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1.
Phytomedicine ; 68: 153153, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32018210

RESUMO

BACKGROUD: Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE: This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS: The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS: Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION: Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.


Assuntos
Colestase/prevenção & controle , Cinamatos/farmacologia , Glucosídeos Iridoides/farmacologia , Hepatopatias/prevenção & controle , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato/toxicidade , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Colestase/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
2.
Phytomedicine ; 68: 153146, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32028183

RESUMO

BACKGROUND: Dipsaci Radix has been clinically used for thousands of years in China for strengthening muscles and bones. Sweroside is the major active iridoid glycoside isolated from Dipsaci Radix. It has been reported that sweroside can promote alkaline phosphatase (ALP) activity in both the human osteosarcoma cell line MG-63 and rat osteoblasts. However, the underlying mechanism involved in these osteoblastic processes is poorly understood. PURPOSE: This study aimed to characterize the bone protective effects of sweroside and to investigate the signaling pathway that is involved in its actions in MC3T3-E1 cells. METHODS: Cell proliferation, differentiation and mineralization were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, ALP test and Alizarin Red S staining, respectively. The concentration of sweroside in intracellular and extracellular fluids was determined by ultra-performance liquid chromatography coupled to triple quadrupole xevo-mass spectrometry (UPLC/TQ-XS-MS). Proteins associated with the osteoblastic signaling pathway were analysed by western blot and immunofluorescence methods. RESULTS: Sweroside did not obviously affect the proliferation but significantly promoted the ALP activity and mineralization of MC3T3-E1 cells. The maximal absorption amount 0.465 ng/ml (1.3 × 10-9 M) of sweroside was extremely lower than the tested concentration of 358.340 ng/ml (10-6 M), indicating an extremely low absorption rate by MC3T3-E1 cells. Moreover, the ALP activity, the protein expression of ER-α and G protein-coupled receptor 30 (GPR30) induced by sweroside were markedly blocked by both the ER antagonist ICI 182780 and the GPR30 antagonist G15. In addition, sweroside also activated the phosphorylation of p38 kinase (p-p38), while the phosphorylation effects together with ALP and mineralization activities were completely blocked by a p38 antagonist, SB203580. Additionally, the phosphorylation of p38 induced by sweroside were markedly blocked by both the ER antagonist ICI 182780 and the GPR30 antagonist G15. CONCLUSIONS: The present study indicated that sweroside, as a potential agent in treatment of osteoporosis, might exert beneficial effects on MC3T3-E1 cells by interaction with the membrane estrogen receptor-α and GPR30 that then activates the p38 signaling pathway. This is the first study to report the specific mechanism of the effects of sweroside on osteoblastic differentiation and mineralization of MC3T3-E1 cells.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Glucosídeos Iridoides/farmacologia , Osteoblastos/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Camundongos , Osteoblastos/metabolismo , Fosforilação/efeitos dos fármacos
3.
Phytochemistry ; 171: 112232, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911266

RESUMO

Corni Fructus, also known as the fruit of Cornus officinalis Sieb. et Zucc., has long been used as a traditional Chinese medicine and is widely consumed as a nutritional food in the form of function drink and wine. Recently, Corni Fructus has attracted considerable interest because of its anti-diabetic effects. A systematic phytochemical investigation of Corni Fructus was performed to find anti-diabetic components, which led to the isolation of 10 unreported iridoid glycosides, cornusdiglycosides A-J (1-8, 9a/9b and 10a/10b). Their chemical structures were determined through spectroscopic analysis (ultraviolet [UV], infrared [IR], high-resolution electrospray ionisation mass spectroscopy [HRESIMS], one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR]). Such morroniside-type diglycosides were first reported from natural sources, and all isolates were evaluated for α-glucosidase inhibitory activity. The results showed that all compounds (1-10) exhibited α-glucosidase (from Saccharomyces cerevisiae) inhibitory activities with IC50 values ranging from 78.9 ± 4.09 to 162.2 ± 9.17 µM, whereas acarbose, the positive control, displayed α-glucosidase inhibitory activity with IC50 value of 118.9 ± 7.89 µM.


