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1.
J Nat Med ; 74(3): 513-524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193805

RESUMO

Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor ß (TGF-ß)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.


Assuntos
Ciclo-Octanos/farmacologia , Células Estreladas do Fígado/metabolismo , Lignanas/farmacologia , Cirrose Hepática/prevenção & controle , Compostos Policíclicos/farmacologia , Schisandra/química , Linhagem Celular , Frutas/química , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cirrose Hepática/patologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Xenobiotica ; 50(9): 1043-1051, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32118504

RESUMO

Pregnane X receptor (PXR) as a ligand dependent transcription factor, is capable of regulating gene expression of cytochromes P450 and transporters involved in xenobiotic/drug metabolism and elimination. Due to the species differences in the regulatory specificity of PXR, gene regulation should not be extrapolated from mammal to fish without research data.The aim of present study was to investigate the effect of 27 natural products on PXR, CYP3A30 and MDR1 genes in channel catfish (Ietalurus punetaus) kidney cells (CC-K). The results showed that bisdemethoxycurcumin, glycyrrhetnic acid, rotenone, artemisinin, dihydroartemisinin, ligustilide and matrine strongly induced the mRNA levels of PXR. Additionally, the up-regulation of CYP3A30 gene ran parallel with PXR gene after the treatment of demethoxycurcumin, glycyrrhetnic acid, artemisinin, matrine, baicalein, schisantherin A, ligustilide, and dihydroartemisinin. Moreover, we found that natural products schisandrin A, schisandrin B, schisandrol A, and schisandrol B significantly up-regulated the mRNA level of MDR1 gene.Our work with a view to provide experimental data support for further research, which will make for the rational application of natural products in channel catfish, such as to avoid adverse herb-drug interactions or accelerating the residue elimination of chemical medicine.


Assuntos
Produtos Biológicos/farmacologia , Biotransformação/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Produtos Biológicos/metabolismo , Linhagem Celular , Ciclo-Octanos/metabolismo , Ciclo-Octanos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dioxóis/metabolismo , Dioxóis/farmacologia , Ictaluridae , Lignanas/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/metabolismo , Compostos Policíclicos/farmacologia , Receptor de Pregnano X/metabolismo
3.
Phytomedicine ; 68: 153147, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32028184

RESUMO

BACKGROUND: Gomisin A (G.A), a lignan compound extracted from the fruits of Schisandra chinensis, is known to exert anti-tumor effects on hepatocarcinoma and colorectal cancer cells. Suppression of proliferation and metastatic abilities of cancer cells are some effective cancer treatment methods. PURPOSE: The objective of this study is to investigate the effects of G.A on metastatic melanoma, and the mechanism by which it affects metastatic melanoma. STUDY DESIGN: The anti-proliferative and anti-metastatic effects of G.A were observed in in vitro and in vivo. METHODS: WST assay and flow cytometry were conducted to investigate the effect of G.A on proliferation, cell cycle arrest, and apoptosis in metastatic melanoma cell lines. Migration and invasion abilities of G.A-treated melanoma cells were observed by wound healing and invasion assays. RESULTS: G.A (25-100 µM) decreased the viability of melanoma cells by inducing cell cycle arrest and apoptosis. These anti-proliferative effects of G.A were found to be mediated by AMPK, ERK, and JNK activation. G.A (5-20 µM) decreased the migration and invasion of melanoma cells by suppressing epithelial-mesenchymal transition (EMT). Consequently, G.A (2-50 mg/kg) inhibited lung metastasis by suppressing EMT and inducing cell cycle arrest and apoptosis in melanoma cells. CONCLUSION: These results conclude that G.A has the potential to reduce metastatic melanoma through its anti-proliferative and anti-metastatic effects.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Lignanas/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 4/metabolismo , Melanoma/metabolismo , Camundongos Endogâmicos C57BL , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Life Sci ; 245: 117357, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31991180

