Publications by authors named "Hongbin Sun"

215 Publications

Structural Basis of VSIG3: The Ligand for VISTA.

Front Immunol 2021 25;12:625808. Epub 2021 Mar 25.

New Drug Screening Center, China Pharmaceutical University, Nanjing, China.

B7 family members and their receptors play key roles in regulating T cell responses, and constitute very attractive targets for developing immunotherapeutic drugs. V-Set and Immunoglobulin domain containing 3 (VSIG3), a ligand for the novel B7 family immune checkpoint V-domain immunoglobulin suppressor of T cell activation (VISTA), can significantly inhibit T cell functions. Inhibitors targeting the VISTA/VSIG3 pathway are of great significance in tumor immunology. Here, we show the crystal structure of the extracellular domain (ECD) of the human VSIG3 protein at 2.64 angstrom resolution, and we produce recombinant human VSIG-3 ECD in both CHO cells and . Furthermore, we demonstrated the interaction of VISTA and VSIG3 by coimmunoprecipitation (Co-IP). Based on protein-protein docking for VISTA and VSIG3, we report a small molecule inhibitor of VSIG3 K284-3046 and evaluate its biological activities . This study was the first to reveal the crystal structure of VSIG3, and provides the structural basis for designing antibodies or compounds for the unique VSIG3/VISTA coinhibitory pathway in the treatment of cancers, autoimmune diseases and may be beneficial of designing vaccines.
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http://dx.doi.org/10.3389/fimmu.2021.625808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027081PMC
March 2021

Depression in patients with epilepsy during the COVID-19 pandemic based on longitudinal self-reporting.

Epileptic Disord 2021 Apr 9. Epub 2021 Apr 9.

Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Department of Neurology, Chengdu, Sichuan, China; University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

The current study screened major depression in people with epilepsy (PWE) during the epidemic of the novel coronavirus-related disease COVID-19, in order to identify whether the outbreak generated negative psychological impact on PWE. A Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E), a self-reporting depression inventory, was applied for rapid detection of major depression. Assessment was carried out online during three different periods (prior to, during, and after the outbreak of COVID-19), with the aim of identifying changes in prevalence of depression and associated risk factors. A total of 158 PWE were recruited into the study (48.7% female). The questionnaire completion rates were 94.3% and 70.9% during and after the outbreak, respectively. The prevalence of depression prior to the epidemic, as the baseline, was 34.8% and increased to 42.3% during the period of the epidemic. Towards the end of the outbreak, the prevalence declined towards the baseline (36.6%). Factors such as living alone (OR = 4.022, 95% CI: 1.158-13.971, P = 0.028) and active seizures before the epidemic (OR = 2.993, 95% CI: 1.197-7.486, P = 0.019) were associated with depression during the epidemic. Monotherapy appeared to be protective against depression (OR = 0. 105, 95% CI: 0.047-0.235, P <0.001). Our results suggest that the pandemic exerts negative influence on PWE's mental health. Depression is one of the common psychological disorders that needs greater attention during this extraordinary period.
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http://dx.doi.org/10.1684/epd.2021.1263DOI Listing
April 2021

Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2-]indoles.

J Org Chem 2021 Mar 29. Epub 2021 Mar 29.

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.
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http://dx.doi.org/10.1021/acs.joc.1c00010DOI Listing
March 2021

Novel core-shell nanocomposite as an effective heterogeneous catalyst for synthesis of benzimidazoles.

Nanotechnology 2021 Mar 16. Epub 2021 Mar 16.

Jiangxi Key Laboratory of Surface Engineering, Jiangxi Science and Technology Normal University, Nanchang, Jiangxi, CHINA.

The core-shell nanocomposite with catalytic metal-organic framework (MOF) shell is more effective and stable than bare MOF. We have successfully designed an effective heterogeneous catalyst for the synthesis of benzimidazole by integrating acidic catalytic activity, promoted aerobic oxidation and magnetic recyclability into core-shell nanocomposite Fe3O4@SiO2@UiO-66. Fe3O4@SiO2 core is encapsulated by the in-situ growing UiO-66 shell, and the UiO-66 shell retains the porous structure and crystallinity of UiO-66 with abundant exposed Lewis acid sites, which shows high catalytic ability for the synthesis of various benzimidazole through the acid-catalyzed condensation and aerobic oxidation with in-situ oxygen. The Fe3O4@SiO2 core provides magnetic recyclability of Fe3O4@SiO2@UiO-66, which maintains high catalytic ability and stability for 6 cycles.
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http://dx.doi.org/10.1088/1361-6528/abef2fDOI Listing
March 2021

Corrigendum to "Protective Effects of Pretreatment with Oleanolic Acid in Rats in the Acute Phase of Hepatic Ischemia-Reperfusion Injury: Role of the PI3K/Akt Pathway".

