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ObjectiveTo investigate the effect and mechanism of total saponins from Panax japonicus （TSPJ） on white adipose tissue （WAT） browning/brown adipose tissue （BAT） activation in C57BL6/J male mice fed on a high-fat diet （HFD）. MethodThirty-two C57BL6/J male mice （8-week-old） were randomly divided into a normal group， a model group， a low-dose TSPJ group， and a high-dose TSPJ group. The mice in the low-dose and high-dose TSPJ groups were given TSPJ for four months by gavage at 25， 75 mg·kg-1·d-1， respectively， and those in the other groups were given 0.5% sodium carboxymethyl cellulose （CMC-Na） accordingly. After four months of feeding， all mice were placed at 4 ℃ for acute cold exposure， and the core body temperature was monitored. Subsequently， all mice were sacrificed， and BAT and inguinal WAT （iWAT） were separated rapidly to detect the corresponding indexes. Hematoxylin-eosin （HE） staining was used to observe the morphological changes in each group. The effect of TSPJ on the mRNA expression of uncoupling protein 1 （UCP1）， fatty acid-binding protein 4 （FABP4）， cytochrome C （CytC）， PR domain-containing protein 16 （PRDM16）， elongation of very long chain fatty acids protein 3 （ELOVL3）， peroxisome proliferator-activated receptor γ （PPARγ）， and peroxisome proliferator-activated receptor-γ coactivator-1α （PGC-1α） in iWAT and BAT was detected by Real-time polymerase chain reaction （Real-time PCR）. Western blot was also used to detect the protein expression of UCP1， PRDM16， PPARγ， and PGC-1α in BAT and iWAT of each group. The effect of TSPJ on UCP1 expression in BAT and iWAT was detected by immunohistochemistry. Result① Compared with the model group， TSPJ could decrease the body weight and proportions of iWAT and BAT in the HFD-induced mice （P<0.05， P<0.01）. ② The body temperature of mice in the model group decreased compared with that in the normal group in the acute cold exposure tolerance test （P<0.05）. The body temperature in the high-dose TSPJ group increased compared with that in the model group （P<0.01）. ③ Compared with the normal group， the model group showed increased adipocyte diameter in iWAT and BAT and decreased number of adipocytes per unit area. Compared with the model group， the TSPJ groups showed significantly reduced cell diameter and increased number of cells per unit area， especially in the high-dose TSPJ group. ④ Compared with the normal group， the model group showed decreased mRNA expression of FABP4， UCP1， CytC， PRDM16， ELOVL3， PGC-1α， and PPARγ in adipose tissues of mice （P<0.05， P<0.01）. Compared with the model group， after intervention with TSPJ， the mRNA expression was significantly up-regulated （P<0.05， P<0.01）. ⑤ Compared with the normal group， the model group showed decreased protein expression of UCP1， PRDM16， PPARγ， and PGC-1α in adipose tissues of mice （P<0.05， P<0.01）. Compared with the model group， after intervention with TSPJ， the protein expression increased significantly （P<0.05， P<0.01）. ConclusionTSPJ could induce the browning of iWAT/BAT activation and enhance adaptive thermogenesis in obese mice induced by HFD. The underlying mechanism may be attributed to the activation of the PPARγ/PGC-1α signaling pathway.
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ObjectiveTo observe the effect of salvianolate on the protein expressions of adenosine monophosphate （AMP）-activated protein kinase （AMPK）， silent information regulator 1 （SIRT1） and peroxisome proliferator-activated receptor-γ coactivator-1α （PGC-1α）， autophagy and apoptosis in kidney tissue of rats with membranous nephropathy （MN）， and to explore its possible molecular mechanism against MN. MethodEighty male SD rats were randomly divided into normal group， model group， benazepril hydrochloride group （10 mg·kg-1）， and salvianolate low-， medium-， and high-dose groups （16.7， 33.3 and 66.7 mg·kg-1）. The rats were modeled by injection of cationized bovine serum albumin （C-BSA） into the tail vein. After successful modeling， rats in the administration groups were given corresponding doses of drugs for 4 consecutive weeks， and then 24-hour urine， serum and kidney tissue were collected for the detection of 24-hour urinary protein （UTP）， blood urea nitrogen （BUN）， serum creatinine （SCr）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， C reactive protein （CRP）， glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， and malondialdehyde （MDA）. The pathological changes of kidneys were observed by light microscope， electron microscope and immunofluorescence. Western blot was used to detect the protein expressions of phospho-AMPK （p-AMPK）， AMPK， phospho-SIRT1 （p-SIRT1）， SIRT1 and PGC-1α in rat kidney tissue. The protein expressions of autophagy-specific gene （Beclin-1）， microtubule-associated protein 1 light chain 3 （LC3） Ⅱ， ubiquitin-binding protein （p62）， B cell lymphoma （Bcl-2）， Bcl-2-associated X （Bax）， and cysteine aspartic protease-7 （Caspase-7） in rat kidney tissue were determined by immunohistochemistry （IHC）. ResultCompared with the conditions in the normal group， the levels of UTP， IL-6， TNF-α， CRP