iridoids and Atherosclerosis

Topics: Animals; Anthocyanins; Atherosclerosis; Cholesterol, Dietary; Cornus; Diet, Atherogenic; Fruit; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Iridoids; Matrix Metalloproteinase 1; Plant Extracts; Rabbits; RNA, Messenger; Vascular Cell Adhesion Molecule-1

Topics: Adipokines; Animals; Anthocyanins; Aorta; Atherosclerosis; Cardiovascular Diseases; Cholesterol, Dietary; Cornus; Humans; Iridoids; Liver; Liver X Receptors; Male; Metabolic Syndrome; Obesity; Plant Extracts; PPAR alpha; PPAR gamma; Rabbits; Triglycerides

To assess geniposide's effects in New Zealand rabbits with high-fat diet induced atherosclerosis and to explore the underpinning mechanisms.. Aorta histological changes were evaluated by intravenous ultrasound (IVUS) and H&E staining. Lipid accumulation in the aortic was quantified by Oil Red O staining. Then, RNA sequencing (RNA-seq) was carried out for detecting differentially expressed genes in rabbit high-fat diet induced atherosclerosis. The levels of the cytokines CRP, IL-1β and IL-10 were determined by ELISA. Protein levels of iNOS and Arg-1 were assessed by Western blot and immunohistochemical staining. The mRNA expression levels of NR4A1, CD14, FOS, IL1A, iNOS and Arg-1 were detected by quantitative real-time PCR (qPCR).. Geniposide markedly reduced the degree of atherosclerotic lesions in aorta tissues. RNA-seq and qPCR demonstrated that NR4A1, CD14, FOS and IL1A mRNA amounts were overtly increased in New Zealand rabbits with high-fat diet induced atherosclerosis. Moreover, geniposide reduced iNOS (M1 phenotype) mRNA and protein amounts as well as IL-1β secretion, which were enhanced in New Zealand rabbits with high-fat diet induced atherosclerosis. Besides, Arg-1 (M2 phenotype) mRNA and protein amounts were significantly increased after geniposide treatment, as well as IL-10 secretion.. These findings suggest that geniposide could inhibit the progression of and stabilize atherosclerotic plaques in rabbits by suppressing M1 macrophage polarization and promoting M2 polarization through the FOS/MAPK signaling pathway.

Topics: Animals; Atherosclerosis; Cytokines; Diet, High-Fat; Disease Progression; Iridoids; Macrophages; Male; MAP Kinase Signaling System; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-fos; Rabbits; RNA, Messenger; Signal Transduction

Topics: Animals; Atherosclerosis; Autophagy; Down-Regulation; Gene Expression; Iridoids; Macrophages; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Phytotherapy; RAW 264.7 Cells; Receptors, Immunologic; Signal Transduction; TOR Serine-Threonine Kinases

Geniposide, the main medicinal ingredient of Gardenia jasminoides Ellis, is known to be a resistant agent to atherosclerosis. Some reports its mechanism against atherosclerosis remains completely unclear. Herein, we have investigated the protective effect of geniposide against atherosclerosis as well as clarified the mechanisms related with inhibiting the formation of foam cells and lowering reverse lipid transport via p38/MAPK signaling pathways. Macrophage Raw264.7 was induced by lysophosphatidic acid (LPA) to form foam cell as a cell model. ApoE

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter 1; Biological Transport; CD36 Antigens; Dose-Response Relationship, Drug; Down-Regulation; Foam Cells; Iridoids; Lipid Metabolism; Male; MAP Kinase Signaling System; Mice; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Scavenger Receptors, Class A; Up-Regulation

Atherosclerosis (AS) is characterized by the significant accumulation of low-density lipoprotein (LDL)-cholesterol in macrophages that reside in the vessel wall and the resultant inflammatory response. Therefore, inhibition of LDL-induced inflammation is a promising interference for AS. Many traditional Chinese medicine prescriptions have been developed for AS treatment. Geniposide (GEN) is an iridoid glycoside mainly found in

Topics: Animals; Atherosclerosis; Foam Cells; Iridoids; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Primary Cell Culture

