Hu M

References (32)

Title : Optimized rat models better mimic patients with irinotecan-induced severe diarrhea - Zheng_2024_Toxicol.Mech.Methods__1
Author(s) : Zheng Z , Du T , Gao S , Yin T , Li L , Zhu L , Singh R , Sun R , Hu M
Ref : Toxicol Mech Methods , :1 , 2024
Abstract : Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.
ESTHER : Zheng_2024_Toxicol.Mech.Methods__1
PubMedSearch : Zheng_2024_Toxicol.Mech.Methods__1
PubMedID: 38390772

Title : Isolation and Identification of Efficient Malathion-Degrading Bacteria from Deep-Sea Hydrothermal Sediment - Ma_2022_Microorganisms_10_
Author(s) : Ma L , Dai X , Ai G , Zheng X , Zhang Y , Pan C , Hu M , Jiang C , Wang L , Dong Z
Ref : Microorganisms , 10 : , 2022
Abstract : The genetic and metabolic diversity of deep-sea microorganisms play important roles in phosphorus and sulfur cycles in the ocean, distinguishing them from terrestrial counterparts. Malathion is a representative organophosphorus component in herbicides, pesticides, and insecticides and is analogues of neurotoxic agent. Malathion has been one of the best-selling generic organophosphate insecticides from 1980 to 2012. Most of the sprayed malathion has migrated by surface runoff to ocean sinks, and it is highly toxic to aquatic organisms. Hitherto, there is no report on bacterial cultures capable of degrading malathion isolated from deep-sea sediment. In this study, eight bacterial strains, isolated from sediments from deep-sea hydrothermal regions, were identified as malathion degradators. Two of the tested strains, Pseudidiomarina homiensis strain FG2 and Pseudidiomarina sp. strain CB1, can completely degrade an initial concentration of 500 mg/L malathion within 36 h. Since the two strains have abundant carboxylesterases (CEs) genes, malathion monocarboxylic acid (MMC alpha and MMC beta) and dibasic carboxylic acid were detected as key intermediate metabolites of malathion degradation, and the pathway of malathion degradation between the two strains was identified as a passage from malathion monocarboxylic acid to malathion dicarboxylic acid.
ESTHER : Ma_2022_Microorganisms_10_
PubMedSearch : Ma_2022_Microorganisms_10_
PubMedID: 36144399

Title : Case Report: Next-Generation Sequencing Identified a Novel Pair of Compound-Heterozygous Mutations of LPL Gene Causing Lipoprotein Lipase Deficiency - Li_2022_Front.Genet_13_831133
Author(s) : Li Y , Hu M , Han L , Feng L , Yang L , Chen X , Du T , Yao H
Ref : Front Genet , 13 :831133 , 2022
Abstract : Lipoprotein lipase deficiency (LPLD) is a rare disease characterized by the accumulation of chylomicronemia with early-onset. Common symptoms are abdominal pain, hepatosplenomegaly, eruptive xanthomas and lipemia retinalis. Serious complications include acute pancreatitis. Gene LPL is one of causative factors of LPLD. Here, we report our experience on an asymptomatic 3.5-month-old Chinese girl with only milky blood. Whole-exome sequencing was performed and identified a pair of compound-heterozygous mutations in LPL gene, c.862G>A (p.A288T) and c.461A>G (p.H154R). Both variants are predicted "deleterious" and classified as "likely pathogenic". This study expanded the LPL mutation spectrum of disease LPLD, thereby offering exhaustive and valuable experience on early diagnosis and proper medication of LPLD.
ESTHER : Li_2022_Front.Genet_13_831133
PubMedSearch : Li_2022_Front.Genet_13_831133
PubMedID: 35309119
Gene_locus related to this paper: human-LPL

Title : Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer's Disease - Hashem_2021_Mol.Neurobiol__
Author(s) : Hashem J , Hu M , Zhang J , Gao F , Chen C
Ref : Molecular Neurobiology , : , 2021
Abstract : Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates beta-amyloid (Abeta) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3beta and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARgamma in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.
ESTHER : Hashem_2021_Mol.Neurobiol__
PubMedSearch : Hashem_2021_Mol.Neurobiol__
PubMedID: 33939165

Title : Irinotecan-mediated diarrhea is mainly correlated with intestinal exposure to SN-38: Critical role of gut Ugt - Sun_2020_Toxicol.Appl.Pharmacol__115032
Author(s) : Sun R , Zhu L , Li L , Song W , Gong X , Qi X , Wang Y , Ghose R , Gao S , Hu M , Liu Z
Ref : Toxicol Appl Pharmacol , :115032 , 2020
Abstract : BACKGROUND AND PURPOSE: Irinotecan-induced diarrhea (IID) results from intestinal damages by its active metabolite SN-38. Alleviation of these damages has focused on lowering luminal SN-38 concentrations. However, it is unclear if the enteric bioavailability of SN-38 is mostly dependent on luminal SN-38 concentrations. EXPERIMENTAL APPROACH: Irinotecan (50mg/kg, i.p. once daily for 6days) was administered to female wildtype FVB, Mdr1a (-/-), Mrp2 (-/-) and Bcrp1 (-/-) mice for pharmacokinetic (PK), toxicokinetic (TK) and biodistribution studies. Plasma PK/TK profiles and tissues drug distribution were determined after first or sixth daily doses, along with activities of blood and gut esterases and intestinal Ugts. Caco-2 cells and bile-cannulate mice were used to further investigate intestinal and biliary disposition of irinotecan and its metabolites. KEY RESULTS: Significant differences in IID severity were observed with the susceptible rank of Bcrp1(-/-)>wildtype FVB>Mdr1a(-/-)>Mrp2(-/-). This rank order did not correlate with biliary excretion rates of SN-38/SN-38G. Rather, the severity was best correlated (R=0.805) with the intestinal ratio of Css SN-38/SN-38G, a measure of gut Ugt activity. On the contrary, IID was poorly correlated with plasma AUC ratio of SN-38/SN-38G (R=0.227). Increased intestinal esterase activities due to repeated dosing and gut efflux transporter functionality are the other key factors that determine SN-38 enteric exposures. CONCLUSION AND IMPLICATIONS: Intestinal SN-38 exposure is mainly affected by intestinal Ugt activities and blood esterase activities, and strongly correlated with severity of IID. Modulating intestinal SN-38 concentration and gut Ugt expression should be the focus of future studies to alleviate IID.
ESTHER : Sun_2020_Toxicol.Appl.Pharmacol__115032
PubMedSearch : Sun_2020_Toxicol.Appl.Pharmacol__115032
PubMedID: 32387182

