Xiao X

References (46)

Title : Therapeutic potential of the medicinal mushroom Ganoderma lucidum against Alzheimer's disease - Chen_2024_Biomed.Pharmacother_172_116222
Author(s) : Chen XJ , Deng Z , Zhang LL , Pan Y , Fu J , Zou L , Bai Z , Xiao X , Sheng F
Ref : Biomed Pharmacother , 172 :116222 , 2024
Abstract : Alzheimer's disease (AD) is a high-incidence neurodegenerative disorder, characterized by cognitive impairment, memory loss, and psychiatric abnormalities. Ganoderma lucidum is a famous medicinal fungus with a long history of dietary intake, containing various bioactive components, and have been documented to exhibit antioxidant, anti-inflammatory, anti-tumor, anti-aging, and immunomodulatory effects, among others. Recent studies have shown that G. lucidum and its components have promising therapeutic potential against AD from various aspects, which can delay the progression of AD, improve cognitive function and quality of life. The underlying mechanisms mainly include inhibiting tau hyperphosphorylation, inhibiting Abeta formation, affecting activated microglia, regulating NF-kappaB/MAPK signalling pathway, inhibiting neuronal apoptosis, modulating immune system, and inhibiting acetylcholinesterase, etc. This paper systematically reviewed the relevant studies on the therapeutic potential of G. lucidum and its active components for treatment of AD, key points related with the mechanism studies and clinical trials have been discussed, and further perspectives have been proposed. Totally, as a natural medicinal mushroom, G. lucidum has the potential to be developed as effective adjuvant for AD treatment owing to its therapeutic efficacy against multiple pathogenesis of AD. Further mechanical investigation and clinical trials can help unlock the complete potential of G. lucidum as a therapeutic option for AD.
ESTHER : Chen_2024_Biomed.Pharmacother_172_116222
PubMedSearch : Chen_2024_Biomed.Pharmacother_172_116222
PubMedID: 38310653

Title : Common single-base insertions in the VNTR of the carboxyl ester lipase (CEL) gene are benign and also likely to arise somatically in the exocrine pancreas - Brekke_2024_Hum.Mol.Genet__
Author(s) : Brekke RS , Gravdal A , El Jellas K , Curry GE , Lin J , Wilhelm SJ , Steine SJ , Mas E , Johansson S , Lowe ME , Johansson BB , Xiao X , Fjeld K , Molven A
Ref : Hum Mol Genet , : , 2024
Abstract : The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1-4.
ESTHER : Brekke_2024_Hum.Mol.Genet__
PubMedSearch : Brekke_2024_Hum.Mol.Genet__
PubMedID: 38483348

Title : Mitochondrial Esterase Activity Measured at the Single Organelle Level by Nano-flow Cytometry - Su_2024_Anal.Chem__
Author(s) : Su L , Gao K , Tian Y , Xiao X , Lu C , Xu J , Yan X
Ref : Analytical Chemistry , : , 2024
Abstract : Monitoring mitochondrial esterase activity is crucial not only for investigating mitochondrial metabolism but also for assessing the effectiveness of mitochondrial-targeting prodrugs. However, accurately detecting esterase activity within mitochondria poses challenges due to its ubiquitous presence in cells and the uncontrolled localization of fluorogenic probes. To overcome this hurdle and reveal variations among different mitochondria, we isolated mitochondria and preserved their activity and functionality in a buffered environment. Subsequently, we utilized a laboratory-built nano-flow cytometer in conjunction with an esterase-responsive calcein-AM fluorescent probe to measure the esterase activity of individual mitochondria. This approach enabled us to investigate the influence of temperature, pH, metal ions, and various compounds on the mitochondrial esterase activity without any interference from other cellular constituents. Interestingly, we observed a decline in the mitochondrial esterase activity following the administration of mitochondrial respiratory chain inhibitors. Furthermore, we found that mitochondrial esterase activity was notably higher in the presence of a high concentration of ATP compared to that of ADP and AMP. Additionally, we noticed a correlation between elevated levels of complex IV and increased mitochondrial esterase activity. These findings suggest a functional connection between the mitochondrial respiratory chain and mitochondrial esterase activity. Moreover, we detected an upsurge in mitochondrial esterase activity during the early stages of apoptosis, while cellular esterase activity decreased. This highlights the significance of analyzing enzyme activity within specific organelle subregions. In summary, the integration of a nano-flow cytometer and fluorescent dyes introduces a novel method for quantifying mitochondrial enzyme activity with the potential to uncover the alterations and unique functions of other mitochondrial enzymes.
ESTHER : Su_2024_Anal.Chem__
PubMedSearch : Su_2024_Anal.Chem__
PubMedID: 38173421

Title : Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency - Lin_2023_Pancreatology_S1424-3903_01834
Author(s) : Lin J , Matiwala N , Curry GE , Wilhelm SJ , Cassidy BM , Lowe ME , Xiao X
Ref : Pancreatology , : , 2023
Abstract : BACKGROUND/OBJECTIVES: Studies of a rare homozygous missense mutation identified in two brothers diagnosed with congenital pancreatic lipase deficiency (CPLD) provided the first definitive evidence linking CPLD with missense mutations in the gene of PNLIP. Herein, we investigated the molecular basis for the loss-of-function in the three novel PNLIP variants (c.305G > A, p.(W102); c.562C > T, p.(R188C); and c.1257G > A, p.(W419)) associated with CPLD. METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress. RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419 variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress. CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419 variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.
ESTHER : Lin_2023_Pancreatology_S1424-3903_01834
PubMedSearch : Lin_2023_Pancreatology_S1424-3903_01834
PubMedID: 37926600
Gene_locus related to this paper: human-PNLIP

Title : Strategy of In Situ Electrochemical Regulation for Highly Enhanced Nonenzymatic Sensing of Carbaryl - Lv_2023_Anal.Chem__
Author(s) : Lv Y , Zhang Y , Yang Y , Li J , Wang J , Xiao X , Zhang M
Ref : Analytical Chemistry , : , 2023
Abstract : Specific and sensitive sensing of most pesticide residues relies on enzymes such as acetylcholinesterase and advanced materials, which need to be loaded on the surface of working electrodes, leading to instability, uneven surface, tedious process, and high cost. Meanwhile, employing certain potential or current in electrolyte solution could also modify the surface in situ and overcome these drawbacks. However, this method is only regarded as electrochemical activation widely applied in the pretreatment of electrodes. In this paper, by means of regulating the electrochemical technique and its parameters, we prepared a proper sensing interface and derivatized the carbaryl (a carbamate pesticide) hydrolyzed form (1-naphthol) to enhance sensing by 100 times within several minutes. After regulation I by chronopotentiometry with 0.2 mA for 20 s or chronoamperometry with 2 V for 10 s, abundant oxygen-containing groups form and the ordered carbon structure is destroyed. Sweeping from -0.5 to 0.9 V through cyclic voltammetry for only one segment, following regulation II, the composition of oxygen-containing groups changes and the disordered structure is alleviated. Finally, on the constructed sensing interface, test by regulation III through differential pulse voltammetry from 0.8 to -0.4 V, resulting in derivatization of 1-naphthol during 0.8-0 V, followed by electroreduction of the derivative at around -0.17 V. Compared with the electro-oxidation peak at 0.5 V in previous reports, it is essential to improve specificity, even toward several other carbamate pesticides with similar structures. Hence, the in situ electrochemical regulation strategy has demonstrated great potential for effective sensing of electroactive molecules.
ESTHER : Lv_2023_Anal.Chem__
PubMedSearch : Lv_2023_Anal.Chem__
PubMedID: 36802553

Title : A colorimetric analytical method based on a TCPP-CuCo(2)O(4)-like peroxidase for the detection of trichlorfon - Xiao_2023_Anal.Methods__
Author(s) : Xiao X , Liao W , Ma R , Huang L , Yang Y
Ref : Anal Methods , : , 2023
Abstract : In this work, a highly sensitive colorimetric sensing platform was designed for the detection of trichlorfon based on inhibiting thiocholine (TCh)-induced redox reaction. 5,10,15,20-Tetracarboxyphenylporphyrin (TCPP) functionalized CuCo(2)O(4) (TCPP-CuCo(2)O(4)) was synthesized to construct a colorimetric sensing platform for trichlorfon. In the presence of H(2)O(2), TCPP-CuCo(2)O(4) can oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue ox-TMB, accompanied by a strong absorption peak at 652 nm, while acetylcholinesterase (AChE) can specifically hydrolyze acetylthiocholine (ATCh) into TCh, which can reduce ox-TMB back into colorless TMB, resulting in a lower absorbance at 652 nm. Trichlorfon can irreversibly inhibit the activity of AChE and thus recover the absorption peak. Under the optimized conditions, detection of trichlorfon has a wide linear range of 40-4000 ng mL(-1) with a linear correlation coefficient of 0.9904. The proposed method can be applied to the detection of trichlorfon in vegetables and has good application prospects.
ESTHER : Xiao_2023_Anal.Methods__
PubMedSearch : Xiao_2023_Anal.Methods__
PubMedID: 37609836

