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Objective To explore and validate the mechanism of Prepared Radix Polygoni Multiflori in the treatment of NAFLD based on network pharmacology and animal non-alcoholic fatty liver disease(NAFLD)model experiments.Methods Consult the literature to compare the differences between Radix Polygoni Multiflori and Prepared Radix Polygoni Multiflori(PRPM).Herb database and SwissADME database were used to screen the active ingredients of Prepared Radix Polygoni Multiflori,SwissTargetPrediction database was used to predict its targets,OMIM,DISGENET and GEENCARDS databases were used to screen the NAFLD-related targets,conduct GO functional enrichment analysis and KEGG pathway enrichment analysis.The active ingredient-target-KEGG signaling pathway-NAFLD network was mapped later.The mice with NAFLD were treated with Prepared Radix Polygoni Multiflori by gavage for 8 weeks;serum triglyceride level and alanine aminotransferase(ALT)activity were measured;the liver lesions were observed by HE staining;the potential mechanism of action of Radix Polygoni Multiflori in the treatment of NAFLD was verified by Western blot.Results The differences between Radix Polygoni Multiflori and PRPM were consulted.Six pharmacological components and 32 potential action targets of Radix Polygoni Multiflori for the treatment of NAFLD were screened by network pharmacology,GO and KEGG pathways were enriched to lipid and atherosclerosis-related pathways,AMPK signaling pathway,etc.;HE staining verified that Prepared Radix Polygoni Multiflori has the function of improving NAFLD and is associated with the alteration of FASN,ACC,SCD protein of AMPK signaling pathway.Conclusion Radix Polygoni Multiflori has the potential to improve NAFLD by regulating FASN,ACC and SCD.
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Objective To investigate the impacts of tanshinone ⅡA(Tan ⅡA)on lipopolysaccharide(LPS)induced proliferation and apoptosis of dental pulp stem cells by regulating the fatty acid synthase(Fas)/fatty acid synthase ligand(FasL)signaling pathway.Methods Identification of human pulp stem cells(hDPSCs)isolated from the third molar of 18~20 years old patients requiring orthodontics.Lps-induced hDPSCs were treated with low,medium and high doses of Tan ⅡA,and then human recombinant FasL protein(rh FasL)was used to intervene the LPS-induced hDPSCs after high dose Tan ⅡA.Proliferation and apoptosis of hDPSCs,levels of tumor necrosis factor-α(TNF-α)and interleukin(IL)-6 in hDPSCs supernatant,proliferating cell nuclear antigen(PCNA),Cleaved aspartate-specific cysteine proteinase-3(Cleaved Caspase-3),Fas,FasL protein expression were detected.Results hDPSCs were successfully isolated.In a dose-dependent manner,Tan ⅡA promoted LPS-induced proliferation,inhibited apoptosis,up-regulated PCNA protein expression,and inhibited TNF-α,IL-6 level,Cleaved Caspase-3,Fas,and FasL protein expression.The effect of rh FasL on LPS-induced dental pulp stem cells was opposite to the above indexes(P<0.05).rh FasL attenuates the effect of high-dose Tan ⅡA on pro-liferation and apoptosis of LPS-induced dental pulp stem cells.Conclusion Tan ⅡA may promote LPS induced hDPSCs proliferation and inhibit apoptosis by inhibiting the Fas/FasL signaling pathway.
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SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.