Title : Short-term exposure to norfloxacin induces oxidative stress, neurotoxicity and microbiota alteration in juvenile large yellow croaker Pseudosciaena crocea - Wang_2020_Environ.Pollut_267_115397
Author(s) : Wang X , Hu M , Gu H , Zhang L , Shang Y , Wang T , Zeng J , Ma L , Huang W , Wang Y
Ref : Environ Pollut , 267 :115397 , 2020
Abstract : In recent years, antibiotics have been widely detected in coastal waters of China, which raising concerns for coastal biodiversity and aquaculture. This study evaluated the effects of short-term exposure of norfloxacin (NOR) on oxidative stress and intestinal health of the large yellow croaker Pseudosciaena crocea. Juvenile fish were exposed to four concentrations of NOR (0.1, 10, 100 and 1000 g/L) for 14 days. The results showed that NOR inhibited growth and threatened the survival of juveniles. According to the changes of intestinal microbiota, we found that NOR led to a significant decrease in intestinal microbiota diversity, with the decreased relative abundance of Proteobacteria, but the increased Tenericutes. From the perspective of microbial function, NOR inhibited metabolism, cellular defence mechanism and information transduction process. In terms of biochemical indicators, NOR caused an increase in malondialdehyde (MDA) level and inhibited superoxide dismutase (SOD) and acetyl cholinesterase (AChE) activities. Catalase (CAT) activity was activated at low concentration but significantly inhibited at high concentration of NOR. Moreover, there was a high correlation between change in biochemical indicators and change in the microbial community. Overall, environmentally relevant concentrations (0.1 g/L) and high concentrations (10, 100 and 1000 g/L) of NOR have negative effects on the defence function and intestinal health of large yellow croaker juveniles.
ESTHER : Wang_2020_Environ.Pollut_267_115397
PubMedSearch : Wang_2020_Environ.Pollut_267_115397
PubMedID: 33254654

Title : Hydroxy-alpha-sanshool isolated from Zanthoxylum bungeanum attenuates learning and memory impairments in scopolamine-treated mice - Zhang_2019_Food.Funct_10_7315
Author(s) : Zhang M , Xie M , Wei D , Wang L , Hu M , Zhang Q , He Z , Peng W , Wu C
Ref : Food Funct , 10 :7315 , 2019
Abstract : Learning and memory impairments are common symptoms of dementia in neurodegenerative disorders. Occasionally, we found that Zanthoxylum bungeanum pericarps (ZBP) significantly activated the spontaneous activity of the hippocampus (HIPP) and paraHIPP (P < 0.001, uncorrected), implying the potential ability of ZBP to improve cognitive impairments. Thus, this study aimed to investigate the improving effect of hydroxy-alpha-sanshool (HAS), a characteristic ingredient of ZBP, against scopolamine (1 mg kg(-1), i.p.)-induced learning and memory deficits. HAS (5 mg kg(-1), p.o.) markedly reversed scopolamine-induced cognitive impairments, as indicated by its performance in the passive avoidance test and Morris water maze test (P < 0.01). Furthermore, HAS (2.5 and 5.0 mg kg(-1), p.o.) also dose-dependently prevented changes in hippocampal neuronal morphology and apoptosis, inhibited acetylcholinesterase (AChE) activity, increased the acetylcholine (ACh) content, and increased the protein and mRNA expression of brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding (p-CREB) compared with those in the model group (P < 0.05 & P < 0.01). These findings demonstrated that HAS attenuated scopolamine-induced cognitive impairments mainly by enhancing the activity of the cholinergic system and increasing the CREB/BDNF signalling pathway.
ESTHER : Zhang_2019_Food.Funct_10_7315
PubMedSearch : Zhang_2019_Food.Funct_10_7315
PubMedID: 31637395

