Effect of fenofibrate on the expression of miR-26a-5p/PTEN in retinal neurons of diabetic mice / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To study the protective effect of fenofibrate on diabetic retinal neurodegeneration and observe its effect on miR-26a-5p and its target gene PTEN in the retinal of diabetic mice.METHODS: Diabetic mice models were established and they were gavaged by fenofibrate. H& E staining and transmission electron microscopy were used to observe the impairments of retinal neurons. Real-time PCR was used to examine the expression of miR-26a-5p, and Western blotting was employed to measure the expression of phosphatase and tensin homologue(PTEN)in the retina of diabetic mice. The expression level of nuclear factor-κB(NF-κB), interleukin-1β(IL-1β)and the morphology of neural tissues were observed.RESULTS: When compared with the diabetic mice, fenofibrate significantly attenuated the damage to retinal ganglion cells and the atrophy of retinal nerve fiber layer. While the level of miR-26a-5p was increased and the levels of PTEN and inflammatory mediators were significantly decreased in the retina of fenofibrate treated diabetic mice, with significant statistical significance(P<0.05).CONCLUSIONS: Fenofibrate protects against diabetic retinal neurodegeneration by upregulating miR-26a-5p and inhibiting PTEN, attenuating the inflammatory response and alleviating retinal cell injury.

Efficacy and safety of Saroglitazar and Fenofibrate in the treatment of diabetic dyslipidaemia: A pilot study

Objectives: Diabetic dyslipidaemia (DD) is characterised by hypertriglyceridaemia and elevated or normal levels of low-density lipoprotein cholesterol and decreased levels of high-density lipoprotein cholesterol with Type 2 diabetes mellitus. Statins and anti-diabetic medication are coprescribed for optimal control. Materials and Methods: The objective of the study was to compare the safety and efficacy of Saroglitazar 4-mg and Fenofibrate 200 mg in combination with low dose Atorvastatin (10 mg) in patients with DD. Run-in period of 4 weeks for life-style and diet modification followed by 12 weeks of treatment with saroglitazar or fenofibrate and low dose of atorvastatin was followed. Primary outcome of this study was an absolute change in serum triglyceride level at baseline and end of treatment period (12 weeks). Secondary outcome was changed from baseline lipid profile, fasting blood glucose and glycosylated haemoglobin (HbA1c) at the end of treatment period. Safety assessment was also done during the duration of study. Results: Forty patients of DD were randomly divided into two groups. One group received Saroglitazar 4 mg along with Atorvastatin 10 mg. Patients in second group received Fenofibrate 200 mg along with Atorvastatin 10 mg. Improvement in deranged lipid levels in both the groups was observed and this difference in improvement statistically was not found to be significant. We also observed that Saroglitazar significantly improves glycaemic profile by decreasing fasting blood sugar levels and HbA1c (P = 0.01, P < 0.01). Adverse events reported during this study were mild and none of the patients reported serious adverse events. Conclusion: Saroglitazar could be a potential drug to control both hyperglycaemia and dyslipidaemia in patients with DD.

Therapeutic potential of PPARα agonist in ligature-induced experimental periodontitis