RESUMO

AIMS: Schisandra is a good choice in Traditional Chinese Medicine for the therapy of cardiovascular diseases, but whether it contains a or some specific component (s) responsible these effects are still unclear. In the present study, we explored whether Schisantherin A (SCA) causes vasorelaxation in isolated rat thoracic aorta. MAIN METHODS: We selected SCA, one of the main monomers of lignans from Schisandra, to examine its vasorelaxant effect on the isolated rat thoracic aorta and also exploited several tool inhibitors to probe its underlying mechanisms. KEY FINDINGS: SCA produced relaxation concentration-dependently on the endothelium-intact (43.56 ± 2.17%) and endothelium-denuded thoracic aorta strips (18.76 ± 3.95%) pre-contracted by phenylephrine (PE). However, after treated with indomethacin or L-NAME, SCA showed only partial vasorelaxant effects. Whereas, this vasorelaxation by SCA was not changed with specific K+-channel inhibitors, i.e. barium chloride (BaCl2), 4-aminopyridine (4-AP), tetraethylamine (TEA), and glibenclamide. SCA had no effect on the aorta strips pre-contracted by PE in neither Ca2+-free nor CaCl2 conditions. But, in the Ca2+ free and high K+ environment, SCA partly abolished the vasocontraction induced by CaCl2. SIGNIFICANCE: It was the first report to demonstrate that SCA had endothelium-dependent and -independent vasorelaxant effects on the isolated rat thoracic aorta, and the underlying mechanisms might be involved into its promoting the production of nitric oxide (NO) and prostacyclin (PGI2), and inhibiting the voltage-dependent calcium channels (VDCCs) opening. This study may partially explain the use of Schisandra in cardiovascular diseases and facilitate further drug development as well.


Assuntos
Aorta Torácica/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Endotélio Vascular/efeitos dos fármacos , Lignanas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Western Blotting , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Phytomedicine ; 66: 153107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790903

RESUMO

BACKGROUND: Gomisin A is a lignan isolated from the hexane of Schisandra chinensis fruit extract with antioxidant properties. Oxidative stress mediated by high glucose is one of the major complications of diabetes mellitus. PURPOSE: This study investigates the role of gomisin A in osteoblast differentiation under high glucose-induced oxidative stress in MC3T3 E1 cells and determines its relationship with heme oxygenase-1 (HO-1) and mitochondrial biogenesis. METHODS: MC3T3 E1 cells were treated by gomisin A following induced by high glucose levels and glucose oxidase to investigate the inhibitory effect of gomisin A against high glucose oxidative stress. Western blot analysis, alizarin red staining, alkaline phosphatase (ALP) activity, analysis of reactive oxygen species (ROS) and confocal microscopy were used to determine mitochondrial biogenesis, oxidative stress, osteoblast differentiation and mineralization. To analyze the role of HO-1, the MC3T3 E1 cells were treated with the HO-1 inhibitor zinc protoporphyrin IX (ZnPP). RESULTS: Gomisin A enhanced the expression of HO-1, increased mitochondrial biogenesis factors (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A), antioxidant enzymes (copper-zinc superoxide dismutases and manganese superoxide dismutase), osteoblast differentiation molecules (bone morphogenic protein-2/7, osteoprotegerin and Runt-related transcription factor-2) and mineralization by upregulation of ALP and alizarin red staining, which were decreased by ZnPP and high glucose oxidative stress. Similarly, gomisin A inhibited ROS which was increased by ZnPP and the high glucose-mediated oxidative stress. CONCLUSIONS: The findings demonstrated the antioxidative effects of gomisin A, and its role in mitochondrial biogenesis and osteoblast differentiation. It potentially regulated osteoblast differentiation under high glucose-induced oxidative stress via upregulation of HO-1 and maintenance of mitochondrial homeostasis. Thus, gomisin A may represent a potential therapeutic agent for prevention of bone fragility fractures and implant failure triggered by diabetes.


