RESUMO
The available scientific literature regarding tanshinones is very abundant, and after its review, it is noticeable that most of the articles focus on the properties of tanshinone I, cryptotanshinone, tanshinone IIA, sodium tanshinone IIA sulfonate and the dried root extract of Salvia miltiorrhiza (Tan- Shen). However, although these products have demonstrated important biological properties in both in vitro and in vivo models, their poor solubility and bioavailability have limited their clinical applications. For these reasons, many studies have focused on the search for new pharmaceutical formulations for tanshinones, as well as the synthesis of new derivatives that improve their biological properties. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2015) on tanshinones in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we offer an update on the last five years of new research on these quinones, focusing on their synthesis, biological activity on noncommunicable diseases and drug delivery systems, to support future research on its clinical applications.
Assuntos
Abietanos/química , Diterpenos/química , Abietanos/síntese química , Abietanos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Salvia miltiorrhiza/química , Salvia miltiorrhiza/metabolismoRESUMO
Heme oxygenase (HO) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. Here we discuss some naturally derived compounds involved in HO-1 induction, their impact in the immune response modulation, and the beneficial effect in diverse autoimmune disorders. We conclude that the use of some compounds from natural sources able to induce HO-1 is an attractive lifestyle toward promoting human health. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity.
Assuntos
Abietanos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Curcumina/uso terapêutico , Heme Oxigenase-1/metabolismo , Quercetina/uso terapêutico , Animais , Autoimunidade , Alimentos , Humanos , Imunomodulação , PlantasRESUMO
RESEARCH QUESTION: Can carnosic acid, (CA) rosmarinic acid (RA) and wogonin (WG) inhibit the growth of cultured human endometrial stromal cells and endometriotic-like lesions induced in a BALB/c model of endometriosis? DESIGN: Primary stromal cell cultures were established from endometrial biopsies from women with endometriosis and controls. The human endometrial stromal cell line T-HESC was also used for in-vitro experiments. Endometriosis was surgically induced in BALB/c mice, which were randomly assigned to CA 2 mg/kg/day (nâ¯=â¯11); CA 20 mg/kg/day (nâ¯=â¯10); RA 1 mg/kg/day (nâ¯=â¯11); RA 3 mg/kg/day (nâ¯=â¯10); WG 20 mg/kg/day (nâ¯=â¯12); intraperitoneal vehicle control (nâ¯=â¯8) or oral vehicle control (nâ¯=â¯11). After surgery, CA and RA were administered intraperitoneally on days 14-28. WG was administered orally by intragastric gavage on days 14-26. RESULTS: CA, RA and WG significantly inhibited in-vitro cell proliferation in primary and T-HESC cell cultures (P < 0.05). CA and WG induced cell cycle arrest of T-HESC at the G2/M phase (P < 0.01). RA reduced intracellular ROS accumulation (P < 0.001), whereas WG increased it (P < 0.05). WG significantly inhibited oestrogen receptor alpha expression in T-HESC (P < 0.01). In-vivo, CA, RA and WG significantly reduced lesions size (P < 0.05). All compounds significantly decreased the percentage of cells in proliferation (P < 0.05) whereas RA and WG further increased the percentage of apoptotic cells (P < 0.05) in endometriotic-like lesions. CONCLUSIONS: The results are promising; further investigation of these compounds as new therapeutics is needed.
