Song X

References (34)

Title : Uptake, accumulation, and degradation of dibutyl phthalate by three wetland plants - Fan_2023_Water.Sci.Technol_88_1508
Author(s) : Fan Y , Li T , Zhang Z , Song X , Cun D , Cui B , Wang Y
Ref : Water Sci Technol , 88 :1508 , 2023
Abstract : The uptake and degradation mechanisms of dibutyl phthalate (DBP) by three wetland plants, namely Lythrum salicaria, Thalia dealbata, and Canna indica, were studied using hydroponics. The results revealed that exposure to DBP at 0.5 mg/L had no significant effect on the growth of L. salicaria and C. indica but inhibited the growth of T. dealbata. After 28 days, DBP concentrations in the roots of L. salicaria, T. dealbata, and C. indica were 8.74, 5.67, and 5.46 mg/kg, respectively, compared to 2.03-3.95 mg/kg in stems and leaves. Mono-n-butyl phthalate concentrations in L. salicaria tissues were significantly higher than those in the other two plants at 23.1, 15.0, and 13.6 mg/kg in roots, stems, and leaves, respectively. The roots of L. salicaria also had the highest concentration of phthalic acid, reaching 2.45 mg/kg. Carboxylesterase, polyphenol oxidase, and superoxide dismutase may be the primary enzymes involved in DBP degradation in wetland plants. The activities of these three enzymes exhibited significant changes in plant tissues. The findings suggest L. salicaria as a potent plant for phytoremediation and use in constructed wetlands for the treatment of DBP-contaminated wastewater.
ESTHER : Fan_2023_Water.Sci.Technol_88_1508
PubMedSearch : Fan_2023_Water.Sci.Technol_88_1508
PubMedID: 37768752

Title : Adipose triglyceride lipase is a therapeutic target in advanced prostate cancer that promotes metabolic plasticity - Awad_2023_Cancer.Res__
Author(s) : Awad D , Cao PHA , Pulliam TL , Spradlin M , Subramani E , Tellman TV , Ribeiro CF , Muzzioli R , Jewell BE , Pakula H , Ackroyd JJ , Murray MM , Han JJ , Leng M , Jain A , Piyarathna B , Liu J , Song X , Zhang J , Klekers AR , Drake JM , Ittmann MM , Coarfa C , Piwnica-Worms D , Farach-Carson MC , Loda M , L SE , Frigo DE
Ref : Cancer Research , : , 2023
Abstract : Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. Better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacological inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that non-canonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies.
ESTHER : Awad_2023_Cancer.Res__
PubMedSearch : Awad_2023_Cancer.Res__
PubMedID: 38038968

Title : Biogenic Selenium Nanoparticles Attenuate Abeta(25-35)-Induced Toxicity in PC12 Cells via Akt\/CREB\/BDNF Signaling Pathway - Qiao_2022_Neurotox.Res__
Author(s) : Qiao L , Chen Y , Dou X , Song X , Xu C
Ref : Neurotox Res , : , 2022
Abstract : Deposition of aggregated amyloid beta (Abeta) protein is considered to be a major causative factor that is associated with the development of oxidative stress and neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Selenium nanoparticles (SeNPs) have been experimentally using for treatment of neurological disease due to their low toxicity, high bioavailability, and multiple bioactivities. This study was conducted to investigate the protective effects of biogenic SeNPs by Lactobacillus casei ATCC 393 against Abeta(25-35)-induced toxicity in PC12 cells and its association with oxidative stress and inflammation. The results showed that SeNPs had no cytotoxicity on PC12 cells. Moreover, SeNPs entered cells through cellular endocytosis, which effectively attenuated Abeta(25-35)-induced toxicity in PC12 cells. In addition, compared with Abeta(25-35) model group, SeNP pretreatment significantly enhanced the antioxidant capacity, inhibited the overproduction of reactive oxygen species (ROS), effectively regulated the inflammatory response, decreased the activity of acetylcholinesterase, significantly reduced the expression level of caspase-1 and the ratio of Bcl-2/Bax, and upregulated the expression level of p53. Furthermore, compared with Abeta(25-35) model group, SeNPs effectively promoted the phosphorylation of Akt and cAMP-response element-binding protein (CREB), and upregulated the expression level of brain-derived neurotrophic factor (BDNF). In addition, the Akt inhibitor (AKT inhibitor VIII, AKTi-1/2) could reverse the protective effects of SeNPs on PC12 cells. The Akt agonist (SC79) had a similar effect on PC12 cells as that of SeNPs. Overall, this study demonstrated that biogenic SeNPs can effectively alleviate the Abeta(25-35)-induced toxicity in PC12 cells via Akt/CREB/BDNF signaling pathway.
ESTHER : Qiao_2022_Neurotox.Res__
PubMedSearch : Qiao_2022_Neurotox.Res__
PubMedID: 36435923

Title : Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats - Zhang_2022_J.Affect.Disord__
Author(s) : Zhang W , Chen Y , Qin J , Lu J , Fan Y , Shi Z , Song X , Li C , Zhao T
Ref : J Affect Disord , : , 2022
Abstract : BACKGROUND: The underlying molecular mechanisms of the excitatory/inhibitory (E/I) imbalance induced by sevoflurane exposure to neonates remain poorly understood. This study aimed to investigate the long-term effects of prolonged sevoflurane exposure to neonatal rats during the peak period of synaptogenesis on the changes of trans-synaptic neurexin-neuroligin interactions, synaptic ultrastructure in the hippocampus and cognition. METHODS: A total of 30 rat pups at postnatal day (P) 7 was randomly divided into two groups: the control group (exposed to 30 % oxygen balanced with nitrogen) and the sevoflurane group (exposed to 2.5 % sevoflurane plus 30 % oxygen balanced with nitrogen) for 6 h. Neurocognitive behaviors were assessed with the Open field test at P23-25 and the Morris water maze test at P26-30. The expression of beta-neurexin (beta-NRX), N-methyl-d-aspartate receptor 2 subunit (NR2A and NR2B), neuroligin-1 (NLG-1), neuroligin-2 (NLG-2), postsynaptic density protein-95 (PSD-95), alpha1-subunit of the gamma-aminobutyric acid A receptor (GABAAalpha1) and gephyrin in the hippocampus at P30 were measured by Western blot. The ultrastructure of synapses was examined under electron microscope. RESULTS: Prolonged sevoflurane exposure at P7 resulted in cognitive deficiency in adolescence, as well as the downregulation of beta-NRX, NR2A, NR2B, NLG-1, and PSD-95, and the upregulation of GABAAalpha1, NLG-2, and gephyrin in the hippocampal CA3 region. Sevoflurane anesthesia also increased the number of symmetric synapses in the hippocampus. CONCLUSIONS: Prolonged sevoflurane exposure during the brain development leads to cognitive deficiency and disproportion of excitatory/inhibitory synapses which may be caused by dysregulated expression of synaptic adhesion molecules of beta-NRX and neuroligins.
ESTHER : Zhang_2022_J.Affect.Disord__
PubMedSearch : Zhang_2022_J.Affect.Disord__
PubMedID: 35691415

Title : The alteration of the expression level of neuropathy target esterase in human neuroblastoma SK-N-SH cells disrupts cellular phospholipids homeostasis - Hou_2022_Toxicol.In.Vitro__105509
Author(s) : Hou WY , Song X , Wang Y , Chang P , Chen R , Wu YJ
Ref : Toxicol In Vitro , :105509 , 2022
Abstract : Neuropathy target esterase (NTE) has been proven to act as a lysophospholipase (LysoPLA) and phospholipase B (PLB) in mammalian cells. In this study, we took human neuroblastoma SK-N-SH cells as the research object and explored the effect of NTE on phospholipid homeostasis. The results showed that phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) levels significantly increased (> 40%), while glycerophosphocholine (GPC) decreased (below 60%) after NTE gene was knockdown in the cells (NTE < 30% of control), which were prepared by gene silencing with dsRNA-NTE. However, in the NTE-overexpressed cells (NTE > 50% of control), which were prepared by expressing recombinant catalytic domain of NTE, LPC remarkably decreased (below 80%) and GPC enhanced (> 40%). Mipafox, a neuropathic organophosphorus compound (OP), significantly inhibited NTE-LysoPLA and NTE-PLB activities (> 95-99% inhibition at 50 microM), which was accompanied with a decreased GPC level (below 40%) although no change of the PC and LPC levels was observed; while paraoxon, a non-neuropathic OP, suppresses neither the activities of NTE-phospholipases nor the levels of PC, LPC, and GPC. Thus, we concluded that both the stable up- or down-regulated expression of NTE gene and the loss of NTE-LysoPLA/PLB activities disrupts phospholipid homeostasis in the cells although the inhibition of NTE activity only decreased GPC content without altering PC and LPC levels.
ESTHER : Hou_2022_Toxicol.In.Vitro__105509
PubMedSearch : Hou_2022_Toxicol.In.Vitro__105509
PubMedID: 36336212

