-specific inhibitor. Our results suggested that TanIIA could induce apoptosis of colorectal cancer and block the cells in G0/G1 phase involved in downregulating the expression of Transgelin-2 through p38MAPK signal pathway.


Assuntos
Apoptose , Neoplasias Colorretais , Abietanos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Humanos , Proteínas dos Microfilamentos , Proteínas Musculares
13.
Comput Math Methods Med ; 2022: 6960304, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199775

RESUMO

Background: Gastric cancer (GC) belongs to a type of the most deadly cancer in the world, and the incidence rate of GC will increase in the coming decades. Tanshinone IIA (Tan IIA) is an active component that separated from Danshen. Tan IIA may also exert its therapeutic effects in disease with intestinal dysbacteriosis, at least partially, via regulating the intestinal microbiome. Nevertheless, it is obscure whether Tanshinone IIA affects the intestinal dysbacteriosis and plays antitumor roles. This research was designed to explore Tanshinone IIA potential on the intestinal dysbacteriosis of GC xenograft mice. Methods: Mouse xenograft GC tumor models were built and treated by Tan IIA. The tumor growth as well as microbiome in the intestinal were compared. Western blot was used to detect the phosphorylation of the NF-κB and expressions of the downstream cytokines IL-6 and IL-1ß. Results: Microbiome in the intestinal was changed in xenograft tumor mice in comparison with the control mice. What is more, Tan IIA could influence the microbiome in the intestinal of the tumor mice. Tan IIA hinders the growth of xenograft tumor and change the microbiome in the intestinal, but intestinal dysbacteriosis condition partially blocked Tan IIA-stimulated antitumor effects. In addition, intestinal dysbacteriosis abrogated Tan IIA-stimulated decrease in the NF-κB signaling in xenograft tumor mice. Conclusions: Tanshinone IIA may inhibit GC tumor growth via affecting the intestinal microbiome through regulating the NF-κB signaling.


Assuntos
Microbioma Gastrointestinal , Neoplasias Gástricas , Abietanos , Animais , Disbiose/tratamento farmacológico , Humanos , Interleucina-6 , Camundongos , NF-kappa B/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Triacetonamina-N-Oxil
14.
Fitoterapia ; 163: 105332, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36243242

RESUMO

Six new compounds (1-6), including two abietane diterpenes (1,2) and four benzofuran neolignans (3-6), along with five known compounds (7-11) were isolated and identified through phytochemical investigation on the resins of Toxicodendron vernicifluum (Toxicodendri Resina). The structures of the new compounds were fully elucidated by their 1D and 2D NMR, HRESIMS, UV, and IR spectroscopic data analyses. The absolute configurations of 1-4 were deduced by comparison of the experimental and calculated electronic circular dichroism (ECD) data. The inhibitory effects of the isolates on myocardial fibrosis induced by TGF-ß were examined, and compounds 1, 5, and 7-10 showed the anti-proliferation of myocardial fibroblasts at the concentrations of 10-40 µM in a dose-dependent manner.


Assuntos
Benzofuranos , Diterpenos , Lignanas , Toxicodendron , Abietanos/farmacologia , Toxicodendron/química , Estrutura Molecular , Resinas Vegetais , Diterpenos/farmacologia
15.
Int J Mol Sci ; 23(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36232298

RESUMO

One of the key areas of interest in pharmacognosy is that of the diterpenoids; many studies have been performed to identify new sources, their optimal isolation and biological properties. An important source of abietane-, pimarane-, clerodane-type diterpenoids and their derivatives are the members of the genus Clerodendrum, of the Lamiaceae. Due to their diverse chemical nature, and the type of plant material, a range of extraction techniques are needed with various temperatures, solvent types and extraction times, as well as the use of an ultrasound bath. The diterpenoids isolated from Clerodendrum demonstrate a range of cytotoxic, anti-proliferative, antibacterial, anti-parasitic and anti-inflammatory activities. This review describes the various biological activities of the diterpenoids isolated so far from species of Clerodendrum with the indication of the most active ones, as well as those from other plant sources, taking into account their structure in terms of their activity, and summarises the methods for their extraction.


Assuntos
Clerodendrum , Diterpenos Clerodânicos , Abietanos/química , Antibacterianos , Clerodendrum/química , Diterpenos Clerodânicos/farmacologia , Estrutura Molecular , Solventes
16.
Phytomedicine ; 107: 154471, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36182795

RESUMO

BACKGROUND: Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood. PURPOSE: We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF. METHODS: In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day. RESULT: The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3. CONCLUSION: Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.