and MDA in the model group were increased （P<0.05） while the levels of SOD and GSH-Px were decreased （P<0.05）， and there was no difference in BUN and SCr. Compared with the model group， the administration groups had lowered UTP， IL-6， TNF-α， CRP and MDA （P<0.05） while elevated SOD and GSH-Px （P<0.05）. It could be seen from hematoxylin and eosin （HE） staining， Masson staining， immunofluorescence and electron microscopy that the pathological damage of rat kidney tissue in the model group was significant， but after treatment with benazepril hydrochloride and salvianolate， the pathological damage of kidney cells was gradually improved. The expressions of p-AMPK/AMPK， p-SIRT1/SIRT1， PGC-1α， Bcl-2， Beclin-1 and LC3Ⅱ in rat kidney in the model group were lower than those in the normal group （P<0.05） while the expressions of Bax， Caspase-7 and p62 were higher （P<0.05）. Compared with the model group， benazepril hydrochloride group and salvianolate groups had an up-regulation in the expressions of p-AMPK/AMPK， p-SIRT1/SIRT1， PGC-1α， Bcl-2， Beclin-1 and LC3Ⅱ in the kidney （P<0.05） while a down-regulation in the expressions of Bax， Caspase-7 and p62 （P<0.05）. ConclusionThe protective effect of salvianolate on the kidneys of MN rats may be related to the activation of AMPK/SIRT1/PGC-1α signaling pathway， the up-regulation of autophagy and the reduction of apoptosis.
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ObjectiveTo reveal the effect of Wenxin prescription on mitochondrial energy metabolism and silent information regulator 1 （SIRT1）/peroxisome proliferator-activated receptor-γ coactivator-1α （PGC-1α）/recombinant estrogen-related receptor α （ERRα） signaling pathway in rats with myocardial ischemia-reperfusion injury. MethodTotally 90 male Wistar rats of SPF grade were randomly assigned into a sham operation group， a model group， and low-， medium-， and high-dose Wenxin prescription groups， with 18 rats in each group. The rats in low-， medium-， and high-dose Wenxin prescription groups were administrated with 0.99， 1.98， and 3.96 g·kg-1 granules by gavage， respectively， and those in the sham operation group and model group with the same amount of normal saline. Twenty-one days after pre-administration， the rat model of myocardial ischemia-reperfusion injury was established by ligation of the left anterior descending coronary artery for 30 min and reperfusion for 2 h， and the rats in the sham operation group were only threaded without ligation. Myocardial infarction area was observed through 2，3，5-triphenyl-2h-tetrazolium chloride （TTC） staining， and the myocardial histopathology through hematoxylin-eosin （HE） staining. The levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH） in serum， cytochrome C oxidase （CCO） and succinate dehydrogenase （SDH） in mitochondrion， and ATP in myocardial tissue were detected according to kit instructions. The mRNA and protein levels of SIRT1， PGC-1α， ERRα， and mitochondrial transcription factor A （TFAM） in myocardial tissue were determined by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the sham operation group， the model group showed broken and disordered myocardial fibers， cytoplasmic edema， and pyknosis and deviation of nuclei. Moreover， the modeling increased the levels of CK-MB and LDH （P<0.05， P<0.01）， lowered the levels of ATP， CCO， and SDH （P<0.05， P<0.01）， and down-regulated the mRNA and protein levels of SIRT1， PGC-1α， ERRα， and TFAM in myocardial tissue （P<0.05， P<0.01）. Compared with the model group， Wenxin prescription reduced the myocardial infarction area （especially in the high-dose group， P<0.01）， restored the pathological changes， lowered the levels of CK-MB and LDH （P<0.05， P<0.01）， increased the levels of ATP， CCO， and SDH （especially in the high-dose group， P<0.01）， and up-regulated the mRNA and protein levels of SIRT1， PGC-1α， ERRα， and TFAM in myocardial tissue （P<0.05， P<0.01）. ConclusionWenxin prescription can protect rats from myocardial ischemia-reperfusion injury by regulating myocardial mitochondrial energy metabolism via the SIRT1/PGC-1α/ERRα signaling pathway.
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OBJECTIVES@#To investigate the effect of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) on liver injury induced by periodontitis in rats.@*METHODS@#Twenty-four male Wistar rats were randomly divided into two groups: control group and periodontitis group, twelve per group. In periodontitis group, the periodontitis models were established for the maxillary first molars in rats by means of "wire ligation+vaccinationwith @*RESULTS@#The probing depth, tooth mobility and sulcus bleeding index in periodontitis group were significantly higher than that in control group. HE staining showed in periodontitis group, hepatic cords ranged disorderly and there were vacuoles in cells and inflammatory cells infiltrated in liver tissues of rats, and there was no obvious abnormality in control group. The qRT-PCR results showed that the mRNA expression levels of @*CONCLUSIONS@#PGC-1α may be involved in the process of periodontitis-induced liver injury in rats.