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To investigate the effect of Gegen Qinlian Decoction(GQD) on enzyme activity, gene expression and methylation level of fatty acid synthase(FASN) in adipose tissue from rats with insulin resistance induced by high-fat diet. The 60% fat-powered high-fat diet was continuously given to male SD rats to induce the insulin resistance model. Then, they were divided into five groups randomly and administrated by gavage every day for 16 weeks with following drugs respectively: 10 mL·kg~(-1)water for control group(C) and insulin resistance model control group(IR), 1.65 g·kg~(-1)GQD per day for low-dose group(GQDL), 4.95 g·kg~(-1)GQD per day for medium-dose group(GQDM), 14.85 g·kg~(-1)GQD per day for high-dose group(GQDH), and 5 mg·kg~(-1) rosiglitazone per day for rosiglitazone group(RGN). Epididymal adipose tissue was taken to determine enzyme activity of FASN by colorimetric method, mRNA expression level of Fasn by quantitative Real-time PCR(Q-PCR) and CpGs methylation level between +313 and +582 by bisulfite sequencing PCR(BSP). These results showed that Fasn expression was significantly lowered in IR model rats compared with the control rats(P<0.01). Enzymatic activity and CpGs methylation level of Fasn in IR group showed downward trends. Low and medium-dose GQD can increase enzyme activity of FASN(P<0.05). Moreover, low-dose GQD increased the total CpGs methylation level of Fasn fragment between +313 and +582 in insulin resistance rats(P<0.05). For GQDM group, the methylation frequency of CpGs at positions +506 and +508(P<0.01) as well as the methylation frequency of CpGs on the binding sites of transcription factorzinc finger protein 161(P<0.05) were significantly increased. The methylation frequency of CpG at +442 position was positively correlated with Fasn expression(P<0.01, r=0.735), and methylation frequencies of CpGs at +345 and +366 positions were positively associated to enzyme activity of FASN respectively(P<0.05, r=0.479; P<0.01, r=0.640). In conclusion, GQD can reverse enzyme activity of FASN and methylation level of Fasn in adipose tissue of insulin resistant rats, and CpG sites at positions +506 and +508 may be the targets of GQD. The methylation level of CpGs at + 345 and + 366 sites were possibly related to FASN activity, while methylation of CpG at + 442 site may be closely correlated with mRNA level of Fasn. In addition, GQD did not significantly change mRNA expression level of Fasn, but effectively reversed enzymatic activity, suggesting that GQD may regulate the post transcriptional expression of Fasn.
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Animals , Male , Rats , Adipose Tissue , Drugs, Chinese Herbal , Fatty Acid Synthases/genetics , Gene Expression , Insulin Resistance/genetics , Methylation , Rats, Sprague-DawleyABSTRACT
The present study aimed to evaluate the occurrence of polymorphisms in Diacylglycerol acyltransferase (DGTA-1 and 2), Fatty acid synthase (FASN), Stearoyl-CoA desaturase (SCD) genes and the Thioesterase domain of FASN (TE-FASN) gene that may be related to the lipid profile. In the experiment, a total of 84 sheep from different genetic groups were used. For the evaluation of the polymorphism of the genes, PCR-Single Strand Conformation Polymorphism (SSCP) technique and subsequent sequencing were used. In DGAT-2 gene, four genotypes were identified with the presence of 6 polymorphisms, with two (c.229T> C; c.255T> C) that resulted into the exchange of phenylalanine by leucine. In FASN gene, two genotypes were identified. In TE-FASN gene, three genotypes and 17 polymorphisms were identified. DGAT-1 and SCD genes did not reveal the occurrence of polymorphism. There was difference in relation to C14: 0, C18: 0 fatty acids and Δ9-desaturase C18 for DGAT-2 gene and of C18: 2ω6t for TE-FASN. There were differences among the genetic groups for C10: 0, C12: 0, C17: 0, C18: 2ω6t, C18: 3ω3, C20: 2, total of ω3, ω3/ω6 and atherogenicity index. There is occurrence of polymorphism of DGAT-2 and TE-FASN genes and these should be further studied in sheep since they revealed influence of the genotypes on the fatty acid profile.(AU)