Title : Antioxidant and Anti-inflammatory Properties Mediate the Neuroprotective Effects of Hydro-ethanolic Extract of Tiliacora triandra Against Cisplatin-induced Neurotoxicity - Huang_2021_J.Inflamm.Res_14_6735
Author(s) : Huang Y , Liu C , Song X , An M , Liu M , Yao L , Famurewa AC , Olatunji OJ
Ref : J Inflamm Res , 14 :6735 , 2021
Abstract : BACKGROUND: Cisplatin (CDDP) is an efficacious anticancer agent used widely in chemotherapy despite its severe side effect related to neurotoxicity. Redox imbalance and inflammatory mechanism have been implicated in the pathophysiology of CDDP-induced neurotoxicity. Herein, we investigated whether Tiliacora triandra (TT) extract could inhibit CDDP-induced redox-mediated neurotoxicity and behavioural deficit in rats. MATERIALS AND METHODS: CDDP-induced redox-mediated neurotoxicity and behavioral deficit in rats. Rats were administered TT for five consecutive weeks (250 and 500 mg/kg bw), while weekly i.p. injection of CDDP commenced on the second week (2.5 mg/kg bw) of the TT administration. RESULTS: CCDDP caused significant body weight reduction and cognitive diminution as revealed by Morris water maze and Y maze tests. In the CDDP-induced cognitive impairment (CICI) rats, there were remarkable increases in the brain levels of TNF-alpha, IL-6 and IL-1beta and malondialdehyde (MDA), whereas catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities considerably decreased compared to normal control. The brain acetylcholinesterase (AChE) activity in CDDP control rats was significantly increased compared to the normal control. The expression of caspase-3 and p53 proteins was upregulated by CDDP injection, whereas Bcl2 was downregulated coupled with histopathological alterations in the rat brain. Interestingly, treatment with TT significantly abated neurobehavioral deficits, MDA and cytokine levels and restored CAT, GPx, GSH, SOD, and AChE activities compared to the CDDP control rats. Caspase-3 level as well as Bcl2 and p53 expressions were modulated with alleviated changes in histopathology. CONCLUSION: The findings highlight neuroprotective and cognitive function improvement efficacy of TT against CICI via redox-inflammatory balance and antiapoptotic mechanism in rats.
ESTHER : Huang_2021_J.Inflamm.Res_14_6735
PubMedSearch : Huang_2021_J.Inflamm.Res_14_6735
PubMedID: 34916822

Title : Protection studies of an excretory-secretory protein HcABHD against Haemonchus contortus infection - Lu_2021_Vet.Res_52_3
Author(s) : Lu M , Tian X , Zhang Y , Wang W , Tian AL , Aimulajiang K , Liu L , Li C , Yan R , Xu L , Song X , Li X
Ref : Vet Res , 52 :3 , 2021
Abstract : Unlike the successful immunization of native H. contortus antigens that contributed to the realization of the first commercial vaccine Barbervax, not many studies revealed the encouraging protective efficacies of recombinant H. contortus antigens in laboratory trials or under field conditions. In our preliminary study, H. contortus alpha/beta-hydrolase domain protein (HcABHD) was demonstrated to be an immunomodulatory excretory-secretory (ES) protein that interacts with goat T cells. We herein evaluated the protective capacities of two HcABHD preparations, recombinant HcABHD (rHcABHD) antigen and anti-rHcABHD IgG, against H. contortus challenge via active and passive immunization trials, respectively. Parasitological parameter, antibody responses, hematological pathology and cytokine profiling in unchallenged and challenged goats were monitored and determined throughout both trials. Subcutaneous administration of rHcABHD with Freund adjuvants elicited protective immune responses in challenged goats, diminishing cumulative fecal egg counts (FEC) and total worm burden by 54.0% and 74.2%, respectively, whereas passive immunization with anti-rHcABHD IgG conferred substantial protection to challenged goats by generating a 51.5% reduction of cumulative FEC and a 73.8% reduction of total worm burden. Additionally, comparable changes of mucosal IgA levels, circulating IgG levels, hemoglobin levels, and serum interleukin (IL)-4 and IL-17A levels were observed in rHcABHD protein/anti-rHcABHD IgG immunized goats in both trials. Taken together, the recombinant version of HcABHD might have further application under field conditions in protecting goats against H. contortus infection, and the integrated immunological pipeline of ES antigen identification, screening and characterization may provide new clues for further development of recombinant subunit vaccines to control H. contortus.
ESTHER : Lu_2021_Vet.Res_52_3
PubMedSearch : Lu_2021_Vet.Res_52_3
PubMedID: 33407892
Gene_locus related to this paper: haeco-CDJ88804

Title : In Vitro and In Vivo Anti-AChE and Antioxidative Effects of Schisandra chinensis Extract: A Potential Candidate for Alzheimer's Disease - Song_2020_Evid.Based.Complement.Alternat.Med_2020_2804849
Author(s) : Song X , Wang T , Guo L , Jin Y , Wang J , Yin G , Jiang K , Wang L , Huang H , Zeng L
Ref : Evid Based Complement Alternat Med , 2020 :2804849 , 2020
Abstract : Acetylcholinesterase (AChE) inhibition and antioxidants are two common strategies for the treatment in the early stage of Alzheimer's Disease (AD). In this study, extracts from nine traditional Chinese medical (TCM) herbs were tested for anti-AChE activity by Ellman's microplate assay and cytotoxicity by CCK-8. Based on its excellent AChE inhibition effect and its lowest cytotoxicity, Schisandra chinensis (SC) extract was selected to do the mechanism research. SC extract protected pheochromocytoma (PC12) cells against H2O2-induced toxicity by improving the cell survival rate in a dose-dependent manner. And it also showed significant free radical (DPPH) scavenging activities, ferric reducing antioxidant power (FRAP), and 2,2'-Azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging. To confirm these results, the scopolamine-induced mice models were utilized in this study. Compared with the positive drug (piracetam), SC could also exhibit similar effects to alleviate the mice's cognitive deficits. Moreover, in the mice brain samples, the AChE activity and malondialdehyde (MDA) levels of SC-treatment group both showed a reverse as compared to model group. Taken together, these results all suggested that SC extract may be a potential therapeutic candidate for AD.
ESTHER : Song_2020_Evid.Based.Complement.Alternat.Med_2020_2804849
PubMedSearch : Song_2020_Evid.Based.Complement.Alternat.Med_2020_2804849
PubMedID: 32148536

Title : A Novel alpha\/beta Hydrolase Domain Protein Derived From Haemonchus contortus Acts at the Parasite-Host Interface - Lu_2020_Front.Immunol_11_1388
Author(s) : Lu M , Tian X , Tian AL , Li C , Yan R , Xu L , Song X , Li X
Ref : Front Immunol , 11 :1388 , 2020
Abstract : The alpha/beta-hydrolase domain (ABHD) proteins belonging to alpha/beta-hydrolase (ABH) superfamily are ubiquitously distributed throughout all the organisms, and their functional roles have been implicated in energy metabolism, cell signaling, growth and development. In our preliminary work, we identified a novel ABHD protein derived from Haemonchus contortus excretory-secretory (ES) proteins (HcESPs) that interacted with host T cells. Here, we demonstrated that H. contortus ABHD (HcABHD) protein, expressed in all life-cycle stages of H. contortus, is a mammalian ABHD17 homolog with immunodiagnostic utility and lipase activity. Given its catalytic activities and immunomodulatory potentials, we further investigated the functional diversity of HcABHD as an individual ES protein in parasite-host interactions. HcABHD protein may serve as depalmitoylase or thioesterase to suppress cell viability, inhibit cell proliferation, induce intrinsic and extrinsic T cell apoptosis, and cause cell cycle arrested at G1 phase. Moreover, recombinant HcABHD stimuli exerted critical controls on T cell cytokine production profiles, predominantly by inhibiting the secretions of interleukin (IL)-4, interferon-gamma (IFN-gama) and transforming growth factor-beta (TGF-beta) 1, and promoting IL-10 production. As the immunomodulator acting at the parasite-host interface, HcABHD protein may have potential applications for the vaccine development of therapeutic intervention. Together, these findings may help illuminate the molecular and particularly immunomodulatory aspects of ES proteins and contribute to an enhanced understanding of parasite immune evasion in H. contortus-host biology.
ESTHER : Lu_2020_Front.Immunol_11_1388
PubMedSearch : Lu_2020_Front.Immunol_11_1388
PubMedID: 32695121
Gene_locus related to this paper: haeco-CDJ88804