Assuntos
Antioxidantes/farmacologia , Ciclo-Octanos/farmacologia , Diabetes Mellitus/tratamento farmacológico , Dioxóis/farmacologia , Glucose/efeitos adversos , Lignanas/farmacologia , Osteogênese/efeitos dos fármacos , Schisandra/química , Animais , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Heme Oxigenase-1/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Biogênese de Organelas , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
6.
Chem Commun (Camb) ; 56(7): 1078-1081, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31872834

RESUMO

A boron dipyrromethene based photosensitiser substituted with a 1,2,4,5-tetrazine moiety has been prepared of which the photoactivity can be activated upon an inverse-electron-demand Diels-Alder reaction with trans-cyclooctene derivatives. By using a biotin-conjugated trans-cyclooctene to tag the biotin-receptor-positive HeLa cells, this photosensitiser exhibits site-specific activation through cycloaddition, leading to high photocytotoxicity.


Assuntos
Compostos de Boro/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/efeitos da radiação , Biotina/análogos & derivados , Biotina/síntese química , Biotina/farmacologia , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Linhagem Celular Tumoral , Reação de Cicloadição , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/efeitos da radiação , Humanos , Luz , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
7.
Molecules ; 24(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597329

RESUMO

The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.


Assuntos
Autofagia/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Glucose/metabolismo , Lignanas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução , Oxigênio/metabolismo , Compostos Policíclicos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ciclo-Octanos/química , Modelos Animais de Doenças , Lignanas/química , Camundongos , Modelos Biológicos , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Policíclicos/química , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
Braz J Med Biol Res ; 52(10): e8385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618367

RESUMO

Malignant melanoma (MM) is one of the malignant tumors with highly metastatic and aggressive biological actions. Schizandrin A (SchA) is a bioactive lignin compound with strong anti-oxidant and anti-aging properties, which is stable at room temperature and is often stored in a cool dry place. Hence, we investigated the effects of SchA on MM cell line A375 and its underlying mechanism. A375 cells were used to construct an in vitro MM cell model. Cell viability, proliferation, apoptosis, and migration were detected by Cell Counting Kit-8, BrdU assay, flow cytometry, and transwell two-chamber assay, respectively. The cell cycle-related protein cyclin D1 and cell apoptotic proteins (Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9) were analyzed by western blot. Alteration of H19 expression was achieved by transfecting with pEX-H19. PI3K/AKT pathway was measured by detecting phosphorylation of PI3K and AKT. SchA significantly decreased cell viability in a dose-dependent manner. Furthermore, SchA inhibited cell proliferation and cyclin D1 expression. SchA increased cell apoptosis along with the up-regulation of pro-apoptotic proteins (cleaved-caspase-3, cleaved-caspase-9, and Bax) and the down-regulation of anti-apoptotic protein (Bcl-2). Besides, SchA decreased migration and down-regulated matrix metalloproteinases (MMP)-2 and MMP-9. SchA down-regulated lncRNA H19. Overexpression of H19 blockaded the inhibitory effects of SchA on A375 cells. SchA decreased the phosphorylation of PI3K and AKT while H19 overexpression promoted the phosphorylation of PI3K and AKT. SchA inhibited A375 cell growth, migration, and the PI3K/AKT pathway through down-regulating H19.


Assuntos
Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Lignanas/farmacologia , Melanoma/patologia , Compostos Policíclicos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
9.
Metab Brain Dis ; 34(6): 1689-1703, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31422511

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases which seriously affect the quality of life of the elderly. Schisandrin (SCH) and nootkatone (NKT) are the two marked active components in ASHP. In this study, the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) as well as its bioactive components on cognitive deficiency and dementia were revealed via Aß1-42-induced AD in mouse. Morris water maze test showed that acute administration of ASHP and SCH + NKT treatments had higher discrimination index in the object recognition task, more quadrant dwell time and shorter escape latency compared with those in the Morris water maze. The levels of TNF-α, IL-1ß and IL-6 were decreased after ASHP and SCH + NKT treatment. The inflammatory response was attenuated by inhibiting TLR4/ NF-κB/ NLRP3 pathway. In addition, ASHP and SCH + NKT treatments significantly restored the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), total antioxidant capacity (T-AOC) and inducible nitric oxide syntheses (iNOS), and the levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO). The histopathological changes of hippocampus were noticeably improved after ASHP and SCH + NKT treatments. These findings demonstrate that ASHP as well as its bioactive components exerted a protective effects on cognitive disorder, inflammatory reaction and oxidative stress.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ciclo-Octanos/uso terapêutico , Lignanas/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Compostos Policíclicos/uso terapêutico , Sesquiterpenos Policíclicos/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Ciclo-Octanos/farmacologia , Modelos Animais de Doenças , Glutationa/metabolismo , Lignanas/farmacologia , Malondialdeído/metabolismo , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Compostos Policíclicos/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Superóxido Dismutase/metabolismo
10.
Chem Biol Interact ; 309: 108675, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31150632