Mediators Inflamm 2020 28;2020:9649787. Epub 2020 Nov 28.

Department of Anesthesiology and Perioperative Medicine, 1st Affiliated Hospital, Nanjing Medical University, Nanjing, China.

[This corrects the article DOI: 10.1155/2014/451826.].
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http://dx.doi.org/10.1155/2020/9649787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735821PMC
November 2020

miR-224, miR-147b and miR-31 associated with lymph node metastasis and prognosis for lung adenocarcinoma by regulating PRPF4B, WDR82 or NR3C2.

PeerJ 2020 24;8:e9704. Epub 2020 Nov 24.

Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Jilin, China.

Background: The present study is to screen lymph node metastasis-related microRNAs (miRNAs) in lung adenocarcinoma (LUAD) and uncover their underlying mechanisms.

Methods: The miRNA microarray dataset was collected from the Gene Expression Omnibus database under accession number GSE64859. The differentially expressed miRNAs (DEMs) were identified using a t-test. Target genes of DEMs were predicted through the miRWalk2.0 database. The function of these target genes was annotated with the clusterProfiler and the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools. Protein-protein interaction network was established using the STRING database to extract hub target genes. The expressions and associations with survival and lymph node metastasis of miRNAs and target genes were validated by analysis of The Cancer Genome Atlas (TCGA) dataset.

Results: Eight DEMs were identified between lymph node metastasis and non-metastasis samples of GSE64859 dataset. miRNA-target gene pairs were predicted between six DEMs and 251 target genes (i.e. hsa-miR-224-PRPF4B, hsa-miR-147b-WDR82 and hsa-miR-31-NR3C2). The clusterProfiler analysis showed WDR82 was involved in the mRNA surveillance pathway, while the GO enrichment analysis using the DAVID database indicated PRPF4B participated in the protein phosphorylation and NR3C2 was related with the transcription, DNA-templated. WDR82 and PRPF4B may be hub genes because they could interact with others. Two DEMs (miR-31-5p and miR-31-3p) and 45 target genes (including PRPF4B and NR3C2) were significantly associated with overall survival. The expressions of miR-224 and miR-147b were validated to be upregulated, while WDR82, PRPF4B and NR3C2 were downregulated in lymph node metastasis samples of TCGA datasets compared with non-metastasis samples. Also, there were significantly negative expression correlations between miR-147b and WDR82, between miR-224 and PRPF4B, as well as between miR-31 and NR3C2 in LUAD samples.

Conclusions: The present study identified several crucial miRNA-mRNA interaction pairs, which may provide novel explanations for the lymph node metastasis and poor prognosis for LUAD patients.
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http://dx.doi.org/10.7717/peerj.9704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694553PMC
November 2020

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy.

Sci Transl Med 2020 11;12(571)

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China.

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8 T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.
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http://dx.doi.org/10.1126/scitranslmed.aaz6667DOI Listing
November 2020

Epilepsy management during epidemic: A preliminary observation from western China.

Epilepsy Behav 2020 12 22;113:107528. Epub 2020 Nov 22.

Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Medical Administration Department, Chengdu 610072, China. Electronic address:

Objective: This study aimed to investigate whether the proposed model could manage patients with epilepsy (PWEs) during the coronavirus disease 2019 (COVID-19) outbreak.

Methods: We used a model to manage the PWEs during the outbreak. Questionnaire survey and hospital data were used to explore whether PWEs under our management were affected by the virus.

Results: A total of 118 (78.7%) PWEs completed the survey. During the "model period," 22.9% (27/118) of the respondents reported antiepileptic drug (AEDs) discontinuity, including six (22.2%) PWEs who failed to purchase AEDs. Of the patients, 40.7% (22/54) failed to attend ordinary clinic, which was higher than that during the "period before model" (7.9%, 5/63). The common causes were movement limits (77.3%) and appointment failure (54.5%). A shift from ordinary clinic toward remote consultation was observed. Of the PWEs, 15.7% (13/83) referred to online pharmacy. 87.5% (14/16) of emergencies related to epilepsy were timely treated. 48.3%of PWEs thought that the epidemic had an impact on accessing medical services. Hospital data indicated that a decline in ordinary clinic visit, inpatient, surgery, and emergency attendance was observed in January and February 2020 and an increase in March 2020, as the epidemic mitigated. By contrast, online clinic visit soared in February, when the outbreak hit hard. In addition, we found no cross-infection of COVID-19 in our hospital and respondents.

