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Highlights for the 6th International Ion Channel Conference: ion channel structure, function, disease and therapeutics.

Acta Pharmaceutica Sinica B.2017;7(6):665-669. doi:10.1016/j.apsb.2017.09.007

To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6th International Ion Channel Conference (IICC-2017) was held between June 23-27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on (1) Ion channel structure and function; (2) Ion channel physiology and human diseases; (3) Ion channels as targets for drug discovery; (4) Technological advances in ion channel research. An insightful overview was presented on the structure and function of the mechanotransduction channelNOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) channel family. Recent studies on Transmembrane protein 16 or Anoctamin-1 (TMEM16A, a member of the calcium-activated chloride channel [CaCC] family) were summarized as well. In addition, topics for ion channel regulation, homeostatic feedback and brain disorders were thoroughly discussed. The presentations at the IICC-2017 offer new insights into our understanding of ion channel structures and functions, and ion channels as targets for drug discovery.

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Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1.

Xuewei CHENG ; Xia LV ; Hengyan QU ; Dandan LI ; Mengmeng HU ; Wenzhi GUO ; Guangbo GE ; Ruihua DONG

Acta Pharmaceutica Sinica B.2017;7(6):657-664. doi:10.1016/j.apsb.2017.07.004

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug-drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risksUGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The ICvalues of icotinib and erlotinib against UGT1A1-mediated NCHN--glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with thevalues of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risksUGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration-time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risksUGT1A1 inhibition.

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Application ofH NMR-based metabolomics for discrimination of different parts and development of a new processing workflow for.

Pingping ZOU ; Yuelin SONG ; Wei LEI ; Jun LI ; Pengfei TU ; Yong JIANG

Acta Pharmaceutica Sinica B.2017;7(6):647-656. doi:10.1016/j.apsb.2017.07.003

(CD) is one of the two authoritative source plants of Cistanches Herba, a well-known medicinal plant. Herein,H NMR spectroscopy was employed to characterize the chemical profile and to distinguish the different parts, as well as to propose a new processing workflow for CD. Signal assignment was achieved by multiple one and two dimensional NMR spectroscopic techniques in combination with available databases and authentic compounds. The upper parts of the plant were distinguished from the lower parts by combiningH NMR spectroscopic dataset with multivariate statistical analysis. A new processing method that hyphenated steaming with freeze-drying, was demonstrated to be superior to either steaming coupled with oven-drying or direct freeze-dryingholisticH NMR-based metabolomic characterization. Phenylethanoid glycosides, mainly echinacoside and acteoside, were screened out and confirmed as the chemical markers responsible for exhibiting the superiority of the new processing workflow, whereas serial primary metabolites, especially carbohydrates and tricarboxylic acid cycle metabolites, were found as the primary molecules governing the discrimination between the upper and lower parts of the plant. Collectively,H NMR spectroscopy was demonstrated as a versatile analytical tool to characterize the chemical profile and to guide the in-depth exploitation of CD by providing comprehensive qualitative and quantitative information.

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8,4'-Oxyneolignane glucosides from an aqueous extract of "ban lan gen" (root) and their absolute configurations.

Lingjie MENG ; Qinglan GUO ; Yufeng LIU ; Jiangong SHI

Acta Pharmaceutica Sinica B.2017;7(6):638-646. doi:10.1016/j.apsb.2017.09.006

Three pairs of glycosidic 8,4'-oxyneolignane diastereoisomers, named isatioxyneolignosides A-F (-), were isolated from an aqueous extract ofroots. Their structures and absolute configurations were elucidated by comprehensive spectroscopic data analysis and enzyme hydrolysis. The validity of Δvalues to distinguishandaryl glycerol units and Cotton effects at 235±5 nm to determine absolute configurations at C-8 in-and their aglycones (-) are discussed.

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Chinese herbal medicine compound Yi-Zhi-Hao pellet inhibits replication of influenza virus infection through activation of heme oxygenase-1.

Jinqiu YIN ; Linlin MA ; Huiqiang WANG ; Haiyan YAN ; Jin HU ; Wen JIANG ; Yuhuan LI

Acta Pharmaceutica Sinica B.2017;7(6):630-637. doi:10.1016/j.apsb.2017.05.006

As a leading cause of respiratory disease, influenza A virus (IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement for new drugs. Compound Yi-Zhi-Hao pellet (CYZH) is a famous traditional Chinese medicine (TCM) used in the clinic, whose formula has been recorded into treat common cold. In this study, we found that CYZH exhibited a broad-spectrum anti-influenza activity and inhibited the expression of viral RNA and proteins. Mechanistically, CYZH had no inhibitory activities against viral protein hemagglutinin and IAV RNA-dependent RNA polymerase. Instead, it induced activation of erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-B), which subsequently upregulated heme oxygenase-1 (HO-1) expression. Also, CYZH protected cells from oxidative damage induced by reactive oxygen series. In conclusions, CYZH inhibits IAV replication, at least partly by activating expression of the Nrf2/HO-1 pathway.