Title : Pharmacodynamic and urinary metabolomics studies on the mechanism of Schisandra polysaccharide in the treatment of Alzheimer's disease - Liu_2019_Food.Funct_10_432
Author(s) : Liu Y , Liu Z , Wei M , Hu M , Yue K , Bi R , Zhai S , Pi Z , Song F
Ref : Food Funct , 10 :432 , 2019
Abstract : Schisandra chinensis (Turcz.) Baill is produced mainly in northeast China, Korea and Japan. Its fruit has been used in food as a nutritional and functional ingredient for centuries. Polysaccharide is an important chemical component in Schisandra. Previous studies have shown that Schisandra polysaccharide (SCP) could be used to improve cognitive function clinically and treat age-related neurodegenerative disorders. In this study, a urinary metabolomics method based on ultra-high-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was established to investigate the change of endogenous metabolites in an amyloid beta-protein (Abeta) 25-35-induced Alzheimer's disease (AD) rat model. Meanwhile, levels of 9 neurotransmitters were evaluated with ultrahigh-performance liquid chromatography-triple-quadrupole mass spectrometry (UHPLC-TQ-MS) to explore the therapeutic mechanisms of SCP on the AD rat model. Additionally, the synthesis of phosphorylated tau protein (p-tau), acetylcholinesterase (AchE) activity and oxidative damage in the brain of the AD rats were assessed using glycogen synthase kinase-3beta (GSK3beta), AchE and antioxidant assays, NOS (nitric oxide synthase) and SOD (superoxide dismutase), respectively. The results indicated that the AD model was established successfully and the inducement of Abeta25-35 caused the phosphorylation of tau protein and the deposition of Abeta. In the AD model rats, the levels of AchE, GSK-3beta and NOS were significantly elevated and SOD activity was reduced. In the hippocampus of the model rats, the contents of gamma-aminobutyric acid, acetylcholine, glycine, norepinephrine, taurine, serotonin and dopamine were significantly decreased and the contents of glutamate and aspartic acid were increased significantly. However, SCP could reduce the degree of phosphorylation of tau protein, the deposition of Abeta and oxidative damage and reverse these changes of neurotransmitters in the AD rats. In a metabolomics study, a total of 38 metabolites were finally identified as potential biomarkers of AD and all of them had a significant recovery compared with the AD model after SCP administration. Metabolomics studies have shown that SCP plays a role in protecting the central nervous system, regulating intestinal microbial metabolism, regulating energy metabolism, and promoting antioxidant effects by regulating the levels of endogenous metabolites in related pathways. This is first report of the use of urine metabolomics combined with the evaluation of 9 neurotransmitter levels to investigate the mechanism of SCP on the treatment of AD.
ESTHER : Liu_2019_Food.Funct_10_432
PubMedSearch : Liu_2019_Food.Funct_10_432
PubMedID: 30623955

Title : Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease - Wang_2019_Eur.J.Med.Chem_168_207
Author(s) : Wang D , Hu M , Li X , Zhang D , Chen C , Fu J , Shao S , Shi G , Zhou Y , Wu S , Zhang T
Ref : Eur Journal of Medicinal Chemistry , 168 :207 , 2019
Abstract : A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50=0.27muM) and good inhibitory activity against AChE (IC50=0.08muM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB=1.24+/-0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.
ESTHER : Wang_2019_Eur.J.Med.Chem_168_207
PubMedSearch : Wang_2019_Eur.J.Med.Chem_168_207
PubMedID: 30822710

Title : New azaphilones and tremulane sesquiterpene from endophytic Nigrospora oryzae cocultured with Irpex lacteus - Zhou_2018_Fitoterapia_130_26
Author(s) : Zhou QY , Yang XQ , Zhang ZX , Wang BY , Hu M , Yang YB , Zhou H , Ding ZT
Ref : Fitoterapia , 130 :26 , 2018
Abstract : Five new metabolites belonging to two backbones of pulvilloric acid-type azaphilone and tremulane sesquiterpene were obtained and their structures were determined by spectral analysis. Based on the biogenesis analysis, tremulane sesquiterpenes were obtained from Irpex lacteus by the stimulation of mixed-culture. The antifungal selectivities of metabolites produced by fungus against their co-culture fungus and common pathogens, exhibited competitive interaction of this mix-culture. The tremulane sesquiterpene conocenol B produced by I. lacteus through the induction of Nigrospora oryzae showed selectivity of anti-fungal activity against its co-culture fungus, N. oryzae, with MICs at 16 mug/mL and 128 mug/mL against I. lacteus. The fungus can metabolize these new compounds to inhibit the growth of co-culture fungus while not inhibiting its own growth. Compound 5 was active against acetylcholinesterase (AChE) with a ratio of 35% at the concentration of 50 muM.
ESTHER : Zhou_2018_Fitoterapia_130_26
PubMedSearch : Zhou_2018_Fitoterapia_130_26
PubMedID: 30076888

Title : Impact of diet on irinotecan toxicity in mice - Mallick_2018_Chem.Biol.Interact_291_87
Author(s) : Mallick P , Shah P , Ittmann MM , Trivedi M , Hu M , Gao S , Ghose R
Ref : Chemico-Biological Interactions , 291 :87 , 2018
Abstract : Irinotecan is highly effective in the treatment of metastatic colorectal cancer as well as many other cancers. However, irinotecan is known to cause severe diarrhea, which pose significant problems in patients undergoing irinotecan based chemotherapy. Dietary and herbal components have shown promise in improving gastrointestinal health. Therefore, we compared the effect of grain-based chow diet containing phytoestrogens and corn/alfalfa as fat source to purified diets containing either animal-derived fat source (lard) or plant-derived fat source (soybean oil) on irinotecan-induced toxicities in mice. The concentration of the toxic metabolite, SN-38, was measured in the serum, and the activity of main enzyme, carboxylesterase (CEs) involved in biotransformation of irinotecan to SN-38 formation was measured in the liver. We found that the grain-based diet was protective against irinotecan-induced diarrhea. Interestingly, purified diet containing lard caused fatty liver in mice, while grain-based chow diet containing corn/alfa-alfa or purified diet with soybean oil did not cause fat deposition in the liver. Serum SN-38 concentration was significantly higher in the mice fed with purified diets compared to the chow-fed mice. Hepatic CEs activity was induced in the presence of irinotecan in mice on purified diets, but not chow diet. These results indicate that components of grain-based natural diet (presumably phytoestrogens and/or the macronutrients balance) compared to purified diets may have a beneficial effect by controlling the adverse effects of irinotecan in cancer patients.
ESTHER : Mallick_2018_Chem.Biol.Interact_291_87
PubMedSearch : Mallick_2018_Chem.Biol.Interact_291_87
PubMedID: 29913120