Assuntos
Cornus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeos/farmacologia , Glucosídeos Iridoides/farmacologia , Compostos Fitoquímicos/farmacologia , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/isolamento & purificação , Conformação Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
4.
J Chromatogr A ; 1609: 460438, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31447207

RESUMO

Plants are an important source of natural iridoids. This study demonstrates for the first time the acetylcholinesterase (AChE) inhibitory activity of iridoids belonging to the class of antirrhinosides. As iridoids distinguish the chemical composition of most species of the Plantaginaceae family, the active AChE inhibitors were investigated in the hydro-alcoholic extract of Anarrhinum pubescens Fresen. High-performance thin-layer chromatography (HPTLC) in combination with the AChE inhibition assay is a time and material saving methodology, and thus was employed to directly point to the individual enzyme inhibitors occurring in the plant. The effect-directed screening successfully discovered three active metabolites. These were characterized as antirrhinoside-derived iridoids. Two of these are here reported as newly isolated natural compounds. Identification of the two new metabolites was based on analysis of their collected spectroscopic data (HRMS, 1D and 2D NMR). Their structures were elucidated to be 6-O-, 6'-O-di-trans-cinnamoyl-antirrhinoside (1) and 5-O-, 6-O-difoliamenthoyl-antirrhinoside (3), while the previously known compound 6-O-foliamenthoyl-(6'-O-cinnamoyl)-antirrhinoside (2) was assigned by extensive analysis of its HRMS and HRMS/MS data. The activity of the isolated compounds was referred to the known AChE inhibitor rivastigmine, i.e. their activity were calculated and expressed as values equivalently to rivastigmine. This neuroprotective potential of iridoids mediated through AChE inhibition promote them to compete as natural curatives for neurodegenerative disorders like Alzheimer's disease.


Assuntos
Acetilcolinesterase/análise , Cromatografia em Camada Delgada/métodos , Ensaios Enzimáticos/métodos , Glucosídeos Iridoides/isolamento & purificação , Plantaginaceae/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/farmacologia , Fluorescência , Glucosídeos Iridoides/farmacologia , Metaboloma , Espectroscopia de Prótons por Ressonância Magnética
5.
Fitoterapia ; 140: 104443, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790767

RESUMO

Aucubin is an iridoid glycoside that is widely prevalent in traditional medicinal herbs, such as Eucommia ulmoides Oliv., Aucuba japonica Thunb. and Plantago asiatica L. This review aims to provide a comprehensive summary of the source, biological activity, pharmacokinetics and toxicology of aucubin with the ultimate objective of providing a guide for future drug development and potential clinical applications of aucubin. Aucubin is a highly active compound possessing extensive biological effects including antioxidant, anti-aging, anti-inflammatory, anti-fibrotic, anti-cancer, hepatoprotective, neuroprotective and osteoprotective properties. Although aucubin has been shown to have poor oral bioavailability in rats, aucubin is widely distributed in multiple organs including kidney, liver, heart, spleen and lung, and there is a sex difference in the absorption of aucubin. Tolerance of aucubin is good and no serious adverse reactions have been observed to date. In short, aucubin is a compound with abundant potential sources, good safety and numerous beneficial biological activities, which exhibits high potential value for use in health care products and pharmaceuticals. In order to accelerate the development and utilization of aucubin-related products, in-depth studies should be focused on the following questions of interest. First, it is necessary to introduce advanced separation and formulation technologies to improve the yield and stability of aucubin products. Second, studies should focus on the specific pharmacological activities of aucubin to determine the structure-activity relationship so as to improve the efficacy and reduce side effects. Finally, clinical studies are needed to confirm the efficacy of aucubin in specific diseases.