Assuntos
Abietanos/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Endometriose/tratamento farmacológico , Flavanonas/farmacologia , Rosmarinus/química , Scutellaria baicalensis/química , Abietanos/química , Abietanos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cinamatos/química , Cinamatos/uso terapêutico , Depsídeos/química , Depsídeos/uso terapêutico , Endometriose/patologia , Feminino , Flavanonas/química , Flavanonas/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Raízes de Plantas/química , Ácido RosmarínicoRESUMO
OBJECTIVE: Salvia miltiorrhiza has long been used to treat systemic sclerosis. Tanshinone IIA, one of the phytochemicals derived from the roots of Salvia miltiorrhiza, exhibits multiple biological activities. The present study aimed to investigate whether tanshinone IIA has an effect on the interleukin-17A-induced functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells. METHODS: Systemic sclerosis patient-derived dermal vascular smooth muscle cells were incubated with various dosages of tanshinone IIA in the presence of interleukin-17A or the serum of systemic sclerosis patients. Cell proliferation was assessed using Cell Counting Kit-8. The expression of collagen 1 and 3 in cells was evaluated by immunofluorescence. Cell migration was measured using a transwell assay. The expression of phospho-extracellular signal-regulated kinase was detected by Western blotting. RESULTS: Our data demonstrate that tanshinone IIA exerts an inhibitory effect on interleukin-17A-induced systemic sclerosis patient-derived dermal vascular smooth muscle cell proliferation, collagen synthesis and migration. CONCLUSION: These findings suggest that tanshinone IIA might serve as a promising therapeutic agent for the treatment of systemic sclerosis.
Assuntos
Abietanos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Interleucina-17/análise , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Abietanos/uso terapêutico , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Far-Western Blotting , Ensaios de Migração Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Colágeno Tipo I/análise , Colágeno Tipo III/análise , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Imunofluorescência , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Reprodutibilidade dos Testes , Salvia miltiorrhiza/química , Escleroderma Sistêmico/metabolismo , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.
Assuntos
Anti-Inflamatórios/uso terapêutico , Mediadores da Inflamação/metabolismo , Inflamação/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Pleurisia/tratamento farmacológico , Rosmarinus/química , Abietanos/isolamento & purificação , Abietanos/farmacologia , Abietanos/uso terapêutico , Adenosina Desaminase/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Carragenina , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Citocinas/genética , Citocinas/metabolismo , Depsídeos/isolamento & purificação , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos , Nitratos/metabolismo , Nitritos/metabolismo , Peroxidase/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta , Pleurisia/induzido quimicamente , Pleurisia/genética , Pleurisia/metabolismo , RNA Mensageiro/metabolismo , Ácido RosmarínicoRESUMO
PURPOSE: To compare the genoprotective and radioprotective effect of carnosol (COL) against damage induced by ionizing radiation with similar effects produced by different antioxidant compounds. METHODS: The genoprotective effect was studied by means of the micronucleus test for antimutagenic activity in which the reduction in the frequency of micronuclei was evaluated in cytokinesis-blocked cells of human lymphocytes. The radioprotective effects were studied by cell viability test (MTT) in PNT2 (normal prostate) and B16F10 (melanoma) cell lines when they were administered before exposure to different X-ray doses (4, 6, 8, 10 and 0 Gy). RESULTS: Carnosol shows a significant genoprotective capacity (p < 0.001) against radiation with a protection factor of 50 %, and a dose-reduction factor of 4.3. Cell survival obtained with COL administered before exposure to 10 Gy of X-rays showed a protection factor of 55.1 %, eliminating 39 % of radiation-induced cell death in normal epithelial cells of prostate (PNT2) (p < 0.001). However, in the melanoma cell lines (B16F10) assayed, COL acted not as a radioprotector, but as a sensitizing agent increasing the cellular death by 34 % (p < 0.01) and producing an enhancement ratio of 2.12. CONCLUSIONS: Carnosol may be developed as a radioprotective agent in the non-tumoral cells. However, in the B10F16 melanoma cells, melanogenesis is activated by COL leading to redistribution of the enzymatic balances of glutathione and cysteine-lyase production, which could compromise the intracellular redox defence system. This effect appears as an increase in the capacity of ionizing radiation-induced damage, and thus exhibits a paradoxical protective effect of COL on melanoma cells.
Assuntos
Abietanos/uso terapêutico , Melanoma/radioterapia , Melanoma/terapia , Neoplasias Cutâneas/radioterapia , Neoplasias Cutâneas/terapia , Animais , Antioxidantes/química , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta à Radiação , Glutationa/metabolismo , Humanos , Linfócitos/efeitos da radiação , Melanoma Experimental , Camundongos , Testes para Micronúcleos , Oxirredução , Radiação Ionizante , Protetores contra Radiação/administração & dosagem , Radiossensibilizantes/administração & dosagem , Pesquisa Translacional Biomédica/métodosRESUMO
In interviews on the traditional herbal medicines of Tupi-Guarany Indians at the herbal market of Asuncion and questionnaire from their users, it was clarified that various useful medicinal plants are available in Paraguay and most of them are generally used without drying. In the search for bioactive substances from those plants, a ß-glucuronidase-inhibitory diterpene called scoparic acid A (SA) was isolated from Scoparia dulcis L. together with scoparic acid B, scoparic acid C, and the aphidicolin-like tetracyclic diterpenes scopadulcic acid A (SDA) and scopadulcic acid B (SDB). HPLC analysis of diterpenes in the individual plants of Paraguayan and Asian S. dulcis revealed the presence of three chemotypes based on major component, i.e., SA type, SDB type, and SDX type containing mainly scopadiol and scopadulciol (SDC). SA and SDB were elucidated to be mainly biosynthesized in the leaves via 2-C-methyl-D-erythritol- 4-phosphate pathway, and a leaf organ culture system containing methyl jasmonate 10 µM was found to enhance the production of diterpenes by activation of Ca-signal transduction systems such as calmodulin and protein kinase C. On the other hand, SDB and SDC were found to show multifaceted pharmacological effects such as inhibitory effects on gastric acid excretion, bone resorption, replication of herpes simplex virus type 1 (HSV-1), etc. In addition, SDC was suggested to be applicable to cancer gene therapy using ganciclovir or acyclovir and the HSV-1 thymidine kinase gene called the suicide gene.
Assuntos
Diterpenos/isolamento & purificação , Diterpenos/uso terapêutico , Medicina Tradicional , Scoparia/química , Abietanos/isolamento & purificação , Abietanos/farmacologia , Abietanos/uso terapêutico , Animais , Reabsorção Óssea/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Diterpenos/farmacologia , Ácido Gástrico/metabolismo , Genes Transgênicos Suicidas , Terapia Genética , Herpesvirus Humano 1/enzimologia , Herpesvirus Humano 1/fisiologia , Humanos , Neoplasias/terapia , Paraguai , Fitoterapia , Ratos , Inquéritos e Questionários , Timidina Quinase/genética , Replicação Viral/efeitos dos fármacosRESUMO
In the present study, we evaluated the effects of extracts and purified compounds from fresh leaves of Rosmarinus officinalis L. Pretreatment with the major anti-inflammatory compounds, carnosic acid (CA) and carnosol (CS), inhibited phorbol 12-myristate 13-acetate (PMA)-induced ear inflammation in mice with an EC(50) of 10.20 µg/cm(2) and 10.70 µg/cm(2), respectively. To further understand the anti-inflammatory mechanism of these compounds, we analyzed the in vivo expression of several inflammation-associated genes in mouse skin by reverse transcriptase-polymerase chain reaction (RT-PCR). Our data showed that CA and CS reduced the expression of IL-1ß and TNF-α but had less effect on fibronectin and ICAM-1 expression. Interestingly, both compounds selectively inhibited COX-2 but not COX-1. Histopathological analysis of hematoxylin and eosin (H&E)-stained tissue revealed a marked reduction in leukocyte infiltration and epidermal ulceration of PMA-treated ears when ears were pretreated with ethanolic extracts or pure CA. In vitro, we showed that ethanolic extract, carnosic acid and carnosol significantly inhibited the overproduction of nitric oxide (NO) in a dose-dependent manner in the RAW 264.7 murine macrophage cell line. For the first time in vivo, we showed that CA and CS differentially regulate the expression of inflammation-associated genes, thus demonstrating the pharmacological basis for the anti-inflammatory properties reported for CA and CS.