Title : Co-exposure to sodium hypochlorite and cadmium induced locomotor behavior disorder by influencing neurotransmitter secretion and cardiac function in larval zebrafish - Ma_2023_Environ.Pollut_342_123070
Author(s) : Ma L , Yang H , Xiao X , Chen Q , Lv W , Xu T , Jin Y , Wang W , Xiao Y
Ref : Environ Pollut , 342 :123070 , 2023
Abstract : Sodium hypochlorite (NaClO) and cadmium (Cd) are widely co-occurring in natural aquatic environment; however, no study has been conducted on effects of their combined exposure on aquatic organisms. To assess effects of exposure to NaClO and Cd in zebrafish larvae, we designed six treatment groups, as follows: control group, NaClO group (300 microg/L), 1/100 Cd group (48 microg/L), 1/30 Cd group (160 microg/L), NaClO+1/100 Cd group, and NaClO+1/30 Cd group analyzed behavior, neurological function and cardiac function. Results revealed that exposure to 1/30 Cd and NaClO+1/30 Cd caused abnormal embryonic development in larvae by altering body morphology and physiological indicators. Combined exposure to NaClO and 1/30 Cd affected the free-swimming activity and behavior of larvae in response to light-dark transition stimuli. Moreover, exposure to 1/30 Cd or NaClO+1/30 Cd resulted in a significant increase in tyrosine hydroxylase and acetylcholinesterase activities, as well as significant changes of various neurotransmitters. Lastly, exposure to 1/30 Cd or NaClO+1/30 Cd influenced the transcription of cardiac myosin-related genes and disturbed the myocardial contractile function. Altogether, our results suggested that combined exposure to NaClO and Cd induced oxidative damage in larvae, resulting in detrimental effects on nervous system and cardiac function, thus altering their swimming behavior.
ESTHER : Ma_2023_Environ.Pollut_342_123070
PubMedSearch : Ma_2023_Environ.Pollut_342_123070
PubMedID: 38056588

Title : Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis - Guo_2023_Mil.Med.Res_10_24
Author(s) : Guo LK , Su Y , Zhang YY , Yu H , Lu Z , Li WQ , Yang YF , Xiao X , Yan H , Lu TL , Li J , Liao YD , Kang ZW , Wang LF , Li Y , Li M , Liu B , Huang HL , Lv LX , Yao Y , Tan YL , Breen G , Everall I , Wang HX , Huang Z , Zhang D , Yue WH
Ref : Mil Med Res , 10 :24 , 2023
Abstract : BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R(2) for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R(2) = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R(2) = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).
ESTHER : Guo_2023_Mil.Med.Res_10_24
PubMedSearch : Guo_2023_Mil.Med.Res_10_24
PubMedID: 37269009

Title : Preclinical mouse model of a misfolded PNLIP variant develops chronic pancreatitis - Zhu_2023_Gut__
Author(s) : Zhu G , Wilhelm SJ , George LG , Cassidy BM , Zino S , Luke CJ , Hanna M , Stone S , Phan N , Matiwala N , Ballentine SJ , Lowe ME , Xiao X
Ref : Gut , : , 2023
Abstract : OBJECTIVE: Increasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism. DESIGN: We created a mouse model of Pnlip p.T221M and characterised the structural and biochemical changes in the pancreas aged 1-12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR. RESULTS: We demonstrated the hallmarks of human CP in Pnlip p.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. The Pnlip p.T221M pancreas had increased ER stress evidenced by dilated ER, increased Hspa5 (BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation of Ddit3 (CHOP), nuclear factor-kappaB and cell death. CONCLUSION: Expression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.
ESTHER : Zhu_2023_Gut__
PubMedSearch : Zhu_2023_Gut__
PubMedID: 36631248

Title : Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes mellitus: A 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial - Xu_2022_Diabetes.Obes.Metab__
Author(s) : Xu J , Ling H , Geng J , Huang Y , Xie Y , Zheng H , Niu H , Zhang T , Yuan J , Xiao X
Ref : Diabetes Obes Metab , : , 2022
Abstract : AIMS: To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl-peptidase-4 (DPP-4) inhibitor, as an add-on therapy in patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with metformin. MATERIALS AND METHODS: In this 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III study, adult T2DM patients with glycated hemoglobin A1c (HbA1c) levels ranging from 7.0-9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108+metformin and placebo+metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add-on therapy to metformin. RESULTS: At week 24, the least-square (LS) mean (standard error [SE]) change from baseline in HbA1c was significantly greater in the DBPR108 group (-0.70% [0.09%]) than that in the placebo group (-0.07% [0.11%]) (P-value <0.001), with a treatment difference of -0.63% (95% confidence interval [CI]: -0.87, -0.39) on full analysis set. A higher proportion of patients achieved an HbA1c >=6.5% (19.7% vs. 8.5%) and HbA1c >=7.0% (50.0% vs. 21.1%) at week 24 in the DBPR108+metformin group. Furthermore, add-on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2-hour postprandial plasma glucose (2-h PPG) without causing weight gain. The overall frequency of adverse events (AEs) was similar between the two groups. CONCLUSIONS: DBPR108 as add-on therapy to metformin offered a significant improvement in glycemic control, was superior to metformin monotherapy (placebo), and was safe and well-tolerated in T2DM patients that is inadequately controlled with metformin. This article is protected by copyright. All rights reserved.
ESTHER : Xu_2022_Diabetes.Obes.Metab__
PubMedSearch : Xu_2022_Diabetes.Obes.Metab__
PubMedID: 35791646

Title : Lipases secreted by a gut bacterium inhibit arbovirus transmission in mosquitoes - Yu_2022_PLoS.Pathog_18_e1010552
Author(s) : Yu X , Tong L , Zhang L , Yang Y , Xiao X , Zhu Y , Wang P , Cheng G
Ref : PLoS Pathog , 18 :e1010552 , 2022
Abstract : Arboviruses are etiological agents of various severe human diseases that place a tremendous burden on global public health and the economy; compounding this issue is the fact that effective prophylactics and therapeutics are lacking for most arboviruses. Herein, we identified 2 bacterial lipases secreted by a Chromobacterium bacterium isolated from Aedes aegypti midgut, Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with broad-spectrum virucidal activity against mosquito-borne viruses, such as dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), yellow fever virus (YFV) and Sindbis virus (SINV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation in the lipase motif of CbAE-1 fully abrogated the virucidal ability. Furthermore, CbAEs also exert lipase-dependent entomopathogenic activity in mosquitoes. The anti-arboviral and entomopathogenic properties of CbAEs render them potential candidates for the development of novel transmission control strategies against vector-borne diseases.
ESTHER : Yu_2022_PLoS.Pathog_18_e1010552
PubMedSearch : Yu_2022_PLoS.Pathog_18_e1010552
PubMedID: 35679229

Title : The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice - Fjeld_2022_Pancreatology__
Author(s) : Fjeld K , Gravdal A , Brekke RS , Alam J , Wilhelm SJ , El Jellas K , Pettersen HN , Lin J , Solheim MH , Steine SJ , Johansson BB , Njlstad PR , Verbeke CS , Xiao X , Lowe ME , Molven A
Ref : Pancreatology , : , 2022
Abstract : Title "Biosensors for the Detection of Enzymes Based on Aggregation-Induced Emission" Journal "Biosensors (Basel)" Volume "12" Page "" "" Medline "36354464" Abstract "Gao_2022_Biosensors.(Basel)_12_" LongText "Gao_2022_Biosensors.(Basel)_12_" Enzymes play a critical role in most complex biochemical processes. Some of them can be regarded as biomarkers for disease diagnosis. Taking advantage of aggregation-induced emission (AIE)-based biosensors, a series of fluorogens with AIE characteristics (AIEgens) have been designed and synthesized for the detection and imaging of enzymes. In this work, we summarized the advances in AIEgens-based probes and sensing platforms for the fluorescent detection of enzymes, including proteases, phosphatases, glycosidases, cholinesterases, telomerase and others. The AIEgens involve organic dyes and metal nanoclusters. This work provides valuable references for the design of novel AIE-based sensing platforms.
ESTHER : Fjeld_2022_Pancreatology__
PubMedSearch : Fjeld_2022_Pancreatology__
PubMedID: 36379850

Title : Learning and memory impairment induced by 1,4-butanediol is regulated by ERK1\/2-CREB-BDNF signaling pathways in PC12 cells - Chen_2022_Metab.Brain.Dis__
Author(s) : Chen C , Bu L , Liu H , Rang Y , Huang H , Xiao X , Ou G , Liu C
Ref : Metabolic Brain Disease , : , 2022
Abstract : 1,4-butanediol (1,4-BD) is a known gamma-hydroxybutyric acid (GHB) precursor which affects the nervous system after ingestion, leading to uncontrolled behavioral consequences. In the present study, we investigated whether 1,4-BD induces oxidative stress and inflammation in PC12 cells and evaluated the toxic effects of 1,4-BD associates with learning and memory. CCK-8 results revealed a dose-effect relationship between the cell viability of PC12 cells and 1,4-BD when the duration of action was 2 h or 4 h. Assay kits results showed that 1,4-BD decreased the levels of Glutathione (GSH), Glutathione peroxidase (GSH-px), Superoxide dismutase (SOD), Acetylcholine (Ach) and increased the levels of Malondialdehyde (MDA), Nitric oxide (NO) and Acetylcholinesterase (AchE). Elisa kits results indicated that 1,4-BD decreased the levels of synaptophysin I (SYN-1), Postsynaptic density protein-95 (PSD-95), Growth associated protein-43 (GAP-43) and increased the levels of Tumor necrosis factor alpha (TNF-alpha) and Interleukin- 6 (IL-6). RT-PCR results showed that the mRNA levels of PSD-95, SYN-1 and GAP-43 were significantly decreased. The expression of phosphorylation extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), phosphorylation cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) proteins were significantly decreased in PC12 cells by protein blotting. Overall, these results suggest that 1,4-BD may affect synaptic plasticity via the ERK1/2-CREB-BDNF pathway, leading to Ach release reduction and ultimately to learning and memory impairment. Furthermore, oxidative stress and inflammation induced by 1,4-BD may also result in learning and memory deficits. These findings will enrich the toxicity data of 1.4-BD associated with learning and memory impairment.
ESTHER : Chen_2022_Metab.Brain.Dis__
PubMedSearch : Chen_2022_Metab.Brain.Dis__
PubMedID: 35348994

