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Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.
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Objective:To observe the effect of quercetin on myelin regeneration in desyelinating mice induced by cuprizone (CPZ).Methods:A total of 50 C57BL/6J mice were randomly divided into normal control group, model group, low, medium and high dose quercetin groups, 10 mice in each group. In addition to the normal control group, mice demyelinating model was induced by feeding with 0.2% CPZ rodent feed. Quercetin solution was administered to the low, medium and high dose quercetin groups at 25, 50 and 100 mg/kg, and to the normal control group and the model group at 1 time/d. After 5 weeks of continuous gavage, the weight of mice was recorded every week, and the experiment of rotating bar was carried out. After 5 weeks, the changes of the myelin sheath in the corpus callosum of mice were observed by luxol fast blue (LFB) and transmission electron microscope (TEM). Immunofluorescence method was used to determine the protein expressions of myelin basic protein (MBP) and oligodendrocyte transcription 2actor (Olig2) in mouse brain tissue. The expression of MBP and cyclic nucleotide-3'phosphate hydrolase (CNPase) in mouse corpus callosum was determined by Western blot.Results:After 2-5 weeks, compared with the model group, the body mass of the medium and high dose quercetin groups significantly increased ( P<0.01), and the score of turning rod significantly increased ( P<0.01). The LFB observation showed that the demyelination score of corpus callosum in low, medium and high dose quercetin groups (2.23 ± 0.25, 1.50 ± 0.15, 1.14 ± 0.97 vs. 2.83 ± 0.18) significantly decreased ( P<0.01). TEM observation showed that the G-ratio value in low, medium and high dose quercetin groups (0.75 ± 0.05, 0.75 ± 0.08, 0.73 ± 0.08 vs. 0.87 ± 0.05) significantly reduced ( P<0.01). Immunofluorescence observation showed that the positive expression of MBP (37.40 ± 2.41, 37.40 ± 1.14 vs. 24.40 ± 3.65) and Olig2 (7.40 ± 1.14, 4.60 ± 1.14 vs. 2.80 ± 0.84) in the medium and high dose quercetin groups significantly increased ( P<0.05). WB showed that the expression of MBP protein (1.32 ± 0.12, 0.80 ± 0.34 vs. 0.21 ± 0.07) and CNPase protein (0.72 ± 0.13, 1.06 ± 0.36 vs. 0.36 ± 0.21) in the medium and high dose quercetin groups significantly increased ( P<0.05). Conclusions:Quercetin (50-100 mg/kg) can reduce myelin injury and promote myelin regeneration in CPZ mice, as a neuroprotective effect on CPZ mice.
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Objective@#To observe the effect of quercetin on myelin regeneration in desyelinating mice induced by cuprizone (CPZ).@*Methods@#A total of 50 C57BL/6J mice were randomly divided into normal control group, model group, low, medium and high dose quercetin groups, 10 mice in each group. In addition to the normal control group, mice demyelinating model was induced by feeding with 0.2% CPZ rodent feed. Quercetin solution was administered to the low, medium and high dose quercetin groups at 25, 50 and 100 mg/kg, and to the normal control group and the model group at 1 time/d. After 5 weeks of continuous gavage, the weight of mice was recorded every week, and the experiment of rotating bar was carried out. After 5 weeks, the changes of the myelin sheath in the corpus callosum of mice were observed by luxol fast blue (LFB) and transmission electron microscope (TEM). Immunofluorescence method was used to determine the protein expressions of myelin basic protein (MBP) and oligodendrocyte transcription 2actor (Olig2) in mouse brain tissue. The expression of MBP and cyclic nucleotide-3'phosphate hydrolase (CNPase) in mouse corpus callosum was determined by Western blot.