Lu H

References (51)

Title : Aquatic photolysis of high-risk fluorinated liquid crystal monomers: Kinetics, toxicity evaluation, and mechanisms - Wu_2024_Water.Res_255_121510
Author(s) : Wu J , Ye W , Feng Y , Lao W , Li J , Lu H , Liu G , Su G , Deng Y
Ref : Water Res , 255 :121510 , 2024
Abstract : Despite the frequent detection of fluorinated liquid-crystal monomers (FLCMs) in the environment, the level of understanding of their fate, toxicity, and transformation remains insufficient. Herein, we investigated the degradation kinetics and mechanism of an FLCM (4-cyano-3-fluorophenyl 4-ethylbenzoate, CEB-F) under ultraviolet (UV) photolysis in aquatic environment. Our findings demonstrated that the UV photolysis of CEB-F followed first-order kinetics. Photodegradation products were identified using liquid chromatography with mass spectrometry, and detailed reaction pathways were proposed. It is postulated that through the attack of reactive oxygen species, hydroxylation, and CO/C-F bond cleavage, CEB-F gradually degraded into small molecular compounds, releasing fluorine ions. Acute immobilization tests with Daphnia magna (D. magna) revealed significant acute toxicity of CEB-F, with LC(50) values ranging from 1.023 to 0.0536 microM over 24 to 96 h, emphasizing the potential high risk of FLCMs in aquatic ecosystems if inadvertently discharged. Interestingly, we found that the toxicity of CEB-F photolysis reaction solutions was effectively reduced. Through catalase and acetylcholinesterase activities analysis along with molecular docking simulation, we proposed differences in the underlying toxicity mechanisms of CEB-F and its photolysis products to D. magna. These findings highlight the potential harmful effects of FLCMs on aquatic ecosystems and enrich our understanding of the photolysis behavior of FLCMs.
ESTHER : Wu_2024_Water.Res_255_121510
PubMedSearch : Wu_2024_Water.Res_255_121510
PubMedID: 38555780

Title : Neuroprotective effects of Shenghui decoction via inhibition of the JNK\/p38 MAPK signaling pathway in an AlCl(3)-induced zebrafish (Danio rerio) model of Alzheimer's disease - Lu_2024_J.Ethnopharmacol__117993
Author(s) : Lu H , Ran S , Zhang Y , Chen Y , Tan A , Wang P
Ref : J Ethnopharmacol , :117993 , 2024
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a multi-factorial degenerative disease, and multi-targeted therapies targeting multiple pathogenic mechanisms should be explored. Shenghui decoction (SHD) is an ancient traditional Chinese medicine (TCM) formula used clinically to alleviate AD. However, the precise mechanism of action of SHD as a therapeutic agent for AD remains unclear. AIM OF THE STUDY: This study investigated the neuroprotective properties and potential mechanisms of action of SHD in mitigating AD-like symptoms induced by AlCl(3) in a zebrafish model. MATERIALS AND METHODS: Active components of SHD were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Zebrafish were exposed to AlCl(3) (200 microg/L) for 30 days to establish an AD zebrafish model. AlCl(3)-exposed zebrafish were treated with SHD or donepezil. Behavioral tests were used to assess learning and memory, locomotor activity, and AD-related anxiety and aggression in AlCl(3)-exposed zebrafish. Nissl staining and transmission electron microscopy were used to evaluate histological alterations in brain neurons. The concentrations of pro-inflammatory cytokines (tumor necrosis factor-alpha, TNF-alpha; interleukin-1beta, IL-1beta) were quantified using Enzyme-linked immunosorbent assay (ELISA). Markers of oxidative stress and cholinergic activity (acetylcholinesterase, AChE) were detected using biochemical assays. Western blotting and immunofluorescence were used to detect the protein expression levels of Abeta, p-tau, PSD-95, synaptophysin, TLR4, phosphorylation of NF-kappaB p65, p38, and JNK. RESULTS: Fifteen SHD compounds were identified by UPLC-MS/MS analysis. SHD improved AlCl(3)-induced dyskinesia, learning and memory impairment, anxiety-like behavior, and aggressive behavior in zebrafish. AlCl(3)-exposed zebrafish showed AD-like pathology, overexpression of Abeta, hyperphosphorylated tau protein, marked neuronal damage, decreased expression of synaptic proteins, synaptophysin, and PSD-95, and impairment of synaptic structural plasticity. These effects were reversed by the SHD treatment. We also observed that SHD ameliorated oxidative stress and decreased AChE activity and inflammatory cytokine levels. These effects are similar to those observed for donepezil. Meanwhile, SHD could decrease the protein expression of TLR4 and inhibit phosphorylation of NF-kappaB, JNK, and p38 MAPK. These results demonstrate that SHD has the potential to exert neuroprotective effects, which may be partly mediated via inhibition of the JNK/p38 MAPK signaling pathway. CONCLUSIONS: Our findings revealed the therapeutic mechanism of SHD in mitigating AD progression and suggested that SHD is a potent neuroprotectant that contributes to the future development of TCM modernization and broader clinical applications.
ESTHER : Lu_2024_J.Ethnopharmacol__117993
PubMedSearch : Lu_2024_J.Ethnopharmacol__117993
PubMedID: 38423408

Title : New advances in clinical application of neostigmine: no longer focusing solely on increasing skeletal muscle strength - Si_2023_Front.Pharmacol_14_1227496
Author(s) : Si S , Zhao X , Su F , Lu H , Zhang D , Sun L , Wang F , Xu L
Ref : Front Pharmacol , 14 :1227496 , 2023
Abstract : Neostigmine is a clinical cholinesterase inhibitor, that is, commonly used to enhance the function of the cholinergic neuromuscular junction. Recent studies have shown that neostigmine regulates the immune-inflammatory response through the cholinergic anti-inflammatory pathway, affecting perioperative neurocognitive function. This article reviews the relevant research evidence over the past 20 years, intending to provide new perspectives and strategies for the clinical application of neostigmine.
ESTHER : Si_2023_Front.Pharmacol_14_1227496
PubMedSearch : Si_2023_Front.Pharmacol_14_1227496
PubMedID: 37601044

Title : Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-kB pathway as a central network - Hu_2023_Fish.Shellfish.Immunol_141_109062
Author(s) : Hu Y , Jia K , Zhou Y , Chen L , Wang F , Yi X , Huang Y , Ge Y , Chen X , Liao D , Peng Y , Meng Y , Liu Y , Luo Q , Cheng B , Zhao Y , Lu H , Yuan W
Ref : Fish Shellfish Immunol , 141 :109062 , 2023
Abstract : Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO(4)) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO(4) and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-kappaB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfalpha), interleukin 6 (il6), interleukin 1beta (il1beta), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.
ESTHER : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedSearch : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedID: 37678480

Title : Downregulation of peripheral luteinizing hormone rescues ovariectomy-associated cognitive deficits in APP\/PS1 mice - Zhang_2023_Neurobiol.Aging_135_60
Author(s) : Zhang YN , Chen XL , Guo LY , Jiang PR , Lu H , Pan K , Guo L , Hu YT , Bao AM
Ref : Neurobiology of Aging , 135 :60 , 2023
Abstract : Alzheimer's disease (AD) is more prevalent in women than men, supposing due to the decline of estrogens in menopause, accompanied by increased gonadotropins such as luteinizing hormone (LH). We and others found that the transcription factor early growth response-1 (EGR1) regulates cholinergic function including the expression of acetylcholinesterase (AChE) and plays a significant role in cognitive decline of AD. Here we investigated in APP/PS1 mice by ovariectomy (OVX) and estradiol (E2) supplementation or inhibition of LH the effect on hippocampus-related cognition and related molecular changes. We found that OVX-associated cognitive impairment was accompanied by increased dorsal hippocampal EGR1 expression, which was rescued by downregulating peripheral LH rather than by supplementing E2. We also found in postmortem AD brains a higher expression of pituitary LH-mRNA and higher EGR1 expression in the posterior hippocampus. Both, in human and mice, there was a significant positive correlation between respectively posterior/dorsal hippocampal EGR1 and peripheral LH expression. We conclude that peripheral increased LH and increased posterior hippocampal EGR1 plays a significant role in AD pathology.
ESTHER : Zhang_2023_Neurobiol.Aging_135_60
PubMedSearch : Zhang_2023_Neurobiol.Aging_135_60
PubMedID: 38185053

Title : LncRNA ABHD11-AS1 promotes tumor progression in papillary thyroid carcinoma by regulating EPS15L1\/EGFR signaling pathway - Lu_2022_Clin.Transl.Oncol_24_1124
Author(s) : Lu H , Zhu C , Chen Y , Ruan Y , Fan L , Chen Q , Wei Q
Ref : Clin Transl Oncol , 24 :1124 , 2022
Abstract : OBJECTIVES: lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) acts as an oncogene involved in papillary thyroid carcinoma (PTC) occurrence and progression. ABHD11-AS1 exerts biologic functions by some miRNAs and proteins to regulate multiple targets. Identification of novel mechanism of ABHD11-AS1 could be helpful in therapeutic targeting for PTC treatment. METHODS: Differentially expressed lncRNAs were selected from TCGA database. qRT-PCR analysis was applied to examine the expression of ABHD11-AS1 in PTC cell lines and tissues. The relationship of ABHD11-AS1 expression and clinicopathological features was analyzed by Kaplan-Meier analysis. Two PTC cell lines (TPC-1 and KTC-1) were transfected with pcDNA 3.1, pcDNA3.1-ABHD11-AS1, si-NC and si-ABHD11-AS1, respectively, to verify the ABHD11-AS1 oncogene-regulating capacity to promote tumor progression. The cell metastasis and proliferation had been evaluated both in vitro and in vivo. RESULTS: High expression of ABHD11-AS1 was found in PTC tissues (P < 0.01), which was significantly correlated with lymph node metastasis (P < 0.05). ABHD11-AS1 overexpression noticeably promoted cell proliferation, migration, and invasion capabilities, which were obviously decreased upon ABHD11-AS1 knockdown. ABHD11-AS1 positively regulated EGFR/EPS15L1 pathway, as EGFR, EPS15L1, STAT3, and p-STAT3 were activated. CONCLUSION: ABHD11-AS1 promotes tumor progression in PTC by regulating EPS15L1/EGFR pathway.
ESTHER : Lu_2022_Clin.Transl.Oncol_24_1124
PubMedSearch : Lu_2022_Clin.Transl.Oncol_24_1124
PubMedID: 35098448
Gene_locus related to this paper: human-ABHD11

