Abstract The present study aimed to explore the holistic mechanism for the antihypertrophic effect of a compound in Chinese medicine, QiShenYiQi Pills (QSYQ) and the contributions of its components to the effect in rats with cardiac hypertrophy (CH). After induction of CH by ascending aortic stenosis, rats were treated with QSYQ, each identified active ingredient (astragaloside IV, 3, 4-dihydroxy-phenyl lactic acid or notoginsenoside R1) from its 3 major herb components or dalbergia odorifera, either alone or combinations, for 1 month. QSYQ markedly attenuated CH, as evidenced by echocardiography, morphology and biochemistry. Proteomic analysis and western blot showed that the majority of differentially expressed proteins in the heart of QSYQ-treated rats were associated with energy metabolism or oxidative stress. Each ingredient alone or their combinations exhibited similar effects as QSYQ but to a lesser extent and differently with astragaloside IV and notoginsenoside R1 being more effective for enhancing energy metabolism, 3, 4-dihydroxy-phenyl lactic acid more effective for counteracting oxidative stress while dalbergia odorifera having little effect on the variables evaluated. In conclusion, QSYQ exerts a more potent antihypertrophic effect than any of its ingredients or their combinations, due to the interaction of its active components through a multi-component and multi-target mode.
Extracellular signal-regulated kinases (ERKs) are pivotal signaling molecules in the RAS-RAF-MEK-ERK signaling pathway and have emerged as potential antitumor targets, providing a promising strategy for tumor therapy. Therefore, the development of antitumor drugs targeting ERK protein has received extensive attention. Here, we developed a compound library based on a series of novel aromatic urea-imidazole salt derivatives and conducted phenotypic screening against various cancer cell lines. Notably, 21y exhibited high efficacy against MCF-7 cells (IC50 = 0.67 μM). Furthermore, label-free drug affinity responsive target stability (DARTS) and LC-MS/MS proteomics techniques revealed that 21y directly targets ERK1/2. Mechanistically, 21y induced cell apoptosis and autophagy-related cell death. In vivo studies confirmed that 21y strongly inhibited tumor growth and lung metastasis in breast cancer. Taken together, 21y targets ERK1/2 as a promising therapeutic agent for breast cancer therapy.
To investigate the phenomenon of Ca(2+) sensitization, we developed a new intact airway and arteriole smooth muscle cell (SMC) "model" by treating murine lung slices with ryanodine-receptor antagonist, ryanodine (50 microM), and caffeine (20 mM). A sustained elevation in intracellular Ca(2+) concentration ([Ca(2+)](i)) was induced in both SMC types by the ryanodine-caffeine treatment due to the depletion of internal Ca(2+) stores and the stimulation of a persistent influx of Ca(2+). Arterioles responded to this sustained increase in [Ca(2+)](i) with a sustained contraction. By contrast, airways responded to sustained high [Ca(2+)](i) with a transient contraction followed by relaxation. Subsequent exposure to methacholine (MCh) induced a sustained concentration-dependent contraction of the airway without a change in the [Ca(2+)](i). During sustained MCh-induced contraction, Y-27632 (a Rho-kinase inhibitor) and GF-109203X (a protein kinase C inhibitor) induced a concentration-dependent relaxation without changing the [Ca(2+)](i). The cAMP-elevating agents, forskolin (an adenylyl cyclase activator), IBMX (a phosphodiesterase inhibitor), and caffeine (also acting as a phosphodiesterase inhibitor), exerted similar relaxing effects. These results indicate that 1) ryanodine-caffeine treatment is a valuable tool for investigating the contractile mechanisms of SMCs while avoiding nonspecific effects due to cell permeabilization, 2) in the absence of agonist, sustained high [Ca(2+)](i) has a differential time-dependent effect on the Ca(2+) sensitivity of airway and arteriole SMCs, 3) MCh facilitates the contraction of airway SMCs by inducing Ca(2+) sensitization via the activation of Rho-kinase and protein kinase C, and 4) cAMP-elevating agents contribute to the relaxation of airway SMCs through Ca(2+) desensitization.
Statement of RetractionStatement of RetractionWe, the Editors and Publisher of the journal Cell Cycle, have retracted the following article:Chunpeng Lu, Yanping Yin, Yongliang Cui, Lili Wang, Yan Bai, Jian Li, Tingting Huang, Maimaiti Reziwanguli, and Lifu Miao. 1,25(OH)2D3 improves blood lipid metabolism, liver function, and atherosclerosis by constraining the TGF-β/Smad signaling pathway in rats with hyperlipidemia. Cell Cycle. 2019;18(22):3111-3124. doi: 10.1080/15384101.2019.1669389.Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as 'Retracted'.View retraction statement:Statement of Retraction: 1,25(OH)2D3 improves blood lipid metabolism, liver function, and atherosclerosis by constraining the TGF-β/Smad signaling pathway in rats with hyperlipidemia
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