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BACKGROUND:In the process of exploring the mechanism of Alzheimer's disease,the important role of bioinformatics for common target screening has been revealed,enabling the use of its screening results as a basis for exploring the therapeutic effects of drugs on the disease. OBJECTIVE:To predict the targets of liraglutide,a glucagon-like peptide-1 receptor agonist,in the treatment of Alzheimer's disease by bioinformatics and molecular biology. METHODS:DisGeNET database and SEA database were used to obtain the common genes of Alzheimer's disease and liraglutide.GO/KEGG enrichment analysis of common targets was conducted using DAVID online database.Protein-protein interaction networks were constructed using STRING database.The optimal dosage of liraglutide was determined using cell counting kit-8 assay.Expression of key proteins was analyzed using immunofluorescence and immunoblotting techniques.The mouse hippocampal neuron HT22 cell line was used for ex vivo experiments,and the cells were randomly divided into three groups:HT22 group,HT22+Aβ group,and HT22+Aβ+Lir group.No special treatment was done in the HT22 group,while Aβ1-42 was used to intervene in the HT22 cell line for 24 hours to construct an Aβ injury cell model in the HT22+Aβ group.In additional to modeling,liraglutide was added to the HT22+Aβ+Lir group for 12 hours. RESULTS AND CONCLUSION:A total of 3 333 genes associated with Alzheimer's disease were screened from DisGeNET database.Then 147 potential targets of liraglutide were obtained from SEA database.Finally,64 common targets of Alzheimer's disease and Liraglutide were determined using R packets.GO/KEGG analysis of common targets using DAVID online database suggested that common targets were mainly enriched in the following biological processes:neuroactive ligand-receptor interaction,renin-angiotensin system,bladder cancer,endopeptidase activity,peptide receptor activity,G protein-coupled peptide receptor activity,and transport vesicles.The obtained 64 common target proteins were imported into SRTING online database for protein-protein interaction network construction,and the top three genes,matrix metalloproteinases 2,9 and interleukin 1β,were obtained.The activity of cultured cells was detected by the cell counting kit-8 kit.Liraglutide at 100 nmol/L was the optimal concentration for antagonizing Aβ1-42.In the western blot and immunofluorescence assays,the expression of matrix metalloproteinases 2,9 and interleukin 1β was significantly increased in the HT22+Aβ group compared with the HT22 group(P＜0.05)but significantly decreased in the HT22+Aβ+Lir group compared with the HT22+Aβ group(P＜0.05).To conclude,the above bioinformatics data and secondary validation of differential genes in the GEO database suggest that both matrix metalloproteinases 2,9 and interleukin 1β could be potential targets of liraglutide in the treatment of Alzheimer's disease.
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BACKGROUND:Studies have found that glucagon-like peptide-1 and its analogues have a significant neuroprotective effect,and some drugs have been applied to the clinical stage Ⅲ study of Alzheimer's disease.However,the mechanism of its neuroprotective effect is still unclear,which needs to be further explored and clarified. OBJECTIVE:To screen out the genes related to the pathogenesis of Alzheimer's disease and the related targets of semaglutide for the treatment of Alzheimer's disease based on bioinformatics and network pharmacology analyses,to identify the potential target genes by comprehensive analysis of the two and to verify them at the cellular level. METHODS:Using DisGeNET database,differentially expressed genes between Alzheimer's disease patients and healthy population were screened out.The chemical structure formula and two-dimensional structure diagram of semaglutide were obtained using PubChem online database.GO/KEGG enrichment analysis was performed using DAVID online database.A protein-protein interaction network was constructed by using the STRING database.The HPA database was used to determine the distribution characteristics of the target proteins in various human tissues.Finally,western blot was used to detect relevant protein expression in HT22 cells after semaglutide intervention. RESULTS AND CONCLUSION:With the dataset in DisGeNET database,3 374 differentially expressed genes between Alzheimer's disease patients and healthy people were obtained,and meanwhile,101 target genes of semaglutide potential drugs were obtained.There were 23 intersection genes between them.Ten key genes were identified based on the protein-protein interaction network,which were silent information regulator 1(SIRT1),CASP9,CCND1,CASP1,KEAP1,DLG4,CASP4,GRB2,GRIA1,and EDNRA.The results of GO gene functional annotation analysis of key genes showed that the positive regulatory activity of cysteine endopeptidase,the positive regulation of proteolysis,and the positive regulation of cysteine endopeptidase involved the cytoplasmic part of the apoptotic activity process;AMPA glutamate receptor complex,inflammatory complex,CARD domain binding,cysteine endopeptidase activity,and cysteine endopeptidase activity were involved in the apoptotic process.The results of KEGG signaling pathway analysis indicated that colorectal cancer,non-small cell carcinoma,and endometrial carcinoma were related to immune infiltration,inflammation and autophagic apoptosis.In addition,according to the association ranking of key genes and their distribution in different tissues of HPA online database,SIRT1 was identified as the most significant differential gene.The expression level of SIRT1 protein was significantly down-regulated in HT22 cells after β-amyloid protein 1-42 treatment,but it could be significantly increased after being treated with semaglutide.To conclude,SIRT1 may be a target gene for semaglutide in the treatment of Alzheimer's disease.