Title : Machine learning-aided engineering of hydrolases for PET depolymerization - Lu_2022_Nature_604_662
Author(s) : Lu H , Diaz DJ , Czarnecki NJ , Zhu C , Kim W , Shroff R , Acosta DJ , Alexander BR , Cole HO , Zhang Y , Lynd NA , Ellington AD , Alper HS
Ref : Nature , 604 :662 , 2022
Abstract : Plastic waste poses an ecological challenge(1-3) and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling(4). Poly(ethylene terephthalate) (PET) accounts for 12% of global solid waste(5), and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products(6-10). Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics(11). Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives(12) between 30 and 50 degreesC and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 C. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale.
ESTHER : Lu_2022_Nature_604_662
PubMedSearch : Lu_2022_Nature_604_662
PubMedID: 35478237
Gene_locus related to this paper: idesa-peth

Title : Molecular mechanism of LIP05 derived from Monascus purpureus YJX-8 for synthesizing fatty acid ethyl esters under aqueous phase - Zhao_2022_Front.Microbiol_13_1107104
Author(s) : Zhao J , Xu Y , Lu H , Zhao D , Zheng J , Lin M , Liang X , Ding Z , Dong W , Yang M , Li W , Zhang C , Sun B , Li X
Ref : Front Microbiol , 13 :1107104 , 2022
Abstract : Fatty acid ethyl esters are important flavor chemicals in strong-flavor Baijiu. Monascus purpureus YJX-8 is recognized as an important microorganism for ester synthesis in the fermentation process. Enzyme LIP05 from YJX-8 can efficiently catalyze the synthesis of fatty acid ethyl esters under aqueous phase, but the key catalytic sites affecting esterification were unclear. The present work combined homology modeling, molecular dynamics simulation, molecular docking and site-directed mutation to analyze the catalytic mechanism of LIP05. Protein structure modeling indicated LIP05 belonged to alpha/beta fold hydrolase, contained a lid domain and a core catalytic pocket with conserved catalytic triad Ser150-His215-Asp202, and the oxyanion hole composed of Gly73 and Thr74. Ile30 and Leu37 of the lid domain were found to affect substrate specificity. The Pi-bond stacking between Tyr116 and Tyr149 played an important role in stabilizing the catalytic active center of LIP05. Tyr116 and Ile204 determined the substrate spectrum by composing the substrate-entrance channel. Residues Leu83, Ile204, Ile211 and Leu216 were involved in forming the hydrophobic substrate-binding pocket through steric hindrance and hydrophobic interaction. The catalytic mechanism for esterification in aqueous phase of LIP05 was proposed and provided a reference for clarifying the synthesis of fatty acid ethyl esters during the fermentation process of strong-flavor Baijiu.
ESTHER : Zhao_2022_Front.Microbiol_13_1107104
PubMedSearch : Zhao_2022_Front.Microbiol_13_1107104
PubMedID: 36713181

Title : Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative - Zeng_2022_Front.Immunol_13_1113070
Author(s) : Zeng Z , Liu R , Cao W , Yang L , Lin Y , Bi X , Jiang T , Deng W , Wang S , Lu H , Sun F , Shen G , Chang M , Lu Y , Wu S , Hao H , Xu M , Chen X , Hu L , Zhang L , Wan G , Xie Y , Li M
Ref : Front Immunol , 13 :1113070 , 2022
Abstract : AIMS: Study of clinical characteristics of hepatitis B virus deoxyribonucleic acid (HBV DNA)-negative, hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-negative patients based on liver histopathology. METHODS: We retrospectively enrolled patients with chronic HBV infection diagnosis at Beijing Ditan Hospital from May 2008 to November 2020. To study the differences between patients with significant hepatic histopathology and those without significant hepatic histopathology. And to study the independent factors of significant hepatic histopathology. RESULTS: 85 HBV DNA-negative and HBeAg-negative patients were 37.90 +/- 10.30 years old, 23.50% of patients with grade of inflammation (G) >1, 35.30% of patients with liver fibrosis stage (S) >1, 44.70% patients were diagnosed with significant hepatic histopathology. Compared to the no significant hepatic histopathology group, another group had older age (41.70 +/- 10.70 vs 34.80 +/- 8.87 years, t=-3.28, P=0.002), higher total bilirubin (TBIL) [14.9(10.3, 22.4) vs 11(8.9, 14.4) micromol/L, z=-2.26, P=0.024], lower cholinesterase (CHE) (t=-2.86, P=0.005, 7388.00 +/- 2156.00 vs 8988.00 +/- 2823.00 U/L) and lower platelet (PLT) (t=2.75, P=0.007, 157.00 +/- 61.40 vs 194.00 +/- 61.00 10^9/L). Abnormal ALT patients are more likely to have significant hepatic histopathology (z=5.44, P=0.020, 66.70% vs 337.50%). G had significant correlation with CHE (P=0.008, r=-0.23), alanine aminotransferase (ALT) (P=0.041, r=0.18), aspartate aminotransferase (AST) (P=0.001, r=0.29). S had significant correlation with TBIL (P = 0.008, r = 0.23), age (P < 0.001, r = 0.32), international normalized ratio (INR) (P = 0.04, r = 0.23), CHE (P < 0.001, r = -0.30), PLT (P < 0.001, r = -0.40) and prothrombin time activity (PTA) (P = 0.046, r = -0.22). Multivariate logistic analysis indicated only age (95%CI=1.014~1.130, OR=1.069, P=0.013) was an impact factor for significant hepatic histopathology. The cutoff point of age was 34.30 years. CONCLUSIONS: A large proportion of chronic HBV infection patients with HBeAg-negative and HBV DNA-negative still have chronic hepatitis. Age is an independent factor for significant hepatic histopathology.
ESTHER : Zeng_2022_Front.Immunol_13_1113070
PubMedSearch : Zeng_2022_Front.Immunol_13_1113070
PubMedID: 36685494

Title : Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property - Liu_2022_Bioorg.Chem_126_105875
Author(s) : Liu W , Wu L , Li D , Huang Y , Liu M , Tian C , Liu X , Jiang X , Hu X , Gao X , Xu Z , Lu H , Zhao Q
Ref : Bioorg Chem , 126 :105875 , 2022
Abstract : Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI(50) = 0.029 microM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD(50)) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC(50) = 0.002 microM) and good selectivity over CDK2 (IC(50) = 0.054 microM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.
ESTHER : Liu_2022_Bioorg.Chem_126_105875
PubMedSearch : Liu_2022_Bioorg.Chem_126_105875
PubMedID: 35623141

Title : Deep learning redesign of PETase for practical PET degrading applications - Lu_2021_Biorxiv__
Author(s) : Lu H , Diaz DJ , Czarnecki NJ , Zhu C , Kim W , Shroff R , Acosta DJ , Alexander B , Cole H , Zhang YJ , Lynd N , Ellington AD , Alper HS
Ref : Biorxiv , : , 2021
Abstract : Plastic waste poses an ecological challenge1. While current plastic waste management largely relies on unsustainable, energy-intensive, or even hazardous physicochemical and mechanical processes, enzymatic degradation offers a green and sustainable route for plastic waste recycling2. Poly(ethylene terephthalate) (PET) has been extensively used in packaging and for the manufacture of fabrics and single-used containers, accounting for 12% of global solid waste3. The practical application of PET hydrolases has been hampered by their lack of robustness and the requirement for high processing temperatures. Here, we use a structure-based, deep learning algorithm to engineer an extremely robust and highly active PET hydrolase. Our best resulting mutant (FAST-PETase: Functional, Active, Stable, and Tolerant PETase) exhibits superior PET-hydrolytic activity relative to both wild-type and engineered alternatives, (including a leaf-branch compost cutinase and its mutant4) and possesses enhanced thermostability and pH tolerance. We demonstrate that whole, untreated, post-consumer PET from 51 different plastic products can all be completely degraded by FAST-PETase within one week, and in as little as 24 hours at 50 C. Finally, we demonstrate two paths for closed-loop PET recycling and valorization. First, we re-synthesize virgin PET from the monomers recovered after enzymatic depolymerization. Second, we enable in situ microbially-enabled valorization using a Pseudomonas strain together with FAST-PETase to degrade PET and utilize the evolved monomers as a carbon source for growth and polyhydroxyalkanoate production. Collectively, our results demonstrate the substantial improvements enabled by deep learning and a viable route for enzymatic plastic recycling at the industrial scale.
ESTHER : Lu_2021_Biorxiv__
PubMedSearch : Lu_2021_Biorxiv__
Gene_locus related to this paper: idesa-peth

Title : The Enhancement Effect of Acetylcholine and Pyridostigmine on Bone-Tendon Interface Healing in a Murine Rotator Cuff Model - Wang_2021_Am.J.Sports.Med__363546520988680
Author(s) : Wang Z , Chen Y , Xiao H , Li S , Zhang T , Hu J , Lu H , Xie H
Ref : Am J Sports Med , :363546520988680 , 2021
Abstract : BACKGROUND: How to improve rotator cuff healing remains a challenge. Little is known about the effect of the parasympathetic transmitter acetylcholine (ACh) and the acetylcholinesterase inhibitor pyridostigmine (PYR), both of which have anti-inflammatory properties, in the healing process of rotator cuff injury. HYPOTHESIS: ACh and PYR could enhance bone-tendon interface healing in a murine model of rotator cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 160 C57BL/6 mice underwent unilateral rotator cuff repair surgery. Fibrin gel (FG) was used as a drug carrier. The mice were randomly assigned to 4 groups with 40 mice per group: FG group (received FG alone), 10(-5) M ACh group (received FG containing 10(-5) M ACh), 10(-6) M ACh group (received FG containing 10(-6) M ACh), and PYR group (received FG containing 25 microg of PYR). Ten mice in each group were euthanized at 2, 4, 8, and 12 weeks postoperatively. Histologic, immunohistochemical, and biomechanical evaluations were performed for analysis. RESULTS: Histologically, fibrocartilage-like tissue was shown at the repaired site. The proteoglycan content of the 10(-5) M ACh group was significantly increased compared with the FG group at 4 weeks. M2 macrophages were identified at the repaired site for all groups at 2 and 4 weeks. At 8 weeks, M2 macrophages withdrew back to the tendon in the FG group, but a number of M2 macrophages were retained at the repaired sites in the ACh and PYR groups. Biomechanically, failure load and stiffness of the ACh and PYR groups were significantly higher than those of the FG group at 4 weeks. The stiffness of the ACh and PYR groups was significantly increased compared with the FG group at 8 weeks (P < .001 for all). At 12 weeks, most of the healing properties of the ACh and PYR groups were not significantly different compared with the FG group. CONCLUSION: ACh and PYR enhanced the early stage of bone-tendon insertion healing after rotator cuff repair. CLINICAL RELEVANCE: These findings imply that ACh and PYR could serve as potential therapeutic strategies for rotator cuff healing.
ESTHER : Wang_2021_Am.J.Sports.Med__363546520988680
PubMedSearch : Wang_2021_Am.J.Sports.Med__363546520988680
PubMedID: 33592162