Assuntos
Cardiotoxicidade , Sistema de Sinalização das MAP Quinases , Animais , Camundongos , Abietanos , Acetilcisteína/farmacologia , Apoptose , Cardiotoxicidade/tratamento farmacológico , Caspase 3 , Caspase 8 , Proteínas Correpressoras , Doxorrubicina/efeitos adversos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno , Chaperonas Moleculares/farmacologia , Miócitos Cardíacos , RNA , Triacetonamina-N-Oxil/farmacologia
17.
Mol Med Rep ; 26(5)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36069225

RESUMO

Tanshinone IIA (Tan 2A) is a lipid­soluble compound extracted from the Chinese herb Danshen (Salvia miltiorrhiza Bunge). It protects neuron and microvascular endothelial cells against hypoxia/ischemia both in vitro and in vivo however the mechanism is not fully known. Glucose transporter 1 (GLUT­1) is ubiquitously expressed in all types of tissue in the human body and serves important physiological functions due to its glucose uptake ability. The present study evaluated the role of Tan 2A in regulating GLUT­1 expression and its potential mechanism. RT­PCR and western Blot were used to detect the expression of GLUT­1. Si RNA mediated knockdown and CHIP assay were used to explore the mechanism of Tan 2A on GLUT­1expression. Tan 2A treatment induced expression of GLUT­1 and subsequently increased glucose uptake in endothelial cells (ECs). Furthermore, mRNA expression levels of vascular endothelial cell growth factor, BCL2 interacting protein 3 and enolase 2, which are target genes for hypoxia­inducible factor­1α (HIF­1α), were significantly upregulated by Tan 2A. Co­immunoprecipitation demonstrated that Tan 2A markedly increased the association of HIF­1α with recombination signal­binding protein for immunoglobulin κJ region (RBPJκ). Moreover, knockdown of HIF­1α and RBPJκ significantly reversed the regulatory effect of Tan 2A on mRNA expression levels of these genes in ECs. The results of the present study suggested that HIF­1α partially mediated the regulatory effect of Tan 2A on GLUT­1 expression in ECs. Therefore, GLUT­1 may be a potential therapeutic target for Tan 2A.


Assuntos
Células Endoteliais , Salvia miltiorrhiza , Abietanos , Células Endoteliais/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , RNA Mensageiro/metabolismo , Salvia miltiorrhiza/química , Transdução de Sinais , Triacetonamina-N-Oxil/metabolismo , Triacetonamina-N-Oxil/farmacologia
18.
Drug Des Devel Ther ; 16: 3197-3213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36158238

RESUMO

Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1α (HIF-1α) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1α regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1α. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1α overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of ß-actin, HIF-1α, PI3K p110α, p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1α to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1α-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1α mediated resistance via targeting PI3K/AKT/HIF-1α signaling pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Abietanos , Actinas/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triacetonamina-N-Oxil/farmacologia
19.
Biomed Res Int ; 2022: 3816258, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36147634

RESUMO

Radix Salvia miltiorrhiza (RSM) is widely used for the clinical improvement of inflammatory diseases. However, the actions of RSM in the treatment of ankylosing spondylitis (AS) have not been fully explored. Therefore, this study was designed to use retrospective clinical data mining approach to understand the effects of RSM on AS-related immuno-inflammatory processes, use network pharmacology to predict therapeutic targets of RSM, and to further investigate the pharmacological molecular mechanism in vitro. RSM treatment has a long-term correlation with the improvement of AS-related immuno-inflammatory indicators through computational models. We established protein-protein interaction networks, conducted KEGG analysis to enrich significant TNF pathways, and finally obtained three core targets of RSM in the treatment of AS, namely, prostaglandin endoperoxide synthase 2 (PTGS2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Screening of RSM active ingredients with node degree greater than 20 yielded cryptotanshinone and tanshinone IIA, and previous studies have reported their anti-inflammatory effects. In vitro, both cryptotanshinone and tanshinone IIA significantly inhibited the expressions of PTGS2, IL-6, and TNF-α in peripheral blood mononuclear cells in AS patients. In conclusion, cryptotanshinone and tanshinone IIA, which are the active components of RSM, may inhibit the activation of TNF signaling pathway in AS patients by downregulating the expression of PTGS2, IL-6, and TNF-α. These findings illustrate that RSM may be a promising therapeutic candidate for AS, but further validation is required.


Assuntos
Medicamentos de Ervas Chinesas , Salvia miltiorrhiza , Espondilite Anquilosante , Abietanos , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2 , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Interleucina-6 , Leucócitos Mononucleares/metabolismo , Farmacologia em Rede , Fenantrenos , Estudos Retrospectivos , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
20.
Toxins (Basel) ; 14(9)2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36136570

RESUMO

Dehydroabietic acid is a tricyclic diterpenoid resin acid isolated from rosin. Dehydroabietic acid and its derivatives showed lots of medical and agricultural bioactivities, such as anticancer, antibacterial, antiviral, antiulcer, insecticidal, and herbicidal activities. This review summarized the research advances on the structural modification and total synthesis of dehydroabietic acid and its derivatives from 2015 to 2021, and analyzed the biotransformation and structure-activity relationships in order to provide a reference for the development and utilization of dehydroabietic acid and its derivatives as drugs and pesticides.


Assuntos
Diterpenos , Praguicidas , Abietanos , Antibacterianos/farmacologia , Antivirais , Diterpenos/química , Diterpenos/farmacologia , Relação Estrutura-Atividade
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