Title : Assessment of a novel device for onsite integrative large-volume solid phase extraction of water samples to enable a comprehensive chemical and effect-based analysis - Schulze_2017_Sci.Total.Environ_581-582_350
Author(s) : Schulze T , Ahel M , Ahlheim J , Ait-Aissa S , Brion F , Di Paolo C , Froment J , Hidasi AO , Hollender J , Hollert H , Hu M , Kloss A , Koprivica S , Krauss M , Muz M , Oswald P , Petre M , Schollee JE , Seiler TB , Shao Y , Slobodnik J , Sonavane M , Suter MJ , Tollefsen KE , Tousova Z , Walz KH , Brack W
Ref : Sci Total Environ , 581-582 :350 , 2017
Abstract : The implementation of targeted and nontargeted chemical screening analysis in combination with in vitro and organism-level bioassays is a prerequisite for a more holistic monitoring of water quality in the future. For chemical analysis, little or no sample enrichment is often sufficient, while bioanalysis often requires larger sample volumes at a certain enrichment factor for conducting comprehensive bioassays on different endpoints or further effect-directed analysis (EDA). To avoid logistic and technical issues related to the storage and transport of large volumes of water, sampling would benefit greatly from onsite extraction. This study presents a novel onsite large volume solid phase extraction (LVSPE) device tailored to fulfill the requirements for the successful effect-based and chemical screening of water resources and complies with available international standards for automated sampling devices. Laboratory recovery experiments using 251 organic compounds in the log D range from -3.6 to 9.4 (at pH7.0) spiked into pristine water resulted in acceptable recoveries and from 60 to 123% for 159 out of 251 substances. Within a European-wide demonstration program, the LVSPE was able to enrich compounds in concentration ranges over three orders of magnitude (1ngL-1 to 2400ngL-1). It was possible to discriminate responsive samples from samples with no or only low effects in a set of six different bioassays (i.e. acetylcholinesterase and algal growth inhibition, androgenicity, estrogenicity, fish embryo toxicity, glucocorticoid activity). The LVSPE thus proved applicable for onsite extraction of sufficient amounts of water to investigate water quality thoroughly by means of chemical analysis and effect-based tools without the common limitations due to small sample volumes.
ESTHER : Schulze_2017_Sci.Total.Environ_581-582_350
PubMedSearch : Schulze_2017_Sci.Total.Environ_581-582_350
PubMedID: 28062104

Title : Benzopyran derivatives from endophytic Daldinia eschscholzii JC-15 in Dendrobium chrysotoxum and their bioactivities - Hu_2017_Nat.Prod.Res__1
Author(s) : Hu M , Yang XQ , Zhou QY , Li SQ , Wang BY , Ruan BH , Yang YB , Zhang ZX , Zhou H , Ding ZT
Ref : Nat Prod Res , :1 , 2017
Abstract : Five new benzopyran derivatives (2-6) and a new natural product (1) were isolated from endophytic Daldinia eschscholzii in Dendrobium chrysotoxum and determined as (R)-2,3-dihydro-2,5-dihydroxy-2-methylchromen-4-one (1), (2R, 4S)-2,3-dihydro-2-methyl-benzopyran-4,5-diol (2), (R)-3-methoxyl-1-(2,6-dihydroxy phenyl)-butan-1-one (3), 7-O-alpha-d-ribosyl-5-hydroxy-2-methyl-4H-chromen-4-one (4), 7-O-alpha-d-ribosyl-2,3-dihydro-5-hydroxy-2-methyl-chromen-4-one (5), daldinium A (6). These compounds were evaluated for their antimicrobial activity, anti-acetylcholinesterase, nitric oxide inhibition, anticoagulant, photodynamic antimicrobial activities and glucose uptake of adipocytes. Some compounds showed photoactive antimicrobial activities and glucose uptake stimulating activities.
ESTHER : Hu_2017_Nat.Prod.Res__1
PubMedSearch : Hu_2017_Nat.Prod.Res__1
PubMedID: 29272956

Title : New bioactive compounds from aquatic endophyte Chaetomium globosum - Ruan_2017_Nat.Prod.Res__1
Author(s) : Ruan BH , Yu ZF , Yang XQ , Yang YB , Hu M , Zhang ZX , Zhou QY , Zhou H , Ding ZT
Ref : Nat Prod Res , :1 , 2017
Abstract : Two new oxidation products-related aureonitol and cytochalasan were isolated from Chaetomium globosum fermented in Chinese yam (Dioscorea opposita) and determined as 10,11-dihydroxyl- aureonitol (1) and yamchaetoglobosin A (2). Compound 2 indicated significant inhibitory effect on nitric oxide production in LPS-activated macrophages, anti-acetylcholinesterase activity with the inhibition ratios of 92.5, 38.2% at 50 muM, and cytotoxicity to HL-60, A-549, SMMC-7721, MCF-7 and SW480 with the range of inhibition ratio at 51-96% for a concentration of 40 muM. Compounds 1, 2 showed weak anticoagulant activity with PT at 16.8 s. Few work was reported on the anti-acetylcholinesterase, and anticoagulant activities of aureonitol, and cytochalasan derivatives. The preliminary structure-activity relationship stated that the oxidation ring-opening in yamchaetoglobosin A can retain the inhibitory effect against NO production and tumor cell.
ESTHER : Ruan_2017_Nat.Prod.Res__1
PubMedSearch : Ruan_2017_Nat.Prod.Res__1
PubMedID: 28927295

