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Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear estrogen receptor family, and they are involved in a variety of physiological and pathological processes in the human body and play important roles in cellular metabolism, inflammation, and cancer. At present, there are three known subtypes of PPAR, i.e., α, β/δ, and γ. Studies have shown that PPARs are highly expressed in the liver and are widely involved in various physiological and pathological activities such as liver energy metabolism, oxidative stress, and inflammation, and they are also closely associated with the progression of liver diseases. This article reviews the role of PPAR in common liver diseases such as viral hepatitis, metabolic associated fatty liver disease, cholestatic liver disease, liver fibrosis, and primary liver cancer, and the current status of their application in the treatment of liver diseases.
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Peroxisome proliferator-activated receptors (PPARs) are widely involved in lipid metabolism, glucose metabolism, cell growth and differentiation, and inflammation in the human body. PPARγ agonists can inhibit skin inflammatory response, protect epidermal barrier function, and repair skin injury. This review summarizes various roles of PPARγ in skin biology, and discusses its function in skin diseases, such as psoriasis and skin tumors.
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Objective:To explore the role of SUMOylaiton of peroxisome proliferator-activated receptor γ (PPARγ) in diabetes mellitus prompted inflammation and atherosclerosis in vascular and endothelial cells.Methods:From September 2014 to January 2017, 32 Sprague-Dawley rats in 14 weeks-old were divided into sham operated group, artery injured without diabetes group, artery injured with diabetes group and ubiquitin-conjugating enzyme 9 (UBC9) transfection group (Group D) by random digits table method with 8 rats each. Model of type 1 diabetes mellitus (T1DM) and rat carotid artery balloon injury was made in the assigned group. One rat was excluded because of model failure in each group. Systolic and diastolic common carotid artery diameter and intimal thickness of injured and healthy common carotid artery were evaluated by vascular ultrasound, and the standardized common carotid artery diastolic diameter (sCADD) was calculated. Histological tests and immunohistochemical staining were performed to evaluate intimal hyperplasia, and the ratio of intimal area to media area was calculated when the media area was equal. Human umbilical vein endothelial cells (HUVEC) were cultured 24 h in high glucose medium with different duration and concentration, and the expression levels of interleukin (IL)-8 and IL-1β mRNA were determined by real time reverse transcription polymerase chain reaction (RT-PCR), the expression level of UBC9 was determined by Western blot method, SUMOylation assay kit was used to evaluate SUMOylation of PPARγ. HUVEC was cultured in vitro and PPAR was stimulated by high glucose at different concentrations and different times PPARγ SUMOylation level. UBC9 was overexpressed by lentivirus in vivo and in vitro, and the PPARγ SUMOylation level was detected.Results:The intimal thickness, intimal area and ratio of intimal area to media area 8 weeks after carotid artery injuring in sham operated group, artery injured without diabetes group and artery injured with diabetes group were increased respectively: (0.026 ± 0.018), (0.084 ± 0.007) and (0.264 ± 0.022) mm; (0.18 ± 0.09) × 10 6, (0.32 ± 0.06) × 10 6 and (1.64 ± 0.22)×10 6 μm 2; 0.345 ± 0.073, 0.570 ± 0.080 and 2.710 ± 0.220, the sCADD was decreased respectively: 0.903 ± 0.084, 0.800 ± 0.071 and 0.330 ± 0.036, and there were statistical differences ( F = 10.40, 9.40, 8.20 and 8.60; P<0.05). After HUVEC was cultured in high glucose for 24 h, the IL-8 mRNA at sugar concentrations of 10, 20 and 40 mmol/L was 1.00 ± 0.11, 3.57 ± 0.22 and 4.07 ± 0.40, the IL-1β mRNA was 1.00 ± 0.07, 3.32 ± 0.29 and 5.13 ± 0.19, and there were statistical differences ( F = 73.05 and 205.80, P<0.05). The level of PPARγ SUMOylation and UBC9 in artery injured with diabetes group were significantly lower than those in artery injured without diabetes group (0.46 ± 0.25 vs. 1.00 ± 0.21 and 0.45 ± 0.02 vs. 1.00 ± 0.07), and there were statistical differences ( P<0.05); there was no statistical difference in PPARγ between 2 groups (0.94 ± 0.07 