Fenofibrate is one of PPAR-alpha (peroxisome proliferator activated receptor alpha) agonists. Fenofibrate decreases effectively triglyceride and increases high density lipoprotein cholesterol level through the effect on lipoprotein lipase, hepatic production and degradation of lipoproteins. Fenofibrate was recommended as the drug for hypertriglyceridemia treatment in European guideline released in 2011. But American heart association guideline in 2013 did not recommend non-statin therapy including fibrate for the prevention of atherosclerotic cardiovascular disease. But fenofibrate is still considered as the important drug for the management of atherogenic dyslipidemia especially in patients with metabolic syndrome and diabetes to reduce the residual risk after statin therapy from the evidence of many studies. Fibrates including bezafibrate, gemfibrozil, and fenofibrate increased serum creatinine level in several studies. But the mechanism of change in renal function is not clear till now. And the reversibility of renal function with drug discontinuation is dependent on the kinds of fibrate. Fenofibrate increased serum creatinine level, decreased albuminuria and renal function was reversible with the drug discontinuation in large clinical trials. In these days renal function change with fenofibrate therapy in Korean patients with hypertriglyceridemia was investigated. Fenofibrate treatment for 2 months increased serum creatinine level significantly and old age was associated with the change of renal function in multivariate analysis. Short-term therapy significantly increased serum creatinine level even within normal range, and this change may be important in some groups especially old age.
Albuminuria ; American Heart Association ; Bezafibrate ; Cardiovascular Diseases ; Cholesterol, HDL ; Creatinine ; Dyslipidemias ; Fenofibrate* ; Fibric Acids ; Gemfibrozil ; Glomerular Filtration Rate ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypertriglyceridemia ; Lipoprotein Lipase ; Lipoproteins ; Multivariate Analysis ; Reference Values ; Triglycerides

BACKGROUNDFibroblast growth factor 21 (FGF21) is a new member of FGF super family that is an important endogenous regulator for systemic glucose and lipid metabolism. This study aimed to explore whether FGF21 reduces atherosclerotic injury and prevents endothelial dysfunction as an independent protection factor.

METHODSThe present study was designed to investigate the changes of FGF21 levels induced by oxidized-low density lipoprotein (ox-LDL), and the changes of apoptosis affected by regulating FGF21 expression. The FGF21 mRNA levels of cultured cardiac microvascular endothelial cells (CMECs) were determined by real time-PCR and the protein concentration in culture media was detected by enzyme-linked immunosorbent assay. We analyzed the different expression levels of untreated controls and CMECs incubated with ox-LDL, and the changes of CMECs apoptosis initiated by the enhancement or suppression of FGF21 levels.

RESULTSThe secretion levels of FGF21 mRNA and protein were significantly upregulated in CMECs incubated with ox-LDL. Furthermore, FGF21 levels increased by 200 µmol/L bezafibrate could reduce CMECs apoptosis, and inhibit FGF21 expression by shRNA induced apoptosis (P < 0.05).

CONCLUSIONSFGF21 may be a signal of injured target tissue, and may play physiological roles in improving the endothelial function at an early stage of atherosclerosis and in stopping the development of coronary heart disease.

Animals ; Apoptosis ; Bezafibrate ; pharmacology ; Cells, Cultured ; Coronary Artery Disease ; prevention & control ; Endothelial Cells ; physiology ; Fibroblast Growth Factors ; analysis ; antagonists & inhibitors ; genetics ; physiology ; Lipoproteins, LDL ; toxicity ; Male ; PPAR alpha ; physiology ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar

The present study demonstrates the effect of fibrates, agonists of PPARalpha on cytokines-induced proliferation in primary cultured astrocytes. Alone or combination treatment with cytokines, such as IL-1beta (10 ng/ml), IFNgamma (10 ng/ml), and TNF-alpha (10 ng/ml) cause a significant increase of cell proliferation in a time-dependent manner. Treatment of astrocytes with bezafibrate and fenofibrate (0, 5, and 10 micrometer) reduced the IFNgamma and IL-1beta-induced cell proliferation in a dose-dependent manner. To address the involvement of IL-6 on the IFNgamma and IL-1beta-induced cell proliferation, released IL-6 level was measured. IFNgamma and IL-1beta cause an increase of released IL-6 protein level in a time-dependent manner. Furthermore, pretreatment with IL-6 antibody (0, 0.1, 1, 2.5, and 5 ng/ml) dose-dependently inhibited the IFNgamma and IL-1beta-induced cell proliferation. However, bezafibrate and fenofibrate did not affect increased mRNA and protein levels of IL-6 in IFNgamma and IL-1beta-stimulated astrocytes. Taken together, these results clearly suggest that activation of PPARalpha attenuates the IFNgamma and IL-1beta-induced cell proliferation through IL-6 independent pathway.
Astrocytes ; Bezafibrate ; Cell Proliferation ; Cytokines ; Fenofibrate ; Fibric Acids ; Interleukin-6 ; PPAR alpha ; RNA, Messenger ; Tumor Necrosis Factor-alpha