@*Results@#After 2-5 weeks, compared with the model group, the body mass of the medium and high dose quercetin groups significantly increased (P<0.01), and the score of turning rod significantly increased (P<0.01). The LFB observation showed that the demyelination score of corpus callosum in low, medium and high dose quercetin groups (2.23 ± 0.25, 1.50 ± 0.15, 1.14 ± 0.97 vs. 2.83 ± 0.18) significantly decreased (P<0.01). TEM observation showed that the G-ratio value in low, medium and high dose quercetin groups (0.75 ± 0.05, 0.75 ± 0.08, 0.73 ± 0.08 vs. 0.87 ± 0.05) significantly reduced (P<0.01). Immunofluorescence observation showed that the positive expression of MBP (37.40 ± 2.41, 37.40 ± 1.14 vs. 24.40 ± 3.65) and Olig2 (7.40 ± 1.14, 4.60 ± 1.14 vs. 2.80 ± 0.84) in the medium and high dose quercetin groups significantly increased (P<0.05). WB showed that the expression of MBP protein (1.32 ± 0.12, 0.80 ± 0.34 vs. 0.21 ± 0.07) and CNPase protein (0.72 ± 0.13, 1.06 ± 0.36 vs. 0.36 ± 0.21) in the medium and high dose quercetin groups significantly increased (P<0.05).@*Conclusions@#Quercetin (50-100 mg/kg) can reduce myelin injury and promote myelin regeneration in CPZ mice, as a neuroprotective effect on CPZ mice.
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Objective To understand the relationship between the infants′iron-deficiency anemia and the dependents′KAP (knowledge,attitude,practice)of iron nutrition,and to provide a theoretical support for the prevention and cure of the infants′iron-eficiency anemia.Methods A total of 960 infants,aging from 6 months to 36 months,were randomly chosen as samples at the child care clinics in Wuhan while they were doing their routine health check-up there.Their hemoglobin was examined.Their dependents were asked to fill in questionnaires about KAP of iron nutrition.Results The ratio of anemia in infants in Wuhan is 26.6%.The ra-tio difference of different age groups has statistical significance(P <0.05).The dependents′KAP of iron nutrition is in direct pro-portion to their educational level and family income.The ratio of anemia in infants is in inverse proportion to their dependents′edu-cational level and family income.The dependents′knowledge,attitude and practice of iron-intake were positively related.The aver-age score of guardian nutrition knowledge(K)was (11.96±3.77)points,the average score of attitude(A)was (7.09±2.80)points while the average score of feeding practice(P)was (18.05±3.60)points.Conclusion Much publicity should be given to the knowl-edge of iron nutrition and it should be conducted from various perspectives,in order to improve the cognitive level of the depend-ents′knowledge of iron nutrition and to lower the ratio of anemia in infants.
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Biomass is an important parameter reflecting the fermentation dynamics. Real-time monitoring of biomass can be used to control and optimize a fermentation process. To overcome the deficiencies of measurement delay and manual errors from offline measurement, we designed an experimental platform for online monitoring the biomass during a 1,3-propanediol fermentation process, based on using the fourier-transformed near-infrared (FT-NIR) spectra analysis. By pre-processing the real-time sampled spectra and analyzing the sensitive spectra bands, a partial least-squares algorithm was proposed to establish a dynamic prediction model for the biomass change during a 1,3-propanediol fermentation process. The fermentation processes with substrate glycerol concentrations of 60 g/L and 40 g/L were used as the external validation experiments. The root mean square error of prediction (RMSEP) obtained by analyzing experimental data was 0.341 6 and 0.274 3, respectively. These results showed that the established model gave good prediction and could be effectively used for on-line monitoring the biomass during a 1,3-propanediol fermentation process.
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Using cheap biomass resources is a hotspot of research on industrial biotechnology. It is difficult for traditional fermentations with single strain to treat so complex components and more impurities, which becomes the key problem in industrialization. In this review, some existing industrial bioprocesses involving microbial consortia were described. Comparison of 1,3-propanediol production by microbial consortia and pure cultures were then introduced and the relationship between cells in microbial consortia were summarized. Finally, the perspective was also addressed to design and apply microbial consortia in the future.