Although fruit and vegetable-rich diets have beneficial effects on cardiovascular diseases, we have little knowledge of the impact of fruits and their constituents, iridoids and anthocyanins, on the l-arginine-ADMA-DDAH pathway. Our previous study demonstrated the modulation of those factors by the oral administration of the cornelian cherry fruit.. We have assessed the effects of the oral administration of two main constituents isolated from the cornelian cherry fruit, iridoid loganic acid and anthocyanins, on l-arginine, its derivatives (ADMA, SDMA), metabolites (DMA, l-citrulline), and the hepatic DDAH activity and its isoform expression in rabbits fed a high-cholesterol diet. We have also analyzed eNOS expression in the thoracic aorta as well as the redox status in blood.. In the present study, we used an animal model of diet induced atherosclerosis. For 60 days, white New Zealand rabbits were fed a standard diet, a 1% cholesterol enriched diet, or concomitantly with the investigated substances. l-arginine, ADMA, SDMA, DMA, and l-citrulline were assessed using the LC-MS/MS method. DDAH activity and redox parameters were analyzed spectrophotometrically. DDAH1 and DDAH2 isoform expressions were assessed by western blotting, mRNA expression of eNOS was quantified by real-time PCR.. We demonstrated that the administration of loganic acid (20 mg/kg b.w.), and to a lesser extent of anthocyanins (10 mg/kg b.w.), caused an increase in the l-arginine level and the l-arginine/ADMA ratio. Also, both substances decreased ADMA, DMA, and l-citrulline, but not SDMA levels. Anthocyanins, but not loganic acid, enhanced the activity of DDAH in the liver. Anthocyanins also significantly enhanced both DDAH1 and DDAH2 expression, while loganic acid to a lesser extent enhanced DDAH1 but not DDAH2 expression. Both loganic acid and anthocyanins pronouncedly increased mRNA expression of eNOS in thoracic aortas. Both loganic acid and anthocyanins reversed the blood glutathione level depleted by dietary cholesterol. Cholesterol feeding decreased the blood GPx level, and the change was not reversed by anthocyanins or loganic acid. We did not observe any significant differences in the blood levels of MDA or SOD among the groups.. Iridoids and anthocyanins may modulate the l-arginine-ADMA pathway in subjects fed a high-cholesterol diet.

Topics: Amidohydrolases; Animals; Anthocyanins; Arginine; Atherosclerosis; Cholesterol, Dietary; Citrulline; Cornus; Dimethylamines; Fruit; Iridoids; Liver; Male; Nitric Oxide Synthase Type III; Rabbits

AMP-activated protein kinase (AMPK) is a drug target for treatment of metabolic and cardiovascular complications. Extracts of Gentianaceace plants exhibit anti-diabetic and anti-atherosclerotic effects, however, whether their phyto-constitutents activate AMPK remains to be determined.. Molecular docking of Gentiana lutea constituents was performed with crystal structure of human α. AG interacts with the α. In conclusion, AG exerts beneficial vasculo-metabolic effects by activating AMPK.. Amarogentin, a naturally occurring secoiridoid glycoside, is a promising lead for design and synthesis of novel drugs for treatment and management of dyslipidemia and cardiovascular diseases.

Topics: AMP-Activated Protein Kinases; Animals; Atherosclerosis; Calorimetry; Diabetes Mellitus, Experimental; Endothelium, Vascular; Enzyme Activation; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Iridoids; Lipids; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Rats; Signal Transduction; Tumor Necrosis Factor-alpha

Cornelian cherry (Cornus mas L.) is a plant growing in southeast Europe, in the past used in folk medicine. There are many previous publications showing the preventive effects of (poly)phenolic compounds, especially anthocyanins, on cardiovascular diseases, but there is a lack of studies comparing the effects of (poly)phenolics and other constituents of fruits.. We have attempted to determine if iridoids and anthocyanins from cornelian cherry fruits may affect the formation of atherosclerotic plaques in the aorta as well as lipid peroxidation and oxidative stress in the livers of cholesterol-fed rabbits.. Fractions of iridoids and anthocyanins were analyzed using the high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) methods. Loganic acid (20 mg/kg b.w.) and a mixture of anthocyanins (10 mg/kg b.w.) were administered orally for 60 days to rabbits fed with 1% cholesterol. Histopathological samples of the aortas and the livers were stained with hematoxylin and eosin. Lipid peroxidation (malondialdehyde - MDA) and redox status (glutathione - GSH, glutathione peroxidase - Gpx and superoxide dismutase - SOD) were analyzed using spectrophotometrical methods.. Both loganic acid (an iridoid) and a mixture of anthocyanins diminished the formation of atherosclerotic plaques in the aorta. Both substances also diminished lipid peroxidation, measured as a decrease of MDA, and attenuated oxidative stress, measured as an increase of GSH in the livers depleted by cholesterol feeding. Unexpectedly, cholesterol feeding decreased the Gpx activity in the liver, which was reversed by both investigated substances.. We have shown that both iridoids and anthocyanins help prevent fed-induced atherosclerosis, and the consumption of fruits rich in these substances may elicit beneficial effects on the cardiovascular system.

