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The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/ß-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
Assuntos
Intestinos , Fígado , Animais , Camundongos , Proliferação de Células , Fígado/metabolismo , PPAR alfa/metabolismo , Proteômica , Células-Tronco/metabolismo , Via de Sinalização Wnt , Intestinos/citologia , Intestinos/metabolismoRESUMO
DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a "second hit" DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology. Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. 18F-FDG autoradiography explored metabolic alterations in brain networks. Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism, specifically in fatty acid ß-oxidation and glucose metabolism. Fenofibrate induced gene expression changes in wt rats but failed in ∆ETorA rats. Fenofibrate increased dystonia-like movements in wt rats but reduced them in ∆ETorA rats. 18F-FDG autoradiography indicated modified glucose metabolism in motor and somatosensory cortices and striatum in both ∆ETorA and wt rats post-injury. Our findings highlight perturbed energy metabolism pathways in DYT-TOR1A dystonia, emphasizing compromised PPARα agonist efficacy in the striatum. Furthermore, we identify impaired glucose metabolism in the brain network, suggesting a potential shift in energy substrate utilization in dystonic DYT-TOR1A rats. These results contribute to understanding the pathophysiology and potential therapeutic targets for DYT-TOR1A dystonia.
Assuntos
Distonia , Distúrbios Distônicos , Fenofibrato , Ratos , Animais , Distonia/genética , Distonia/metabolismo , Roedores/metabolismo , Fluordesoxiglucose F18 , PPAR alfa/metabolismo , Distúrbios Distônicos/genética , Encéfalo/metabolismo , Metabolismo Energético , GlucoseRESUMO
BACKGROUND: The beneficial effects of fenofibrate on atherosclerotic cardiovascular disease (ASCVD) outcomes in patients with diabetes and statin treatment are unclear. We investigated the effects of fenofibrate on all-cause mortality and ASCVD in patients with diabetes, high triglyceride (TG) levels and statin treatment. METHODS: We performed a nationwide propensity-score matched (1:1) cohort study using data from the National Health Information Database in the Republic of Korea from 2010 to 2017. The study included 110,723 individuals with diabetes, TG levels ≥ 150 mg/dL, and no prior diagnoses of ASCVD who used statins and fenofibrate, and an equal matched number of similar patients who used statins alone (control group). The study outcomes included newly diagnosed myocardial infarction (MI), stroke, both (MI and/or stroke), and all-cause mortality. RESULTS: Over a mean 4.03-year follow-up period, the hazard ratios (HR) for outcomes in the fenofibrate group in comparison to the control group were 0.878 [95% confidence interval (CI) 0.827-0.933] for MI, 0.901 (95% CI 0.848-0.957) for stroke, 0.897 (95% CI 0.858-0.937) for MI and/or stroke, and 0.716 (95% CI 0.685-0.749) for all-cause death. These beneficial effects of fenofibrate were consistent in the subgroup with TG 150-199 mg/dL but differed according to low-density lipoprotein cholesterol (LDL-C) levels. CONCLUSION: In this nationwide propensity-score matched cohort study involving individuals with diabetes and TG ≥ 150 mg/dL, the risk of all-cause death and ASCVD was significantly lower with fenofibrate use in conjunction with statin treatment compared to statin treatment alone. However, this finding was significant only in individuals with relatively high LDL-C levels.
Assuntos
Biomarcadores , Bases de Dados Factuais , Fenofibrato , Fatores de Risco de Doenças Cardíacas , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipolipemiantes , Pontuação de Propensão , Humanos , Fenofibrato/uso terapêutico , Fenofibrato/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Hipolipemiantes/uso terapêutico , Hipolipemiantes/efeitos adversos , Idoso , Resultado do Tratamento , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Medição de Risco , Fatores de Tempo , Biomarcadores/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/mortalidade , Diabetes Mellitus/sangue , Triglicerídeos/sangue , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/sangue , Causas de Morte , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/sangue , Estudos Retrospectivos , Fatores de Proteção , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/sangueRESUMO
The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate.
Assuntos
Fenofibrato , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Fator 15 de Diferenciação de Crescimento/farmacologia , Fator 15 de Diferenciação de Crescimento/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Transição Epitelial-Mesenquimal , Lipídeos , Proliferação de CélulasRESUMO
BACKGROUND: Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large-scale randomised trials have yet investigated this hypothesis. METHODS: LENS is a streamlined randomised double-masked placebo-controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non-referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. RESULTS: Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. CONCLUSIONS: LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid-2024. TRIAL REGISTRATIONS: NCT03439345; ISRCTN15073006; EuDRACT 2016-002656-24.