O presente estudo teve o objetivo de avaliar a ocorrência de polimorfismos nos genes Diacilglicerol aciltransferase (DGTA1 e 2), Ácido graxo sintase (FASN), Estearoil-CoA dessaturase (SCD) e o Domínio da tioesterase do gene FASN (TE-FASN), que possam estar relacionados ao perfil lipídico. No experimento, foram utilizados um total de 84 ovinos de diferentes grupos genéticos. Para avaliação do polimorfismo dos genes, foi utilizada a técnica de polimorfismo de conformação de cadeia simples (PCR-SSCP) e posterior sequenciamento. No gene DGAT-2, foram identificados quatro genótipos com a presença de seis polimorfismos, com dois (c.229T>C; c.255T>C) que resultaram na troca da fenilalanina por leucina. No gene FASN, foram identificados dois genótipos. No gene TE-FASN, foram identificados três genótipos e 17 polimorfismos. Os genes DGAT-1 e SCD não revelaram a ocorrência de polimorfismo. Houve diferença em relação aos ácidos graxos C14:0, C18:0 e ∆9-desaturaseC18 para o gene DGAT-2 e de C18:2ω6t para TE-FASN. Houve diferença entre os grupos genéticos para C10:0, C12:0, C17:0, C18:2ω6t, C18:3ω3, C20:2, total de ω3, ω3/ω6 e índice de aterogenicidade. Há ocorrência de polimorfismo dos genes DGAT-2 e TE-FASN, e estes devem ser mais estudados em ovinos, pois revelaram influência dos genótipos sobre o perfil de ácidos graxos.(AU)
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Animals , Polymorphism, Genetic/genetics , Sheep/metabolism , Fatty Acids/analysis , Fatty Acids/classificationABSTRACT
Objective@#Hepatocellular carcinoma (HCC) is one of the most common malignant tumor worldwide. Metastasis is a marker of cancer deterioration in patients with liver cancer and a major cause of death. In order to develop effective therapeutic strategies, it is urgent to study the molecular basis of liver cancer metastasis.@*Methods@#Immunohistochemistry was used to detect the expression of fatty acid synthase (FASN) in HCC. Wound healing and transwell cell invasion assays was used to confirm the role of FASN in liver cancer migration and invasion. Proteins that interacted with FASN were identified using iTRAQ (isobaric tag for relative and absolute quantification). Co-immunoprecipitation (Co-IP) and cellular immunofluorescence analysis were used to assess the interaction between FASN and signal transduction and transcription activator 3 (STAT3). The expression of STAT3, p-STAT3, matrix metalloproteinase (MMP)-2 and MMP-9 was detected after FASN knockdown using Western blot method. Statistical analysis was performed using the t-test.@*Results@#Immunohistochemistry showed that the expression of FASN in HCC tissue was higher than that in adjacent tissues. iTRAQ, Co-IP and immunofluorescence analysis revealed that FASN interacted with STAT3. Western blot analysis showed that the expression of p-STAT3, MMP-2 and MMP-9 decreased after FASN knockdown.@*Conclusion@#FASN may promote the metastasis of liver cancer by interacting with STAT3 and affecting the expression of MMP-2/MMP-9.
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Objective: To investigate the effects of Exendin-4 (Ex-4) on the expressions of lipid metabolism related genes in the human liver cancer HepG2 cells with insulin resistance (IR), and to elucidate the effect of Ex-4 in improvement of IR. Methods: The HepG2 cells in logarithmic growth phase were induced into IR model with high concentration of insulin, then divided into control group (HepG2 cells), IR group (HepG2 cells were treated with insulin, HepG2-IR cells), and Ex-4 group (HepG2-IR cells were treated with Ex-4). Glucose oxidase (GOD-POD) kit was used to detect the consumption of glucose. The cell morphology and intracellular lipid drip formation were observed by Oil red O staining. The triglyceride (TG) level in cells was detected by kit; qRT-PCR was used to detect the mRNA expression levels of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), sterol regulatory element-binding protein-1c (SREBP-lc) and apolipoprotein B100 (apoBlOO). Results: Compared with control group (HepG2 cells), the glucose consumption in the HepG2-IR cells in IR group was significantly decreased (P<0. 01). Compared with IR group, the glucose consumption in the HepG2-IR cells in Ex-4 group was increased (P<0. 05). The Oil O red staining results showed that compared with control group, the fat percentage in the HepG2-IR cells in IR group was increased (P<0. 05); compared with IR group, the fat percentage in Ex-4 group was decreased (P< 0.05). Compared with control group, the level of TG in the cells in IR group was significantly increased (P< 0. 01); compared with IR group, the level of TG in the cells in Ex-4 group was significantly decreased (P<0. 05). The qT-PCR results showed that compared with control group, the expression levels of ACC FAS and SREBP-lc mRNA in the cells in IR group were increased (P<0. 01), and the expression level of apoBlOO mRNA was decreased (P<0. 05); compared with IR group, the expression levels of ACC, FAS and SREBP-lc mRNA in the cells in Ex-4 group were decreased (P<0. 05), and the expression level of apoBlOO mRNA was increased (P< 0.01). Conclusion: Ex-4 can regulate the expressions of lipid metabolism related genes in the HepG2 cells and improve IR.
