Isoglutaminyl Cyclase Overexpression Enhances KYSE30 Cancer Cell Proliferation and Migration via the MAPK Signaling Pathway.

To understand how upregulated isoglutaminyl cyclase (isoQC) is involved in the initiation of diseases such as cancer, we developed a human KYSE30 carcinoma cell model in which isoQC was stably overexpressed. GO and KEGG analysis of the DEGs (228) and DEPs (254) respectively implicated isoQC on the proliferation invasion and metastasis of cells and suggested that isoQC might participate in the regulation of MAPK, RAS, circadian rhythm, and related pathways. At the functional level, isoQC-overexpressing KYSE30 cells showed enhanced proliferation, migration, and invasion capacity. Next, we decided to study the precise effect of isoQC overexpression on JNK, p-JNK, AKT, p-AKT, ERK, p-ERK, and PER2, as RNA levels of these proteins are significantly correlated with signal levels indicated in RNA-Seq analysis, and these candidates are the top correlated DEPs enriched in RT-qPCR analysis. We saw that only p-ERK expression was inhibited, while PER2 was increased. These phenotypes were inhibited upon exposure to PER2 inhibitor KL044, which allowed for the restoration of p-ERK levels. These data support upregulated isoQC being able to promote cancer cell proliferation and migration in vitro, likely by helping to regulate the MAPK and RAS signaling pathways, and the circadian protein PER2 might be a potential mediator.

Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3ß.

Alzheimer's disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3ß (GSK-3ß) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 µM), although the potency was increased by 2' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3ß-specific inhibitory activity (2, IC50 = 0.0021 µM), and the electron-withdrawing group and 2' and 3' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3ß-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3ß. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3ß, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.

Discovery of potential scaffolds for glutaminyl cyclase inhibitors: Virtual screening, synthesis, and evaluation.

Glutaminyl cyclase (QC) plays a crucial role in the early stages of Alzheimer's disease (AD), thus inhibition of QC may be a promising strategy for the treatment of early AD. Therefore, QC inhibitors with novel chemical scaffolds may contribute to the development of additional anti-AD agents. We conducted a virtual screening of 3 million compounds from the Chemdiv and Enamine databases, to discover potential scaffolds for QC inhibitors. Three scaffolds, 120974, 147706, and 141449, were selected from this structure-based virtual screening through a combination of pharmacophore modeling, a receptor-ligand pharmacophore model, and the GALAHAD model, and furtherly filtered by chelation with zinc ion and docking properties. Consequently, three compounds, 1, 2, and 3, were designed and synthesized based on these three scaffolds, respectively. The IC50 of compounds 1 and 3 against QC were 14.19 ± 4.21 and 4.34 ± 0.35 µM, respectively. Our results indicate that the new scaffolds selected using a virtual screening process exhibit potential as novel QC inhibitors.

Gypenoside L Inhibits Proliferation of Liver and Esophageal Cancer Cells by Inducing Senescence.

Senescence is an irreversible state of cell cycle arrest that can be triggered by multiple stimuli, such as oxygen reactive species and DNA damage. Growing evidence has proven that senescence is a tumor-suppressive approach in cancer treatment. Therefore, developing novel agents that modulate senescence may be an alternative strategy against cancer. In our study, we investigated the inhibitory effect of gypenoside L (Gyp-L), a saponin isolated from Gynostemma pentaphyllum, on cancer cell growth. We found that Gyp-L increased the SA-ß-galactosidase activity, promoted the production of senescence-associated secretory cytokines, and inhibited cell proliferation of human liver and esophageal cancer cells. Moreover, Gyp-L caused cell cycle arrest at S phase, and activated senescence-related cell cycle inhibitor proteins (p21 and p27) and their upstream regulators. In addition, Gyp-L activated p38 and ERK MAPK pathways and NF-κB pathway to induce senescence. Consistently, adding chemical inhibitors efficiently counteracted the Gyp-L-mediated senescence, growth inhibition, and cell cycle arrest in cancer cells. Furthermore, treatment with Gyp-L, enhanced the cytotoxicity of clinic therapeutic drugs, including 5-fluorouracil and cisplatin, on cancer cells. Overall, these results indicate that Gyp-L inhibits proliferation of cancer cells by inducing senescence and renders cancer cells more sensitive to chemotherapy.