Assuntos
Glucosídeos Iridoides/farmacologia , Glucosídeos Iridoides/toxicidade , Animais , Humanos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/toxicidade , Plantas Medicinais/química
6.
Acta Cir Bras ; 34(11): e201901102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31859816

RESUMO

PURPOSE: To investigate the effect of Picroside II on testicular ischemia and reperfusion (l/R) injury and the underlying mechanism. METHODS: Sprague-Dawley rats were randomly divided into 4 groups: sham operated group (Sham), Sham with Picroside II treatment group (Sham+ Pic II), l/R group (l/R) and l/R with Picroside II treatment group (I/R+ Pic II). l/R model was established by rotating the left testis 720° in a clock-wise direction for 4 hours. The histopathologic and spermatogenetic evaluation was performed. The apoptosis changes and the levels of HO-1 (heme oxygenase-1), MPO (myeloperoxidase), NOX (NADPH oxidase), SOD (superoxide dismutase), XO (xanthine oxidase) and NOS (nitric oxide synthase) were measured. RESULTS: The seminiferous tubules were damaged in l/R rats, but Picroside II alleviated the changes induced by l/R. The increased level of apoptosis was decreased by Picroside II (P=0.01, 9.05±0.35 vs. 4.85±0.25). The activities of HO-1, MPO, NOX, XO and MDA content were increased and the SOD activity was decreased in l/R (P<0.05) and could be reversed by Picroside II (P=0.03, 405.5±7.5 vs. 304±17U/mgprot; P=0.02, 0.99±0.05 vs. 0.52±0.04 mgprot; P=0.01, 260+7 vs. 189±2 mgprot; P=0.04, 10.95+0.55 vs. 8.75+0.35 U/mgprot; P=0.045, 6.8+0.7 vs. 3.75+0.35 mgprot; P=0.04, 44.5+3.5 vs. 57.5+3.5 mgprot). Western blot showed that the expression of iNOS, nNOS and eNOS were increased in l/R (P<0.05); however, they were decreased after Picroside II treatment (P<0.05). CONCLUSION: Picroside II attenuated testicular I/R injury in rats mainly through suppressing apoptosis and oxidative stress through reduction of nitric oxide synthesis.


Assuntos
Apoptose/efeitos dos fármacos , Cinamatos/farmacologia , Glucosídeos Iridoides/farmacologia , Óxido Nítrico/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Testículo/irrigação sanguínea , Animais , Western Blotting , Heme Oxigenase-1/análise , Marcação In Situ das Extremidades Cortadas , Masculino , Malondialdeído/análise , NADP/análise , Peroxidase/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Reprodutibilidade dos Testes , Superóxido Dismutase/análise , Testículo/patologia , Xantina Oxidase/análise
7.
Acta cir. bras ; 34(11): e201901102, Nov. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1054682

RESUMO

Abstract Purpose: To investigate the effect of Picroside II on testicular ischemia and reperfusion (l/R) injury and the underlying mechanism. Methods: Sprague-Dawley rats were randomly divided into 4 groups: sham operated group (Sham), Sham with Picroside II treatment group (Sham+ Pic II), l/R group (l/R) and l/R with Picroside II treatment group (I/R+ Pic II). l/R model was established by rotating the left testis 720° in a clock-wise direction for 4 hours. The histopathologic and spermatogenetic evaluation was performed. The apoptosis changes and the levels of HO-1 (heme oxygenase-1), MPO (myeloperoxidase), NOX (NADPH oxidase), SOD (superoxide dismutase), XO (xanthine oxidase) and NOS (nitric oxide synthase) were measured. Results: The seminiferous tubules were damaged in l/R rats, but Picroside II alleviated the changes induced by l/R. The increased level of apoptosis was decreased by Picroside II (P=0.01, 9.05±0.35 vs. 4.85±0.25). The activities of HO-1, MPO, NOX, XO and MDA content were increased and the SOD activity was decreased in l/R (P<0.05) and could be reversed by Picroside II (P=0.03, 405.5±7.5 vs. 304±17U/mgprot; P=0.02, 0.99±0.05 vs. 0.52±0.04 mgprot; P=0.01, 260+7 vs. 189±2 mgprot; P=0.04, 10.95+0.55 vs. 8.75+0.35 U/mgprot; P=0.045, 6.8+0.7 vs. 3.75+0.35 mgprot; P=0.04, 44.5+3.5 vs. 57.5+3.5 mgprot). Western blot showed that the expression of iNOS, nNOS and eNOS were increased in l/R (P<0.05); however, they were decreased after Picroside II treatment (P<0.05). Conclusion: Picroside II attenuated testicular I/R injury in rats mainly through suppressing apoptosis and oxidative stress through reduction of nitric oxide synthesis.