Assuntos
Retinopatia Diabética , Fenofibrato , Humanos , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Idoso , Fenofibrato/uso terapêutico , Seleção de Pacientes , Escócia/epidemiologia , Hipolipemiantes/uso terapêutico , Progressão da Doença , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Projetos de Pesquisa , AdultoRESUMO
AIM: Previous studies have shown that fenofibrate improves outcomes such as albuminuria and estimated glomerular filtration rate decline. We hypothesize that fenofibrate has renoprotective effects and prevents or delays the development of end-stage renal disease. The objective of this study is to investigate the risk of incident end-stage renal disease in relation to fenofibrate treatment in patients who are already taking statins. MATERIALS AND METHODS: We performed a nationwide population-based cohort study using data from the Korea National Health Information Database from 2010 to 2017. Among adults using statins, 413 715 fenofibrate users were compared with 413 715 fenofibrate non-users after 1:1 age, sex and triglyceride matching. The endpoint of this study was incident end-stage renal disease. RESULTS: During a median 3.96-year follow-up, the incidence per 1000 person years of end-stage renal disease was lower in fenofibrate users than in fenofibrate non-users (0.885 vs. 0.960, p < 0.0001). The hazard ratio for end-stage renal disease was lower (0.763, 95% confidence interval 0.710-0.821) in fenofibrate users. This association was significant in patients with hypertension, proteinuria and an estimated glomerular filtration rate <60 mL/min/1.732. CONCLUSIONS: Fenofibrate use in patients taking statins with either hypertension, proteinuria, or decreased estimated glomerular filtration rate is associated with a low risk of incident end-stage renal disease. To confirm the renoprotective effect of fenofibrate in chronic kidney disease, a randomized controlled trial is warranted.
RESUMO
Phototherapy is the standard treatment for neonatal jaundice. We aimed to review the efficacy and safety of fenofibrate as an adjunct therapy. Twelve databases were searched and a systematic review and meta-analysis were conducted. Mean change (MC), mean difference (MD), and risk ratios (RR) with a 95% confidence interval (CI) were calculated using a random effects model. The GRADE approach was used to evaluate the evidence's certainty. Nine randomized trials were included. The MC of total serum bilirubin (mg/dL) was significant at 12, 24, 36, 48, and 72 h with respective MC (95% CI) values of -0.46 (-0.61, -0.310), -1.10 (-1.68, -0.52), -2.06 (-2.20, -1.91), -2.15 (-2.74, -1.56), and -1.13 (-1.71, -0.55). The FEN + PT group had a shorter duration of phototherapy (MD: -14.36 h; 95% CI: -23.67, -5.06) and a shorter hospital stay (MD: -1.40 days; 95% CI: -2.14, -0.66). There was no significant difference in the risk of complications (RR: 0.89; 95% CI: 0.54, 1.46) or the need for exchange transfusion (RR: 0.58; 95% CI: 0.12, 2.81). The certainty of the evidence was very low for all outcomes. In conclusion, fenofibrate might be a safe adjunct to neonatal phototherapy. Larger randomized controlled trials are needed for the confirmation of these results.
Assuntos
Fenofibrato , Hiperbilirrubinemia Neonatal , Icterícia Neonatal , Recém-Nascido , Humanos , Fenofibrato/efeitos adversos , Hiperbilirrubinemia Neonatal/terapia , Icterícia Neonatal/terapia , Fototerapia/efeitos adversos , Fototerapia/métodos , Fatores de TempoRESUMO
Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.
Assuntos
Biogênese de Organelas , Peroxissomos , Camundongos , Animais , Peroxissomos/metabolismo , Mitocôndrias/metabolismo , Fígado/metabolismo , AutofagiaRESUMO
BACKGROUND: Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model. METHODS: Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1ß, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated. RESULTS: VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen. CONCLUSION: Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.