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Animals , Male , Rats , Liver/injuries , PPAR gamma , Periodontitis/pathology , Rats, WistarABSTRACT
OBJECTIVE@#To investigate the cardioprotective effect of Danqi Tablet (DQT, ) on ischemic heart model rats and the regulative effect on energy metabolism through peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).@*METHODS@#Rat ischemic heart model was induced by ligation of left anterior descending coronary artery. Totally 40 Sprague-Dawley rats were randomly divided into sham group, model group, DQT group (1.5 mg/kg daily) and trimetazidine (TMZ) group (6.3 mg/kg daily) according to a random number table, 10 rats in each group. Twenty-eight days after continuous administration, cardiac function was assessed by echocardiography and the structures of myocardial cells were observed by hematoxylin-eosin staining. The level of adenosine triphosphate (ATP) in myocardial cells was measured by ATP assay kit. Expressions level of key transcriptional regulators, including PGC-1α, Sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and downstream targets of PGC-1α, such as mitofusin 1 (MFN1), mitofusin 2 (MFN2) and superoxide dismutase 2 (SOD2) were measured by Western blot. Expression level of PGC-1α was examined by immunohistochemical staining.@*RESULTS@#The rat ischemic heart model was successfully induced and the heart function in model group was compromised. Compared with the model group, DQT exerted cardioprotective effects, up-regulated the ATP production in myocardial cells and inhibited the infiltration of inflammatory cells in the margin area of infarction of the myocardial tissues (P<0.01). The expressions of PGC-1α, SIRT1 and AMPK were increased in the DQT group (all P<0.05). Furthermore, the downstream targets, including MFN1, MFN2 and SOD2 were up-regulated (P<0.05 or P<0.01). Compared with the TMZ group, the expression levels of PGC-1α, MFN1 and SOD2 were increased by DQT treatment (P<0.05 or P<0.01).@*CONCLUSION@#DQT regulated energy metabolism in rats with ischemic heart model through AMPK/SIRT1 -PGC-1α pathway. PGC-1α might serve as a promising target in the treatment of ischemic heart disease.
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OBJECTIVE@#This research is to investigate the antihyperglycaemic activity and the underlying mechanisms of action of the ethylacetate extract of Chlorophytum alismifolium (EACA) tubers in a type 2 diabetes model.@*METHODS@#The tubers were processed and sequentially extracted in hexane followed by ethylacetate, using a Soxhlet apparatus, and subjected to gas chromatography-mass spectrometry (GC-MS). The acute toxicity of EACA was investigated in albino Wistar rats. An antihyperglycaemic study was carried out using high-fat diet (pelletized diet and margarine in the ratio of 10:1 and 20% fructose solution) and streptozotocin-induced hyperglycaemic Wistar rats. The effects of the extract (150, 300 and 600 mg/kg) on blood glucose level, insulin, peroxisome proliferator-activated receptor-γ (PPAR-γ) and dipeptidyl peptidase-4 (DPP-4) were evaluated using enzyme-linked immunosorbent assay.@*RESULTS@#The oral median lethal dose in Wistar rats was estimated to be > 5000 mg/kg. Treatment with EACA at all doses significantly reduced the fasting blood glucose levels, compared to the hyperglycaemic control, and over time. Administration of EACA increased the serum insulin and PPAR-γ levels while decreasing DPP-4 levels. GC-MS analysis revealed the presence of 13 compounds, with isothiazole and isoxazolidine covering total area of 24.6% and 22.69%, respectively.@*CONCLUSION@#The findings from this study showed that EACA has important compounds with beneficial effect in type 2 diabetes and acts by increasing insulin secretion and PPAR-γ level and decreasing DPP-4 activity.