Title : Enantioselective bioaccumulation and toxicity of rac-sulfoxaflor in zebrafish (Danio rerio) - Deng_2022_Sci.Total.Environ_817_153007
Author(s) : Deng Y , Wang R , Song B , Yang Y , Hu D , Xiao X , Chen X , Lu P
Ref : Sci Total Environ , 817 :153007 , 2022
Abstract : Sulfoxaflor is a fourth-generation neonicotinoid insecticide mainly used to control sap-feeding pests. In this study, four stereoisomers of sulfoxaflor were separated using HPLC, and the absolute configurations of three stereoisomers were identified via single-crystal X-ray diffraction. First, the stability and isomerization of the four enantiomers and rac-sulfoxaflor in water and seven organic solvents were investigated. All enantiomers were extremely unstable in water with isomerization rates above 20%. The racemate did not isomerize in any of the solutions and was stable in water (degradation rate less than 7%). Therefore, we studied the acute toxicity, enantioselective behavior, and enzymatic activities of rac-sulfoxaflor in zebrafish. The bioaccumulation experiment demonstrated that the bioconcentration of sulfoxaflor in zebrafish was enantioselective, and the four enantiomers accumulated in zebrafish in the order (+)-2S,3S-sulfoxaflor > (-)-2R,3R-sulfoxaflor > (+)-2R,3S-sulfoxaflor > (-)-2S,3R-sulfoxaflor. The effect of rac-sulfoxaflor on the enzymatic activities of zebrafish showed that superoxide dismutase and glutathione-S-transferase activities and malondialdehyde content were significantly enhanced as compared to those in control, whereas acetylcholinesterase was significantly reduced in the sulfoxaflor exposure treatment (p < 0.05), indicating that sulfoxaflor caused oxidative lesions and induced enzymatic activity in zebrafish. This study provides important information on the enantioselective behavior and toxic effects of sulfoxaflor, which can help assess the potential ecological risk of chiral pesticides to aquatic organisms.
ESTHER : Deng_2022_Sci.Total.Environ_817_153007
PubMedSearch : Deng_2022_Sci.Total.Environ_817_153007
PubMedID: 35026276

Title : Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality - Kim_2022_JAMA.Netw.Open_5_e2234221
Author(s) : Kim HS , Xiao X , Byun J , Jun G , DeSantis SM , Chen H , Thrift AP , El-Serag HB , Kanwal F , Amos CI
Ref : JAMA Netw Open , 5 :e2234221 , 2022
Abstract : IMPORTANCE: Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. OBJECTIVE: To investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021. EXPOSURES: Self-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index <=30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment. MAIN OUTCOMES AND MEASURES: The primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models. RESULTS: A total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity. CONCLUSIONS AND RELEVANCE: This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.
ESTHER : Kim_2022_JAMA.Netw.Open_5_e2234221
PubMedSearch : Kim_2022_JAMA.Netw.Open_5_e2234221
PubMedID: 36190732

Title : The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity - Gravdal_2021_J.Biol.Chem_296_100661
Author(s) : Gravdal A , Xiao X , Cnop M , El Jellas K , Johansson S , Njolstad PR , Lowe ME , Johansson BB , Molven A , Fjeld K
Ref : Journal of Biological Chemistry , 296 :100661 , 2021
Abstract : Variable number of tandem repeat (VNTR) sequences in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which is specifically expressed in pancreatic acinar cells and encodes the digestive enzyme carboxyl ester lipase. Rare single-base deletions (DELs) within the first (DEL1) or fourth (DEL4) VNTR segment of CEL cause maturity-onset diabetes of the young, type 8 (MODY8), an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Studies on the DEL1 variant have suggested that MODY8 is initiated by CEL protein misfolding and aggregation. However, it is unclear how the position of single-base deletions within the CEL VNTR affects pathogenic properties of the protein. Here, we investigated four naturally occurring CEL variants, arising from single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, and DEL13). When the four variants were expressed in human embryonic kidney 293 cells, only DEL1 and DEL4 led to significantly reduced secretion, increased intracellular aggregation, and increased endoplasmic reticulum stress compared with normal CEL protein. The level of O-glycosylation was affected in all DEL variants. Moreover, all variants had enzymatic activity comparable with that of normal CEL. We conclude that the longest aberrant protein tails, resulting from single-base deletions in the proximal VNTR segments, have highest pathogenic potential, explaining why DEL1 and DEL4 but not DEL9 and DEL13 have been observed in patients with MODY8. These findings further support the view that CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to endoplasmic reticulum stress and activation of the unfolded protein response.
ESTHER : Gravdal_2021_J.Biol.Chem_296_100661
PubMedSearch : Gravdal_2021_J.Biol.Chem_296_100661
PubMedID: 33862081

Title : Enzyme-Responsive Aqueous Two-Phase Systems in a Cationic-Anionic Surfactant Mixture - Xiao_2021_Langmuir__
Author(s) : Xiao X , Qiao Y , Xu Z , Wu T , Wu Y , Ling Z , Yan Y , Huang J
Ref : Langmuir , : , 2021
Abstract : Enzyme-instructed self-assembly is an increasingly attractive topic owing to its broad applications in biomaterials and biomedicine. In this work, we report an approach to construct enzyme-responsive aqueous surfactant two-phase (ASTP) systems serving as enzyme substrates by using a cationic surfactant (myristoylcholine chloride) and a series of anionic surfactants. Driven by the hydrophobic interaction and electrostatic attraction, self-assemblies of cationic-anionic surfactant mixtures result in biphasic systems containing condensed lamellar structures and coexisting dilute solutions, which turn into homogeneous aqueous phases in the presence of hydrolase (cholinesterase). The enzyme-sensitive ASTP systems reported in this work highlight potential applications in the active control of biomolecular enrichment/release and visual detection of cholinesterase.
ESTHER : Xiao_2021_Langmuir__
PubMedSearch : Xiao_2021_Langmuir__
PubMedID: 34714092

Title : Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial - Wang_2020_Curr.Med.Res.Opin_36_1107
Author(s) : Wang W , Yao J , Guo X , Guo Y , Yan C , Liu K , Zhang Y , Wang X , Li H , Wen Z , Li S , Xiao X , Liu W , Li Z , Zhang L , Shao S , Ye S , Qin G , Li Y , Li F , Zhang X , Li X , Peng Y , Deng H , Xu X , Zhou L , Huang Y , Cao M , Xia X , Shi M , Dou J , Yuan J
Ref : Curr Med Res Opin , 36 :1107 , 2020
Abstract : Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 +/- 0.77 in placebo group, -0.51 +/- 0.71, -0.75 +/- 0.73, and -0.57 +/- 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c >=7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program.
ESTHER : Wang_2020_Curr.Med.Res.Opin_36_1107
PubMedSearch : Wang_2020_Curr.Med.Res.Opin_36_1107
PubMedID: 32338063

Title : Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding - Cassidy_2020_Hum.Mutat_41_1967
Author(s) : Cassidy BM , Zino S , Fjeld K , Molven A , Lowe ME , Xiao X
Ref : Hum Mutat , 41 :1967 , 2020
Abstract : Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p>=.001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation.
ESTHER : Cassidy_2020_Hum.Mutat_41_1967
PubMedSearch : Cassidy_2020_Hum.Mutat_41_1967
PubMedID: 32906201
Gene_locus related to this paper: human-CEL