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BACKGROUND:The threaded conical implant has a good ability to control micro movements and is conducive to immediate loading.However,the effects of double-threaded conical cylindrical implants and conical cylindrical implants on stress distribution and initial stability of implant-bone interface after immediate loading have not been reported. OBJECTIVE:To investigate the impact of double-threaded conical cylindrical implants and conical cylindrical implants on the biological distribution of the implant and the surrounding bone interface during immediate loading in the mandibular molar region. METHODS:(1)Three-dimensional finite element analysis:Conical beam CT scans of the mandible and first molar of a volunteer were used to develop a basal model of the mandible.The double-threaded conical cylindrical implants and conical cylindrical implants were assembled with the mandibular models,and an immediate-load(or delayed implantation)implant model(a total of four models)for the first mandibular molar was established.Loads in four directions(100 N):axial,lingual and buccal 45°,mesial and distal,and buccal and lingual,were applied to the central fossa of each model's crown.Three-dimensional finite element method was used to analyze the implant displacement and the stress distribution at the implant-bone interface.(2)In vitro experiment:With the assistance of the oral implant robot,the double-threaded conical cylindrical implants and conical cylindrical implants were implanted on the same artificial bone pieces,separately,and the immediate load model of immediate implant implantation(or delayed implantation)was established in vitro(a total of four groups of models).Osstell resonance frequency analyzer and SmartPeg sensor were used to measure the implant stability coefficient in four vertical directions:front,rear,left,and right measurements,evaluate the initial stability,and verify the finite element analysis results. RESULTS AND CONCLUSION:(1)The displacement difference between double-threaded conical cylindrical implants and conical cylindrical implants was small when the immediate loading of delayed implantation was applied,but the maximum stress value of conical cylindrical implant-bone interface was greater than that of double-threaded conical cylindrical implant-bone interface.When the immediate loading of immediate implantation was applied,the maximum stress value and the maximum displacement of bone around the implant appeared when the load was applied in mesiodistal direction.The stress value of the conical cylindrical implant reached 298.84 MPa and the maximum displacement was 0.31 mm,both of which were larger than that of the double-threaded conical cylindrical implant.(2)The results of in vitro experiments showed that the stability coefficient of the double-threaded conical cylindrical implant was greater than that of the conical cylindrical implant.(3)Compared with the conical cylindrical implant,the double-threaded conical cylindrical implant has higher initial stability under immediate loading,suggesting that the use of double-threaded conical cylindrical implant should be given priority in clinical immediate loading.
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The kidney is the body's most important organ and the protein components in urine could be detected for diagnosing certain diseases. The amount of IgG protein in urine could be used to determine the degree of kidney function damage. IgG protein in human urine was detected by vertical flow paper-based microfluidic chip, double-antibody sandwich immunoreaction, and cell phone image processing. The results showed that using an IgG antibody concentration of 500 μg/mL and a gold standard antibody concentration of 100 μg/mL, the image signal showed a good linear relationship in the range of IgG concentration of 0.2-3.2 μg/mL, with R2=0.973 3 achieved. A complete set of detection devices were designed and the detection method showed good non-specificity.
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Humans , Microfluidics , Immunoglobulin G , Kidney , Microfluidic Analytical TechniquesABSTRACT
Objective To explore the antitumor small molecules targeting the ubiquitin–proteasome system (UPS) on the basis of active molecules from traditional Chinese medicine. Methods UbG76V-GFP stably expressing cell line was constructed to screen novel small molecule inhibitors targeting UPS. The fluorogenic substrates of Suc-LLVY-AMC, Z-LLE-AMC, and Boc-LRR-AMC were used to assess the effect of dioscin on the 20S proteasome hydrolase activity. The Ub-AMC substrate was used to evaluate the effect of dioscin on the intracellular deubiquitinating enzyme activity. Western blot was used to detect the effect of dioscin on intracellular ubiquitination levels. CCK-8 and colony formation assays were used to detect the inhibitory effect of dioscin on the tumor cell proliferation. Results Dioscin is a UPS inhibitor discovered through the UbG76V-GFP reporter system. It enhances intracellular ubiquitination and inhibits tumor cell proliferation and colony formation by targeting deubiquitinating enzymes. Conclusion Dioscin could significantly inhibit tumor cell proliferation by targeting ubiquitin–proteasome.