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Objective? To?investigate?the?effect?of?histone?methyltransferase?(EZH2)?inhibitor?on?the?polarization??of?peritoneal?macrophages?in?septic?mice.? Methods? Thirty-six?healthy?male?C57BL/6J?mice?were?divided?into?three?groups?by?random?number?table?method?(n?=?12):?sham?operated?group?(Sham?group),?sepsis?model?group?(CLP?group)??and?EZH2?inhibitor?treatment?group?(CLP+3-DZNeP?group).?Sepsis?animal?model?was?established?by?cecum?ligation?and?puncture?(CLP);?Sham?group?was?challenged?only?by?cecum?traction?without?ligation.?3-Deazaneplanocin?A?(3-DZNeP)?1?mg/kg?was?intraperitoneal?injected?24?hours?before?and?1?hour?after?CLP?in?CLP+3-DZNeP?group.?Eight?mice?in?each?group?were?sacrificed?at?24?hours?after?surgery.?The?levels?of?proinflammatory?cytokines?interleukin-6??(IL-6)?and?tumor?necrosis?factor-α(TNF-α)?in?peritoneal?lavatory?fluid?were?detected?by?high?throughput?liquid?protein?chip.?The?expression?levels?of?inducible?nitrogenase?(iNOS)?and?macrophage?mannose?receptor?(CD206)?were?analyzed?by?flow?cytometry.?Mouse?peritoneal?macrophages?were?isolated?and?purified?by?adherent?method,?the?protein?expressions?of?EZH2,?peroxisome?proliferator-activated?receptorγ(PPARγ)?were?detected?by?Western?Blot.?The?remaining?4?mice?? were?sacrificed?at?48?hours?after?surgery,?the?histopathological?changes?of?lung?and?kidney?tissue?were?evaluated?by?hematoxylin-eosin?(HE)?staining.? Results? Compared?with?Sham?group,?the?infiltration?of?inflammatory?cells?in?lung?and?kidney?of?the?CLP?group,?the?levels?of?IL-6?and?TNF-α?in?peritoneal?lavatory?fluid?were?significant?increased??[IL-6?(ng/L):?7?794.75±405.56?vs.?78.63±74.09,?TNF-α(ng/L):?147.25±25.19?vs.?18.20±5.03,?both?P?<?0.01],?the?percentage?of?M1?type?macrophages?was?significantly?increased?[iNOS+?F4/80+:?(13.18±8.80)%?vs.?(1.57±0.77)%,?P?<?0.05],?and?the?protein?expression?of?EZH2?was?significantly?increased?(EZH2/GAPDH:?0.84±0.11?vs.?0.11±0.03,?P?<?0.01),?while?the?protein?expression?of?PPARγ?was?significantly?decreased?(PPARγ/GAPDH:?0.09±0.01?vs.?0.27±0.09,?P?<?0.01).?Compared?with?CLP?group,?the?histopathological?changes?of?lung?and?kidney?in?CLP+3-DZNeP?group?were?significantly?alleviated,?the?levels?of?IL-6?and?TNF-α?in?peritoneal?lavatory?fluid?were?significantly?decreased?[IL-6?(ng/L):?4?207.10±876.60?vs.?7?794.75±405.56,?TNF-α(ng/L):?63.00±25.37?vs.?147.25±25.19,?both?P <?0.01?],?the?percentage?of?M1?type?macrophages?was?significantly?decreased?[iNOS+?F4/80+:?(3.64±0.89)%?vs.?(13.18±8.80)%,??P?<?0.05],?while?the?percentage?of?M2?type?macrophages?was?significantly?increased?[CD206+?F4/80+:?(17.68±5.63)%?vs.?(7.60±3.17)%,?P?<?0.01],?the?protein?expression?of?EZH2?was?significantly?decreased?(EZH2/GAPDH:?0.53±0.09?vs.?0.84±0.11,?P?<?0.05),?and?the?protein?expression?of?PPARγ?was?significantly?increased?(PPARγ/GAPDH:?0.39±0.14?vs.?0.09±0.01,?P?<?0.05).? Conclusions? Sepsis?induces?high?expression?of?EZH2?in?peritoneal?macrophages,?and?may?induce?polarization?of?M1?type?macrophages?by?inhibiting?the?expression?of?PPARγ?protein.?EZH2?inhibitor?3-DZNeP?can?lessen?the?inflammatory?cytokines?release?by?inhibiting?the?M1?type?macrophages?polarization.
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OBJECTIVE： To investigate the effects of total flavonoids from Psidium guajava leaves （GLTF） on the related factors for estrogen-associated receptor γ（ERRγ）/cyclic adenosine monophosphate responsive element binding protein H（CREBH）pathway in liver of type 2 diabetes mellitus（T2DM）model mice， and to investigate the specific mechanism of its hypoglycemic effect. METHODS： Healthy male ICR mice were collected. T2DM models were established by high-sugar and high-fat diet feeding combined with repeated intraperitoneal injection of low dose streptozotocin. According to the blood glucose value， model mice were randomly divided into model group， metformin group（positive control， 0.17 g/kg），Xiaoke jiangtang capsule group（positive control， 0.75 g/kg），GLTF low-dose and high-dose groups（0.047， 0.094 g/kg）， with 12 mice in each group. Another 12 normal mice were included in normal group. Except that normal group and model group were given constant volume of water intragastrically， other groups were given relevant solution 10 mL/kg intragastrically， qd， for consecutive 21 d. After administration， fasting blood glucose and serum insulin levels of mice were measured and insulin sensitivity index （ISI） was calculated. Histopathological changes of liver and pancreas were observed by HE staining. The protein expressions of ERRγ and CREBH in liver tissues were detected by immunoblotting. The mRNA expression of peroxisome proliferator-activated receptor-γ coactivator-1α（PGC1α）and CREB protein co-activator 2（TORC2）in liver tissue of mice were measured by RT-PCR. RESULTS： Compared with normal group， the levels of fasting blood glucose and serum insulin in T2DM mice were significantly increased in model group， while ISI was decreased significantly （P＜0.01）. The pathological changes of liver tissue were obvious and a large number of vacuoles could be seen. The number and volume of islets in pancreatic tissue decreased， and islet cells showed mild vacuolar lesions. The protein expression of ERRγ and CREBH， mRNA expression of PGC1α and TORC2 in liver tissue were increased significantly （P＜0.01）. Compared with model group， above blood glucose， insulin indexes and pathological changes were improved significantly in GLTF groups. Protein expression of ERRγ and CREBH， mRNA expression of PGC1α and TORC2 in liver tissue were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： GLTF showed obvious hypoglycemic effect on T2DM model mice； its mechanism might be related to inhibiting ERRγ/CREBH signaling pathway.