Title : Astragalus Polysaccharide Suppresses 6-Hydroxydopamine-Induced Neurotoxicity in Caenorhabditis elegans - Li_2016_Oxid.Med.Cell.Longev_2016_4856761
Author(s) : Li H , Shi R , Ding F , Wang H , Han W , Ma F , Hu M , Ma CW , Huang Z
Ref : Oxid Med Cell Longev , 2016 :4856761 , 2016
Abstract : Astragalus membranaceus is a medicinal plant traditionally used in China for a variety of conditions, including inflammatory and neural diseases. Astragalus polysaccharides are shown to reduce the adverse effect of levodopa which is used to treat Parkinson's disease (PD). However, the neuroprotective effect of Astragalus polysaccharides per se in PD is lacking. Using Caenorhabditis elegans models, we investigated the protective effect of astragalan, an acidic polysaccharide isolated from A. membranaceus, against the neurotoxicity of 6-hydroxydopamine (6-OHDA), a neurotoxin that can induce parkinsonism. We show that 6-OHDA is able to degenerate dopaminergic neurons and lead to the deficiency of food-sensing behavior and a shorter lifespan in C. elegans. Interestingly, these degenerative symptoms can be attenuated by astragalan treatment. Astragalan is also shown to alleviate oxidative stress through reducing reactive oxygen species level and malondialdehyde content and increasing superoxide dismutase and glutathione peroxidase activities and reduce the expression of proapoptotic gene egl-1 in 6-OHDA-intoxicated nematodes. Further studies reveal that astragalan is capable of elevating the decreased acetylcholinesterase activity induced by 6-OHDA. Together, our results demonstrate that the protective effect of astragalan against 6-OHDA neurotoxicity is likely due to the alleviation of oxidative stress and regulation of apoptosis pathway and cholinergic system and thus provide an important insight into the therapeutic potential of Astragalus polysaccharide in neurodegeneration.
ESTHER : Li_2016_Oxid.Med.Cell.Longev_2016_4856761
PubMedSearch : Li_2016_Oxid.Med.Cell.Longev_2016_4856761
PubMedID: 27885333

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

Title : Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury -
Author(s) : Zhang J , Teng Z , Song Y , Hu M , Chen C
Ref : Journal of Cerebral Blood Flow & Metabolism , 35 :706 , 2015
PubMedID: 25826320

Title : Structure of Drosophila Oskar reveals a novel RNA binding protein - Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_11541
Author(s) : Yang N , Yu Z , Hu M , Wang M , Lehmann R , Xu RM
Ref : Proc Natl Acad Sci U S A , 112 :11541 , 2015
Abstract : Oskar (Osk) protein plays critical roles during Drosophila germ cell development, yet its functions in germ-line formation and body patterning remain poorly understood. This situation contrasts sharply with the vast knowledge about the function and mechanism of osk mRNA localization. Osk is predicted to have an N-terminal LOTUS domain (Osk-N), which has been suggested to bind RNA, and a C-terminal hydrolase-like domain (Osk-C) of unknown function. Here, we report the crystal structures of Osk-N and Osk-C. Osk-N shows a homodimer of winged-helix-fold modules, but without detectable RNA-binding activity. Osk-C has a lipase-fold structure but lacks critical catalytic residues at the putative active site. Surprisingly, we found that Osk-C binds the 3'UTRs of osk and nanos mRNA in vitro. Mutational studies identified a region of Osk-C important for mRNA binding. These results suggest possible functions of Osk in the regulation of stability, regulation of translation, and localization of relevant mRNAs through direct interaction with their 3'UTRs, and provide structural insights into a novel protein-RNA interaction motif involving a hydrolase-related domain.
ESTHER : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_11541
PubMedSearch : Yang_2015_Proc.Natl.Acad.Sci.U.S.A_112_11541
PubMedID: 26324911

Title : A high-carbohydrate diet effects on the A allele of hepatic lipase polymorphism on the apoB100\/apoAI ratio in young Chinese males - Hu_2013_Adv.Clin.Exp.Med_21_751
Author(s) : Hu M , Li Z , Fang DZ
Ref : Adv Clin Exp Med , 21 :751 , 2013
Abstract : BACKGROUND: Diet induces changes in plasma lipid profiles, and the plasma lipid profiles vary among different genetic backgrounds. OBJECTIVES: The aim of this study was to investigate how a high-carbohydrate (high-CHO) diet interacts with hepatic lipase G-250A promoter polymorphism to affect the ratios of plasma lipids and apolipoproteins (apo) in a young Chinese population. MATERIAL AND
METHODS: Experiments were conducted on 56 university students. A stabilization diet was given for 7 days and a high-CHO diet was followed for 6 days. The diets used in this study were described by Song et al. and the following parameters were evaluated: total plasma triglyceride (TG), total plasma cholesterol (TC), plasma high-density lipoprotein cholesterol (HDL-C), plasma low-density lipoprotein cholesterol (LDL-C), apoB100 and apoAI. The plasma lipids and apoB100/apoAI ratios were also calculated and hepatic lipase G-250A polymorphism was analyzed.
RESULTS: At baseline, no significant difference was detected for subjects with different genotypes and genders. All the parameters showed significant differences before and after the high-CHO diet, and these differences are gender-specific: after the high-CHO diet, the TG/HDL-C ratios significantly increased in females (GG genotype: P = 0.004; A carriers: P = 0.005). The TC/HDL-C ratios significantly decreased in GG genotype males (P = 0.007), A carrier males (P < 0.0001) and A carrier females (P = 0.016) and the LDL-C/HDL-C ratios significantly decreased in the GG genotype males (P = 0.011), A carrier males (P < 0.0001) and A carrier females (P = 0.001). However, comparing the apoB100/apoAI ratio before and after the high-CHO diet, a significant difference only existed in male A carriers (P = 0.009).
CONCLUSIONS: The results of this study show that the high-CHO diet induces the positive effects on the lipid ratios in general, only except the TG/HDL-C ratio in females. Noticeably, the decreased apoB100/apoAI ratio is associated with the A allele of hepatic lipase G-250A polymorphism only in young Chinese males.
ESTHER : Hu_2013_Adv.Clin.Exp.Med_21_751
PubMedSearch : Hu_2013_Adv.Clin.Exp.Med_21_751
PubMedID: 23457133