Title : Bioactive compounds of African star apple (Chrysophyllum albidum G. Don) and its modulatory effect on metabolic activities linked to type 2 diabetes in isolated rat psoas muscle - Erukainure_2020_J.Food.Biochem__e13576
Author(s) : Erukainure OL , Salau VF , Xiao X , Matsabisa MG , Koorbanally NA , Islam MS
Ref : J Food Biochem , :e13576 , 2020
Abstract : The infusion of Chrysophyllum albidum was investigated for its antidiabetic mechanism by studying its ability to promote glucose uptake and utilization as well as its modulatory effect on metabolic activities linked to type 2 diabetes in isolated psoas muscle. Isolated psoas muscle was incubated with different concentrations of the infusion in the presence of glucose at 37 degC for 2 hr. The infusion improved muscle glucose uptake, with concomitant elevated muscular levels of glutathione, superoxide dismutase, catalase, and ectonucleotidase activities, while depleting malondialdehyde, nitric oxide, adenosine triphosphatase, acetylcholinesterase, glycogen phosphorylase, glucose 6-phosphatase, fructose-1,6-biphosphatase, and lipase activities. It also maintained muscular morphology, while increasing magnesium, calcium, and iron levels. The infusion inhibited alpha-glucosidase and alpha-amylase activities in vitro. LC-MS analysis of the infusion revealed the presence of phenolics. These results indicate that C. albidum may mediate antidiabetic activities by stimulating muscle glucose uptake and modulation of key metabolisms linked to diabetes. PRACTICAL APPLICATIONS: The African star apple is among the underutilized fruits consumed for nutritional and medicinal purposes in Western Africa. The fruits are usually wasted during its season leading to postharvest loss owing to poor utilization. The present study gives credence to its use in treating diabetes and its complications. Thus, the fruits can be utilized in the development of cheap and affordable nutraceuticals for the management of diabetes which has been reported for its high-cost treatment. Utilization of the fruits will also reduce its postharvest loss and improve its economic values.
ESTHER : Erukainure_2020_J.Food.Biochem__e13576
PubMedSearch : Erukainure_2020_J.Food.Biochem__e13576
PubMedID: 33270256

Title : Inhibition of acetylcholinesterase activity and beta-amyloid oligomer formation by 6-bromotryptamine A, a multi-target anti-Alzheimer's molecule - Jin_2020_Oncol.Lett_19_1593
Author(s) : Jin X , Wang M , Shentu J , Huang C , Bai Y , Pan H , Zhang D , Yuan Z , Zhang H , Xiao X , Wu X , Ding L , Wang Q , He S , Cui W
Ref : Oncol Lett , 19 :1593 , 2020
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by learning and memory impairments. Recent studies have suggested that AD can be induced by multiple factors, such as cholinergic system dysfunction and beta-amyloid (Abeta) neurotoxicity. It was reported that 6-bromo-N-propionyltryptamine could treat neurological diseases, including AD. In the present study, 6-bromotryptamine A, a derivative of 6-bromo-N-propionyltryptamine, was synthesized by the condensation of 2-(6-bromo-1H-indol-3-yl)ethan-1-amine and 2-(4-bromophenyl)acetic acid, and was used as a potential anti-AD molecule. Furthermore, scopolamine can induce impairments of learning and memory, and was widely used to establish AD animal models. The results demonstrated that 6-bromotryptamine A significantly prevented scopolamine-induced short-term cognitive impairments, as revealed by various behavioral tests in mice. Furthermore, an acetylcholinesterase (AChE) activity assay revealed that 6-bromotryptamine A directly inhibited AChE activity. Notably, it was observed that 6-bromotryptamine A blocked the formation of Abeta oligomer, as evaluated by the dot blot assay. All these results suggested that 6-bromotryptamine A may be used to prevent impairments in short-term learning and memory ability possibly via the inhibition of AChE and the blockade of Abeta oligomer formation.
ESTHER : Jin_2020_Oncol.Lett_19_1593
PubMedSearch : Jin_2020_Oncol.Lett_19_1593
PubMedID: 31966085

Title : Dacryodes edulis (G. Don) H.J. Lam modulates glucose metabolism, cholinergic activities and Nrf2 expression, while suppressing oxidative stress and dyslipidemia in diabetic rats - Erukainure_2020_J.Ethnopharmacol__112744
Author(s) : Erukainure OL , Ijomone OM , Chukwuma CI , Xiao X , Salau VF , Islam MS
Ref : J Ethnopharmacol , :112744 , 2020
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Dacryodes edulis L. is an evergreen tree indigenous to western and eastern Africa which is utilized for nutritional and medicinal purposes. Folklorically, different parts of the tree are used in treating and managing diabetes and its complications. AIMS: The antidiabetic effect of the butanol fraction of D. edulis ethanol extract (BFDE) was studied in fructose-streptozotocin induced type 2 diabetic rats. METHODS: The ethanol extract was fractionated to yield the hexane, dichloromethane, ethyl acetate, butanol and aqueous fractions. The in vitro antidiabetic activities of the fractions were determined by their ability to inhibit alpha-glucosidase activity. BDFE was the most active and showed no cytotoxic effect while stimulating glucose uptake in 3T3-L1 adipocytes. Thus, selected for in vivo study. Diabetic rats were grouped into 4. The negative control group was administered water only, another group was treated with metformin (200mg/kg bodyweight), while the other groups were administered BDFE at 150 and 300mg/kg bodyweight respectively. Two other groups consisting of normal rats were given water and BFDE (300mg/kg bodyweight) respectively, with the formal serving as normal control. After 6 weeks of intervention, the rats were humanely sacrificed. RESULTS: Treatment with the fraction significantly (p<0.05) reduced the blood glucose level of the diabetic rats, with concomitant increase in serum insulin secretion. It also caused significant (p<0.05) elevation of reduced glutathione level, superoxide dismutase, catalase, alpha-amylase, and ATPase activities, with concomitant depletion in myeloperoxidase activity, NO and MDA levels of the serum and pancreas. The pancreatic morphology and beta-cell function were significantly improved in BFDE-treated rats, with restoration of the pancreatic capillary networks. Treatment with BFDE significantly (p<0.05) inhibited the activities of glycogen phosphorylase, fructose 1,6 biphosphatase, glucose 6 phosphatase, and acetylcholinesterase, while suppressing the expression of Nrf2. HPLC analysis revealed the presence of gallic acid, vanillic acid, vanillin, and (-)-epicatechin in the fraction. CONCLUSION: These results portray the antidiabetic and antioxidative properties of BFDE, which may be a synergistic consequence of the identified phenolics.
ESTHER : Erukainure_2020_J.Ethnopharmacol__112744
PubMedSearch : Erukainure_2020_J.Ethnopharmacol__112744
PubMedID: 32165174

Title : 9-Methylfascaplysin Is a More Potent Abeta Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells - Sun_2019_Mar.Drugs_17_
Author(s) : Sun Q , Liu F , Sang J , Lin M , Ma J , Xiao X , Yan S , Naman CB , Wang N , He S , Yan X , Cui W , Liang H
Ref : Mar Drugs , 17 : , 2019
Abstract : beta-Amyloid (Abeta) is regarded as an important pathogenic target for Alzheimer's disease (AD), the most prevalent neurodegenerative disease. Abeta can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Abeta aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Abeta fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Abeta fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Abeta directly reduced Abeta oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Abeta42 with polar binding energy. Hydrogen bonds and pi(-)pi interactions between the key amino acid residues of Abeta42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Abeta oligomer, Abeta modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Abeta neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Abeta aggregation along with other target mechanisms.
ESTHER : Sun_2019_Mar.Drugs_17_
PubMedSearch : Sun_2019_Mar.Drugs_17_
PubMedID: 30781608

Title : Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis - Lasher_2019_Am.J.Gastroenterol_114_974
Author(s) : Lasher D , Szabo A , Masamune A , Chen JM , Xiao X , Whitcomb DC , Barmada MM , Ewers M , Ruffert C , Paliwal S , Issarapu P , Bhaskar S , Mani KR , Chandak GR , Laumen H , Masson E , Kume K , Hamada S , Nakano E , Seltsam K , Bugert P , Muller T , Groneberg DA , Shimosegawa T , Rosendahl J , Ferec C , Lowe ME , Witt H , Sahin-Toth M
Ref : Am J Gastroenterol , 114 :974 , 2019
Abstract : OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.
ESTHER : Lasher_2019_Am.J.Gastroenterol_114_974
PubMedSearch : Lasher_2019_Am.J.Gastroenterol_114_974
PubMedID: 30789418
Gene_locus related to this paper: human-PNLIP

Title : ABAD\/17beta-HSD10 reduction contributes to the protective mechanism of huperzine a on the cerebral mitochondrial function in APP\/PS1 mice - Xiao_2019_Neurobiol.Aging_81_77
Author(s) : Xiao X , Chen Q , Zhu X , Wang Y
Ref : Neurobiology of Aging , 81 :77 , 2019
Abstract : Huperzine A (HupA) is a kind of Lycopodium alkaloid with potential disease-modifying qualities that has been reported to protect against beta-amyloid (Abeta)-mediated mitochondrial damage in Alzheimer's disease. However, the fundamental molecular mechanism underlying the protective action of HupA against Abeta-mediated mitochondrial malfunction is not completely understood. Recently, the mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) protein has been reported to facilitate Abeta-induced mitochondrial damage, resulting in mitochondrial malfunction and cell death. Our study found that HupA, but not the acetylcholinesterase inhibitor tacrine, reduced the deposition of Abeta and the ABAD level, and further reduced Abeta-ABAD complexes, thereby improving cerebral mitochondrial function in APP/PS1 mice. This was accompanied by attenuated reactive oxygen species overload, as well as increases adenosine triphosphate levels. Moreover, HupA decreased the release of cytochrome-c from mitochondria and the level of cleaved caspase-3, thereby increasing dissociated brain cell viability in APP/PS1 mice. Thus, our study demonstrated that a reduction in ABAD was involved in the protective mechanism of HupA on the cerebral mitochondrial function in APP/PS1 mice.
ESTHER : Xiao_2019_Neurobiol.Aging_81_77
PubMedSearch : Xiao_2019_Neurobiol.Aging_81_77
PubMedID: 31252207

Title : Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer's Disease: in Vitro and in Vivo Evidence - Pan_2019_ACS.Chem.Neurosci_10_4741
Author(s) : Pan H , Qiu H , Zhang K , Zhang P , Liang W , Yang M , Mou C , Lin M , He M , Xiao X , Zhang D , Wang H , Liu F , Li Y , Jin H , Yan X , Liang H , Cui W
Ref : ACS Chem Neurosci , 10 :4741 , 2019
Abstract : Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a beta-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and beta-amyloid (Abeta) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Abeta oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Abeta-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood-brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment.
ESTHER : Pan_2019_ACS.Chem.Neurosci_10_4741
PubMedSearch : Pan_2019_ACS.Chem.Neurosci_10_4741
PubMedID: 31639294

Title : A Possible Mechanism: Vildagliptin Prevents Aortic Dysfunction through Paraoxonase and Angiopoietin-Like 3 - Zhang_2018_Biomed.Res.Int_2018_3109251
Author(s) : Zhang Q , Xiao X , Zheng J , Li M , Yu M , Ping F , Wang T , Wang X
Ref : Biomed Res Int , 2018 :3109251 , 2018
Abstract : The collected data have revealed the beneficial effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the vascular endothelium, including vildagliptin. However, the involved mechanisms are not yet clear. In this study, Sprague-Dawley rats were randomly divided into the following four groups: control, diabetic, diabetic + low-dose vildagliptin (10 mg/kg/d), and diabetic + high-dose vildagliptin (20 mg/kg/d). The diabetic model was created by feeding a high-fat diet for four weeks and injection of streptozotocin. Then, vildagliptin groups were given oral vildagliptin for twelve weeks, and the control and diabetic groups were given the same volume of saline. The metabolic parameters, endothelial function, and whole genome expression in the aorta were examined. After 12 weeks of treatment, vildagliptin groups showed significantly reduced blood glucose, blood total cholesterol, and attenuated endothelial dysfunction. Notably, vildagliptin may inhibit angiopoietin-like 3 (Angptl3) and betaine-homocysteine S-methyltransferase (Bhmt) expression and activated paraoxonase-1 (Pon1) in the aorta of diabetic rats. These findings may demonstrate the vasoprotective pathway of vildagliptin in vivo.
ESTHER : Zhang_2018_Biomed.Res.Int_2018_3109251
PubMedSearch : Zhang_2018_Biomed.Res.Int_2018_3109251
PubMedID: 29951533

Title : Effects of soil acidification on the toxicity of organophosphorus pesticide on Eisenia fetida and its mechanism - Zou_2018_J.Hazard.Mater_359_365
Author(s) : Zou X , Xiao X , Zhou H , Chen F , Zeng J , Wang W , Feng G , Huang X
Ref : J Hazard Mater , 359 :365 , 2018
Abstract : Organophosphorus pesticides (OPs) have been widely used to control agricultural insects. Soil acidification is a major problem in soil of intensive agricultural systems, especially in red soil with a low pH buffer capacity. However, the effects of soil acidification on the toxicity of pesticides are still unclear. In the present study, the toxicity of three OPs on E. fetida was determined at individual (14-day lethal test) and biochemical levels (antioxidative defence enzymes) by using acidified soils (pH=5.5, 4.3 and 3.1). The results showed that the toxicity of tested OPs was slightly increased with the decrease of soil pH. To interpret the phenomena, an optimum Quantitative Structure Activity Relationship (QSAR) model was developed based on the toxicity mechanism and the partial least squares regression (PLS) method. The model indicated bioavailability and toxicodynamics are key factors of soil acidification affecting the toxicity of the OPs. Further results revealed the bioavailability of the OPs was strongly related to their hydrolysis and biodegradation character, whereas the effects of soil acidification on toxicodynamics were mainly caused by the interaction between the acetylcholinesterase (AchE) and the OPs. Results will increase understanding of the effects of soil acidification on the toxicity of pesticides and its mechanism.
ESTHER : Zou_2018_J.Hazard.Mater_359_365
PubMedSearch : Zou_2018_J.Hazard.Mater_359_365
PubMedID: 30048951

Title : Identification and characterization of a novel alkalistable and salt-tolerant esterase from the deep-sea hydrothermal vent of the East Pacific Rise - Yang_2018_Microbiolopen_7_e00601
Author(s) : Yang X , Wu L , Xu Y , Ke C , Hu F , Xiao X , Huang J
Ref : Microbiologyopen , 7 :e00601 , 2018
Abstract : A novel esterase gene selected from metagenomic sequences of deep-sea hydrothermal vents was successfully expressed in Escherichia coli. The recombinant protein (est-OKK), which belongs to the lipolytic enzyme family V, exhibited high activity toward pNP-esters with short acyl chains and especially p-nitrophenyl butyrate. Site-mutagenesis results confirmed that est-OKK contains the nonclassical catalytic tetrad predicted by alignment and computational modeling. The est-OKK protein is a moderately thermophilic enzyme that is relatively thermostable, and highly salt-tolerant, which remained stable in 3 mol/L NaCl for 6 hr. The est-OKK protein showed the considerable alkalistability, displayed optimal activity at pH 9.0 and maintained approximately 70% of its residual activity after incubation at pH 10 for 4 hr. Furthermore, the est-OKK activity was strongly resistant to a variety of metal ions such as Co(2+) , Zn(2+) , Fe(2+) , Na(+) , and K(+) ; nonionic detergents such as Tween-20, Tween-80; and organic solvents such as acetone and isopropanol. Taken together, the novel esterase with unique characteristics may give us a new insight into the family V of lipolytic enzymes, and could be a highly valuable candidate for biotechnological applications such as organic synthesis reactions or food and pharmaceutical industries.
ESTHER : Yang_2018_Microbiolopen_7_e00601
PubMedSearch : Yang_2018_Microbiolopen_7_e00601
PubMedID: 29504251
Gene_locus related to this paper: 9bact-a0a2s1gux0

Title : A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis - Xiao_2016_J.Biol.Chem_291_23224
Author(s) : Xiao X , Jones G , Sevilla WA , Stolz DB , Magee KE , Haughney M , Mukherjee A , Wang Y , Lowe ME
Ref : Journal of Biological Chemistry , 291 :23224 , 2016
Abstract : Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP.
ESTHER : Xiao_2016_J.Biol.Chem_291_23224
PubMedSearch : Xiao_2016_J.Biol.Chem_291_23224
PubMedID: 27650499
Gene_locus related to this paper: human-CEL

Title : Genome and Transcriptome Sequences Reveal the Specific Parasitism of the Nematophagous Purpureocillium lilacinum 36-1 - Xie_2016_Front.Microbiol_7_1084
Author(s) : Xie J , Li S , Mo C , Xiao X , Peng D , Wang G , Xiao Y
Ref : Front Microbiol , 7 :1084 , 2016
Abstract : Purpureocillium lilacinum is a promising nematophagous ascomycete able to adapt diverse environments and it is also an opportunistic fungus that infects humans. A microbial inoculant of P. lilacinum has been registered to control plant parasitic nematodes. However, the molecular mechanism of the toxicological processes is still unclear because of the relatively few reports on the subject. In this study, using Illumina paired-end sequencing, the draft genome sequence and the transcriptome of P. lilacinum strain 36-1 infecting nematode-eggs were determined. Whole genome alignment indicated that P. lilacinum 36-1 possessed a more dynamic genome in comparison with P. lilacinum India strain. Moreover, a phylogenetic analysis showed that the P. lilacinum 36-1 had a closer relation to entomophagous fungi. The protein-coding genes in P. lilacinum 36-1 occurred much more frequently than they did in other fungi, which was a result of the depletion of repeat-induced point mutations (RIP). Comparative genome and transcriptome analyses revealed the genes that were involved in pathogenicity, particularly in the recognition, adhesion of nematode-eggs, downstream signal transduction pathways and hydrolase genes. By contrast, certain numbers of cellulose and xylan degradation genes and a lack of polysaccharide lyase genes showed the potential of P. lilacinum 36-1 as an endophyte. Notably, the expression of appressorium-formation and antioxidants-related genes exhibited similar infection patterns in P. lilacinum strain 36-1 to those of the model entomophagous fungi Metarhizium spp. These results uncovered the specific parasitism of P. lilacinum and presented the genes responsible for the infection of nematode-eggs.
ESTHER : Xie_2016_Front.Microbiol_7_1084
PubMedSearch : Xie_2016_Front.Microbiol_7_1084
PubMedID: 27486440
Gene_locus related to this paper: purli-a0a2u3dwt4 , purli-lcse

