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Background/Purpose: NF-κB family of transcription factors are the major contributors to malignant tumor progression, maintenance of cancer stemness, and enhancement of chemoresistance. Fenofibrate, a lipid-lowering drug, has been considered as a candidate for repurposing in the treatment of cancer through various pathways involved in apoptosis, cell cycle, migration, and invasion, including NF-κB. Nevertheless, whether fenofibrate possesses the potential to inhibit cancer stemness remained to be examined. Methods: Cytotoxicity of fenofibrate was estimated by MTT assay. The cells expressing stemness marker were detected by flow cytometry using ALDEFLUOR™ Kit. The secondary sphere formation assay was used to assess the self-renewal ability. Transwell system was used to evaluate migration and invasion capacities. NF-κB expression was measured by the immunoblotting system. Results: In the present study, we demonstrated that fenofibrate inhibited cell viability, expression of stemness marker, self-renewal, migration, and invasion capacities in a dose-dependent manner. Of note, fenofibrate targeted cancer stem cells of oral squamous cell carcinoma (OSCC-CSCs) and had minimal effects on normal cells. Moreover, administration of fenofibrate at a lower concentration was sufficient to diminish the expression of NF-κB p50 and p65. Conclusion: This study demonstrated that the inhibitory effects of fenofibrate on OSCC-CSCs properties may be associated with downregulation of NF-κB. These results indicated that administration of fenofibrate may serve as an alternative strategy for OSCC therapy.

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases. In most cases, NAFLD progresses from benign steatosis to steatohepatitis (NASH), and then to cirrhosis. No treatment is currently approved for NAFLD/NASH in the clinic. Fenofibrate (FENO) has been clinically used to treat dyslipidemia for more than a half century, but its effects on NASH are not established. FENO's half-life is quite different between rodent and human. The aim of this study was to investigate the potential of pharmacokinetic-based FENO regime for NASH treatment and the underlying mechanisms. Methods: Two typical mouse NASH models, methionine-choline deficient (MCD) diet-fed mice and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, were used. MCD model was designed as therapeutic evaluation in experiment 1 and CDAHFD model was designed as preventive in experiment 2. Three doses of FENO (5, 25, 125 mg/kg), two times a day (BID), were administered to the above models. Serum markers of liver injury, cholestasis, and the histology of liver tissues were investigated. Normal mice were used as a model in experiment 3 for toxicity evaluation, Quantitative-PCR and Western Blot assays were used to investigate the inflammatory responses, bile acid synthesis as well as lipid catabolism. Results: Mice on the MCD and CDAHFD diets developed steatohepatitis as expected. Treatment with FENO (25 mg/kg·BID) significantly decreased hepatic steatosis, inflammation and fibrosis in both therapeutic and preventive models. In the MCD model, the therapeutic action of FENO (25 mg/kg·BID) and 125 mg/kg·BID on histopathology and the expression of inflammatory cytokines were comparable. In reducing macrophage infiltration and bile acid load, FENO (25 mg/kg·BID) was superior to 125 mg/kg·BID. In all the aspects mentioned above, FENO (25 mg/kg·BID) was the best among the 3 doses in the CDAHFD model. In a third experiment, the effects of FENO (25 mg/kg·BID) and 125 mg/kg·BID on lipid catabolism were comparable, but 125 mg/kg·BID increased the expression of inflammatory factors and bile acid load. In both models, FENO (5 mg/kg·BID) showed little effect in hepatic steatosis and inflammation, neither the adverse effects. FENO (125 mg/kg·BID) aggravated liver inflammation, increased bile acid synthesis, and promoted the potential of liver proliferation. In toxicity risk assay, FENO (25 mg/kg·BID) treatment showed low potential to trigger bile acid synthesis, inflammation and hepatocyte proliferation. Conclusion: A new regime, FENO (25 mg/kg·BID) is potentially a therapeutic strategy for the NASH treatment. Translational medicine is warranted to prove its effectiveness in the clinic. [ABSTRACT FROM AUTHOR]