Assuntos
Animais , Masculino , Testículo/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Cinamatos/farmacologia , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Glucosídeos Iridoides/farmacologia , Óxido Nítrico/biossíntese , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Distribuição Aleatória , Western Blotting , Ratos Sprague-Dawley , Peroxidase/análise , Marcação In Situ das Extremidades Cortadas , Heme Oxigenase-1/análise , Malondialdeído/análise , NADP/análise
8.
Fitoterapia ; 139: 104365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647954

RESUMO

As a folk medicine, Phlomis likiangensis is traditionally used in China to activate collaterals and protect cardiovascular system. We hypothesized that the beneficial effects of Phlomis likiangensis may be related to vasodilatation. In the present study, twelve known iridoid glucosides (1-12) were isolated from Phlomis likiangensis. The vasodilatory effects and the underlying mechanisms of the main components (iridoid glucosides) of Phlomis likiangensis on rat aortic rings were investigated. The result showed that iridoid glucosides significantly increased the vasodilatation in rat aortic rings, which was abolished by removing the endothelium of the vessels or by eliminating the generation of nitric oxide. Finally, the structure-activity relationship of compounds 1-12 was also speculated. Our findings provide the first evidence that the iridoid glucosides of Phlomis likiangensis may be the pharmacodynamic basis for its traditional efficacy.


Assuntos
Glucosídeos Iridoides/farmacologia , Phlomis/química , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , China , Células Endoteliais/efeitos dos fármacos , Técnicas In Vitro , Glucosídeos Iridoides/química , Masculino , Estrutura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Plantas Medicinais/química , Ratos , Ratos Sprague-Dawley , Rizoma/química , Relação Estrutura-Atividade , Vasodilatação , Vasodilatadores/química
9.
Med Sci Monit ; 25: 6649-6659, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31484919

RESUMO

BACKGROUND Chondrocyte dysfunction and apoptosis are 2 major features during the progression of osteoarthritis. Catalpol, an iridoid glycoside isolated from the root of Rehmannia, is a valuable medication with anti-inflammatory, anti-oxidative, and anti-apoptotic effects in various diseases. However, whether catalpol protects against osteoarthritis has not been investigated. MATERIAL AND METHODS To assess the role of catalpol in osteoarthritis and the potential mechanism of action, chondrocytes were treated with interleukin (IL)-1ß and various concentrations of catalpol. Catabolic metabolism, apoptotic level and relative signaling pathway were measured by western blot, real-time polymerase chain reaction and immunofluorescence staining. Meanwhile, we assess the cartilage degeneration in an experimental rat model using Safranin O fast green staining and cartilage was graded according to the Osteoarthritis Research Society International (OARSI) system. RESULTS The results showed that catalpol prevented chondrocyte apoptotic level triggered by IL-1ß, suppressed the release of catabolic enzymes, and inhibited the degradation of extracellular matrix induced by IL-1ß. Catalpol also inhibited the nuclear factor kappa B (NF-kappaB) pathway, reduced the production of inflammatory cytokines (IL-6, tumor necrosis factor-alpha) in IL-1ß-treated chondrocytes, and partially reversed cartilage degeneration in the knee joint in animal model of osteoarthritis. CONCLUSIONS Our work suggested that catalpol treatment attenuates IL-1ß-induced inflammatory response and catabolism in rat chondrocytes by inhibiting the NF-kappaB pathway, suggesting the therapeutic potential of catalpol for the treatment of osteoarthritis.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/patologia , Matriz Extracelular/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Glucosídeos Iridoides/farmacologia , Proteínas ADAMTS/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
J Zhejiang Univ Sci B ; 20(10): 816-827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489801