Abstract Inflammation-related immune responses and bone metabolism lead to extensive tooth loss in periodontitis. Objective: This study aims to investigate the effect of peroxisome proliferator-activated receptor (PPAR) alpha agonist anti-inflammatory treatment in vitro and in ligature-induced experimental periodontitis in vivo . Methodology: Splenocytes were isolated from C57BL/6J mice and cultured for 48 hours under the following conditions: control, P. gingivalis lipopolysaccharide (LPS) (1 µg/ml); experimental, LPS (1 µg/ml) + PPARα agonist (fenofibrate) at 1, 10, 50, 100 µM. MRNA and secreted protein levels of TNF-α expression were detected by RT-qPCR and ELISA, respectively. Silk ligatures (7-0) were tied around maxillary second molars of C57BL/6J mice for two weeks. Optimized doses of fenofibrate (50 µM) and vehicle control were injected into the contralateral side of the palatal gingiva on days three, six, and nine. At day 14, bone resorption, osteoclastogenesis, and gingival mRNA expression levels of TNF-α, IL-1β, IL-6, and RANKL/OPG were measured by micro-computed tomography, Tartrate-resistant acid phosphatase (TRAP) staining, and Real-time quantitative PCR, respectively. Results: TNF-α expression in cultured spleen cells were significantly increased in the presence of LPS, when compared with the control group, and significantly reduced by fenofibrate treatment in a dose-dependent manner from 1-100 µM (p<0.05). Gingival mRNA levels of TNF-α, IL-1β, IL-6, and the ratio of RANKL/OPG, were significantly decreased after injection of fenofibrate, when compared to the control side (p<0.05). Periodontal bone loss and TRAP positive cell formation were significantly decreased on the side with an injection of fenofibrate, as compared to the control side (p<0.05). Conclusions: An anti-inflammatory treatment, PPARα agonist, inhibited inflammation and periodontal bone loss in ligature-induced experimental periodontitis.

A systematic review of preclinical animal studies on fenofibrate's potential role in type 1 diabetic micro-vascular complications

Abstract Fenofibrate is a peroxisome-proliferator-activator α agonist and it is a widely used drug for hyperlipidemia since its approval in 2004. So, in this review we are focusing on the effect of fenofibric acid's mechanism to alleviate type 1 diabetic micro vascular complications like diabetic retinopathy, diabetic cardiomyopathy in animal models, since the drug is safe, efficacious and more economical when compared with the currently available treatment strategies for juvenile diabetic complications and also a profound observation is needed due to the rarity of research in these therapeutic areas. Important preclinical animal studies published from January 2001 to June 2020 were recognised from databases like PubMed and Cochrane central register of controlled trials. Reviewers screened the articles based on the selection criteria and risk of bias was determined using Systematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies. Our literature search yielded a total of 5 studies and after pooling up the data from the 5 preclinical studies, we found that Fenofibrate have the efficacy to prevent type 1 diabetic complications, chiefly diabetic retinopathy and those mechanisms are dependent on peroxisome-proliferator-activator and fibroblast growth factor-21 pathways. Fenofibrate is a well safe and moreover, cost effective medication in preventing type 1 diabetic micro vascular complications especially diabetic retinopathy and also in maintaining the glucose homeostasis in apart from its anti-dyslipidemic effect.

Research advances in obeticholic acid and fibrates in treatment of primary biliary cholangitis with poor response or intolerance to ursodeoxycholic acid / 临床肝胆病杂志

Poor response or intolerance to ursodeoxycholic acid may occur in the treatment of primary biliary cholangitis (PBC), and after switch to obeticholic acid or fibrates alone or in combination, poor response or intolerance is also observed in some treatment regimens. Clinical studies on obeticholic acid and fibrates will gradually solve these issues, and obeticholic acid/fibrates combined with ursodeoxycholic acid is safe and effective in PBC patients without advanced liver cirrhosis.

Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptor α / 中国天然药物

Nonalcoholic fatty liver disease (NAFLD) is regarded as the most common liver disease with no approved therapeutic drug currently. Silymarin, an extract from the seeds of Silybum marianum, has been used for centuries for the treatment of various liver diseases. Although the hepatoprotective effect of silybin against NAFLD is widely accepted, the underlying mechanism and therapeutic target remain unclear. In this study, NAFLD mice caused by methionine-choline deficient (MCD) diet were orally administrated with silybin to explore the possible mechanism and target. To clarify the contribution of peroxisome proliferator-activated receptor α (PPARα), PPARα antagonist GW6471 was co-administrated with silybin to NAFLD mice. Since silybin was proven as a PPARα partial agonist, the combined effect of silybin with PPARα agonist, fenofibrate, was then evaluated in NAFLD mice. Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARα and its targets. As expected, silybin significantly protected mice from MCD-induced NAFLD. Furthermore, silybin reduced lipid accumulation via activating PPARα, inducing the expression of liver cytosolic fatty acid-binding protein, carnitine palmitoyltransferase (Cpt)-1a, Cpt-2, medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1, and suppressing fatty acid synthase and acetyl-CoA carboxylase α. GW6471 abolished the effect of silybin on PPARα signal and hepatoprotective effect against NAFLD. Moreover, as a partial agonist for PPARα, silybin impaired the powerful lipid-lowering effect of fenofibrate when used together. Taken together, silybin protected mice against NAFLD via activating PPARα to diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARα agonists for NAFLD therapy.

