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  • Altogether the results of this study

    2020-05-26

    Altogether, the results of this study demonstrate that peripheral blockade of both ETA and ETB receptors reduces tumor-induced facial heat hyperalgesia and increased spontaneous grooming, without modifying ongoing nociception. It is possible to suggest that bosentan is acting upon both receptors present in primary sensory afferents, or is causing the blockade of ETA, and mainly ETB receptors, present in tumor cells, promoting the blockade of endothelin-1 release from these cells, which in both cases will prevent peripheral nociceptor sensitization (Barr, Kam, Khodorova, Montmayeur, & Strichartz, 2011; Khodorova et al., 2009; Schmidt, Hamamoto, Simone, & Wilcox, 2010; Schmidt, 2014; Smith et al., 2014).
    Funding sources This study was supported by National Council for Scientific and Technological Development (CNPq), grant #477679/2012-9. The first author received PhD. scholarship by Coordination for the Improvement of Higher Education Personnel (CAPES) during the study development.
    Conflict of interest
    Acknowledgements The group is grateful to CNPq and CAPES for their funding support. We thank Dr. Sandra Coccuzzo Sampaio (Butantan Institute, Sao Paulo, Brazil) for kindly donating the Walker-256B tumor cells. We also thank Dr. Alexandra Acco, M.Sc. Eder Gambeta and M.Sc. Larissa Galuppo for technical support.
    Introduction Pulmonary arterial hypertension (PAH) is a progressive and chronic disease characterized by an abnormal vascular proliferation and remodeling that increases pulmonary arterial pressure and vascular resistance. PAH is defined as a mean pulmonary arterial pressure ≥ 25 mm Hg, a pulmonary arterial wegde pressure ≤ 15 mm Hg and a pulmonary vascular resistance > 3 UW·m2 assessed by right Cy3 NHS ester (non-sulfonated) catheterization [1]. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) [1] are one of the three different lines of treatment for PAH available nowadays, as well as prostanoids and phosphodiesterase type 5 inhibitors. Protanoids stimulate the cAMP pathway to increase pulmonary vasodilation. Phosphodiesterase type 5 inhibitors increase smooth muscle cell cGMP levels and promote pulmonary vascular dilation and remodeling. Endothelin-1 is involved in an aberrantly activated process of mitogenesis, angiogenesis, fibrosis and inflammation that occurs in pulmonary vessels in patients with PAH [2]. Macitentan is an orally active, potent and dual endothelin receptor antagonist which inhibits endothelin-1 from binding to endothelinA and endothelinB receptors [2]. It has a slow receptor dissociation kinetic compared to other endothelin receptor antagonists that contribute to a sustained receptor binding [3] and to a greater affinity with lipophilic membranes. This enables an enhanced tissue penetration without interfering to bile acid secretion and therefore reducing the risk of hepatoxicity [5].
    Financial support
    Conflicts of interest
    Introduction Hepatocellular carcinoma (HCC) is a malignancy that originates from the liver, with its morbidity rate ranking fourth in all malignancies and the mortality rate ranking third. Guangxi is a region with high morbidity rate of HCC (National Health Commission of the People\'s Republic of China, 2017; Fu and Wang, 2018; Li et al., 2018a; Ozakyol, 2017; Sun et al., 2018). Multiple factors contributed to the initiation of HCC, including environmental influences and the genetic susceptibility. The risk factors in the environment involved the infection of viral hepatitis, intake of aflatoxin, alcohol addiction and the use of oral contraceptive (Brandi et al., 2017; Xu et al., 2017; Zheng et al., 2017). Currently, the treatment for HCC mainly depends on the operation, with assistance of combined therapies. However, the treatment usually seemed unsatisfactory due to undiagnosed initiation, advanced stages when diagnosed, high recurrence rate, drug resistance, etc. (Ayuso et al., 2018; Crocetti et al., 2017; Foerster et al., 2018; Katsura et al., 2017; Kim et al., 2017; Mao et al., 2018; Reig et al., 2018; Shiina et al., 2018; Wu et al., 2018; Xu et al., 2018). The trend of precision medicine has marked the start of using molecularly targeted therapy against malignant tumors, and the discovery of novel molecular targets with the diagnostic and prognostic value has laid the foundation for targeted therapy (Amicone and Marchetti, 2018; Chen et al., 2018; Dhanasekaran et al., 2018; Li et al., 2018c; Song et al., 2018; Yao et al., 2018).