Structure-based lead discovery for protein kinase C zeta inhibitor design by exploiting kinase–inhibitor complex crystal structure data and potential therapeutics for preterm labour

Qing-Chun Shao,Cui-Juan Zhang,Jie Li 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.9

The protein kinase C (PKC) is a family of serine/threonine kinases with a broad range of cellular targets. Members of the PKC family participate at the diverse biologicalevents involved in cellular proliferation, differentiationand survival. The PKCisoformzeta (PKCf) is an atypicalmember that has recently been found to play an essential rolein promoting human uterine contractility and thus been raisedas a new target for treating preterm labour and other tocolyticdiseases. In this study, an integrative protocol was describedto graft hundreds of inhibitor ligands from their complexcrystal structures with cognate kinases into the active pocketof PKCf and, based on the modeled structures, to evaluate thebinding strength of these inhibitors to the non-cognate PKCfreceptor by using a consensus scoring strategy. A total of 32inhibitors with top score were compiled, and eight out of themwere tested for inhibitory potency against PKCf. Consequently,five compounds, i.e. CDK6 inhibitor fisetin, PIM1inhibitor myricetin, CDK9 inhibitor flavopiridol and PknBinhibitor mitoxantrone as well as the promiscuous kinaseinhibitor staurosporine showed high or moderate inhibitoryactivity on PKCf, with IC50 values of 58 ± 9, 1.7 ± 0.4,108 ± 17, 280 ± 47 and 0.019 ± 0.004 lM, respectively,while other three compounds, including two marketed drugsdasatinib and sunitinib as well as the Rho inhibitor fasudil,have not been detected to possess observable activity. Next,based on the modeled structure data we modified three flavonoidkinase inhibitors, i.e. fisetin, myricetin and flavopiridol,to generate a number of more potential molecularentities, two of which were found to have a moderatelyimproved activity as compared to their parent compounds.

The Effects of Ginsenoside Rb1 on JNK in Oxidative Injury in Cardiomyocytes

Chun-Su Yuan,Jing Li,Zuo-Hui Shao,Jing-Tian Xie,Chong-Zhi Wang,Srinivasan Ramachandran,Jun-Jie Yin,Han Aung,Chang-Qing Li,Gina Qin,Terry Vanden Hoek 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.7

Reactive oxygen species (ROS) can induce oxidative injury via iron interactions (i.e. Fenton chemistry and hydroxyl radical formation). Our prior work suggested that American ginseng berry extract and ginsenoside Re were highly cardioprotective against oxidant stress. To extend this study, we evaluated the protective effect of protopanaxadiol-type ginsenoside Rb1 (gRb1)on H2O2-induced oxidative injury in cardiomyocytes and explored the ROS-mediated intracellular signaling mechanism. Cultured embryonic chick cardiomyocytes (4-5 day) were used. Cell death was assessed by propidium iodide and lactate dehydrogenase release. Pretreatment with gRb1 (0.01, 0.1, or 1 μM) for 2 h and concurrent treatment with H2O2 (0.5 mM) for 2 h resulted in a dose-dependent reduction of cell death, 36.6 ± 2.9% (n = 12, p < 0.05), 30.5 ± 5.1% (n = 12, p < 0.05) and 28.6 ± 3.1% (n = 12, p < 0.01) respectively, compared to H2O2-exposed cells (48.2 ± 3.3%, n = 12). This cardioprotective effect of gRb1 was associated with attenuated intracellular ROS generation as measured by 6-carboxy-2’, 7’-dichlorodihydrofluorescein diacetate, preserved the mitochondrial membrane potential as determined using JC-1. In the ESR study, gRb1 exhibited the scavenging DPPH and hydroxyl radical activities. Furthermore, our data showed the increased JNK phosphorylation (p-JNK) in H2O2-exposed cells was suppressed by the pretreatment with gRb 1 (1 μM) (p < 0.01). Co-treatment of gRb1 with a specific inhibitor of JNK SP600125 (10 μM) further reduced the p-JNK and enhanced the cell survival after H2O2exposure. Collectively, our results suggest that gRb1 conferred cardioprotection that was mediated via attenuating ROS and suppressing ROS-induced JNK activation.