Clinical Study and Literature Analysis of Rhabdomyolysis in Hypothyroidism Caused by Fenofibrate / 中国药学杂志

OBJECTIVE: To explore clinical characteristics of rhabdomyolysis caused by fenofibrate in patients with hypothyroidism. METHODS: A clinical case was analyzed and summarized the literature of adverse reactions of rhabdomyolysis caused by fenofibrate in patients with hypothyroidism reported in China and abroad. RESULTS: A 25-year-old female with hyperlipidemia combined with hypothyroidism developed rhabdomyolysis at 12th day after taking fenofibrate. Before the occurrence of rhabdomyolysis, highlevelof TSH was detected. After occurrence of adverse reactions, the patient stopped taking fenofibrate, rehydrated and alkalized urine. Then the patient recovered and discharged. In the literature review, 11 cases of rhabdomyolysis with fenofibrate in hypothyroidism were included. The age range was 25-68. The sex ratio was 1∶2. On thyroid function, there were 3 cases unknown, 6 cases with hypothyroidism and 2 cases with FT4 at the lowest normal limit. On doses of fenofibrate, there were 9 cases under the instructions, and 3 cases beyond the recommendations in labeling. Most adverse drug reactions (ADRs) occurred at the third to 60th day after taking fenofibrate. Ten patients recovered and 2 patients improved. CONCLUSION: Hypothyroidism would be a risk factor for rhabdomyolysis caused by fenofibrate. Thyroid function should be monitored in patients taking fenofibrate with hypothyroidism.

Effect of fenofibrate on the diversity of intestinal flora in a mouse model of nonalcoholic fatty liver disease / 临床肝胆病杂志

ObjectiveTo investigate the effect of fenofibrate on the diversity of intestinal flora in mice with nonalcoholic fatty liver disease (NAFLD). MethodsA total of 30 mice were randomly divided into normal group, high-fat group, and fenofibrate treatment group, with 10 mice in each group. The mice in the high-fat group and the fenofibrate treatment group were given high-fat diet intervention for 14 weeks, and those in the normal group were given normal diet for 14 weeks. After 10 weeks of dietary intervention, the mice in the fenofibrate treatment group were given fenofibrate by gavage and high-fat diet for another 4 weeks, and the change in body weight was monitored during the whole process. Fecal samples were collected after 14 weeks, and high-throughput sequencing 16S rRNA was used to investigate the diversity and difference of intestinal flora. Liver tissue samples were collected, and HE staining and oil red O staining were performed to observe the degree of steatosis. A one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. ResultsAfter 10 weeks of intervention, the fenofibrate treatment group had a significantly lower body weight than the high-fat group (P＜0.05). The results of HE staining and oil red O staining showed that the fenofibrate treatment group had a significantly lower degree of fat deposition than the high-fat group. There was a significant difference in intestinal flora between the fenofibrate treatment group and the high-fat group, while there was no significant difference in intestinal flora between the fenofibrate treatment group and the normal group. The fenofibrate treatment group had significant increases in the abundance of Bacteroidetes, Verrucomicrobia, Faecalibaculum, Muribaculaceae_norank, and Akkermansia and significant reductions in the abundance of Firmicutes, Actinobacteria, Clostridium, Turicibacter, and Bifidobacterium. ConclusionThe increases in the abundance of Bacteroidetes and Verrucomicrobia and the reductions in the abundance of Firmicutes and Actinobacteria suggest that fenofibrate may have positive significance in the treatment of NAFLD.

