Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Zhao, Ning; Fu, Xiangwei; Du, Liqing; Cheng, Xiang; Du, Yumin; Liao, Yuhua

doi:10.1159/000366343

Cited by 36 publications

(38 citation statements)

References 33 publications

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“…39, 40 In brief, NRVM and H9C2 cells were loaded with 2 μ M Fluo-4/AM (Molecular Probes, Carlsbad, CA, USA, #F14201) for 30 min, washed three times with HEPES buffer that contained (in mM) 130 NaCl, 4.7 KCl, 2.0 CaCl 2 ,1.2 MgSO 4 , 1.2 KH 2 PO 4 , 10 HEPES and 11 glucose at pH 7.4. Cells in 96-wells plate were illuminated at 488 nm and fluorescence emissions at 525 nm were captured with the Enspire Multimode Plate Reader (PerkinElmer, Boston, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes

Cheng

Zhao

et al. 2017

Cell Death Dis

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Transient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R). Recently, we found that treatment with a selective TRPV4 antagonist HC-067047 significantly reduced infarct size, decreased troponin T levels and improved cardiac function in murine model myocardial I/R. This study was undertaken to investigate the mechanism underlying TRPV4-mediated myocardial I/R injury. To mimic myocardial I/R injury, we established a hypoxia/reoxygenation (H/R) model in H9C2 cells and neonatal rat ventricle myocytes (NRVMs) in vitro. TRPV4 mRNA and protein expression was confirmed in the H9C2 and NRVM, whereas functional TRPV4 activity was assessed from Ca2+ influx response to a TRPV4 agonist GSK1016790A. TRPV4 functional expression was significantly enhanced during H/R. Furthermore, H/R increased the intracellular Ca2+ concentration ([Ca2+]i) and induced cell injury, which were reversed by HC-067047 but was further aggravated by GSK1016790A. Moreover, HC-067047 treatment significantly alleviated the increase of reactive oxygen species (ROS) generation, the depolarization of mitochondrial membrane potential (Δψm) and the opening of mitochondrial permeability transition pore (mPTP) during H/R. On the contrary, GSK1016790A exacerbated those effects. Meanwhile, increase in [Ca2+]i and ROS induced by activation of TRPV4 was almost abolished when cells were cultured in Ca2+-free medium. In addition, ROS scavenger NAC obviously reversed activation of TRPV4-induced changes of Δψm and mPTP opening. Finally, we confirmed the direct roles of TRPV4 on cardiac injury and ROS generation in murine model myocardial I/R in vivo. In conclusion, activation of TRPV4 induces Ca2+ influx in cardiomyocytes, with subsequent ROS release, depolarizing of Δψm, opening mPTP, inducing injury and TRPV4 has key roles during I/R via these pathways.

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Section: Methodsmentioning

confidence: 99%

Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes

Cheng

Zhao

et al. 2017

Cell Death Dis

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“…Proteins were visualized using an enhanced chemiluminescence kit (Pierce). The intensity of the β-actin (1:1,000; Abcam, Cambridge, MA, USA) band was used as a loading control for the comparison between samples, as previously described ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis

Zhao

Dong

et al. 2015

International Journal of Molecular Medicine

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Post-operative atrial fibrillation (AF) remains a common cause of morbidity. Increasing evidence indicates that inflammation and atrial fibrosis contribute to the pathogenesis of this condition. Interleukin (IL)-17A, a potent pro-inflammatory cytokine, has been implicated in the development of a number of cardiovascular diseases. However, its role in post-operative AF remains unknown. In the present study, sterile pericarditis (SP) was induced in rats by the epicardial application of sterile talc. AF was induced by transesophageal burst pacing. Western blot analysis was applied to quantify the expression of IL-17A. Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA). Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Histological analyses were performed to determine the extent of tissue inflammation and fibrosis. The rats with SP presented with a shorter refractoriness, a higher incidence and duration of AF, an enhanced susceptibility to developing AF, increased mRNA levels of AF-related pro-inflammatory cytokines (IL-6, IL-1β and TGF-β1), as well as marked atrial inflammation and fibrosis. The atrial IL-17A levels were elevated and correlated with the probability of developing AF. Treatment with anti-IL-17A monoclonal antibody decreased the levels of atrial IL-17A, prolonged refraction and markedly suppressed the development of AF. Simultaneously, inflammation and fibrosis were alleviated, which was further demonstrated by a decreased expression of AF-related pro-inflammatory cytokines, a down-regulation in fibrosis-related mRNA expression (Col-1, Col-3 and α-SMA) and by the decreased activity of MMP-2/9 and TIMPs. Thus, the findings of our study indicate that IL-17A may play a pathogenic role in post-operative AF by inducing inflammation and fibrosis in rats with SP.

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“…Acacetin is the aglycone of tilianin and is also derived from DML and propolis . Acacetin exhibits antitumor effects against breast, prostate, lung, liver and stomach cancers . Given their numerous pharmacological properties, tilianin and acacetin are good candidates for drug development.…”

Section: Introductionmentioning

confidence: 99%

Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes

Dai

Luo

Wang

et al. 2015

Biopharm & Drug Disp

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Flavonoids occur naturally as glucosides and aglycones. Their common phenolic hydroxyl groups may trigger extensive UDP-glucuronosyltransferase (UGT)- catalysed metabolism. Unlike aglycones, glucosides contain glucose moieties. However, the influence of these glucose moieties on glucuronidation of glucosides and aglycones remains unclear. In this study, the flavonoid glucoside tilianin and its aglycone acacetin were used as model compounds. The glucuronidation characteristics and enzyme kinetics of tilianin and acacetin were compared using human UGT isoforms, liver microsomes and intestinal microsomes obtained from different animal species. Tilianin and acacetin were metabolized into different glucuronides, with UGT1A8 produced as the main isoform. Assessment of enzyme kinetics in UGT1A8, human liver microsomes and human intestinal microsomes revealed that compared with tilianin, acacetin displayed lower Km (0.6-, 0.7- and 0.6-fold, respectively), higher Vmax (20-, 60- and 230-fold, respectively) and higher clearance (30-, 80- and 300-fold, respectively). Furthermore, glucuronidation of acacetin and tilianin showed significant species- and gender-dependent differences. In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species- and gender-dependent differences between glucosides and aglycones is crucial for the development of drugs from flavonoids.

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Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Cited by 36 publications

References 33 publications

Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes

Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes

Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis

Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes

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