Conclusion: We demonstrated a much-needed model to manage the PWEs during the outbreak. We believed that the core architecture of this model was suitable for the management of other chronic diseases.
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http://dx.doi.org/10.1016/j.yebeh.2020.107528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680647PMC
December 2020

Developing a Novel Gold(III) Agent to Treat Glioma Based on the Unique Properties of Apoferritin Nanoparticles: Inducing Lethal Autophagy and Apoptosis.

J Med Chem 2020 11 13;63(22):13695-13708. Epub 2020 Nov 13.

State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University, Guilin, Guangxi 541003, China.

Effective delivery of anticancer agents across the blood-brain barrier (BBB) required innovative strategies to achieve glioma regression. To resolve this problem, we proposed to develop a metal agent that target and treat glioma based on the unique property of apoferritin (AFt) nanoparticles (NPs). Thus, we synthesized a series of Au(III) 3-(4-metyl piperidine)thiosemicarbazides compounds and analyzed their structure-activity relationships, obtaining a Au agent (C6) with remarkable cytotoxicity in glioma. Moreover, we confirmed that C6 kills glioma cells by inducing lethal autophagy and apoptosis. Importantly, our results revealed that the successfully constructed apoferritin-C6 NPs (AFt-C6 NPs) can effectively cross the BBB, inhibit glioma growth, and selectively accumulate in tumors.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01257DOI Listing
November 2020

Synthesis and anti-inflammatory activity of saponin derivatives of δ-oleanolic acid.

Eur J Med Chem 2021 Jan 14;209:112932. Epub 2020 Oct 14.

Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin, 541004, China. Electronic address:

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.
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http://dx.doi.org/10.1016/j.ejmech.2020.112932DOI Listing
January 2021

Abnormal neurite orientation dispersion and density imaging of white matter in children with primary nocturnal enuresis.

Neuroimage Clin 2020 20;28:102389. Epub 2020 Aug 20.

Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Several lines of evidence indicate that multiple abnormalities of gray matter are related to the pathogenesis of primary nocturnal enuresis (PNE); however, few studies have been conducted with respect to abnormalities in white matter (WM) of children with PNE. The present work investigated the microstructure of WM in children with PNE using a neurite orientation dispersion and density imaging (NODDI) method. NODDI data were obtained from 29 children with PNE (age = 9.8 ± 1.2 years, 59% males) and 34 healthy controls (age = 10.3 ± 1.6 years, 56% males) in this study. Multi-b-value diffusion-weighted imaging data were acquired with a 3 T MR system, and the orientation dispersion index (ODI) and neurite density index (NDI) maps were calculated. Tract-Based Spatial Statistics analyses of WM tracts were performed with ODI and NDI maps in children with PNE and controls. Children with PNE had lower ODIs in WM fiber tracts of the bilateral superior longitudinal fasciculus (SLF) and higher ODIs in the bilateral internal capsule (IC) and right anterior thalamic radiation (ATR) than controls. PNE children also had lower NDIs in the bilateral IC and the cingulum and higher NDIs in the bilateral SLF. These changes in NODDI indices, which indicated abnormal neural maturation of the WM microstructures, may be related to abnormal sleep and enuresis in children with PNE.
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http://dx.doi.org/10.1016/j.nicl.2020.102389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490590PMC
August 2020

68Ga-PSMA-11 PET/CT combining ADC value of MRI in the diagnosis of naive prostate cancer: Perspective of radiologist.

Medicine (Baltimore) 2020 Sep;99(36):e20755

Department of Nuclear Medicine.

Ga-PSMA-11 positron emission computed tomography /computed tomography (PET/CT) is more sensitive than magnetic resonance imaging (MRI) in detecting prostate cancer (PCa). We evaluated the value of Ga-PSMA-11 PET/CT with MRI in treatment-naive PCa.This retrospective study was approved by the hospital ethics committee. The MRI and Ga-PSMA-11 PET/CT imaging data of 63 cases of highly suspected PCa were enrolled in this study. The SUVmax and apparent diffusion coefficient (ADC), and their ratio, were assessed as diagnostic markers to distinguish PCa from benign disease.There were 107 prostate lesions detected in 63 cases. Forty cases with 64 malignant primary lesions were confirmed PCa, whereas 23 cases had 43 benign lesions. PSMA-avid lesions correlated with hypointense signal on ADC maps and hyperintense signal on diffusion-weighted imaging. The ADC of PCa was lower than that of benign lesions, and SUVmax and SUVmax/ADC of PCa was higher than that of benign lesions (P < .01). ADC had significant negative correlation with Gleason score (GS) and SUVmax, SUVmax, and SUVmax/ADC positively correlated with GS. From ROC analysis, we established cutoff values of ADC, SUVmax, and SUVmax/ADC at 1.02 × 10mm/s, 11.72, and 12.35, respectively, to differentiate PCa from benign lesions. The sensitivity, specificity, and AUC were 90.6%, 58.1%, and 0.816 for ADC, 67.2%, 97.7%, and 0.905 for SUVmax, and 81.2%, 88.4%, and 0.929 for SUVmax/ADC, respectively.Ga-PSMA-11 PET/CT combined with MRI offers higher diagnostic efficacy in the detection of PCa than either modality alone.
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http://dx.doi.org/10.1097/MD.0000000000020755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478544PMC
September 2020

Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice.

CNS Neurosci Ther 2021 Feb 30;27(2):220-232. Epub 2020 Aug 30.

Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute, School of Medicine, Southeast University, Nanjing, China.

Introduction: The two-pore domain potassium channel TREK-1 is a member of background K channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of TREK-1 in the action of antidepressants, and its antagonists might be potentially effective antidepressants. However, the mechanisms underlying the actions of TREK-1 are not yet fully understood.

Methods: The expression of TREK-1 was examined in a mouse model of chronic unpredictable mild stress (CUMS) using immunoblotting. Neuron-specific genetic manipulation of TREK-1 was performed through adeno-associated virus. Behavioral tests were performed to evaluate depression-related behaviors. Electrophysiological recordings were used to evaluate synaptic plasticity. Golgi staining was used to examine neuroplasticity.

Results: TREK-1 expression was increased in the mouse hippocampus after CUMS. Knockdown of TREK-1 in hippocampal neurons significantly attenuated depressive-like behaviors and prevented the decrease of CUMS-induced synaptic proteins in mice. Further examination indicated that neuron-specific knockdown of TREK-1 in the hippocampus prevented stress-induced impairment of glutamatergic synaptic transmission in the CA1 region. Moreover, chronic TREK-1 inhibition protected against CUMS-induced depressive-like behaviors and impairment of synaptogenesis in the hippocampus.

Conclusion: Our results indicate a role for TREK-1 in the modulation of synaptic plasticity in a mouse model of depression. These findings will provide insight into the pathological mechanism of depression and further evidence for a novel target for antidepressant treatment.
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http://dx.doi.org/10.1111/cns.13450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816204PMC
February 2021

Metabolism-Associated Molecular Patterns (MAMPs).

Trends Endocrinol Metab 2020 10 14;31(10):712-724. Epub 2020 Aug 14.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Zhuji Biomedical Institute, School of Pharmaceutical Sciences, Wenzhou Medical University, Zhuji, Zhejiang 311800, China. Electronic address:

Metabolic diseases pose a tremendous health threat in both developed and developing countries. The pathophysiology of metabolic diseases is complex but has been shown to be closely associated with sterile inflammation, which is initiated by various danger molecules derived from metabolic overload, such as oxidized low-density lipoproteins (OxLDLs), free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), and cholesterol. These danger signals are sensed by pattern recognition receptors (PRRs) to activate proinflammatory signaling pathways and promote the release of proinflammatory mediators, leading to chronic low-grade inflammation. Although these harmful metabolic stimuli are generally regarded as damage-associated molecular patterns (DAMPs), a more specific definition and accurate classification for these DAMPs is still missing. In this opinion, we classify the harmful metabolic stimuli that can incite inflammatory responses and tissue damage via instigating PRRs as metabolism-associated molecular patterns (MAMPs), and we summarize their roles in metaflammation-mediated metabolic diseases.
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http://dx.doi.org/10.1016/j.tem.2020.07.001DOI Listing
October 2020

Automatic Generation Control Based on Multiple Neural Networks With Actor-Critic Strategy.

IEEE Trans Neural Netw Learn Syst 2020 Jul 14;PP. Epub 2020 Jul 14.

As the conventional automatic generation control (AGC) is inadequate to deal with the strong random disturbance issues induced by the ever-increasing penetration of renewable energy to the power grids, this article proposes a deep-reinforcement-learning-based three-network double-delay actor-critic (TDAC) control strategy for AGC to handle the above problem, which is mainly developed by multiple neural networks to fit the system action strategies and evaluate the value. The proposed strategy can increase the exploration efficiency and the quality of AGC and improve the system control performance using the modified actor-critic (AC) method with incentive heuristic mechanism, while a novel iterative way of the value function is also used to reduce the bias of optimization effectively for achieving optimal coordinated control of the power grid. The simulations are provided in the work to show the control performance of the strategy. Compared with other smart methods, the simulation study demonstrates that TDAC has excellent exploratory stability and learning ability. Meanwhile, it also can improve the dynamic performance of the power system and achieve the regional optimal coordinated control.
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http://dx.doi.org/10.1109/TNNLS.2020.3006080DOI Listing
July 2020

Characterization of an alternative BAK-binding site for BH3 peptides.

Nat Commun 2020 07 3;11(1):3301. Epub 2020 Jul 3.

Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.

Many cellular stresses are transduced into apoptotic signals through modification or up-regulation of the BH3-only subfamily of BCL2 proteins. Through direct or indirect mechanisms, these proteins activate BAK and BAX to permeabilize the mitochondrial outer membrane. While the BH3-only proteins BIM, PUMA, and tBID have been confirmed to directly activate BAK through its canonical BH3 binding groove, whether the BH3-only proteins BMF, HRK or BIK can directly activate BAK is less clear. Here we show that BMF and HRK bind and directly activate BAK. Through NMR studies, site-directed mutagenesis, and advanced molecular dynamics simulations, we also find that BAK activation by BMF and possibly HRK involves a previously unrecognized binding groove formed by BAK α4, α6, and α7 helices. Alterations in this groove decrease the ability of BMF and HRK to bind BAK, permeabilize membranes and induce apoptosis, suggesting a potential role for this BH3-binding site in BAK activation.
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http://dx.doi.org/10.1038/s41467-020-17074-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335050PMC
July 2020

N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies.

Eur J Med Chem 2020 Aug 5;199:112279. Epub 2020 May 5.

Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC = 40.8 nM, K = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC = 29.6 nM) and RS4; 11 (IC = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2020.112279DOI Listing
August 2020

Nontechnical Losses Detection Through Coordinated BiWGAN and SVDD.

IEEE Trans Neural Netw Learn Syst 2020 Jun 4;PP. Epub 2020 Jun 4.

Nontechnical losses (NTLs) are estimated to be considerable and increasing every year. Recently, high-resolution measurements from globally laid smart meters have brought deeper insights on users' consumption patterns that can be exploited potentially by NTL detection. However, consumption-pattern-based NTL detection is now facing two major challenges: the inefficiency of harnessing high dimensionality and the severe lack of fraudulent samples. To overcome them, an NTL detection model based on deep learning and anomaly detection is proposed in this article, namely bidirectional Wasserstein GAN and support vector data description-based NTL detector (BSBND). Motivated by the powerful ability of generative adversarial networks (GANs) to learn deep representation from high-dimensional distributions of data, in the BSBND, we utilized a BiWGAN for feature extraction from high-dimensional raw consumption records, and a one-class classifier trained only on benign samples--SVDD--is adopted to map features into judgments. Moreover, a novel alternate coordinating algorithm is proposed to optimize the cooperation between the upstream BiWGAN and the downstream SVDD, and also, an interpreting algorithm is proposed to visualize the basis of each fraudulent judgment. Case studies have demonstrated the superiority of the BSBND over the state of the arts, the powerful feature extraction ability of BiWGAN, and also the effectiveness of the proposed coordinating and interpreting algorithms.
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http://dx.doi.org/10.1109/TNNLS.2020.2994116DOI Listing
June 2020

In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing.

J Chem Inf Model 2020 06 9;60(6):3265-3276. Epub 2020 Jun 9.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Cyclic GMP-AMP synthase (cGAS) has been recently uncovered to be a promising therapeutic target for immune-associated diseases. Until now, only a few inhibitors have been identified through high-throughput screening campaigns. Here, we reported the discovery of novel inhibitors for the catalytic domain of human cGAS (h-cGAS) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGAS in complex with PF-06928215, a known inhibitor of h-cGAS, followed by molecular dynamics simulations on this complex structure. Four fragment hits were identified by the virtual screening together with a thermal shift assay. The crystal structures of these four compounds in complex with h-cGAS were subsequently determined, and the binding modes of the compounds were similar to those predicted by molecular docking, supporting the reliability of the docking model. In addition, an enzyme activity assay identified compound (IC = 29.88 ± 3.20 μM) from the compounds predicted by the virtual screening. A similarity search of compound followed by a second virtual screening led to the discovery of compounds (IC = 13.1 ± 0.09 μM) and (IC = 4.9 ± 0.26 μM) as h-cGAS inhibitors with improved potency. Therefore, the present study not only provides the validated hit compounds for further development of h-cGAS inhibitors but also demonstrates a cross-validation study of virtual screening, in vitro experimental assays, and crystal structure determination.
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http://dx.doi.org/10.1021/acs.jcim.0c00171DOI Listing
June 2020

Evaluation of Exosomal miRNA in Blood as a Potential Diagnostic Biomarker for Human Non-Small Cell Lung Cancer.

Med Sci Monit 2020 May 23;26:e924721. Epub 2020 May 23.

Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China (mainland).

BACKGROUND Tumor-derived exosomes have been used as diagnostic biomarkers to discriminate between tumor patients and healthy people. This study explored the roles of exosomal miRNAs in lung adenocarcinoma metastasis by microarray and developed a novel method for diagnosis of lung adenocarcinoma. MATERIAL AND METHODS Four lung adenocarcinoma patients' peripheral blood, including 2 metastasis and 2 N-metastasis, were used for exosomes miRNA microarray analysis. Exosomes were extracted by ultracentrifugation and identified by transmission electron microscopy. All the raw data were normalized by R software with limma packet. qRT-PCR was used to validate the microarray results. A549 cells were used to identify the functions of miR-4448. Western blot, qRT-PCR, RNAi, CCK8, and transwell invasion assay were used to verify the metastasis and proliferation abilities. RESULTS miR-4436a and miR-4687-5p were upregulated between the metastasis and N-metastasis group, while miR-22-3p, miR-3666, miR-4448, miR-4449, miR-6751-5p and miR-92a-3p were downregulated. miR-4448 was also downregulated between the metastasis and control group, whereas there was no significant difference between the N-metastasis group and control group. qRT-PCR confirmed the downregulation of miR-4448 in exosomes from lung adenocarcinoma patients compared with N-metastasis patients and healthy people. CCK8 and transwell invasion assay showed that A549 cells transfected with miR-4448 inhibitor had higher proliferation and metastasis ability. qRT-PCR and Western blot confirmed the high expression of MMP2 and MMP9 in A549 cells transfected with miR-4448 inhibitor. CONCLUSIONS miR-4448 can inhibit A549 cell proliferation and metastasis. miR-4448 in exosomes has the potential to serve as a diagnostic marker of patients with adenocarcinoma metastasis.
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http://dx.doi.org/10.12659/MSM.924721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261001PMC
May 2020

Dietary Melatonin Therapy Alleviates the Lamina Cribrosa Damages in Patients with Mild Cognitive Impairments: A Double-Blinded, Randomized Controlled Study.

Med Sci Monit 2020 May 7;26:e923232. Epub 2020 May 7.

Department of Neurosurgery, Liaohe Oil Gem Flower Hospital, Panjin, Liaoning, China (mainland).

BACKGROUND Alzheimer's disease (AD) is a degenerative disease that is characterized by massive neuron devastations in the hippocampus and cortex. Mild cognitive impairment (MCI) is the transitory stage between normality and AD dementia. This study aimed to investigate the melatonin induced effects on the lamina cribrosa thickness (LCT) of patients with MCI. MATERIAL AND METHODS The LCT data of patients with MCI were compared to LCT data of healthy controls. Subsequently, all MCI patients were randomly assigned into an experimental group (with melatonin treatment) or a placebo group (without any melatonin treatment). RESULTS The LCT of MCI patients decreased significantly compared with healthy controls. The univariate analysis showed that the lower the Mini Mental State Examination (MMSE) score (P=0.038; 95% CI: 0.876, -0.209), the smaller hippocampus volume (P=0.001; 95% CI: -1.594, -2.911), and the upregulated level of cerebrospinal fluid (CSF) T-tau (P=0.036; 95% CI: 2.546, -0.271) were associated significantly with the thinner LCT in MCI patients. There were 40 patients in the experimental group and 39 patients in the placebo group. The mean age of the experimental group was not significantly different from the placebo group (66.3±8.8 versus 66.5±8.3; P>0.05). The LCT and hippocampus volume of the melatonin treated group were significantly larger compared with the placebo group (P<0.001). On the other hand, the CSF T-tau level of the melatonin treated group was significantly lower compared with the untreated group (P<0.001). CONCLUSIONS LCT assessment might allow early diagnosis of MCI. Dietary melatonin therapy could provide an effective medication for MCI patients with LCT alterations.
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http://dx.doi.org/10.12659/MSM.923232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233010PMC
May 2020

Discovery of Ubiquitin-Specific Protease 7 (USP7) Inhibitors with Novel Scaffold Structures by Virtual Screening, Molecular Dynamics Simulation, and Biological Evaluation.

J Chem Inf Model 2020 06 23;60(6):3255-3264. Epub 2020 Apr 23.

Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.

USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation, and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC = 18.40 ± 1.75 μM, Ub-Rho assay IC = 7.75 μM). The binding affinity between USP7 (USP7 catalytic domain) and this hit compound was confirmed with a value of 4.46 ± 0.86 μM. Preliminary in vitro studies disclosed its antiproliferative activity on human prostate cancer cell line LNCaP with an IC value of 15.43 ± 3.49 μM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7 and the ligands, including the reference compound and compound , providing some important information for improving the bioactivity of . This hit compound will serve as a promising starting point for facilitating the further discovery of novel USP7 inhibitors.
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http://dx.doi.org/10.1021/acs.jcim.0c00154DOI Listing
June 2020

Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y inhibitor.

Br J Clin Pharmacol 2020 09 17;86(9):1860-1874. Epub 2020 Jun 17.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Aims: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects.

Methods: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open-label, 2-period cross-over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7.

Results: After a loading dose, the AUC of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28-fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs.

Conclusions: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.
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http://dx.doi.org/10.1111/bcp.14296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444798PMC
September 2020

Effect of intensive self-management education on seizure frequency and quality of life in epilepsy patients with prodromes or precipitating factors.

Seizure 2020 May 5;78:38-42. Epub 2020 Mar 5.

Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China. Electronic address:

Purpose: To explore the impact of an intensive self-management education strategy on seizure frequency and quality of life in patients with epileptic seizures with prodromes or precipitating factors. The intensive self-management education included monthly education sessions on prodromes and precipitating factors aiming to help patients to adopt self-management strategies.

Methods: Adult patients with epilepsy (PWE) able to identify prodromes or precipitating factors of their seizures were randomly assigned to an intensive education group (IEG) (n = 45) or a regular education group(REG) (n = 47). All patients received a single face-to-face self-management education session at the time of enrollment. Both groups of patients received monthly telephone follow-up for 1 year. PWE in the IEG received intensive education during each follow-up call. Primary outcomes were seizure frequency, quality of life(Quality of life in epilepsy-31 inventory scores, QOLIE 31), and drug adherence(Morisky medication adherence scale,MMAS).

Results: At the end of the 1-year follow-up period, seizure frequency in the IEG was significantly lower than at baseline (p < 0.001), but not in the REG(p = 0.085). Quality of life had improved significantly in the IEG (p < 0.001), but not in the REG (p = 0.073). Drug adherence was better in the IEG than in the REG (p = 0.003), and there were fewer accidental injuries in the IEG than the REG (p = 0.031).

Conclusions: In PWE aware of seizure prodromes or precipitating factors, intensive self-management education may reduce seizure frequency, improve quality of life, increase adherence with antiepileptic medication and reduce accidental injuries caused by seizures.
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http://dx.doi.org/10.1016/j.seizure.2020.03.003DOI Listing
May 2020

Mechanism of cargo recognition by retromer-linked SNX-BAR proteins.

PLoS Biol 2020 03 9;18(3):e3000631. Epub 2020 Mar 9.

Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.

Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.
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http://dx.doi.org/10.1371/journal.pbio.3000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082075PMC
March 2020

Nondestructive evaluation of steel-concrete composite structure using high-frequency ultrasonic guided wave.

Ultrasonics 2020 Apr 1;103:106096. Epub 2020 Feb 1.

Department of Civil and Environmental Engineering, University of Nebraska-Lincoln, 1110 S 67th St., Omaha, NE 68182, USA. Electronic address:

Steel-concrete modular construction is increasingly used in nuclear structure construction. Conventional nondestructive testing methods are not able to detect internal concrete defects because the thick concrete wall is covered by steel plates. An ultrasonic guided method is proposed to detect honeycombs and voids around cross tie bars by using the tie bar as the waveguide. Guided wave dispersion curves are analyzed for the two-layer system (tie bar embedded in concrete). The high order longitudinal mode L(0,8) is selected as the working mode due to its lowest attenuation. Ultrasonic attenuations were measured on naked bars and bars embedded in concrete. Material damping coefficients of the steel bar were calibrated on the naked bar. Three tie bars with different bonding conditions in concrete (solid, with honeycomb and void) were tested at early age, 7 days and 110 days. The experimental results demonstrate that ultrasonic guided wave attenuation can be used to identify internal defect and evaluate the tie bar/concrete bonding condition at both early and late ages.
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http://dx.doi.org/10.1016/j.ultras.2020.106096DOI Listing
April 2020

Human Serum Albumin-Based Dual-Agent Delivery Systems for Combination Therapy: Acting against Cancer Cells and Inhibiting Neovascularization in the Tumor Microenvironment.

Mol Pharm 2020 04 4;17(4):1405-1414. Epub 2020 Mar 4.

State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi 541004 China.

To cause tumor regression by acting against cancer cells and inhibiting neovascularization in the tumor microenvironment, we constructed human serum albumin (HSA)-based delivery systems of 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone-copper(II) [Cu(Ap44mT)]Cl and paclitaxel to improve both the therapeutic efficacy and the targeting ability . X-ray crystallography and matrix-assisted laser desorption/ionization time-of-flight mass spectra confirmed that [Cu(Ap44mT)]Cl complexed with HSA, whereas paclitaxel was tethered to the HSA complex by a linker sensitive to the active matrix metalloproteinase 2 (MMP2) protein. Up to 78% of paclitaxel was released from HSA within 2 h owing to MMP2 protein cleavage. In addition, a large amount of Cu(Ap44mT) was released from HSA in a pH 4.7 buffer. results revealed the following: (1) the tumor inhibitory rates of the HSA conjugate and the two-agent combination were 72.1 and 50.7%, respectively; (2) the inhibition rate of tumor angiogenesis of the HSA conjugate (73.3%) was higher than that of the two-agent combination (52.4%); (3) the increased amount of Cu in the tumor treated with the HSA conjugate was about 2-fold that in the tumor treated with the two-agent combination. Obviously, the HSA conjugate not only possessed a stronger capacity to inhibit neovascularization and the growth of liver tumors but also improved the targeting ability compared to the combination of the two agents alone.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00133DOI Listing
April 2020

Optimising epilepsy management with a smartphone application: a randomised controlled trial.

Med J Aust 2020 04 24;212(6):258-262. Epub 2020 Feb 24.

Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan, China.

Objective: To assess whether a practical intervention based upon a smartphone application (app) would improve self-management and seizure control in adults with epilepsy.

Design, Setting: Randomised, controlled trial in western China, December 2017 to August 2018.

Participants: 380 eligible people with epilepsy were recruited; 327 completed the 6-month follow-up (176 in the app group, 151 in the control group).

Main Outcome Measures: Self-management of epilepsy (measured with the validated Chinese Epilepsy Self-Management Scale, C-ESMS) and self-reported seizure frequency.

Results: In the intention-to-treat analysis, the mean C-ESMS score increased significantly in the app group between baseline and the 6-month evaluation (from 121.7 [SD, 12.1] to 144.4 [SD, 10.0]; P < 0.001); improvements on the information management, medication management, and safety management subscales were also statistically significant. At 6 months, the mean overall C-ESMS score for the app group was significantly higher than that for the control group (125.4 [SD, 1.5];  P < 0.001). The proportion of patients who were seizure-free at the 6-month follow-up was larger for the app than the control group (54 of 190, 28% v 22 of 190, 12%), as was the proportion with reductions in frequency of between 75 and 100% (22 of 190, 12% v 8 of 190, 4%). Changes in C-ESMS score were not statistically associated with seizure frequency.

Conclusions: Using a smartphone app improved epilepsy self-management scores in people in western China. It should be further tested in larger populations in other areas. Our preliminary investigation of building digital communities for people with epilepsy should encourage similar approaches to managing other chronic diseases.

Trial Registration: Chinese Clinical Trial Registry, ChiCTR1900026864, 24 October 2019.
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http://dx.doi.org/10.5694/mja2.50520DOI Listing
April 2020

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation.

J Chem Inf Model 2020 03 20;60(3):1717-1727. Epub 2020 Feb 20.

Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound was well characterized as a novel lead compound for developing potent and selective PPARα agonists.
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http://dx.doi.org/10.1021/acs.jcim.9b00838DOI Listing
March 2020