Title : Toxicological and biochemical analyses demonstrate no toxic effect of Bt maize on the Folsomia candida - Jiang_2020_PLoS.One_15_e0232747
Author(s) : Jiang Z , Zhou L , Wang B , Wang D , Wu F , Yin J , Song X
Ref : PLoS ONE , 15 :e0232747 , 2020
Abstract : The potential effects of Bt (Bacillus thuringiensis) maize on non-target organisms must be conducted before the Bt maize is commercially planted. Folsomia candida is one of the non-target organisms of Bt maize, also as an important indicator of soil quality and environmental pollution. In this study, a 90-day F. candida feeding test were conducted to evaluate the potential effects of two Bt maize lines IE09S034 and BT799 and their non-Bt conventional isolines Zong 31 and Zheng 58. The results show that Bt maize lines had no significant effects on the survival rate, reproduction, adult body length, larval body length, and the activities of acetyl cholinesterase, catalase and superoxide dismutase on the F. candida. Namely, Bt maize had no toxic effects on the F. candida.
ESTHER : Jiang_2020_PLoS.One_15_e0232747
PubMedSearch : Jiang_2020_PLoS.One_15_e0232747
PubMedID: 32374765

Title : A Review of the Pharmacological Properties of Psoralen - Ren_2020_Front.Pharmacol_11_571535
Author(s) : Ren Y , Song X , Tan L , Guo C , Wang M , Liu H , Cao Z , Li Y , Peng C
Ref : Front Pharmacol , 11 :571535 , 2020
Abstract : Psoralen is the principal bioactive component in the dried fruits of Cullen corylifolium (L.) Medik (syn. Psoralea corylifolia L), termed "Buguzhi" in traditional Chinese medicine (TCM). Recent studies have demonstrated that psoralen displays multiple bioactive properties, beneficial for the treatment of osteoporosis, tumors, viruses, bacteria, and inflammation. The present review focuses on the research evidence relating to the properties of psoralen gathered over recent years. Firstly, multiple studies have demonstrated that psoralen exerts strong anti-osteoporotic effects via regulation of osteoblast/osteoclast/chondrocyte differentiation or activation due to the participation in multiple molecular mechanisms of the wnt/beta-catenin, bone morphogenetic protein (BMP), inositol-requiring enzyme 1 (IRE1)/apoptosis signaling kinase 1 (ASK1)/c-jun N-terminal kinase (JNK) and the Protein Kinase B(AKT)/activator protein-1 (AP-1) axis, and the expression of miR-488, peroxisome proliferators-activated receptor-gamma (PPARgamma), and matrix metalloproteinases (MMPs). In addition, the antitumor properties of psoralen are associated with the induction of ER stress-related cell death via enhancement of PERK: Pancreatic Endoplasmic Reticulum Kinase (PERK)/activating transcription factor (ATF), 78kD glucose-regulated protein (GRP78)/C/EBP homologous protein (CHOP), and 94kD glucose-regulated protein (GRP94)/CHOP signaling, and inhibition of P-glycoprotein (P-gp) or ATPase that overcomes multidrug resistance. Furthermore, multiple articles have shown that the antibacterial, anti-inflammatory and neuroprotective effects of psoralen are a result of its interaction with viral polymerase (Pol), destroying the formation of biofilm, and regulating the activation of tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin 4/5/6/8/12/13 (IL-4/5/6/8/12/13), GATA-3, acetylcholinesterase (AChE), and the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the toxic effects and mechanisms of action of psoralen have also been reviewed.
ESTHER : Ren_2020_Front.Pharmacol_11_571535
PubMedSearch : Ren_2020_Front.Pharmacol_11_571535
PubMedID: 33013413

Title : Latrophilin mediates insecticides susceptibility and fecundity through two carboxylesterases, esterase4 and esterase6, in Tribolium castaneum - Wei_2019_Bull.Entomol.Res__1
Author(s) : Wei L , Gao S , Xiong W , Liu J , Mao J , Lu Y , Song X , Li B
Ref : Bull Entomol Res , :1 , 2019
Abstract : Latrophilin (LPH) is known as an adhesion G-protein-coupled receptor which involved in multiple physiological processes in organisms. Previous studies showed that lph not only involved the susceptibility to anticholinesterase insecticides but also affected fecundity in Tribolium castaneum. However, its regulatory mechanisms in these biological processes are still not clear. Here, we identified two potential downstream carboxylesterase (cce) genes of Tclph, esterase4 and esterase6, and further characterized their interactions with Tclph. After treatment of T. castaneum larvae with carbofuran or dichlorvos insecticides, the transcript levels of Tcest4 and Tcest6 were significantly induced from 12 to 72 h. RNAi against Tcest4 or Tcest6 led to the higher mortality compared with the controls after the insecticides treatment, suggesting that these two genes play a vital role in detoxification of insecticides in T. castaneum. Furthermore, with insecticides exposure to Tclph knockdown beetles, the expression of Tcest4 was upregulated but Tcest6 was downregulated, indicating that beetles existed a compensatory response against the insecticides. Additionally, RNAi of Tcest6 resulted in 43% reductions in female egg laying and completely inhibited egg hatching, which showed the similar phenotype as that of Tclph knockdown. These results indicated that Tclph affected fecundity by positively regulating Tcest6 expression. Our findings will provide a new insight into the molecular mechanisms of Tclph involved in physiological functions in T. castaneum.
ESTHER : Wei_2019_Bull.Entomol.Res__1
PubMedSearch : Wei_2019_Bull.Entomol.Res__1
PubMedID: 30789108

Title : Bisphenol A Exposure and Sperm ACHE Hydroxymethylation in Men - Song_2019_Int.J.Environ.Res.Public.Health_16_
Author(s) : Song X , Miao M , Zhou X , Li D , Tian Y , Liang H , Li R , Yuan W
Ref : Int J Environ Research Public Health , 16 : , 2019
Abstract : Exposure to bisphenol A (BPA) has been shown to impact human sperm quality. The epigenetic mechanisms underlying the effect remain unknown. The acetylcholinesterase (ACHE) gene is a sperm-expressed gene encoding the acetylcholine hydrolyzing enzyme acetylcholinesterase and participates in the apoptosis of cells, including sperm. This study aimed to examine whether BPA exposure is associated with the hydroxymethylation level of the sperm ACHE gene. A total of 157 male factory workers were studied, among whom 74 had BPA exposure in the workplace (BPA exposure group) and 83 had no BPA exposure in the workplace (control group). Urine samples were collected for BPA measurement and semen samples were collected to assay for ACHE hydroxymethylation. Sperm ACHE hydroxymethylation level was higher in the BPA exposure group (p = 0.041) compared to the control group. When subjects were categorized according to tertiles of detected BPA level, higher ACHE hydroxymethylation levels were observed for the lowest, middle, and top tertiles compared to those with BPA below the limit of detection (LOD). In a linear regression analysis adjusted for confounders, a positive linear association between urine BPA concentration and 5-hydroxymethylcytosine (5hmC) rate of the sperm ACHE gene was observed, although the association did not reach statistical significance in all categories after being stratified by the BPA tertile. In conclusion, 5hmC of the sperm ACHE gene was positively associated with BPA exposure, which may provide supportive evidence for BPA's effects on male fertility or other health endpoints.
ESTHER : Song_2019_Int.J.Environ.Res.Public.Health_16_
PubMedSearch : Song_2019_Int.J.Environ.Res.Public.Health_16_
PubMedID: 30626059

