We have previously reported that L-arginine, a nitric oxide synthase substrate, inhibits the basolateral 10-pS Cl- channel through the cGMP/PKG signaling pathway in the thick ascending limb (TAL). As a NO releasing agent, the effect of S-nitroso-N-acetyl-penicillamine (SNAP) on the channel activity was examined in thick ascending limb of C57BL/6 mice in the present study. SNAP inhibited the basolateral 10-pS Cl- channel in a dose-dependent manner with an IC50 value of 6.6 μM. The inhibitory effect of SNAP was abolished not only by NO scavenger (carboxy-PTIO) but also by blockers of soluble guanylate cyclase (ODQ or LY-83583), indicating that the cGMP-dependent signaling pathway is involved. Moreover, the inhibitory effect of SNAP on the channel was strongly attenuated by a protein kinase G (PKG)-specific inhibitor, KT-5823, but not by the PDE2 inhibitor, BAY-60-7550. We concluded that SNAP inhibited the basolateral 10-pS Cl- channels in the TAL through a cGMP/PKG signaling pathway. As the 10-pS Cl- channel is important for regulation of NaCl absorption along the nephron, these data suggest that SNAP might be served as a regulator to prevent high-salt absorption related diseases, such as hypertension.

2022-02-01·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids2区 · 生物学

Endothelin-1 induces lipolysis through activation of the GC/cGMP/Ca2+/ERK/CaMKIII pathway in 3T3-L1 adipocytes

2区 · 生物学

Article

作者: Ho, Low-Tone ; Kwok, Ching-Fai ; Chen, Chien-Wei ; Yang, De-Ming ; Lien, Chih-Chan ; Liu, Shui-Yu ; Yin, Wei-Hsian ; Chen, Luen-Kui ; Juan, Chi-Chang

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide produced and secreted mainly by endothelial cells. Recent studies indicate that ET-1 can regulate lipid metabolism, which may increase the risk of insulin resistance. Our previous studies revealed that ET-1 induced lipolysis in adipocytes, but the underlying mechanisms were unclear. 3T3-L1 adipocytes were used to investigate the effect of ET-1 on lipolysis and the underlying mechanisms. Glycerol levels in the incubation medium and hormone-sensitive lipase (HSL) phosphorylation were used as indices for lipolysis. ET-1 significantly increased HSL phosphorylation and lipolysis, which were completely inhibited by ERK inhibitor (PD98059) and guanylyl cyclase (GC) inhibitor (LY83583). LY83583 reduced ET-1-induced ERK phosphorylation. A Ca²⁺-free medium and PLC inhibitor caused significant decreases in ET-1-induced lipolysis as well as ERK and HSL phosphorylation, and IP₃ receptor activator (D-IP₃) increased lipolysis. ET-1 increased cGMP production, which was not affected by depletion of extracellular Ca²⁺. On the other hand, LY83583 diminished the ET-1-induced Ca²⁺ influx. Transient receptor potential vanilloid-1 (TRPV-1) antagonist and shRNA partially inhibited ET-1-induced lipolysis. ET-1-induced lipolysis was completely suppressed by CaMKIII inhibitor (NH-125). These results indicate that ET-1 stimulates extracellular Ca²⁺ entry and activates the intracellular PLC/IP₃/Ca²⁺ pathway through a cGMP-dependent pathway. The increased cytosolic Ca²⁺ that results from ET-1 treatment stimulates ERK and HSL phosphorylation, which subsequently induces lipolysis. ET-1 induces HSL phosphorylation and lipolysis via the GC/cGMP/Ca²⁺/ERK/CaMKIII signaling pathway in 3T3-L1 adipocytes.

2021-09-01·Bioorganic Chemistry2区 · 化学

Design, synthesis and investigation of the mechanism of action underlying anti-leukemic effects of the quinolinequinones as LY83583 analogs

2区 · 化学

Article

作者: Sever, Belgin ; Ciftci, Halil I ; Tateishi, Hiroshi ; Bayrak, Nilüfer ; Fujita, Mikako ; Yıldız, Mahmut ; Otsuka, Masami ; Yıldırım, Hatice ; Tuyun, Amaç Fatih

Literature conclusively shows that one of the quinolinequinone analogs (6-anilino-5,8-quinolinequinone), referred to as LY83583 hereafter, an inhibitor of guanylyl cyclase, was used as the inhibitor of the cell proliferation in cancer cells. In the present work, a series of analogs of the LY83583 containing alkoxy group(s) in aminophenyl ring (AQQ1-15) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against four different cancer cell lines (K562, Jurkat, MT-2, and HeLa) and human peripheral blood mononuclear cells (PBMCs) by MTT assay. The analog (AQQ13) was identified to possess the most potent cytotoxic activity against K562 human chronic myelogenous (CML) cell line (IC₅₀ = 0.59 ± 0.07 μM) with significant selectivity (SI = 4.51) compared to imatinib (IC₅₀ = 5.46 ± 0.85 μM; SI = 4.60). Based on its superior cytotoxic activity, the analog AQQ13 was selected for further mechanistic studies including determination of its apoptotic effects on K562 cell line via annexin V/ethidium homodimer III staining potency, ABL1 kinase inhibitory activity, and DNA cleaving capacity. Results ascertained that the analog AQQ13 induced apoptosis in K562 cell line with notable DNA-cleaving activity. However, AQQ13 demonstrated weak ABL1 inhibition indicating the correlation between anti-K562 and anti-ABL1 activities. In continuance, respectively conducted in silico molecular docking and Absorption, Distribution, Metabolism, and Excretion (ADME) studies drew attention to enhanced binding interactions of AQQ13 towards DNA and its high compatibility with the potential limits of specified pharmacokinetic parameters making it as a potential anti-leukemic drug candidate. Our findings may provide a new insight for further development of novel quinolinequinone-based anticancer analogs against CML.

100 项与 LY-83583 相关的药物交易

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