To establish a new high-throughput screening model for the agonist of PPARdelta, PPARdelta gene was obtained by reverse transcriptase-polymerase chain reaction (RT-PCR), and subcloned to pGEM-T Vector for sequencing, then the PPARdelta fragment was excised by restriction enzymes, and inserted into pTARGET Vector to construct expression vector pTARGET-ppARdelta. Insert three copies of PPRE into pGl3-promoter vector to construct expression vector pGl3-PPRE x 3-luc. The vector pTARGET-ppARdelta was transiently cotransfected with pGl3-PPRE x 3-luc into different cell lines to assay the expression levels of luciferase. The PPARdelta agonist screening model was established and optimized. Bezafibrate and linoleic acid can induce the expression of luciferase significantly and in a dose-dependent manner. This method can be used for high throughput screening for the agonist of PPARdelta, which might become lead compounds for new anti-atheroscleriosis or anti-adiposity drugs.
3T3 Cells ; Animals ; Bezafibrate ; pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; methods ; Genetic Vectors ; chemistry ; genetics ; HeLa Cells ; Humans ; Linoleic Acid ; pharmacology ; Lipids ; chemistry ; Luciferases ; genetics ; metabolism ; Mice ; PPAR delta ; agonists ; genetics ; Recombinant Fusion Proteins ; genetics ; metabolism ; Transfection ; methods

OBJECTIVETo investigate the effects and related mechanisms of bezafibrate, a ligand of peroxisome proliferator-activated receptors alpha (PPARalpha), on endothelial nitric oxide synthase (eNOS).

METHODSFirstly, in cultured bovine aorta endothelial cells (BAEC), the effects of bezafibrate on eNOS mRNA and protein levels were investigated by Northern blot and Western blot. The half-life of eNOS mRNA and NO production determined from BAECs treated with bezafibrate were performed by real-time quantitative PCR and NO assay. Next, the effects of bezafibrate on signal pathways in BAEC, through inhibitors of PPARalpha, PI3 kinase and MAPK, were investigated by Western blot. Then luciferase reporter gene driven by human eNOS promoter were cloned and transfected endothelial cells to see the effects of bezafibrate on eNOS promoter-driven luciferase activity.

RESULTSIn cultured BAEC, bezafibrate significantly upregulated eNOS expressions at protein and mRNA levels in a concentration-dependent fashion (50 - 200 micromol/L) (P < 0.05), and increased nitric oxide (NO) production, respectively[control (14.97 +/- 1.29) micromol/L, different concentration groups (25.12 +/- 1.25) micromol/L, (30.12 +/- 1.85) micromol/L, (33.47 +/- 1.22) micromol/L], and enhanced phosphorylation of eNOS-ser-1179 site (P < 0.05), but not eNOS-thr-497 site. Through real-time quantitative PCR, bezafibrate prolonged eNOS mRNA half-life from 3.1 hour to 6.1 hour were demonstrated. Further studies showed that bezafibrate treatments significantly enhanced dose-dependently luciferase activity (relative luciferase activity in 100 micromol/L and 200 micromol/L groups 4429.43 +/- 391.41 and 6187.5 +/- 307.53), compared with untreated luciferase reporter gene group (3361.81 +/- 316.85) (P < 0.05 and P < 0.01, respectively), and induced MAPK phosphorylation expression (P < 0.05 and P < 0.01, respectively). Then these effects of bezafibrate upregulated eNOS expressions could be blocked by PPARalpha antagonist, MAPK and PI3K inhibitor while not affected by PKC and MEK inhibitor (P < 0.01).