Comparison of Atorvastatin and Fenofibrate in Dyslipidemia

Background: Abnormalities in plasma lipoproteins and deranged lipid metabolism rank as most firmly established and best understood risk factor for atherosclerosis Lipid regulating drugs, may be prescribed if, dietary therapy and lifestyle modification fails to adequately normalize blood lipid levels. The European / Atherosclerosis Society and National Cholesterol Education Programme (NCEP) consider fibric acid derivatives (Fibrates) and Hydroxy Methylglutaryl CoA reductase inhibitors (HMG CoA reductase inhibitors) to be effective therapy for combined dyslipidernia . The aim of present study was to compare the efficacy of Atorvastatin and Fenofibrate on various aspects of lipid profile viz. total cholesterol, serum LDL-C, serum VLDL, serum HDL-C and serum triglycerides in Indian patients having dyslipidemia. Methods: This study was conducted on 100 patients with abnormal lipid profile attending the OPD/Wards of Department of Medicine, Guru Nanak Dev Hospital, attached to Government Medical College, Amritsar. Results: The patients were randomly divided into 2 groups of 50 each, group A and B. Group A were put on Atorvastatin 10-20 mg daily and Group B were put on micronized Fenofibrate 200mg daily. Conclusion: The study concluded that none of these drugs were independently able to achieve NCEP ATP III goals. Atorvastatin has main effect or total serum cholesterol and LDL-C whereas Fenofibrate has main effect on serum triglycerides, VLDL-C and HDL-C .Combination of these may be tried to achieve the desired goal.

Pathogenesis, histopathologic findings and treatment modalities of lipoprotein glomerulopathy: A review / Patogênese, achados histopatológicos e modalidades de tratamento da glomerulopatia por lipoproteínas: Uma revisão

Abstract Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE.

Resumo A glomerulopatia por lipoproteínas (GLP) é uma patologia rara que causa síndrome nefrótica e/ou insuficiência renal. Na microscopia, a GLP é caracterizada pela presença de trombos de lipoproteínas em capilares glomerulares dilatados devido a diferentes mutações no gene da ApoE. O gene da ApoE está localizado no cromossomo 19q13.2 e pode ser identificado em quase todas as lipoproteínas séricas. A ApoE age como fator de proteção na arterioesclerose por conta de sua interação com a depuração de lipoproteínas mediada por receptores e com o receptor de colesterol. Dentre os polimorfismos mais comuns destacam-se ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3 e ApoE4/4. A GLP pode acometer indivíduos de todas as faixas etárias, com discreta predominância do sexo masculino. Pacientes afetados tipicamente apresentam dislipidemia, hiperlipoproteinemia tipo III e proteinúria. O tratamento da GLP é conduzido com fenofibrato, antilipêmicos, corticosteroides, LDL-aferese, troca de plasma, antiplaquetários, anticoagulantes, uroquinase e transplante renal. Recidiva no enxerto renal indica a existência de componentes patogênicos do complexo humoral extraglomerular resultante de metabolismo lipoproteico anômalo, possivelmente associado a ApoE.

Biochemistry and Molecular Biology of Mechanisms of Action of Fibrates – An Overview

