Nitric oxide (NO) is an essential endogenous vasodilator to maintain vascular homeostasis, whose effects are mainly mediated by NO-dependent soluble guanylate cyclase (sGC) which catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a critical mediator of vascular relaxation. YC-1, a novel NO-independent sGC stimulator, was first introduced as an inhibitor of platelet aggregation and thrombosis. Accumulating studies revealed that YC-1 has multiple medication potentials to use for a broad spectrum of diseases ranging from cardiovascular diseases to cancers. In contrast to NO donors, YC-1 has a more favorable safety profile and low medication tolerance. In this chapter, we introduce canonical and pathological roles of NO, review activations, and regulatory mechanisms of YC-1 on NO-independent sGC/cGMP pathway and present the potential pharmacological applications and molecular mechanisms of YC-1.
The vasorelaxing effect of N-benzylsecoboldine on the rat thoracic aorta was investigated, and we also compare it with nifedipine and cromakalim. In high K^+ (60 mM) medium, Ca^2+ (0.03-3 mM)-induced vasoconstriction was inhibited concentration-dependently by N-benzylsecoboldine, whereas this contraction was not altered by cromakalim. Cromakalim relaxed aortic rings precontracted with 15 but not 60 mM of K^+. N-benzylsecoboldine and nifedipine were more potent and effective in producing relaxation in 60 mM than in 15 mM K^+ - induced contraction. N-benzylsecoboldine was found to be an α(1)-adrenoceptorblocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine (PE)-induced contraction (pA(2)=6.31 ±0.04, pA(10)in=5.41 ±0.03). This relaxing effect of N-benzylsecoboldine was not antagonized by indomethacin or methylene blue, and still persisted in endothelium-denuded aorta or in the presence of nifedipine ( 1 µM). The increase of inositol monophosphate caused by PE in rat aorta was significantly suppressed by N-benzylsecoboldine, but not by nifedipine or cromakalim. High concentration of N-benzylsecoboldine (100 µM) did not affect the contraction induced by B-HT 920, serotonin or PGF(2α),. Glibenclamide and charybdotoxin did not affect the relaxation of N-benzylsecoboldine in aortic rings precontracted with PE. Neither cGMP nor cAMP levels were changed by N-benzylsecoboldine. We suggest that N-benzylsecoboldine relaxes rat thoracic aorta by suppressing the Ca^2+ influx and also has antagonistic effect on α(1)-adrenoceptors.
Angiotenisn 1–7 (Ang 1–7) is considered to play an opposing role to angiotensin II (Ang II). However, the modulation of MMPs and TIMPs by Ang 1–7 is largely unclear in cardiocytes, and the counteractive effects of Ang 1–7 on Ang II‐mediated MMPs and TIMPs expression need to be identified. We examined the mRNA expression of MMPs and TIMPs in human cardiac fibroblasts (HCF) and cardiac myocytes (HCM) stimulated by Ang II or Ang 1–7, and analyzed the antagonistic effects of Ang 1–7 to Ang II. Ang II decreased transcript expression of MMP‐1, MMP‐2, TIMP‐1, TIMP‐2 and TIMP‐3, but downregulated MMP‐9 expression in the HCF cells. Transcript expression of MMP‐9 and TIMP‐2 were downregulated by Ang 1–7 in the cells. In the HCM cells, Ang II induced MMP‐1 and MMP‐9 expression, but all of examined MMPs and TIMPs, except MMP‐9, were markedly decreased by Ang 1–7. Ang 1–7 could counteract the effects of Ang II‐mediated regulations on MMP‐1, MMP‐9 and TIMP‐1 in the HCF cells. The regulations of all examined MMPs by Ang II were reversed to basal expression by Ang 1–7 in the HCM cells. Opposite regulation in the examined MMPs and TIMPs expression was found between Ang II and Ang 1–7, and the antagonistic effects of Ang 1–7 to Ang II were also identified. These results might raise a potential role of Ang 1–7 to attenuate Ang II‐induced ECM remodeling in heart. This work was supported by National Science Council (NSC 95‐2313‐B‐009‐002‐MY3), Taiwan.
Non‐small cell lung cancer (NSCLC), the most common type of lung cancer, has the problems such as less sensitivity to chemotherapy and resistance to tyrosine kinase inhibitors. Kruppel‐like factor 2 (KLF2) has been reported to have the potential activities in tumor suppression and immune regulation. The expression level of KLF2 is lower in NSCLC and negatively correlated with the stages of tumor progression and lymph node metastasis. To date, not only no KLF2‐promoting compounds have been developed, but no related studies on its anti‐tumor efficacy in vivo have been verified. Therefore, the purposes of this study were focused on the potential and related mechanisms of KLF2 applied as a targeted molecule for NSCLC therapy. Our data indicated that the intervention of lovastatin markedly up‐regulated protein expression of KLF2 in A549 human non‐small cell lung cancer cells. Moreover, KLF2 siRNA intervention could significant inhibit serum‐induced cell growth in A549 cells. The analysis result of the Ingenuity pathway analysis (IPA) showed that several intracellular molecules, such as AKT, mTOR and FOXO1, maybe the potential upstream regulators to involve in KLF2 expression. Besides, the experimental data also evidenced that lovastatin can suppress activations of AKT and mTOR proteins as well as to reduce protein expression of FOXO1. In summary, these results suggested that intensifying KLF2 expression could apply as a feasible therapeutic strategy to improve NSCLC therapy, and statinoid compounds have potential to be developed as KLF2 activator. In addition, activations or expressions of AKT‐mTOR pathway and FOXO1 may be attributed to suppression of KLF2 in NSCLC cells, such as A549 cells.
Non‐small cell lung cancer (NSCLC) is generally insensitive to chemotherapy, and Antrodia cinnamomea (AC) has a long history used as a natural remedy for health improvement. The present study attempted to explore the anti‐cancer activity and mechanisms of the ethanolic extract of AC (EEAC) in human lung epithelial carcinoma A549 cell lines, a NSCLC cells. The results showed that EEAC treatment markedly decreased cell viability, arrested cell cycle in G0/G1 phase, and increased the activation of AMPK as well as downregulated the phosphorylation of Akt, mTOR, RB and ERK 1/2 proteins. Additionally, EEAC inhibited cell migration and reduced the expression level of matrix metalloproteinase (MMP)‐2 and 9 proteins. It has also noticed that EEAC can suppress the expression of Cav‐1 protein to enhance the chemotherapy sensitivity of A549 cells to paclitaxel. Our study suggested that EEAC might have potential activities to be developed as adjuvant remedy for lung cancer chemotherapy.
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