CONCLUSIONSBezafibrate can upregulate eNOS expression, enhance eNOS-ser-1179 site phosphorylation, increase NO production and stabilize eNOS mRNA through PPARalpha dependent pathway and PPARalpha independent MAPK and PI3K pathways. This mechanism provides additional anti-atherosclerotic and anti-hypertension benefits of bezafibrate in addition of lipid-lowering effects.

Animals ; Bezafibrate ; pharmacology ; Cattle ; Cells, Cultured ; Endothelial Cells ; drug effects ; metabolism ; Endothelium, Vascular ; Gene Expression Regulation ; MAP Kinase Signaling System ; Nitric Oxide Synthase Type III ; genetics ; metabolism ; PPAR alpha ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism

Bezafibrate, a fibric acid derivative related to clofibrate, is being used increasingly in the treatment of hypertriglycemia. It is relatively well tolerated at usual dosage, and has a low incidence of adverse reactions. But we had recently observed a reversible deterioration of renal function requiring hemodialysis, presumed to be caused by bezafibrate treatment in a patient with diabetic nephropathy. A 55 year old man was admitted with complaints of general weakness and painful lower extremities. He had taken bezafibrate (200 mg every 12 hours) for the previous 4 months because of hypertriglycemia. After admission, the drug was withdrawn, and he was treated conservatively management with hydration and diuretics for bezafibrate induced rhabdomyolysis. Nevertheless, his symptom was not improved, so he was taken even hemodialysis. These findings suggested that bezafibrate should be admistered with great caution to patient with renal insufficiency. When it is admistered, CK, LDH, aldolase, and sGOT levels have to be checked for early detection of potential side effect.
Aspartate Aminotransferases ; Bezafibrate* ; Clofibrate ; Diabetic Nephropathies ; Diuretics ; Fructose-Bisphosphate Aldolase ; Humans ; Incidence ; Lower Extremity ; Middle Aged ; Renal Dialysis ; Renal Insufficiency ; Rhabdomyolysis*

Suction-assisted lipoplasty is now flrequently-performed pre cedure in plastic surgery, but it has several drawback including bleeding contour irregularity due to its traumatic nature. The recently introduced ultrasound-assisted lipoplasty (UAL) technique uses ultrasonic energy which has specificity in lower density tissue like fat tissue. Therefore, UAL can minimize these compli cations. We performed UAL in 21 patients from OCt. 1988 to Jun 1999. There were 17 females and 4 males, and patient age ranged from 18 to 52 years(average 40 years). A total of 58 areas were operated on for an averge of 28 areas per patient. We used a fivestage technique consisting of tumescent infiltration, ultrasonund treatment, emulsion suction, endermology, and postperative pressuregarment application. Total volume (fluid and fat) removed ranged from 200 to 4,050 cc(averge 1,750 cc) per patient and the lipocrit within the aspirate was 4-8%, which was significantly lower compared with traditional liposuction Residual emulsion was evacuated by endermology and pressuregarment was applied to all patients for postoperative 2-3 months. Pestoperative complications were seroma, induration, and paresthesia, but all these problems resolved spontaneously within a month. One patient required secondary UAL for correction of excess fat at the medial knee. We believe that UAL is a safe and excellent technology in liposuction because of reduced surgical bleeding and good contral of body contour.
Bezafibrate ; Cations ; Female ; Hemorrhage ; Humans ; Knee ; Lipectomy ; Male ; Paresthesia ; Sensitivity and Specificity ; Seroma ; Suction ; Surgery, Plastic ; Ultrasonics