Title : A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding - Szabo_2015_Biochim.Biophys.Acta_1852_1372
Author(s) : Szabo A , Xiao X , Haughney M , Spector A , Sahin-Toth M , Lowe ME
Ref : Biochimica & Biophysica Acta , 1852 :1372 , 2015
Abstract : Congenital pancreatic triglyceride lipase (PNLIP) deficiency is a rare disorder with uncertain genetic background as most cases were described before gene sequencing was readily available. Recently, two brothers with PNLIP deficiency were found to carry a homozygous missense mutation, c.662C>T (p.T221M) in the PNLIP gene (J. Lipid Res. 2014. 55:307-312). Molecular modeling suggested the substitution would change the orientation of residues in the catalytic site and disrupt the function of p.T221M PNLIP. To test the effect of the p.T221M mutation on PNLIP function, we expressed wild-type and p.T221M PNLIP in human embryonic kidney (HEK) 293A cells and dexamethasone-differentiated AR42J rat acinar cells. In both cellular models, wild-type PNLIP was secreted into the conditioned medium where it was readily detectable by protein staining, immunoblot or lipase activity assays. In contrast, mutant p.T221M was not secreted into the medium, but it was present in cell lysates where it accumulated in the insoluble fraction. Intracellular retention of mutant p.T221M resulted in endoplasmic reticulum (ER) stress as measured by elevated XBP1 splicing and increased levels of ER chaperones. Our results demonstrate that the presence of methionine at position 221 in the PNLIP protein sequence causes misfolding and aggregation of the p.T221M mutant inside the cell. The consequent loss of enzyme secretion adequately explains the clinical phenotype of PNLIP deficiency reported for homozygous carriers of p.T221M. Furthermore, the ability of mutant p.T221M to induce ER stress suggests that this form of PNLIP deficiency might cause acinar cell damage as well.
ESTHER : Szabo_2015_Biochim.Biophys.Acta_1852_1372
PubMedSearch : Szabo_2015_Biochim.Biophys.Acta_1852_1372
PubMedID: 25862608
Gene_locus related to this paper: human-PNLIP

Title : The resurrection genome of Boea hygrometrica: A blueprint for survival of dehydration - Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
Author(s) : Xiao L , Yang G , Zhang L , Yang X , Zhao S , Ji Z , Zhou Q , Hu M , Wang Y , Chen M , Xu Y , Jin H , Xiao X , Hu G , Bao F , Hu Y , Wan P , Li L , Deng X , Kuang T , Xiang C , Zhu JK , Oliver MJ , He Y
Ref : Proc Natl Acad Sci U S A , 112 :5833 , 2015
Abstract : "Drying without dying" is an essential trait in land plant evolution. Unraveling how a unique group of angiosperms, the Resurrection Plants, survive desiccation of their leaves and roots has been hampered by the lack of a foundational genome perspective. Here we report the approximately 1,691-Mb sequenced genome of Boea hygrometrica, an important resurrection plant model. The sequence revealed evidence for two historical genome-wide duplication events, a compliment of 49,374 protein-coding genes, 29.15% of which are unique (orphan) to Boea and 20% of which (9,888) significantly respond to desiccation at the transcript level. Expansion of early light-inducible protein (ELIP) and 5S rRNA genes highlights the importance of the protection of the photosynthetic apparatus during drying and the rapid resumption of protein synthesis in the resurrection capability of Boea. Transcriptome analysis reveals extensive alternative splicing of transcripts and a focus on cellular protection strategies. The lack of desiccation tolerance-specific genome organizational features suggests the resurrection phenotype evolved mainly by an alteration in the control of dehydration response genes.
ESTHER : Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
PubMedSearch : Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
PubMedID: 25902549
Gene_locus related to this paper: 9lami-a0a2z7c6k4 , 9lami-a0a2z7bgj4

Title : The beta5-Loop and Lid Domain Contribute to the Substrate Specificity of Pancreatic Lipase-related Protein 2 (PNLIPRP2) - Xiao_2015_J.Biol.Chem_290_28847
Author(s) : Xiao X , Lowe ME
Ref : Journal of Biological Chemistry , 290 :28847 , 2015
Abstract : Pancreatic triglyceride lipase (PNLIP) is essential for dietary fat digestion in children and adults, whereas a homolog, pancreatic lipase-related protein 2 (PNLIPRP2), is critical in newborns. The two lipases are structurally similar, yet they have different substrate specificities. PNLIP only cleaves neutral fats. PNLIPRP2 cleaves neutral and polar fats. To test the hypothesis that the differences in activity between PNLIP and PNLIPRP2 are governed by surface loops around the active site, we created multiple chimeras of both lipases by exchanging the surface loops singly or in combination. The chimeras were expressed, purified, and tested for activity against various substrates. The structural determinants of PNLIPRP2 galactolipase activity were contained in the N-terminal domain. Of the surface loops tested, the lid domain and the beta5-loop influenced activity against triglycerides and galactolipids. Any chimera on PNLIP with the PNLIPRP2 lid domain or beta5-loop had decreased triglyceride lipase activity similar to that of PNLIPRP2. The corresponding chimeras of PNLIPRP2 did not increase activity against neutral lipids. Galactolipase activity was abolished by the PNLIP beta5-loop and decreased by the PNLIP lid domain. The source of the beta9-loop had minimal effect on activity. We conclude that the lid domain and beta5-loop contribute to substrate specificity but do not completely account for the differing activities of PNLIP and PNLIPRP2. Other regions in the N-terminal domain must contribute to the galactolipase activity of PNLIPRP2 through direct interactions with the substrate or by altering the conformation of the residues surrounding the hydrophilic cavity in PNLIPRP2.
ESTHER : Xiao_2015_J.Biol.Chem_290_28847
PubMedSearch : Xiao_2015_J.Biol.Chem_290_28847
PubMedID: 26494624
Gene_locus related to this paper: human-PNLIP , human-PNLIPRP2

Title : The Arg92Cys colipase polymorphism impairs function and secretion by increasing protein misfolding - Xiao_2013_J.Lipid.Res_54_514
Author(s) : Xiao X , Ferguson MR , Magee KE , Hale PD , Wang Y , Lowe ME
Ref : J Lipid Res , 54 :514 , 2013
Abstract : Colipase is essential for efficient fat digestion. An arginine-to-cysteine polymorphism at position 92 of colipase (Arg92Cys) associates with an increased risk for developing type-2 diabetes through an undefined mechanism. To test our hypothesis that the extra cysteine increases colipase misfolding, thereby altering its intracellular trafficking and function, we expressed Cys92 colipase in HEK293T cells. Less Cys92 colipase is secreted and more is retained intracellularly in an insoluble form compared with Arg92 colipase. Nonreducing gel electrophoresis suggests the folding of secreted Cys92 colipase differs from Arg92 colipase. Cys92 colipase misfolding does not trigger the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress. The ability of secreted Cys92 colipase to stimulate pancreatic triglyceride lipase (PTL) is reduced with all substrates tested, particularly long-chain triglycerides. The reaction of Cys92 colipase with triolein and Intralipid has a much longer lag time, reflecting decreased ability to anchor PTL on those substrates. Our data predicts that humans with the Arg92Cys substitution will secrete less functional colipase into the duodenum and have less efficient fat digestion. Whether inefficient fat digestion or another property of colipase contributes to the risk for developing diabetes remains to be clarified.
ESTHER : Xiao_2013_J.Lipid.Res_54_514
PubMedSearch : Xiao_2013_J.Lipid.Res_54_514
PubMedID: 23204298

Title : Identification of amino acids in human colipase that mediate adsorption to lipid emulsions and mixed micelles - Ross_2013_Biochim.Biophys.Acta_1831_1052
Author(s) : Ross LE , Xiao X , Lowe ME
Ref : Biochimica & Biophysica Acta , 1831 :1052 , 2013
Abstract : The adsorption of colipase is essential for pancreatic triglyceride lipase activity and efficient dietary fat digestion. Yet, little is known about which specific amino acids in the hydrophobic surface of colipase influence adsorption. In this study, we systematically substituted alanine or tryptophan at residues implicated in adsorption of colipase to an interface. We expressed, purified recombinant colipase mutants and characterized the ability of each alanine mutant to restore activity to lipase in the presence of bile salts. The functions of L16A, Y55A, I79A and F84A colipase were most impaired with activities ranging from 20 to 60% of wild-type colipase. We next characterized the fluorescence properties of the tryptophan mutants in the absence and presence of bile-salt-oleic acid mixed micelles. We performed steady-state emission spectra to determine peak shift and I330/I350 ratio and acrylamide quenching curves to characterize the environment of the residues. The analysis supports a model of adsorption that includes residues Leu 34 and Leu 36 on the 2nd loop, Tyr 55 and Tyr 59 on the 3rd loop and Ile 75 and Ile 79 on the 4th loop. The analysis confirms that Phe 84 is not part of the adsorption surface and likely stabilizes the conformation of colipase. Contrary to the predictions of computer modeling, the results provide strong support for an essential role of Tyr 55 in colipase adsorption to mixed micelles. The results indicate that the adsorption of colipase to mixed micelles is mediated by specific residues residing in a defined surface of colipase.
ESTHER : Ross_2013_Biochim.Biophys.Acta_1831_1052
PubMedSearch : Ross_2013_Biochim.Biophys.Acta_1831_1052
PubMedID: 23470256