Assuntos
Injúria Renal Aguda , Febuxostat , Fator 2 Relacionado a NF-E2 , NF-kappa B , Ratos Wistar , Transdução de Sinais , Vancomicina , Animais , Masculino , Ratos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Antibacterianos/farmacologia , Antibacterianos/toxicidade , Ciclo-Oxigenase 2/metabolismo , Febuxostat/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama , Transdução de Sinais/efeitos dos fármacos , Vancomicina/toxicidade , Vancomicina/farmacologiaRESUMO
Bone is a complex tissue that fulfills the role of a resistance structure. This quality is most commonly assessed by bone densitometry, but bone strength may not only be related to bone mineral density but also to the preservation of bone cytoarchitectonics. The study included two groups of rats, ovariectomized and non-ovariectomized. Each group was divided into three batches: control, simvastatin-treated, and fenofibrate-treated. In the ovariectomized group, hypolipidemic treatment was instituted at 12 weeks post ovariectomy. One rat from each of the 6 batches was sacrificed 8 weeks after the start of treatment in the group. The experimental study was performed using a Bruker Minispec mq 20 spectrometer operating at a frequency of 20 MHz, subsequently also performed by 1H T2-T2 molecular exchange maps. The results were represented by T2-T2 molecular exchange maps that showed, comparatively, both pore size and their interconnectivity at the level of the femoral epiphysis, being able to evaluate both the effect of estrogen on bone tissue biology and the effect of the lipid-lowering medication, simvastatin, and fenofibrate, in both the presence and absence of estrogen. T2-T2 molecular exchange maps showed that the absence of estrogen results in an increase in bone tissue pore size and interconnectivity. In the presence of estrogen, lipid-lowering medication, both simvastatin and fenofibrate alter bone tissue cytoarchitectonics by reducing pore interconnectivity. In the absence of estrogen, fenofibrate improves bone tissue cytoarchitectonics, the T2-T2 molecular exchange map being similar to that of non-osteoporotic bone tissue.
RESUMO
We investigated the age-related effects of the lipid-lowering drug fenofibrate on renal stress-associated effectors. Young and old rats were fed standard chow with 0.1% or 0.5% fenofibrate. The kidney cortex tissue structure showed typical aging-related changes. In old rats, 0.1% fenofibrate reduced the thickening of basement membranes, but 0.5% fenofibrate exacerbated interstitial fibrosis. The PCR array for stress and toxicity-related targets showed that 0.1% fenofibrate mildly downregulated, whereas 0.5% upregulated multiple genes. In young rats, 0.1% fenofibrate increased some antioxidant genes' expression and decreased the immunoreactivity of oxidative stress marker 4-HNE. However, the activation of cellular antioxidant defenses was impaired in old rats. Fenofibrate modulated the expression of factors involved in hypoxia and osmotic stress signaling similarly in both age groups. Inflammatory response genes were variably modulated in the young rats, whereas old animals presented elevated expression of proinflammatory genes and TNFα immunoreactivity after 0.5% fenofibrate. In old rats, 0.1% fenofibrate more prominently than in young animals induced phospho-AMPK and PGC1α levels, and upregulated fatty acid oxidation genes. Our results show divergent effects of fenofibrate in young and old rat kidneys. The activation of multiple stress-associated effectors by high-dose fenofibrate in the aged kidney warrants caution when applying fenofibrate therapy to the elderly.
Assuntos
Fenofibrato , Humanos , Ratos , Animais , Idoso , Fenofibrato/farmacologia , Antioxidantes/farmacologia , Rim/metabolismo , Hipolipemiantes/farmacologia , Expressão GênicaRESUMO
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.
Assuntos
Acetil-CoA Carboxilase , Fenofibrato , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica , Humanos , Acetil-CoA Carboxilase/antagonistas & inibidores , Apolipoproteínas B/biossíntese , Fenofibrato/uso terapêutico , Fenofibrato/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/biossíntese , Triglicerídeos/sangue , LDL-Colesterol/biossínteseRESUMO
BACKGROUND & AIMS: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). METHODS: This was a nationwide observational cohort study conducted from August 2017 until June 2021. RESULTS: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. CONCLUSION: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.
Assuntos
Colangite , Cirrose Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Fosfatase Alcalina , Alanina Transaminase , Ácidos Fíbricos/uso terapêutico , Bilirrubina , Colangite/tratamento farmacológicoRESUMO
Fenofibrate (FEN) is an antilipidemic drug that increases the activity of the lipoprotein lipase enzyme, thus enhancing lipolysis; however, it may cause myopathy and rhabdomyolysis in humans. Coenzyme Q10 (CoQ10) is an endogenously synthesized compound that is found in most living cells and plays an important role in cellular metabolism. It acts as the electron carrier in the mitochondrial respiratory chain. This study aimed to elucidate FEN-induced skeletal muscle changes in rats and to evaluate CoQ10 efficacy in preventing or alleviating these changes. Forty adult male rats were divided equally into four groups: the negative control group that received saline, the positive control group that received CoQ10, the FEN-treated group that received FEN, and the FEN + CoQ10 group that received both FEN followed by CoQ10 daily for 4 weeks. Animals were sacrificed and blood samples were collected to assess creatine kinase (CK). Soleus muscle samples were taken and processed for light and electron microscopic studies. This study showed that FEN increased CK levels and induced inflammatory cellular infiltration and disorganization of muscular architecture with lost striations. FEN increased the percentage of degenerated collagen fibers and immune expression of caspase-3. Ultrastructurally, FEN caused degeneration of myofibrils with distorted cell organelles. Treatment with CoQ10 could markedly ameliorate these FEN-induced structural changes and mostly regain the normal architecture of muscle fibers due to its antifibrotic and antiapoptotic effects. In conclusion, treatment with CoQ10 improved muscular structure by suppressing oxidative stress, attenuating inflammation, and inhibiting apoptosis.