vs. 1.00 ± 0.04, P>0.05). The UBC9 and PPARγ SUMOylation at sugar concentrations of 0, 10, 20 and 40 mmol/L were decreased respectively (0.99 ± 0.05, 0.80 ± 0.06 and 0.62 ± 0.05; 1.00 ± 0.05, 0.57 ± 0.13 and 0.55 ± 0.08), and there were statistical differences ( F = 21.02 and 14.31, P<0.05); there was no statistical difference in PPARγ (1.00 ± 0.03, 0.90 ± 0.04 and 0.91 ± 0.05; F = 3.11, P>0.05). In HUVEC cultured in high glucose medium (20 mmol/L) for 6, 12, 24 and 48 h, the UBC9 and PPARγ SUMOylation were downregulated progressively (1.00 ± 0.09, 0.75 ± 0.05, 0.70 ± 0.08, 0.38 ± 0.04 and 0.35 ± 0.03; 1.00 ± 0.03, 0.86 ± 0.01, 0.59 ± 0.01, 0.51 ± 0.11 and 0.35 ± 0.08), and there were statistical differences ( F = 36.06 and 33.13, P<0.05); but there was no statistical difference in PPARγ (1.00 ± 0.03, 1.14 ± 0.02, 1.18 ± 0.17, 0.98 ± 0.01 and 1.04 ± 0.05; F = 1.90, P>0.05). After overexpression of UBC9 in rats with diabetes, histological analysis showed that UBC9 in artery injured without diabetes group, artery injured with diabetes group and UBC9 transfection group was 1.53 ± 0.18, 1.00 ± 0.22 and 3.62 ± 0.35, there was statistical difference ( F = 5.64, P<0.05). Ultrasonic test results show that in artery injured without diabetes group, artery injured with diabetes group and UBC9 transfection group intimal thickness was increased respectively: (0.077 ± 0.015), (0.216 ± 0.007) and (0.125 ± 0.014) mm, and there was statistical difference ( F = 27.18, P<0.05). Histological analysis showed that intimal area in artery injured without diabetes group, artery injured with diabetes group and UBC9 transfection group was (0.335 ± 0.066) ×10 6, (1.053 ± 0.103) ×10 6 and (0.544 ± 0.040) ×10 6 μm 2, the ratio of intimal area to media area was 0.63 ± 0.063, 2.03 ± 0.052 and 0.93 ± 0.100, there were statistical differences ( F = 13.58 and 53.96, P<0.05). Conclusions:Diabetes mellitus could inhibit the PPARγ SUMOylaiton and prompt inflammation and atherosclerosis in vascular and endothelial cells. Upregulation of PPARγ SUMOylaiton though UBC9 overexpressioncould play a protecting role in diabetes mellitus prompted atherosclerosis.
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Objective:To evaluate the role of peroxidase proliferator-activated receptor γ (PPARγ)/nuclear factor kappa B (NF-κB) signaling pathway in sodium butyrate-induced reduction of intestinal ischemia-reperfusion (I/R) injury in mice.Methods:Thirty-two SPF-grade healthy adult male C57BL/6J mice, aged 7-9 weeks, weighing 20-25 g, were divided into 4 groups ( n=8 each) using a random number table method: sham operation group (Sham group), intestinal I/R group (IIR group), sodium butyrate group (NaB group) and PPARγ inhibitor GW9662 group (GW9662 group). The model of intestinal I/R was established by occlusion of superior mesenteric artery for 45 min followed by 2-h reperfusion in anesthetized animals.GW9662 2 mg/kg was intraperitoneally injected at 1 h before ischemia in GW9662 group, and sodium butyrate 500 mg/kg was intraperitoneally injected at 30 min before ischemia in NaB and GW9662 groups.Blood samples were obtained via cardiac puncture at 2 h of reperfusion, and the animals were then sacrificed.The intestinal tissues were removed for determination of diamine oxidase (DAO), tumor necrosis factorα (TNF-α) and interleukins 6 (IL-6) concentrations in serum (by enzyme-linked immunosorbent assay) and the expression of PPAR and NF-κB p65 (by Western blot). The damage to intestinal mucous membrane was assessed and scored according to Chiu. Results:Compared with group Sham, the Chiu′s score was significantly increased, levels of DAO, TNF-α and IL-6 in serum and intestinal tissues were increased, expression of PPARγ was down-regulated, and expression of NF-κB p65 was up-regulated in group IIR ( P<0.05). Compared with group IIR, the Chiu′s score, levels of DAO, TNF-α and IL-6 in serum and intestinal tissues were decreased, and expression of PPARγ was up-regulated in group NaB, and expression of NF-κB p65 was up-regulated in NaB and GW9662 groups ( P<0.05). Compared with group NaB, the Chiu′s score, levels of DAO, TNF-α and IL-6 in serum and intestinal tissues were increased, and expression of PPARγ was down-regulated, and expression of NF-κB p65 was up-regulated in group GW9662 ( P<0.05). Conclusion:The mechanism by which sodium butyrate reduces intestinal I/R injury may be related to activating PPARγ/NF-κB signaling pathway and inhibiting inflammatory responses in mice.