Title : Porcine pancreatic lipase related protein 2 has high triglyceride lipase activity in the absence of colipase - Xiao_2013_Biochim.Biophys.Acta_1831_1435
Author(s) : Xiao X , Ross LE , Sevilla WA , Wang Y , Lowe ME
Ref : Biochimica & Biophysica Acta , 1831 :1435 , 2013
Abstract : Efficient dietary fat digestion is essential for newborns who consume more dietary fat per body weight than at any other time of life. In many mammalian newborns, pancreatic lipase related protein 2 (PLRP2) is the predominant duodenal lipase. Pigs may be an exception since PLRP2 expression has been documented in the intestine but not in the pancreas. Because of the differences in tissue-specific expression, we hypothesized that the kinetic properties of porcine PLRP2 would differ from those of other mammals. To characterize its properties, recombinant porcine PLRP2 was expressed in HEK293T cells and purified to homogeneity. Porcine PLRP2 had activity against tributyrin, trioctanoin and triolein. The activity was not inhibited by bile salts and colipase, which is required for the activity of pancreatic triglyceride lipase (PTL), minimally stimulated PLRP2 activity. Similar to PLRP2 from other species, PLRP2 from pigs had activity against galactolipids and phospholipids. Importantly, porcine PLRP2 hydrolyzed a variety of dietary substrates including pasteurized human mother's milk and infant formula and its activity was comparable to that of PTL. In conclusion, porcine PLRP2 has broad substrate specificity and has high triglyceride lipase activity even in the absence of colipase. The data suggest that porcine PLRP2 would be a suitable lipase for inclusion in recombinant preparations for pancreatic enzyme replacement therapy.
ESTHER : Xiao_2013_Biochim.Biophys.Acta_1831_1435
PubMedSearch : Xiao_2013_Biochim.Biophys.Acta_1831_1435
PubMedID: 23770034
Gene_locus related to this paper: pig-a0a287b364

Title : Soluble epoxide hydrolase dimerization is required for hydrolase activity - Nelson_2013_J.Biol.Chem_288_7697
Author(s) : Nelson JW , Subrahmanyan RM , Summers SA , Xiao X , Alkayed NJ
Ref : Journal of Biological Chemistry , 288 :7697 , 2013
Abstract : Soluble epoxide hydrolase (sEH) plays a key role in the metabolic conversion of the protective eicosanoid 14,15-epoxyeicosatrienoic acid to 14,15-dihydroxyeicosatrienoic acid. Accordingly, inhibition of sEH hydrolase activity has been shown to be beneficial in multiple models of cardiovascular diseases, thus identifying sEH as a valuable therapeutic target. Recently, a common human polymorphism (R287Q) was identified that reduces sEH hydrolase activity and is localized to the dimerization interface of the protein, suggesting a relationship between sEH dimerization and activity. To directly test the hypothesis that dimerization is essential for the proper function of sEH, we generated mutations within the sEH protein that would either disrupt or stabilize dimerization. We quantified the dimerization state of each mutant using a split firefly luciferase protein fragment-assisted complementation system. The hydrolase activity of each mutant was determined using a fluorescence-based substrate conversion assay. We found that mutations that disrupted dimerization also eliminated hydrolase enzymatic activity. In contrast, a mutation that stabilized dimerization restored hydrolase activity. Finally, we investigated the kinetics of sEH dimerization and found that the human R287Q polymorphism was metastable and capable of swapping dimer partners faster than the WT enzyme. These results indicate that dimerization is required for sEH hydrolase activity. Disrupting sEH dimerization may therefore serve as a novel therapeutic strategy for reducing sEH hydrolase activity.
ESTHER : Nelson_2013_J.Biol.Chem_288_7697
PubMedSearch : Nelson_2013_J.Biol.Chem_288_7697
PubMedID: 23362272
Gene_locus related to this paper: human-EPHX2

Title : Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers - Hartz_2012_Arch.Gen.Psychiatry_69_854
Author(s) : Hartz SM , Short SE , Saccone NL , Culverhouse R , Chen L , Schwantes-An TH , Coon H , Han Y , Stephens SH , Sun J , Chen X , Ducci F , Dueker N , Franceschini N , Frank J , Geller F , Gubjartsson D , Hansel NN , Jiang C , Keskitalo-Vuokko K , Liu Z , Lyytikainen LP , Michel M , Rawal R , Rosenberger A , Scheet P , Shaffer JR , Teumer A , Thompson JR , Vink JM , Vogelzangs N , Wenzlaff AS , Wheeler W , Xiao X , Yang BZ , Aggen SH , Balmforth AJ , Baumeister SE , Beaty T , Bennett S , Bergen AW , Boyd HA , Broms U , Campbell H , Chatterjee N , Chen J , Cheng YC , Cichon S , Couper D , Cucca F , Dick DM , Foroud T , Furberg H , Giegling I , Gu F , Hall AS , Hallfors J , Han S , Hartmann AM , Hayward C , Heikkila K , Hewitt JK , Hottenga JJ , Jensen MK , Jousilahti P , Kaakinen M , Kittner SJ , Konte B , Korhonen T , Landi MT , Laatikainen T , Leppert M , Levy SM , Mathias RA , McNeil DW , Medland SE , Montgomery GW , Muley T , Murray T , Nauck M , North K , Pergadia M , Polasek O , Ramos EM , Ripatti S , Risch A , Ruczinski I , Rudan I , Salomaa V , Schlessinger D , Styrkarsdottir U , Terracciano A , Uda M , Willemsen G , Wu X , Abecasis G , Barnes K , Bickeboller H , Boerwinkle E , Boomsma DI , Caporaso N , Duan J , Edenberg HJ , Francks C , Gejman PV , Gelernter J , Grabe HJ , Hops H , Jarvelin MR , Viikari J , Kahonen M , Kendler KS , Lehtimaki T , Levinson DF , Marazita ML , Marchini J , Melbye M , Mitchell BD , Murray JC , Nothen MM , Penninx BW , Raitakari O , Rietschel M , Rujescu D , Samani NJ , Sanders AR , Schwartz AG , Shete S , Shi J , Spitz M , Stefansson K , Swan GE , Thorgeirsson T , Volzke H , Wei Q , Wichmann HE , Amos CI , Breslau N , Cannon DS , Ehringer M , Grucza R , Hatsukami D , Heath A , Johnson EO , Kaprio J , Madden P , Martin NG , Stevens VL , Stitzel JA , Weiss RB , Kraft P , Bierut LJ
Ref : Arch Gen Psychiatry , 69 :854 , 2012
Abstract : CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD </=10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset </=16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
ESTHER : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedSearch : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedID: 22868939

Title : Efficient display of active Geotrichum sp. lipase on Pichia pastoris cell wall and its application as a whole-cell biocatalyst to enrich EPA and DHA in fish oil - Pan_2012_J.Agric.Food.Chem_60_9673
Author(s) : Pan XX , Xu L , Zhang Y , Xiao X , Wang XF , Liu Y , Zhang HJ , Yan YJ
Ref : Journal of Agricultural and Food Chemistry , 60 :9673 , 2012
Abstract : Geotrichum sp. lipase (GSL) was first displayed on the cell wall of Pichia pastoris on the basis of the a-agglutinin anchor system developed in Saccharomyces cerevisiae . Surface display levels were monitored using Western blotting, immunofluorescence miscroscopy, and fluorescence-activated cell sorting analysis. Lipase activity of the yeast whole cells reached a maximum at 273 +/- 2.4 U/g of dry cells toward olive oil after 96 h of culture at 30 degrees C, with optimal pH and temperature at 7.5 and 45 degrees C, respectively. Displayed GSL exhibited relatively high stability between pH 6.0 and 8.0 and retained >70% of the maximum activity. The surface-displayed lipase retained 80% of its original activity after incubation at 45 degrees C for 4 h. Moreover, the GSL-displaying yeast whole cells were then used as a biocatalyst to enrich eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil on the basis of selective hydrolysis. As a result, EPA and DHA increased from 1.53 and 24.1% in the original fish oil to 1.85 and 30.86%, which were increases of 1.21- and 1.29-fold, respectively. The total yield of EPA and DHA reached 46.62%.
ESTHER : Pan_2012_J.Agric.Food.Chem_60_9673
PubMedSearch : Pan_2012_J.Agric.Food.Chem_60_9673
PubMedID: 22934819

Title : Pancreatic lipase-related protein-2 (PLRP2) can contribute to dietary fat digestion in human newborns - Xiao_2011_J.Biol.Chem_286_26353
Author(s) : Xiao X , Mukherjee A , Ross LE , Lowe ME
Ref : Journal of Biological Chemistry , 286 :26353 , 2011
Abstract : In newborn mice, PLRP2 is essential for fat digestion. In human infants, the role of PLRP2 in fat digestion is unclear, as it has poor activity against long-chain triglycerides in vitro. Also, many infants carry a genetic polymorphism resulting in a truncated protein, PLRP2 W340X, which may impact function significantly. We re-examined the properties of recombinant human PLRP2 and studied the impact of W340X mutation on its function. In the presence of bile salt micelles and colipase, human PLRP2 hydrolyzed long-chain tri-, di-, and monoglycerides. It hydrolyzed triolein at a level much lower than that of pancreatic triglyceride lipase, but close to that of carboxyl ester lipase, after a long lag phase, which could be eliminated by the addition of oleic acids. Human PLRP2 W340X was poorly secreted and largely retained inside the cell. The retention of the mutant protein triggered endoplasmic reticulum stress and unfolded protein responses. Our results show that earlier studies underestimated human PLRP2 activity against triolein by employing suboptimal assay conditions. In vivo, dietary fat emulsions contain fatty acids as a result of the action of gastric lipase. Consequently, PLRP2 can contribute to fat digestion during early infancy. Furthermore, infants with homozygous W340X alleles will not secrete functional PLRP2 and may have inefficient dietary fat digestion, particularly when breastfeeding is unavailable. Additionally, the aberrant folding of W340X mutant may cause chronic cellular stress and increase susceptibility of pancreatic exocrine cells to other metabolic stressors.
ESTHER : Xiao_2011_J.Biol.Chem_286_26353
PubMedSearch : Xiao_2011_J.Biol.Chem_286_26353
PubMedID: 21652702

