RESUMO
Brain edema after ischemic stroke could worsen cerebral injury in patients who received intravenous thrombolysis. Cornus officinalis Sieb. et Zucc., a long-established traditional Chinese medicine, is beneficial to the treatment of neurodegenerative diseases including ischemic stroke. In particular, its major component, cornel iridoid glycoside (CIG), was evidenced to exhibit neuroprotective effects against cerebral ischemic/reperfusion injury (CIR/I). Aimed to explore the effects of the CIG on brain edema of the CIR/I rats, the CIG was analyzed with the main constituents by using HPLC. The molecular docking analysis was performed between the CIG constituents and AQP4-M23. TGN-020, an AQP4 inhibitor, was used as a comparison. In the in vivo experiments, the rats were pre-treated with the CIG and were injured by performing middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, the rats were examined for neurological function, pathological changes, brain edema, and polarized Aqp4 expressions in the brain. The HPLC analysis indicated that the CIG was composed of morroniside and loganin. The molecular docking analysis showed that both morroniside and loganin displayed lower binding energies to AQP4-M23 than TGN-020. The CIG pre-treated rats exhibited fewer neurological function deficits, minimized brain swelling, and reduced lesion volumes compared to the MCAO/R rats. In the peri-infarct and infarct regions, the CIG pre-treatment restored the polarized Aqp4 expression which was lost in the MCAO/R rats. The results suggested that the CIG could attenuate brain edema of the cerebral ischemia/reperfusion rats by modulating the polarized Aqp4 through the interaction of AQP4-M23 with morroniside and loganin.
Assuntos
Aquaporina 4 , Edema Encefálico , Cornus , Glicosídeos Iridoides , Iridoides , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Masculino , Ratos , Aquaporina 4/metabolismo , Encéfalo/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Cornus/química , Glicosídeos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/isolamento & purificação , Iridoides/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Three undescribed seco-iridoid glycosides, one undescribed flavonoid glycoside, and three known glycosides were isolated and identified from Gentiana olivieri Griseb. The structures of these compounds were determined through spectroscopic analysis and ECD calculations. Olivierisecosides NP (1-3) were identified as aromatic conjugated seco-iridoid glucosides, among them olivierisecoside N was representing a particularly rare subtype known as the morroniside seco-iridoids. The compounds 2, 3, 5, and 6 exhibited significant inhibition of COX-2 expression, particularly compound 5 which demonstrated the most pronounced inhibitory activity with IC50 value of 23.33 ± 0.51 µM. This study provides evidence for the potential development and utilization of G. olivieri as a source of anti-inflammatory components.
Assuntos
Anti-Inflamatórios , Flavonoides , Gentiana , Glicosídeos , Glicosídeos Iridoides , Compostos Fitoquímicos , Gentiana/química , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/química , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Glicosídeos/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/química , Animais , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/isolamento & purificação , Glicosídeos Iridoides/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Camundongos , China , Células RAW 264.7RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Morinda officinalis How. is a commonly used traditional Chinese herb with the pharmacological properties of tonifying liver and kidney, and enhancing bone and muscle. Iridoid glycosides are the predominant components of this plant, including monotropein, asperuloside, deacetylasperuloside and deacetylasperulosidic acid with their contents reaching more than 2%. Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA), but liver injury induced by MTX limits its wider use for RA. Morindaofficinalis iridoid glycoside (MOIG) is reported as having anti-RA and hepatoprotective effects, but the exact efficacy on MTX-induced liver injury and the underlying molecular mechanism remain unclear. AIM: To elucidate the mitigating effect of MOIG against liver injury in RA rats treated with MTX, and explore the possible mechanism. MATERIALS AND METHODS: The effect and mechanism of MOIG were investigated in Wistar rats with collagen-induced arthritis (CIA) which were then treated with MTX, and MTX-induced hepatocyte injury in vitro. Network pharmacological and transcriptomic analyses were conducted to predict the possible mechanisms of MOIG in mitigating MTX-induced liver injury, and lipidomic analysis was performed to further verify the regulatory effects of MOIG on lipid metabolism. BRL-3A hepatocytes were used to evaluate the regulatory effects of MOIG against MTX-associated liver injury. RESULTS: MOIG treatment enhanced the anti-RA effect of MTX, and mitigated oxidative damage, inflammation and apoptosis of liver tissues in CIA rats treated with MTX. Network pharmacological and transcriptomic analyses demonstrated that MOIG attenuated liver injury by regulating autophagy and lipid metabolism. The result of lipidomic analysis showed that MOIG reversed the disturbance of lipid metabolism of the liver tissue in CIA rats after MTX treatment. In addition, MOIG also inhibited the apoptosis, reduced the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ALT) and alanine aminotransferase (AST), regulated oxidative stress, and increased the formation of autophagosome and translocation of LC3 in the nucleus and expression of autophagy regulatory genes Beclin-1, ATG5, LC3â ¡, ATG7 and ATG12 in hepatocytes subjected to MTX damage. CONCLUSION: Our findings demonstrated that MOIG could ameliorate MTX-induced liver injury in the treatment of RA through increasing hepatocyte autophagy and improving lipid metabolism homeostasis.