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Objective To investigate the effect of berberine on proliferation of neural stem cells(NSCs)induced by hydrogen peroxide(H2O2). Methods NSCs from Sprague-Dawley rats were isolated and purified by suspension culture. Cells were divided into a control group,H2O2group(NSCs exposed to H2O2injury),berberine group(NSCs were incubated with berberine concentrations ranging from 0.5 to 20 μmol/L and exposed to H2O2), and DAPT(a blocker of the Notch signaling pathway)group. Cell viability was evaluated using the Cell Counting Kit-8 assay. Proliferation of NSCs was evaluated by a neurosphere formation assay and Ki67 protein expression. Expression of key proteins in the Notch signaling pathway(including notch1 and hes1)in response to berberine treatment or DAPT(a Notch inhibitor)was determined by Western blotting. Results Cell viability of NSCs was significantly increased by berberine compared with the H2O2group. The neurosphere growth assay showed that 5 or 10 μmol/L berberine increased NSC proliferation. The ratio of Ki67 +/DAPI cells and notch1 and hes1 protein expression increased significantly compared with the H2O2group. Conclusions Berberine treatment upregulates Notch signaling in NSCs,whereas DAPT attenuates these effects. Berberine is a drug that promotes NSC proliferation and exerts a protective effect on NSCs via the Notch signaling pathway.
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Objective To explore the characteristics of emotional identification and emotional intel-ligence of the adolescent methamphetamine addicts,and analyze the correlation between the emotional identi-fication and emotional intelligence.Methods 47 adolescent methamphetamine addicts ( experimental group) and 47 healthy volunteers ( control group) were tested by a self-designed questionnaire,Baron Emo-tional Quotient Inventory ( EQ-i) and experiments of emotional identification.Results The scores of correct responses of positive mood and negative mood of the adolescent methamphetamine addicts ( respectively 28.62±10.60,50.83±18.58) were lower than the healthy volunteers (respectively 32.91±7.30, t=-2.29, P0.05) .In the dimension of emotional intelligence,the individual components,the general state of mind,the management of pressure,and the adaptive composition were related to the emotional identification( r 1=0.39, r 2=-0.33, r 3=-0.39, r 4=0.32) .Conclusion The adolescent methamphetamine addicts had some de-fects on the emotional identification and lack of responsibility and impulse control ability.The emotional in-telligence had influence on their emotional identification.
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Objective To examine the impact on impulsivity trait by monoamine oxidase A variable nucleotide tan?dem repeat (MAOA-VNTR) genotype and children’s abuse experience. Methods The self-reported questionnaire of Bar?ratt Impulsiveness Scale (BIS), Childhood Trauma Questionnaire (CTQ) were conducted in 403 normal Han female adoles?cents from north-west of China. The DNA were extracted from their venous blood sample and were genotyped for the MAOA-VNTR polymorphism. A linear regression model was used to investigate the main effects of MAOA-VNTR and children's abuse, and their interaction effect on impulsivity. Results The main effect of Children’s maltreatment experi?ence on trait impulsivity was significant (P0.05). Conclusion The MAOA-VNTR genotype may not be involved in the female adolescents’impulsivity traits related to childhood maltreat?ment.
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VE: Chitosan and sodium tripolyphosphate were used as Complex matrix material for preparing pellets loading sodium diclofenac and its properties were studied. METHODS Chitosantripolyphosphate sodium polyelectrolyte was prepared according to the principle of static electricity polymerization. Its properties and structure characteristics were further investigated. The preparation process, effective factors and the optimal condition for the pellets loading sodium diclofenac were studied. RESULTS IR indicated that the structure of compound contained -NH3+-O-P group. DTA demonstrated that polyelectrolyte had an exothermic peak. There was no interaction between the drug and expedient. SEM showed that the surface of the pellets was regular, dense and the structure of the surface wasn't consistent with the inner. The pellets prepared by this method were uniform, round, well-distributed, hardy, good-mobility and its average diameter was about 10mm. CONCLUSION Chitosan-tripolyphosphate sodium polyelectrolyte could be used as a good matrix material for preparing pellets.