RESUMO

Catalpol is the main active ingredient of an extract from Radix rehmanniae, which in a previous study showed a protective effect against various types of tissue injury. However, a protective effect of catalpol on uterine inflammation has not been reported. In this study, to investigate the protective mechanism of catalpol on lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and mouse endometritis, in vitro and in vivo inflammation models were established. The Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway and its downstream inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence techniques. The results from ELISA and qRT-PCR showed that catalpol dose-dependently reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, and IL-6, and chemokines such as C-X-C motif chemokine ligand 8 (CXCL8) and CXCL5, both in bEECs and in uterine tissue. From the experimental results of WB, qRT-PCR, and immunofluorescence, the expression of TLR4 and the phosphorylation of NF-κB p65 were markedly inhibited by catalpol compared with the LPS group. The inflammatory damage to the mouse uterus caused by LPS was greatly reduced and was accompanied by a decline in myeloperoxidase (MPO) activity. The results of this study suggest that catalpol can exert an anti-inflammatory impact on LPS-induced bEECs and mouse endometritis by inhibiting inflammation and activation of the TLR4/NF-κB signaling pathway.


Assuntos
Endometrite/tratamento farmacológico , Inflamação/prevenção & controle , Glucosídeos Iridoides/farmacologia , NF-kappa B/fisiologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/fisiologia , Animais , Bovinos , Quimiocinas/genética , Citocinas/genética , Células Epiteliais/efeitos dos fármacos , Feminino , Glucosídeos Iridoides/uso terapêutico , Lipopolissacarídeos/farmacologia , Camundongos
11.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 85-90, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31472052

RESUMO

To investigate the effect of gentiopicrin on the expressions of inflammatory factors in human fibroblast-like synoviocytes (HFLS) and the underlying mechanism. Human fibroblast-like synoviocytes (HFLS) were cultured in vitro at 37 °C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5 % fetal bovine serum (FBS) in a humidified incubator containing 5 % CO2. Cell viability was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-tetrazolium bromide (MTT) assay, while real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expressions of interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) mRNAs. The expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) were determined using Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-1ß and IL-6 in cell lysate. Treatment with 5-25 µM gentiopicrin did not significantly affect the number of viable cells, when compared with control group (p > 0.05). However, at 50 and 100 µM gentiopicrin, the number of viable cells were significantly increased, relative to control group (p < 0.05). Results of qRT-PCR showed that the expression levels of IL-1ß and IL-6 mRNAs were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently decreased their expression levels compared with TNF-α group (p < 0.05). Western blotting results showed that the expressions of p-p38MAPK and NF-κB-p65 proteins were significantly upregulated in TNF-α group, when compared with control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently down-regulated the expression of these proteins compared with TNF-α group (p < 0.05). The levels of IL-1ß and IL-6 in cell lysate were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin, and p38MAPK/NF-κB pathway inhibitors (SB203580 and BAY11-7082) significantly reduced the levels of these inflammatory factors compared with TNF-α group (p < 0.05).  Gentiopicrin has therapeutic potential for Rheumatoid arthritis (RA  ) through a mechanism involving the inhibition of p38MAPK/NF-κB pathway.


Assuntos
Fibroblastos/metabolismo , Glucosídeos Iridoides/farmacologia , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Sinoviócitos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Artrite Reumatoide/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Imidazóis/farmacologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Glucosídeos Iridoides/administração & dosagem , NF-kappa B/metabolismo , Nitrilos/farmacologia , Extratos Vegetais/administração & dosagem , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Chem Biodivers ; 16(11): e1900421, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487435

RESUMO

Phytochemical study on the fruit of Cornus officinalis Sieb. et Zucc. yielded two new iridoid glucosides, named cornusglucoside A (1) and cornusglucoside B (2). The structures of 1 and 2 were elucidated via comprehensive NMR and HR-ESI-MS data analysis. Additionally, their inhibitory effects on IL-6-induced STAT3 activation were assessed.