RESUMO

Liver fibrosis is a progression of chronic liver disease with lacks effective therapies at present. Schisandrin B (Sch B), a bioactive compound extracted from the traditional Chinese medicine Schisandra chinensis, was reported to benefit liver diseases. This study aimed to investigate the therapeutic effects and molecular mechanisms of Sch B against CCl4-induced liver fibrosis in rats. RNA sequencing and transcriptome analysis were performed collaboratively, including analysis of differential gene expression, gene ontology (GO) analysis, pathway analysis and pathway-act-network analysis. The results demonstrated that Sch B effectively alleviated CCl4-induced liver damage and fibrosis in rats, as evidenced by improved liver function and decreased extracellular matrix deposition. Furthermore, 4440 (1878 up-regulated, 2562 down-regulated) genes in the model group versus (vs) normal group, 4243 (2584 up-regulated, 1659 down-regulated) genes in Sch B-treated group vs model group were identified as differentially expressed genes (DEGs). Subsequently, GO analysis revealed that DEGs were mainly enriched in metabolism, oxidation-reduction, endoplasmic reticulum stress and apoptosis-related biological processes. Pathway analysis suggested that Sch B up-regulated cytochrome P450 drug metabolism, PPAR signaling pathways, and down-regulated glutathione metabolism pathways. In addition, the regulatory patterns of Sch B on key genes and pathways were also confirmed. In conclusion, our study demonstrated Sch B alleviated CCl4-induced liver fibrosis by multiple modulatory mechanisms, which provide new clues for further pharmacological study of Sch B.


Assuntos
Lignanas/farmacologia , Cirrose Hepática/patologia , Fígado/metabolismo , Compostos Policíclicos/farmacologia , Transcriptoma , Animais , Apoptose/efeitos dos fármacos , Tetracloreto de Carbono/toxicidade , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Lignanas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa , Compostos Policíclicos/química , Compostos Policíclicos/uso terapêutico , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Ratos , Ratos Wistar , Schisandra/química , Schisandra/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos
11.
Phytomedicine ; 62: 152955, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146168

RESUMO

BACKGROUND: Angiotensin II (Ang II)-induced chronic inflammation and oxidative stress often leads to irreversible vascular injury, in which the endothelial to mesenchymal transition (EndMT) in the endothelial layers are involved. Schisandrin B (Sch B), a natural product isolated from traditional Schisandra chinensis, has been reported to exert vascular protective properties with unclear mechanism. HYPOTHESIS/PURPOSE: This study investigated the protective effects and mechanism of Sch B against Ang II-induced vascular injury. METHODS: C57BL/6 mice were subcutaneous injected of Ang II for 4 weeks to induce irreversible vascular injury. In vitro, Ang II-induced HUVECs injury was used to study the underlying mechanism. The markers of EndMT, inflammation and oxidative stress were studied both in vitro and in vivo. RESULTS: Pre-administration of Sch B effectively attenuated phenotypes of vascular EndMT and fibrosis in Ang II-treated animals, accompanied with decreased inflammatory cytokine and ROS. The in vitro data from HUVECs suggest that Sch B directly targets NF-κB activation to suppress Ang II-induced EndMT and vascular injury. The activation of EndMT in the presence of Ang II is regulated by the NF-κB, a common player in inflammation and oxidative stress. Ang II-induced inflammation and oxidative stress also contributed to vascular EndMT development and Sch B inhibited inflammation/ROS-mediated EndMT by suppressing NF-κB. CONCLUSION: EndMT contributes to vascular injury in Ang II-treated mice, and it can be prevented via suppressing NF-κB activation by Sch B treatment. These results also imply that NF-κB might be a promising target to attenuate vascular remodeling induced by inflammation and oxidative stress through an EndMT mechanism.