Assuntos
Artrite Experimental , Autofagia , Doença Hepática Induzida por Substâncias e Drogas , Glicosídeos Iridoides , Metabolismo dos Lipídeos , Fígado , Metotrexato , Morinda , Ratos Wistar , Animais , Metotrexato/toxicidade , Morinda/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Autofagia/efeitos dos fármacos , Ratos , Glicosídeos Iridoides/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Masculino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacosRESUMO
Neuroblastoma, a prevalent extracranial solid tumor in children, arises from undifferentiated nerve cells. While tumor vasculature, often characterized by increased permeability, influences metastasis and recurrence, the direct impact of blood-borne molecules on tumor progression remains unclear. In the present study, we focused on the effect of exposure to albumin, one of the most abundant proteins in the serum, on human neuroblastoma cells. Albumin exposure elevated oxidative stress and led to mitochondria dysfunction via the activation of TGFß and PI3K pathways, accompanied by an increase in the metastatic and invasive properties of neuroblastoma cells. Proteins relevant to the induction of autophagy were upregulated in response to prolonged albumin exposure. Additionally, pre-exposure to albumin before treatment resulted in increased resistance to paclitaxel. Two valeriana-type iridoid glycosides, patrisophoroside and patrinalloside, recently isolated from Nardostachys jatamansi significantly mitigated the effect of albumin on oxidative stress, cell invasiveness, and chemoresistance. These findings illuminate the potential role of blood-borne molecules, such as albumin, in the progression and metastasis of neuroblastoma, as well as the possible therapeutic implications of valeriana-type iridoid glycosides in anti-cancer treatment.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Glicosídeos Iridoides , Neuroblastoma , Paclitaxel , Humanos , Neuroblastoma/patologia , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/farmacologia , Glicosídeos Iridoides/farmacologia , Linhagem Celular Tumoral , Invasividade Neoplásica , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Valeriana/química , Albumina Sérica/metabolismoRESUMO
Iridoid glycosides extract, which is the main active extract of Ajuga decumbens Thunb, has been proved to have anti-breast cancer activity in previous studies. However, it is still unknown whether 8-O-acetylharpagide, a main active compound in the extract, has anti-breast cancer activity. In this study, 4 T1 breast cancer mice model was first successfully established. Then the anti-breast cancer effect of 8-O-acetylharpagide was systematically investigated. Feces were collected for metabolomics and 16S rRNA analysis to assess the potential mechanism. The results showed that 8-O-acetylharpagide was effective in reducing 4 T1 mouse tumor volume and weight compared with the model group. Metabolome analysis revealed 12 potential metabolite biomarkers in feces, mainly involved in primary bile acid biosynthesis and arachidonic acid metabolism. The 16S rRNA sequencing results demonstrated that 8-O-acetylharpagide modulated the abundance of the intestinal flora in 4 T1 mice. Spearman correlation analysis showed that calcitriol and prostaglandin G2 strongly correlated with Akkermansia, Firmicutes and Muribaculum. Overall, the active compound 8-O-acetylharpagide could inhibit significantly breast cancer growth in 4 T1 breast cancer model mice. The mechanism of the anti-breast cancer effect of 8-O-acetylharpagide may be related to the regulation of primary bile acid biosynthesis and arachidonic acid metabolism and modulation of the abundance of Akkermansia and Firmicutes.