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OBJECTIVE: To observe the impact of electroacupuncture (EA) on liver lipid metabolism and expression of hepatic sirtuin 1(Sirt1) and peroxisome proliferator activated receptor γ(PPARγ) of abdominal obese rats induced by high-fat diet. METHODS: Eighteen male SD rats were divided into blank control, model and EA groups (n＝6 per group). The abdominal obesity model was established by feeding the rats with high-fat diet for 12 weeks. EA (2 Hz/15 Hz, 1.5 mA) was applied to bilateral "Daimai"(GB26) for 20 min every time, once every other day for 8 weeks. Rats of the model group were also restrained for 20 min. The body mass and abdominal circumference were measured every week, and the contents of serum cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), aspartate aminotransferase (AST) were detected by using an automated biochemical analyzer. Histopathological changes of the liver tissues were observed under microscope after oil red "O" staining. The expression of hepatic Sirt1 and PPARγ mRNAs and proteins were detected using quantitative real time PCR and Western blot, separately. RESULTS: After modeling, the body weight and abdominal circumference, and serum TC, TG, ALT and AST contents, and expression of hepatic PPARγ mRNA and protein were significantly increased (P<0.001, P<0.01, P<0.05), and the expression levels of hepatic Sirt1 mRNA and protein obviously down-regulated (P<0.05, P<0.01) in the model group. Following EA intervention, the increased body weight and abdominal circumference, and serum TC, TG, ALT and AST contents, and hepatic PPARγ mRNA and protein expression were remarkably suppressed (P<0.05, P<0.01), and the decreased hepatic Sirt1 mRNA and protein were remarkably up-regulated (P<0.001，P<0.05). The lipid droplets in hepatocytes were reduced in the EA group relevant to the model group. CONCLUSION: EA intervention can significantly improve the liver lipid metabolism of abdominal obese rats, which is possibly related with its effect in up-regulating the expression of hepatic Sirt1 mRNA and protein, and in down-regulating the expression of hepatic PPARγ mRNA and protein.
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OBJECTIVE:To screen the agonist active ingredients of peroxisome proliferator-activated receptor-γ (PPAR-γ) in flavonoids from Artemisia ordosica,and provide reference for finding antidiabetic agents in A.ordosica.METHODS:Using known PPAR-γagonist rosiglitazone as positive control,molecular docking technology was conducted for docking one by one for 18 flavonoids and PPAR-7 targets obtained from A.ordosica.It was compared with binding affinities and binding modes of compounds and PPAR-7 targets,and the possible PPAR-γ agonist ingredients in A.ordosica were screened.RESULTS:5 flavonoids showed good docking affinities,in which,compound 3 (5,3',4'-trihydroxy-7-methoxyflavone) showed the highest (-8.3 kcal/mol).Docking mode analysis showed that the phenol oxygen on ring A and ring B of the flavonoids with LBD active site of PPAR-γ formed one (Tyr327) or two hydrogen bonding (Tyr327,Arg288),which played an important role in the binding of flavonoids and PPAR-γ and the stability of PPAR-γ conformation.CONCLUSIONS:Results of virtual screening in molecular docking technology indicate that flavonoids (mostly containing multiple free phenolic hydroxyl groups) in can easily form good docking mode and high affinity with PPAR-γ,showing potential antidiabetic activity.The study can provide reference for further research of chemical ingredients for the treatment of type 2 diabetes.