PXR- and CAR-mediated herbal effect on human diseases.

The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that regulate a broad range of genes involved in drug metabolism and transport. A variety of naturally occurring compounds present in herbal medicines were identified as ligands of PXR and CAR. Recently, accumulative evidences have revealed the PXR- and CAR-mediated herbal effect against multiple human diseases, including inflammatory bowel disease (IBD), cholestatic liver disease, and jaundice. The current review summarized the recent progress in identifying the expanding libraries of herbal medicine as ligands for PXR and CAR. Moreover, the potential for herbal medicines as promising therapeutic agents which were mainly regulated through PXR/CAR signaling pathways was also discussed. The discovery of herbal medicines as modulators of PXR and CAR, and their PXR- and CAR-mediated effect on human diseases will provide a basis for rational drug design, and eventually be explored as a novel therapeutic approach against human diseases. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Silver-catalyzed decarboxylative C(sp2)-C(sp3) coupling reactions via a radical mechanism.

A silver catalyzed decarboxylative C(sp2)-C(sp3) coupling of vinylic carboxylic acids with alcohols, alkylbenzenes, cycloalkanes and cyclic ethers was developed by using DTBP as an oxidant. This reaction tolerates a wide range of substrates, and products are obtained in good to excellent yields. The reaction also shows good stereoselectivity, and only trans-isomers are obtained. In addition, a radical pathway would be involved to facilitate this decarboxylative C(sp2)-C(sp3) coupling reaction.

SUMOylation of pregnane X receptor suppresses rifampicin-induced CYP3A4 and P-gp expression and activity in LS174T cells.

The pregnane X receptor (PXR) has been well-established as a critical mediator in regulating important drug metabolizing enzymes and transporter proteins, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Previous studies identified that PXR served as a molecular target of SUMOylation. However, the impact of SUMOylation of PXR on its transcriptional activity in regulating the expression/activity of the target genes is poorly investigated. In the current study, we established cell-based models of SUMOylated PXR in LS174T cells to investigate the impact of SUMOylation of PXR on regulating the expression/activity of CYP3A4 and P-gp. Our results revealed that rifampicin-induced PXR transactivation of the CYP3A4 and P-gp promoter was suppressed by SUMOylation of PXR in reporter gene assay. The mRNA and protein expression of CYP3A4 and P-gp was also suppressed. Moreover, CYP3A4 enzymatic assay and Rho123 intracellular assay revealed that rifampicin-induced CYP3A4 and P-gp activity was also suppressed by SUMOylated PXR. Our data collectively indicated for the first time that SUMOylation of PXR exerts suppressive effect on rifampicin-induced expression and activity of CYP3A4 and P-gp, which suggest that alteration in the SUMOylation status of PXR will be expected to affect the CYP3A4 mediated drug metabolism and P-gp mediated drug transport.

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats.

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

[Effects of SUMO specific protease 1 on hPXR-mediated P-gp gene expression].

The study aimed to investigate the effects of small ubiquitin-related modifier (SUMO) specific protease 1 (SENP1) on human PXR-mediated MDR1 transcriptional activity and mRNA expression. Empty vector and expression plasmids, including PXR, SENP1 and SENP1 mutant (SENP1m) were transiently transfected into HepG2 and LS174T cells using Lipo2000. Transcriptional activity was detected by dual luciferase reporter gene assay, and mRNA level was measured using real-time polymerase chain reaction. The results showed that SENP1 could remarkably reduce the rifampicin (RIF)-induced MDR1 reporter activity and mRNA level in hPXR over expressed HepG2 and LS174T cells (P < 0.05), whereas adding SENP1m restored the RIF-induced increases (P < 0.05). These results indicated that SENP1 could repress the RIF-induced hPXR-mediated MDR1 transcriptional activity and mRNA expression.

Low dose of oleanolic acid protects against lithocholic acid-induced cholestasis in mice: potential involvement of nuclear factor-E2-related factor 2-mediated upregulation of multidrug resistance-associated proteins.

Oleanolic acid (OA) is a natural triterpenoid and has been demonstrated to protect against varieties of hepatotoxicants. Recently, however, OA at high doses was reported to produce apparent cholestasis in mice. In this study, we characterized the protective effect of OA at low doses against lithocholic acid (LCA)-induced cholestasis in mice and explored further mechanisms. OA cotreatment (5, 10, and 20 mg/kg, i.p.) significantly improved mouse survival rate, attenuated liver necrosis, and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; more importantly, serum total bile acids and bilirubin, as well as hepatic total bile acids were also remarkably reduced. Gene and protein expression analysis showed that hepatic expression of multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4 was significantly increased by OA cotreatment, whereas other bile acid metabolism- and transport-related genes, including Na+/taurocholate cotransporter, organic anion transporter 1b2, bile salt export pump, multidrug resistance protein 3, Cyp3a11, Cyp2b10, Sulfotransferase 2a1 (Sult2a1), and UDP-glucuronosyltransferase 1a1 (Ugt1a1), were only slightly changed. OA also caused increased nuclear factor-E2-related factor (Nrf2) mRNA expression and nuclear protein accumulation, whereas nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor were not significantly influenced by OA. Luciferase (Luc) assays performed in HepG2 cells illustrated that OA was a strong Nrf2 agonist with moderate PXR and weak FXR agonism. Finally, in mouse primary cultured hepatocytes, OA dose- and time-dependently induced expression of Mrp2, Mrp3, and Mrp4; however, this upregulation was abrogated when Nrf2 was silenced. In conclusion, OA produces a protective effect against LCA-induced hepatotoxicity and cholestasis, possibly due to Nrf2-mediated upregulation of Mrp2, Mrp3, and Mrp4.

Resveratrol suppresses the inducible expression of CYP3A4 through the pregnane X receptor.

The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene-transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16α-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators.

DreamAnime: Learning Style-Identity Textual Disentanglement for Anime and Beyond.

Text-to-image generation models have significantly broadened the horizons of creative expression through the power of natural language. However, navigating these models to generate unique concepts, alter their appearance, or reimagine them in unfamiliar roles presents an intricate challenge. For instance, how can we exploit language-guided models to transpose an anime character into a different art style, or envision a beloved character in a radically different setting or role? This paper unveils a novel approach named DreamAnime, designed to provide this level of creative freedom. Using a minimal set of 2-3 images of a user-specified concept such as an anime character or an art style, we teach our model to encapsulate its essence through novel "words" in the embedding space of a pre-existing text-to-image model. Crucially, we disentangle the concepts of style and identity into two separate "words", thus providing the ability to manipulate them independently. These distinct "words" can then be pieced together into natural language sentences, promoting an intuitive and personalized creative process. Empirical results suggest that this disentanglement into separate word embeddings successfully captures a broad range of unique and complex concepts, with each word focusing on style or identity as appropriate. Comparisons with existing methods illustrate DreamAnime's superior capacity to accurately interpret and recreate the desired concepts across various applications and tasks. Code is available at https://github.com/chnshx/DreamAnime.

Effect of Wuzhi tablet (Schisandra sphenanthera extract) on the pharmacokinetics of cyclosporin A in rats.