Assuntos
Neoplasias da Mama , Metaboloma , Animais , Camundongos , Feminino , Metaboloma/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Fezes/microbiologia , Fezes/química , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolômica/métodos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos Endogâmicos BALB CRESUMO
Two new iridoid glycosides, piasezkiiosides A (1) and B (2), were isolated from aqueous extract of the whole plant of Rehmannia piasezkii. Their structures were established from the spectroscopic data, chemical transformation, and X-ray diffraction analysis. Compound 1 exhibited weak hepatoprotective activity against APAP-induced HepG2 cell damage.
Assuntos
Glicosídeos Iridoides , Rehmannia , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Glicosídeos Iridoides/isolamento & purificação , Humanos , Células Hep G2 , Estrutura Molecular , Rehmannia/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificaçãoRESUMO
Two previously undescribed iridoid glycosides, 6'-O-trans-feruloyl-(4S,6R)-3,4-dihydro-3ß-ethoxypaederoside (1) and 6'-O-trans-caffeoyl-(4S,6R)-3,4-dihydro-2'-O-3α-paederoside (2), were isolated from the 90% EtOH extract of the air dried aerial parts of Paederia Foetida. Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The two isolated iridoid glycosides were tested in vivo for their antinociceptive properties. As a result, 2 showed potent antinociceptive effect and its ID50 value (53.4 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.
Assuntos
Analgésicos , Glicosídeos Iridoides , Componentes Aéreos da Planta , Estrutura Molecular , Animais , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/isolamento & purificação , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Glicosídeos Iridoides/isolamento & purificação , Componentes Aéreos da Planta/química , Camundongos , Ressonância Magnética Nuclear Biomolecular , Acetaminofen , Aspirina/farmacologia , Aspirina/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Masculino , EstereoisomerismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cornel iridoid glycosides (CIG) are extracted from Corni fructus, a herbal medicine used in traditional Chinese medicine to treat diabetes. However, the antidiabetic effects of CIG and the underlying metabolic mechanisms require further exploration. AIM OF THE STUDY: This study aimed to assess the antidiabetic effects and metabolic mechanism of CIG by performing metabolomic analyses of serum and urine samples of rats. MATERIALS AND METHODS: A rat model of type 2 diabetes mellitus (T2DM) was established by administering a low dose of streptozotocin (30 mg/kg) intraperitoneally after 4 weeks of feeding a high-fat diet. The model was evaluated based on several parameters, including fasting blood glucose (FBG), random blood glucose (RBG), urine volume, liver index, body weight, histopathological sections, and serum biochemical parameters. Subsequently, serum and urine metabolomics were analyzed using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS). Data were analyzed using unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA). Differential metabolites were examined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways to explore the underlying mechanisms. RESULTS: After 4 weeks of treatment with different doses of CIG, varying degrees of antidiabetic effects were observed, along with reduced liver and pancreatic injury, and improved oxidative stress levels. Compared with the T2DM group, 19 and 23 differential metabolites were detected in the serum and urine of the CIG treatment group, respectively. The key metabolites involved in pathway regulation include taurine, chenodeoxycholic acid, glycocholic acid, and L-tyrosine in the serum and glycine, hippuric acid, phenylacetylglycine, citric acid, and D-glucuronic acid in the urine, which are related to lipid, amino acid, energy, and carbohydrate metabolism. CONCLUSIONS: This study confirmed the antidiabetic effects of CIG and revealed that CIG effectively controlled metabolic disorders in T2DM rats. This seems to be meaningful for the clinical application of CIG, and can benefit further studies on CIG mechanism.