Assuntos
Angiotensina II/efeitos adversos , Anti-Inflamatórios/farmacologia , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Subunidade p50 de NF-kappa B/metabolismo , Compostos Policíclicos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Células Cultivadas , Ciclo-Octanos/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Fibrose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Transdução de Sinais/efeitos dos fármacos
12.
Biomed Pharmacother ; 115: 108922, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048190

RESUMO

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking prognostic and effective therapeutic targets currently. In this study, we evaluated the toxic potential of schisandrin A (SchA), a bioactive phytochemical found in Schisandra chinensis in TNBC. The anti-cancer effect and underlying mechanism of SchA on MDA-MB-231 and BT-549 cells were determined in vitro and in xenograft mouse model. Our data show that SchA markedly inhibited the growth of TNBC cells via induction of cell cycle arrest and cell apoptosis. Moreover, over activation of Wnt signaling was observed in TNBC cells, which was significantly suppressed by the treatment of SchA. Also, SchA treatment activated ER stress in TNBC cells. Finally, we verified these inhibitory effects of SchA in the MDA-MB-231 xenograft mouse model. In conclusion, SchA effectively inhibited TNBC in preclinical models by inducing cell cycle arrest and apoptosis via regulating Wnt/ER stress signaling pathway. All of these data indicate that SchA could be a potential candidate for the treatment of TNBC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ciclo-Octanos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Octanos/uso terapêutico , Feminino , Humanos , Lignanas/uso terapêutico , Camundongos , Compostos Policíclicos/uso terapêutico , Schisandra , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934777

RESUMO

Lignans from Schisandra chinensis (Turcz.) Baill can ameliorate cognitive impairment in animals with Alzheimer's disease (AD). However, the metabolism of absorbed ingredients and the potential targets of the lignans from S. chinensis in animals with AD have not been systematically investigated. Therefore, for the first time, we performed an in-vivo ingredient analysis and implemented a target-network pharmacology strategy to assess the effects of lignans from S. chinensis in rats with AD. Ten absorbed prototype constituents and 39 metabolites were identified or tentatively characterized in the plasma of dosed rats with AD using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Based on the results of analysis of the effective constituents in vivo, the potential therapeutic mechanism of the effective constituents in the rats with AD was investigated using a target-network pharmacology approach and independent experimental validation. The results showed that the treatment effects of lignans from S. chinensis on cognitive impairment might involve the regulation of amyloid precursor protein metabolism, neurofibrillary tangles, neurotransmitter metabolism, inflammatory response, and antioxidant system. Overall, we identified the effective components of lignans in S. chinensis that can improve the cognitive impairment induced by AD and proposed potential therapeutic metabolic pathways. The results might serve as the basis for a fundamental strategy to explore effective therapeutic drugs to treat AD.


Assuntos
Cromatografia Líquida de Alta Pressão , Lignanas/química , Lignanas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Schisandra/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Biomarcadores , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Redes e Vias Metabólicas , Estrutura Molecular , Neurônios/metabolismo , Neurotransmissores/metabolismo , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Ratos
14.
Drugs ; 79(7): 705-714, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30972660