PURPOSE: Cryopreservation has been the standard method of storing hematopoietic cells for the past 20 years, but this prdegrees Cedure is laborious and expensive. So, we evaluated the hematopoietic recovery of stored PBSCs at 4degrees C for a variable storage period MATERIALS AND METHODS: Eight leukapheresis products were kept unprdegrees Cessed at 4degrees C for 96 hours. To evaluate the effect of storage period on the hematopoietic recovery of PBSCs, assays for viability of mononuclear cells (MNCs), CFU-GM colony counts and CD34 cell counts were performed every 24 hours after PBSC collection. We tried to compare hematopoetic recovery of stored PBSCs at 4degrees C with that of cryopreserved PBSCs by using repeated measures ANOVA. RESULTS: Viability of MNCs, CFU-GM colony counts and CD34 cell counts were monitored at 24 hour, 48 hour, 72 hour and 96 hour after PBSC collection. Data are expressed as percentage of baseline value and shown as mean s.d.; MNCs viability (96+/-2%, 94+/-2%, 92+/-2%, 88+/- 3%), CFU-GM colony counts (87+/-10%, 79+/-11%, 65+/-13%, 56+/-15%), and CD34 cell counts (93+/-13%, 93+/-12%, 88+/-14%, 85+/-19%). After storing PBSCs at 4degrees C for 96 hours, viability of MNCs and CFU-GM colony counts were significantly reduced (p<0.05) except CD34 cell concentration (p>0.05). Prdegrees Cedures of controlled-rate freezing and thawing resulted in a notable loss of viability (77+/-9%) and CFU-GM colony count (71+/-29%). CFU-GM colony counts of 72 hour-stored PBSCs at 4degrees C was similar to those of cryopreserved PBSCs. CONCLUSION: If G-CSF mobilized PBSCs are stored at 4degrees C in less than 72 hours after collection, those hematopoietic recovery would be comparable to that of cryopreserved stem cells which are achieved by the rate-control freezer.
Bezafibrate ; Cell Count ; Cryopreservation ; Freezing ; Granulocyte Colony-Stimulating Factor ; Granulocyte-Macrophage Progenitor Cells ; Leukapheresis ; Stem Cells*

To evaluate the sensitivity and specificity of transthoracic fine needle aspiration cytology(TFNAC) in the preoperative diagnosis of pulmonary nodules, a retrospective analysis was carried out on a consecutive series of 200 TFNACs. They included 186 primary malignant tumors, 66 squamous cell carcinomas, 65 adenocarcinomas, 36 small cell carcinomas, 7 large cell carcinomas, 4 carcinoids, 8 others, 9 metastatic tumors, and 5 benign tumors. On cytohistologic correlation of malignant pulmonary tumors, the pro- cedure had a sensitivity of 97.3% and a specificity of 100%. A 86.6% correct correlation between the cytologic and histologic diagnoses was achieved. Five out of the 7 undifferentiated large cell carcinomas, 10 out of the 65 adenocarcinomas, 2 out of the 36 small cell carcinomas, and 2 out of the 66 squamous cell carcinomas were turned out to be mistyped in cytologic diagnosis. We concluded that TFNAC is a highly sensitive and specific preoperative diagnostic procedure in the investigation of patients with discrete pulmonary nodules in whom the specific cell type of the malignant neoplasm has important implications in treatment modality and prognosis.
Adenocarcinoma ; Bezafibrate ; Biopsy, Fine-Needle ; Carcinoid Tumor ; Carcinoma, Large Cell ; Carcinoma, Small Cell ; Carcinoma, Squamous Cell ; Diagnosis ; Endometrial Neoplasms ; Female ; Humans ; Hydronephrosis* ; Kidney* ; Natural History* ; Papanicolaou Test ; Prognosis ; Retrospective Studies ; Sensitivity and Specificity

Primary success rate of endonasal dacryocystorhinostomy has been reported lower than that of conventional cedure. Gradual stenosis of mucosal ostium would progress until 6 to 10 months following operation and a longterm follow-up should be necessary. Endonasal dacryocystorhinostomy was performed in 100 patients[118 eyes]between July 1993 and March 1998 at the Department of Ophthalmology, Yeungnam University College of Medicine. After the follow-up period of 1 to 4 years[average 16.2 months], longterm success rate, postoperative omplications, and factors to affect success rate were studied. The success rate of primary operation was 89.83%, and the success rate after secondary revision of the ostium was up to 99.15%. Granulation tissue formation was the most common postoperative complication, and other complications included protrusion of silicone tube, membranous obstruction, partial obstruction of common canaliculus, canaliculitis and prolapse of orbital fat. Factors to obtain good success rate were careful and acurate surgical technique to achieve large mucosal ostium, postoperative management, antibiotics and steroid medication, etc. Long-term surgical efficacy of endonasal dacryocystorhinostomy was similar to skin approach and secondary success rate following revision was very satisfactory.
Anti-Bacterial Agents ; Bezafibrate ; Constriction, Pathologic ; Dacryocystorhinostomy ; Follow-Up Studies ; Granulation Tissue ; Ophthalmology ; Orbit ; Postoperative Complications ; Prolapse ; Silicones ; Skin ; Canaliculitis