Topics: Animals; Anthocyanins; Antioxidants; Atherosclerosis; Cornus; Diet; Fruit; Iridoids; Phytotherapy; Plant Extracts; Rabbits

Atherosclerosis is a chronic inflammatory disease of the vascular walls. ApoCIII is an independent factor which promotes atherosclerotic processes. This study aimed to investigate whether Loganin administration inhibits the inflammatory response in vitro and in vivo. In the apoCIII-induced mouse adipocytes, the levels of cytokines, including TNF-α, MCP-1 and IL-6 were determined by enzyme-linked immunosorbent assay and their gene expressions were measured through RT-PCR. The phosphorylation of nuclear factor-κB (NF-κB) proteins was analyzed by Western blotting. Our results showed that Loganin markedly decreased TNF-α, MCP-1 and IL-6 concentrations as well as their gene expressions. Western blotting analysis indicated that Loganin suppressed the activation of NF-κB signaling. In the Tyloxapol-treated mouse model, Loganin reduced the contents of TC and TG in mouse serum. The results of Oil Red-O Staining showed that Loganin reduced the production of lipid droplets. So it is suggested that Loganin might be a potential therapeutic agent for preventing the inflammation stress in vitro and in vivo.

Topics: 3T3 Cells; Adipocytes; Animals; Anti-Inflammatory Agents; Atherosclerosis; Chemokine CCL2; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Iridoids; Lipid Metabolism; Mice; NF-kappa B; Phosphorylation; Polyethylene Glycols; Signal Transduction; Tumor Necrosis Factor-alpha

Cardiovascular benefits of fruits are attributed mainly to their (poly)phenolic constituents, especially anthocyanins. The main aim of our study is to compare effects of iridoids and anthocyanins from one fruit on diet-induced atherosclerosis. The cornelian cherry is a native or cultivated plant that grows in many European countries, used in cuisine and folk medicine. In our previous study, we showed its constituents and proved that oral administration of lyophilized fruits to hypercholesterolemic rabbits had preventive effects on atherosclerosis through the activation of PPARα expression. In this study, we have compared the effects of the main constituents of the cornelian cherry:iridoid loganic acid and anthocyanins.. Our experiment followed the model used in our previous study, in which rabbits were fed 1% cholesterol.. We showed that both loganic acid (20 mg/kg b.w.) and a mixture of anthocyanins (10 mg/kg b.w.) administered orally for 60 days had a positive impact on dyslipidemia caused by cholesterol-rich diet, although the effects of anthocyanins were more pronounced. Anthocyanins decreased total and LDL-cholesterol and triglycerides and increased HDL-cholesterol. Loganic acid showed similar effects, but only the triglycerides and HDL-cholesterol changes achieved statistical significance. Anthocyanins, and to a lesser extent loganic acid, significantly decreased intima thickness and intima/media ratio in the thoracic aorta. Both substances decrease ox-LDL in the plasma. Anthocyanins significantly increased expression of PPARγ and α in the liver. Loganic acid also increased their expression, but to a lesser extent. Conversely, loganic acid showed pronounced anti-inflammatory effects, decreasing TNF-α and IL-6 activity.. Our results imply that both substances have a positive effect on factors contributing to the development of diet-induced atherosclerosis. Our results also indicate the potential health benefits of fruits containing anthocyanins and iridoids, and support the idea of creating composed phytopharmaceuticals containing both groups of substances.

Topics: Animals; Anthocyanins; Atherosclerosis; Body Weight; Cornus; Diet; Fruit; Inflammation; Interleukin-6; Iridoids; Lipoproteins, LDL; Liver; Phytotherapy; Plant Extracts; PPAR alpha; Rabbits; Triglycerides; Tumor Necrosis Factor-alpha