Title : An acetylcholinesterase biosensor based on doping Au nanorod@SiO2 nanoparticles into TiO2-chitosan hydrogel for detection of organophosphate pesticides - Cui_2019_Biosens.Bioelectron_141_111452
Author(s) : Cui HF , Zhang TT , Lv QY , Song X , Zhai XJ , Wang GG
Ref : Biosensors & Bioelectronics , 141 :111452 , 2019
Abstract : A stable and sensitive electrochemical acetylcholinesterase (AChE) biosensor for detection of organophosphorus pesticides (OPs) was developed by doping Au nanorods (AuNRs)@mesoporous SiO2 (MS) core-shell nanoparticles into CS/TiO2-CS (CS denotes for chitosan) immobilization matrix. AuNRs@MS core-shell nanoparticles were synthesized and characterized. The doping and the biosensor fabrication process were probed and confirmed by scanning electron microscopy and electrochemistry techniques. The doping conditions were optimized. The matrix both before and after AChE immobilization had a mesoporous nanostructure. The nanoparticles dispersed homogeneously within the matrix. The doping significantly enhanced the electro-conductivity of the TiO2-CS hydrogel, and dramatically improved the bioelectrocatalytic activity and OPs detection sensitivity of the AChE immobilized matrix. The detection linear ranges for both dichlovos (DDVP) and fenthion were from 0.018muM (4.0ppb) to 13.6muM, and the limit of detection (LOD) was 5.3nM (1.2ppb) and 1.3nM (0.36ppb), respectively. The biosensor exhibited high reproducibility and accuracy in detecting OPs spiked vegetable juice samples. In addition, it exhibited very high detection stability and storage stability. The developed AChE biosensor was provided to be a promisingly applicable tool for OPs detection with high reliability, simplicity, and rapidness.
ESTHER : Cui_2019_Biosens.Bioelectron_141_111452
PubMedSearch : Cui_2019_Biosens.Bioelectron_141_111452
PubMedID: 31252259

Title : Impact of dipeptidyl-peptidase 4 inhibitors on cardiovascular diseases - Xie_2018_Vascul.Pharmacol_109_17
Author(s) : Xie W , Song X , Liu Z
Ref : Vascul Pharmacol , 109 :17 , 2018
Abstract : Dipeptidyl peptidase 4 (DPP-4) inhibitor is a novel group of medicine employed in type 2 diabetes mellitus (T2DM),which improves meal stimulated insulin secretion by protecting glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) from enzymatic degradation. Cardiovascular diseases are serious complications and leading causes of mortality among individuals with diabetes mellitus. Glycemic control per se seems to fail in preventing the progression of diabetic cardiovascular complications. DPP-4 has the capability to inactivate not only incretins, but also a series of cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. Pre-clinical studies suggested that DPP-4 inhibitors may have potential cardiovascular protective effects in addition to their antidiabetic actions. In recent years, a number of clinical trials have been conducted to evaluate the effect of different DPP-4 inhibitors on the cardiovascular system. We herein review the available clinical studies in cardiovascular effects played by each DPP-4 inhibitor and discuss the prospective application of DPP-4 inhibitors on cardiovascular diseases.
ESTHER : Xie_2018_Vascul.Pharmacol_109_17
PubMedSearch : Xie_2018_Vascul.Pharmacol_109_17
PubMedID: 29879463

Title : DWARF14, A Receptor Covalently Linked with the Active Form of Strigolactones, Undergoes Strigolactone-Dependent Degradation in Rice - Hu_2017_Front.Plant.Sci_8_1935
Author(s) : Hu Q , He Y , Wang L , Liu S , Meng X , Liu G , Jing Y , Chen M , Song X , Jiang L , Yu H , Wang B , Li J
Ref : Front Plant Sci , 8 :1935 , 2017
Abstract : Strigolactones (SLs) are the latest confirmed phytohormones that regulate shoot branching by inhibiting bud outgrowth in higher plants. Perception of SLs depends on a novel mechanism employing an enzyme-receptor DWARF14 (D14) that hydrolyzes SLs and becomes covalently modified. This stimulates the interaction between D14 and D3, leading to the ubiquitination and degradation of the transcriptional repressor protein D53. However, the regulation of SL perception in rice remains elusive. In this study, we provide evidences that D14 is ubiquitinated after SL treatment and degraded through the 26S proteasome system. The Lys280 site of the D14 amino acid sequence was important for SL-induced D14 degradation, but did not change the subcellular localization of D14 nor disturbed the interaction between D14 and D3, nor D53 degradation. Biochemical and genetic analysis indicated that the key amino acids in the catalytic center of D14 were essential for D14 degradation. We further showed that D14 degradation is dependent on D3 and is tightly correlated with protein levels of D53. These findings revealed that D14 degradation takes place following D53 degradation and functions as an important feedback regulation mechanism of SL perception in rice.
ESTHER : Hu_2017_Front.Plant.Sci_8_1935
PubMedSearch : Hu_2017_Front.Plant.Sci_8_1935
PubMedID: 29170677

Title : A highly stable acetylcholinesterase biosensor based on chitosan-TiO2-graphene nanocomposites for detection of organophosphate pesticides - Cui_2017_Biosens.Bioelectron_99_223
Author(s) : Cui HF , Wu WW , Li MM , Song X , Lv Y , Zhang TT
Ref : Biosensors & Bioelectronics , 99 :223 , 2017
Abstract : A highly stable electrochemical acetylcholinesterase (AChE) biosensor for detection of organophosphorus pesticides (OPs) was developed simply by adsorption of AChE on chitosan (CS), TiO2 sol-gel, and reduced graphene oxide (rGO) based multi-layered immobilization matrix (denoted as CS@TiO2-CS/rGO). The biosensor fabrication conditions were optimized, and the fabrication process was probed and confirmed by scanning electron microscopy and electrochemical techniques. The matrix has a mesoporous nanostructure. Incorporation of CS and electrodeposition of a CS layer into/on the TiO2 sol-gel makes the gel become mechanically strong. The catalytic activity of the AChE immobilized CS@TiO2-CS/rGO/glassy carbon electrode to acetylthiocholine is significantly higher than those missing any one of the component in the matrix. The detection linear range of the biosensor to dichlorvos, a model OP compound, is from 0.036muM (7.9 ppb) to 22.6muM, with a limit of detection of 29nM (6.4 ppb) and a total detection time of about 25min. The biosensor is very reproducibly and stable both in detection and in storage, and can accurately detect the dichlorvos levels in cabbage juice samples, providing an efficient platform for immobilization of AChE, and a promisingly applicable OPs biosensor with high reliability, simplicity, and rapidness.
ESTHER : Cui_2017_Biosens.Bioelectron_99_223
PubMedSearch : Cui_2017_Biosens.Bioelectron_99_223
PubMedID: 28763783

Title : Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts - Ma_2016_Nat.Commun_7_10740
Author(s) : Ma L , Chen Z , Huang da W , Kutty G , Ishihara M , Wang H , Abouelleil A , Bishop L , Davey E , Deng R , Deng X , Fan L , Fantoni G , FitzGerald M , Gogineni E , Goldberg JM , Handley G , Hu X , Huber C , Jiao X , Jones K , Levin JZ , Liu Y , Macdonald P , Melnikov A , Raley C , Sassi M , Sherman BT , Song X , Sykes S , Tran B , Walsh L , Xia Y , Yang J , Young S , Zeng Q , Zheng X , Stephens R , Nusbaum C , Birren BW , Azadi P , Lempicki RA , Cuomo CA , Kovacs JA
Ref : Nat Commun , 7 :10740 , 2016
Abstract : Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses.
ESTHER : Ma_2016_Nat.Commun_7_10740
PubMedSearch : Ma_2016_Nat.Commun_7_10740
PubMedID: 26899007
Gene_locus related to this paper: pnec8-a0a0w4zi95 , pnemu-m7nra0 , pnej8-l0pgn2 , pnemu-m7nsb0

Title : In vitro acaricidal activity of 1,8-cineole against Sarcoptes scabiei var. cuniculi and regulating effects on enzyme activity - Hu_2015_Parasitol.Res_114_2959
Author(s) : Hu Z , Chen Z , Yin Z , Jia R , Song X , Li L , Zou Y , Liang X , He C , Yin L , Lv C , Zhao L , Su G , Ye G , Shi F
Ref : Parasitol Res , 114 :2959 , 2015
Abstract : 1,8-Cineole found in many essential oils is a monoterpene and acts as a repellent against Sarcoptes scabiei var. cuniculi. In the present study, the acaricidal activity of 1,8-cineole against S. scabiei var. cuniculi was evaluated and the acaricidal mechanism was also investigated by assaying enzyme activities. The results showed that the lethal concentration of 50 % (LC50) value (95 % confidence limit (CL)) and the lethal time of 50 % (LT50) value (95 % CL) of 1,8-cineole were 2.77 mg/mL and 3.606 h, respectively. The pathological changes under transmission electron microscopy showed that the morphology of the mitochondria was abnormal, the cell nuclear membrane was damaged, and the nuclear chromatin was dissoluted. The activities of superoxide dismutase (SOD), glutathione-s-transferases (GSTs), monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) were significantly changed after treatment with 1,8-cineole for 4, 8, 12, and 24 h. SOD and GSTs are associated with the protection mechanism of scabies mites. And, the activities of SOD and GSTs were increased as compared with the control group. MAO, AChE, and NOS are associated with the nervous system of scabies mites. The activity of MAO was increased whereas the AChE was suppressed. The activity of NOS was suppressed in the high-dose group whereas increased in the middle-dose group and low-dose group. These results indicated that the mechanism of 1,8-cineole mainly attributed to the changes of these enzyme activities related to the nervous system of scabies mites.
ESTHER : Hu_2015_Parasitol.Res_114_2959
PubMedSearch : Hu_2015_Parasitol.Res_114_2959
PubMedID: 25924796

Title : A Novel alpha\/beta-Hydrolase Gene IbMas Enhances Salt Tolerance in Transgenic Sweetpotato - Liu_2014_PLoS.One_9_e115128
Author(s) : Liu D , Wang L , Zhai H , Song X , He S , Liu Q
Ref : PLoS ONE , 9 :e115128 , 2014
Abstract : Salt stress is one of the major environmental stresses in agriculture worldwide and affects crop productivity and quality. The development of crops with elevated levels of salt tolerance is therefore highly desirable. In the present study, a novel maspardin gene, named IbMas, was isolated from salt-tolerant sweetpotato (Ipomoea batatas (L.) Lam.) line ND98. IbMas contains maspardin domain and belongs to alpha/beta-hydrolase superfamily. Expression of IbMas was up-regulated in sweetpotato under salt stress and ABA treatment. The IbMas-overexpressing sweetpotato (cv. Shangshu 19) plants exhibited significantly higher salt tolerance compared with the wild-type. Proline content was significantly increased, whereas malonaldehyde content was significantly decreased in the transgenic plants. The activities of superoxide dismutase (SOD) and photosynthesis were significantly enhanced in the transgenic plants. H2O2 was also found to be significantly less accumulated in the transgenic plants than in the wild-type. Overexpression of IbMas up-regulated the salt stress responsive genes, including pyrroline-5-carboxylate synthase, pyrroline-5-carboxylate reductase, SOD, psbA and phosphoribulokinase genes, under salt stress. These findings suggest that overexpression of IbMas enhances salt tolerance of the transgenic sweetpotato plants by regulating osmotic balance, protecting membrane integrity and photosynthesis and increasing reactive oxygen species scavenging capacity.
ESTHER : Liu_2014_PLoS.One_9_e115128
PubMedSearch : Liu_2014_PLoS.One_9_e115128
PubMedID: 25501819
Gene_locus related to this paper: ipoba-a0a076l3m2

Title : Plant-Generated Artificial Small RNAs Mediated Aphid Resistance - Guo_2014_PLoS.One_9_e97410
Author(s) : Guo H , Song X , Wang G , Yang K , Wang Y , Niu L , Chen X , Fang R
Ref : PLoS ONE , 9 :e97410 , 2014
Abstract : BACKGROUND: RNA silencing is an important mechanism for regulation of endogenous gene expression and defense against genomic intruders in plants. This natural defense system was adopted to generate virus-resistant plants even before the mechanism of RNA silencing was unveiled. With the clarification of that mechanism, transgenic antiviral plants were developed that expressed artificial virus-specific hairpin RNAs (hpRNAs) or microRNAs (amiRNAs) in host plants. Previous works also showed that plant-mediated RNA silencing technology could be a practical method for constructing insect-resistant plants by expressing hpRNAs targeting essential genes of insects. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we chose aphid Myzus persicae of order Hemiptera as a target insect. To screen for aphid genes vulnerable to attack by plant-mediated RNA silencing to establish plant aphid resistance, we selected nine genes of M. persicae as silencing targets, and constructed their hpRNA-expressing vectors. For the acetylcholinesterase 2 coding gene (MpAChE2), two amiRNA-expressing vectors were also constructed. The vectors were transformed into tobacco plants (Nicotiana tabacum cv. Xanti). Insect challenge assays showed that most of the transgenic plants gained aphid resistance, among which those expressing hpRNAs targeting V-type proton ATPase subunit E-like (V-ATPaseE) or tubulin folding cofactor D (TBCD) genes displayed stronger aphicidal activity. The transgenic plants expressing amiRNAs targeting two different sites in the MpAChE2 gene exhibited better aphid resistance than the plants expressing MpAChE2-specific hpRNA. CONCLUSIONS/SIGNIFICANCE: Our results indicated that plant-mediated insect-RNA silencing might be an effective way to develop plants resistant to insects with piercing-sucking mouthparts, and both the selection of vulnerable target genes and the biogenetic type of the small RNAs were crucial for the effectiveness of aphid control. The expression of insect-specific amiRNA is a promising and preferable approach to engineer plants resistant to aphids and, possibly, to other plant-infesting insects.
ESTHER : Guo_2014_PLoS.One_9_e97410
PubMedSearch : Guo_2014_PLoS.One_9_e97410
PubMedID: 24819752

Title : The oyster genome reveals stress adaptation and complexity of shell formation - Zhang_2012_Nature_490_49
Author(s) : Zhang G , Fang X , Guo X , Li L , Luo R , Xu F , Yang P , Zhang L , Wang X , Qi H , Xiong Z , Que H , Xie Y , Holland PW , Paps J , Zhu Y , Wu F , Chen Y , Wang J , Peng C , Meng J , Yang L , Liu J , Wen B , Zhang N , Huang Z , Zhu Q , Feng Y , Mount A , Hedgecock D , Xu Z , Liu Y , Domazet-Loso T , Du Y , Sun X , Zhang S , Liu B , Cheng P , Jiang X , Li J , Fan D , Wang W , Fu W , Wang T , Wang B , Zhang J , Peng Z , Li Y , Li N , Chen M , He Y , Tan F , Song X , Zheng Q , Huang R , Yang H , Du X , Chen L , Yang M , Gaffney PM , Wang S , Luo L , She Z , Ming Y , Huang W , Huang B , Zhang Y , Qu T , Ni P , Miao G , Wang Q , Steinberg CE , Wang H , Qian L , Liu X , Yin Y
Ref : Nature , 490 :49 , 2012
Abstract : The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.
ESTHER : Zhang_2012_Nature_490_49
PubMedSearch : Zhang_2012_Nature_490_49
PubMedID: 22992520
Gene_locus related to this paper: cragi-k1qzk7 , cragi-k1rad0 , cragi-k1p6v9 , cragi-k1pa46 , cragi-k1pga2 , cragi-k1pp63 , cragi-k1pwa8 , cragi-k1q0b1.1 , cragi-k1q0b1.2 , cragi-k1q1h2 , cragi-k1q2z6 , cragi-k1qaj8 , cragi-k1qaw5 , cragi-k1qhl5 , cragi-k1qly1 , cragi-k1qqb1.1 , cragi-k1qqb1.2 , cragi-k1qs61 , cragi-k1qs99 , cragi-k1qwl6 , cragi-k1r068 , cragi-k1r0n3.1 , cragi-k1r0n3.2 , cragi-k1r0r4 , cragi-k1r1i9 , cragi-k1r8q9 , cragi-k1rgi1 , cragi-k1rig4 , cragi-k1s0a7.1 , cragi-k1s0a7.2 , cragi-k1s0a7.3 , cragi-k1q6q0 , cragi-k1rru1 , cragi-k1qfi4 , cragi-k1qvm5 , cragi-k1qq58 , cragi-k1qdc0 , cragi-k1r754 , cragi-k1pje5 , cragi-k1qca6 , cragi-k1qdt5 , cragi-k1qkz7 , cragi-k1rgd2 , cragi-k1puh6 , cragi-k1raz4 , cragi-k1qqj4 , cragi-k1rbs1

Title : Dynamic evolution of oryza genomes is revealed by comparative genomic analysis of a genus-wide vertical data set - Ammiraju_2008_Plant.Cell_20_3191
Author(s) : Ammiraju JS , Lu F , Sanyal A , Yu Y , Song X , Jiang N , Pontaroli AC , Rambo T , Currie J , Collura K , Talag J , Fan C , Goicoechea JL , Zuccolo A , Chen J , Bennetzen JL , Chen M , Jackson S , Wing RA
Ref : Plant Cell , 20 :3191 , 2008
Abstract : Oryza (23 species; 10 genome types) contains the world's most important food crop - rice. Although the rice genome serves as an essential tool for biological research, little is known about the evolution of the other Oryza genome types. They contain a historical record of genomic changes that led to diversification of this genus around the world as well as an untapped reservoir of agriculturally important traits. To investigate the evolution of the collective Oryza genome, we sequenced and compared nine orthologous genomic regions encompassing the Adh1-Adh2 genes (from six diploid genome types) with the rice reference sequence. Our analysis revealed the architectural complexities and dynamic evolution of this region that have occurred over the past approximately 15 million years. Of the 46 intact genes and four pseudogenes in the japonica genome, 38 (76%) fell into eight multigene families. Analysis of the evolutionary history of each family revealed independent and lineage-specific gain and loss of gene family members as frequent causes of synteny disruption. Transposable elements were shown to mediate massive replacement of intergenic space (>95%), gene disruption, and gene/gene fragment movement. Three cases of long-range structural variation (inversions/deletions) spanning several hundred kilobases were identified that contributed significantly to genome diversification.
ESTHER : Ammiraju_2008_Plant.Cell_20_3191
PubMedSearch : Ammiraju_2008_Plant.Cell_20_3191
PubMedID: 19098269

Title : Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2 - Yang_2007_Mol.Pharmacol_72_686
Author(s) : Yang J , Shi D , Yang D , Song X , Yan B
Ref : Molecular Pharmacology , 72 :686 , 2007
Abstract : Carboxylesterases constitute a class of enzymes that play important roles in the hydrolytic metabolism of drugs and other xenobiotics. Patients with liver conditions such as cirrhosis show increased secretion of proinflammatory cytokines [e.g., interleukin-6 (IL-6)] and decreased capacity of hydrolysis. In this study, we provide a molecular explanation linking cytokine secretion directly to the decreased capacity of hydrolytic biotransformation. In both primary hepatocytes and HepG2 cells, treatment with IL-6 decreased the expression of human carboxyl-esterases HCE1 and HCE2 by as much as 60%. The decreased expression occurred at both mRNA and protein levels, and it was confirmed by enzymatic assay. In cotransfection experiments, both HCE1 and HCE2 promoters were significantly repressed, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting that transrepression is responsible for the suppressed expression. In addition, pretreatment with IL-6 altered the cellular responsiveness in an opposite manner of overexpression of HCE1 and HCE2 toward various ester therapeutic agents (e.g., clopidogrel). Transfection of HCE1, for example, decreased the cytotoxicity induced by antithrombogenic agent clopidogrel, whereas pretreatment with IL-6 increased the cytotoxicity. Such a reversal was observed with other ester drugs, including anticancer agent irinotecan and anti-influenza agent oseltamivir. The altered cellular responsiveness was observed when drugs were assayed at sub- and low-micromolar concentrations, suggesting that suppressed expression of carboxylesterases by IL-6 has profound pharmacological consequences, particularly with those that are hydrolyzed in an isoform-specific manner.
ESTHER : Yang_2007_Mol.Pharmacol_72_686
PubMedSearch : Yang_2007_Mol.Pharmacol_72_686
PubMedID: 17537833
Gene_locus related to this paper: human-CES1 , human-CES2

Title : Nucleoside ester prodrug substrate specificity of liver carboxylesterase - Landowski_2006_J.Pharmacol.Exp.Ther_316_572
Author(s) : Landowski CP , Lorenzi PL , Song X , Amidon GL
Ref : Journal of Pharmacology & Experimental Therapeutics , 316 :572 , 2006
Abstract : Carboxylesterases are among the best characterized prodrug-hydrolyzing enzymes involved in the activation of several therapeutic carbamate and ester prodrugs. The broad specificity of these enzymes makes them amenable for designing prodrugs. Porcine liver carboxylesterase 1 specificity for amino acid esters of three nucleoside analogs [floxuridine, gemcitabine, and 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole] was evaluated to assess optimal structural preferences for prodrug design. The amino acid promoiety and the esterification site influenced carboxylesterase hydrolysis rates up to 1164-fold and the binding affinity up to 26-fold. Carboxylesterase (CES) 1 exhibited high-catalytic efficiency hydrolyzing prodrugs containing a phenylalanyl moiety but was over 100-fold less efficient with valyl or isoleucyl prodrugs, regardless of the nucleoside or esterification site. CES1 catalytic efficiency was 2-fold higher with 5' phenylalanyl monoesters than the corresponding 3' esters of floxuridine. This preference was reversed with phenylalanyl gemcitabine prodrugs, evident from a 2-fold preference for 3' monoesters over 5' esters. The newly characterized esterase valacyclovirase was several hundred-fold more efficient (up to 19,000-fold) than carboxylesterase in hydrolyzing amino acid esters but similar in apparent binding affinity. The specific activities of the two enzymes with several amino acid ester prodrugs clearly suggest that initial hydrolysis rates are relatively low for prodrugs with isoleucyl, aspartyl, and lysyl promoieties for both enzymes compared with those with phenylalanyl, valyl, prolyl, and leucyl progroups. The low relative hydrolysis rates of isoleucyl, aspartyl, and lysyl prodrugs may facilitate prolonged systemic disposition of the nucleoside analogs for improved therapeutic action.
ESTHER : Landowski_2006_J.Pharmacol.Exp.Ther_316_572
PubMedSearch : Landowski_2006_J.Pharmacol.Exp.Ther_316_572
PubMedID: 16223870
Gene_locus related to this paper: pig-EST1

Title : Amino acid ester prodrugs of the anticancer agent gemcitabine: synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport - Song_2005_Mol.Pharm_2_157
Author(s) : Song X , Lorenzi PL , Landowski CP , Vig BS , Hilfinger JM , Amidon GL
Ref : Mol Pharm , 2 :157 , 2005
Abstract : Gemcitabine, a clinically effective nucleoside anticancer agent, is a polar drug with low membrane permeability and is administered intravenously. Further, extensive degradation of gemcitabine by cytidine deaminase to an inactive metabolite in the liver affects its activity adversely. Thus, strategies that provide both enhanced transport and high metabolic bioevasion would potentially lead to oral alternatives that may be clinically useful. The objective of this study was to evaluate whether amino acid ester prodrugs of gemcitabine would (a) facilitate transport across intestinal membranes or across cells that express hPEPT1 and (b) provide resistance to deamination by cytidine deaminase. 3'-Monoester, 5'-monoester, and 3',5'-diester prodrugs of gemcitabine utilizing aliphatic (L-valine, D-valine, and L-isoleucine) and aromatic (L-phenylalanine and D-phenylalanine) amino acids as promoieties were synthesized and evaluated for their affinity and direct hPEPT1-mediated transport in HeLa/hPEPT1 cells. All prodrugs exhibited enhanced affinity (IC(50): 0.14-0.16 mM) for the transporter. However, only the 5'-L-valyl and 5'-L-isoleucyl monoester prodrugs exhibited (a) increased uptake (11.25- and 5.64-fold, respectively) in HeLa/hPEPT1 cells compared to HeLa cells and (b) chemical stability in buffers, that were comparable to valacyclovir, a commercially marketed oral amino acid ester prodrug. The widely disparate enzymatic bioconversion profiles of the 5'-L-valyl and 5'-L-isoleucyl prodrugs in Caco-2 cell homogenates along with their significant resistance to deamination by cytidine deaminase suggest that the disposition of gemcitabine following oral administration would be controlled by the rate of bioconversion following transport across the intestinal epithelial membrane. The combined results also suggest that it may be possible to modulate these characteristics by the choice of the amino acid promoiety.
ESTHER : Song_2005_Mol.Pharm_2_157
PubMedSearch : Song_2005_Mol.Pharm_2_157
PubMedID: 15804190