The complexity of the tissue is mainly due to the fact that bone is the result of a permanent process of osteogenesis and bone resorption, and the balance between these two processes ensures the health of the tissue. This balance, as it has been shown, can be influenced by a very large number of factors, and most evidence supports the importance and role of the hormonal factor as one of the main determinants in the development of osteoporosis. Alongside this, it is important to assess the influence that chronic medication, such as lipid-lowering medication can have on bone tissue, besides the hormonal factor. Osteoporosis, the main chronic pathology of bone tissue, is assessed from the perspective of bone mineral density, but this assessment cannot provide information on the cytoarchitectonics of bone tissue, which is particularly important when talking about bone as a resistance structure, since the main complication of osteoporosis is the fracture produced on pathological bone. The measurement of 2D T2-T2 molecular exchange maps allows the assessment of bone tissue cytoarchitectonics because it offers the possibility to appreciate both the pores and their communication, thus providing a picture of the resistance that a bone structure may have under the influence of hormonal factors, correlated or not with various medications that may influence the organic matrix or inorganic component of bone tissue. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase inhibitors (statins), lipoprotein lipase activators (PPARα agonists) or fibrates are commonly used for controlling increased lipid levels in hyperlipidemia. Fenofibrate (FEN) belongs to the second generation prodrug fibric acid (isobutyric acid) derivative belonging to lipoprotein lipase activator class of drug. Results of clinical studies suggest that FEN can substantially reduce severe acute respiratory syndrome coronavirus 2. alpha and beta variant infection in human cell efficiently. This review article provides an in-depth examination of critical analytical methodologies used in the pharmaceutical analysis of FEN in pure forms, biological samples and pharmaceuticals. According to literature study reports several analytical techniques have been used for determination of FEN alone or in the combined dosage forms. Based on the literature, it was determined that high-performance liquid chromatography and UV/vis-spectrophotometry are the most widely used methods for FEN analysis. Sahoo et al. have developed the best HPLC method in bulk and pharmaceutical dosage form with the retention time of 19.268 min using phosphate buffer (pH 3.0): acetonitrile in the ratio of 30:70 (% v/v) as mobile phase. The information presented here may provide a solid foundation for future research on FEN in the field of drug analysis. [ABSTRACT FROM AUTHOR]

There are limited treatments currently available for retinal diseases such as age-related macular degeneration (AMD). Cell-based therapy holds great promise in treating these degenerative diseases. Three-dimensional (3D) polymeric scaffolds have gained attention for tissue restoration by mimicking the native extracellular matrix (ECM). The scaffolds can deliver therapeutic agents to the retina, potentially overcoming current treatment limitations and minimizing secondary complications. In the present study, 3D scaffolds made up of alginate and bovine serum albumin (BSA) containing fenofibrate (FNB) were prepared by freeze-drying technique. The incorporation of BSA enhanced the scaffold porosity due to its foamability, and the Maillard reaction increased crosslinking degree between ALG with BSA resulting in a robust scaffold with thicker pore walls with a compression modulus of 13.08 KPa suitable for retinal regeneration. Compared with ALG and ALG-BSA physical mixture scaffolds, ALG-BSA conjugated scaffolds had higher FNB loading capacity, slower release of FNB in the simulated vitreous humour and less swelling in water and buffers, and better cell viability and distribution when tested with ARPE-19 cells. These results suggest that ALG-BSA MR conjugate scaffolds may be a promising option for implantable scaffolds for drug delivery and retinal disease treatment. [ABSTRACT FROM AUTHOR]

• Anti-VEGF is not sustainable for all age-related macular degeneration (AMD) patients. New treatments should be studied. • Methotrexate, fenofibrate, levodopa, and metformin have promising effects in AMD. • Medications including hydralazine & minoxidil have potential adverse effects on AMD. • Continued research of systemic drugs may assist in developing new AMD treatment. Age-related macular degeneration (AMD) is the leading cause of severe loss of central vision among people over 50. The pathophysiology of the disease is multifactorial and can be attributed to genetics, aging, inflammation, environmental factors, and lifestyle factors including smoking, diet, obesity, and alcohol consumption. While there is no treatment for dry AMD, the current standard treatment for wet AMD is an intraocular injection of anti-vascular endothelial growth factor—an effective, yet expensive, therapy that requires ongoing treatment. As the aging population continues to grow, and AMD diagnoses continue to rise, new treatments should be explored to reduce vision complications and decrease treatment burdens. Many systemic conditions have progressive pathological changes that may affect AMD, particularly those affecting systemic vasculature like diabetes and cardiovascular status. Consequently, systemic drugs used to treat coexistent systemic diseases may influence some of the pathogenic mechanisms of AMD and lead its progression or delay. In this review we explore the current literature to summarize the findings of the reported effects of antihypertensive, immunosuppressants, cholesterol lowering agents, nonsteroidal anti-inflammatory drugs, dopamine precursors, hypoglycemic agents, and anticoagulants on AMD. [ABSTRACT FROM AUTHOR]