Assuntos
Abietanos/uso terapêutico , Inflamação/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Rosmarinus/química , Pele/efeitos dos fármacos , Abietanos/farmacologia , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Relação Dose-Resposta a Droga , Fibronectinas/genética , Fibronectinas/metabolismo , Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Extratos Vegetais/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/metabolismo , Pele/patologia , Acetato de Tetradecanoilforbol , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: The aim of this report was to isolate, identify and assess the gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean medicinal plant Sphacele chamaedryoides (Balbis) Briq. (Lamiaceae). METHODS: The isolated compounds were identified by spectroscopic means. The gastroprotective effect of the compounds was studied on the HCl/EtOH-induced gastric lesions model in mice. The cytotoxicity of the compounds was assessed on human normal lung fibroblasts (MRC-5) and gastric adenocarcinoma cells (AGS). KEY FINDINGS: From the aerial parts of the plant, five phenolic and five p-quinone abietanes, the sesquiterpene spathulenol and two flavonoids were obtained. The main diterpene from the plant was carnosol (7:). Lansoprazole at 20 mg/kg reduced gastric lesions by 64.7% (P < 0.01), being statistically similar to carnosol at doses of 10 and 20 mg/kg; the percent lesion reduction with 7: at 5 mg/kg was 49.3%. At a single oral dose of 5 mg/kg, the diterpenes bearing a p-quinone moiety - 6,7-dehydroroyleanone (1), royleanone (2), 7,20-epoxyroyleanone (3), taxoquinone (5) and horminone (6) - presented a gastroprotective effect of 54.4, 70.8, 65.0, 35.8 and 52.7%, respectively. Of the C-7 hydroxy derivatives, the activity was much lower for the 7beta-OH isomer. The phenolic diterpenes 7 and 7-oxo-11,12,14-trihydroxy-8,11,13-abietatrien-20-al (8) inhibited gastric lesions by 49.3 and 53.0%, respectively. Royleanone (2), 7,20-epoxyroyleanone (3), horminone (6), 8 and spathulenol proved to be cytotoxic with IC50 values in the range of 11-67 microm. The selective cytotoxicity of compounds 1 (IC50: 61 and 366 microm) and 5 (IC50: 310 and 27 microm) against AGS cells and fibroblasts, respectively, merit additional studies. CONCLUSIONS: All the abietanes obtained from S. chamaedryoides present either one or two phenolic OH groups, a quinone system, or both. Several compounds present in the plant showed higher gastroprotective effect than lansoprazole. The cytotoxic effect of most compounds was found at fairly high concentrations and lacked cell specificity. Further studies are required using different tumour cell lines and viability/proliferation assays to assess the specificity of the isolated compounds. The selective cytotoxicity of compounds 1 and 5 against AGS cells and fibroblasts, respectively, merit additional studies.
Assuntos
Abietanos/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Antiulcerosos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Lamiaceae/química , Neoplasias Gástricas/tratamento farmacológico , Estômago/efeitos dos fármacos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Abietanos/isolamento & purificação , Abietanos/farmacologia , Animais , Antiulcerosos/isolamento & purificação , Antiulcerosos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Lansoprazol , Pulmão , Masculino , Camundongos , Fitoterapia , Componentes Aéreos da Planta , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estômago/patologiaRESUMO
The gastrointestinal activity of hydroalcoholic extract (HE) of Salvia officinalis was evaluated in a model of ethanol-induced gastric lesion. HE showed excellent activity, with ID(50) 84.0 (54.8-128.9) mg/kg. The acetic acid-induced ulcer and the total acidity of the gastric secretion were also reduced by HE, and, in vitro experiments, the H(+),K(+)-ATPase activity was inhibited. Carnosol was identified as a possible active constituent for the gastroprotective effect of HE.