Assuntos
Cornus/química , Frutas/química , Glucosídeos Iridoides/isolamento & purificação , Células Hep G2 , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Conformação Molecular , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo
13.
Am J Chin Med ; 47(6): 1253-1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488034

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder associated with features of metabolic syndrome and oxidative stress. We examined the mechanism by which the combined extracts of Rhus verniciflua and Eucommia ulmoides extracts (ILF-RE) regulate hepatic dyslipidemia in an established NAFLD model, high-fat diet (HFD)-induced lipid dysmetabolism in rats. ILF-RE attenuated alanine aminotransferase (ALT) by 1.5% (p<0.05), aspartate aminotransferase (AST) by 1.5% (p<0.05), triglycerides by 1.5% (p<0.05), cholesterol by 2.0% (p<0.05), and lipid peroxidation by 1.5% (p<0.05) in the NAFLD model. ILF-RE, recently shown to have anti-oxidant properties, also inhibited hepatic ROS accumulation by 1.68% (p<0.05) and regulated ER-redox imbalance, a key phenomenon of ER stress. Due to nutrient overload stress-associated protein folding, ER stress and downstream SREBP-lipogenic transcription signaling were highly activated, and the mTORC1-AMPK axis was also disturbed, leading to hepatic steatosis. ILF-RE results in recovery from hepatic conditions induced by nutrient-based protein folding stress signaling and the ER stress-SREBP and AMPK-mTORC1-SREBP1 axes. Based on these results, ILF-RE is suggested to be a potential therapeutic strategy for hepatic steatosis and may represent a promising novel agent for the prevention and treatment of NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eucommiaceae/química , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Glucosídeos Iridoides/uso terapêutico , Iridoides/isolamento & purificação , Iridoides/farmacologia , Iridoides/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
Am J Chin Med ; 47(6): 1193-1221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488038

RESUMO

Veronica is the largest genus in the flowering plant family Plantaginaceae and comprises approximately 500 species. The genus was formerly placed in the Scrophulariaceae family, some species of which have been used in traditional medicine for the treatment of influenza, respiratory diseases, hemoptysis, laryngopharyngitis, cough, hernia, cancer, edema, and wounds. This review comprehensively summarizes the current information on the traditional uses, phytochemistry, and pharmacology of the genus Veronica on the basis of articles published from 1970 to 2018. More than 260 compounds have been isolated, and chemotaxonomic investigations of Veronica have revealed that iridoid glucosides - including aucubin, catalpol, and 6-O-catalpol derivatives - are characteristic of this genus. Modern pharmacological studies and clinical practice have demonstrated that extracts or monomeric compounds from Veronica have several pharmacological actions, such as anti-inflammatory, anti-oxidative, anticancer, antibacterial, anti-angiogenic, antineurodegenerative, neuroprotective, and hepatoprotective effects both in vivo and in vitro.


Assuntos
Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Veronica/química , Inibidores da Angiogênese , Animais , Antibacterianos , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Antioxidantes , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Humanos , Glucosídeos Iridoides/química , Medicina Tradicional , Conformação Molecular , Fármacos Neuroprotetores , Fitoterapia , Terpenos/síntese química , Terpenos/isolamento & purificação , Terpenos/farmacologia
15.
BMC Complement Altern Med ; 19(1): 244, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488111

RESUMO

BACKGROUND: Catalpol, a natural iridoid glycoside in Rehmannia glutinosa, can alleviate proteinuria associated with diabetic nephropathy (DN), however, whether catalpol has a protective effect against podocyte injury in DN remains unclear. METHODS: In this study, we used a high glucose (HG)-induced podocyte injury model to evaluate the protective effect and mechanism of catalpol against HG-induced podocyte injury. Cell viability was determined by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by commercial assay kits. Cell apoptosis and reactive oxygen species (ROS) were determined by using flow cytometry. Tumour necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl2-associated x (Bax), cleaved caspase-3, nicotinamide adenine dinucleotide phosphate oxidase enzyme 4 (NOX4), toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), p38 mitogen-activated protein kinase (p38 MAPK), phosphorylated p38 MAPK (p-p38 MAPK), nuclear factor kappa B inhibitor alpha (IκBα) and phosphorylated IκBα (p-IκBα) were measured by western blotting. In addition, Bcl-2, Bax, caspase-3 and nuclear factor kappa B (NF-κB) levels were determined by immunofluorescence staining. RESULTS: Catalpol significantly increased cell viability and decreased LDH release in HG-induced podocyte injury. Catalpol significantly decreased ROS generation, apoptosis, level of MDA, levels of inflammatory cytokine TNF-α, IL-1ß, and IL-6 and increased SOD activity in HG-induced podocyte injury. Moreover, catalpol significantly decreased expression of cleaved caspase-3, Bax, NOX4, TLR4, MyD88, p-p38 MAPK, p-IκBα and NF-κB nuclear translocation, as well as increased Bcl-2 expression in HG-induced podocyte injury. CONCLUSION: Catalpol can protect against podocyte injury by ameliorating apoptosis and inflammation. These protective effects may be attributed to the inhibition of NOX4, which alleviates ROS generation and suppression of the TLR4/MyD88 and p38 MAPK signaling pathways to prevent NF-κB activation. Therefore, catalpol could be a promising drug for the prevention of DN.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glucose/efeitos adversos , Glucosídeos Iridoides/farmacologia , Podócitos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Glucose/análise , Glucose/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Podócitos/citologia , Podócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rehmannia/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
J Nat Med ; 73(4): 761-768, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31190267