Title : Prognostic Significance of Hematopoietic-cell Serglycin for the Survival of Hepatocellular Carcinoma: A Single-center Retrospective Study - Li_2021_Comb.Chem.High.Throughput.Screen_24_986
Author(s) : Li Y , Chen H , Lu H , Zou Z
Ref : Comb Chem High Throughput Screen , 24 :986 , 2021
Abstract : AIM AND OBJECTIVE: Inflammation-related changes in peripheral blood cells and blood proteins are prognostic factors for survival in hepatocellular carcinoma (HCC), but their usefulness is limited by an active bacterial infection. This study investigated whether infection interfered with the predictive value of serglycin, a proteoglycan found in hematopoietic cells, on survival in HCC. MATERIALS AND METHODS: Patients with hepatitis B virus (HBV)-induced HCC, 100 without and 30 with a bacterial infection, and 30 healthy adult controls were enrolled retrospectively. Baseline clinical data collected before treatment with transarterial chemoembolization (TACE) was evaluated, and serglycin expression was assayed by flow cytometry. Receiver operating characteristic (ROC) curve analysis identified serglycin cutoff values for patient stratification. Cox regression and Kaplan-Meier analyses were performed to identify predictors of overall survival (OS). RESULTS: Serglycin levels in peripheral blood cells were higher in both groups of HCC patients than in the control group. Cholinesterase, lung metastasis, average neutrophil serglycin fluorescence intensity, and aspartate aminotransferase levels were associated with survival risk. Barcelona Clinic Liver Cancer stage A was associated with a good prognosis of OS. CONCLUSION: The intensity of serglycin fluorescence in peripheral neutrophils was independently predictive of survival in HCC, and its value was not limited by a bacterial infection. The method presented here is a simple and feasible way to predict prognosis in HCC patients with TACE.
ESTHER : Li_2021_Comb.Chem.High.Throughput.Screen_24_986
PubMedSearch : Li_2021_Comb.Chem.High.Throughput.Screen_24_986
PubMedID: 33081679

Title : Chlorogenic acid alleviates thioacetamide-induced toxicity and promotes liver development in zebrafish (Danio rerio) through the Wnt signaling pathway - Liu_2021_Aquat.Toxicol_242_106039
Author(s) : Liu Y , Guo J , Zhang J , Deng Y , Xiong G , Fu J , Wei L , Lu H
Ref : Aquat Toxicol , 242 :106039 , 2021
Abstract : Chlorogenic acid (CGA) is a phenylpropanoid compound that is well known to improve the antioxidant capacity and other biological activities. However, the roles of CGA in the liver development of organisms are unclear. In the present study, we aimed to investigate the function of CGA in the hepatic development in thioacetamide (TAA)-induced zebrafish embryos. We found that CGA exerted certain beneficial effects on zebrafish larvae from TAA-exposed zebrafish embryos, such as increasing the liver size, body length, heart rate, acetylcholinesterase activity, and motor ability. In addition, CGA displayed an antioxidant effect on TAA-induced zebrafish embryos by enhancing the activities of superoxide dismutase (SOD), catalase (CAT), and glucose-6-phosphate dehydrogenase (G6PDH), and decreasing of the contents of malondialdehyde (MDA), reactive oxygen species (ROS), and nitric oxide (NO). The results of western blotting analysis showed that CGA inhibited cell apoptosis by increasing the levels of Bcl2 apoptosis regulator and decreasing the levels of Bcl2 associated X (Bax), apoptosis regulator and tumor protein P53. Moreover, CGA promoted cell proliferation in TAA-induced zebrafish larvae, as detected using proliferating cell nuclear antigen fluorescence immunostaining. In addition, CGA inhibited the expression of Wnt signaling pathway genes Dkk1 (encoding Dickkopf Wnt signaling pathway inhibitors), and promoted the expression of Lef1 (encoding lymphoid enhancer binding factor 1) and Wnt2bb (encoding wingless-type MMTV integration site family, member 2Bb). When the Wnt signal inhibitor IWR-1 was added, there was no significant change in liver development in the IWR-1 + TAA group compared with the IWR-1 + TAA + CGA group (p <0.05), which suggested that CGA regulates liver development via Wnt signaling pathway. Overall, our results suggested that CGA might alleviate TAA-induced toxicity in zebrafish and promote liver development through the Wnt signaling pathway, which provides a basis for the therapeutic effect of CGA on liver dysplasia.
ESTHER : Liu_2021_Aquat.Toxicol_242_106039
PubMedSearch : Liu_2021_Aquat.Toxicol_242_106039
PubMedID: 34856462

Title : SERS-ELISA determination of human carboxylesterase 1 using metal-organic framework doped with gold nanoparticles as SERS substrate - Feng_2021_Mikrochim.Acta_188_280
Author(s) : Feng J , Lu H , Yang Y , Huang W , Cheng H , Kong H , Li L
Ref : Mikrochim Acta , 188 :280 , 2021
Abstract : By in situ synthesis of gold nanoparticles (AuNPs) within the acid-etched (AE) MIL-101 (Cr) framework, AE-MIL-101 (Cr) nanocomposites embedded with AuNPs (AuNP/AE-MIL-101 (Cr)) were prepared as surface-enhanced Raman scattering (SERS) substrate. AuNPs are uniformly distributed and stabilized inside the metal-organic framework (MOF), thus forming more SERS hotspots. The SERS performance of AuNP/AE-MIL-101 (Cr) was evaluated using 4-mercaptophenylboronic acid (4-MPBA), 4-mercaptobenzoic acid (4-MBA), benzidine, and rhodamine 6G (R6G). The SERS substrate displays satisfying stability with very low background signal. When benzidine is used as the Raman reporter, the limit of detection (LOD) can reach 6.7 x 10(-13) mol.L(-1), and the relative standard deviation (RSD) of the intra- and inter-batch repetitive tests is less than 5.2%. On this basis, we developed a method for the detection of human carboxylesterase 1 (hCE 1) in human serum using AuNP/AE-MIL-101 (Cr) nanocomposite as SERS substrate and enzyme-linked immunosorbent assay (ELISA) colorimetric substrate as SERS marker. This method was used to determine hCE 1 in clinical serum samples without complicated sample pretreatment, and the detection results were consistent with the data determined by ELISA. In the concentration range 0.1-120 ng.mL(-1), the SERS signal intensity of benzidine at 1609 cm(-1) gradually decreases with the increase of hCE 1 concentration (R(2) = 0.9948). The average recoveries of hCE 1 in human serum are in the range 84 to 108%, with RSDs lower than 7.7%. By using AuNP/acid etching-MIL-101(Cr) metal organic framework (MOF) as SERS substrate and enzyme-linked immunosorbent assay (ELISA) colorimetric substrate as the SERS marker, a rapid and sensitive method for the determination of human carboxylesterase 1 (hCE1) in human serum samples has been developed.
ESTHER : Feng_2021_Mikrochim.Acta_188_280
PubMedSearch : Feng_2021_Mikrochim.Acta_188_280
PubMedID: 34331134

Title : N-MYC Downstream Regulated Gene 4 (NDRG4), a Frequent Downregulated Gene through DNA Hypermethylation, plays a Tumor Suppressive Role in Esophageal Adenocarcinoma - Cao_2020_Cancers.(Basel)_12_
Author(s) : Cao L , Hu T , Lu H , Peng D
Ref : Cancers (Basel) , 12 : , 2020
Abstract : The incidence of esophageal adenocarcinoma (EAC) has been rising dramatically in the past few decades in the United States and Western world. The N-myc downregulated gene 4 (NDRG4) belongs to the human NDRG family. In this study, we aimed to identify the expression levels, regulation, and functions of NDRG4 in EAC. Using an integrative epigenetic approach, we identified genes showing significant downregulation in EAC and displaying upregulation after 5-Aza-deoxycitidine. Among these genes, likely to be regulated by DNA methylation, NDRG4 was among the top 10 candidate genes. Analyses of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) data sets and EAC tissue samples demonstrated that NDRG4 was significantly downregulated in EAC (p < 0.05). Using Pyrosequencing technology for quantification of DNA methylation, we detected that NDRG4 promoter methylation level was significantly higher in EAC tissue samples, as compared to normal esophagus samples (p < 0.01). A strong inverse correlation between NDRG4 methylation and its gene expression levels (r = -0.4, p < 0.01) was observed. Treatment with 5-Aza restored the NDRG4 expression, confirming that hypermethylation is a driving force for NDRG4 silencing in EAC. Pathway and gene set enrichment analyses of TCGA data suggested that NDRG4 is strongly associated with genes related to cell cycle regulation. Western blotting analysis showed significant downregulation of Cyclin D1, CDK4 and CDK6 in EAC cells after overexpression of NDRG4. Functionally, we found that the reconstitution of NDRG4 resulted in a significant reduction in tumor cell growth in two-dimensional (2D) and three-dimensional (3D) organotypic culture models and inhibited tumor cell proliferation as indicated by the EdU (5-ethynyl-2'-deoxyuridine) proliferation assay.
ESTHER : Cao_2020_Cancers.(Basel)_12_
PubMedSearch : Cao_2020_Cancers.(Basel)_12_
PubMedID: 32927604

Title : Diosgenin alleviates hypercholesterolemia via SRB1\/CES-1\/CYP7A1\/FXR pathway in high-fat diet-fed rats - Yu_2020_Toxicol.Appl.Pharmacol__115388
Author(s) : Yu L , Lu H , Yang X , Li R , Shi J , Yu Y , Ma C , Sun F , Zhang S , Zhang F
Ref : Toxicol Appl Pharmacol , :115388 , 2020
Abstract : Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150mg/kg/d), high-dose DG (HDG) group (300mg/kg) and Simvastatin (Sim) group (4mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7alpha- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.
ESTHER : Yu_2020_Toxicol.Appl.Pharmacol__115388
PubMedSearch : Yu_2020_Toxicol.Appl.Pharmacol__115388
PubMedID: 33383043

Title : Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo - Tora_2020_J.Med.Chem_63_1660
Author(s) : Tora G , Kim SH , Pi Z , Johnson JA , Jiang J , Phillips M , Lloyd J , Abell LM , Lu H , Locke G , Adam LP , Taylor DS , Yin X , Behnia K , Zhao L , Yang R , Basso M , Caporuscio C , Chen AY , Liu E , Kirshgessner T , Onorato JM , Ryan C , Traeger SC , Gordon D , Wexler RR , Finlay HJ
Ref : Journal of Medicinal Chemistry , 63 :1660 , 2020
Abstract : Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
ESTHER : Tora_2020_J.Med.Chem_63_1660
PubMedSearch : Tora_2020_J.Med.Chem_63_1660
PubMedID: 31990537