Assuntos
Fenofibrato , Doenças Musculares , Humanos , Adulto , Masculino , Ratos , Animais , Fenofibrato/farmacologia , Fenofibrato/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Fibras Musculares EsqueléticasRESUMO
PURPOSE OF REVIEW: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline-recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals. RECENT FINDINGS: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients.
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Anticolesterolemiantes , Aterosclerose , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , LDL-Colesterol , Ezetimiba/uso terapêutico , Dislipidemias/tratamento farmacológico , Quimioterapia Combinada , Aterosclerose/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Resultado do TratamentoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries and China. Fenofibrate (FNB) can activate peroxisome proliferator-activated receptor α (PPARα) to increase fatty acid oxidation and ameliorate NAFLD. However, the application of FNB is limited in clinic due to its poor water solubility and low oral bioavailability. In this study, FNB-loaded nanoparticles (FNB-NP) based on a reactive oxygen species (ROS)-responsive peroxalate ester derived from vitamin E (OVE) and an amphiphilic conjugate 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG) were developed to enhance the preventive effects of FNB against NAFLD. In in vitro studies, FNB-NP displayed a high encapsulation efficiency of 97.25 ± 0.6% and a drug loading efficiency of 29.67 ± 0.1%, with a size of 197.0 ± 0.2 nm. FNB released from FNB-NP was dramatically accelerated in the medium with high H2O2 concentrations. Moreover, FNB-NP exhibited well storage stability and plasma stability. In pharmacokinetic (PK) studies, FNB-NP, compared with FNB crude drug, significantly increased the AUC0ât and AUC0â∞ of the plasma FNB acid by 3.3- and 3.4-fold, respectively. In pharmacodynamics (PD) studies, compared with an equal dose of FNB crude drug, FNB-NP more significantly reduced hepatic lipid deposition via facilitating FNB release in the liver and further upregulating PPARα expression in NAFLD mice. Meanwhile, oxidative stress in NAFLD was significantly suppressed after FNB-NP administration, suggesting that OVE plays a synergistic effect on antioxidation. Therefore, ROS-sensitive FNB delivery formulations FNB-NP enhance the preventive effects of FNB against NAFLD and could be further studied as a promising drug for the treatment of NAFLD in clinic.
Assuntos
Fenofibrato , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fenofibrato/uso terapêutico , Fenofibrato/farmacocinética , PPAR alfa/metabolismo , PPAR alfa/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARß/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome Metabólica/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , PPAR alfa/metabolismo , Inflamação/metabolismo , Lipídeos/uso terapêuticoRESUMO
Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200-230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1ß, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination.
Assuntos
Fenofibrato , Insuficiência Renal , Ratos , Masculino , Animais , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Pioglitazona/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/farmacologia , Fenofibrato/farmacologia , Fenofibrato/metabolismo , Rim , Doxorrubicina/efeitos adversos , Estresse Oxidativo , Hipoglicemiantes/farmacologia , ApoptoseRESUMO
Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n = 119) were allocated to four groups and gavaged with either 10 mL·kg-1 body mass 0.5% dimethyl sulfoxide, 100 mg·kg-1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.
Assuntos
Fenofibrato , Masculino , Ratos , Animais , Feminino , Fenofibrato/farmacologia , Frutose/efeitos adversos , Ratos Sprague-Dawley , Dieta , Colesterol , TriglicerídeosRESUMO
In 6002 Australian adults with type 2 diabetes and a median 5-year follow-up in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, baseline socioeconomic status (SES) and self-reported education level were not related to development of on-trial sight-threatening diabetic retinopathy. Similarly, in a retinal photography substudy (n = 549), two-step diabetic retinopathy progression was not related to SES or education.