Human Papillomavirus Vaccine Awareness, Acceptability, and Decision-Making Factors among Chinese College Students

Wang, Shao-Ming,Zhang, Shao-Kai,Pan, Xiong-Fei,Ren, Ze-Fang,Yang, Chun-Xia,Wang, Zeng-Zhen,Gao, Xiao-Hong,Li, Man,Zheng, Quan-Qing,Ma, Wei,Zhao, Fang-Hui,Qiao, You-Lin,Sivasubramaniam, Priya Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.7

Background: College students are recommended as the target groups for catch-up human papillomavirus (HPV) vaccination. Systematical exploration of awareness, acceptability, and decision-making factors of HPV vaccination among Chinese college students has been limited. Materials and Methods: A multi-center survey was conducted in mainland China between November 2011 and May 2012. College students aged 18-22 years were stratified by their grade, gender, and major for sampling. Socio-demographic and HPV-related information such as knowledge, perceptions, acceptability, and attitudes were collected through a questionnaire. Results: A total of 3,497 undergraduates completed the questionnaire, among which 1,686 were males. The acceptability of the HPV vaccine was high (70.8%). Undergraduates from high-level universities, at lower grade, or with greater prior knowledge of HPV vaccines showed higher acceptability of HPV vaccination ($p_{trend}$ <0.001). Additionally, undergraduates with vaccination experience outside the National Expanded Program on Immunization (OR=1.29; 95%CI: 1.10-1.51) or fear of HPV-related diseases (OR=2.79; 95%CI: 2.28-3.41) were more willing to accept HPV vaccination. General knowledge of HPV vaccine was low among undergraduates, and safety was a major concern (71.05%). The majority of students wished to pay less than 300RMB for HPV vaccine and chose the Chinese Center for Disease Control and Prevention as the most appropriate venue for vaccination. Conclusions: Although most undergraduates demonstrate positive attitudes towards HPV vaccination, challenges pertaining to introduction exist in China. Corresponding proactive education and governmental subsidy to do so are urgently needed by this age-group population. Suggestions and potential strategies indicated may help shape the future HPV vaccination program in China.

Growth and Differentiation Effects of Homer3 on a Leukemia Cell Line

Li, Zheng,Qiu, Hui-Ying,Jiao, Yang,Cen, Jian-Nong,Fu, Chun-Mei,Hu, Shao-Yan,Zhu, Ming-Qing,Wu, De-Pei,Qi, Xiao-Fei Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.4

The Homer protein family, also known as the family of cytoplasmic scaffolding proteins, which include three subtypes (Homer1, Homer2, Homer3). Homer3 can regulate transcription and play a very important role in the differentiation and development for some tissues (e.g. muscle and nervous systems). The current studies showed that Homer3 abnormal expression changes in acute myeloid leukemia (AML). Forced expression of Homer3 in transfected K562 cells inhibited proliferation, influenced the cell cycle profile, affected apoptosis induced by $As_2O_3$ through inhibition of Bcl2 expression, and also promoted cell differentiation induced by 12-O-tetra decanoylphorbol-acetate (TPA). These results showed that Homer3 is a novel gene which plays a certain role in the occurrence and development of AML.

Molecular and Cellular Microbiology / Biomedical Sciences : Surface-Displayed IL-10 by Recombinant Lactobacillus plantarum Reduces Th1 Responses of RAW264.7 Cells Stimulated with Poly(I:C) or LPS

( Ruo Peng Cai ),( Yan Long Jiang ),( Wei Yang ),( Wen Tao Yang ),( Shao Hua Shi ),( Chun Wei Shi ),( Jing Tao Hu ),( Wei Gu ),( Li Ping Ye ),( Fang Yu Zhou ),( Qing Long Gong ),( Wen Yu Han ),( Guil 한국미생물 · 생명공학회 2016 Journal of microbiology and biotechnology Vol.26 No.2

Recently, poly-γ-glutamic acid synthetase A (pgsA) has been applied to display exogenous proteins on the surface of Lactobacillus casei or Lactococcus lactis, which results in a surfacedisplayed component of bacteria. However, the ability of carrying genes encoded by plasmids and the expression efficiency of recombinant bacteria can be somewhat affected by the longer gene length of pgsA (1,143 bp); therefore, a truncated gene, pgsA, was generated based on the characteristics of pgsA by computational analysis. Using murine IL-10 as an exogenous gene, recombinant Lactobacillus plantarum was constructed and the capacity of the surface-displayed protein and functional differences between exogenous proteins expressed by these strains were evaluated. Surface expression of IL-10 on both recombinant bacteria with anchorins and the higher expression levels in L. plantarum-pgsA’-IL-10 were confirmed by western blot assay. Most importantly, up-regulation of IL-1β, IL-6, TNF-α, IFN-γ, and the nuclear transcription factor NF-κB p65 in RAW264.7 cells after stimulation with Poly(I:C) or LPS was exacerbated after co-culture with L. plantarum-pgsA. By contrast, IL-10 expressed by these recombinant strains could reduce these factors, and the expression of these factors was associated with recombinant strains that expressed anchorin (especially in L. plantarum-pgsA’-IL-10) and was significantly lower compared with the anchorin-free strains. These findings indicated that exogenous proteins could be successfully displayed on the surface of L. plantarum by pgsA or pgsA’, and the expression of recombinant bacteria with pgsA’ was superior compared with bacteria with pgsA.