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-limiting side effects of cancer chemotherapy. Although the control of CIPN is important, it is difficult to manage with currently available therapeutic drugs. Therefore, there is a need for novel therapeutic agents for treating CIPN. Goshajinkigan (GJG) is a Kampo formula composed of ten crude drugs. While GJG has been used for the treatment of CIPN, the active constituents of GJG and their underlying mechanisms of pharmacological effects are still unknown. Our previous study revealed that repetitive oral administration of the water extract of Plantaginis Semen, a crude drug ingredient of GJG, inhibited the mechanical allodynia induced by an intraperitoneal injection of paclitaxel in mice. To elucidate the active compounds of Plantaginis Semen, activity-guided separation of the water extract of Plantaginis Semen was performed. From the active fraction, four iridoids (1-4) were identified. Repetitive oral administration of aucubin (1) at 100 or 30 mg/kg and 100 mg/kg of the fraction crude 3 [primarily comprised of pedicularis-lactone (3)], showed anti-allodynic activity, suggesting 1 and 3 could be some of the active compounds responsible for the anti-allodynic property of Plantaginis Semen and GJG. Our study establishes that oral administration of 1 has potent anti-allodynic effect in addition to the activity of intraperitoneally administered 1 reported previously. Identification of active anti-allodynic compounds found in Kampo formulations will support the development of novel therapies for the management of CIPN in cancer patients.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hiperalgesia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Extratos Vegetais/farmacologia , Plantago/química , Animais , Hiperalgesia/induzido quimicamente , Glucosídeos Iridoides/farmacologia , Iridoides/farmacologia , Lactonas/farmacologia , Masculino , Medicina Kampo , Camundongos , Camundongos Endogâmicos C57BL , Paclitaxel/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente
17.
Curr Med Chem ; 26(33): 6149-6173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218947

RESUMO

Catalpol, a famous molecule of iridoids, possesses extensive pharmacological activities. Our studies found that compounds with low-polarity substituents at the 6-O position of catalpol exhibited higher NF-κB inhibitory potency than catalpol. However, catalpol derivatives are not much focused. Here this review provides extensive coverage of naturally occurring catalpol derivatives discovered from 1888 until 2018. It covers their distribution, chemotaxonomic significance, chemical structures, and bioactivities from more than 200 peer-reviewed articles, and highlights the structure-activity relationship of catalpol derivatives.


Assuntos
Glucosídeos Iridoides/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Artrite/tratamento farmacológico , Humanos , Glucosídeos Iridoides/farmacologia , Glucosídeos Iridoides/uso terapêutico , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Neoplasias/tratamento farmacológico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Plantas/química , Plantas/metabolismo
18.
Molecules ; 24(10)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137813

RESUMO

Chronic obstructive pulmonary disease (COPD) is a major inflammatory lung disease characterized by irreversible and progressive airflow obstruction. Although corticosteroids are often used to reduce inflammation, steroid therapies are insufficient in patients with refractory COPD. Both serum amyloid A (SAA) and IL-33 have been implicated in the pathology of steroid-resistant lung inflammation. Picroside II isolated from Pseudolysimachion rotundum var. subintegrum (Plantaginaceae) is a major bioactive component of YPL-001, which has completed phase-2a clinical trials in chronic obstructive pulmonary disease patients. In this study, we investigated whether picroside II is effective in treating steroid refractory lung inflammation via the inhibition of the SAA-IL-33 axis. Picroside II inhibited LPS-induced SAA1 expression in human monocytes, which are resistant to steroids. SAA induced the secretion of IL-33 without involving cell necrosis. Picroside II, but not dexamethasone effectively inhibited SAA-induced IL-33 expression and secretion. The inhibitory effect by picroside II was mediated by suppressing the mitogen-activated protein kinase (MAPK) p38, ERK1/2, and nuclear factor-κB pathways. Our results suggest that picroside II negatively modulates the SAA-IL-33 axis that has been implicated in steroid-resistant lung inflammation. These findings provide valuable information for the development of picroside II as an alternative therapeutic agent against steroid refractory lung inflammation in COPD.


Assuntos
Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Glucocorticoides/farmacologia , Interleucina-33/metabolismo , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Plantaginaceae/química , Proteína Amiloide A Sérica/metabolismo , Cinamatos/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Glucosídeos Iridoides/química , Lipopolissacarídeos/farmacologia , Pulmão/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Células THP-1 , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Transcrição Genética/efeitos dos fármacos
19.
Exp Mol Pathol ; 109: 51-60, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31145886

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with high rates of recurrence and mortality worldwide. Unfortunately, effective strategies for the management of HCC are still unsatisfactory. The aim of this investigation is to explore the effects of catalpol on HCC progression and investigated the mechanistic functions of catalpol in HCC. Catalpol significantly suppressed cell viability, caused the suppression in colony growth, decreased number of invaded and migrated HCC cells, and increased the rates of apoptotic cells and proportions of HCC cells at G0/G1 cell cycle phase. Furthermore, catalpol dramatically up-regulated miR-22-3p expression in HCC cells, and knockdown of miR-22-3p attenuated the anti-tumor effects of catalpol in HCC. Additionally, results from luciferase reporter assay demonstrated that miR-22-3p targeted the metastasis associated 1 family member 3 (MTA3) 3'untranslated region (3'UTR), and miR-22-3p down-regulated MTA3 expression in HCC cells. Overexpression of MTA3 enhanced HCC cell proliferative abilities, increased the number of invasive and migratory HCC cells, and also attenuated the anti-tumor potentials of catalpol in HCC. Catalpol suppressed HCC tumor growth and increased miR-22-3p expression, while down-regulated MTA3 expression in dissected tumor tissues from xenograft nude mice. Collectively, our results for the first time revealed the anti-tumor potentials of catalpol in HCC, and the anti-tumor effects mediated by catalpol were via modulating the miR-22-3p/MTA3 axis in HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucosídeos Iridoides/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/genética , Proteínas de Neoplasias/genética , Regiões 3' não Traduzidas/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biochimie ; 165: 90-99, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31078585

RESUMO

The cardioprotection of catalpol and its mechanism in diabetic cardiomyopathy (DCM) remains unclear. Here, mouse cardiomyocytes were treated with high glucose (HG) to establish a model of cellular injury induced by HG. In vitro experiments were carried out and confirmed that Catalpol attenuated HG-induced long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (Neat1) expression in mouse cardiomyocytes. Mechanistically, luciferase reporter analysis indicated that Neat1 could decrease the transcription of miR-140-5p to positively regulate histone deacetylase 4 (HDAC4) expression. Notably, overexpression of miR-140-5p or silencing of HDAC4 rescued Neat1-induced cardiomyocyte apoptosis. DCM was induced in male C57BL/6 mice by intraperitoneal injection with streptozotocin (STZ) combined with a high-fat/high-sugar diet. Further in vivo experiments identified that Catalpol alleviated myocardial damage by regulating Neat1/miR-140-5p/HDAC4 axis in DCM mice. Thus, our results demonstrated that Catalpol could exert cardioprotective effect against DCM via Neat1/miR-140-5p/HDAC4 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Histona Desacetilases/metabolismo , Glucosídeos Iridoides/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Animais , Cardiotônicos/uso terapêutico , Glucosídeos Iridoides/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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