RESUMO

A gradual rise in drug-resistant trends among Gram-negative organisms, especially carbapenem-resistant (CR) Enterobacteriaceae (CRE), CR-Pseudomonas aeruginosa, and extensively-drug-resistant (XDR) Acinetobacter baumannii, poses an enormous threat to healthcare systems worldwide. In the last decade, many pharmaceutical companies have devoted enormous resources to the development of new potent antibiotics against XDR Gram-negative pathogens, particularly CRE. Some of these novel antibiotics against CRE strains are ß-lactam/ß-lactamase-inhibitor combination agents, while others belong to the non-ß-lactam class. Most of these antibiotics display good in vitro activity against the producers of Ambler class A, C, and D ß-lactamase, although avibactam and vaborbactam are not active in vitro against metallo-ß-lactamase (MßL) enzymes. Nevertheless, in vitro efficacy against the producers of some or all class B enzymes (New Delhi MßL, Verona integron-encoded MßL, etc) has been shown with cefepime-zidebactam, aztreonam-avibactam, VNRX-5133, cefiderocol, plazomicin, and eravacycline. As of Feburary 2019, drugs approved for treatment of some CRE-related infections by the US Food and Drug Administration included ceftazidime-avibactam, meropenem-vaborbactam, plazomicin, and eravacycline. Although active against extended-spectrum and AmpC ß-lactamase-producing Enterobacteriaceae, delafloxacin does not show in vitro activity against CRE. Murepavadin is shown to be specifically active against CR- and colistin-resistant P. aeruginosa strains. Despite successful development of novel antibiotics, strict implementation of an antibiotic stewardship policy in combination with the use of well-established phenotypic tests and novel multiplex PCR methods for detection of the most commonly encountered ß-lactamases/carbapenemases in hospitals is important for prescribing effective antibiotics against CRE and decreasing the resistance burden due to CRE.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Proteínas de Bactérias/farmacologia , Cefalosporinas/farmacologia , Ciclo-Octanos/farmacologia , Combinação de Medicamentos , Humanos , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , beta-Lactamases/farmacologia , beta-Lactamas/farmacologia
15.
Eur J Pharmacol ; 854: 9-21, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951716

RESUMO

Colitis-associated cancer (CAC) has a close relationship with ulcerative colitis (UC). Therapeutic effect of Schisandrin B (SchB) on UC and CAC remains largely unknown. We investigated the preventative effect of SchB on the dextran sulphate sodium (DSS) model of UC and azoxymethane (AOM)/DSS model of CAC. Furthermore, focal adhesion kinase (FAK) activation and influence on commensal microbiota are important for UC treatment. Impact on FAK activation by SchB in UC development was evaluated in vivo and vitro. We also conducted 16S rRNA sequencing to detect regulation of gut microbiota by SchB. Enhanced protection of intestinal epithelial barrier by SchB through activating FAK contributed to protective effect on colon for the fact that protection of SchB can be reversed by inhibition of FAK phosphorylation. Furthermore, influence on gut microbiota by SchB also played a significant role in UC prevention. Our results revealed that SchB was potent to prevent UC by enhancing protection of intestinal epithelial barrier and influence on gut microbiota, which led to inhibition of CAC. SchB was potential to become a new treatment for UC and prevention of CAC.


Assuntos
Colite Ulcerativa/prevenção & controle , Neoplasias do Colo/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Animais , Células CACO-2 , Colite Ulcerativa/complicações , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Neoplasias do Colo/complicações , Ciclo-Octanos/farmacologia , Citoproteção/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células HCT116 , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Phytomedicine ; 59: 152760, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004881