Assuntos
Diabetes Mellitus Tipo 2 , Medicamentos de Ervas Chinesas , Ratos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/uso terapêutico , Glicemia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/análise , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolômica/métodosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Nyctanthes arbor-tristis Linn. has been used by Ayruvedic physicians for the cure of different diseases including ulcers, gastric and inflammatory diseases. AIM OF THE STUDY: To isolate and identify compounds from this source and investigate their therapeutic potential for the treatment of gastric ulcer and related disorders. MATERIAL AND METHODS: The ethanol extract of fresh aerial parts of N. arbor-tristis was used in the present studies which was subjected to a bio-assay guided fractionation followed by chromatographic separations. The structures of pure compounds were elucidated using various spectroscopic techniques. The inhibition of urease enzyme was evaluated by weatherburn indophenol method. Molecular docking studies were determined by using Molecular Operating Environment (MOE) version 2020.0901 version. The intracellular ROS production from phagocytes was determined by chemiluminescence assay and NO generation was detected by Griess method. The proinflammatory cytokine TNF-α was quantified by ELISA. Cytotoxic activity was assessed by MTT assay. RESULTS: One previously undescribed iridoid glycoside arborside F (1) and four known iridoid glycosides arborside A (2), arborside C (3), loganin (4) and 7-O-trans-cinnamoyl-6ß-hydroxyloganin (5) were isolated and characterized in the present studies and their urease inhibitory activity was determined. Among these, 2 and 5 showed strong urease inhibition (IC50 = 12.1 ± 1.74 and 14.1 ± 0.59 µM respectively) (standard acetohydroxamic acid IC50 = 20.3 ± 0.42 µM), whereas rest of compounds showed moderate to low inhibition. Kinetic studies revealed that compounds 2 and 5 possess competitive type of inhibition. Molecular docking showed polar and non-polar interactions of compounds 2 and 5 with urease enzyme residues. Compounds 2 and 3 showed inhibition of ROS from whole blood (IC50 = 1.6 ± 0.3 and 2.5 ± 0.09 µg/mL respectively) and PMNs (IC50 = 1.5 ± 0.03 and 1.4 ± 0.0 µg/mL respectively). Compound 2 significantly inhibited nitric oxide and proinflammatory cytokine TNF-α (IC50 = 18.2 ± 3.0 and 73.8 ± 6.6 µg/mL respectively). Compounds 1, 4 and 5 were inactive on ROS. All isolated compounds were non-toxic on normal mouse fibroblasts (NIH-3T3) cells. CONCLUSIONS: The ethno pharmacological repute of N. arbor-tristis in treating gastric and anti-inflammatory ailments is supported by present studies which resulted in isolation of a potent urease inhibitory and anti-inflammatory agent arborside A (2) a potential anti-ulcer and anti-inflammatory drug lead.
Assuntos
Extratos Vegetais , Urease , Camundongos , Animais , Extratos Vegetais/uso terapêutico , Glicosídeos Iridoides/farmacologia , Cinética , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa , Anti-Inflamatórios/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The desiccative ripe fruits of Gardenia (Gardenia jasminoides Ellis) (called Zhizi in China) are known with cold character and the effects of reducing fire except vexed, clearing away heat evil, and cooling blood and eliminating stasis. Zhizi is often clinical formulated to treat various types of fever. Fever is a sign of inflammation and, geniposide from Zhizi has been proved with anti-inflammatory in various inflammatory models. AIM OF STUDY: The aim of this study was to investigate the antipyretic role of geniposide with three classical inflammatory fever models and explore the underlying mechanisms. MATERIALS AND METHODS: Water extract (WE), high polar part (HP), iridoid glycoside part (IG), and gardenia yellow pigment part (GYP) from Gardeniae Fructus (GF) were obtained from Zhizi. The antipyretic activities of these composes were tested with dry yeast induced fever rats. Geniposide was further purified from IG and the antipyretic activity was evaluated by gavage, intraperitoneal injection, and caudal intravenous injection to rats of fever induced by dry yeast, lipopolysaccharide (LPS), and 2, 4-dinitrophenol (DNP) in rats. Then, the mechanism of geniposide by intragastric administration was studied. The contents of thermoregulatory mediators and inflammatory factors relating to TLR4/NF-κB pathway in serum were determined by ELISA and Western blot, and the pathological changes of the hypothalamus were observed by HE staining. RESULTS: The temperature was decreased by geniposide in the three fever model rats. Geniposide can not only inhibit the increase of inflammatory factors in serum but also protect the hypothalamus from fever pathological damage in the three fever models. Western blot showed that geniposide could inhibit the TLR4/NF-κB pathway. CONCLUSION: Geniposide exerts antipyretic effect in febrile rats through modulating the TLR4/NF-κB signaling pathway.