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Nonalcoholic fatty liver disease (NAFLD) is the manifestation of metabolic syndrome in the liver and is closely associated with glucose and lipid metabolism disorders, and they interact as both cause and effect of each other, with insulin resistance as the common pathogenesis. About three quarters of patients with obesity and type 2 diabetes mellitus have NAFLD, and current guidelines recommend reducing metabolic risk factors and treating metabolic syndrome as the primary treatment goals for patients with NAFLD. Although there are no approved drugs for the treatment of NASH at present, the hypoglycemic drugs on the market can bring varying degrees of benefits to NAFLD patients while lowering blood glucose. This article reviews the prospects of three types of hypoglycemic drugs on the market (thiazolidinediones, GLP-1 receptor agonists, and SGLT-2 inhibitors) in the treatment of NAFLD.
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Aim of Study: This study is to investigate the effects of a novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist TZD18 on cell growth, apoptosis, caspase activity, mitochondrial membrane potential, cytochrome c release, and apoptotic-related protein expression in MKN-45 cells. Materials and Methods: 3-(4, 5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide assay against various human cancer cell lines was performed to investigate the whether TZD18 could in reduce the proliferation rates of cancer cells. The percentages of apoptotic cells and mitochondrial membrane potential level were determined by flow cytometry. The subcellular localization of cytochrome c was examined by immunofluorescence microscopy. Western blotting assay was performed to reveal the expression of apoptosis-related proteins. Results: The results showed that the administration of TZD18 could inhibit the growth of MKN-45 cells in a dose- and time-dependent manner. In addition, the apoptotic ratio increased sharply along with a significant increase of caspase activities, mitochondrial membrane potential, and cytochrome c release following TZD18 exposure. The expression of Bax and p27kip1 increased significantly, whereas the expression level of Bcl-2 protein was downregulated. Conclusion: These results indicated that the administration of PPAR α/γ agonist TZD18 may inhibit cell growth by inducing the apoptotic process in MKN-45 cells
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Liver fibrosis has a complex pathogenesis, and at present, the research mainly focuses on hepatic stellate cells (HSC). Many stimulating factors and regulatory pathways have been found to promote the activation of HSC. This article reviews the recent research findings on several major cytokines and peroxisome proliferator-activated receptor γ and research hotspots in recent years, including the association of microRNAs, long non-coding RNA, and exosomes with HSC activation. This article also introduces potential targets for the treatment of liver fibrosis and new markers for noninvasive diagnosis of liver diseases and proposes that chemical drugs or traditional Chinese medicine compounds which act on the targets of HSC activation can be formulated, in order to make a breakthrough in the therapeutics of liver fibrosis.
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Liver fibrosis has a complex pathogenesis, and at present, the research mainly focuses on hepatic stellate cells (HSC). Many stimulating factors and regulatory pathways have been found to promote the activation of HSC. This article reviews the recent research findings on several major cytokines and peroxisome proliferator-activated receptor γ and research hotspots in recent years, including the association of microRNAs, long non-coding RNA, and exosomes with HSC activation. This article also introduces potential targets for the treatment of liver fibrosis and new markers for noninvasive diagnosis of liver diseases and proposes that chemical drugs or traditional Chinese medicine compounds which act on the targets of HSC activation can be formulated, in order to make a breakthrough in the therapeutics of liver fibrosis.
