Title: A network pharmacology-based approach to explore the therapeutic potential of Sceletium tortuosum in the treatment of neurodegenerative disorders Luo Y, Shan L, Xu L, Patnala S, Kanfer I, Li J, Yu P, Jun X Ref: PLoS ONE, 17:e0273583, 2022 : PubMed
Sceletium tortuosum (SCT) has been utilized medicinally by indigenous Koi-San people purportedly for mood elevation. SCT extracts are reported to be neuroprotective and have efficacy in improving cognition. However, it is still unclear which of the pharmacological mechanisms of SCT contribute to the therapeutic potential for neurodegenerative disorders. Hence, this study investigated two aspects-firstly, the abilities of neuroprotective sub-fractions from SCT on scavenging radicals, inhibiting some usual targets relevant to Alzheimer's disease (AD) or Parkinson's disease (PD), and secondly utilizing the network pharmacology related methods to search probable mechanisms using Surflex-Dock program to show the key targets and corresponding SCT constituents. The results indicated sub-fractions from SCT could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, inhibit acetylcholinesterase (AChE), monoamine oxidase type B (MAO-B) and N-methyl-D-aspartic acid receptor (NMDAR). Furthermore, the results of gene ontology and docking analyses indicated the key targets involved in the probable treatment of AD or PD might be AChE, MAO-B, NMDAR subunit2B (GluN2B-NMDAR), adenosine A2A receptor and cannabinoid receptor 2, and the corresponding constituents in Sceletium tortuosum might be N-trans-feruloyl-3-methyldopamine, dihydrojoubertiamine and other mesembrine type alkaloids. In summary, this study has provided new evidence for the therapeutic potential of SCT in the treatment of AD or PD, as well as the key targets and notable constituents in SCT. Therefore, we propose SCT could be a natural chemical resource for lead compounds in the treatment of neurodegenerative disorders.
Title: Pharmacokinetic and Metabolic Studies of ADTM: A Novel Danshensu Derivative Confers Cardioprotection by HPLC-UV and LC-MS/MS Li S, Shan L, Zhang Z, Li W, Liao K, Sheng X, Yu P, Wang Y Ref: Journal of Chromatography Sci, 53:872, 2015 : PubMed
(R)-(3,5,6-Trimethylpyrazinyl) methyl-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (ADTM) is a novel Danshensu (DSS) derivative regarded as a potential new agent for the treatment of myocardial ischemia. A validated high performance liquid chromatography (HPLC) approach with a detection limit of 5 ng/mL was used for pharmacokinetic evaluation of ADTM in rat plasma. The intra- and interday precision in terms of relative standard deviation were <4.98 and 4.84%, respectively, at concentration levels of 0.02, 0.20 and 0.80 microg/mL. ADTM's absolute oral bioavailability value was 30.4% and t1/2 was 34.33 +/- 11.51 and 29.94 +/- 8.19 min after oral and intravenous administration of 20 mg/kg. In addition, the major metabolites both in vitro and in vivo were 2-hydroxymethy-3,5,6-trimethylpyrazin and DSS. The results indicated that the hydrolysis was the main metabolic pathway of ADTM, and carboxylesterase may play an important role in ADTM's metabolism. The present work provides basic information for ADTM's further preclinical research and DSS's chemical structure modification.
Title: The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms Shan L, Yu XC, Liu Z, Hu Y, Sturgis LT, Miranda ML, Liu Q Ref: Journal of Biological Chemistry, 284:1419, 2009 : PubMed
Two members of the angiopoietin-like family of proteins, ANGPTL3 and ANGPTL4, have been shown to play important roles in modulating lipoprotein metabolism in the body. Both proteins were found to suppress lipoprotein lipase (LPL) activity in vitro as well as in vivo. However, their mechanisms of inhibition remained poorly understood. Using enzyme kinetic analysis with purified recombinant proteins, we have found key mechanistic differences between ANGPTL3 and ANGPTL4. ANGPTL3 reduced LPL catalytic activity but did not significantly alter its self-inactivation rate. In contrast, ANGPTL4 suppressed LPL by accelerating the irreversible inactivation of LPL. Furthermore, heparin was able to overcome the inhibitory effect of ANGPTL3 on LPL but not that of ANGPTL4. Site-directed mutagenesis demonstrated the critical function of Glu(40) in ANGPTL4. In contrast, when cysteine residues involved in disulfide bond formation were mutated to serines, ANGPTL4 retained its activity. Taken together, our data provide a more detailed view of the structure and mechanisms of these proteins. The finding that ANGPTL3 and ANGPTL4 inhibit LPL activity through distinct mechanisms indicates that the two proteins play unique roles in modulation of lipid metabolism in vivo.