Assuntos
Antipiréticos , Gardenia , Ratos , Animais , NF-kappa B/metabolismo , Antipiréticos/farmacologia , Antipiréticos/uso terapêutico , Receptor 4 Toll-Like , Frutas/metabolismo , Saccharomyces cerevisiae , Iridoides/farmacologia , Iridoides/uso terapêutico , Transdução de Sinais , Glicosídeos Iridoides/farmacologiaRESUMO
Six new iridoid glycosides were isolated from the ethyl acetate fraction of the whole plants of Hedyotis diffusa Willd. They were identified as E-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (1), Z-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (2), E-6-O-caffeoyl scandoside methyl ester (3), E-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (4), Z-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (5), and E-6-O-p-coumaroyl-4'-O-acetyl scandoside methyl ester (6). The structures of them were elucidated based on unambiguous spectroscopic data (UV, IR, HRESIMS, and NMR). They were screened for anti-inflammatory effect, antioxidant effect, antitumor effect, and neuroprotective effect and did not show potent activities.
Assuntos
Ácidos Cumáricos , Hedyotis , Glicosídeos Iridoides , Glicosídeos Iridoides/farmacologia , Hedyotis/química , Antioxidantes , Espectroscopia de Ressonância Magnética , Ésteres , Glicosídeos/farmacologiaRESUMO
Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.
Assuntos
Flavonoides , Glicosídeos , Lignanas , Folhas de Planta , Folhas de Planta/química , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Animais , Camundongos , Células PC12 , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/isolamento & purificação , Estrutura Molecular , Lignanas/química , Lignanas/farmacologia , Lignanas/isolamento & purificação , Ratos , Células RAW 264.7 , Vaccinium/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Iridoides/química , Iridoides/farmacologia , Iridoides/isolamento & purificação , Glicosídeos Iridoides/química , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/isolamento & purificação , Espécies Reativas de Oxigênio , Picratos/farmacologiaRESUMO
Four new iridoid glycosides (1-4), rehmaglutosides L-O, were isolated from the air-dried roots of Rehmannia glutinosa. Their structures were established from the spectroscopic data obtained and by chemical evidence. The known mellittoside (5) and ajugol (6) were also obtained in the current investigation, and the structure of mellittoside was unequivocally defined using X-ray diffraction data. Compounds 1-6 were tested for their cytotoxicity against five human tumor cell lines and proliferation effects on Lactobacillus Reuteri.
Assuntos
Glicosídeos , Rehmannia , Humanos , Glicosídeos/farmacologia , Glicosídeos/química , Rehmannia/química , Glicosídeos Iridoides/farmacologiaRESUMO
Seven new secoiridoid glycosides (1-7), together with a known analogue (8), were isolated from the fruits of Ligustrum lucidum. Their structures with absolute configurations were determined by HR-ESI-MS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectroscopic analysis, as well as biogenetic consideration. Compounds 1 and 2 are the first examples of secoiridoid glycoside dimers featuring a rare rearranged oleoside-type secoiridoid moiety, and compounds 3-7 represent a new class of oleoside-type secoiridoid glycosides with unusual stereochemistry at C-1 position. A plausible biosynthetic pathway for this group of unusual secoiridoid glycosides was also proposed herein. In addition, the isolates were evaluated for their in vitro anti-inflammatory activity, and all tested compounds exhibited modest inhibitory effects against nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.
Assuntos
Glicosídeos Iridoides , Ligustrum , Glicosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Ligustrum/química , Estrutura Molecular , Frutas/química , Anti-Inflamatórios/farmacologia , Glicosídeos/farmacologia , Glicosídeos/análiseRESUMO
The ethanol extract of the Gentiana olivieri Griseb plant was subjected to an investigation to ascertain the presence of its iridoid constituents. By means of HPLC and TLC monitoring, a total of thirteen previously unreported seco-iridoid glucosides olivierisecoside A-M, as well as seven known seco-iridoid glycosides and one known iridoid glycoside were isolated. Their structures were elucidated by a comprehensive spectroscopic data analysis and ECD calculations. The absolute configuration of olivierisecoside D was further confirmed through single-crystal X-ray diffraction analysis. All the identified compounds were characterized as aromatic conjugated seco-iridoid glucosides, with olivierisecoside F-I representing a particularly rare subtype known as the morroniside type seco-iridoids. In vitro testing of the isolated compounds revealed their potential anti-inflammatory and hepatoprotective effects. The results showed olivieroside B and 6'-gentisoyl-8-epi-kingiside have good anti-inflammatory activities in LPS induced RAW264.7 cells. Additionally, olivierisecoside M exhibited some improvements in PA-induced L02 and HepG2 cells damage, known compound loganin showed slight hepatoprotective effect in PA-induced HepG2 cells damage.