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Objective To investigate the role of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) in high-fat diet-induced insulin resistance (IR) and mitochondrial degeneration in skeletal muscle.Methods Wistar rats were randomly divided into a normal chow (NC)group (n =10) and a high-fat diet(HFD)group (n =10).After eight weeks,fasting plasma glucose(FBG) levels,fasting insulin(FINS) levels and glucose infusion rates (GIR) in each group were measured (n=3).Samples of rat skeletal muscle were harvested.L6 myoblasts were divided into a control group,a PA group (cells were cultured in palmitic acid),a pcDNA3 group (cells were transfected by the plasmid pcDNA3)and a pcDNA3-PGC1α group (cells were transfected by the PGC1α-overexpressiorn plasmid).Expression levels of PGC1α,nuclear respiratory factor 1 (NRF1),uncoupling protein 3 (UCP3),and cytochrome C oxidase 1 (COX1) in skeletal muscle and L6 myoblasts were measured by real-time PCR and Western blotting.Results Levels of FBG and insulin were higher and those of GIR were lower in the HFD group than in the NC group,(6.0±0.7)mmol/L vs.(5.0±0.4)mmol/L、(23.3±3.0)mU/L vs.(12.9±1.8)mU/L、(14.2±1.8)％ vs.(22.6±2.4)％ (t =-3.578,-6.679,6.265,respectively,P ＜ 0.05).Expression levels of PGC1α,NRF1,UCP3,and COX1 were down in skeletal muscle in the HFD group compared with those in the NC group(P ＜0.05).In L6 myoblasts cultured with palmitic acid,the expression of PGC1 α,NRF1,UCP3,and COX1 were down compared with their expression in the NC group (P ＜ 0.05).However,the altered expression of PGC1α,NRF1,UCP3,and COX1 was reversed by transfecting with PGC1α-overexpression plasmids (F =30.079,96.883,226.772,respectively,P ＜ 0.001).Conclusions High-fat diets can lead to insulin resistance and decreased expression of mitochondrial energy metabolism-related genes,which can be reversed by PGC1α.The decreased expression of PGC1α may mediate the high-fat diet-induced mitochondrial dysfunction and IR.
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Objective@#To explore the regulatory mechanism of E2F1 transcription factor on M2 macrophages in full-thickness skin defect wounds of mice.@*Methods@#E2F1 gene knockout heterozygotes C57BL/6 mice and wild-type C57BL/6 mice were introduced and self-reproduced. Two weeks after birth, E2F1 gene knockout homozygotes mice and wild-type mice were identified by polymerase chain reaction (PCR). Twelve identified 6-8 weeks old male E2F1 gene knockout homozygotes C57BL/6 mice and wild-type C57BL/6 mice were selected respectively according to the random number table and set as E2F1 gene knockout group and wild-type group. A full-thickness skin defect wound was made on the back of each mouse. On post injury day (PID) 2 and 7, 6 mice in each group were selected according to the random number table and sacrificed, and the wound tissue was excised. The expression of CD68 and CD206 double positive M2 macrophages was observed by immunofluorescence method, and the percentage of CD206 positive cells was calculated. The protein expression of CD206 was detected by Western blotting. The mRNA expression of arginase 1 was detected by real-time fluorescent quantitative reverse transcription PCR (RT-PCR). Wound tissue specimens of the two groups on PID 7 were obtained, and the protein and mRNA expressions of peroxisome proliferator-activated receptor gamma (PPAR-γ) were detected by Western blotting and real-time fluorescent quantitative RT-PCR respectively. The above-mentioned experiments were repeated four times. Three specimens of wound tissue of mice in wild-type group on PID 7 were obtained to detect the relationship between E2F1 and PPAR-γ by co-immunoprecipitation and Western blotting, and this experiment was repeated two times. Data were processed with unpaired t test.@*Results@#The size of PCR products of E2F1 gene knockout homozygotes C57BL/6 mice and wild-type C57BL/6 mice were 227 and 172 bp respectively, which were the same as those of the designed DNA fragments. On PID 2 and 7, the number of CD68 and CD206 double positive M2 macrophages in the wound tissue of mice in E2F1 gene knockout group was more than that of wild-type group, and the percentages of CD206 positive cells in the wound tissue of mice in E2F1 gene knockout group were (0.234±0.032)% and (0.584±0.023)% respectively, which were significantly higher than (0.129±0.017)% and (0.282±0.071)% of wild-type group (t=3.29, 3.54, P<0.05). On PID 2 and 7, the protein expression of CD206 in the