Title: The effect of ultrasound on lipase-catalyzed hydrolysis of soy oil in solvent-free system Liu Y, Jin Q, Shan L, Shen W, Wang X Ref: Ultrason Sonochem, 15:402, 2008 : PubMed
Comparative studies of lipase-catalyzed hydrolysis of soy oil in solvent-free system were carried out in shaking bath and in ultrasonic bath. A suitable ultrasonic power of 1.64 W cm(-2) was determined to guarantee satisfactory hydrolysis extent and lipase activity. The influence of temperature, pH, enzyme concentration and water/oil ratio was investigated subsequently. Compared with that in shaking bath, optimum temperature and inactivation temperature of lipase in ultrasonic bath were about 5-10 degrees C higher, while pH effect in ultrasonic bath was similar; ultrasound also led to a smooth increase of reaction rate at relatively higher enzyme loading and less use of water to saturate hydrolysis substrate. In optimum conditions, the overall hydrolysis reaction rate in the ultrasonic bath process was above 2-fold than that in the shaking bath process.
Title: Solvent-free synthesis of glyceryl ferulate using a commercial microbial lipase Sun S, Shan L, Jin Q, Liu Y, Wang X Ref: Biotechnol Lett, 29:945, 2007 : PubMed
A process was optimized for the enzymatic synthesis of glyceryl ferulate with a yield of up to 96% using a vacuum-rotary evaporation strategy under following conditions: 15 mmol glycerol, 1.5 mmol ethyl ferulate, 170 mg Candida antarctica lipase, at 60 degrees C for 10 h and under a vacuum of 10 mm Hg. The immobilized lipase can be used 10 times.
Title: Structural and mechanistic analysis of two prolyl endopeptidases: role of interdomain dynamics in catalysis and specificity Shan L, Mathews, II, Khosla C Ref: Proc Natl Acad Sci U S A, 102:3599, 2005 : PubMed
Prolyl endopeptidases (PEPs) are a unique class of serine proteases with considerable therapeutic potential for the treatment of celiac sprue. The crystal structures of two didomain PEPs have been solved in alternative configurations, thereby providing insights into the mode of action of these enzymes. The structure of the Sphingomonas capsulata PEP, solved and refined to 1.8-A resolution, revealed an open configuration of the active site. In contrast, the inhibitor-bound PEP from Myxococcus xanthus was crystallized (1.5-A resolution) in a closed form. Comparative analysis of the two structures highlights a critical role for the domain interface in regulating interdomain dynamics and substrate specificity. Structure-based mutagenesis of the M. xanthus PEP confirms an important role for several interfacial residues. A salt bridge between Arg-572 and Asp-196/Glu-197 appears to act as a latch for opening or closing the didomain enzyme, and Arg-572 and Ile-575 may also help secure the incoming peptide substrate to the open form of the enzyme. Arg-618 and Asp-145 are responsible for anchoring the invariant proline residue in the active site of this postproline-cleaving enzyme. A model is proposed for the docking of a representative substrate PQPQLPYPQPQLP in the active site, where the N-terminal substrate residues interact extensively with the catalytic domain, and the C-terminal residues stretch into the propeller domain. Given the promise of the M. xanthus PEP as an oral therapeutic enzyme for treating celiac sprue, our results provide a strong foundation for further optimization of the PEP's clinically useful features.
