title: Inhibition of Helicobacter pylori and Its Associated Urease by Palmatine: Investigation on the Potential Mechanism.
abstract: In this paper, we evaluated the anti-Helicobacter pylori activity and the possible inhibitory effect on its associated urease by Palmatine (Pal) from Coptis chinensis, and explored the potential underlying mechanism. Results indicated that Pal exerted inhibitory effect on four tested H. pylori strains (ATCC 43504, NCTC 26695, SS1 and ICDC 111001) by the agar dilution test with minimum inhibitory concentration (MIC) values ranging from 100 to 200 μg/mL under neutral environment (pH 7.4), and from 75 to 100 μg/mL under acidic conditions (pH 5.3), respectively. Pal was observed to significantly inhibit both H. pylori urease (HPU) and jack bean urease (JBU) in a dose-dependent manner, with IC50 values of 0.53 ± 0.01 mM and 0.03 ± 0.00 mM, respectively, as compared with acetohydroxamic acid, a well-known urease inhibitor (0.07 ± 0.01 mM for HPU and 0.02 ± 0.00 mM for JBU, respectively). Kinetic analyses showed that the type of urease inhibition by Pal was noncompetitive for both HPU and JBU. Higher effectiveness of thiol protectors against urease inhibition than the competitive Ni2+ binding inhibitors was observed, indicating the essential role of the active-site sulfhydryl group in the urease inhibition by Pal. DTT reactivation assay indicated that the inhibition on the two ureases was reversible, further supporting that sulfhydryl group should be obligatory for urease inhibition by Pal. Furthermore, molecular docking study indicated that Pal interacted with the important sulfhydryl groups and inhibited the active enzymatic conformation through N-H ∙ π interaction, but did not interact with the active site Ni2+. Taken together, Pal was an effective inhibitor of H. pylori and its urease targeting the sulfhydryl groups, representing a promising candidate as novel urease inhibitor. This investigation also gave additional scientific support to the use of C. chinensis to treat H. pylori-related gastrointestinal diseases in traditional Chinese medicine. Pal might be a potentially beneficial therapy for gastritis and peptic ulcers induced by H. pylori infection and other urease-related diseases.
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Jiang-Tao
authors.initials: JT
authors.lastname: Zhou
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Cai-Lan
authors.initials: CL
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Tan
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Zhi-Zhun
authors.initials: ZZ
authors.lastname: Mo
authors.affiliation: The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Yao-Xing
authors.initials: YX
authors.lastname: Dou
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Zi-Ren
authors.initials: ZR
authors.lastname: Su
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Xie
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000494:pharmacology*; D020134:Catalytic Domain; D039323:Coptis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D016481:Helicobacter Infections / Q000188:drug therapy; D016480:Helicobacter pylori / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009532:Nickel / Q000737:chemistry; D010936:Plant Extracts / Q000378:metabolism; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014510:Urease / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001600:Berberine Alkaloids; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D013438:Sulfhydryl Compounds; D009532:Nickel; D014510:Urease; C005413:palmatine