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OBJECTIVE: To observe the effect of electroacupuncture(EA) of "Fenglong" (ST 40) and "Sanyinjiao" (SP 6) on lipid metabolic disorder, insulin resistance (IR) and expression of sterol regulatory element blinding protein-1 (SREBP-1) c and fatty acid synthase (FAS) proteins in the liver tissue in hyperlipidemia rats with IR, so as to reveal its mechanisms underlying improvement of IR. METHODS: Forty male SD rats were randomly divided into blank control, model, medication and EA groups (n=8 in each group). The IR model was established by feeding the rat with high-fat diet. Rats of the medication group were treated by intragastric administration of pioglitazone (10 mL/kg). For rats of the EA group, EA (2 Hz/100 Hz,1 mA) was applied to bilateral ST 40 and SP 6, once daily for 14 days. The insulin sensitivity index (ISI) was assessed by calculating 60-120 min glucose infusion rate (GIR 60-120) with euglycemic hyperinsulinemic clamp in reference to Kraegen's and colleagues' methods. Fasting blood samples (10 mL) were collected and analyzed for fasting blood glucose (FBG) using enzyme method, serum fasting insulin(FINS) using ELISA, free fatty acid(FFA) using spectrophotometry, and total triglyceride(TG) and total cholesterol(TC) employing glycerine phosphate oxidase peroxidase (GPO-PAP) assay, low density lipoprotein(LDL), high density lipoprotein(HDL) levels using combined filiter paper activity and lipase activity methods, respectively. The IR level was assessed by calculating homeostatic model assessment of insulin resistance (HOMA-IR) using the formula (FBG×FINS)/22.5. The expression levels of SREBP-1 c and FAS proteins in the liver tissue were detected by Western blot. RESULTS: Following modeling, the GIR 60-120 and serum HDL were significantly decreased(P0.05). CONCLUSION: EA intervention is able to improve the disorder of lipid metabolism of IR rats, which may be associated with its effects in reducing the expression of SREBP-1 c and FAS proteins and in lowering the synthesis of fatty acid.