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Objective Recent studies have shown that inflammatory cytokines are involved in the occurrence and development of diabetes mellitus .The article aimed to investigate the effects of anti-inflammatory drug--diacerein on hepatic PPAR-γand GLUT-2 protein expression and its role in the regulation of glucose and lipid metabolism in rats with type 2 diabetes mellitus ( T2DM) . Methods 55 male SD rats were randomly divided into 4 groups:normal control group (n=10), T2DM group (n=15), pioglitazone intervention group(n=15), and diacerein treatment group(n=15) .Rats in normal control group were fed with normal diet , the other 3 groups were fed with high fat diet .At the end of 8th experi-ment week, rats in 3 groups fed with high fat diet were treated with intraperitoneal injection of 30mg/kg streptozotocin ( STZ) solution, while rats in normal control group were injected with the same volume of sterile sodium citrate solution .At the end of 10th week, OGTT modeling rats were screened .Rats in pioglitazone intervention group were treated with 10 mg/kg pioglitazone by intragastric administra-tion, rats in diacerein group was treated with 50mg/kg diacerein by intragastric administration , and rats in normal control group and T2DM group were given the same volume of normal saline .The intervention lasted 4 weeks.At the end of 8th, 10th and 14th week, the blood examination of glycolipid , FINS, IL-1βand liver function indexes was done on fasting rats .Fourteenth weeks later , after getting blood samples , all rats were sacrificed and liver tissues were isolated .Western blot was applied in the detection of PPAR γand immu-nohistochemistry was applied to detect GLUT-2 protein in livers. Results At the end of 8th week, the FBG level in pioglitazone in-tervention group increased compared with normal control group ( P0 .05) show-ing higher levels compared with T 2DM group ( P<0.01).At 14th weekend, the GLUT-2 expression levels in normal control group (0.209±0.023), pioglitazone intervention group (0.226±0.017) and diacerein treatment group (0.232±0.012) were higher than that of T2DM group (0.173±0.009,P<0.01);and the GLUT-2 expression levels in pioglitazone intervention group and diacerein treatment group were higher than that of normal control group (P<0.05).The expression level of liver PPAR-γwas in positive correlation with those of GLUT-2 protein, HDL-C, FINS, ISI ( r=0.815, 0.780, 0.747, P<0.01) and in negative correlation with those of FBG , HbA1c, TC, TG, AST, ALT, IL-1β(r=-0.465,-5.716,-0.615,-0.675,-0.617,-0.521,-4.827, P<0.05). Conclusion Diacerein can enhance liver PPAR-γand GLUT-2 expression levels and reduce the levels of IL-1β, HbA1c and blood lipid, thus im-prove insulin resistance in T 2DM rats.
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AIM:To investigate the effect of gestational diabetes mellitus ( GDM) on glucose-lipid metabolism in the offspring mice and the underlying mechanisms .METHODS:Wild-type female mice were intraperitoneally injected with streptozotocin at 30 mg/kg in the second trimester of pregnancy to establish GDM model .Normal saline was used as control.F1 offspring mice were fed for 8 weeks after birth.The blood glucose and lipid levels were detected randomly .The mRNA levels of p300 and p300/CBP-associated factor ( PCAF) were detected by qPCR .The expression of peroxisome pro-liferator-activated receptor-γ( PPAR-γ) , glucose transporter typer 4 ( GLUT-4 ) and medium-chain acyl-CoA dehydroge-nase ( MCAD) at mRNA and protein levels was determined by qPCR and Western blot .ChIP-qPCR was employed to ana-lyze the binding status of p 300 with the promoter of PPAR-γand the acetylation level of histone H 3 in the promoter region of PPAR-γ.RESULTS:Blood glucose and total cholesterol levels were significant increased in the offspring mice ( P<0.05).The expression levels of p300, PPAR-γ, GLUT-4 and MCAD were decreased compared with the control group (P<0.05).Binding affinity of p300 with the promoter of PPAR-γwas reduced (P<0.05).The level of acetylated his-tone H3 in the promoter region of PPAR-γwas decreased significantly ( P<0.05) .CONCLUSION:Regulation of PPAR-γexpression by p300 may induce glucose-lipid metabolism disorder in the cardiomyocytes of GDM offspring mice .
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Objective To study the functions of peroxisome proliferator-activated receptorγ(PPARγ), retinoic acid X receptor α (RXRα) and cyclooxygenase 2 (COX-2) in the carcinogenesis of cervical squamous cell carcinoma (SCC). Methods The expressions of PPARγ, RXRα and COX-2 in 17 cases of normal cervical epithelium (NCE), 72 cases of squamous intraepithelial lesion (SIL) and 42 cases of cervical SCC were detected with immunohistochemical method respectively. Results The positive expression rates of PPARγ in the NCE, SIL and cervical SCC group were 23.5 % (4/17), 58.3 % (42/72) and 83.3 % (35/42) respectively; the positive expression rates of RXRα in the NCE, SIL and cervical SCC group were 29.4 %(5/17), 54.2 % (39/72) and 90.5 % (38/42) respectively. No significant expression of COX-2 was found in the NCE, while the positive expression rates of COX-2 in SIL and cervical SCC were 36.1 % (26/72) and 57.1 %(24/42) respectively. The positive expression rates of PPARγ, RXRαand COX-2 in high-grade SIL group were higher than those in low-grade SIL group (all P<0.05). In cervical SCC group, the positive expression rate of COX-2 with lymph node metastasis was higher than that without lymph node metastasis (χ2= 3.98, P= 0.04). Conclusion PPARγ, RXRαand COX-2 might be all involved in the carcinogenesis of SCC.
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Objective To study the functions of peroxisome proliferator-activated receptorγ(PPARγ), retinoic acid X receptor α (RXRα) and cyclooxygenase 2 (COX-2) in the carcinogenesis of cervical squamous cell carcinoma (SCC). Methods The expressions of PPARγ, RXRα and COX-2 in 17 cases of normal cervical epithelium (NCE), 72 cases of squamous intraepithelial lesion (SIL) and 42 cases of cervical SCC were detected with immunohistochemical method respectively. Results The positive expression rates of PPARγ in the NCE, SIL and cervical SCC group were 23.5 % (4/17), 58.3 % (42/72) and 83.3 % (35/42) respectively; the positive expression rates of RXRα in the NCE, SIL and cervical SCC group were 29.4 %(5/17), 54.2 % (39/72) and 90.5 % (38/42) respectively. No significant expression of COX-2 was found in the NCE, while the positive expression rates of COX-2 in SIL and cervical SCC were 36.1 % (26/72) and 57.1 %(24/42) respectively. The positive expression rates of PPARγ, RXRαand COX-2 in high-grade SIL group were higher than those in low-grade SIL group (all P<0.05). In cervical SCC group, the positive expression rate of COX-2 with lymph node metastasis was higher than that without lymph node metastasis (χ2= 3.98, P= 0.04). Conclusion PPARγ, RXRαand COX-2 might be all involved in the carcinogenesis of SCC.
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Peroxisome proliferator-activated receptor gamma (PPAR-γ),a member of the nuclear receptor superfamily,plays a great role in delaying or even preventing the occurrence and/or development of diabetic retinopathy (DR),a complicated out-of-control waterfall-like pathophysiological processes.DR is characterized by pathways,such as inflammatory reactions,the generation of advanced glycation end products,oxidative stress,protein kinase C and so on.As one of the most important metabolic homeostasis and adipocyte differentiation regulator,the single nucleotide polymorphism and molecular structure of PPAR-γ have been proven to impact on anti-inflammation,anti-neovascularization and fibration,antioxidation,insulin sensitizer and anti-apoptosis in DR.This review provided a summary of the function and mechanism researches on PPAR-γand offered new ideas of prevention and therapy in DR.
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AIM:To observe the effect of rosiglitazone (RGZ) pretreatment on the expression of peroxisome proliferator-activated receptor γ( PPARγ) , nuclear factor E2-related factor 2 ( Nrf2 ) and heme oxygenase-1 ( HO-1 ) in the microglia cells activated by thrombin.METHODS:Microglia cells were obtained from the brain tissues of the newborn rats and were primarily cultured in vitro.After cultured for 14 d, the microglia cells were used in the experiment.The iso-lated microglia cells were randomly divided into normal control group, thrombin stimulation group ( TH group) , rosiglita-zone intervention group ( RGZ +TH group ) and retinoic acid intervention group ( RA +TH group ) .The expression of PPARγ, Nrf2 and HO-1 was observed by immunocytochemistry, real-time PCR and Western blot.RESULTS:The number of positive staining cells of PPARγ, Nrf2 and HO-1 in TH group, RGZ+TH group and RA+TH group were increased re-markably as compared with control group.The significant increases in PPARγ, Nrf2 and HO-1 were observed in RGZ+TH group compared with other groups.The mRNA expression of PPARγ, Nrf2 and HO-1 in RGZ+TH group was increased significantly as compared with TH group, control group or RA+TH group (P<0.01), Besides, the mRNA expression of Nrf2 and HO-1 in RA+TH group was decreased as compared with TH group or RGZ+TH group (P<0.01).The protein levels of PPARγ, Nrf2 and HO-1 in RGZ+TH group were significantly increased as compared with TH group, control group or RA+TH group (P<0.01).The protein expression of Nrf2 and HO-1 in RA+TH group was decreased as com-pared with TH group or RGZ+TH group (P<0.01).CONCLUSION:Rosiglitazone pretreatment might increase the ex-pression of PPARγ, Nrf2 and HO-1 in the microglia cells activated by thrombin.By inhibiting the expression of Nrf2 after RA pretreatment, the expression of the downstream gene HO-1 is also influenced.The anti-oxidative stress effects of rosigli-tazone might be achieved partly by modulating Nrf2 to control the downstream gene HO-1.