Assuntos
Gentiana , Glicosídeos Iridoides , Glicosídeos Iridoides/farmacologia , Gentiana/química , Glucosídeos Iridoides/farmacologia , Glicosídeos/farmacologia , Glicosídeos/química , Iridoides/farmacologia , Iridoides/química , Anti-Inflamatórios/farmacologiaRESUMO
Three undescribed glycoside constituents, macrophyllosides E-G and a pair of iridoid glycosides genticrasides A/B, together with eleven known glycoside compounds were isolated from the roots of Gentiana crassicaulis Duthie ex Burk. Their structures were identified by means of spectra analysis and data comparison with previous literatures. Interestingly, the glucose moieties in macrophylloside E and F possess free anomeric hydroxy groups. Genticrasides A/B, identified as a pair of iridoid originated lactones, have not been reported from Gentianaceae family up to now. The anti-inflammatory effects of selected compounds were also evaluated through the nitric oxide (NO) production inhibition in lipopolysaccharides (LPS)-induced RAW264.7 macrophage cells. In which, macrophyllosides G and D showed NO inhibitory activities with rates of 76.14±4.02 % and 52.44±8.29 % at 100â µg/mL.
Assuntos
Gentiana , Gentiana/química , Raízes de Plantas/química , Glicosídeos Iridoides/farmacologia , Iridoides/análise , Macrófagos , Óxido NítricoRESUMO
Eight previously undescribed iridoid glycosides together with 20 known congeners were isolated from the aerial parts of Paederia scandens (Lour.) Merrill (Rubiaceae). Their structures incorporating absolute configurations were elucidated based on the comprehensive analyses of NMR data, HR-ESI-MS spectrometry, and ECD data. The potential anti-inflammatory activities of the isolated iridoids were evaluated in lipopolysaccharide-stimulated RAW 264.7 macrophages. Compound 6 significantly inhibited the production of nitric oxide with an IC50 value of 15.30 µM. The results of immunoblotting, qPCR, and immunofluorescence staining assays revealed that compound 6 exhibited anti-inflammatory activity by suppressing nuclear translocation of NF-κB and reducing the expression of COX-2, iNOS, IL-1ß, and IL-6. These results provide a basis for further development and utilization of P. scandens as a natural source of potential anti-inflammatory agents.
Assuntos
Glicosídeos Iridoides , Rubiaceae , Glicosídeos Iridoides/farmacologia , Iridoides/farmacologia , Iridoides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , NF-kappa B , Rubiaceae/química , Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/farmacologia , Óxido NítricoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Lamiophlomis rotata (Benth.) Kudo (L. rotata), a Tibetan medicinal plant, is used to treat "yellow-water diseases", such as skin disease, jaundice and rheumatism. Our previous study showed that the iridoid glycoside extract of L. rotata (IGLR) is the major constituent of skin wound healing. However, the role of IGLR in the biological process of trauma repair and the probable mechanism of the action remain largely unknown. AIM OF THE STUDY: To investigate the role of IGLR in the biological process of trauma repair and the probable mechanism of the action. MATERIALS AND METHODS: The role of IGLR in wound healing was investigated by overall skin wound in mice with Hematoxylin and Eosin (H&E) and Masson trichrome staining. The anti-inflammatory, angiogenesis-promoting and fibril formation effects of IGLR were visualized in wound skin tissue by immunofluorescence staining, and the proinflammatory factors and growth factors were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophages, dermal fibroblasts, and endothelial cells were cultured to measure the direct/indirect interaction effects of IGLR on the proliferation and migration of cells, and flow cytometry was employed to assess the role of IGLR on macrophage phenotype. Network pharmacology combined with Western blot experiments were conducted to explore possible mechanisms of the actions. RESULTS: IGLR increased the expression of CD206 (M2 markers) through the RAS/p38 MAPK/NF-κB signaling pathway during wound injury in vivo and in vitro. IGLR suppressed the inflammatory cytokines iNOS, IL-1ß and TNF-α in the early stage of wound healing. During the proliferation step of wound repair, IGLR promoted angiogenesis and fibril formation by increasing the expression of VEGF, CD31, TGF-ß and α-SMA in wound tissue, and similar results were verified by RT-PCR and ELISA. In a paracrine mechanism, the extract promoted the proliferation of dermal fibroblasts, and endothelial cells were founded by the conditioned medium (CM). CONCLUSION: IGLR induced M2 macrophage polarization in the early stage of wound healing; in turn, IGLR played a key role in the transition from inflammation to cell proliferation during the biological process of wound healing.