wound tissue of mice in E2F1 gene knockout group were 1.00±0.23 and 1.63±0.26 respectively, which were significantly higher than 0.43±0.06 and 0.97±0.08 of wild-type group (t=2.41, 2.45, P<0.05). On PID 2 and 7, the mRNA expressions of arginase 1 in the wound tissue of mice in E2F1 gene knockout group were 0.482±0.105 and 0.195±0.031 respectively, which were significantly higher than 0.163±0.026 and 0.108±0.017 of wild-type group (t=3.04, 2.86, P<0.05). On PID 7, the protein and mRNA expressions of PPAR-γ in the wound tissue of mice in E2F1 gene knockout group were 0.61±0.12 and 0.51±0.13 respectively, which were significantly higher than 0.20±0.04 and 0.20±0.04 of wild-type group (t=3.36, 2.86, P<0.05). On PID 7, detection of the wound tissue of mice in wild-type group showed that PPAR-γ had unidirectional effect on E2F1.@*Conclusions@#E2F1 transcription factor affects the polarization of M2 macrophages by inhibiting the expression of PPAR-γ, thereby inhibiting the healing process of full-thickness skin defect wounds in mice.
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Peroxisome proliferator activated receptors (PPARs) are ligand activated nuclear transcription factors and one of the members of the non steroidal nuclear receptor superfamily.It can be divided into PPAR alpha,PPAR beta / delta and PPAR gamma three subtypes according to the different of its structure and function.Previous studies showed that PPARs participated in biochemical reactions and the regulation of other important biological activities such as lipogenesis,glucose metabolism,inflammation,insulin sensitivity and so on.Recent researches showed that PPARs also had effect of anti-fibrosis,protecting ischemia-reperfusion injury and inhibiting the growth and differentiation of tumor cells.This article reviewed the recent research progress of PPARs in these liver diseases.
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OBJECTIVE To invest igate the therapeutic effect and mechanism of PPAR gamma agonist on allergic rhinitis(AR) in mice. METHODS AR murine model was established by OVA sensitization and challenge. The behavior observation was used to understand the improvement effect of PIO on AR symptoms. The morphological characteristics of nasal tissues were observed by HE staining. The total RNA was extracted to investigate the level of mRNA expression of Foxp3, T-bet and GATA-3. The changes of CD4+Foxp3+T cells in spleen of mice were analyzed by flow cytometry. RESULTS BALB/c mice received OVA sensitization followed by OVA intranasal challenge, the frequencies of sneezing and nose-scratching increased signif icantly in AR group compared with control group. The frequencies decreased significantly in PIO group, compared with AR group. The continuity of nasal mucosa ciliated columnar epithelium in AR group was destroyed and appeared to be repaired in PIO group. Inflammatory cells infiltration was also markedly decreased by PIO treatment. PIO significantly increased the expression of Foxp3 mRNA(P ＜0.001) compared with AR and control group. There was no significant difference in T-bet between PIO group and AR group, but the expression of GATA-3 mRA in PIO group was significantly lower than AR group. The proportion of CD4+Foxp3+T cells in AR group (4.43％±0.25％) decreased compared with control group (5.19％±0.39％) (P ＜0.001). PIO treatment induced production of Tregs (6.35％±0.37％) compaered with control group(P ＜0.001). CONCLUSION PPAR-gamma agonist can effectively alleviate allergic symptoms of mice and regulate the balance of Th1/Th2. The role of PPAR gamma agonist in the treatment of AR may be the amplification of Tregs by promoting Foxp3 expression.
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Neuronal death is thought to be irreversible.In optic nerve-related diseases,the death and axonal loss of retinal ganglion cells could lead to irreversible visual impairment.A large number of studies support the hypothesis that the peroxisome proliferator-activated receptors (PPARs),once activated by particular ligands,could have a potential neuroprotective effect on the peripheral organs and the central nervous system suffering from acute or chronic injury.Optic nerve belongs to the extension of white matter in the central nervous system and shares similar pathophysiological processes with the central nervous system,which makes PPARs a hot spot in the field of optic nerve protection.This paper reviewed the effect of PPARs in optic nerve protection and its possible mechanism.