RESUMO

BACKGROUND: With increasing use of pharmaceuticals, drug-induced liver injury (DILI) has become a significant therapeutic challenge to physicians all over the world. Drugs based on Schisandra fruits (SF for short, the fruits of Schisandra chinensis or Schisandra sphenanthera) or synthetic analogues of schisandrin C, are commonly prescribed for treating DILI in China. PURPOSE: This review summarizes the literature regarding the application of SF-derived drugs in patients with DILI and current understanding of mechanisms underlying the protective effects of SF against liver injury. METHODS: Keywords related to drug-induced liver injury and Schisandra fruits were searched in the following databases: Pubmed, Cochrane Library, Google Scholar, LiverTox, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal database (VIP), and Wanfang database. All studies, published in English or Chinese, were included. Clinical study exclusion criteria: if patients received other Chinese herbal medicines in a study, the study will not be included in this review. RESULTS: Clinical studies have shown that SF-derived drugs are effective in inhibiting drug-induced elevation of serum levels of alanine aminotransferase, aspartate transaminase and total bilirubin. Cellular and animal studies have demonstrated that crude SF extracts, lignan compounds found in SF, and SF-derived drugs are effective in protecting the liver against xenobiotic-induced injury. Regulation of cytochrome P450 enzyme activity, anti-oxidation, anti-inflammation and acceleration of liver regeneration are involved in the hepatoprotective mechanisms of SF. CONCLUSION: SF-derived drugs are effective in ameliorating DILI in China. To verify the clinical efficacy of these drugs, high-quality clinical studies are needed.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Frutas/química , Lignanas/uso terapêutico , Fígado/efeitos dos fármacos , Compostos Policíclicos/uso terapêutico , Schisandra/química , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , China , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Lignanas/farmacologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Fígado/patologia , Regeneração Hepática/efeitos dos fármacos , Fitoterapia , Compostos Policíclicos/farmacologia
17.
Eur J Pharmacol ; 855: 10-19, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31028739

RESUMO

The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a significant challenge for patients with non-small cell lung cancer (NSCLC). During the past few years, a correlation between EGFR TKIs resistance and dysregulation of IKKß/NF-κB signaling has been increasingly suggested. However, few studies have focused on the effects of combining IKK/NF-κB and EGFR inhibitors to overcome EGFR TKIs resistance. In this study, we discovered that Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis, could synergize with the EGFR receptor inhibitor Gefitinib to inhibit cell growth, induce cell cycle arrest and apoptosis of HCC827/GR cells. Sch A effectively suppressed the phosphorylation of IKKß and IκBα, as well as the nuclear translocation of NF-κB p65, and showed high and selective affinity for IKKß in surface plasmon resonance (SPR) experiments, indicating that Sch A was a selective IKKß inhibitor. Molecular modeling between IKKß and Sch A suggested that Sch A formed key hydrophobic interactions with IKKß, which may contribute to its potent IKKß inhibitory effect. These findings suggest a novel approach to improve poor clinical outcomes in EGFR TKIs therapy, by combining it with Sch A.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo-Octanos/farmacologia , Gefitinibe/farmacologia , Quinase I-kappa B/metabolismo , Lignanas/farmacologia , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Compostos Policíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Quinase I-kappa B/química , Simulação de Dinâmica Molecular , Conformação Proteica
18.
Cancer Biomark ; 24(4): 497-508, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909188

RESUMO

OBJECTIVE: Schizandrin A (SchA) exerts anticancer potential. However, the effects of SchA on thyroid cancer (TC) have not been clear illuminated. Therefore, we investigated the effects of SchA on TC cell line TPC-1 and the underlying mechanisms. METHODS: TPC-1 cells were treated with SchA and/or transfected with miR-429 mimic, anti-miR-429 and their corresponding negative controls (NC). Cell viability, proliferation, migration, invasion and cell apoptosis were examined by CCK-8 assay, bromodeoxyuridine, modified two-chamber migration assay, Millicell Hanging Cell Culture and flow cytometry analysis, respectively. The expression of miR-429, p16, Cyclin D1, cyclin-dependent kinases 4 (CDK4), matrix metalloprotein (MMP)-2, MMP-9 and Vimentin was detected by qRT-PCR. All protein expression was examined by western blot. RESULTS: SchA inhibited cell proliferation, metastasis and induced cell apoptosis. Moreover, SchA negatively regulated miR-429 expression. Treatment with miR-429 mimic and SchA reversed the results led by SchA and NC. Furthermore, the phosphorylation ß-catenin, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) were statistically down-regulated by SchA while co-treatment with miR-429 mimic and SchA led to the opposite trend. Moreover, miR-429 knockdown showed contrary results. CONCLUSION: SchA inhibits cell proliferation, migration, invasion and inactivates Wnt/ß-catenin and MEK/ERK signaling pathways by down regulating miR-429.


Assuntos
Ciclo-Octanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lignanas/farmacologia , MicroRNAs/genética , Compostos Policíclicos/farmacologia , Neoplasias da Glândula Tireoide/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Octanos/química , Humanos , Lignanas/química , Sistema de Sinalização das MAP Quinases , Compostos Policíclicos/química , Interferência de RNA , Neoplasias da Glândula Tireoide/metabolismo , Via de Sinalização Wnt
19.
Biochem Cell Biol ; 97(6): 681-692, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30817212

RESUMO

BACKGROUND: To address the molecular mechanism of the anti-inflammation effects of schisandrin B (Sch B) in atherosclerosis, we examined injured HMEC-1, HBMEC, and HUVEC-12 cells induced by high glucose (HG). METHODS: Western blot was performed to detect the levels of the proteins Hsp27, Noxa, TLR5, p-IκBα, and p-p65 in HG-induced cells, while ELISA was used to analyze the inflammatory cytokines TNF-α, IL-6, MCP-1, and IL-1ß in cells with Hsp27 or Noxa stable expression. RESULTS: Overexpression of Hsp27 upregulated the inflammatory cytokines and the release of IκBα, promoted transportation of p65 into the nucleus, and lastly, affected the inflammation process, while Sch B counteracted the upregulation. In addition, the effect of Noxa overexpression, which is different from Hsp27 overexpression, was consistent with that of Sch B treatment. CONCLUSIONS: Sch B may inhibit the inflammatory cascade and alleviate the injury to HMEC-1, HBMEC, and HUEVC-12 cells caused by HG by regulating the Noxa/Hsp27/NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Glucose/antagonistas & inibidores , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Lignanas/farmacologia , NF-kappa B/antagonistas & inibidores , Compostos Policíclicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Octanos/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glucose/farmacologia , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
20.
J Biochem Mol Toxicol ; 33(5): e22301, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30801894

RESUMO

Schizandrin is a major bioactive constituent of Schisandra chinensis (Turcz.) Baill with antioxidant and anti-inflammatory properties. The objective of this study was to explore the potential effects of schizandrin on a cell model of myocarditis. The H9c2 cells were treated with schizandrin alone or in combination with lipopolysaccharide (LPS), after which, cell survival, migration, and the release of inflammatory cytokines were assessed. Moreover, downstream effectors and signaling pathways were studied to reveal the possible underlying mechanism. As a result, LPS stimulation induced significant cell damage as cell viability was repressed and the apoptosis was induced. In the meantime, LPS promoted the release of proinflammatory cytokines including interleukin 1ß (IL-1ß), IL-8, IL-6, and tumor necrosis factor (TNF-α) while repressing the release of the anti-inflammatory cytokine IL-10. Schizandrin could promote H9c2 cell migration and long-term treatment (7 days) enhanced cell viability. More interestingly, pretreatment with schizandrin attenuated LPS-induced cell loss and inflammatory response. Besides this, Smad3 was a downstream effector of schizandrin. The beneficial effects of schizandrin on the H9c2 cells were attenuated when Smad3 was overexpressed. Moreover, the silencing of Smad3 deactivated c-Jun N-terminal kinase (JNK) and nuclear factor κB (NF-κB) pathways. This study preliminarily demonstrated that schizandrin prevented LPS-induced injury in the H9c2 cells and promoted the recovery of myocardial tissues by enhancing cell viability and migration. Schizandrin conferred its beneficial effects possibly by downregulating Smad3 and inhibiting the activation of JNK and NF-κB pathways.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Lignanas/farmacologia , Lipopolissacarídeos/toxicidade , Mioblastos Cardíacos/metabolismo , Compostos Policíclicos/farmacologia , Proteína Smad3/biossíntese , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Octanos/química , Citocinas/biossíntese , Humanos , Lignanas/química , MAP Quinase Quinase 4/metabolismo , Mioblastos Cardíacos/patologia , NF-kappa B/metabolismo , Compostos Policíclicos/química , Schisandra/química , Transdução de Sinais/efeitos dos fármacos
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