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Male guinea pigs were placed on ordinary or high lipid diet for 30-36 weeks with various amounts of ascorbic acid (Vc) intake. The daily dose of low level intake was 0.7-1.2mg. The normal one was 2.5-5mg. The high dose was 30-45mg. The various amounts of Vc intake did not affect the cholesterol contents in serum and liver. The animals fed low level Vc were without "overt signs of deficiency, but morphological changes of aorta were developed in these animals either on ordinary or high lipid diet. On high lipid diet, the pathological changes of the vessels (aorta and arteriols in cardiac muscles) of animals fed low level of Vc were more severe than those of animals fed normal level, and those of animals fed high dose were the least severe.The result of this study suggested that the presence of a link between Vc and the integrity of the vessels. Prolonged low intake of YC may be regarded as being one of the causal factors in the development of arteriosclerosis. The requirements of Vc for subjects with high cholesterol level may be more than those of normal subjects.
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Pressed biscuits were fortified with gelatin encapsulated VA powder, VC phosphate Mg and VB2 tetrabutyrate. The biological effects of these vita-rains were examined by human experiments. In 7 days of the experimental period, the subjects of the 1st group (10 male adults) took the fortified biscuit freely which contained 7500 IU VA powder, 5.16 mg B2 tetrabutyrate ( = 3mg VB2) and 308mg VC phosphate ( = 140 mgVC) in 750 g. The 2nd group took 250 g biscuit freely containing the same amount of vitamin and unfortified pressed biscuit. The 3rd group took only the unfortified ones freely. 5 days before or after fhe experimental period the subjects ate vitamin restricted diets. The nutritional status of VB2 was estimated by 24 hrs. urinary VB2 values, that of VC by urinary and fasting plasma VC levels, and that of VA by fasting plasma VA values.The urinary levels of VB2, VC and plasma values of VC of group 1 and 2 at the end of the experimental period were significantly higher than those of the pre-experimental period. They were also higher than those of group 3. On the 5th day of the post-experimental period, the status of VB2 and VC of group 1 and 2 was still better than that of group 3. Because the subjects were not in VA deficiency, the plasma levels of VA were kept steady.The stabilities of these vitamins in the fortified pressed biscuit were compared with those of ordinary vitamins. Stored in 85% RH 32℃ for 20 months, encapsulated VA powder retained 76%, VC phosphate 84%, but the ordinary VA only 14%, VC 29%. Stored in room temp. 75% RH for 2 years, the VA encapsulated powder retained 73%, VC phosphate 96%, but ordinary VA only 8%, VC 22.3%. In room temp. for 2 years, encapsulated VA powder retained 87%, VC phosphate almost did not lost, but ordinary VA retained 8%, VC retained 25% only. The stability of the VB2 tetrabutyrate was almost the same as that of VB2. It was shown by the guinea pig growth experiment that VC phosphate in pressed biscuit stored 20 months possessed the same biological effect as VC crystal.
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Tie effects of L-ascorbate 2-sulfate(AAS) on fatty liver and hyperli-pemia of rat and guinea pigs induced by various treatments were studied. The results showed that AAS lowered cholesterol and total lipid levels in the serum and liver of rats fed diets supplemented with lard and cholesterol, while ascorbic acid had no obvious effect. In guinea pigs, AAS not only lowered serum lipid values and liver cholesterol, triglyceride and total lipid levels of DDT treated animals, but also prevented from decline of body weights of these animals. It also had the same effects to lower the serum and liver lipid values of those animals fed pentabarbital or high lipid diet.Remarkable increases of the lipid peroxide value of animals given high doses of AsA were observed, but no such effect occurred in those fed AAS.
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The effects of 4 kinds of edible oils on serum lipid levels, morphological changes of cardiovascular tissues, fatty acid compositions of various tissues and platelet function in rats had been observed. 40 adult Wistar rats fed semi-synthetic diet containing edible oil to supply 41% energy were divided into 5 group, i. e. control group (18.7% energy from fat), soy bean oil group, peanut oil group, lard group and rape seed oil group. The animals were fed the diets and water ad libitum for 2 months. The results showed that the lard gave the most serious detrimental effect but the soy bean oil was the least. The difference between these two groups was significant. The platelet number was 223?109/L and aggregation rate was 21.8% of the soy bean oil group but. the lard group 149?109/L and 30.2%. The composition (%) of PUFA in tissues was higher and that of saturated fatty acid was tower in soy bean ou group than those in lard group.Electron microscopical studies showed that the animals with vascular endothelial cells changes were more and the pathological changes were more serious in the lard group than those in the soy bean group.All groups except rape seed oil group increased weights in the experi-mental period at the similar rate. Rape seed oil group gained very little weights and aggregated more C22:1 especially in myocardium.