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Objective To evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) in exogenous protectin D1 ( PD1)-induced reduction of endotoxin-induced acute lung injury (ALI) in mice. Methods Thirty-two clean-grade healthy male BABL∕C mice, weighing 20-25 g, aged 6-8 weeks, were divided into 4 groups (n＝8 each) using a random number table method: sham operation group (group S), ALI group, PD1 group and PPARγ antagonist GW9662 group. Mice underwent oral tra-cheal intubation, normal saline was instilled, and 1 h later normal saline was injected via the tail vein in group S. Mice underwent oral tracheal intubation, lipopolysaccharide (LPS) 3 mg∕kg was instilled, and 1 h later normal saline was injected via the tail vein in group ALI. Mice underwent oral tracheal intubation, LPS 3 mg∕kg was instilled, and 1 h later PD1 200 ng was injected via the tail vein in group PD1. Mice un-derwent oral tracheal intubation, LPS 3 mg∕kg was instilled, and 1 h later GW9662 1 mg∕kg and PD1 200 ng were injected via the tail vein in group GW9662. Mice were sacrificed at 24 h after intratracheal instilla-tion of LPS, the left lung was lavaged with phosphate buffer solution, and the broncho-alveolar lavage fluid (BALF) was collected for determination of neutrophil count and concentrations of interleukin-1beta ( IL-1β), tumor necrosis factor-alpha ( TNF-α) and IL-6 ( by enzyme-linked immunosorbent assay). Right lung tissues were obtained and cut into sections which were stained with haematoxylin and eosin and exam-ined with a light microscope for microscopic examination of the pathological changes which were scored (lung injury score) and for determination of the expression of PPARγ in lung tissues. Results Compared with group S, the neutrophil counts in BALF, concentrations of IL-1β, TNF-α and IL-6 and lung injury score were significantly increased, and the expression of PPARγ was down-regulated in group ALI ( P＜0. 01). Compared with group ALI, the neutrophil counts in BALF, concentrations of IL-1β, TNF-α and IL-6 and lung injury score were significantly decreased, and the expression of PPARγ was up-regulated in group PD1 (P＜0. 01). Compared with group PD1, the neutrophil counts in BALF, concentrations of IL-1β, TNF-α and IL-6 and lung injury score were significantly increased, and the expression of PPARγ was down-regulated in group GW9662 ( P＜0. 01). Conclusion PPARγ activation is involved in exogenous protectin D1-induced reduction of LPS-induced ALI in mice.
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Neuronal death is thought to be irreversible. In optic nerve-related diseases, the death and axonal loss of retinal ganglion cells could lead to irreversible visual impairment. A large number of studies support the hypothesis that the peroxisome proliferator-activated receptors (PPARs), once activated by particular ligands, could have a potential neuroprotective effect on the peripheral organs and the central nervous system suffering from acute or chronic injury. Optic nerve belongs to the extension of white matter in the central nervous system and shares similar pathophysiological processes with the central nervous system, which makes PPARs a hot spot in the field of optic nerve protection. This paper reviewed the effect of PPARs in optic nerve protection and its possible mechanism.
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Objective To investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors and pulse pressure (PP) as well as the relationships between gene-gene interaction between PPARα/δ/γ genes and PP.Methods A total of 820 subjects,with 550 females and 270 males,were recruited from a cohort study of “Prevention of Metabolic Syndrome and Multi-metabolic Disorders in Jiangsu Province of China Study (PMMJS)”.Ten SNPs of PPARα/δ/γ genes were selected.GMDR software (version 1.0.1) was used to evaluate the gene-gene interactions among PPARs SNPs associated with PP.Results The mean levels of PP in people with mutant genotype of rs1805192 in PPARγ genes (PA+AA) showed a significant increase by 1.341 mmHg (95％CI:0.431-2.252 mmHg) when compared to the persons with wild genotype (PP).In the subgroup of subjects with more than 30 mmHg levels of PP,a six-locus model comprised rs135539 of PPARα,rs2016520 of PPARδ,rs10865710,rs1805192,rs709158 and rs3856806 of PPARγshowed a highest level of prediction accuracy (0.577) and displayed a better cross-validation consistency (10/10).In the subgroup of subjects with less than 40 mmHg levels of PP,a two-locus model was statistically associated with PP with 0.628 of prediction accuracy and 10/10 of cross-validation consistency.Conclusion PPARγrs1805192 was associated with the occurrence of PP.Gene-gene interactions among rs135539 of PPARα,rs2016520 of PPARδ,rs10865710,rs1805192,rs709158 and rs3856806 of PPARγ were all significantly related to PP.