Title : Five novel and highly efficient endophytic fungi isolated from Huperzia serrata expressing huperzine A for the treatment of Alzheimer's disease - Wen-Xia_2020_Appl.Microbiol.Biotechnol_104_9159
Author(s) : Wen-Xia H , Zhong-Wen H , Min J , Han Z , Wei-Ze L , Li-Bin Y , Fei L , Lu H , Ning Z , Xiao-Feng L
Ref : Applied Microbiology & Biotechnology , 104 :9159 , 2020
Abstract : Huperzine A (Hup A) is an important drug for treating Alzheimer's disease (AD) and mainly extracted from the Huperzia serrata (Thunb.) Trevis. (Lycopodiaceae) (HS). Nevertheless, the content of Hup A in HS is very low of 0.007% with growing circle of 8 to 10 years, and the chemical synthesis of Hup A still has some insurmountable limitations in the industrialized production. So, the available resources of Hup A for clinical treatment of AD are scarce. The purpose of this work was to construct a biosynthesis platform based on the endophytic fungi from HS. In this work, five endophytic fungi Mucor racemosus NSH-D, Mucor fragilis NSY-1, Fusarium verticillioides NSH-5, Fusarium oxysporum NSG-1, and Trichoderma harzianum NSW-V were firstly found and isolated from the Chinese folk medicine HS, which were identified according to their morphological characteristics and nuclear ribosomal DNA ITS sequences. The highest efficient fungus could effectively biosynthesize Hup A in a liquid culture of 319.8 +/- 0.17 mg/L which were 112 times higher than that of other reported conventional endophytic fungi. Moreover, these fungi with higher hereditary stability could possess the initial expressing ability of Hup A after 40 generations, and the expressed Hup A from these biosynthesis systems has prior physicochemical properties, a better inhibition activity of acetylcholinesterase and a lower cytotoxicity compared with the listed active pharmaceutical ingredients (APIs) of Hup A. These results provide promising alternative resources for producing Hup A at an industrial scale by biosynthesis, and it may also shed light on millions of AD patients. KEY POINTS: Five novel endophytic fungi with high stability could highly express prior Hup A Graphical abstract.
ESTHER : Wen-Xia_2020_Appl.Microbiol.Biotechnol_104_9159
PubMedSearch : Wen-Xia_2020_Appl.Microbiol.Biotechnol_104_9159
PubMedID: 32970179

Title : The immunotoxicity and neurobehavioral toxicity of zebrafish induced by famoxadone-cymoxanil - Cheng_2020_Chemosphere_247_125870
Author(s) : Cheng B , Zhang H , Hu J , Peng Y , Yang J , Liao X , Liu F , Guo J , Hu C , Lu H
Ref : Chemosphere , 247 :125870 , 2020
Abstract : As a new protective and therapeutic fungicide, studies on famoxadone-cymoxanil are rare, and its toxicity to aquatic organisms has not been reported. In the present study, zabrafish embryos were exposed to several concentrations of famoxadone-cymoxanil at 10 hpf. Then, the changes of their shape, heart rate, development and function of innate and adaptive immune cells, oxidative stress, apoptosis, the expression of apoptosis-related genes and immune-related genes, the locomotor behavior were observed and detected in acute toxicity of famoxadone-cymoxanil. Our studies showed that, after exposure to famoxadone-cymoxanil, zebrafish embryos had decreased heart rate, shortened body length, swollen yolk sac. Secondly, the number of innate and adaptive immune cells was significantly reduced; and neutrophil migration and retention at the injury area were inhibited, indicating the developmental toxicity and immunotoxicity of famoxadone-cymoxanil on the zebrafish. We also found that the oxidative stress related indicators of embryos were changed significantly, and apoptosis were substantially increased. Further investigation of changes of some key genes in TLR signaling including TLR4, MYD88 and NF-kappaB p65 revealed that the mRNA expression of these genes was up-regulated. Meanwhile, the mRNA expression of some proinflammatory cytokines such as TNF-alpha, IFN-gamma, IL6 and IL-1beta was also up-regulated. In addition, the activity, the total distance, time and average speed were decreased along with the increase of exposure concentration. The absolute turn angle, sinuosity and the enzymatic activity of acetylcholinesterase (AChE) were also increased. These results suggested that famoxadone-cymoxanil can induce developmental toxicity, immunotoxicity and neurobehavioral toxicity in zebrafish larvae.
ESTHER : Cheng_2020_Chemosphere_247_125870
PubMedSearch : Cheng_2020_Chemosphere_247_125870
PubMedID: 31931321

Title : Effects of lincomycin hydrochloride on the neurotoxicity of zebrafish - Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
Author(s) : Cheng B , Jiang F , Su M , Zhou L , Zhang H , Cao Z , Liao X , Xiong G , Xiao J , Liu F , Lu H
Ref : Ecotoxicology & Environmental Safety , 201 :110725 , 2020
Abstract : Lincomycin hydrochloride is one of the commonly used drugs in clinic. However, it has many side effects on patients, and its mechanism is still poorly understood. In this study, 6 h post-fertilization (6 hpf) zebrafish embryos were exposed to several concentrations of lincomycin hydrochloride (15, 30, 60 mug/mL) for up to 24 or 96 hpf to detect their developmental toxicity and neurotoxicity, and to 6 days post-fertilization (6 dpf) to detect their behavioral toxicity. Our results showed that lincomycin hydrochloride could lead to embryonic head deformities (unclear ventricles, smaller ventricles, fewer new neurons). The studies showed that the frequency of spontaneous tail flick of zebrafish embryo increased at 24 hpf, and the lincomycin hydrochloride exposed zebrafish embryos showed increased heart rate, shorter body length, and yolk sac edema with severe pericardial edema at 96 hpf. The studies also showed that lincomycin hydrochloride increased oxidative stress level, Acetylcholinesterase (AChE) activity, ATPase activity and apoptosis in zebrafish larvae. In addition, the swimming behavior of zebrafish larvae decreased with the increase of lincomycin hydrochloride concentration, but the angular velocity and meandering degree increased, which might be due to the decreased activity of AChE and ATPase, as well as the decreased expression of genes related to neurodevelopment and neurotransmitter system, leading to the change of their motor behaviors. In summary, we found that lincomycin hydrochloride induced developmental toxicity and neurotoxicity in zebrafish larvae, contributing to a more comprehensive evaluation of the safety of the drug.
ESTHER : Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
PubMedSearch : Cheng_2020_Ecotoxicol.Environ.Saf_201_110725
PubMedID: 32474209

Title : Variation in metabolism and degradation of di-n-butyl phthalate (DBP) by high- and low-DBP accumulating cultivars of rice (Oryza sativa L.) and crude enzyme extracts - Zhu_2019_Sci.Total.Environ_668_1117
Author(s) : Zhu TK , Du PP , Zeng LJ , Lu H , Zhao HM , Li YW , Mo CH , Cai QY
Ref : Sci Total Environ , 668 :1117 , 2019
Abstract : Crops can take up and accumulate di-n-butyl phthalate (DBP), an extensively used plasticizer with endocrine disrupting effect, which poses potential risk to human health. Our previous study found the genotype variation in accumulation of DBP by different cultivars of rice (Oryza sativa L.). Nevertheless, the effect of DBP metabolism in vivo on the accumulation variation among different plant cultivars remains unknown. In this study, metabolism variation of DBP by low (Fengyousimiao) and high (Peizataifeng) DBP-accumulating cultivars of rice and the key enzymes involving in DBP metabolism in rice plants were investigated using in vivo exposure of rice plants and in vitro exposure of root crude enzyme extracts. Both mono-n-butyl phthalate (MBP) and phthalic acid (PA) were detected as DBP metabolites in all rice tissues (i.e., roots, stems, leaves) and crude enzyme extracts with MBP predominance. DBP metabolism occurred simultaneously when DBP uptake with the highest metabolism in roots in vivo. Degradation of DBP in root crude enzyme extracts fitted well with the first order kinetics (R(2)=0.49-0.76, P<0.05). The activity of carboxylesterase (CXE) in root crude enzyme extracts was significantly positively correlated with DBP degradation rates. CXE played an important role in DBP metabolism of rice plants, confirming by the fact that triphenyl phosphate of CXE inhibitor could inhibit DBP metabolism of in vivo and in vitro exposure. This result was further confirmed by in vitro degradation of DBP with the commercial pure CXE. The crude enzyme solution from roots of Fengyousimiao with higher CXE activity had significantly higher DBP degradation rates than that of Peizataifeng. However, Fengyousimiao with lower tolerance to DBP stress and higher inhibition by triphenyl phosphate displayed lower DBP metabolism ability in vivo than Peizataifeng.
ESTHER : Zhu_2019_Sci.Total.Environ_668_1117
PubMedSearch : Zhu_2019_Sci.Total.Environ_668_1117
PubMedID: 31018452

Title : Neuroprotective Effect of Resveratrol via Activation of Sirt1 Signaling in a Rat Model of Combined Diabetes and Alzheimer's Disease - Ma_2019_Front.Neurosci_13_1400
Author(s) : Ma X , Sun Z , Han X , Li S , Jiang X , Chen S , Zhang J , Lu H
Ref : Front Neurosci , 13 :1400 , 2019
Abstract : Background: Alzheimer's disease (AD) and diabetes mellitus (DM) often coexist in patients because having one of these conditions increases risk for the other. These two diseases share several pathophysiological mechanisms, such as specific inflammatory signaling pathways, oxidative stress, and cell apoptosis. It is still unclear exactly which mechanisms associated with DM are responsible for increased AD risk. Studies have found that even transient elevation of brain Abeta levels can allow T2DM to slightly disrupt the neural milieu in a way that encourages pathologies associated with the onset of memory deficits and AD. A recent study argues that a potential common pathogenetic mechanism underlying both DM and AD is evidenced by the cooccurrence of amyloid brain legions and deposits containing both tau and Abeta in pancreatic beta cells. Given these links, an investigation detailing disease mechanisms as well as treatment options for patients with cooccurring DM and AD is urgently needed. The biological effects of resveratrol relevant to DM and AD treatment include its abilities to modulate oxidative stress and reduce inflammation. A rat model of DM and concomitant AD was created for this study using intraperitoneal injection of streptozotocin and hippocampal injection of Abeta1-40 to characterize resveratrol's potential protective action. Results: Resveratrol significantly increased the Sirt1 expression, inhibited the memory impairment, the increased acetylcholinesterase, malondialdehyde, interleukin-1beta and interleukin 6 levels, and the decreased levels of choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione in this rat model of diabetes and concomitant AD. The Sirt 1 inhibitor EX527 partially reversed the effects of resveratrol. Conclusion: This study suggests that resveratrol may have a neuroprotective action through activation of Sirt1 signaling in diabetes and AD with concurrent onset.
ESTHER : Ma_2019_Front.Neurosci_13_1400
PubMedSearch : Ma_2019_Front.Neurosci_13_1400
PubMedID: 32038127