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Objective: To explore the value of CYP2C19 genotype polymorphisms for guiding the strategy of anti-platelet therapy in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) with clinical prognosis. Methods: A total of 326 CAD patients with PCI treatment received CYP2C19 genotype examination. According to CYP2C19 polymorphisms, the patients were divided into 3 groups. The patients with CYP2C19*1/*1, fast metabolism were defined as Routine group, who received clopidogrel 75 mg/day,n=128. The patients with CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*3, CYP2C19*2/*2, CYP2C19*3/*3, medium and slow metabolism were further divided into 2 groups as High clopidogrel group, who received clopidogrel 150 mg/day,n=99 and Ticagrelor group, who received ticagrelor 90 mg/bid,n=99. The changes of platelet aggregation rate (PAgT) at before and 1, 3, 6 months after PCI were observed, the major adverse cardiac events (MACE) and bleeding condition were compared among different groups at 6 months after PCI. Results: The PAgT was similar between High clopidogrel group and Routine group at 1, 3, 6 months after PCI, P>0.05;while compared with High clopidogrel group and Routine group, the PAgT decreased in Ticagrelor group at 1, 3, 6 months after PCI,P0.05; while compared with High clopidogrel group and Routine group, Ticagrelor group had much less MACE occurrence,P0.05. Conclusion: High dose clopidogrel does not increase MACE occurrence in CAD patients with CYP2C19 medium and slow metabolism after PCI. Ticagrelor may decrease PAgT and MACE occurrence without elevating the major bleeding events.
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Bio-refinery using cheap biomass focuses mainly on strain improvement and fermentation strategies whereas less effort is made on down-stream processing. Using cheap biomass more impurities are introduced into the fermentation broths than mono-sugar substrate, thus down-stream processing for bio-based chemicals becomes the key problem in industrial production. The technique called salting-out extraction (SOE) was introduced in this review, which is used to separate target products from fermentation broth on the basis of partition difference of chemicals in two phases formed by mixing salts and organic solvents (or amphipathic chemicals) with broth at suitable ratios. The effect of solvents and salts on the formation of two aqueous phases, especially short chain alcohols and inorganic salts, and the application of SOE in recovery of bio-based chemicals, such as lactic acid, 1,3-propanediol, 2,3-butanediol and acetoin were summarized. The bio-chemicals were efficiently recovered from fermentation broth, and most of the impurities (cells and proteins) were removed in the same step. This technique is promising in the separation of bio-based chemicals, especially the recovery of hydrophilic molecules with low molecular weights.
Subject(s)
Butylene Glycols , Metabolism , Chemical Fractionation , Methods , Fermentation , Lactic Acid , Metabolism , Osmolar Concentration , Propylene Glycols , Metabolism , Sodium Chloride , Chemistry , Solvents , ChemistryABSTRACT
Objective To investigate the application of real-time gray-scale contrast enhanced ultrasound (CEUS)imaging in the diagnosis of fallopian tube obstruction.Methods Forty-six females with infertility in the period of 3-7 days after menses were inspected by transvaginal CEUS,and the transmission of contrast agents in the fallopian tubes was observed.Then they were inspected by routine iodic X-ray salpingography.Later the value of real-time gray-scale CEUS in diagnosis of fallopian tube was evaluated.Results The sensitivity of CEUS indiagnosis of fallopian tubal unobstruction,obstruction and open without freely was 92.0%,87.1%,36.4%respectively;the specificity was 85.7%,96.7%,93.7%;the accurate was 89.1%,93.5%,84.7%;the Kappa was 0.78,0.85,0.16 with X-ray salpingography.The concordance was 83.7% between CEUS and X-ray salpingography.Conclusions There were no significant difference between CEUS and X-ray salpingography in diagnosis of fallopian tube unobstruction or obstruction,and the former method is safer and more convenient that is suitable to become an valuable method in inspecting of infertility.