Fu L

References (19)

Title : LET-767 determines lipid droplet protein targeting and lipid homeostasis - Fu_2024_J.Cell.Biol_223_
Author(s) : Fu L , Zhang J , Wang Y , Wu H , Xu X , Li C , Li J , Liu J , Wang H , Jiang X , Li Z , He Y , Liu P , Wu Y , Zou X , Liang B
Ref : Journal of Cell Biology , 223 : , 2024
Abstract : Lipid droplets (LDs) are composed of a core of neutral lipids wrapped by a phospholipid (PL) monolayer containing several hundred proteins that vary between different cells or organisms. How LD proteins target to LDs is still largely unknown. Here, we show that RNAi knockdown or gene mutation of let-767, encoding a member of hydroxysteroid dehydrogenase (HSD), displaced the LD localization of three well-known LD proteins: DHS-3 (dehydrogenase/reductase), PLIN-1 (perilipin), and DGAT-2 (diacylglycerol O-acyltransferase 2), and also prevented LD growth in Caenorhabditis elegans. LET-767 interacts with ARF-1 (ADP-ribosylation factor 1) to prevent ARF-1 LD translocation for appropriate LD protein targeting and lipid homeostasis. Deficiency of LET-767 leads to the release of ARF-1, which further recruits and promotes translocation of ATGL-1 (adipose triglyceride lipase) to LDs for lipolysis. The displacement of LD proteins caused by LET-767 deficiency could be reversed by inhibition of either ARF-1 or ATGL-1. Our work uncovers a unique LET-767 for determining LD protein targeting and maintaining lipid homeostasis.
ESTHER : Fu_2024_J.Cell.Biol_223_
PubMedSearch : Fu_2024_J.Cell.Biol_223_
PubMedID: 38551495

Title : RhlA Exhibits Dual Thioesterase and Acyltransferase Activities during Rhamnolipid Biosynthesis - Tang_2023_ACS.Catal_13_5759
Author(s) : Ting Tang T , Fu L , Xie W , Luo Y , Zhang Y , Zhang J , Si T
Ref : ACS Catal , 13 :5759 , 2023
Abstract : Rhamnolipids (RLs) are a desirable class of biosurfactants originating from Pseudomonas aeruginosa. Rhamnosyltransferase 1 chain A (RhlA) catalyzes the formation of -3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs) to constitute the RL lipid moiety, and the molecular structure of this moiety exerts major impacts on the physiochemical and biological properties of corresponding RLs. However, the catalytic mechanism and sequence-structurefunction relationship of RhlA remain elusive. Here, we report the X-ray crystal structure of P. aeruginosa RhlA with an a/-hydrolase fold and a canonical nucleophile/histidine/acidic catalytic triad. Unexpectedly, free 3-hydroxy fatty acids within a secondary ligand-binding pocket were observed in the crystal of RhlA, which is traditionally considered an acyltransferase that acts only on acyl carrier protein (ACP)-bound substrates. In vitro isotopic labeling, enzyme kinetics experiments, and QM/MM simulations confirmed that free -hydroxy fatty acids are a reaction intermediate during HAA synthesis. Moreover, first-shell residue mutations that targeted different ligand-binding pockets resulted in distinct modulation patterns for the two acyl chain lengths of HAAs. In conclusion, the revealed biosynthetic mechanism may guide future engineering for the biosynthesis of designer RLs.
ESTHER : Tang_2023_ACS.Catal_13_5759
PubMedSearch : Tang_2023_ACS.Catal_13_5759
PubMedID:
Gene_locus related to this paper: pseae-rhla