Title : Exposure to diclofop-methyl induces immunotoxicity and behavioral abnormalities in zebrafish embryos - Cao_2019_Aquat.Toxicol_214_105253
Author(s) : Cao Z , Zou L , Wang H , Zhang H , Liao X , Xiao J , Zhang S , Lu H
Ref : Aquat Toxicol , 214 :105253 , 2019
Abstract : Diclofop-methyl (DM) is widely used in agriculture and may lead to serious toxicity. However, a limited number of studies have been performed to evaluate the toxicity of DM in the immune and nervous systems of animals. Here, we utilized a good vertebrate model, zebrafish, to evaluate the toxicity of DM during the developmental process. Exposure of zebrafish embryos to 0.1, 0.3 and 0.5mg/l DM from 6h post fertilization (hpf) to 72 hpf induced developmental abnormalities, such as shorter body lengths and yolk sac edemas. The number of immune cells in zebrafish larvae was significantly reduced, but the inflammatory response was not influenced by DM treatment. The expression of immune-related genes were downregulated and the levels of oxidative stress were upregulated by DM exposure. Moreover, locomotor behaviors were inhibited by DM exposure. Therefore, our results suggest that DM has the potential to induce immunotoxicity and cause behavioral changes in zebrafish larvae. This study provides new evidence of the influence of DM exposure on aquatic ecosystems.
ESTHER : Cao_2019_Aquat.Toxicol_214_105253
PubMedSearch : Cao_2019_Aquat.Toxicol_214_105253
PubMedID: 31352076

Title : Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase - Kim_2019_Bioorg.Med.Chem.Lett_29_1918
Author(s) : Kim SH , Johnson JA , Jiang J , Parkhurst B , Phillips M , Pi Z , Qiao JX , Tora G , Ye Chen A , Liu E , Yin X , Yang R , Zhao L , Taylor DS , Basso M , Behnia K , Onorato J , Chen XQ , Abell LM , Lu H , Locke G , Caporuscio C , Adam LP , Gordon D , Wexler RR , Finlay HJ
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :1918 , 2019
Abstract : A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough>15 fold over mouse plasma EL IC50 over 4days).
ESTHER : Kim_2019_Bioorg.Med.Chem.Lett_29_1918
PubMedSearch : Kim_2019_Bioorg.Med.Chem.Lett_29_1918
PubMedID: 31176700
Gene_locus related to this paper: human-LIPG

Title : Clethodim exposure induced development toxicity and behaviour alteration in early stages of zebrafish life - Wang_2019_Environ.Pollut_255_113218
Author(s) : Wang H , Zhou L , Meng Z , Su M , Zhang S , Huang P , Jiang F , Liao X , Cao Z , Lu H
Ref : Environ Pollut , 255 :113218 , 2019
Abstract : Clethodim is one of the most widely used herbicides in agriculture, however, its potential toxic effects on organisms and the underlying toxicity mechanism are still poorly understood. In this study, zebrafish embryos at 6h post-fertilization (hpf) were exposed to 10mg/L, 20mg/L, and 30mg/L clethodim for up to 24 hpf, and zebrafish larvae at 6 days post-fertilization (dpf) were exposed to the same density gradient for 24h. Our results showed that clethodim could cause head and cardiovascular malformations in embryos: blurred brain ventricles, unapparent brain regions, condensation of nucleus and cytoplasm in brain cells, increased intercellular space, developmental malformations of eyes and ears, reduced neonatal neurons, disorder migration of neural ridge cells; morphological aberrations of the vascular ICM, slowing of heart beat and blood flow, reduction of circulating red blood cells, and delayed development of head and tail blood vessels. These defects could be a result of clethodim-induced oxidative stress and decreased acetylcholinesterase (AChE) activity, which in turn affected the expression of neurodevelopmental genes, decreased ATPase activity, and ultimately led to developmental malformations. The swimming behaviour of zebrafish larvae was observed to decrease with increasing concentration of clethodim exposure, but the angular velocity and mobility increased. These could be due to reduced AChE activity and disturbed gene expression of GABA, dopamine and glutamatergic neurotransmitter systems, which thus altered the locomotor behaviour. In summary, we found that clethodim induces developmental toxicity and neurotoxicity in zebrafish embryos and larvae.
ESTHER : Wang_2019_Environ.Pollut_255_113218
PubMedSearch : Wang_2019_Environ.Pollut_255_113218
PubMedID: 31541821

Title : Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships - Zhang_2018_Cell_174_1450
Author(s) : Zhang P , Lu H , Peixoto RT , Pines MK , Ge Y , Oku S , Siddiqui TJ , Xie Y , Wu W , Archer-Hartmann S , Yoshida K , Tanaka KF , Aricescu AR , Azadi P , Gordon MD , Sabatini BL , Wong ROL , Craig AM
Ref : Cell , 174 :1450 , 2018
Abstract : Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development.
ESTHER : Zhang_2018_Cell_174_1450
PubMedSearch : Zhang_2018_Cell_174_1450
PubMedID: 30100184

Title : Characterization of the population structure, drug resistance mechanisms and plasmids of the community-associated Enterobacter cloacae complex in China - Zhou_2018_J.Antimicrob.Chemother_73_66
Author(s) : Zhou K , Yu W , Cao X , Shen P , Lu H , Luo Q , Rossen JWA , Xiao Y
Ref : J Antimicrob Chemother , 73 :66 , 2018
Abstract : OBJECTIVES: To investigate the population structure, drug resistance mechanisms and plasmids of community-associated Enterobacter cloacae complex (CA-ECC) isolates in China. METHODS: Sixty-two CA-ECC isolates collected from 31 hospitals across China were typed by hsp60 typing and MLST. ESBL and AmpC-overexpression phenotype was determined by double-disc synergy test. Replicon typing and conjugation were performed for plasmid analysis. All ESBL-positive isolates and representative conjugants were subjected to detailed characterization by WGS. RESULTS: Enterobacter hormaechei and Enterobacter kobei were predominant in our collections. MLST distinguished 46 STs with a polyclonal structure. ST591 was the most prevalent clone detected in northern China. Twenty-two isolates (35.5%) were ESBL positive and half of them were E. kobei. ESBL positivity was related to ESBL production (15/22) and to AmpC overexpression (18/22). Core-genome phylogenetic analysis identified intra- and inter-regional dissemination of ESBL-producing E. kobei clones. ESBL producers were exclusively classified as E. hormaechei and E. kobei, and blaCTX-M-3 was the most prevalent ESBL genotype (10/15) detected in four different environments. In the ESBL-positive population, the ESBL producers encoded more drug resistance genes (8-24 genes) by carrying more plasmids (1-3 plasmids) than the non-ESBL-producing isolates, resulting in an inter-group difference in drug susceptibilities. IncHI-type plasmids were prevalent in the ESBL producers (12/15). All IncHI2-type plasmids (n = 11) carried ESBL genes and shared a similar backbone to p09-036813-1A_261 recovered from Salmonella enterica in Canada. CONCLUSIONS: The species-specific distribution, species-dependent ESBL mechanism and endemic plasmids identified in our study highlight the necessity for tailored surveillance of CA-ECC in the future.
ESTHER : Zhou_2018_J.Antimicrob.Chemother_73_66
PubMedSearch : Zhou_2018_J.Antimicrob.Chemother_73_66
PubMedID: 29088362
Gene_locus related to this paper: 9entr-a0a2j0pr84

Title : Biodegradation pathway of di-(2-ethylhexyl) phthalate by a novel Rhodococcus pyridinivorans XB and its bioaugmentation for remediation of DEHP contaminated soil - Zhao_2018_Sci.Total.Environ_640-641_1121
Author(s) : Zhao HM , Hu RW , Chen XX , Chen XB , Lu H , Li YW , Li H , Mo CH , Cai QY , Wong MH
Ref : Sci Total Environ , 640-641 :1121 , 2018
Abstract : A novel bacterial strain designated as Rhodococcus pyridinivorans XB, capable of utilizing various endocrine disruptor phthalates or phthalic acid (PA) as sole source of carbon and energy, was isolated from activated sludge. Under the optimal culture conditions (pH7.08, 30.4 degrees C, inoculum size (OD600 nm) of 0.6) obtained by response surface methodology, di-(2-ethylhexyl) phthalate (DEHP, 200mg/L) could be degraded by strain XB with a removal rate of 98% within 48h. Under the observation of an atomic force microscope, it was confirmed that DEHP did not inhibit the growth of strain XB which might produce some extracellular polymeric substances as a response to DEHP stress, resulting in rapid degradation of DEHP. At initial concentrations of 50-800mg/L DEHP, its degradation curves were well fitted with the first-order kinetic model, and the half-life of DEHP degradation varied from 5.44 to 23.5h. The degradation intermediates of DEHP were identified by both GC-MS and high performance liquid chromatography-time of flight-mass spectrometry (HPLC-TOF-MS). Significant up-regulation was observed for the relative expression levels of genes (i.e., phthalate hydrolase, PA 3,4-dioxygenase, protocatechuate 3,4-alpha and 3,4-beta dioxygenase) involved in DEHP degradation determined by real-time quantitative PCR (RT-qPCR). A DEHP biodegradation pathway by strain XB was proposed based on the identified intermediates and the degrading genes. Bioaugmentation of DEHP-contaminated soils with strain XB could efficiently promote DEHP removal, offering great potential in bioremediation of DEHP-contaminated environment.
ESTHER : Zhao_2018_Sci.Total.Environ_640-641_1121
PubMedSearch : Zhao_2018_Sci.Total.Environ_640-641_1121
PubMedID: 30021277

Title : Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase - Johnson_2018_ACS.Med.Chem.Lett_9_1263
Author(s) : Johnson JA , Tora G , Pi Z , Phillips M , Yin X , Yang R , Zhao L , Chen AY , Taylor DS , Basso M , Rose A , Behnia K , Onorato J , Chen XQ , Abell LM , Lu H , Locke G , Caporuscio C , Galella M , Adam LP , Gordon D , Wexler RR , Finlay HJ
Ref : ACS Med Chem Lett , 9 :1263 , 2018
Abstract : Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an alpha-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
ESTHER : Johnson_2018_ACS.Med.Chem.Lett_9_1263
PubMedSearch : Johnson_2018_ACS.Med.Chem.Lett_9_1263
PubMedID: 30613337
Gene_locus related to this paper: human-LIPG

Title : Insecticidal and Acetylcholinesterase Inhibition Activity of Veratrum nigrum Alkaloidal Extract against the German Cockroach (Blattella germanica) - Cai_2018_J.Arthropod.Borne.Dis_12_414
Author(s) : Cai X , Li Q , Xiao L , Lu H , Tang J , Huang J , Yuan J
Ref : J Arthropod Borne Dis , 12 :414 , 2018
Abstract : Background: Veratrum nigrum (Liliaceae) is perennial medicinal plant widely used to treat various conditions. To determine its insecticidal properties against the German cockroach (Blattella germanica), several laboratory tests were carried out. Methods: A 4kg dry sample of V. nigrum root was purchased from the medicinal material market in Yunnan Province in 2015, China. In contact toxicity tests, V. nigrum alkaloidal extract was topically applied to the abdomen of cockroaches using a micro-applicator. In vitro acetylcholinesterase (AChE) activity tests were performed using a modified Ellman method. Results: Veratrum nigrum alkaloidal extract was toxic to male adults and 4(th) nymphs cockroaches, with median lethal dose (LD50) values of 14.90mug/insect, 14.21mug/insect for adults and 41.45mug/insect, 39.01mug/insect for 4(th) nymphs after 24h and 48h exposure, respectively. There was a significant difference between adults and nymphs in terms of tolerance to V. nigrum alkaloidal extract. There was no significant difference in mortalities at 24h and 48h, the lethal effect of V. nigrum alkaloidal extract on German cockroach was quick. AChE activity tests showed that V. nigrum alkaloidal extract had an excellent inhibitory effect on AChE: inhibition in the 4(th) nymphs and male adults had 50% inhibiting concentration (IC50) values of 3.56mg/ml and 5.78mg/ml respectively. The inhibitory effect of AChE activity was positively correlated with inhibitory time (0-20min), at a concentration of 1mg/ml, inhibition of nymph and adult AChE activity had 50% inhibiting time (IT50) values of 8.34min and 16.75min, respectively. Conclusion: V. nigrum may be explored as a potential natural insecticide for control of the German cockroach.
ESTHER : Cai_2018_J.Arthropod.Borne.Dis_12_414
PubMedSearch : Cai_2018_J.Arthropod.Borne.Dis_12_414
PubMedID: 30918910

Title : Muscarinic cholinergic signaling and overactive bladder-like symptoms associated with invasive bladder cancer - Wei_2018_Oncol.Lett_16_775
Author(s) : Wei W , Wang M , Li Y , Meng Q , Tang Y , Lu H , Yu W , Cheng Q , Xu L , Jian S , Wu Y , Yi X , Xie K
Ref : Oncol Lett , 16 :775 , 2018
Abstract : The objective of the present study was to explore the association between muscarinic cholinergic signaling and urothelial bladder tumors. Possible associations among overactive bladder (OAB) symptoms and bladder tumors were retrospectively investigated using a multicenter Chinese database with prospectively collected data since 2010. Firstly, it was demonstrated that OAB symptoms, such as urgency, were more severe in patients with invasive bladder cancer and were associated with a reduced prognosis. Following this, muscarinic cholinergic receptor 3 (M3R) expression in urothelium was determined to be lower in invasive cancer tissue than in adjacent non-cancerous tissue, yet M3R upregulation was associated with a reduced progression free survival (PFS) time. Additionally, it was also demonstrated that muscarinic cholinergic receptor 2 (M2R) was upregulated in the sub-urothelium, and this was also associated with a reduced PFS time. Furthermore, it was determined that cholinesterase and acetylcholinesterase were lower in invasive cancer than in non-invasive cancer. In conclusion, the results indicated that M3R expression was downregulated in invasive bladder cancer, which may have a role as a protective anti-oncogene, in contrast to its oncogenic role in numerous other cancer types. Therefore, muscarinic cholinergic signaling may be a novel therapeutic target for treating bladder cancer.
ESTHER : Wei_2018_Oncol.Lett_16_775
PubMedSearch : Wei_2018_Oncol.Lett_16_775
PubMedID: 29963145

Title : Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2 - Connor_2016_Neuron_91_1052
Author(s) : Connor SA , Ammendrup-Johnsen I , Chan AW , Kishimoto Y , Murayama C , Kurihara N , Tada A , Ge Y , Lu H , Yan R , LeDue JM , Matsumoto H , Kiyonari H , Kirino Y , Matsuzaki F , Suzuki T , Murphy TH , Wang YT , Yamamoto T , Craig AM
Ref : Neuron , 91 :1052 , 2016
Abstract : Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.
ESTHER : Connor_2016_Neuron_91_1052
PubMedSearch : Connor_2016_Neuron_91_1052
PubMedID: 27608760

Title : [The value of determination of serum cholinesterase levels in judgment of severity and prognosis in patients with severe pneumonia] - Mo_2016_Zhonghua.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_28_38
Author(s) : Mo X , Tang H , Zeng L , Lu H , Guo L , Ma Z
Ref : Zhonghua Wei Zhong Bing Ji Jiu Yi Xue , 28 :38 , 2016
Abstract : OBJECTIVE: To investigate the value of serum cholinesterase (S-ChE) levels in judgment of severity and prognosis in patients with severe pneumonia.
METHODS: The clinical data of patients with severe pneumonia, who were admitted to the Department of Internal Medicine in the First Affiliated Hospital of Sun Yat-sen University, or the Department of Neurology in the Third People's Hospital of Foshan from May 2011 to May 2015, whose hospital time was longer than 24 hours, were retrospectively analyzed. They were divided into survival group and death group according to the final outcome. Lab data, acute physiology and chronic health evaluation II (APACHE II) score, multiple organ dysfunction syndrome (MODS) score, the improved pneumonia score of British Thoracic Society (confusion, uremia, respiratory, blood pressure, age 65 years, CURB-65), and S-ChE levels of all patients were collected after they were hospitalized into the intensive care unit (ICU) within 24 hours. Independent risk factors for prognosis were analyzed by binary logistic regression analysis, and receiver operating characteristic curve (ROC) was plotted. Best truncation point analysis was used to compare their estimated value for prognosis of patients with severe pneumonia.
RESULTS: Eighty-six patients with severe pneumonia were studied. Among them 46 patients survived, and 40 patients died. By the single factor analysis, the following lab data in the death group were found significantly lower than those in the survival group: S-ChE levels (kU/L: 2.748+/-0.826 vs. 4.489+/-1.360, t' = 7.274, P = 0.000), arterial partial pressure of oxygen [PaO2 (mmHg, 1 mmHg = 0.133 kPa): 52.55+/-18.29 vs. 60.83+/-16.65, t = 2.196, P = 0.031], oxygenation index (mmHg: 114.20+/-48.01 vs. 167.10+/-69.68, t' = 4.229, P = 0.000), and carbon dioxide combining power [CO2-CP (mmol/L): 22.85+/-5.44 vs. 26.00+/-7.63, t' = 2.225, P = 0.029]. The following clinical data were significantly higher in the death group than those in the survival group, namely body temperature (centigrade: 38.67+/-1.18 vs. 37.74+/-1.18, t = -3.627, P = 0.000), pulse (bpm: 130.65+/-15.72 vs. 107.26+/-19.61, t' = -6.133, P = 0.000), the ratio of concomitant chronic lung disease [45.0% (18/40) vs. 13.0% (6/46), chi(2) = 10.860, P = 0.001], fraction of inspired oxygen [FiO2: 0.495 (0.410, 0.600) vs. 0.380 (0.290, 0.500), Z = -3.265, P = 0.001], APACHE II score (25.80+/-5.07 vs. 16.39+/-5.12, t =-8.540, P = 0.000), CURB-65 score [3 (3, 4) vs. 2 (1, 2), Z = -5.562, P = 0.000], MODS score (8.15+/-2.49 vs. 4.35+/-2.01, t = -7.832, P = 0.000), international normalized ratio [INR: 1.22 (1.08, 1.31) vs. 1.07 (1.00, 1.10), Z = -4.231, P = 0.000], and activated partial thromboplastin time [APTT (s): 33.80 (32.13, 38.75) vs. 28.50 (25.70, 36.00), Z = -3.482, P = 0.000]. Binary logistic regression analysis showed that, S-ChE levels, APACHE II score and MODS score were found to be the independent risk factors for prognosis in the patients with severe pneumonia, respectively [S-ChE: odds ratio (OR) = 0.084, 95% confidence interval (95%CI) = 0.017-0.424, P = 0.003; APACHE II score: OR = 1.675, 95%CI = 1.098-2.556, P = 0.017; MODS score: OR = 2.189, 95%CI = 1.262-3.800, P = 0.005]. The area under ROC (AUC) for S-ChE levels, APACHE II score and MODS score were 0.874+/-0.036, 0.889+/-0.033 and 0.884+/-0.035, respectively (all P > 0.05 as compared between any two means). At the best truncation points of S-ChE levels, APACHE II score and MODS score were 3.372 kU/L, 19.5 score, and 6.5 score respectively. The sensitivity, specificity, positive predictive value and negative predictive value in predicting death risk in patients with severe pneumonia were (80.0%, 78.0%, 76.19% and 81.82%), (95.0%, 70.0%, 73.08% and 94.12%) and (70.0%, 91.0%, 87.50%, 77.78%), respectively. If S-ChE levels was combined with APACHE II score or combined with MODS score, the sensitivity, specificity, positive predictive value and negative predictive value [S-ChE levels combined APACHE II score: 100%, 92.0%, 93.75% and 100%; S-ChE levels combined MODS score: all 100%] were higher than single power of S-ChE levels, APACHE II score or MODS score.
CONCLUSIONS: S-ChE levels can be considered as an effective and practical index to estimate the severity and prognosis in patients with severe pneumonia. The combined application of S-ChE levels and APACHE II score or MODS score can obviously improve the prognostic power in patients with severe pneumonia.
ESTHER : Mo_2016_Zhonghua.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_28_38
PubMedSearch : Mo_2016_Zhonghua.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_28_38
PubMedID: 26805533

Title : The Report of Sustained Low-Efficiency Dialysis (SLED) Treatment in Fifteen Patients of Severe Snakebite - Cheng_2014_Cell.Biochem.Biophys_69_71
Author(s) : Cheng J , Wang D , Hu S , Jiang H , Lu H , Lei Q , Liu J , Yuan F , Chen R
Ref : Cell Biochem Biophys , 69 :71 , 2014
Abstract : To investigate the therapeutic efficacy of sustained low-efficiency dialysis (SLED) in severe snakebite patients. Fifteen patients of severe snakebite was treated with SLED from July 2005 to August 2009 were included in the study. Central venous access was established in all patients. SLED was administered using Dialog(+) dialyzer (B. Braun, Germany). SLED sessions were 6-12 h in duration at a blood flow rate of 200 ml/min and a dialysate flow rate of 300 ml/min. Heparin or low molecular weight heparin was used as anticoagulant. Biochemical indicators, APACHE II scores before and after SLED, and clinical outcomes were evaluated. The levels of serum creatinine, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, creatine kinase isozyme MB, and creatine kinase were significantly lower than the level before SLED (P < 0.05); the level of cholinesterase was significantly higher after SLED (P < 0.01); the APACHE II score before SLED was 14.1 +/- 3.8, but decreased significantly to 7.9 +/- 1.4, 6.2 +/- 1.1, and 4.2 +/- 0.8 on days 1, 2, and 7 after SLED, respectively (P < 0.01). Three patients died on days 1, 3, and 4 after SLED, respectively. The remaining twelve patients were either cured or showed improvement at the time of discharge. The survival rate was 80 % where as mortality was 20 %. SLED may be an effective treatment option in severe snakebite patients. It can reduce mortality, thereby, resulting in increased survival rates.
ESTHER : Cheng_2014_Cell.Biochem.Biophys_69_71
PubMedSearch : Cheng_2014_Cell.Biochem.Biophys_69_71
PubMedID: 24068524