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Objective To examine the mRNA and protein expression of peroxisome proliferator-activated receptors (PPAR) and fatty acid binding protein-4 (FABP-4) in placenta, and to investigate their correlation with the prognosis of pre- eclampsia. Methods The data of 177 women who delivered from January 2013 to December 2015 in Chinese People′ s Liberation Army No.94 Hospital were collected. Among them, 60 cases were term pregnancy and not in labor (TN); 46 cases were term pregnancy with preeclampsia and not in labor (TPE); 42 cases were preterm pregnancy and not in labor (PN); 29 cases were preterm pregnancy with pre-eclampsia and not in labor (PPE). Real-time PCR and western blot were used to examine the PPAR and FABP-4 mRNA expression and protein expression in placentas. And linear correlation was used to analyze the relationship between PPAR and FABP-4 protein expression and the prognosis of pre-eclampsia. Results (1)Real-time PCR showed that:① PPAR-α, PPAR-β mRNA expression were not statistically different between placentas from TN and TPE (P>0.05), but PPAR-γ mRNA level in TPE (0.59±0.17) was significantly lower than that in TN (0.81±0.19, P0.05). However,PPAR-γ mRNA in the PPE group (0.33±0.14) was significantly lower than that in PN (0.52±0.16, P<0.01), and FABP-4 mRNA level in the PPE group (0.80±0.29) was significantly higher than in the PN group (0.63±0.22, P<0.01).(2)Western-blot showed the same tendency as the mRNA results. ①There were no statistical differences in the protein expression of PPAR-α, PPAR-β, not in term groups(TN and TPE), nor in premature groups (PN and PPE). PPAR-γ protein level in the TPE group (0.46 ± 0.17) was significantly lower than that in TN (0.65±0.20, P<0.01) and FABP-4 protein level in the TPE group (0.60± 0.19) was significantly higher than that in the TN group (0.50±0.21, P<0.05). ②The PPAR-γ protein level in the PPE group (0.30±0.16) was significantly lower than that in the PN group (0.61±0.16, P<0.05), while the FABP-4 protein expression in the PPE group (0.58±0.19) was significantly higher than that in the PN group (0.40±0.19, P<0.05).(3)Linear correlation showed that:①PPAR-γ protein expression correlated negatively with FABP-4 protein expresssion [P<0.01, R2=0.12 in the term groups(TN+TPE), R2=0.15 in the premature groups(PN+PPE)]. ②PPAR-γ protein expression correlated negatively with blood pressure recovery time, 24-hour urinary protein quantification and blood lipid recovery time (P<0.01, R2=0.37,0.35,0.18). FABP-4 protein expression correlated positively with lipid recovery time and blood cholesterol concentrations (P<0.01, R2=0.13,0.25). Conclusions The expression of PPAR-γ decreases in placentas from patients with pre-eclampsia, while the expression of FABP-4 increases. The expression of FABP-4 correlates negatively with the expression of PPAR-γ, and both are associated with the prognosis of pre-eclampsia.
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AIM: To investigate the phenomenon that miR-let-7d regulates the proliferation and invasion abilities of the lung cancer cells through nuclear receptor peroxisome proliferator-activated receptors γ (PPARγ).METHODS: The relation between PPARγ and microRNA was analyzed by bioinformatics.The plasmid reporter assay was used to verify that PPARγ was the target of miR-let-7d.The lung cancer cell line with low expression of PPARγ was selected from different lung cancer cell lines by Western blot.The regulatory role of miR-let-7d in the lung cancer cells was determined by dual luciferase labeling and Western blot.The effect of miR-let-7d on the proliferation ability of lung cancer cells was detected by colony formation assay, the effect of miR-let-7d on the invasive ability of lung cancer cells was detected by Transwell invasion assay.RESULTS: The results of bioinformatic analysis showed that miR-let-7d regulated the expression of PPARγ, and the 3'UTR of PPARγ contained 2 functional miR-let-7d binding sites, indicating that PPARγ is a direct target of miR-let-7d.miR-let-7d was able to directly regulate the expression of PPARγ at mRNA and protein levels.Transfection of miR-let-7d inhibitor promoted the proliferation and invasion abilities of lung cancer cells by increasing the expression of PPARγ.CONCLUSION: miR-let-7d increases the expression of tumor suppressor PPARγ to inhibit the proliferation and invasive abilities of lung cancer cells.