Title : A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein - Kim_2004_Mol.Pharm_1_117
Author(s) : Kim I , Song X , Vig BS , Mittal S , Shin HC , Lorenzi PJ , Amidon GL
Ref : Mol Pharm , 1 :117 , 2004
Abstract : Biphenyl hydrolase-like protein (BPHL, NCBI accession number NP_004323) is a novel human serine hydrolase recently identified as a human valacyclovirase, catalyzing the hydrolytic activation of the antiviral prodrugs valacyclovir and valganciclovir. The substrate specificity of BPHL was investigated with a series of amino acid ester prodrugs of the therapeutic nucleoside analogues: acyclovir, zidovudine, floxuridine, 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole, and gemcitabine. The hydrolysis of typical esterase and aminopeptidase substrates by BPHL was also investigated. The results indicate that the substrate specificity of BPHL is largely determined by the amino acid acyl promoiety, and is less sensitive to the nucleoside parent drugs. For all nucleoside parent drugs, BPHL preferred the hydrophobic amino acids valine, phenylalanine, and proline over the charged amino acids lysine and aspartic acid. The position and monoester or diester form of the prodrug were also important, with BPHL exhibiting higher affinity for the 5'-esters than for the 3'-esters and the 3',5'-diesters irrespective of amino acid type. Further, the presence of the 3'-amino acid ester considerably reduced the hydrolysis rate of the 5'-amino acid ester functionality. BPHL exhibited stereoselectivity with an L/D specificity ratio of 32 for 5'-valyl floxuridine and 1.5 for 5'-phenylalanyl floxuridine. The substrate specificity suggests that the substrate-binding pocket of BPHL has a hydrophobic acyl binding site which can accommodate the positively charged alpha-amino group, while having an alcohol leaving group binding site that can accommodate nucleoside analogues with a relatively generous spatial allowance. In conclusion, BPHL catalyzes the hydrolytic activation of amino acid esters of a broad range of therapeutic nucleoside analogues in addition to valacyclovir and valganciclovir and has considerable potential for utilization as an activation target for design of antiviral and anticancer nucleoside analogue prodrugs.
ESTHER : Kim_2004_Mol.Pharm_1_117
PubMedSearch : Kim_2004_Mol.Pharm_1_117
PubMedID: 15832508
Gene_locus related to this paper: human-BPHL

Title : Intramolecular disulfide bonds are required for folding hydrolase B into a catalytically active conformation but not for maintaining it during catalysis - Song_2004_Biochem.Biophys.Res.Commun_319_1072
Author(s) : Song X , Gragen S , Li Y , Ma Y , Liu J , Yang D , Matoney L , Yan B
Ref : Biochemical & Biophysical Research Communications , 319 :1072 , 2004
Abstract : Carboxylesterases represent a large class of hydrolytic enzymes that are involved in lipid metabolism, pharmacological determination, and detoxication of organophosphorus pesticides. These enzymes have several notable structural features including two intramolecular disulfide bonds. This study was undertaken to test the hypothesis that the disulfide bonds are required during catalysis by stabilizing the catalytically active conformation. Hydrolase B, a rat liver microsomal carboxylesterase, was reduced by dithiothreitol, electrophoretically separated and assayed for hydrolysis. Contrary to the hypothesis, reduced hydrolase B was as active as the native enzyme on the hydrolysis of 1-naphthylacetate, and sulfhydryl alkylation following reduction caused no changes in the hydrolytic activity. Interestingly, substitution of a disulfide bond-forming cysteine with an alanine caused marked reduction or complete loss of the catalytic activity, suggesting that disulfide bond formation plays a role in the biosynthetic process of hydrolase B. In support of this notion, refolding experiments restored a significant amount of hydrolytic activity when hydrolase B was unfolded with urea alone. In contrast, little activity was restored when unfolding was performed in the presence of reducing agent dithiothreitol. These results suggest that formation of the disulfide bonds plays a critical role in folding hydrolase B into the catalytically active conformation, and that the disulfide bonds play little role or function redundantly in maintaining this conformation during catalysis.
ESTHER : Song_2004_Biochem.Biophys.Res.Commun_319_1072
PubMedSearch : Song_2004_Biochem.Biophys.Res.Commun_319_1072
PubMedID: 15194477

Title : Interactive effects of paraoxon and pyridostigmine on blood-brain barrier integrity and cholinergic toxicity - Song_2004_Toxicol.Sci_78_241
Author(s) : Song X , Pope C , Murthy R , Shaikh J , Lal B , Bressler JP
Ref : Toxicol Sci , 78 :241 , 2004
Abstract : The effect of the organophosphorous insecticide paraoxon on the integrity of the blood-brain barrier (BBB) and permeability of pyridostigmine (PYR), a peripheral inhibitor of cholinesterase activity, was examined in Long Evans rats. The integrity of the BBB was examined by measuring the number of capillaries leaking horseradish peroxidase, which was injected into the heart. Treatment with paraoxon at 100 microg/kg, intramuscularly, resulted in a 3- to 4-fold increase in the number of leaky capillaries in young rats (25 to 30 days old) but not in older rats (90 days old). Interestingly, young rats treated with PYR (30 mg/kg, po) 50 min before treatment with paraoxon showed an inhibited effect of paraoxon on the BBB. Furthermore, no increase in the degree of inhibition of acetylcholinesterase activity was observed in young rats treated with PYR before paraoxon compared with young rats treated with paraoxon alone. Cholinergic toxicity, as assessed by changes in behavior, was not observed in young rats treated with paraoxon alone; but, slight signs of cholinergic toxicity were observed in rats treated with PYR. Young rats treated with both PYR and paraoxon did not exhibit more extensive signs of toxicity than rats treated with paraoxon alone or PYR alone. The results indicate that treatment with paraoxon can compromise BBB permeability at dosages that do not induce cholinergic toxicity, but only in young rats. Also, PYR pre-exposure appears to protect the BBB from the paraoxon-induced alterations.
ESTHER : Song_2004_Toxicol.Sci_78_241
PubMedSearch : Song_2004_Toxicol.Sci_78_241
PubMedID: 14976354

Title : Epoxide hydrolase-catalyzed resolution of ethyl 3-phenylglycidate using whole cells of Pseudomonas sp - Li_2003_Biotechnol.Lett_25_2113
Author(s) : Li C , Liu Q , Song X , Di D , Ji A , Qu Y
Ref : Biotechnol Lett , 25 :2113 , 2003
Abstract : A Pseudomonas sp. was isolated with enantioselective epoxide hydrolase activity to ethyl 3-phenylglycidate. Cells grown on sucrose and suspended in 10% (v/v) dimethyl formamide as co-solvent produced (2R,3S) ethyl 3-phenylglycidate with 95% ee and 26% yield in 12 h from 0.2% (w/v) of the racemate.
ESTHER : Li_2003_Biotechnol.Lett_25_2113
PubMedSearch : Li_2003_Biotechnol.Lett_25_2113
PubMedID: 14969419

Title : Neither forced running nor forced swimming affect acute pyridostigmine toxicity or brain-regional cholinesterase inhibition in rats - Tian_2002_Toxicology_176_39
Author(s) : Tian H , Song X , Bressler J , Pruett S , Pope CN
Ref : Toxicology , 176 :39 , 2002
Abstract : Stress-induced change in the distribution of the drug pyridostigmine (PYR) has been proposed as a contributing factor to unexplained illnesses in Persian Gulf War veterans. We evaluated the effects of two stress models, forced running and forced swimming, on acute PYR (30 mg/kg, p.o.) toxicity and cholinesterase (ChE) inhibition in the blood and selected brain regions of young adult male Sprague-Dawley rats (6 weeks of age). Plasma corticosterone levels were measured at 0, 1 and 3 h after termination of forced swimming or forced running to confirm the induction of stress. PYR was given either immediately before stress (15 min swimming; 20 min running) or immediately after stress (15 min swimming; 90 min running) and cholinergic toxicity and ChE inhibition were evaluated at 1, 2 or 4 h after PYR exposure. Additionally, rats were subjected to either swimming (15 min) or running (90 min) stress, anesthetized, injected with horseradish peroxidase (HRP, 100 mg/kg, transcardial) and brain-regional HRP activity measured as an indicator of altered blood-brain barrier integrity. Both forced swimming and forced running resulted in significant elevations of plasma corticosterone levels. PYR caused cholinergic toxicity at all time-points evaluated. Swimming and running stress had little influence on expression of PYR-induced toxicity, however. Blood ChE activity was generally inhibited 77-91% at 1-4 h after PYR, but rats pretreated with PYR prior to forced swimming showed lesser inhibition (64%) 1 h after dosing, possibly because of swimming-induced hypothermia and delayed absorption of the drug. Minimal changes in ChE activity were noted in frontal cortex, cerebellum and hippocampus following PYR exposure (maximal inhibition 28%), and neither swimming nor running stress affected the degree of inhibition. Neither stress model increased HRP accumulation in any brain region. The results suggest that stress associated with forced running or forced swimming has little effect on acute PYR toxicity, entry of PYR into the brain or PYR-induced brain-regional ChE inhibition.
ESTHER : Tian_2002_Toxicology_176_39
PubMedSearch : Tian_2002_Toxicology_176_39
PubMedID: 12062928