Coronary angioplasty is the most widely used technique for removing atherosclerotic plaques in blood vessels. The regeneration of the damaged intima layer after this treatment is still one of the major challenges in the field of cardiovascular tissue engineering. Different polymers have been used in scaffold manufacturing in order to improve tissue regeneration. Elastin-mimetic polymers are a new class of molecules that have been synthesized and used to obtain small diameter fibers with specific morphological characteristics. Elastin-like polymers produced by recombinant techniques and called elastin-like recombinamers (ELRs) are particularly promising due to their high degree of functionalization. Generally speaking, ELRs can show more complex molecular designs and a tighter control of their sequence than other chemically synthetized polymers Rodriguez Cabello et al (2009 Polymer 50 5159-69, 2011 Nanomedicine 6 111-22). For the fabrication of small diameter fibers, different ELRs were dissolved in 2,2,2-fluoroethanol (TFE). Dynamic light scattering was used to identify the transition temperature and get a deep characterization of the transition behavior of the recombinamers. In this work, we describe the use of electrospinning technique for the manufacturing of an elastic fibrous scaffold; the obtained fibers were characterized and their cytocompatibility was tested in vitro. A thorough study of the influence of voltage, flow rate and distance was carried out in order to determine the appropriate parameters to obtain fibrous mats without beads and defects. Moreover, using a rotating mandrel, we fabricated a tubular scaffold in which ELRs containing different cell adhesion sequences (mainly REDV and RGD) were collected. The stability of the scaffold was improved by using genipin as a crosslinking agent. Genipin-ELRs crosslinked scaffolds  show a good stability and fiber morphology. Human umbilical vein endothelial cells  were used to assess the in vitro bioactivity of the cell adhesion domains within the backbone of the ELRs.

Topics: Amino Acid Sequence; Atherosclerosis; Biocompatible Materials; Cell Adhesion; Cell Survival; Cross-Linking Reagents; Dynamic Light Scattering; Elastin; Human Umbilical Vein Endothelial Cells; Humans; Iridoids; Microscopy, Electron, Scanning; Nanofibers; Polymers; Tissue Engineering; Tissue Scaffolds

Hwangryunhaedok-tang (HHT) is a traditional herbal medicine that is used for the treatment of fever, inflammation, gastritis, and hypertension. In this study, we performed simultaneous determination of the five components, geniposide (1), baicalin (2), coptisine (3), palmatine (4), and berberine (5) in HHT by using a high-performance liquid chromatography-photodiode array (HPLC-PDA) analysis. We also evaluated the antioxidative activity of HHT and compounds 1-5 by measuring their effects on low-density lipoprotein (LDL) oxidation and antiproliferative abilities in vascular smooth muscle cells (VSMCs).. Five compounds were separated within 40 min by using a Gemini C18 column (temp. 35°C; two-component gradient elution; flow rate 1.0 mL/min; detector 240 and 277 nm). The activities of HHT and compounds 1-5 were tested with the radical scavengers 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt and 2,2-diphenyl-1-picrylhydrazyl, in thiobarbituric acid reactive substance assays, and in relative electrophoretic mobility assays using CuSO4-induced LDL oxidation systems. The antiproliferative effects of samples on platelet-derived growth factor (PDGF)-induced VSMC proliferation were studied by using a cell proliferation assay.. Regression analysis of the five major compounds showed good linearity (r (2) ≥ 0.9997) in different concentration ranges. The recoveries of the five compounds were in the range 86.31-110.78%, with relative standard deviations below 2.1%; those of intra- and interday precision were 0.04-3.78% and 0.04-1.69%, respectively. HHT reduced the oxidation properties of LDL induced by CuSO4 and inhibited cell proliferation in PDGF-treated VSMCs. Among the five components, compound 2 could effectively suppress LDL oxidation and PDGF-induced VSMC proliferation.. The established HPLC-PDA method will help to improve quality control of HHT. The results demonstrate that HHT has antiatherosclerotic activity and that it functions by modulating LDL oxidation and VSMC proliferation. The effects of HHT may be attributed, at least I part, to compound 2.

Topics: Animals; Antioxidants; Atherosclerosis; Berberine; Berberine Alkaloids; Biphenyl Compounds; Cell Proliferation; Chromatography, High Pressure Liquid; Coptis; Drugs, Chinese Herbal; Flavonoids; Gardenia; Iridoids; Lipoproteins, LDL; Medicine, Korean Traditional; Muscle, Smooth, Vascular; Phellodendron; Phytotherapy; Picrates; Platelet-Derived Growth Factor; Rats; Regression Analysis; Scutellaria