In our previous reports, Wuzhi tablet (an herbal preparation of ethanol extract of Wuweizi (Schisandra sphenanthera)) can significantly increase the blood concentration of tacrolimus and paclitaxel in rats by inhibiting the CYP3A-mediated metabolism and the P-gp-mediated efflux. Cyclosporin A (CsA), a well-known immunosuppressant agent, is also a substrate of CYP3A and P-gp. Therefore, this study aimed to investigate whether and how WZ affects pharmacokinetics of CsA in rats. The AUC0-48 h and Cmax of CsA were increased by 40.1% and 13.1%, respectively, with a single oral co-administration of WZ and high dose of CsA (37.8 mg/kg). Interestingly, after a single oral co-administration of WZ and low dose of CsA (1.89 mg/kg), the AUC0-36 h and Cmax of CsA were dramatically increased by 293.1% (from 1103.2 ± 293.0 to 4336.5 ± 1728.3 ng.h/mL; p < 0.05) and 84.1% (from 208.5 ± 67.9 to 383.1 ± 92.5 ng/mL; p < 0.05), respectively. The CL/F was decreased from 1.7 L/h/kg to 0.5 L/h/kg. Thus, the effect of WZ on high dose of CsA was not significant, but pharmacokinetic parameters of CsA at low dose were significantly influenced by co-administration of WZ. The herb-drug interaction should be taken into consideration at this situation.

Panel-Page-Aware Comic Genre Understanding.

Using a sequence of discrete still images to tell a story or introduce a process has become a tradition in the field of digital visual media. With the surge in these media and the requirements in downstream tasks, acquiring their main topics or genres in a very short time is urgently needed. As a representative form of the media, comic enjoys a huge boom as it has gone digital. However, different from natural images, comic images are divided by panels, and the images are not visually consistent from page to page. Therefore, existing works tailored for natural images perform poorly in analyzing comics. Considering the identification of comic genres is tied to the overall story plotting, a long-term understanding that makes full use of the semantic interactions between multi-level comic fragments needs to be fully exploited. In this paper, we propose [Formula: see text]Comic, a Panel-Page-aware Comic genre classification model, which takes page sequences of comics as the input and produces class-wise probabilities. [Formula: see text]Comic utilizes detected panel boxes to extract panel representations and deploys self-attention to construct panel-page understanding, assisted with interdependent classifiers to model label correlation. We develop the first comic dataset for the task of comic genre classification with multi-genre labels. Our approach is proved by experiments to outperform state-of-the-art methods on related tasks. We also validate the extensibility of our network to perform in the multi-modal scenario. Finally, we show the practicability of our approach by giving effective genre prediction results for whole comic books.

Design, synthesis and anti-AD effects of dual inhibitor targeting glutaminyl cyclase/GSK-3ß.

Alzheimer's disease (AD), multifactorial disease, is recognized as one of the most common forms of dementia, and the efficacy of anti-AD drugs is limited clinically. Up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3ß (GSK-3ß) have been identified as two critical elements involved in AD recently. Here, a series of novel chemicals containing maleimide and imidazole motif were designed and synthesized as dual inhibitors targeting QC and GSK-3ß. Based on primary screening, compound 2 (2.26 µM), 5 (2.37 µM), 8 (1.34 µM), 21 (2.44 µM), 25 (0.36 µM), 27 (1.76 µM), 28 (1.04 µM), 33 (2.08 µM) and 34 (2.33 µM) exhibited notable human QC (hQC) inhibitory potency, while compound 1 (0.014 µM), 7 (0.04 µM), 8 (0.057 µM), 19 (0.034 µM), 24 (0.014 µM), 32 (0.032 µM), 38 (0.051 µM), 39 (0.044 µM), 44 (0.048 µM), 47 (0.011 µM), 49 (0.021 µM) and so on showed remarkable GSK-3ß inhibitory activities. And as expected, these chemicals possessed significant inhibitory potency on both hQC and GSK-3ß, such as compound 1 (2.80 and 0.014 µM), 8 (1.34 and 0.057 µM), 25 (0.36 and 0.15 µM), 27 (1.76 and 0.069 µM), 28 (1.04 and 0.090 µM), 33 (2.08 and 0.19 µM), 34 (2.33 and 0.11 µM), 35 (2.55 and 0.14 µM), 36 (2.34 and 0.11 µM), etc. Subsequent in vivo studies demonstrated that compound 8 attenuated cognitive deficits and decreased the anxiety-like behavior in 3 × Tg-AD mice. The treatment decreased both pE-Aß and Aß accumulation by inhibiting the activity of QC, and decreased the hyperphosphorylation of Tau by reducing the levels of GSK-3ß in the brains of AD mice. Results obtained in this research suggested that these novel compounds could be supposed as potential anti-AD agents targeting QC and GSK-3ß.