Title : Optimal dose of zinc supplementation for preventing aluminum-induced neurotoxicity in rats - Lu_2013_Neural.Regen.Res_8_2754
Author(s) : Lu H , Hu J , Li J , Pang W , Hu Y , Yang H , Li W , Huang C , Zhang M , Jiang Y
Ref : Neural Regen Res , 8 :2754 , 2013
Abstract : Zinc supplementation can help maintain learning and memory function in rodents. In this study, we hypothesized that zinc supplementation could antagonize the neurotoxicity induced by aluminum in rats. Animals were fed a diet containing different doses of zinc (50, 100, 200 mg/kg) for 9 weeks, and orally administered aluminum chloride (300 mg/kg daily) from the third week for 7 consecutive weeks. Open-field behavioral test results showed that the number of rearings in the group given the 100 mg/kg zinc supplement was significantly increased compared with the group given the 50 mg/kg zinc supplement. Malondialdehyde content in the cerebrum was significantly decreased, while dopamine and 5-hydroxytryptamine levels were increased in the groups given the diet supplemented with 100 and 200 mg/kg zinc, compared with the group given the diet supplemented with 50 mg/kg zinc. The acetylcholinesterase activity in the cerebrum was significantly decreased in the group given the 100 mg/kg zinc supplement. Hematoxylin-eosin staining revealed evident pathological damage in the hippocampus of rats in the group given the diet supplemented with 50 mg/kg zinc, but the damage was attenuated in the groups given the diet supplemented with 100 and 200 mg/kg zinc. Our findings suggest that zinc is a potential neuroprotective agent against aluminum-induced neurotoxicity in rats, and the optimal dosages are 100 and 200 mg/kg.
ESTHER : Lu_2013_Neural.Regen.Res_8_2754
PubMedSearch : Lu_2013_Neural.Regen.Res_8_2754
PubMedID: 25206586

Title : RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice - Peng_2013_Drug.Metab.Dispos_41_2175
Author(s) : Peng L , Cui JY , Yoo B , Gunewardena SS , Lu H , Klaassen CD , Zhong XB
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 41 :2175 , 2013
Abstract : Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.
ESTHER : Peng_2013_Drug.Metab.Dispos_41_2175
PubMedSearch : Peng_2013_Drug.Metab.Dispos_41_2175
PubMedID: 24080161

Title : SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties - Han_2013_Nature_503_72
Author(s) : Han K , Holder JL, Jr. , Schaaf CP , Lu H , Chen H , Kang H , Tang J , Wu Z , Hao S , Cheung SW , Yu P , Sun H , Breman AM , Patel A , Lu HC , Zoghbi HY
Ref : Nature , 503 :72 , 2013
Abstract : Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
ESTHER : Han_2013_Nature_503_72
PubMedSearch : Han_2013_Nature_503_72
PubMedID: 24153177

Title : Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors - Husson_2012_Curr.Biol_22_743
Author(s) : Husson SJ , Costa WS , Wabnig S , Stirman JN , Watson JD , Spencer WC , Akerboom J , Looger LL , Treinin M , Miller DM, 3rd , Lu H , Gottschalk A
Ref : Current Biology , 22 :743 , 2012
Abstract : BACKGROUND: Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single-neuron mRNA profiling of PVD.
RESULTS: Selectively photoactivating PVD, FLP, and downstream interneurons via Channelrhodopsin-2 (ChR2) enabled the functional dissection of this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca(2+) channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD's dynamic range and that GTL-1 may amplify its signals. These channels act cell autonomously in PVD, downstream of primary mechanosensory molecules.
CONCLUSIONS: Our work implicates TRPM channels in modifying excitability of and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologs, if functionally conserved, may denote valid targets for novel analgesics.
ESTHER : Husson_2012_Curr.Biol_22_743
PubMedSearch : Husson_2012_Curr.Biol_22_743
PubMedID: 22483941

Title : Astrocyte dysfunction associated with cerebellar attrition in a Nijmegen breakage syndrome animal model - Galron_2011_J.Mol.Neurosci_45_202
Author(s) : Galron R , Gruber R , Lifshitz V , Lu H , Kirshner M , Ziv N , Wang ZQ , Shiloh Y , Barzilai A , Frenkel D
Ref : Journal of Molecular Neuroscience , 45 :202 , 2011
Abstract : Nijmegen breakage syndrome (NBS) is a genomic instability disorder caused by hypomorphic mutations in the Nbs1 gene. When Nbs1 is conditionally inactivated in the central nervous system of mice (Nbs1-CNS-Delta), they suffer from severe cerebellar atrophy, ataxia, and white matter damage. Here, we show that conditional inactivation of the murine Nbs1 gene has a profound effect on the integrity and the functionality of the glial cells, which suggests their crucial role in the pathogenesis of NBS. Interestingly, in Nbs1-CNS-Delta mice, the dramatic reduction in the numbers of Purkinje and granule cells was also linked to a reduction of microglial cells but not to astrocytes (GFAP+), suggesting an impairment in astrocytic functionality. Nbs1 levels were dramatically reduced in adult astrocyte isolated from Nbs1-CNS-Delta mice, suggesting a major role in cerebellar pathology. In order to investigate the effect of Nbs1 deletion on astrocyte activity, we investigated glutamine synthetase levels in astrocyte and discovered 40% reduction as compared to WT. Furthermore, we found a significant reduction in the secretion of neurotrophic factors, such as brain-derived neurotrophic factor and neurotrophin 3. Understanding the contribution of malfunctioning astrocytes to the etiology of NBS can elucidate a hitherto unknown aspect of this disorder.
ESTHER : Galron_2011_J.Mol.Neurosci_45_202
PubMedSearch : Galron_2011_J.Mol.Neurosci_45_202
PubMedID: 21279473

Title : Two new complete genome sequences offer insight into host and tissue specificity of plant pathogenic Xanthomonas spp - Bogdanove_2011_J.Bacteriol_193_5450
Author(s) : Bogdanove AJ , Koebnik R , Lu H , Furutani A , Angiuoli SV , Patil PB , Van Sluys MA , Ryan RP , Meyer DF , Han SW , Aparna G , Rajaram M , Delcher AL , Phillippy AM , Puiu D , Schatz MC , Shumway M , Sommer DD , Trapnell C , Benahmed F , Dimitrov G , Madupu R , Radune D , Sullivan S , Jha G , Ishihara H , Lee SW , Pandey A , Sharma V , Sriariyanun M , Szurek B , Vera-Cruz CM , Dorman KS , Ronald PC , Verdier V , Dow JM , Sonti RV , Tsuge S , Brendel VP , Rabinowicz PD , Leach JE , White FF , Salzberg SL
Ref : Journal of Bacteriology , 193 :5450 , 2011
Abstract : Xanthomonas is a large genus of bacteria that collectively cause disease on more than 300 plant species. The broad host range of the genus contrasts with stringent host and tissue specificity for individual species and pathovars. Whole-genome sequences of Xanthomonas campestris pv. raphani strain 756C and X. oryzae pv. oryzicola strain BLS256, pathogens that infect the mesophyll tissue of the leading models for plant biology, Arabidopsis thaliana and rice, respectively, were determined and provided insight into the genetic determinants of host and tissue specificity. Comparisons were made with genomes of closely related strains that infect the vascular tissue of the same hosts and across a larger collection of complete Xanthomonas genomes. The results suggest a model in which complex sets of adaptations at the level of gene content account for host specificity and subtler adaptations at the level of amino acid or noncoding regulatory nucleotide sequence determine tissue specificity.
ESTHER : Bogdanove_2011_J.Bacteriol_193_5450
PubMedSearch : Bogdanove_2011_J.Bacteriol_193_5450
PubMedID: 21784931
Gene_locus related to this paper: xanax-XAC4055 , xanca-CATD , xanca-estA1 , xanca-XCC0080 , xanca-XCC3164 , xanor-q5h5n1

Title : Effects of low-intensity microwave radiation on Tribolium castaneum physiological and biochemical characteristics and survival - Lu_2010_J.Insect.Physiol_56_1356
Author(s) : Lu H , Zhou J , Xiong S , Zhao S
Ref : J Insect Physiol , 56 :1356 , 2010
Abstract : The red flour beetle, Tribolium castaneum (Coleoptera: Tenebrionidae) is a widespread pest that lives in, and feeds on, wheat flour. Here, we studied the effects of low-intensity microwave radiation (LIMR;
ESTHER : Lu_2010_J.Insect.Physiol_56_1356
PubMedSearch : Lu_2010_J.Insect.Physiol_56_1356
PubMedID: 20438733

Title : Complete genome sequence of the extremophilic Bacillus cereus strain Q1 with industrial applications - Xiong_2009_J.Bacteriol_191_1120
Author(s) : Xiong Z , Jiang Y , Qi D , Lu H , Yang F , Yang J , Chen L , Sun L , Xu X , Xue Y , Zhu Y , Jin Q
Ref : Journal of Bacteriology , 191 :1120 , 2009
Abstract : Bacillus cereus strain Q1 was isolated from a deep-subsurface oil reservoir in the Daqing oil field in northeastern China. This strain is able to produce biosurfactants and to survive in extreme environments. Here we report the finished and annotated genome sequence of this organism.
ESTHER : Xiong_2009_J.Bacteriol_191_1120
PubMedSearch : Xiong_2009_J.Bacteriol_191_1120
PubMedID: 19060151
Gene_locus related to this paper: bacah-a0rer5 , bacan-BA0954 , bacan-BA3703 , bacan-BA4338 , bacan-BA5009 , bacan-DHBF , bacc1-q73br9 , bacce-BC0192 , bacce-BC0968 , bacce-BC1788 , bacce-BC2141 , bacce-BC2171 , bacce-BC4102 , bacce-BC4854 , bacce-BC4862 , bacce-BC5130 , bacce-c2mr40 , bacce-PHAC , bacce-q72yu1 , bacce-q736x9 , baccq-b9j170 , baccr-pepx , baccz-q636u4 , bacti-q3elq7

