tilianin and Disease-Models--Animal

Acacetin 7-O-β-D-glucoside (tilianin) is a major constituent of Agastache rugosa, a traditional medicine that has long been used for the treatment of gastrointestinal disorders. Tilianin has a wide variety of pharmacological properties such as cardioprotective, neuroprotective, and anti-atherogenic activities. We recently discovered that tilianin has the ability to suppress MUC5AC expression in vitro. In addition, we have established an in vivo model of allergic asthma using house dust mite (HDM) that can be applied to tilianin.. We investigated the effects of tilianin on airway inflammation in a HDM-induced asthma mouse model and associated mechanisms.. Tilianin was treated in splenocytes cultured in Th0 condition and HDM-stimulated bone marrow-derived dendritic cells (BMDCs), and their mRNA expression and cytokines production were determined by quantitative real-time PCR and ELISA. To evaluate the effects of tilianin in an allergic asthma model, mice were sensitized and challenged with HDM. Tilianin was administered prior to challenge by oral gavage and airway hyper-reactivity (AHR) to methacholine, inflammatory cell infiltration, cytokine levels, and airway remodeling were assessed.. Tilianin inhibited the production of Th2-related cytokines in splenocytes, which play pivotal roles in allergic airway inflammation. When treated in HDM-stimulated BMDCs, tilianin decreased Th2-skewing cytokine IL-33 and transcription factor IRF4. On the contrary, tilianin increased Th1-skewing regulators, IL-12 and IRF1. In an HDM-induced asthmatic mouse model, tilianin attenuated AHR and airway inflammation. Tilianin suppressed the expression of Th2-related cytokines, IL-13 and IL-33 in lung tissues. As seen in HDM-stimulated BMDCs, tilianin also downregulated the expression of the transcription factor IRF4 but not IRF1.. Taken together, these results suggest that tilianin attenuates HDM-induced allergic airway inflammation by inhibiting Th2-mediated inflammation through the selective inhibition of the IRF4-IL-33 axis in dendritic cells.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Cytokines; Dendritic Cells; Disease Models, Animal; Down-Regulation; Female; Flavonoids; Glycosides; Hypersensitivity; Interferon Regulatory Factors; Interleukin-33; Lung; Mice, Inbred BALB C; Pyroglyphidae; Th2 Cells

Diabetic cardiomyopathy (DCM) is a chronic multifactorial complication of type-2 diabetes mellitus, leading to heart failure. A combination of multifaceted therapeutics for the management of DCM is needed. Here, we investigated the combined effect of syringin and tilianin on DCM by evaluating cardiac function, inflammation, oxidative stress, apoptosis and mitochondrial function, and explored the contribution of TLR4/NF-κB/NLRP3 and PGC1α/SIRT3 pathways in diabetic rats and hyperglycemic-H9c2 cells. Syringin and tilianin (50 and 60 mg/kg, i.p, respectively) were administered for eight weeks, individually or in combination, to healthy and type-2 diabetic Sprague-Dawley rats. Myocardial function was recorded using a carotid catheter, mitochondrial and histopathological changes were evaluated by fluorometric and staining methods, cardiac markers and signaling pathways' proteins expression were measured through ELISA and immunoblotting. In comparison to individual treatments, combination of syringin and tilianin effectively exerted antidiabetic effects and improved cardiac function and DCM markers, reduced NLRP3/IL-6/IL-1β/TNF-α expression, and suppressed diabetes/hyperglycemia‑induced oxidative stress in rats' heart and H9c2 cells, as demonstrated by decreased 8-isoprostane, and increased superoxide dismutase-2 levels. Mitochondrial membrane depolarization and ROS production were inhibited, and caspase-3 and Bax/Bcl2 expression downregulated by combination therapy. Combined treatment markedly inhibited up-regulation of TLR4, MyD88 and NF-κB in diabetic rats. Finally, inhibition of PGC1α/SIRT3 pathway by 3-TYP in hyperglycemic H9c2-cells reversed the beneficial effects of combination therapy on cardiomyocytes injury and NF-κB/NLRP3/IL-1β expression, without affecting TLR4/MyD88 expression. Syringin plus tilianin synergistically inhibited the diabetes-induced cardiac functional, biochemical and histopathological changes in DCM. Crosstalk between TLR4/NF-κB/NLRP3 and PGC1α/SIRT3/mitochondrial pathways contributed to this protection.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Synergism; Flavonoids; Glucosides; Glycosides; Inflammasomes; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phenylpropionates; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirtuins; Toll-Like Receptor 4

Topics: Agastache; Animals; Chemokine CXCL2; Disease Models, Animal; Flavonoids; Glycosides; Glycyrrhiza; Glycyrrhizic Acid; Interleukin-17; Lung; Male; Mice; Mice, Inbred BALB C; Plant Extracts; Pneumonia; Polymerase Chain Reaction; Pulmonary Disease, Chronic Obstructive; Signal Transduction; STAT3 Transcription Factor