Title : Testing insecticidal activity of novel chemically synthesized siRNA against Plutella xylostella under laboratory and field conditions - Gong_2013_PLoS.One_8_e62990
Author(s) : Gong L , Chen Y , Hu Z , Hu M
Ref : PLoS ONE , 8 :e62990 , 2013
Abstract : BACKGROUND: Over the last 60 years, synthetic chemical pesticides have served as a main tactic in the field of crop protection, but their availability is now declining as a result of the development of insect resistance. Therefore, alternative pest management agents are needed. However, the demonstration of RNAi gene silencing in insects and its successful usage in disrupting the expression of vital genes opened a door to the development of a variety of novel, environmentally sound approaches for insect pest management. METHODOLOGY/PRINCIPAL FINDINGS: Six small interfering RNAs (siRNAs) were chemically synthesized and modified according to the cDNA sequence of P. xylostella acetylcholine esterase genes AChE1 and AChE2. All of them were formulated and used in insecticide activity screening against P. xylostella. Bioassay data suggested that Si-ace1_003 and Si-ace2_001 at a concentration of 3 microg cm(-2) displayed the best insecticidal activity with 73.7% and 89.0%, mortality, respectively. Additional bioassays were used to obtain the acute lethal concentrations of LC50 and LC90 for Si-ace2_001, which were 53.66 microg/ml and 759.71 microg/ml, respectively. Quantitative Real-time PCR was used to confirm silencing and detected that the transcript levels of P. xylostella AChE2 (PxAChE2) were reduced by 5.7-fold compared to the control group. Consequently, AChE activity was also reduced by 1.7-fold. Finally, effects of the siRNAs on treated plants of Brassica oleracea and Brassica alboglabra were investigated with different siRNA doses. Our results showed that Si-ace2_001 had no negative effects on plant morphology, color and growth of vein under our experimental conditions. CONCLUSIONS: The most important finding of this study is the discovery that chemically synthesized and modified siRNA corresponding to P. xylostella AChE genes cause significant mortality of the insect both under laboratory and field conditions, which provides a novel strategy to control P. xylostella and to develop bio-pesticides based on the RNA interference technology.
ESTHER : Gong_2013_PLoS.One_8_e62990
PubMedSearch : Gong_2013_PLoS.One_8_e62990
PubMedID: 23667556

Title : Contribution of carboxylesterase in hamster to the intestinal first-pass loss and low bioavailability of ethyl piperate, an effective lipid-lowering drug candidate - Lu_2011_Drug.Metab.Dispos_39_796
Author(s) : Lu Y , Bao N , Borjihan G , Ma Y , Hu M , Yu C , Li S , Jia J , Yang D , Wang Y
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 39 :796 , 2011
Abstract : Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters K(m) and V(max) of 7.56 +/- 1.491 muM and 0.16 +/- 0.008 nmol . min(-1) . mg protein(-1), respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.
ESTHER : Lu_2011_Drug.Metab.Dispos_39_796
PubMedSearch : Lu_2011_Drug.Metab.Dispos_39_796
PubMedID: 21346005

Title : Poster: In Vitro neuroprotective effects of ABT-779, a positive allosteric modulator of alpha7 nAChRs -
Author(s) : Hu M , Li J , Malysz J , Esbenshade TA , Lee C-H , Gopalakrishnan M
Ref : Biochemical Pharmacology , 82 :1042 , 2011
PubMedID:

Title : Poster: A-582941, a pro-cognitive alpha7 nAChR agonist, differentially modulates mitochondrial membrane potential -
Author(s) : Namovic M , Hu M , Abraham V , Towne D , Lee C-H , Gopalakrishnan M , Esbenshade T , Donnelly-Roberts D
Ref : Biochemical Pharmacology , 82 :1027 , 2011
PubMedID:

Title : In vitro pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107 - Malysz_2010_J.Pharmacol.Exp.Ther_334_863
Author(s) : Malysz J , Anderson DJ , Gronlien JH , Ji J , Bunnelle WH , Hakerud M , Thorin-Hagene K , Ween H , Helfrich R , Hu M , Gubbins E , Gopalakrishnan S , Puttfarcken PS , Briggs CA , Li J , Meyer MD , Dyhring T , Ahring PK , Nielsen EO , Peters D , Timmermann DB , Gopalakrishnan M
Ref : Journal of Pharmacology & Experimental Therapeutics , 334 :863 , 2010
Abstract : Enhancement of alpha7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective alpha7 nAChR agonist, 5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107). ABT-107 displayed high affinity binding to alpha7 nAChRs [rat or human cortex, [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1 ]heptane (A-585539), K(i) = 0.2-0.6 nM or [(3)H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non-alpha7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman alpha3beta4, chimeric (alpha6/alpha3)beta4, or 5-HT(3A) receptors, and weak or negligible Ca(2+) responses in human neuroblastoma IMR-32 cells (alpha3* function) and human alpha4beta2 and alpha4beta4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat alpha7 nAChR current responses in oocytes (EC(50), 50-90 nM total charge, approximately 80% normalized to acetylcholine) that were enhanced by the positive allosteric modulator (PAM) 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744). In rat hippocampus, ABT-107 alone evoked alpha7-like currents, which were inhibited by the alpha7 antagonist MLA. In dentate gyrus granule cells, ABT-107 enhanced spontaneous inhibitory postsynaptic current activity when coapplied with A-867744. In the presence of an alpha7 PAM [A-867744 or N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596)], the addition of ABT-107 elicited MLA-sensitive alpha7 nAChR-mediated Ca(2+) signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity alpha7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.
ESTHER : Malysz_2010_J.Pharmacol.Exp.Ther_334_863
PubMedSearch : Malysz_2010_J.Pharmacol.Exp.Ther_334_863
PubMedID: 20504915