Title : A chemical-genetic approach to study G protein regulation of beta cell function in vivo - Guettier_2009_Proc.Natl.Acad.Sci.U.S.A_106_19197
Author(s) : Guettier JM , Gautam D , Scarselli M , Ruiz de Azua I , Li JH , Rosemond E , Ma X , Gonzalez FJ , Armbruster BN , Lu H , Roth BL , Wess J
Ref : Proc Natl Acad Sci U S A , 106 :19197 , 2009
Abstract : Impaired functioning of pancreatic beta cells is a key hallmark of type 2 diabetes. beta cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific beta cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that beta cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific beta cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in beta cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (G(q/11) versus G(s)). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either beta cell G(q/11) or G(s) G proteins. Here we report the findings that conditional and selective activation of beta cell G(q/11) signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated beta cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of beta cell G(s) triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of beta cell function in vivo.
ESTHER : Guettier_2009_Proc.Natl.Acad.Sci.U.S.A_106_19197
PubMedSearch : Guettier_2009_Proc.Natl.Acad.Sci.U.S.A_106_19197
PubMedID: 19858481

Title : Overexpression of acetylcholinesterase inhibited cell proliferation and promoted apoptosis in NRK cells - Jin_2004_Acta.Pharmacol.Sin_25_1013
Author(s) : Jin QH , He HY , Shi YF , Lu H , Zhang XJ
Ref : Acta Pharmacol Sin , 25 :1013 , 2004
Abstract : AIM: To study the potential function of acetylcholinesterase (AChE) in apoptosis through overexpression of AChE in Normal Rat Kidney (NRK) cells.
METHODS: AChE activity was detected by the method of Karnovsky and Roots. Activated caspase-3 was analyzed by Western blotting and immunofluorescence with antibody special to activated caspase-3 fragment. The expression plasmids were constructed in pcDNA3.1 containing AChE gene or a fragment of AChE antisense that were got from RT-PCR. Stable expression cell lines were selected by G418 in cells transfected by lipofection. AChE expression was analyzed by RT-PCR and Western blotting. The proliferation rates of transfected cells were examined by the growth curve and cloning efficiency. MTT assay was used to analyze the cell viability.
RESULTS: The proliferation rate of the cells transfected with AChE was retarded and the cloning efficiency was lower (28.2 %+/-3.1 % and 48.7 %+/-2.1 %) than cells transfected with vector (56.1 %+/-0.3 %) or AChE-antisense (77.7 %+/-2.2 %). After 2 d the various clone types were deprived of serum, the residue cell viability were 10.4 %+/-4.6 % and 12.6 %+/-6.7 % in the cells transfected with AChE, and 27.4 %+/-3.5 % in cells with vector, and 50.3 %+/-7.8 % in cells with AChE-antisense. CONCLUSION: During apoptosis, increase of AChE protein is to inhibit cell proliferation, and then to promote apoptosis in NRK cells.
ESTHER : Jin_2004_Acta.Pharmacol.Sin_25_1013
PubMedSearch : Jin_2004_Acta.Pharmacol.Sin_25_1013
PubMedID: 15301733

Title : A key role for ALD1 in activation of local and systemic defenses in Arabidopsis - Song_2004_Plant.J_40_200
Author(s) : Song JT , Lu H , McDowell JM , Greenberg JT
Ref : Plant J , 40 :200 , 2004
Abstract : The Arabidopsis thaliana agd2-like defense response protein1 (ald1) mutant was previously found to be hypersusceptible to the virulent bacterial pathogen Pseudomonas syringae and had reduced accumulation of the defense signal salicylic acid (SA). ALD1 was shown to possess aminotransferase activity in vitro, suggesting it generates an amino acid-derived defense signal. We now find ALD1 to be a key defense component that acts in multiple contexts and partially requires the PHYTOALEXIN DEFICIENT4 (PAD4) defense regulatory gene for its expression in response to infection. ald1 plants have increased susceptibility to avirulent P. syringae strains, are unable to activate systemic acquired resistance and are compromised for resistance to the oomycete pathogen Peronospora parasitica in mutants with constitutively active defenses. ALD1 and PAD4 can act additively to control SA, PATHOGENESIS RELATED GENE1 (PR1) transcript and camalexin (an antimicrobial metabolite) accumulation as well as disease resistance. Finally, ALD1 and PAD4 can mutually affect each other's expression in a constitutive defense mutant, suggesting that these two genes can act in a signal amplification loop.
ESTHER : Song_2004_Plant.J_40_200
PubMedSearch : Song_2004_Plant.J_40_200
PubMedID: 15447647

Title : Expression and kinetic analysis of the substrate specificity of modules 5 and 6 of the picromycin\/methymycin polyketide synthase - Yin_2003_J.Am.Chem.Soc_125_5671
Author(s) : Yin Y , Lu H , Khosla C , Cane DE
Ref : Journal of the American Chemical Society , 125 :5671 , 2003
Abstract : Picromycin synthase (PICS) is a multifunctional, modular polyketide synthase (PKS) that catalyzes the conversion of methylmalonyl-CoA to narbonolide and 10-deoxymethynolide, the macrolide aglycone precursors of the antibiotics picromycin and methymycin, respectively. PICS modules 5 and 6 were each expressed in Escherichia coli with a thioesterase domain at the C-terminus to allow release of polyketide products. The substrate specificity of PICS modules 5+TE and 6+TE was investigated using N-acetylcysteamine thioesters of 2-methyl-3-hydroxy-pentanoic acid as diketide analogues of the natural polyketide chain elongation substrates. PICS module 5+TE could catalyze the chain elongation of only the syn diketide (2S,3R)-4, while PICS module 6+TE processed both syn diastereomers, (2S,3R)-4 and (2R,3S)-5, with a 2.5:1 preference in k(cat)/K(m) for 5 but did not turn over either of the two anti diketides. The observed substrate specificity patterns are in contrast to the 15-100:1 preference for 4 over 5 previously established for several modules of the closely related erythromycin PKS, 6-deoxyerythronolide B synthase (DEBS).
ESTHER : Yin_2003_J.Am.Chem.Soc_125_5671
PubMedSearch : Yin_2003_J.Am.Chem.Soc_125_5671
PubMedID: 12733905

Title : Expression, site-directed mutagenesis, and steady state kinetic analysis of the terminal thioesterase domain of the methymycin\/picromycin polyketide synthase - Lu_2002_Biochemistry_41_12590
Author(s) : Lu H , Tsai SC , Khosla C , Cane DE
Ref : Biochemistry , 41 :12590 , 2002
Abstract : The thioesterase (TE) domain of the methymycin/picromycin synthase (PICS) was functionally expressed in Escherichia coli, and the optimal N-terminal boundary of the recombinant TE was determined. A series of diketide-N-acetylcysteamine (SNAC) thioesters were tested as substrates. PICS TE showed a strong preference for the 2-methyl-3-ketopentanoyl-SNAC substrate 5 over the stereoisomers of the reduced diketides 1-4, with an approximately 1.6:1 preference for the (2R,3S)-2-methyl-3-hydroxy diastereomer 2 over the (2S,3R)-diketide 1. The closely related DEBS TE, the thioesterase from the 6-deoxyerythronolide B synthase, showed a more marked 4.4:1 preference for 2 over 1, with only a slightly greater preference for the 3-ketoacyl-SNAC substrate 5. The roles of several active site residues in PICS TE were examined by site-directed mutagenesis. Serine 148, which is part of the apparent catalytic triad consisting of S148, H268, and D176, was found to be essential for thioesterase activity, while replacement of D176 with asparagine (D176N) gave a mutant thioesterase that retained substantial, albeit reduced, hydrolytic activity toward diketide-SNAC substrates. Mutation of E187 and R191, each of which is thought to play a role in substrate binding, had only minor effects on the relative specificity for diketide substrates 1, 2, and 5. Finally, when PICS TE was fused to the C-terminus of DEBS module 3, the resultant chimeric protein converted diketide 1 with methylmalonyl-CoA to triketide ketolactone 6 with improved catalytic efficiency compared to that of the previously developed DEBS module 3-(DEBS)TE construct.
ESTHER : Lu_2002_Biochemistry_41_12590
PubMedSearch : Lu_2002_Biochemistry_41_12590
PubMedID: 12379101
Gene_locus related to this paper: strve-PIKAIV

Title : Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases - Tsai_2002_Biochemistry_41_12598
Author(s) : Tsai SC , Lu H , Cane DE , Khosla C , Stroud RM
Ref : Biochemistry , 41 :12598 , 2002
Abstract : Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.
ESTHER : Tsai_2002_Biochemistry_41_12598
PubMedSearch : Tsai_2002_Biochemistry_41_12598
PubMedID: 12379102
Gene_locus related to this paper: sacer-ery3 , strve-PIKAIV

Title : [Environmental pollution, human exposure and its health effect of sodium pentachlorophenate in schistosomiasis prevalent area] - Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
Author(s) : Zheng X , Feng Y , Jiang X , Lu H , Wan Y , Fang YQ , Li YP , Huang XY , Li ZL , Fu WZ , Wang XH , Lin YZ , Zhang Z
Ref : Wei Sheng Yan Jiu , 26 :24 , 1997
Abstract : Sodium pentachlorophenate (Na-PCP) has been used in China for years as an molluscacide to kill oncomelania, which is an intermediate host of Schistosome. To evaluate the effects of its long-term successive usage on environment, human exposure and health, studies were carried out in Sichuan, Jiangxi, Jiangsu and Fujian provinces, with a time gap of more than one month between sample collection and last spray of Na-PCP. Results indicated that PCP contents in surface water, soil, sediment, animals and plants were significantly higher in studied areas than in control areas. The daily intake and the content in urine of PCP were also sigificantify higher in studied areas. But, there was no difference on physical and biochemical examinations except that a 22%-28% decrease of blood cholinesterase activity was found in studied areas. The health effect of impurities in Na-PCP, dioxins and furans, was assessed and discussed.
ESTHER : Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
PubMedSearch : Zheng_1997_Wei.Sheng.Yan.Jiu_26_24
PubMedID: 15747456

Title : Cloning and characterization of a human protein phosphatase 1-encoding cDNA - Song_1993_Gene_129_291
Author(s) : Song Q , Khanna KK , Lu H , Lavin MF
Ref : Gene , 129 :291 , 1993
Abstract : While sequence information is available for a number of eukaryotic protein phosphatase 1 (PP1)-encoding genes, the cloning and characterization of a complete human pp1 gene has not been reported. We have used two conserved regions within the pp1 family of genes to synthesize oligodeoxyribonucleotide primers for the amplification of a 438-bp sequence from human mRNA. This DNA fragment was sequenced to verify that it corresponded to a pp1 cDNA and it was used to screen a human cDNA library to isolate a full-length clone. The deduced amino acid (aa) sequence identified a protein of 330 aa in length. Comparison with the rabbit pp1 cDNA sequence showed some nucleotide differences, largely at the third position of the codon, with complete concordance at the aa level. Northern blot analysis revealed an mRNA of approximately 1.6 kb.
ESTHER : Song_1993_Gene_129_291
PubMedSearch : Song_1993_Gene_129_291
PubMedID: 8392016