Topics: AMP-Activated Protein Kinases; Animals; Disease Models, Animal; Energy Metabolism; Flavonoids; Glycosides; Male; Mitochondria, Heart; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1

Our previous research demonstrated that tilianin protects the myocardium in a myocardial ischemia reperfusion injury (MIRI) rat model and has prominent pharmacological potential as a cardiovascular drug. Our study aimed to investigate the molecular signaling implicated in the improvement of myocardial survival induced by tilianin, a flavonoid antioxidant. Tilianin (2.5, 5, and 10 mg/kg/d) or saline was orally administered to rats for 14 days. On the 15th day, ischemia was induced by ligating the left anterior descending artery for 45 min, followed by 4 h of reperfusion. The levels of MIRI-induced serum myocardial enzymes and cardiomyocyte apoptosis as well as infarct size were examined to assess the cardioprotective effects. Cardiac tissues were collected for western blot analyses to determine the protein expression of anti-apoptotic signaling molecules. In MIRI-treated rats, our results revealed that pre-administration of high dose-tilianin the reduced release of LDH, MDA, and CK-MB and increased the plasma SOD level, and significantly attenuated the infarct size. Western blot analysis showed that a remarkable rise in expression of Bcl-2 and XIAP, and decline in expression of Bax, Smac/Diablo, HtrA2/Omi, cleaved caspase-3, caspase-7 and caspase-9 was observed in the myocardium. The apoptosis index of cardiomyocytes further supports the cardioprotective effect of tilianin. Additionally, compared with the MIRI model group, pretreatment with high dose-tilianin group upregulated phosphorylated Akt and PI3K. In contrast, using the PI3K inhibitor LY294002 to block Akt activation effectively inhibited the protective effects of tilianin against MIRI. Tilianin pretreatment was beneficial for activating the PI3K/Akt signaling pathway and inhibiting myocardial apoptosis.

Topics: Administration, Oral; Animals; Apoptosis; Cardiotonic Agents; Chromones; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme Inhibitors; Flavonoids; Glycosides; Male; Molecular Structure; Morpholines; Myocardial Reperfusion Injury; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Random Allocation; Rats, Sprague-Dawley; Signal Transduction

Tilianin, the main effective flavonoid monomer enriched from Dracocephalum moldavuca L., has been shown to have cardioprotective effects. However, the mechanism of tilianin cardioprotection remains largely unknown. The present study aimed to investigate the effects of tilianin preconditioning on myocardial ischemia/reperfusion injury and to analyze the possible mechanism of action. A total of 48 male Sprague Dawley rats were randomized into sham, model myocardial ischemia/reperfusion injury (MI/RI), propranolol hydrochloride positive control, and high‑, medium‑ and low‑dose tilianin groups (n=8 each). The rats in the tilianin groups were perfused with either 1.5, 2.5 or 5.0 mg/kg/d tilianin a week prior to surgery. The positive control group were perfused with 25 mg/kg/d propranolol. Saline was administered to the sham surgery and the MI/RI groups. The MI/RI model was established by ligating the left anterior descending coronary artery for 30 min, which was subsequently removed and the mice were observed for 120 min prior to sacrifice. Na+‑K+‑ATPase, Ca2+‑ATPase, nitric oxide (NO), nitric oxide synthase (NOS) and endothelial system‑related factors were analyzed using the respective detection kits. Immunohistochemistry was used to determine the expression levels of Bcl‑2 and Bax. Caspase‑3 activity was measured by quantitative polymerase chain reaction. The results showed that tilianin preconditioning significantly increased ATPase activity (P<0.01 and P<0.05) as compared with the model group. With regards to the regulation of endothelial function, significant decreases (P<0.01 and P<0.05) were detected in the serum NO levels and myocardial NOS activity when tilianin was administered to MI/RI rats, as compared with the model group, . In addition, the tilianin drug groups exhibited dose‑dependent reductions in the serum levels of endothelin 1 and thromboxane B2, and increases in the serum levels of calcitonin gene‑related peptide and 6‑keto prostaglandin F1a as compared with the model group (P<0.01 and P<0.05). Notably, the administration of tilianin significantly inhibited apoptosis, as evidenced by an increase in Bcl‑2 expression, and reductions in Bax and caspase‑3 mRNA expression levels (P<0.01 and P<0.05). These data indicate that pretreatment with tilianin exerts potent cardioprotective effects in rats with MI/RI. The anti‑MI/RI effects comprised relieving calcium overload, correction of energy metabolism, improvement of endothelial function and inhib

Topics: Animals; bcl-2-Associated X Protein; Calcium-Transporting ATPases; Cardiotonic Agents; Caspase 3; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Flavonoids; Glycosides; Male; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase; Proto-Oncogene Proteins c-bcl-2; Rats; Sodium-Potassium-Exchanging ATPase