Atherosclerosis is a systemic inflammatory disease characterized by the accumulation of dendritic cells (DCs) and other types of immune cells in atherosclerotic plaque. In this study, baicalin and geniposide were isolated from Scutellaria baicalensis Georgi and Gardenia jasminoids Ellis, which are the plants used in traditional Chinese medicine to treat a variety of inflammatory diseases. We then investigated whether baicalin and geniposide could induce regression of atherosclerotic lesions in ApoE-/- mice fed a high cholesterol diet and used as a model of atherosclerosis. Following model induction, these mice were treated with baicalin (100mg/kg), geniposide (100mg/kg), and then a mixture containing baicalin (100mg/kg) and geniposide (100mg/kg) administered daily by gavage for a period of 12weeks. The combined administration of baicalin and geniposide significantly reduced atherosclerotic lesions, and modulated the phenotype of dendritic cells in bone marrow and atherosclerotic plaque. Geniposide lowered both plasma lipid levels and DC numbers, while baicalin administered either alone or in combination with geniposide did not decrease plasma lipids. Our results suggest that baicalin and geniposide may have immune-regulatory effects and prevent the formation of atherosclerotic lesions by decreasing the DC numbers, and inhibit DC maturation in bone marrow and infiltration into lesions.

Topics: Administration, Oral; Animals; Aorta, Abdominal; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Dendritic Cells; Diet, High-Fat; Flavonoids; Iridoids; Lipids; Male; Mice, Inbred C57BL; Mice, Knockout

Baicalin and geniposide, which are respectively isolated from Scutellariae radix and Gardenia jasminoides, have been known to exhibit a number of pharmacological effects, including anti-inflammatory and anti-oxidant. Here, we primarily aimed to observe the protective effects of these two Chinese herbs on inhibiting the development of atherosclerosis in apolipoprotein E knockout mice via lipids regulation and immunoregulation. After the ApoE-/- mice with high-cholesterol diet had received 12-weeks׳ oral administration of either baicalin or geniposide (100 mg/kg), atherosclerotic plaque areas in aorta were measured and exhibited a prominent decrease in the treated mice. We then assayed serum lipids levels, serum Treg-cell-associated cytokines (TGF-β1 and IL-10) and the frequency of splenic Treg cells. We found that geniposide notably decreased serum TC and LDL-c. Both baicalin and geniposide treated mice showed much more splenic Treg cells and the correlated cytokines (TGF-β1 and IL-10). Foxp3, as the marker of Treg cell, was detected in atherosclerotic lesions, and we found that Foxp3 expression at both mRNA and protein levels was up-regulated in addition to increased Foxp3 positive Treg cells detected by immunohistochemistry in baicalin or geniposide treated mice. In conclusion, baicalin and geniposide up-regulated the expression of foxp3, promoted the number and function of Treg cells and ameliorated the atherosclerotic lesions progression partly through lipids regulation and immunoregulation.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Flavonoids; Forkhead Transcription Factors; Interleukin-10; Iridoids; Lipids; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Phytotherapy; Spleen; T-Lymphocytes, Regulatory; Transforming Growth Factor beta1

Cornelian cherry (Cornus mas L.) fruits have been used in traditional cuisine and in folk medicine in various countries. This study was conducted to evaluate the constituents and impact of cornelian cherry (C. mas L.) fruits lyophilisate on lipid levels, PPARα protein expression, atheromatous changes in the aorta, oxido-redox state, and proinflammatory cytokines in hypercholesterolemic rabbits. The HPLC-MS method was used for determining active constituents in cornelian cherry. In a subsequent in vivo study the protective effect of the cornelian cherry on diet-induced hyperlipidemia was studied using a rabbit model fed 1% cholesterol. Cornelian cherry (100mg/kg b.w.) or simvastatin (5mg/kg b.w.) were administered orally for 60 days. Two iridoids - loganic acid and cornuside - and five anthocyanins were identified as the main constituents of the cornelian cherry. The administering of the cornelian cherry led to a 44% significant decrease in serum triglyceride levels, as well as prevented development of atheromatous changes in the thoracic aorta. Cornelian cherry significantly increased PPARα protein expression in the liver, indicating that its hypolipidemic effect may stem from enhanced fatty acid catabolism. Simvastatin treatment did not affect PPAR-α expression. Moreover, the cornelian cherry had a significant protective effect on diet-induced oxidative stress in the liver, as well as restored upregulated proinflammatory cytokines serum levels. In conclusion, we have shown loganic acid to be the main iridoid constituent in the European cultivar of the cornelian cherry, and proven that the cornelian cherry could have protective effects on diet-induced hypertriglicerydemia and atherosclerosis through enhanced PPARα protein expression and via regulating oxidative stress and inflammation.

Topics: Animals; Anthocyanins; Aorta, Thoracic; Atherosclerosis; Cornus; Fruit; Hypertriglyceridemia; Inflammation; Iridoids; Lipid Peroxidation; Liver; Molecular Structure; Oxidative Stress; PPAR alpha; Rabbits; Triglycerides