Title : Acute and Repeated Restraint Stress Have Little Effect on Pyridostigmine Toxicity or Brain Regional Cholinesterase Inhibition in Rats - Song_2002_Toxicol.Sci_69_157
Author(s) : Song X , Tian H , Bressler J , Pruett S , Pope C
Ref : Toxicol Sci , 69 :157 , 2002
Abstract : Pyridostigmine, a carbamate cholinesterase (ChE) inhibitor, has been used for decades in the treatment of the autoimmune disorder myasthenia gravis and was used prophylactically to protect soldiers from possible organophosphorus nerve agent exposures during the Persian Gulf War. Pyridostigmine is a charged, quaternary compound and thus would not be expected to easily pass the blood-brain barrier. Some studies have suggested, however, that stress may alter blood-brain barrier integrity and allow pyridostigmine to enter the brain. We evaluated the effects of acute and repeated restraint stress on functional signs of cholinergic toxicity (i.e., autonomic dysfunction and involuntary movements) and brain regional cholinesterase inhibition following either acute or repeated pyridostigmine exposures. The acute, oral maximum-tolerated dosage (MTD) of pyridostigmine was estimated at 30 mg/kg. Peak ChE inhibition in whole blood occurred from 0.5 to 4 h after MTD exposure, whereas minimal (<20%) brain ChE inhibition was noted. For acute restraint studies, rats were either (1) restrained for 90 min and then given pyridostigmine (30 mg/kg, po), (2) given pyridostigmine and immediately restrained for 60 min, or (3) restrained for 3 h, given pyridostigmine, and restrained for an additional 60 min. In all cases, rats were evaluated for cholinergic toxicity (SLUD signs and involuntary movements) and sacrificed 1 h after pyridostigmine treatment. Plasma corticosterone was significantly elevated immediately after a single 60-min session of acute restraint stress, but returned to control levels by 1 and 3 h later. Pyridostigmine-induced toxicity was not enhanced nor was brain ChE inhibition altered by acute restraint stress. Blood-brain barrier permeability, assessed by accumulation of horseradish peroxidase in brain regions following intracardiac injection, was not increased by restraint stress. For repeated restraint studies, rats were given pyridostigmine (0, 3, or 10 mg/kg/day) immediately prior to daily restraint (60 min) for 14 consecutive days. Plasma corticosterone was elevated at 1 and 7 days but not at 14 days. Pyridostigmine-treated rats in both dosage groups exhibited slight signs of toxicity for the first 3-5 days, after which cholinergic signs dissipated. Repeated restraint had little effect on functional signs of pyridostigmine toxicity, however. Whole blood and diaphragm ChE were markedly reduced 1 h after the last treatment, but stress had no influence on ChE inhibition in either peripheral or central tissues. The results suggest that acute and repeated restraint stress have little effect on pyridostigmine neurotoxicity or apparent entry of pyridostigmine into the brain.
ESTHER : Song_2002_Toxicol.Sci_69_157
PubMedSearch : Song_2002_Toxicol.Sci_69_157
PubMedID: 12215670

Title : Modeling the developmental neurotoxicity of chlorpyrifos in vitro: macromolecule synthesis in PC12 cells - Song_1998_Toxicol.Appl.Pharmacol_151_182
Author(s) : Song X , Violin JD , Seidler FJ , Slotkin TA
Ref : Toxicol Appl Pharmacol , 151 :182 , 1998
Abstract : Exposure to apparently subtoxic doses of chlorpyrifos during late stages of brain development affects cell acquisition through a mixture of cholinergic and noncholinergic mechanisms. In the current study, we modeled these effects in vitro using rat pheochromocytoma (PC12), a cell line that, upon nerve-growth factor (NGF)-induced differentiation, develops the appearance and function of cholinergic target neurons, including the expression of cholinergic receptors. In the undifferentiated state (no NGF), chlorpyrifos evoked an immediate (1 h), robust, concentration-dependent inhibition of DNA synthesis as evaluated by [3H]thymidine incorporation, with a threshold of 0.5-1.5 microg/ml. Continuous exposure for up to 24 h maintained the same degree of inhibition. The effects were selective for DNA synthesis, as much smaller inhibitions were found for synthesis of RNA or protein. In contrast, direct cholinergic stimulation of the cells by 100 microM nicotine had much smaller effects on DNA synthesis. Moreover, the effects of chlorpyrifos on DNA synthesis could not be blocked by nicotinic or muscarinic antagonists, confirming that the effects were not mediated primarily through cholinergic hyperstimulation consequent to cholinesterase inhibition or to direct receptor-mediated effects. When PC12 cells underwent NGF-induced differentiation, the rate of cell replication fell dramatically and neurite extension was evident both from morphological examination and from biochemical markers (increased protein:DNA ratio). After introduction of NGF, chlorpyrifos maintained its ability to inhibit DNA synthesis acutely. However, the ability to inhibit RNA and protein synthesis initially intensified and then disappeared, indicating a shift in macromolecular targets as differentiation proceeded. We also tested the effects of long-term exposure to chlorpyrifos during the process of NGF-induced differentiation. Continuous chlorpyrifos exposure resulted in severe reductions in macromolecule synthesis and a deficit in the total number of cells, effects similar to those seen with chlorpyrifos treatment in vivo. At the highest concentrations, neurite extension was also inhibited. Our results suggest that chlorpyrifos can interact directly with developing neural cells to inhibit replication and neuritic outgrowth.
ESTHER : Song_1998_Toxicol.Appl.Pharmacol_151_182
PubMedSearch : Song_1998_Toxicol.Appl.Pharmacol_151_182
PubMedID: 9705902

Title : Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade - Song_1997_Toxicol.Appl.Pharmacol_145_158
Author(s) : Song X , Seidler FJ , Saleh JL , Zhang J , Padilla S , Slotkin TA
Ref : Toxicol Appl Pharmacol , 145 :158 , 1997
Abstract : Developmental neurotoxicity caused by chlorpyrifos exposure is generally thought to target cholinesterase but chlorpyrifos may also act on cellular intermediates, such as adenylyl cyclase, that serve global functions in the coordination of cell development. In the current study, neonatal rats were exposed to apparently subtoxic doses of chlorpyrifos (no weight loss, no mortality) either on Postnatal Days 1-4 or on Postnatal Days 11-14, and the effects on components of the adenylyl cyclase cascade were evaluated in brain regions that are enriched (forebrain) or sparse (cerebellum) in cholinergic innervation, as well as in a nonneural tissue (heart). In all three, chlorpyrifos evoked deficits in multiple components of the adenylyl cyclase cascade: expression and activity of adenylyl cyclase itself, functioning of G-proteins that link neurotransmitter and hormone receptors to cyclase activity, and expression of neurotransmitter receptors that act through this cascade. Disruption of signaling function was not restricted to transduction of cholinergic signals but rather extended to adrenergic signals as well. In most cases, the adverse effects were not evident during the immediate period of chlorpyrifos administration, but appeared after a delay of several days. These results suggest that chlorpyrifos can affect cell development by altering the activity and reactivity of the adenylyl cyclase signaling cascade, a major control point for trophic regulation of cell differentiation. The effects are not restricted to cholinergic targets, nor even to the central nervous system. Hence, disruption of cell development by chlorpyrifos is likely to be more widespread than previously thought.
ESTHER : Song_1997_Toxicol.Appl.Pharmacol_145_158
PubMedSearch : Song_1997_Toxicol.Appl.Pharmacol_145_158
PubMedID: 9221834