Title : Molecular, morphological and behavioral alterations of zebrafish (Danio rerio) embryos\/larvae after clorprenaline hydrochloride exposure - Wang_2023_Food.Chem.Toxicol_176_113776
Author(s) : Wang B , Wang A , Xu C , Tong Z , Wang Y , Zhuo X , Fu L , Yao W , Wang J , Wu Y
Ref : Food & Chemical Toxicology , 176 :113776 , 2023
Abstract : Chlorprenaline hydrochloride (CLOR) is a typical representative of beta-adrenergic agonists that may be used illegally as a livestock feed additive and may have adverse impacts on the environment. In the present study, zebrafish embryos were exposed to CLOR to investigate its developmental toxicity and neurotoxicity. The results demonstrated that CLOR exposure led to adverse effects on developing zebrafish, such as morphological changes, a high heart rate, and increased body length, resulting in developmental toxicity. Moreover, the up-regulation of activities of superoxide dismutase (SOD) and catalase (CAT) and the enhancement of malondialdehyde (MDA) content illustrated that CLOR exposure activated oxidative stress in exposed zebrafish embryos. Meanwhile, CLOR exposure also caused alterations in locomotive behavior in zebrafish embryos, including an increase in acetylcholinesterase (AChE) activity. Quantitative polymerase chain reaction (QPCR) results showed that the transcription of genes related to the central nervous system (CNS) development, namely, mbp, syn2a, alpha1-tubulin, gap43, shha, and elavl3, indicated that CLOR exposure could lead to neurotoxicity in zebrafish embryos. These results showed that CLOR exposure could cause developmental neurotoxicity in the early stages of zebrafish development and that CLOR might induce neurotoxicity by altering the expression of neuro-developmental genes, elevating AChE activity, and activating oxidative stress.
ESTHER : Wang_2023_Food.Chem.Toxicol_176_113776
PubMedSearch : Wang_2023_Food.Chem.Toxicol_176_113776
PubMedID: 37059383

Title : Mono-2-ethylhexylphthalate (MEHP) is a potent agonist of human TRPA1 channel - Goh_2023_Chemosphere__140740
Author(s) : Goh M , Fu L , Seetoh WG , Koay A , Hua H , Tan SM , Tay SH , Jinfeng EC , Abdullah N , Ng SY , Lakshmanan M , Arumugam P
Ref : Chemosphere , :140740 , 2023
Abstract : Phthalates are extensively used as plasticizers in diverse consumer care products but have been reported to cause adverse health effects in humans. A commonly used phthalate, di-2-ethylhexylphthalate (DEHP) causes developmental and reproductive toxicities in humans, but the associated molecular mechanisms are not fully understood. Mono-2-ethylhexylphthalate (MEHP), a hydrolytic product of DEHP generated by cellular esterases, is proposed to be the active toxicant. We conducted a screen for sensory irritants among compounds used in consumer care using an assay for human Transient Receptor Potential A1 (hTRPA1). We have identified MEHP as a potent agonist of hTRPA1. MEHP-induced hTRPA1 activation was blocked by the TRPA1 inhibitor A-967079. Patch clamp assays revealed that MEHP induced inward currents in cells expressing hTRPA1. In addition, the N855S mutation in hTRPA1 associated with familial episodic pain syndrome decreased MEHP-induced hTRPA1 activation. In summary, we report that MEHP is a potent agonist of hTRPA1 which generates new possible mechanisms for toxic effects of phthalates in humans.
ESTHER : Goh_2023_Chemosphere__140740
PubMedSearch : Goh_2023_Chemosphere__140740
PubMedID: 38006918

Title : Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationship between tumor invasion and metastasis - Zhang_2021_Front.Med__
Author(s) : Zhang J , Song Y , Shi Q , Fu L
Ref : Front Med , : , 2021
Abstract : Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the de novo synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K-AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial-mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.
ESTHER : Zhang_2021_Front.Med__
PubMedSearch : Zhang_2021_Front.Med__
PubMedID: 33973101
Gene_locus related to this paper: human-FASN , human-MGLL

Title : Synthesis, biological evaluation and molecular modeling of benzofuran piperidine derivatives as Abeta antiaggregant - Chowdhury_2021_Eur.J.Med.Chem_222_113541
Author(s) : Chowdhury SR , Gu J , Hu Y , Wang J , Lei S , Tavallaie MS , Lam C , Lu D , Jiang F , Fu L
Ref : Eur Journal of Medicinal Chemistry , 222 :113541 , 2021
Abstract : A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Abeta antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Abeta antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Abeta peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC(50) = 61 microM and self induced Abeta (25-35) aggregation 45.45%), to increase its activity toward AD related targets. The most interesting multifunctional Abeta antiaggregants were compounds 3a, 3h and 3i, highlighting 3h as potent Abeta antiaggregant and good antiacetylholinesterase inhibitor (self induced Abeta (25-35) aggregation 57.71% and hAChE IC(50) = 21 microM), with good neuroprotective and antioxidant activity. In addition, these three most promising compounds prevent intracellular reactive oxygen species (ROS) formation and cell apoptosis induced by Abeta(25-35) peptides in SH-SY5Y cells. Molecular docking studies were also accomplished to understand the binding interaction of these compounds on Abeta monomer, Abeta fibril and AChE. Based on all data, compounds 3a, 3h and 3i were concluded as potent multifunctional Abeta antiaggregant, useful candidate for the treatment of AD.
ESTHER : Chowdhury_2021_Eur.J.Med.Chem_222_113541
PubMedSearch : Chowdhury_2021_Eur.J.Med.Chem_222_113541
PubMedID: 34116326

Title : Behaviors and biochemical responses of macroinvertebrate Corbicula fluminea to polystyrene microplastics - Fu_2021_Sci.Total.Environ_813_152617
Author(s) : Fu L , Xi M , Nicholaus R , Wang Z , Wang X , Kong F , Yu Z
Ref : Sci Total Environ , 813 :152617 , 2021
Abstract : Microplastic, a well-documented emerging contaminant, is widespread in aquatic environments resulting from the production and fragmentation of large plastics items. The knowledge about the chronic toxic effects and behavioral toxicity of microplastics, particularly on freshwater benthic macroinvertebrates, is limited. In this study, adult Asian clams (Corbicula fluminea) were exposed to gradient microplastic solutions for 42 days to evaluate behavioral toxicity and chronic biotoxicity. The results showed that microplastics caused behavior toxicity, oxidative stress, and tissue damage in high-concentration treatments. Siphoning, breathing, and excretion was significantly inhibited (p < 0.05) at high-concentration treatments, suggesting that high-concentration microplastics induced behavioral toxicity in C. fluminea. Malondialdehyde content, superoxide dismutase, catalase, and glutathione reductase activities were significantly enhanced (p < 0.05) and the acetylcholinesterase was significantly inhibited (p < 0.05) throughout the exposure period in high-concentration treatments. Enzymes associated with energy supply were significantly higher at high-concentration microplastics treatments on D7 and D21. However, they recovered to a normal level on D42. The instability of the enzymes indicated that high-concentration microplastics induced oxidative stress and disorder in neurotransmission and energy supply. The gills of C. fluminea in treatments underwent cilia degeneration, which indicated that microplastics caused tissue damage in the gills. The analysis of integrated biomarker response values revealed that high-concentration microplastics led to long-term effects on the health of C. fluminea. In conclusion, continuous exposure to microplastics (10 mg L(-1)) would damage physical behavior and the antioxidant system of C. fluminea.
ESTHER : Fu_2021_Sci.Total.Environ_813_152617
PubMedSearch : Fu_2021_Sci.Total.Environ_813_152617
PubMedID: 34963588

Title : Ensemble machine learning to evaluate the in vivo acute oral toxicity and in vitro human acetylcholinesterase inhibitory activity of organophosphates - Wang_2021_Arch.Toxicol__
Author(s) : Wang L , Ding J , Shi P , Fu L , Pan L , Tian J , Cao D , Jiang H , Ding X
Ref : Archives of Toxicology , : , 2021
Abstract : Organophosphates (OPs) are hazardous chemicals widely used in industry and agriculture. Distribution of their residues in nature causes serious risks to humans, animals, and plants. To reduce hazards from OPs, quantitative structure-activity relationship (QSAR) models for predicting their acute oral toxicity in rats and mice and inhibition constants concerning human acetylcholinesterase were developed according to the bioactivity data of 456 unique OPs. Based on robust, two-dimensional molecular descriptors and quantum chemical descriptors, which accurately reflect OP electronic structures and reactivities, the influences of eight machine-learning algorithms on the prediction performance of the QSAR models were explored, and consensus QSAR models were constructed. Several strict model validation indices and the results of applicability domain evaluations show that the established consensus QSAR models exhibit good robustness, practical prediction abilities, and wide application scopes. Poor correlation was observed between acute oral toxicity at the mammalian level and the inhibition constants at the molecular level, indicating that the acute toxicity of OPs cannot be evaluated only by the experimental data of enzyme inhibitory activity, their toxicokinetic characteristics must also be considered. The constructed QSAR models described herein provide rapid, theoretical assessment of the bioactivity of unstudied or unknown OPs, as well as guidance for making decisions regarding their regulation.
ESTHER : Wang_2021_Arch.Toxicol__
PubMedSearch : Wang_2021_Arch.Toxicol__
PubMedID: 33934188

Title : Responses of Asian clams (Corbicula fluminea) to low concentration cadmium stress: Whether the depuration phase restores physiological characteristics - Wang_2021_Environ.Pollut_284_117182
Author(s) : Wang Z , Kong F , Fu L , Li Y , Li M , Yu Z
Ref : Environ Pollut , 284 :117182 , 2021
Abstract : The effect of low concentration Cd stress on bivalves is unclear. In this study, Asian clams (Corbicula fluminea) were continuously exposed to 0, 0.05, 0.10, and 0.20 mg/L Cd for 14 d (exposure phase) and to artificial freshwater for 7 d (depuration phase). A total of 16 variables were measured to explore the toxic effects on C. fluminea. All physiological characteristics were significantly inhibited in the treatments (p < 0.05), and the negative effects of Cd did not return to normal levels in the short term. Tissue damage was found in the feet and gills of C. fluminea in all the treatments. On the 7th day (D7), enzyme activity in all the treatments was significantly higher (p < 0.05) than in the control group. Acetylcholinesterase, superoxide dismutase, and catalase activities were enhanced on D14 in all the treatments. However, only glutathione S-transferase activity was significantly higher in all the treatments (p < 0.05) than in the control group on D21. The instability of the enzymes indicated that the adaptability of C. fluminea became stronger throughout the experiment. In each group, the maximum bioaccumulation of Cd followed the order: 0.20 mg/L > 0.05 mg/L > 0.10 mg/L, which might be caused by the filtration capacity of C. fluminea in the 0.05-mg/L group, which was higher than that of the 0.10-mg/L group. Thus, low Cd concentrations effect the physiological characteristics, tissue health, and antioxidant system of C. fluminea and may require a long recovery time to be restored to normal levels.
ESTHER : Wang_2021_Environ.Pollut_284_117182
PubMedSearch : Wang_2021_Environ.Pollut_284_117182
PubMedID: 33901982

Title : A tacrine-tetrahydroquinoline heterodimer potently inhibits acetylcholinesterase activity and enhances neurotransmission in mice - Ip_2021_Eur.J.Med.Chem_226_113827
Author(s) : Ip FCF , Fu G , Yang F , Kang F , Sun P , Ling CY , Cheung K , Xie F , Hu Y , Fu L , Ip NY
Ref : Eur Journal of Medicinal Chemistry , 226 :113827 , 2021
Abstract : Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC(50) < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration.
ESTHER : Ip_2021_Eur.J.Med.Chem_226_113827
PubMedSearch : Ip_2021_Eur.J.Med.Chem_226_113827
PubMedID: 34530383

Title : Genome-wide analysis of the serine carboxypeptidase-like protein family in Triticum aestivum reveals TaSCPL184-6D is involved in abiotic stress response - Xu_2021_BMC.Genomics_22_350
Author(s) : Xu X , Zhang L , Zhao W , Fu L , Han Y , Wang K , Yan L , Li Y , Zhang XH , Min DH
Ref : BMC Genomics , 22 :350 , 2021
Abstract : BACKGROUND: The serine carboxypeptidase-like protein (SCPL) family plays a vital role in stress response, growth, development and pathogen defense. However, the identification and functional analysis of SCPL gene family members have not yet been performed in wheat. RESULTS: In this study, we identified a total of 210 candidate genes encoding SCPL proteins in wheat. According to their structural characteristics, it is possible to divide these members into three subfamilies: CPI, CPII and CPIII. We uncovered a total of 209 TaSCPL genes unevenly distributed across 21 wheat chromosomes, of which 65.7% are present in triads. Gene duplication analysis showed that ~ 10.5% and ~ 64.8% of the TaSCPL genes are derived from tandem and segmental duplication events, respectively. Moreover, the Ka/Ks ratios between duplicated TaSCPL gene pairs were lower than 0.6, which suggests the action of strong purifying selection. Gene structure analysis showed that most of the TaSCPL genes contain multiple introns and that the motifs present in each subfamily are relatively conserved. Our analysis on cis-acting elements showed that the promoter sequences of TaSCPL genes are enriched in drought-, ABA- and MeJA-responsive elements. In addition, we studied the expression profiles of TaSCPL genes in different tissues at different developmental stages. We then evaluated the expression levels of four TaSCPL genes by qRT-PCR, and selected TaSCPL184-6D for further downstream analysis. The results showed an enhanced drought and salt tolerance among TaSCPL184-6D transgenic Arabidopsis plants, and that the overexpression of the gene increased proline and decreased malondialdehyde levels, which might help plants adapting to adverse environments. Our results provide comprehensive analyses of wheat SCPL genes that might work as a reference for future studies aimed at improving drought and salt tolerance in wheat. CONCLUSIONS: We conducte a comprehensive bioinformatic analysis of the TaSCPL gene family in wheat, which revealing the potential roles of TaSCPL genes in abiotic stress. Our analysis also provides useful resources for improving the resistance of wheat.
ESTHER : Xu_2021_BMC.Genomics_22_350
PubMedSearch : Xu_2021_BMC.Genomics_22_350
PubMedID: 33992092

Title : Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors - Shen_2020_Eur.J.Med.Chem_208_112850
Author(s) : Shen J , Deng X , Sun R , Tavallaie MS , Wang J , Cai Q , Lam C , Lei S , Fu L , Jiang F
Ref : Eur Journal of Medicinal Chemistry , 208 :112850 , 2020
Abstract : Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC(50) = 79 nM) and d1 (IC(50) = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC(50) = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC(50) = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
ESTHER : Shen_2020_Eur.J.Med.Chem_208_112850
PubMedSearch : Shen_2020_Eur.J.Med.Chem_208_112850
PubMedID: 32987315

Title : The rs1051931 G>A Polymorphism in the PLA2G7 Gene Confers Resistance to Immunoglobulin Therapy in Kawasaki Disease in a Southern Chinese Population - Gu_2020_Front.Pediatr_8_338
Author(s) : Gu X , Lin W , Xu Y , Che D , Tan Y , Lu Z , Pi L , Fu L , Zhou H , Jiang Z
Ref : Front Pediatr , 8 :338 , 2020
Abstract : Background: Kawasaki disease (KD) is a common cardiovascular disease in infants and young children, with fever, rash, and conjunctivitis as the main clinical manifestations, which can lead to the occurrence of coronary aneurysms. Intravenous immunoglobulin (IVIG) is the preferred treatment for KD patients, but 10-20% of patients are resistant to IVIG. Lipoprotein-associated phospholipase A 2 (Lp-PLA2) is a potential therapeutic target for coronary atherosclerotic heart disease, and the polymorphism of Phospholipase A2 Group VII (PLA2G7) is closely related to the activity of Lp-PLA2, of which rs1051931 is the strongest. Therefore, the rs1051931 polymorphism may be a predictor of IVIG resistance in KD patients. Methods: A total of 760 KD cases, including 148 IVIG-resistant patients and 612 IVIG-responsive patients, were genotyped for rs1051931 in PLA2G7, we compared the effects of rs1051931 on IVIG treatment in KD patients by odds ratios (OR) and 95% confidence interval (CI). Results: The homozygous mutation AA may be a protective factor for IVIG resistance in KD patients (adjusted OR = 3.47, 95% CI = 1.14-10.57, P = 0.0284) and is more evident in patients with KD aged <60 months (adjusted OR = 3.68, 95% CI = 1.10-12.28, P = 0.0399). Conclusions: The PLA2G7 rs1051931 G>A polymorphism may be suitable as a biomarker for the diagnosis or prognosis of IVIG resistance in KD in a southern Chinese population.
ESTHER : Gu_2020_Front.Pediatr_8_338
PubMedSearch : Gu_2020_Front.Pediatr_8_338
PubMedID: 32656171
Gene_locus related to this paper: human-PLA2G7

Title : Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors - Deng_2018_Bioorg.Med.Chem_26_903
Author(s) : Deng X , Shen J , Zhu H , Xiao J , Sun R , Xie F , Lam C , Wang J , Qiao Y , Tavallaie MS , Hu Y , Du Y , Li J , Fu L , Jiang F
Ref : Bioorganic & Medicinal Chemistry , 26 :903 , 2018
Abstract : The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC(50): 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC(50): 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.
ESTHER : Deng_2018_Bioorg.Med.Chem_26_903
PubMedSearch : Deng_2018_Bioorg.Med.Chem_26_903
PubMedID: 29373269

Title : Cigarette Smoke-Induced Pulmonary Inflammation and Autophagy Are Attenuated in Ephx2-Deficient Mice - Li_2017_Inflammation_40_497
Author(s) : Li Y , Yu G , Yuan S , Tan C , Lian P , Fu L , Hou Q , Xu B , Wang H
Ref : Inflammation , 40 :497 , 2017
Abstract : Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function. Additionally, CS can induce autophagy which contributes to COPD. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy. For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo. Adult male wild-type (WT) C57BL/6J and Ephx2-/- mice were exposed to air or CS for 12 weeks, and lung inflammatory responses, air space enlargement (emphysema), lung function, and autophagy were assessed. Lungs of Ephx2-/- mice had a less pronounced inflammatory response and less autophagy with mild distal airspace enlargement accompanied by restored lung function and steady weight gain. These findings support the idea that Ephx2 may hold promise as a therapeutic target for COPD induced by CS, and it may be protective property by inhibiting autophagy.
ESTHER : Li_2017_Inflammation_40_497
PubMedSearch : Li_2017_Inflammation_40_497
PubMedID: 28028752

Title : Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry - Song_2014_Virology_471-473C_49
Author(s) : Song W , Wang Y , Wang N , Wang D , Guo J , Fu L , Shi X
Ref : Virology , 471-473C :49 , 2014
Abstract : Middle East respiratory syndrome coronavirus (MERS-CoV) infects host cells through binding the receptor binding domain (RBD) on its spike glycoprotein to human receptor dipeptidyl peptidase 4 (hDPP4). Here, we report identification of critical residues on hDPP4 for RBD binding and virus entry through analysis of a panel of hDPP4 mutants. Based on the RBD-hDPP4 crystal structure we reported, the mutated residues were located at the interface between RBD and hDPP4, which potentially changed the polarity, hydrophobic or hydrophilic properties of hDPP4, thereby interfering or disrupting their interaction with RBD. Using surface plasmon resonance (SPR) binding analysis and pseudovirus infection assay, we showed that several residues in hDPP4-RBD binding interface were important on hDPP4-RBD binding and viral entry. These results provide atomic insights into the features of interactions between hDPP4 and MERS-CoV RBD, and also provide potential explanation for cellular and species tropism of MERS-CoV infection.
ESTHER : Song_2014_Virology_471-473C_49
PubMedSearch : Song_2014_Virology_471-473C_49
PubMedID: 25461530
Gene_locus related to this paper: human-DPP4

Title : Natural Dibenzo-alpha-Pyrones and Their Bioactivities - Mao_2014_Molecules_19_5088
Author(s) : Mao Z , Sun W , Fu L , Luo H , Lai D , Zhou L
Ref : Molecules , 19 :5088 , 2014
Abstract : Natural dibenzo-alpha-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-alpha-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-alpha-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-alpha-pyrones are also discussed.
ESTHER : Mao_2014_Molecules_19_5088
PubMedSearch : Mao_2014_Molecules_19_5088
PubMedID: 24759070

Title : Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4 - Wang_2013_Cell.Res_23_986
Author(s) : Wang N , Shi X , Jiang L , Zhang S , Wang D , Tong P , Guo D , Fu L , Cui Y , Liu X , Arledge KC , Chen YH , Zhang L , Wang X
Ref : Cell Res , 23 :986 , 2013
Abstract : The spike glycoprotein (S) of recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) targets the cellular receptor, dipeptidyl peptidase 4 (DPP4). Sequence comparison and modeling analysis have revealed a putative receptor-binding domain (RBD) on the viral spike, which mediates this interaction. We report the 3.0 A-resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4. Our results show that MERS-CoV RBD consists of a core and a receptor-binding subdomain. The receptor-binding subdomain interacts with DPP4 beta-propeller but not its intrinsic hydrolase domain. MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor-binding subdomain. Mutagenesis studies have identified several key residues in the receptor-binding subdomain that are critical for viral binding to DPP4 and entry into the target cell. The atomic details at the interface between MERS-CoV RBD and DPP4 provide structural understanding of the virus and receptor interaction, which can guide development of therapeutics and vaccines against MERS-CoV infection.
ESTHER : Wang_2013_Cell.Res_23_986
PubMedSearch : Wang_2013_Cell.Res_23_986
PubMedID: 23835475
Gene_locus related to this paper: human-DPP4

Title : Cholinesterase inhibitors and adverse pulmonary events in older people with chronic obstructive pulmonary disease and concomitant dementia: a population-based, cohort study - Stephenson_2012_Drugs.Aging_29_213
Author(s) : Stephenson A , Seitz DP , Fischer HD , Gruneir A , Bell CM , Gershon AS , Fu L , Anderson GM , Austin PC , Rochon PA , Gill SS
Ref : Drugs & Aging , 29 :213 , 2012
Abstract : BACKGROUND: Cholinesterase inhibitors (ChEIs) are a mainstay treatment for individuals with dementia. ChEIs may worsen airflow obstruction because of their pro-cholinergic properties. OBJECTIVE: The objective of this study was to evaluate the risk of serious pulmonary complications in the elderly with concomitant chronic obstructive pulmonary disease (COPD) and dementia who were receiving ChEIs. METHODS: This was a population-based, cohort study conducted between 2003 and 2010 in residents of Ontario, Canada. Subjects were over the age of 66 years and had concomitant dementia and COPD, identified using linked administrative databases. Exposure to ChEIs was determined using a drug benefits database. The primary outcome was an emergency room (ER) visit or hospitalization for COPD. The risk difference at 60 days and the relative risk (RR) for study outcomes were estimated in the propensity score-matched sample. RESULTS: Of 266,840 individuals with COPD, 45,503 had a concomitant diagnosis of dementia. A total of 7166 unexposed subjects were matched to subjects newly exposed to ChEIs. New users of ChEIs were not at significantly higher risk of ER visits or hospitalizations for COPD (RR 0.90; 95% CI 0.76, 1.07) or COPD exacerbations (RR 1.02; 95% CI 0.91, 1.15). Furthermore, ER visits for any respiratory diagnoses were not increased among new users of ChEIs (RR 1.02; 95% CI 0.87, 1.19) when compared with non-users. Sub-group analyses were consistent with the main analysis. CONCLUSIONS: In a large cohort of elderly individuals with COPD and dementia, new users of ChEIs had a similar risk for adverse pulmonary outcomes as those who were not receiving ChEIs.
ESTHER : Stephenson_2012_Drugs.Aging_29_213
PubMedSearch : Stephenson_2012_Drugs.Aging_29_213
PubMedID: 22332932