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Objective:To investigate the effects of Exendin-4 (Ex-4) on the expressions of lipid metabolism related genes in the human liver cancer HepG2 cells with insulin resistance (IR),and to elucidate the effect of Ex-4in improvement of IR.Methods:The HepG2 cells in logarithmic growth phase were induced into IR model with high concentration of insulin,then divided into control group (HepG2 cells),IR group (HepG2 cells were treated with insulin,HepG2-IR cells),and Ex-4 group (HepG2-IR cells were treated with Ex-4).Glucose oxidase (GOD-POD)kit was used to detect the consumption of glucose.The cell morphology and intracellular lipid drip formation were observed by Oil red O staining.The triglyceride (TG) level in cells was detected by kit;qRT-PCR was used to detect the mRNA expression levels of acetyl-CoA carboxylase (ACC),fatty acid synthase (FAS),sterol regulatory element-binding protein-1c (SREBP-1c) and apolipoprotein B100 (apoB100).Results:Compared with control group (HepG2 cells),the glucose consumption in the HepG2-IR cells in IR group was significantly decreased (P<0.01).Compared with IR group,the glucose consumption in the HepG2-IR cells in Ex-4 group was increased (P<0.05).The Oil O red staining results showed that compared with control group,the fat percentage in the HepG2-IR cells in IR group was increased (P<0.05);compared with IR group,the fat percentage in Ex-4 group was decreased (P<0.05).Compared with control group,the level of TG in the cells in IR group was significantly increased (P<0.01);compared with IR group,the level of TG in the cells in Ex-4 group was significantly decreased (P<0.05).The qT-PCR results showed that compared with control group,the expression levels of ACC FAS and SREBP-1cmRNA in the cells in IR group were increased (P<0.01),and the expression level of apoB100 mRNA was decreased (P<0.05);compared with IR group,the expression levels of ACC,FAS and SREBP-1c mRNA in the cells in Ex-4 group were decreased (P<0.05),and the expression level of apoB100 mRNA was increased (P<0.01).Conclusion:Ex-4 can regulate the expressions of lipid metabolism related genes in the HepG2 cells and improve IR.
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PURPOSE: The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in Vitro and in vivo. MATERIALS AND METHODS: We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of 5×105 U87 cells and treatedwith metformin, TMZ, and the combination for 4weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway. RESULTS: The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ. CONCLUSION: The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in Vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.
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Animals , Mice , AMP-Activated Protein Kinases , Apoptosis , Blotting, Western , Cell Line , Cell Survival , Fluorescent Antibody Technique , Glioblastoma , In Vitro Techniques , Metformin , Phosphorylation , SirolimusABSTRACT
Objective To explore the effect of betulinic acid on NAFLD and its mechanism. Methods We used the high-fat diet animal models, with or without feeding the standard chow diet containing betulinic acid for 2 months. During this period, the body weight was monitored regularly and metabolism cage was used to monitor the energy metabolism of the animals. After killing the mice, molecular biological analysis was performed on serum and tissue related to liver. Results In diet induced obese mice animal experiments, the mice body weight had been reduced and NAFLD had been improved significantly by betulinic acid. The various indexs of serum and liver tissue had also been significantly improved. The metabolic rate increased significantly. Fatty acid synthase gene and protein levels were significantly lower. Furthermore, FAS activity was significantly lower than the control mice. Liver FAS activity of the high fat mice and the high fat mice treated with betulinic acid were (1873.6 ± 85.7) and (1181.6 ± 85.7) pmol NADPH/ min/ mg protein, respectively. Conclusion Betulinic acid inhibited FAS at expression and activity level, and improved lipid deposition in liver.
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Objective To investigate the expression level of fatty acid synthase (FASN) in different grades ofgliomas and its relationship with glioma malignancy.Methods Glioma U87 and U373 cell lines were routinely cultured in vitro;immunofluorescence assay was performed to detect the cellular localization of FASN in glioma U87 and U373 cell lines.Sixty-seven human glioma samples,collected in our hospital from March 2012 to March 2013,were used in our study;grade Ⅰ was noted in three samples by WHO grading,grade Ⅱ in 29,graded Ⅲ in 22,and grade Ⅳ in 13;immunohistochemistry was performed to detect the expression levels of FASN,CD34 and Ki-67 and microvascular density (MVD) in these human glioma samples.Spearman's correlation was used to analyze the relationship between FASN expression and both Ki-67 expression and MVD in human gliomas.Results (1) FASN could express in the cytoplasm of glioma U87 and U373 cell lines.(2) immumohistochemical staining indicated that FASN mainly located in the cytoplasm,Ki-67 in the cell nucleus,and CD34 in the cytomembrane.FASN expression in samples of grade Ⅰ (3.3683±0.6549) was significantly lower than that in samples of grade Ⅱ (4.0512±0.4859,P<0.05),and FASN expression in samples of grade Ⅲ (4.1881±0.5755) was significantly lower than that in samples of grade Ⅳ (4.6996±0.5164,P<0.05);MVD in samples of grade Ⅱ was significantly smaller than that in samples of grade Ⅲ(P<0.05),and MVD in samples of grade Ⅲ was significantly lower than that in samples of grade Ⅳ(P<0.05);Ki-67 expression in samples of grade Ⅱ was significantly lower than that in samples of grade Ⅲ (P<0.05).(3) There was a positive and significant correlation between FASN expression and MVD (r=0.606,P=0.030);a positive and significant correlation between FASN expression and Ki-67 was also noted (r=0.636,P=0.014).Conclusion High expression level of FASN indicates high proliferation capability and high blood supply in haman gliomas.
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Objective To investigate the expressions of RNA-binding protein human antigen R(HuR), fatty acid binding protein type 4(FABP4),fatty acid synthetase(FASN),and lipoprotein lipase(LPL)during the differentiation of human adipocytes, and to explore their possible roles. Methods Human adipose-derived mesenchymal stem cells were induced by adipogenic differentiation,and the adipogenesis of cells was observed by oil red O staining. The expressions of HuR,FABP4,FASN,and LPL mRNA and protein were detected by real-time PCR and Western blotting. After HuR was silenced by siRNA, the change of adipogenesis for human adipose-derived mesenchymal stem cells was observed and the expressions of adipogenic genes were detected. Results The expressions of HuR,FABP4,FASN,and LPL mRNA and protein were significantly increased after human adipose-derived mesenchymal stem cells were induced to differentiate into adipocytes(all P<0.01). After HuR expression was down-regulated by siRNA,the adipogenic level of human adipose-derived mesenchymal stem cells was reduced,with decreased protein levels of FABP4,FASN,and LPL(all P<0.05),which were without changes for their mRNA levels. Conclusion HuR promotes the differentiation of human adipocytes mainly via regulating the changes of FABP4,FASN,and LPL protein levels.
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Objective To observe the effect of fenofibrate intervention on high-fructose-feeding-induced liver steatosis in rats and explore the possible mechanism. Methods Male Wistar rats were randomly divided into control group ,high fructose group and fenofibrate group[fenofibrate intervention started after 8 weeks of high fructose feeding ,30 mg/(kg · d)]. Rats were sacrificed after 12-week of high fructose feeding. Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),free triglyceride(TG)and liver TG content were determined;protein levels of fatty acid synthase(FAS),endoplasmic reticulum stress mark-er Bip and autophagy markers such as Atg7,Beclin1,LC3 and the related pathway mTOR in liver tissues were de-tected. Results Compared with those in control group and fenofibrate group,serum AST,serum total cholesterol, blood free TG and hepatic TG were significantly increased in high-fructose group(P < 0.01). The protein expres-sion of Fas,Bip and mTOR were significantly increased in high-fructose group compared with those in control group and fenofibrate group;the protein expression of Atg7,beclin1 and LC3 were significantly decreased in high-fructose group compared with those in control group and fenofibrate group. Conclusions Long-term high-fructose-feeding induces fatty liver and liver cell injury ,and may affect ERS and autophagy. High-fructose-feeding-in-duced fatty liver may be improved by fenofibrate and its underlying mechanism might be associated with Fas,ERS and autophagy in liver.
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Objective To study the expression and significance of fatty acid synthase ligand ( sFas ) and soluble fatty acid synthase receptor (sFasL) on the neoadjuvant chemotherapy of breast cancer.Methods 84 cases of patients with breast cancer neoadjuvant chemotherapy were recorded from January 2015 to January 2016 in our hospital as breast cancer group,another 84 cases of healthy subjects as control group,the two groups were measured sFas,the positive rate of sFasL.At the same time,respectively before and after neoadjuvant chemotherapy, detection of patients serum sFas, sFasL levels and breast cancer.According to the clinical curative effect were divided into effective group and ineffective group , compared two groups of serum sFas, sFasL levels.Results Breast cancer group called sFas and sFasL positive rate was 58.33% (49/84) and 100.00%(84/84),were significantly higher than that of control group 38.10%(32/84) and 0.00% (0/84);The level of sFas in patients with neoadjuvant chemotherapy was significantly lower than that of neoadjuvant chemotherapy, and the level of sFas in neoadjuvant chemotherapy group was significantly higher than that in ineffective group, the difference was statistically significant (P<0.05).Conclusion In the course of neoadjuvant chemotherapy for breast cancer,the efficacy of neoadjuvant chemotherapy can be effectively detected by detecting the level of serum sFas in patients with breast cancer , while sFasL has no significant change in the neoadjuvant chemotherapy of breast cancer.