Fibrates are a class ofmedication that mainly lowers theblood triglyceride levels. Theyreduce the LDL andincrease the levels of HDL C, in the blood.Clofibrate,the first member to bediscovered in 1962, and introduced in USA in 1967, is withdrawnin 2002, due to unexplained hepatomegaly,hepato-toxicity and possible risk of hepatic cancer. Other fibrates are introduced in the late 1970s and early1980s, such as gemfibrozil in the United States and bezafibrate and ciprofibrate in Europe. Their lipid lowering effects are found to decrease CVS risk , progression of atherosclerosis and metabolic syndrome, macrovascular and microvascular diabetic complications like stroke, myocardial infarction, peripheral vascular diseaseand diabeticretinopathy .Various clinical trials like VA-HIT trial (Veterans Affairs High-Density LipoproteinCholesterol Intervention Trial) , FIELD trail. (the Fenofibrate Intervention and Event Lowering in Diabetes) Helsinki Heart Study,ACCORD -Lipid trial (The lipid component of the Action to Control Cardiovascular Risk in Diabetes trial ) and BIP (Bezafibrate Infarction Prevention Study) trial andangiography trials, like LOCAT(LopidCoronary Angiography Trial) and BECLAIT(Bezafibrate Coronary Atherosclerosis Intervention Trial)demonstrated thebeneficial effects of gemfibrozil and fenofibrate.Their mechanism of action remained obscure for three decades,ie till 1990s, when theirmode of actionwas found. The Mechanism of action of fibrates include limitation of substrate availability for triglyceride synthesis in the liver, promotion of the action of lipoprotein lipase, (LPL)modulation of low density lipoprotein receptor/ligand interaction and stimulation of reverse cholesterol transport The biochemical and molecular mechanisms involvingthevariousenzymes like LCAT (Lecithin-cholesterol acyl transferase)andCYP7A1 etc. (cholesterol 7-alpha-monooxygenase or cytochromeP450 7A1 (CYP7A1)) , transporters like ABC , CETP (ATP-binding cassette transporter, Cholesterol ester binding protein) and NTCP,OATP (Na+-dependent taurocholate transporter/ organic anion transporters) . These are the.) andnuclear factors like LXR, PPAR alfa etc. (liver orphan receptorα , and peroxisome proliferative nuclear factor) , in relation to the mechanismsof action of fibrates are discussed . Areas of current interests in literature are briefed.

Comparative study of efficacy and safety of omega 3 fatty acids and fenofibrate with background atorvastatin therapy in patients of atherogenic dyslipidaemia

Background: Trials of atorvastatin combined either with fenofibrate or with omega-3 fatty acids (O3FA) have shown promising results in atherogenic dyslipidemia but there are very few studies where both these TGs lowering agents have been compared with each other. This study was conducted to compare efficacy and safety of these two agents on lipid profile of patients of atherogenic dyslipidaemia on background statin therapy and also to monitor effects of these interventions on serum uric acid (SUA) levels.Methods: About 90 patients of dyslipidemia were randomised to 3 groups and received O3FA (2000 mg), fenofibrate (80 mg) or dietary restrictions, each with atorvastatin (20 mg) in background for a period of 90 days. Total cholesterol (TC), HDL-C,TGs, LDL-C, SGOT and SGPT levels were done at baseline, 6 weeks and 12 weeks. Other parameters (SUA and BMI) were done at baseline and 12 weeks.Results: Both group 1 (O3FA) and group 2 (fenofibrate) showed highly significant fall in TG levels (p <0.001) in comparison to group 3 (dietary restrictions) whereas comparative TG reduction between groups 1 and group 2 was not significant. Group 2 also showed significant fall in LDL-C levels (p <0.01) in comparison to group 3. LDL-C reduction, TG reduction and SUA reduction was more in group 2 compared to group 1 followed by group 3. No significant difference was observed in the incidence of adverse effects in three study groups.Conclusions: Combination of fenofibrate and atorvastatin was more effective than that of omega-3 fatty acid and atorvastatin, in lowering serum TG and LDL-C levels. There was a significant reduction in SUA levels in all three groups, but combination of fenofibrate and atorvastatin again showed better outcomes. With respect to the safety, all the 3 groups were comparable. O3FA, however, may be a good alternative to fibrates in patients not tolerating latter.

The Effect of Water-Soluble Excipients on the Inclusion Complex of Fenofibrate and Hydroxypropyl-β-Cyclodextrin / 中国药学杂志

OBJECTIVE: To study the effect of water-soluble materials on the inclusion complex of fenofibrate and hydroxypropyl-β-cyclodextrin. METHODS: The inclusion complex of fenofibrate/hydroxypropyl-β-cyclodextrin and the ternary system containing water-soluble materials were obtained by ball milling. The inclusion complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (XRD), Fourier-transformed infrared spectrophotometry (FTIR), 1H-NMR spectroscopy, as well as in vitro dissolution and stability test. RESULTS: The stability tests and in vitro dissolution results showed that the addition of water-soluble materials could improve the stability constant and inclusion efficiency of the inclusion complex. Moreover, the addition of hydroxypropyl methylcellulose(HPMC) could result in a more stable complex and the in vitro dissolution rate of complex was also increased. CONCLUSION: The addition of appropriate water-soluble materials could enhance the inclusion efficiency of hydroxypropyl-β-cyclodextrin with drugs and form a more stable system.