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Objective To investigate the dual pharmacology characteristics of a new structural telmisartan derivative Tek- 1 based on angiotensin II (ANGII) receptor I (AT1) and peroxisome proliferator-activated receptor-γ (PPARγ) and the influence of Tek- 1 on blood pressure in spontaneously hypertensive rats (SHR). Methods The AT1 receptor affinity of Tek- 1 was explored through radioligand binding assay on rat primary vascular smooth muscle cells; the PPARγ agonistic activity of Tek-1 was explored using PPARγ-responsive element-luciferase report assay; the antagonistic effect of Tek-1 on AT1receptor activation induced by ANGII was explored using intracellular calcium mobilization detection assay; the effect of Tek-1 on the regulation of systolic blood pressure (SBP) was evaluated in SHR in vivo. Results Tek-1 and telmisartan had high affinity to AT1 receptor, their Ki values for AT1 receptor were 1.1×10-9 and 2.3×10-10mol/L, respectively. Tek-1 and telmisartan could activate PPARγ ranging from 0.1 to 10 μmol/L in a concentration-dependent manner. The relative lucifarase activity induced by Tek-1 and telmisartan were 1.56±0.08 and 1.39±0.14 fold at 10 μmol/L. Compared with solvent group, the effect of AT1 agonist ANGII were inhibited by Tek-1 in a concentration-dependent manner with IC50 value of 1.02±0.1 nmol/L ranging from 0.0128 to 1 μmol/L. SHR were randomly administered telmisartan (5 or 10 mg/kg) and Tek-1 (1 mg/kg, 5 mg/kg or 10 mg/kg) orally each day for one week every day. After 1-week treatment, compared with the baseline SBP and DBP in the pretreatment of SHR, telmisartan in the dose of 5 and 10 mg/kg both showed significantly decreased SBP (P < 0.01) and DBP (P < 0.05). Tek-1 in the dose of 1, 5 and 10 mg/kg also significantly decreased SBP (P < 0.05); however, only the high dose of 10 mg/kg Tek-1 showed a significant decrease in DBP (P < 0.05). Conclusion Tek-1 Behaveds as an ATI blocker with partial PPARγ agonist activity in vitro and attenuates the blood pressure in SHR in vivo.
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Objective To investigate the effect of PGC-1 on hepatic glucose metabolism of type 2 diabetes by observing its changes in the liver of OLETF rats. Methods OLETF rats were observed,even-aged LETO rats were controled. Oral glucose tolerance test, Fasting Insulin, triglyceride and total cholesterol were measured and then the protein level of PGC-1 , phosphoenolpyruvate earboxykinase and uncoupling protein 2 of liver tissue were detected by Western blot respectively in 8,18 and 28 weeks. Results (1)OLETF rats had significantly higher levels than LETO rats, in body weight, OGTT2h blood glucose and TG at 18th, 28th week. The levels of Fasting Insulin of OLETF rats were higher while insulin sensitive index were lower than that of LETO rats at 28th week. (2)Protein expressions in the livers: PGC-1 of OLETF rats was lower than that of LETO rats at 18th and 28th week. PEPCK of OLETF rats was more while UCP2 was lower than that of LETO rats at 28th week. Conclusions OLETF rats showed pathological phenotypes of type 2 diabetes. The changes of PGC-1 , PEPCK and UCP2 in 28-weeks OLETF rat suggested that PGC-1 plays an important role in the liver glycometabolism in type 2 diabetes.
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Alzheimer's disease (AD) is a neurodegenerative disorder and its reported pathophysiological features in the brain include the deposition of amyloid beta peptide, chronic inflammation, and cognitive impairment. The incidence of AD is increasing worldwide and researchers have studied various aspects of AD pathophysiology in order to improve our understanding of the disease. Thus far, the onset mechanisms and means of preventing AD are completely unknown. Peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) is a protein related to various cellular mechanisms that lead to the alteration of downstream gene regulation. It has been reported that PGC-1α could protect cells against oxidative stress and reduce mitochondrial dysfunction. Moreover, it has been demonstrated to have a regulatory role in inflammatory signaling and insulin sensitivity related to cognitive function. Here, we present further evidence of the involvement of PGC-1α in AD pathogenesis. Clarifying the relationship between PGC-1α and AD pathology might highlight PGC-1α as a possible target for therapeutic intervention in AD.
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Alzheimer Disease , Amyloid beta-Peptides , Brain , Incidence , Inflammation , Insulin Resistance , Neurodegenerative Diseases , Oxidative Stress , Pathology , PeroxisomesABSTRACT
Endurance exercise training such as marathon can increase the ability of exercise performance. Muscle glycogen is associated with an exercise performance, because glycogen depletion is primary causes of muscle fatigue. This review summarizes the glycogen saving effect according to duration of endurance exercise training. Long-term endurance exercise-induced mitochondrial biogenesis contributes to glycogen saving effect that is reduced glycogen breakdown and lactate accumulation. Glycogen sparing is due to a smaller decrease in adenosine triphosphate and phosphocreatine and a smaller increase in inorganic phosphate in the working muscles. It takes required endurance exercise training for about 4 weeks or more. Single bout or short-term endurance exercise is not sufficient to bring an increase in functional mitochondria. But peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) increases rapidly after single bout of endurance exercise. PGC-1α downregulates glycogenolytic and glycolytic enzymes to reduce muscle glycogen breakdown and lactic acid accumulation after short-term endurance exercise.