Title : Kinetic properties of mouse pancreatic lipase-related protein-2 suggest the mouse may not model human fat digestion - Xiao_2011_J.Lipid.Res_52_982
Author(s) : Xiao X , Ross LE , Miller RA , Lowe ME
Ref : J Lipid Res , 52 :982 , 2011
Abstract : Genetically engineered mice have been employed to understand the role of lipases in dietary fat digestion with the expectation that the results can be extrapolated to humans. However, little is known about the properties of mouse pancreatic triglyceride lipase (mPTL) and pancreatic lipase-related protein-2 (mPLRP2). In this study, both lipases were expressed in Pichia Pastoris GS115, purified to near homogeneity, and their properties were characterized. Mouse PTL displayed the kinetics typical of PTL from other species. Like mPTL, mPLRP2 exhibited strong activity against various triglycerides. In contrast to mPTL, mPLRP2 was not inhibited by increasing bile salt concentration. Colipase stimulated mPLRP2 activity 2- to 4-fold. Additionally, mPTL absolutely required colipase for absorption to a lipid interface, whereas mPLRP2 absorbed fully without colipase. mPLRP2 had full activity in the presence of BSA, whereas BSA completely inhibited mPTL unless colipase was present. All of these properties of mPLRP2 differ from the properties of human PLRP2 (hPLRP2). Furthermore, mPLRP2 appears capable of compensating for mPTL deficiency. These findings suggest that the molecular mechanisms of dietary fat digestion may be different in humans and mice. Thus, extrapolation of dietary fat digestion in mice to humans should be done with care.
ESTHER : Xiao_2011_J.Lipid.Res_52_982
PubMedSearch : Xiao_2011_J.Lipid.Res_52_982
PubMedID: 21382969
Gene_locus related to this paper: human-PNLIPRP2 , human-PNLIPRP3 , mouse-1plip , mouse-LIPR2

Title : [Heterologous expression and characterization of Yarrowia lipolytica lipase 4 and lipase 5 in Pichia pastoris] - Zhao_2011_Wei.Sheng.Wu.Xue.Bao_51_1374
Author(s) : Zhao H , Xiao X , Xu L , Liu Y , Yan Y
Ref : Wei Sheng Wu Xue Bao , 51 :1374 , 2011
Abstract : OBJECTIVE: To clone cDNA sequences of lipase 4 (LIP4) and lipase 5 (LIPS), analyze gene structures and express them in Pichia pastoris so as to investigate their enzymatic characteristics. METHODS: We first cloned cDNA sequences of LIP4 and LIP5 by reverse transcription PCR and analyzed their gene structures by SignalP 3.0. Then, intracellular expression vectors pPIC3. 5K-Lip4, pPIC3. 5K-Lip5 and inducible secretion vectors pPIC9K-Lip4, pPIC9K-Lip5 were constructed. All vectors were transformed into Pichia pastoris GS115 by electroporation, resulting in a series of engineered strains. After fermentation and NTA-Ni resin purification, the enzymatic properties of LIP4 and LIP5 were examined. RESULTS: The cloned cDNA sequences revealed that there was no intron in both of Lip4 and Lip5. The two lipases both contained catalytic triads and conserved GHSLG motifs. Their optimal substrate, pH, temperature were respectively pNP-caprylate (C8), 7.0 and 40 degrees C. The activities of LIP4 and LIPS were 10.16 U/mg and 5.1 U/mg, respectively. It was found that LIP4 was more sensitive to the variations of pH and temperature than LIP5. LIP4 and LIP5 could both be stimulated by Ca2+, besides LIPS could also be activated by Mg2+. They were both strongly inhibited by Hg2+, Phenylmethanesulfonyl fluoride (PMSF) and Dithiothreitol (DTT). CONCLUSION: The cloning of Lip4 and Lip5, expression in P. pastoris and characterization of their properties would offer a solid basis for their large-scale production and future application. In addition, the results also enriched the data for a systematic research on the lipase gene family of Y. lipolytica.
ESTHER : Zhao_2011_Wei.Sheng.Wu.Xue.Bao_51_1374
PubMedSearch : Zhao_2011_Wei.Sheng.Wu.Xue.Bao_51_1374
PubMedID: 22233059

Title : Trp-107 and trp-253 account for the increased steady state fluorescence that accompanies the conformational change in human pancreatic triglyceride lipase induced by tetrahydrolipstatin and bile salt - Bourbon-Freie_2009_J.Biol.Chem_284_14157
Author(s) : Bourbon-Freie A , Dub RE , Xiao X , Lowe ME
Ref : Journal of Biological Chemistry , 284 :14157 , 2009
Abstract : The conformation of a surface loop, the lid, controls activity of pancreatic triglyceride lipase (PTL) by moving from a position that sterically hinders substrate access to the active site into a new conformation that opens and configures the active site. Movement of the lid is accompanied by a large change in steady state tryptophan fluorescence. Although a change in the microenvironment of Trp-253, a lid residue, could account for the increased fluorescence, the mechanism and tryptophan residues have not been identified. To identify the tryptophan residues responsible for the increased fluorescence and to gain insight into the mechanism of lid opening and the structure of PTL in aqueous solution, we examined the effects of mutating individual tryptophan residues to tyrosine, alanine, or phenylalanine on lipase activity and steady state fluorescence. Substitution of tryptophans 86, 107, 253, and 403 reduced activity against tributyrin with the largest effects caused by substituting Trp-86 and Trp-107. Trp-107 and Trp-253 fluorescence accounts for the increased fluorescence emissions of PTL that is stimulated by tetrahydrolipstatin and sodium taurodeoxycholate. The largest contribution is from Trp-107. Contrary to the prediction from the crystal structure of PTL, Trp-107 is likely exposed to solvent. Both tetrahydrolipstatin and sodium taurodeoxycholate are required to produce the increased fluorescence in PTL. Alone, neither is sufficient. Colipase does not significantly influence the conformational changes leading to increased emission fluorescence. Thus, Trp-107 and Trp-253 contribute to the change in steady state fluorescence that is triggered by mixed micelles of inhibitor and bile salt. Furthermore, the results suggest that the conformation of PTL in solution differs significantly from the conformation in crystals.
ESTHER : Bourbon-Freie_2009_J.Biol.Chem_284_14157
PubMedSearch : Bourbon-Freie_2009_J.Biol.Chem_284_14157
PubMedID: 19346257
Gene_locus related to this paper: human-PNLIP

Title : Environmental adaptation: genomic analysis of the piezotolerant and psychrotolerant deep-sea iron reducing bacterium Shewanella piezotolerans WP3 - Wang_2008_PLoS.One_3_e1937
Author(s) : Wang F , Wang J , Jian H , Zhang B , Li S , Zeng X , Gao L , Bartlett DH , Yu J , Hu S , Xiao X
Ref : PLoS ONE , 3 :e1937 , 2008
Abstract : Shewanella species are widespread in various environments. Here, the genome sequence of Shewanella piezotolerans WP3, a piezotolerant and psychrotolerant iron reducing bacterium from deep-sea sediment was determined with related functional analysis to study its environmental adaptation mechanisms. The genome of WP3 consists of 5,396,476 base pairs (bp) with 4,944 open reading frames (ORFs). It possesses numerous genes or gene clusters which help it to cope with extreme living conditions such as genes for two sets of flagellum systems, structural RNA modification, eicosapentaenoic acid (EPA) biosynthesis and osmolyte transport and synthesis. And WP3 contains 55 open reading frames encoding putative c-type cytochromes which are substantial to its wide environmental adaptation ability. The mtr-omc gene cluster involved in the insoluble metal reduction in the Shewanella genus was identified and compared. The two sets of flagellum systems were found to be differentially regulated under low temperature and high pressure; the lateral flagellum system was found essential for its motility and living at low temperature.
ESTHER : Wang_2008_PLoS.One_3_e1937
PubMedSearch : Wang_2008_PLoS.One_3_e1937
PubMedID: 18398463
Gene_locus related to this paper: shepw-b8ci75 , shepw-b8cib3 , shepw-b8ciu7 , shepw-b8cld5 , shepw-b8cll2 , shepw-b8clm3 , shepw-b8cls4 , shepw-b8ct86 , shepw-b8ctf0 , shepw-b8ctt3 , shepw-b8cuq7 , shepw-b8cuu6 , shepw-b8cuz1 , shepw-b8cvm0 , shepw-b8cqh1 , shepw-b8cgv9 , shepw-b8chj5 , shepw-b8cpv3 , shepw-b8civ4 , shepw-b8cn18

Title : Corrigendum to 'Protection against ischemic injury in primary cultured mouse astrocytes by bis(7)-tacrine, a novel acetylcholinesterase inhibitor' -
Author(s) : Wu D , Xiao X , Ng AK , Chen PM , Chung W , Lee NT , Carlier PR , Pang Y , Yu AC , Han Y
Ref : Neuroscience Letters , 290 :84 , 2000
PubMedID: 10925180