Assuntos
Iridoides , NF-kappa B , Animais , Camundongos , Células Endoteliais , Glicosídeos Iridoides/farmacologia , Iridoides/farmacologia , Macrófagos , Cicatrização , Extratos Vegetais/farmacologia , Lamiaceae/químicaRESUMO
BACKGROUND: Hastatoside is an iridoid glycoside extracted from the herb, Verbena officinalis, that exerts various pharmacological effects, including anti-inflammatory, sleep-promoting, and analgesic effects. However, only a few studies have reported the efficacy of hastatoside in liver fibrosis. Liver fibrosis is a pathophysiological process, and its persistence can seriously affect the quality of life and well-being of the patients. HYPOTHESIS/PURPOSE: This study aimed to investigate the role of hastatoside on liver fibrosis and its possible underlying mechanisms. METHODS: C57BL/6 J mice with carbon tetrachloride (CCl4)-induced hepatic fibrosis were used as the in vivo models. Histological features of the liver were observed using Masson's trichrome and hematoxylin-eosin staining. Alanine aminotransferase and aspartate aminotransferase levels and the hepatic fibrosis indices (type 3 procollagen, laminin, and hyaluronic acid) were measured using corresponding assay kits. LX-2 human hepatic stellate cells (HSCs) stimulated with the transforming growth factor ß1 were used as the vitro models. Transfection of the glycogen synthase kinase (GSK)-3ß small interfering RNA (siRNA) and ß-catenin plasmids was also performed in vitro. Protein levels of GSK-3ß, phospho-GSK-3ß (Ser 9), α-smooth muscle actin, collagen type I alpha 1, c-Myc, cyclin D1, and ß-catenin were determined via western blotting. Moreover, the p-GSK-3ß:GSK-3ß ratio was calculated to determine the GSK-3ß activity. RESULTS: Hastatoside prevented CCl4-induced liver injury and histological damage. It inhibited the upregulation of α-SMA and Col1α1 levels in a CCl4-induced mouse hepatic fibrosis model. In vitro, hastatoside inhibited the proliferation and activation of HSCs by decreasing the expression levels of cyclin D1 and c-Myc and the proportion of LX-2 cells activated in the G0/G1 phase. Molecular docking results showed that hastatoside bound to GSK-3ß. Hastatoside significantly increased the GSK-3ß activity and inhibited the downstream effector expression of ß-catenin. CONCLUSION: These findings suggest that hastatoside can bind to GSK-3ß and promote its activity, while inhibiting the GSK-3ß downstream effector expression of ß-catenin, thereby inhibiting the activation and proliferation of HSCs, which further prevents the development of liver fibrosis. These results provide innovative insights into the underlying liver fibrosis. Moreover, hastatoside is a potential anti-fibrosis monomer that can potentially be used for the treatment of liver fibrosis.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Glicogênio Sintase Quinase 3 beta , Glicosídeos Iridoides , Animais , Humanos , Camundongos , beta Catenina/metabolismo , Ciclina D1/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Estreladas do Fígado , Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Qualidade de Vida , Transdução de Sinais , Glicosídeos Iridoides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológicoRESUMO
Four novel iridoid glycosides neocornuside E-H (1-4), together with nine known ones (5-13), were isolated from fruits of Cornus officinalis. Their chemical structures were determined on the basis of spectroscopic analyses and comparing of the literature data. All of the isolated compounds were evaluated for their antidiabetic activity in insulin resistant HepG2 cells. Compounds 2, 4, 5, 8, and 12 exhibited antidiabetic activities with EC50 values of 40.12, 2.54, 70.43, 15.31, and 4.86 µM, respectively. Flow Sight cytometry analysis indicated that compounds 2, 4, 5, 8, and 12 improved the ability of 2-NBDG uptake of insulin-induced HepG2 cells.