Prevention and treatment research of fenofibrate for diabetic retinopathy and its clinical translation / 中华实验眼科杂志

Diabetes is a worldwide prevalent disease and diabetic retinopathy (DR) is one of the common complications, which is vision threatening and even leading to blindness.The current management of DR includes laser retina photocoagulation, vitrectomy, and frequent intravitreal anti-vascular endothelial growth factor (VEGF) agents.However, these measures do not target the root cause and their efficacy is limited.Fenofibrate is a blood lipid lowering therapeutics and its metabolite, fenofibric acid, is responsible for the pharmacology effect.Two large clinical trials (FIELD and ACCORD-Eye) have demonstrated oral fenofibrate retarded progression of DR and the needs for laser retinopexy.The animal and cell researches have revealed that fenofibric acid attenuated overexpression of basement membrane and VEGF, protected the tight junctions of endothelial cells and vascular permeability, as well as inhibited cells migration and neovascularization via suppression of inflammatory cytokines.These pharmacological effects might be materialized through several pathways, such as PPAR-α, MAPK and nuclear factor-κB (NF-кB). Blood-ocular barrier is a significant limiting factor for therapeutics reaching retina after systemic administration.Local ocular application of fenofibric acid may achieve better efficacy through improving therapeutic concentration in the eye.This drug may be delivered either by eye drop formulation or a sustained delivery device under conjunctiva or sub-Tenon.

Prevention and treatment research of fenofibrate for diabetic retinopathy and its clinical translation / 中华实验眼科杂志

Diabetes is a worldwide prevalent disease and diabetic retinopathy ( DR) is one of the common complications,which is vision threatening and even leading to blindness. The current management of DR includes laser retina photocoagulation,vitrectomy,and frequent intravitreal anti-vascular endothelial growth factor ( VEGF) agents. However,these measures do not target the root cause and their efficacy is limited. Fenofibrate is a blood lipid lowering therapeutics and its metabolite, fenofibric acid, is responsible for the pharmacology effect. Two large clinical trials ( FIELD and ACCORD-Eye) have demonstrated oral fenofibrate retarded progression of DR and the needs for laser retinopexy. The animal and cell researches have revealed that fenofibric acid attenuated overexpression of basement membrane and VEGF,protected the tight junctions of endothelial cells and vascular permeability,as well as inhibited cells migration and neovascularization via suppression of inflammatory cytokines. These pharmacological effects might be materialized through several pathways, such as PPAR-α, MAPK and nuclear factor-κB ( NF-кB ) . Blood-ocular barrier is a significant limiting factor for therapeutics reaching retina after systemic administration. Local ocular application of fenofibric acid may achieve better efficacy through improving therapeutic concentration in the eye. This drug may be delivered either by eye drop formulation or a sustained delivery device under conjunctiva or sub-Tenon.

Effects of Bezafibrate and Fenofibrate on the Proliferation of Lung Adenocarcinoma PC- 9 Cells and the Expression of c-myc / 中国药房

OBJECTIVE： To study the effects of bezafibrate （BEZ） and fenofibrate （FEN） on the proliferation of lung adenocarcinoma PC-9 cells and the expression of c-myc. METHODS： The effects of BEZ and FEN （12.5， 25， 50， 100， 200       μmol/L） on the survival rate of PC-9 cells were detected by CCK8 method. PC-9 cells were divided into administration group and control group. Administration group was given low， medium and high concentration （25， 50， 100 μmol/L） of BEZ and FEN； control group was treated with dimethyl sulfoxide for 48 h. Cell cycle distribution and apoptosis were detected by flow cytometry. qRT-PCR was used to detect mRNA relative expression of c-myc in cells. The protein relative expression of c-myc in cells were detected by Western blot assay. RESULTS： The survival rates of PC-9 cells were （80.76±3.2）％， （74.35±5.06）％， （62.8±1.23）％， （59.03±1.55）％， （39.8±1.01）％ under the action of above concentration of BEZ； and the survival rates of PC-9 cells were （74.46±1.30）％， （61.91±4.77）％， （48.95±2.8）％， （37.05±1.55）％， （32.49±1.36）％ under the action of FEN. Compared with control group， G1 phase cell ratio increased significantly in medium and high concentration groups of BEZ and FEN； the apoptotic rate of PC-9 cells was increased significantly in low， medium and high concentration groups of BEZ and FEN； mRNA and protein relative expression of c-myc were decreased significantly， with statistical significance （P＜0.05）. CONCLUSIONS： BEZ and FEN can inhibit the proliferation of PC-9 cells， and down-regulate c-myc expression.