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Mitochondrial uncoupler triclosan induces vasorelaxation of rat arteries.

Xiyue ZHANG ; Xinzi ZHANG ; Yanqiu ZHANG ; Mingyu LIU ; Jing JIN ; Jie YAN ; Xin SHEN ; Nan HU ; Deli DONG

Acta Pharmaceutica Sinica B.2017;7(6):623-629. doi:10.1016/j.apsb.2017.06.001

Our previous studies found that mitochondrial uncouplers induced vasodilation. Triclosan, the broad spectrum antibacterial agent, is the active ingredient in soaps and toothpastes. It was reported that triclosan induced mitochondrial uncoupling, so we aim to investigate the effects of triclosan on vascular function of rat mesenteric arteries and aorta. The isometric tension of rat mesenteric artery and thoracic aorta was recorded by multi-wire myograph system. The cytosolic [Ca], mitochondrial reactive oxygen species (mitoROS), and mitochondrial membrane potential of smooth muscle cells (A10 cells) were measured using laser scanning confocal microscopy. Triclosan treatment relaxed phenylephrine (PE)- and high K(KPSS)-induced constriction, and pre-treatment with triclosan inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, triclosan also relaxed PE- and KPSS-induced constriction. Triclosan induces vasorelaxation without involving Kchannel activation in smooth muscle cells of arteries. Triclosan treatment increased cytosolic [Ca], mitochondrial ROS production and depolarized mitochondrial membrane potential in A10 cells. In conclusion, triclosan induces mitochondrial uncoupling in vascular smooth muscle cells and relaxes the constricted rat mesenteric arteries and aorta of rats. The present results suggest that triclosan would indicate vasodilation effect if absorbed excessively.

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The current agonists and positive allosteric modulators of7 nAChR for CNS indications in clinical trials.

Taoyi YANG ; Ting XIAO ; Qi SUN ; Kewei WANG

Acta Pharmaceutica Sinica B.2017;7(6):611-622. doi:10.1016/j.apsb.2017.09.001

The alpha-7 nicotinic acetylcholine receptor (7 nAChR), consisting of homomeric7 subunits, is a ligand-gated Ca-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of7 nAChR modulators used in clinical trials.

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Molecular cloning and functional identification of sterol C24-methyltransferase gene from.

Hongyu GUAN ; Yujun ZHAO ; Ping SU ; Yuru TONG ; Yujia LIU ; Tianyuan HU ; Yifeng ZHANG ; Xianan ZHANG ; Jia LI ; Xiaoyi WU ; Luqi HUANG ; Wei GAO

Acta Pharmaceutica Sinica B.2017;7(5):603-609. doi:10.1016/j.apsb.2017.07.001

Sterol C24-methyltransferase (SMT) plays multiple important roles in plant growth and development. SMT1, which belongs to the family of transferases and transforms cycloartenol into 24-methylene cycloartenol, is involved in the biosynthesis of 24-methyl sterols. Here, we report the cloning and characterization of a cDNA encoding a sterol C24-methyltransferase from().(GenBank access number KU885950) is a 1530 bp cDNA with a 1041 bp open reading frame predicted to encode a 346-amino acid, 38.62 kDa protein. The polypeptide encoded by thecDNA was expressed and purified as a recombinant protein from() and showed SMT activity. The expression ofwas highly up-regulated incell suspension cultures treated with methyl jasmonate (MeJA). Tissue expression pattern analysis showed higher expression in the phellem layer compared to the other four organs (leaf, stem, xylem and phloem), which is about ten times that of the lowest expression in leaf. The results are meaningful for the study of sterol biosynthesis ofand will further lay the foundations for the research in regulating both the content of other main compounds and growth and development of

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Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system.

Liqian CI ; Zhigang HUANG ; Yu LIU ; Zhepeng LIU ; Gang WEI ; Weiyue LU

Acta Pharmaceutica Sinica B.2017;7(5):593-602. doi:10.1016/j.apsb.2017.03.002

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-basedhydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitivehydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH-basedhydrogels (NFGs) were evaluated with respect to rheology, drug release,vaginal mucosal adhesion,intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NHis capable of forming a thermosensitivehydrogel with sustained drug release properties. An interaction between positively charged F127-NHand negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin.andfluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-basedhydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.

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extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice.

Xuezhen ZENG ; Xi LI ; Chenshu XU ; Fulin JIANG ; Yufei MO ; Xiaomei FAN ; Yaoting LI ; Yiming JIANG ; Dongshun LI ; Min HUANG ; Huichang BI

Acta Pharmaceutica Sinica B.2017;7(5):583-592. doi:10.1016/j.apsb.2017.04.002

Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ), a preparation of extract fromthat is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.

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