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Objective:To screen fatty acid synthase (FAS) inhibitors from natural products and study their inhibitory effects on the proliferation of MCF-7 breast cancer cells.Methods: CCK-8 method was used to detect the inhibitory effects of Fructus Amomi, Polygonum cuspidatum Sieb, Cinnamomi Ramulus and their main compounds, such as polydatin, resveratrol and cinnamic acid on the proliferation of MCF-7 breast cancer cells for 24 h.Results: The results showed that the IC50 values of the 60% ethanol extracts of Fructus Amomi, Polygonum cuspidatum Sieb, and Cinnamomi Ramulus were 24.86μg/ml, 153.67 μg/ml and 178 μg/ml respectively. The IC50 value of Resveratrol was 61.75 μg/ml. The inhibitory effect of Resveratrol was better than that of Polygonum cuspidatum Sieb. Cinnamic acid, the main component of Cinnamomi Ramulus had better inhibitory activity at lower concentration.Conclusion: The 60% ethanol extracts of Fructus Amomi, Polygonum cuspidatum Sieb, and Cinnamomi Ramulus all showed inhibitory effects on the proliferation of MCF-7 breast cancer cells in a dose-dependent manner. Among them, Fructus Amomi had the best inhibitory activity.
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Objective To investigate the effect and mechanism of liver X receptor ( LXR ) agonist on expression of fatty acid synthase( FAS) in diabetic kidney. Methods In the part of in vivo study, immunostaining was used to detect the FAS protein expression in kidney. 16-week-old male db/db mice on C57BL/6 background were administered via gavage a LXR synthetic agonist, TO901317, at a dose of 3 mg · kg-1 · d-1 or vehicle ( 0. 5%Carboxymethyl Cellulose Sodium, CMC-Na) alone for 7 d;Quantitative RT-PCR and Western blot were used to detect mRNA and protein levels of FAS and SREBP-1. In the part of in vitro study, MCT cell(a mouse murine proximal tubule cell line)was treated with 10μmol/L TO901317 for 24 h or transfected with active SREBP-1c expression vector (SREBP-1cN). HEK293 cells(a human renal tubule cell line)were transfected with mFAS-(1. 7 kb)-luc, LXR expression vector or SREBP-1cN for 12 h. Quantitative RT-PCR and luciferase reproter assay were utilized to examine FAS mRNA level and FAS promoter activity. Results FAS was abundantly expressed in renal cortex, with low expresson in renal glomeruli. The mRNA and protein expressious of FAS in kidney of db/db mice were lowered compared with db/m mice. TO90137 treatment increased FAS mRNA expression by 1. 3-fold. TO901317 increased expression of SREBP-1 in kidneys of db/m and db/db mice by 5. 1-fold and 17-fold, respectively. TO901317 and overexpression of SREBP-1c increased expression of FAS in MCT cells by 1. 5-fold and 1. 8-fold. Transcription activity of FAS were induced by TO901317, LXR, and SREBP-1cN overexpressions in HEK293 cells. Conclusions Both direct(LXRE)and indirect(SREBP-1c)mechanisms may contribute to the up-regulation of FAS expression by LXR in renal proximal tubule cells.