Anti-Hypertensive Action of Fenofibrate via UCP2 Upregulation Mediated by PPAR Activation in Baroreflex Afferent Pathway / 神经科学通报·英文版

Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.

Effect of fenofibrate on acute and subacute inflammation in male Wistar rats

Background: The objective of the study was to investigate the effect of fenofibrate on acute and subacute models of inflammation in adult male Wistar rats.Methods: After obtaining clearance from Institutional Animal Ethics Committee, six adult male Wistar rats were allocated to each of the three groups i.e. control, aspirin and fenofibrate. Acute inflammation was studied using carrageenan induced rat paw oedema and the volume displacement due to paw oedema was measured using the plethysmograph. Subacute inflammation was studied using foreign body insertion (cotton pellet and grass pith) models. Dry granuloma weight and histopathological examination of the granuloma were the outcome measures for measuring subacute inflammation. The percentage inhibition of inflammation with aspirin and fenofibrate was calculated in both acute and subacute models. The experiments were conducted according to the guidelines of the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA). The mean volume displacement obtained with a plethysmograph, the mean dry weight of granuloma and the percentage inhibition with aspirin and fenofibrate were analyzed by one way analysis of variance (ANOVA) using Graph pad prism software.Results: Aspirin and fenofibrate significantly reduced both acute and subacute inflammation (p<0.001). Dunnet’s test showed a significant difference in the study groups when compared to the control. The reduction of inflammation with fenofibrate was comparable to aspirin.Conclusions: Oral fenofibrate showed significant anti-inflammatory activity, which was comparable to aspirin, in both acute as well as sub-acute models of inflammation. This anti-inflammatory effect may benefit atherosclerosis in patients receiving fenofibrate for hyperlipidemia.

Efficiency of fenofibrate in facilitating the reduction of central macular thickness in diabetic macular edema

Purpose: The purpose of this study is to study the benefit of addition of oral fenofibrate to the current regimen of diabetic macular edema (DME) management and quantify its effect on macular thickness and visual function in DME. Methods: Fifty-three eyes of 50 patients were randomized into treatment (Group A) (oral fenofibrate 160 mg/day) and control groups (Group B). Both groups underwent treatment of DME as per the standard treatment protocol of our hospital including intravitreal injections (anti-vascular endothelial growth factor/steroid) and grid laser. Patients were followed up every 2 months to note the visual acuity and central macular thickness (CMT) for 6 months. Results: Our groups were matched with respect to age (P = 0.802), mean diabetic age (P = 0.878), serum HbA1C levels (P = 0.523), and serum triglyceride levels (P = 0.793). The mean reduction in CMT was 136 ? in Group A and 83 ? in Group B at the end of 6 months. This difference was statistically significant (P = 0.031). Visual acuity improvement was 0.15 in Group A and 0.11 in Group B at the end of 6 months (P = 0.186). On subgroup analysis in Group A, we found that there was no difference in reduction of CMT between hypertensives and normotensives (P = 0.916), in patients with normal triglyceride levels and increased triglyceride levels (P = 0.975). Conclusion: Addition of fenofibrate to the standard protocol of DME management seems to facilitate reduction of CMT and probably have an added benefit on the visual functions.

Neither polyphenol-rich red wine nor fenofibrate affects the onset of type-1 diabetes mellitus in the BB rat / 한국실험동물학회지

Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when β-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted β-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances.