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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Interestingly, the BK channel is recently reported to be highly expressed in the lysosomal membrane (Cao et al., 2015b; Wang et al., 2017). The lysosomal localization of the BK channel is determined by two dileucine motifs, D(485)ACLI and D(731)PLLI, located in the RCK domain in the large cytoplasmic C-terminus (Cao et al., 2015b). In agreement with what was known for BK channel on the PM, an increase in the cytosolic Ca2+ concentration dramatically increases BK currents and shifts the voltage dependence of channel activation to more negative potentials (Cao et al., 2015b; Wang et al., 2017). This shift of voltage dependence makes BK easily activated in response to a local Ca2+ increase upon the opening of lysosomal Ca2+ release channels (Berkefeld et al., 2010; Fakler and Adelman, 2008; Salkoff et al., 2006). Like the BK channel in the PM, the lysosomal BK channel is inhibited by paxilline, quinidine, clofilium and iberiotoxin (Garrity et al., 2016; Wang et al., 2017) but activated by NS1619 (Bentzen et al., 2014; Olesen et al., 1994) and isopimaric acid (Garrity et al., 2016; Wang et al., 2017; Yamamura et al., 2001). These data indicate that the BK channel in lysosomes functions in the same manner as its PM counterpart.
Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents
Published in Expert Opinion on Therapeutic Patents, 2019
Further natural RXR modulators were discovered in a computer-assisted screening for RXR ligands where isopimaric acid (15), dehydroabietic acid (16) and valerenic acid (1) were identified as natural RXR agonists (Figure 6). Isopimaric acid (15) and dehydroabietic acid (16) showed micromolar potency on all three subtypes with moderate transactivation efficacy in a Gal4 hybrid reporter gene assays. Valerenic acid (1, Figure 1), in contrast to 15 and 16, revealed remarkable selectivity for RXRβ (RXRα: EC50 = 27 µM, ninefold activation; RXRβ: EC50 = 5 µM, 69-fold activation; RXRγ: EC50 = 43 µM, fourfold activation) without activating other nuclear receptors like RARs, PPARs, LXRs and FXR [10].
The use of terpenes and derivatives as a new perspective for cardiovascular disease treatment: a patent review (2008–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Eric Aian P. Silva, Jéssica S. Carvalho, Adriana G. Guimarães, Rosana de S.S. Barreto, Márcio R.V. Santos, André S. Barreto, Lucindo J. Quintans-Júnior
In relation to treatment of metabolic disorders, such as hyperglycemia and hyperlipidemia, were found four patents in that area. In 2009, Jeong et al. [30], from South Korea, patented an extract for prevention and treatment of cardiovascular disease from Torreya nucifera which has a novel abietane diterpenoid namely 12-hydroxyabietic-8,11,13-trien-18-dimethylacetyl (2). The extract has also other terpenes, such as isopimaric acid, dehydroabietinol, kayadiol, and δ-cadinol. The compounds was tested in infusion and the methanolic phase. The results showed great antioxidative activity to low-density lipoprotein (LDL) by TBARS method and also significantly inhibited Acyl-CoA and cholesterol acyltransferase (ACAT), thus reducing blood LDL cholesterol and total cholesterol. Thus, this compound may provide a novel drug for the prevention and treatment of cardiovascular diseases such as hyperlipidemia and atherosclerosis, which can be caused by oxidation of LDL. Additionally, a toxicity test in mice was performed, which they were treated orally once (100, 500, and 1,000 mg/kg, p.o) and no toxicity was detected neither from weight changes, hematological and biochemical tests nor autopsy.