Title : Pharmacology of alpha7 nicotinic acetylcholine receptor mediated extracellular signal-regulated kinase signalling in PC12 cells - El Kouhen_2009_Br.J.Pharmacol_156_638
Author(s) : El Kouhen R , Hu M , Anderson DJ , Li J , Gopalakrishnan M
Ref : British Journal of Pharmacology , 156 :638 , 2009
Abstract : BACKGROUND AND PURPOSE: Neuronal nicotinic acetylcholine receptors (nAChR) can modulate cell survival and memory processing. The involvement of specific nAChR subtypes in downstream signalling events has been ill defined thus far, because of a lack of subtype-selective ligands. In this study, we investigated activation and modulation of alpha7 nAChR-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) in PC12 cells, using selective agonists and positive allosteric modulators. EXPERIMENTAL APPROACH: We used undifferentiated PC12 cells endogenously expressing alpha7 nAChR for both biochemical and functional studies. ERK phosphorylation changes were measured by using a novel In-Cell Western procedure. alpha7 nAChR-mediated Ca(2+) signalling was determined by using the fluorometric imaging plate reader assay. KEY
RESULTS: Robust induction of ERK phosphorylation followed exposure of PC12 cells to the selective agonist PNU-282987 in the presence of the alpha7 nAChR modulator PNU-120596. ERK phosphorylation was transient and was attenuated by the selective antagonist methyllycaconitine. Consistent with allosteric modulation of alpha7 nAChRs, PNU-120596 enhanced both the agonist potency and efficacy in activating ERK. Moreover, alpha7 nAChR agonists could be quantitatively differentiated based on their potency in activating ERK signalling. The rank order of potencies correlated fairly well with the corresponding binding K(i) values of these alpha7 nAChR agonists. CONCLUSIONS AND IMPLICATIONS: The present work extends previous observations demonstrating the involvement of alpha7 nAChRs in ERK1/2 phosphorylation in PC12 cells. The In-Cell Western procedure allowed a detailed investigation of alpha7 nAChR function and downstream ERK signalling in response to agonist and allosteric modulators.
ESTHER : El Kouhen_2009_Br.J.Pharmacol_156_638
PubMedSearch : El Kouhen_2009_Br.J.Pharmacol_156_638
PubMedID: 19226255

Title : Poster: Positive allosteric modulation of alpha7 neuronal nicotinic acetylcholine receptors: Lack of mechanism-based evidence for cytotoxicity in PC12 cells and rat primary cortical neurons -
Author(s) : Hu M , Gopalakrishnan M , Li J
Ref : Biochemical Pharmacology , 78 :904 , 2009
PubMedID:

Title : Poster: In vitro pharmacological profile of a novel alpha4\/beta2 positive allosteric modulator NS9283 (A-969933) -
Author(s) : Malysz J , Dyhring T , Ahring PK , Olsen GM , Peters D , Gronlien JH , Wetterstrand C , Ween H , Haakerud M , Thorin-Hagene K , Andersen E , Anderson DJ , Hu M , Kroeger PE , Lee CHL , Gopalakrishnan M , Timmermann DB
Ref : Biochemical Pharmacology , 78 :919 , 2009
PubMedID:

Title : Positive allosteric modulation of alpha7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neurons - Hu_2009_Br.J.Pharmacol_158_1857
Author(s) : Hu M , Gopalakrishnan M , Li J
Ref : British Journal of Pharmacology , 158 :1857 , 2009
Abstract : BACKGROUND AND PURPOSE: alpha7-Nicotinic acetylcholine receptors (alpha7 nAChRs) play an important role in cognitive function. Positive allosteric modulators (PAMs) amplify effects of alpha7 nAChR agonist and could provide an approach for treatment of cognitive deficits in neuropsychiatric diseases. PAMs can either predominantly affect the apparent peak current response (type I) or increase both the apparent peak current response and duration of channel opening, due to prolonged desensitization (type II). The delay of receptor desensitization by type II PAMs raises the possibility of Ca2+-induced toxicity through prolonged activation of alpha7 nAChRs. The present study addresses whether type I and II PAMs exhibit different cytotoxicity profiles. EXPERIMENTAL APPROACH: The present studies evaluated cytotoxic effects of type I PAM [N-(4-chlorophenyl)]-alpha-[(4-chlorophenyl)-aminomethylene]-3-methyl-5-isoxazole acet-amide (CCMI) and type II PAM 1-[5-chloro-2,4-dimethoxy-phenyl]-3-[5-methyl-isoxazol-3-yl]-urea (PNU-120596), or 4-[5-(4chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulphonamide (A-867744). The studies used cultures of PC12 cells and primary cultures of rat cortical neuronal cells. KEY
RESULTS: Our results showed that neither type I nor type II PAMs had any detrimental effect on cell integrity or cell viability. In particular, type II PAMs did not affect neuron number and neurite outgrowth under conditions when alpha7 nAChR activity was measured by Ca2+ influx and extracellular signal-regulated kinases 1 and 2 phosphorylation, following exposure to alpha7 nAChR agonists. CONCLUSIONS AND IMPLICATIONS: This study demonstrated that both type I and type II alpha7 nAChR selective PAMs, although exhibiting differential electrophysiological profiles, did not exert cytotoxic effects in cells endogenously expressing alpha7 nAChRs.
ESTHER : Hu_2009_Br.J.Pharmacol_158_1857
PubMedSearch : Hu_2009_Br.J.Pharmacol_158_1857
PubMedID: 20050184

Title : Poster: Profile of A-716096, a novel thiazolylidine positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor -
Author(s) : Donnelly-Roberts D , Malysz J , Faghih R , Gronlien H , Haakerud M , Thorin-Hagne K , Ween H , Gopalakrishnan SM , Hu M , Li J , Anderson DJ , Kohlhaas KL , Namovic M , Radek R , Robb H , Briggs CA , Bitner RS , Bunnelle WH , Gopalakrishnan M
Ref : Biochemical Pharmacology , 78 :912 , 2009
PubMedID:

Title : Role of GSK-3beta activation and alpha7 nAChRs in Abeta(1-42)-induced tau phosphorylation in PC12 cells - Hu_2008_J.Neurochem_106_1371
Author(s) : Hu M , Waring JF , Gopalakrishnan M , Li J
Ref : Journal of Neurochemistry , 106 :1371 , 2008
Abstract : Beta-amyloid peptide 1-42 (Abeta(1-42)) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Abeta(1-42) can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Abeta(1-42)-induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Abeta(1-42) increased phosphorylation of tau at serine-202 as detected by AT8 antibody. This Abeta(1-42)-induced tau phosphorylation paralleled phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at tyrosine-216 (GSK-3beta-pY216), which was partially inhibited by the GSK-3beta inhibitor, CHIR98023. Abeta(1-42)-induced tau phosphorylation and increase in GSK-3beta-pY216 phosphorylation were also partially attenuated by alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) selective ligands including agonist A-582941 and antagonists methyllycaconitine and alpha-bungarotoxin. The alpha7 nAChR agonist and the GSK-3beta inhibitor had no additive effect. These observations suggest that alpha7 nAChR modulation can influence Abeta(1-42)-induced tau phosphorylation, possibly involving GSK-3beta. This study provides evidence of nAChR mechanisms underlying Abeta(1-42) toxicity and tau phosphorylation, which, if translated in vivo, could provide additional basis for the utility of alpha7 nAChR ligands in the treatment of Alzheimer's disease.
ESTHER : Hu_2008_J.Neurochem_106_1371
PubMedSearch : Hu_2008_J.Neurochem_106_1371
PubMedID: 18485099

Title : High content screen microscopy analysis of A beta 1-42-induced neurite outgrowth reduction in rat primary cortical neurons: neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands - Hu_2007_Brain.Res_1151_227
Author(s) : Hu M , Schurdak ME , Puttfarcken PS , El Kouhen R , Gopalakrishnan M , Li J
Ref : Brain Research , 1151 :227 , 2007
Abstract : beta-Amyloid peptide 1-42 (A beta(1-42)) is generated from amyloid precursor protein (APP) and associated with neurodegeneration in Alzheimer's disease (AD). A beta(1-42) has been shown to be cytotoxic when incubated with cultured neurons. However, APP transgenic mice over-expressing A beta(1-42) do not show substantial loss of neurons, despite deficits in learning and memory. It is thus emerging that A beta(1-42)-induced memory deficits may involve subtler neuronal alternations leading to synaptic deficits, prior to frank neurodegeneration in AD brains. In this study, high content screen (HCS) microscopy, an advanced high-throughput cellular image processing and analysis technique, was utilized in establishing an in vitro model of A beta(1-42)-induced neurotoxicity utilizing rat neonatal primary cortical cells. Neurite outgrowth was found to be significantly reduced by A beta(1-42) (300 nM to 30 microM), but not by the scrambled control peptide control, in a time- and concentration-dependent manner. In contrast, no reduction in the total number of neurons was observed. The A beta(1-42)-induced reduction of neurite outgrowth was attenuated by the NMDA receptor antagonist memantine and the alpha 7 nicotinic acetylcholine receptor (nAChR) selective agonist PNU-282987. Interestingly, the alpha 7 nAChR antagonist methyllycaconitine also significantly prevented reduction in A beta(1-42)-induced neurite outgrowth. The observed neuroprotective effects could arise either from interference of A beta(1-42) interactions with alpha 7 nAChRs or by modification of receptor-mediated signaling pathways. Our studies demonstrate that reduction of neurite outgrowth may serve as a model representing A beta(1-42)-mediated neuritic and synaptic toxicity, which, in combination of HCS, provides a high-throughput cell-based assay that can be used to evaluate compounds with neuroprotective properties in neurons.
ESTHER : Hu_2007_Brain.Res_1151_227
PubMedSearch : Hu_2007_Brain.Res_1151_227
PubMedID: 17449017

Title : Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways - Hu_2002_Mol.Cell.Neurosci_21_616
Author(s) : Hu M , Liu QS , Chang KT , Berg DK
Ref : Molecular & Cellular Neurosciences , 21 :616 , 2002
Abstract : Activity-dependent gene expression is essential for form and function in the nervous system. Best understood is the role of glutamatergic signaling in controlling such events, but nicotinic signaling can also regulate transcription. We show here that nicotine can alter gene expression in rat hippocampal neurons, as reflected by activation of the transcription factor CREB and appearance of the immediate early gene product c-Fos. The process depends on both CaM and MAP kinases and on calcium release from internal stores. Part of the nicotinic effect is mediated via glutamatergic transmission, even in the absence of action potentials. Voltage-gated calcium channels are not necessary for nicotine-induced activation of CREB in hippocampal neurons. The low levels of sustained nicotinic stimulation required for transcriptional effects are consistent with those likely to be achievable either by the normal septal cholinergic innervation of the hippocampus or by repeated tobacco usage.
ESTHER : Hu_2002_Mol.Cell.Neurosci_21_616
PubMedSearch : Hu_2002_Mol.Cell.Neurosci_21_616
PubMedID: 12504594