ABSTRACT
OBJECTIVE: To evaluate in Wistar rats the effect of chronic use of high fructose corn syrup on serum lipids, body weight, energy intake regulation, and expression of associated genes. METHODS: For 11 weeks, male rats were fed a standard diet with either water (control) or 15% high fructose corn syrup solution, or fed a high-fat diet. The rats' food intake and body weight were measured weekly. Expression of leptin and fatty acid synthase genes was quantified in their brain and adipose tissue upon sacrifice at age 119 days using real-time polymerase chain reaction. RESULTS: The intake of 15% high fructose corn syrup did not affect the rats' weight, only the rats on the high-fat diet gained significant weight. The rats in both diets had lower levels of leptin expression and high levels of fatty acid synthase in the brain, which were associated with high serum triglycerides. CONCLUSION: Fifteen percent high fructose corn syrup intake and the high-fat diet reduced leptin gene expression in the brain of Wistar rats, with differential effects on weight gain.
OBJETIVO: Avaliar em ratos Wistar o efeito do consumo crônico de xarope de milho com alta concentração de frutose sobre os lipídeos séricos, peso corporal, regulação da ingestão energética e expressão de genes associados. MÉTODOS: Durante 11 semanas, ratos machos foram alimentados com uma dieta padrão com água (controle) ou 15% de xarope de milho com alta concentração de frutose, ou com uma dieta hiperlipídica. A ingestão alimentar e o peso corporal dos ratos foram medidos semanalmente. Os animais foram sacrificados com 119 dias de vida, e as expressões gênicas de leptina e da sintetase de ácidos graxos foram quantificadas no cérebro e no tecido adiposo usando a reação em cadeia da polimerase em tempo real. RESULTADOS: O consumo de 15% de xarope de milho com alto teor de frutose não afetou o peso dos animais, somente os ratos da dieta hiperlipídica aumentaram de peso significativamente. Nas dietas hiperlipídica e com alto teor de frutose, foram evidentes expressões mais baixas de leptina e mais altas de sintetase de ácidos graxos no cérebro, assim como concentrações mais altas de triacilglicerídeos séricos. CONCLUSÃO: Ingestão de xarope de milho com alta concentração de frutose a 15% ou de dieta hiperlipídica diminuíram a expressão gênica de leptina no cérebro de ratos Wistar, com diferentes efeitos sobre o aumento de peso.
Subject(s)
Animals , Guinea Pigs , Rats , Body Weight , Leptin , Fatty Acids , Diet, High-Fat , High Fructose Corn Syrup , FructoseABSTRACT
It has been proved that FAS is a potent oncogene. Its expression and activity is normal in most of the non-neoplastic cells, but it is over-expressed and associated with poor prognosis in several human malignancies. Recent studies show that FAS inhibitor can induce significant anti-tumor effect. It reduces cell proliferation,enhances apopto-sis,inhibits tumor invasion and metastasis,while it is also an chemosensitization for other chemotherapy drugs. In this paper, the anti-tumor mechanism of FAS inhibitors is reviewed to prospect the research direction of its anti-tumor ef-fect.
ABSTRACT
Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that plays a critical role in lipogenesis. This lipogenic enzyme has gained importance beyond its physiological role due to its implications in several clinical conditions-cancers, obesity, and diabetes. This has made FASN an attractive pharmacological target. Here, we have attempted to predict the theoretical models for the human enoyl reductase (ER) and beta-ketoacyl reductase (KR) domains based on the porcine FASN crystal structure, which was the structurally closest template available at the time of this study. Comparative modeling methods were used for studying the structure-function relationships. Different validation studies revealed the predicted structures to be highly plausible. The respective substrates of ER and KR domains-namely, trans-butenoyl and beta-ketobutyryl-were computationally docked into active sites using Glide in order to understand the probable binding mode. The molecular dynamics simulations of the apo and holo states of ER and KR showed stable backbone root mean square deviation trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of residues in the most favorable region for ER and 90.3% for the KR domain, respectively. Thus, the predicted models yielded significant insights into the substrate binding modes of the ER and KR catalytic domains and will aid in identifying novel chemical inhibitors of human FASN that target these domains.