Upregulation of Glutaminyl Cyclase Contributes to ERS-Induced Apoptosis in PC12 Cells.

Glutaminyl cyclase (QC) is responsible for converting the N-terminal glutaminyl and glutamyl of the proteins into pyroglutamate (pE) through cyclization. It has been confirmed that QC catalyzes the formation of neurotoxic pE-modified Aß in the brain of AD patients. But the effects of upregulated QC in diverse diseases have not been much clear until recently. Here, RNA sequencing was applied to identify differentially expressed genes (DEGs) in PC12 cells with QC overexpressing or knockdown. A total of 697 DEGs were identified in QC overexpressing cells while only 77 in QC knockdown cells. Multiple bioinformatic approaches revealed that the DEGs in QC overexpressing group were enriched in endoplasmic reticulum stress (ERS) related signaling pathways. The gene expression patterns of 23 DEGs were confirmed by RT-qPCR, in which the genes related to ERS showed the highest consistency. We also revealed the protein levels of GRP78, PERK, CHOP, and PARP-1, and caspase family was significantly upregulated by overexpressing QC. Moreover, overexpressing QC significantly increased apoptosis of PC12 cells in a time dependent manner. However, no significant alteration was observed in QC knockdown cells. Therefore, our study indicated that upregulated QC could induce ERS and apoptosis, which consequently trigger diseases by catalyzing the generation of pE-modified mediators.

Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism.

Objective: The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy. Methods: A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients. Results: A significant effect of the patient age and ABCB1 genotypes was observed on the VPA oral clearance (CL/F) in the final PPK model. Compared with patients with the ABCB1 rs3789243 AA genotype, CL/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and ABCB1 genotype was constructed based on the final PPK model. Conclusion: This study quantitatively investigated the effects of patient age and ABCB1 rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.

Post-translational modification of pregnane x receptor.

Pregnane x receptor (PXR, NR1I2) was originally characterized as a broad spectrum entero-hepatic xenobiotic 'sensor' and master-regulator of drug inducible gene expression. A compelling description of ligand-mediated gene activation has been unveiled in the last decade that firmly establishes this receptor's central role in the metabolism and transport of xenobiotics in mammals. Interestingly, pharmacotherapy with potent PXR ligands produces several profound side effects including decreased capacities for gluconeogenesis, lipid metabolism, and inflammation; likely due to PXR-mediated repression of gene expression programs underlying these pivotal physiological functions. An integrated model is emerging that reveals a sophisticated interplay between ligand binding and the ubiquitylation, phosphorylation, SUMOylation, and acetylation status of this important nuclear receptor protein. These discoveries point to a key role for the post-translational modification of PXR in the selective suppression of gene expression, and open the door to the study of completely new modes of regulation of the biological activity of PXR.

Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors.

Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.

Repurposing FDA-Approved Compounds for the Discovery of Glutaminyl Cyclase Inhibitors as Drugs Against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative causes of dementia, the pathology of which is still not much clear. It's challenging to discover the disease modifying agents for the prevention and treatment of AD over the years. Emerging evidence has been accumulated to reveal the crucial role of up-regulated glutaminyl cyclase (QC) in the initiation of AD. In the current study, the QC inhibitory potency of a library consisting of 1621 FDA-approved compounds was assessed. A total of 54 hits, 3.33 % of the pool, exhibited QC inhibitory activities. The Ki of the top 5 compounds with the highest QC inhibitory activities were measured. Among these selected hits, compounds affecting neuronal signaling pathways and other mechanisms were recognized. Moreover, several polyphenol derivatives with QC inhibitory activities were also identified. Frameworks and subsets contained in these hits were analyzed. Taken together, our results may contribute to the discovery and development of novel QC inhibitors as potential anti-AD agents.