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Objective@#To investigate the role of the glycogen synthase kinase 3β (GSK3β) and the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway in acute liver failure and related mechanisms in a mouse model of acute liver failure induced by D-galactosamine/lipopolysaccharide (D-GalN/LPS).@*Methods@#C57BL/6 mice were given intraperitoneal injection of D-GalN/LPS to establish a mouse model of acute liver failure. SB216763 was used to inhibit the activity of GSK3β and PPARα siRNA was used to inhibit the expression of PPARα. Western blotting was used to measure the expression of PPARα protein. The changes in liver pathology were observed to evaluate liver injury, and the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to assess liver function. Quantitative real-time PCR was used to measure the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-12p40 (IL-12p40), and PPARα. A one-way analysis of variance was used for comparison of means between multiple groups; the least significant difference test was used for data with homogeneity of variance, and the Games-Howell method was used for data with heterogeneity of variance.@*Results@#In the mice with liver failure induced by D-GalN/LPS, GSK3β inhibition promoted the mRNA and protein expression of PPARα (F = 13.18 and 301.36, P = 0.00 and 0.00). In the mice with acute liver failure induced by D-GalN/LPS, GSK3β inhibition alleviated liver bleeding, inflammation, and necrosis and reduced the serum levels of ALT (F = 25.16, P = 0.000) and AST (F = 12.96, P = 0.001), as well as the mRNA expression of TNF-α (F = 32.17, P = 0.00), IL-1β (F = 11.57, P = 0.005), and IL-12p40 (F = 14.17, P = 0.015) in liver tissue. The inhibition of PPARα expression reversed the liver-protecting effect of GSK3β inhibition, which manifested as aggravation in liver bleeding, inflammation, and necrosis, increases in the serum levels of ALT (F = 25.16, P = 0.001) and AST (F = 12.96, P = 0.000), and an increase in the mRNA expression of TNF-α (F = 32.17, P = 0.00), IL-1β (F = 11.57, P = 0.024), and IL-12p40 (F = 14.17, P = 0.001) in liver tissue.@*Conclusion@#In mice with acute liver failure induced by D-GalN/LPS, the GSK3β-PPARα-inflammatory factor signaling pathway may play an important role. GSK3β inhibition has a protective effect in mice with acute liver failure possibly by activating the inhibitory inflammatory factor of PPARα.
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Objective To investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors and pulse pressure (PP) as well as the relationships between gene-gene interaction between PPARα/δ/γ genes and PP.Methods A total of 820 subjects,with 550 females and 270 males,were recruited from a cohort study of “Prevention of Metabolic Syndrome and Multi-metabolic Disorders in Jiangsu Province of China Study (PMMJS)”.Ten SNPs of PPARα/δ/γ genes were selected.GMDR software (version 1.0.1) was used to evaluate the gene-gene interactions among PPARs SNPs associated with PP.Results The mean levels of PP in people with mutant genotype of rs1805192 in PPARγ genes (PA+AA) showed a significant increase by 1.341 mmHg (95％CI:0.431-2.252 mmHg) when compared to the persons with wild genotype (PP).In the subgroup of subjects with more than 30 mmHg levels of PP,a six-locus model comprised rs135539 of PPARα,rs2016520 of PPARδ,rs10865710,rs1805192,rs709158 and rs3856806 of PPARγshowed a highest level of prediction accuracy (0.577) and displayed a better cross-validation consistency (10/10).In the subgroup of subjects with less than 40 mmHg levels of PP,a two-locus model was statistically associated with PP with 0.628 of prediction accuracy and 10/10 of cross-validation consistency.Conclusion PPARγrs1805192 was associated with the occurrence of PP.Gene-gene interactions among rs135539 of PPARα,rs2016520 of PPARδ,rs10865710,rs1805192,rs709158 and rs3856806 of PPARγ were all significantly related to PP.