Pre-metabolic syndrome (pre-MetS) may represent the best transition phase to start treatments aimed at reducing cardiometabolic risk factors of MetS. In this study, we investigated the effects of the marine microalga Tisochrysis lutea F&M-M36 (T. lutea) on cardiometabolic components of pre-MetS and its underlying mechanisms. Rats were fed a standard (5% fat) or a high-fat diet (20% fat) supplemented or not with 5% of T. lutea or fenofibrate (100 mg/Kg) for 3 months. Like fenofibrate, T. lutea decreased blood triglycerides (p < 0.01) and glucose levels (p < 0.01), increased fecal lipid excretion (p < 0.05) and adiponectin (p < 0.001) without affecting weight gain. Unlike fenofibrate, T. lutea did not increase liver weight and steatosis, reduced renal fat (p < 0.05), diastolic (p < 0.05) and mean arterial pressure (p < 0.05). In visceral adipose tissue (VAT), T. lutea, but not fenofibrate, increased the β3-adrenergic receptor (β3ADR) (p < 0.05) and Uncoupling protein 1 (UCP-1) (p < 0.001) while both induced glucagon-like peptide-1 receptor (GLP1R) protein expression (p < 0.001) and decreased interleukin (IL)-6 and IL-1β gene expression (p < 0.05). Pathway analysis on VAT whole-gene expression profiles showed that T. lutea up-regulated energy-metabolism-related genes and down-regulated inflammatory and autophagy pathways. The multitarget activity of T. lutea suggests that this microalga could be useful in mitigating risk factors of MetS. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effects of the hypolipemic drug fenofibrate (FF) and aging on the expression of factors/enzymes involved in brown adipose tissue (BAT) function and browning of white adipose tissue epididymal (eWAT) and subcutaneous (sWAT) depots. Young-adult and old male Wistar rats were fed standard chow (control) or supplemented with 0.1% or 0.5% FF for 30 days. Tissue samples were analysed for gene expression and protein content, and stained with Oil Red O or hematoxylin and eosin. In BAT of young rats, 0.5% FF increased only Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 1 (CITED1) protein content and Fgf21 and Gpr109A mRNA expression. The expression of oxidative metabolism related genes (Pgc1a, Cpt1b, Mcad) decreased after 0.5% FF. In BAT of old rats, FF did not affect UCP1 and CITED1 content and had little effect on gene expression. Oil Red O staining of BAT revealed no changes in lipid droplet area upon treatment in either age group. In eWAT of young rats, 0.1FF elevated UCP1 protein content and Ucp1, Pgc-1a, and Mcad expression, whereas 0.5% FF increased PPARa content and Pgc-1a, Cpt1b, Mcad, and Gpr109A levels. In eWAT of old rats, only 0.1FF increased Pgc1a and Mcad expression. In both age groups median cell area of eWAT adipocytes was reduced after 0.5% FF. In sWAT Ucp1 gene expression was very low and UCP1 protein was undetectable. FF upregulated Ucp1, Cited1, Eva1, and Cpt1b expression in sWAT of young rats, with diminished effects in old rats. In both age groups 0.5% FF increased Fgf21 expression in sWAT. Median cell area of sWAT adipocytes decreased only in young rats treated with 0.5% FF. Our results reveal that fenofibrate differentially affects gene expression in BAT, with diminished effects in old compared to young rats. In WAT of young rats FF modestly stimulates the expression of factors/enzymes involved in lipid oxidative metabolism and browning. Aging reduces both these effects. Gpr109A may present a novel gene target upregulated by FF in BAT and eWAT. [ABSTRACT FROM AUTHOR]

The objective of study was to investigate the effects of different doses of simvastatin and fenofibrate on malondialdehyde (MDA) and reduced glutathione (GSH) in the plasma, liver, and brain tissue of male normolipidaemic and hyperlipidaemic rats. Normolipidaemic (Wistar) rats were receiving 10 or 50 mg/kg a day of simvastatin or 30 or 50 mg/kg a day of fenofibrate. Hyperlipidaemic (Zucker) rats were receiving 50 mg/kg/day of simvastatin or 30 mg/kg/day of fenofibrate. Control normolipidaemic and hyperlipidaemic rats were receiving saline. Simvastatin, fenofibrate, and saline were administered by gavage for three weeks. In normolipidaemic rats simvastatin and fenofibrate showed similar and dose-independent effects on plasma and brain MDA and GSH concentrations. Generally, plasma and brain MDA decreased, while brain GSH concentration increased. In hyperlipidaemic rats simvastatin did not affect plasma and brain MDA and GSH concentrations but significantly decreased liver GSH. Fenofibrate decreased plasma and liver MDA but increased brain MDA. In both rat strains fenofibrate significantly decreased liver GSH concentrations, most likely because fenofibrate metabolites bind to GSH. Our findings suggest that simvastatin acts as an antioxidant only in normolipidaemic rats, whereas fenofibrate acts as an antioxidant in both rat strains. [ABSTRACT FROM AUTHOR]

Objective: To describe the therapeutic protocol used to normalize severe hypertriglyceridemia in a dog. Case Summary: A 7‐month‐old, 1.2‐kg female Pomeranian presented with acute polyuria, polydipsia, and ocular discoloration. Diagnoses included diabetic ketosis, severe hypertriglyceridemia (>225 mmol/L [>20,000 mg/dl]), lipemia retinalis, and bilateral uveitis. The triglyceride concentration was near normal within 2 days of initiating treatment with fenofibrate, regular insulin constant rate infusion (CRI), manual therapeutic plasma exchange (TPE), and a low‐fat diet. All clinical signs resolved. The dog has had no relapse of hypertriglyceridemia at the time of writing the manuscript, 6 months later, with continued treatment of diabetes mellitus. New or Unique Information Provided: This is the first case report documenting the combination of fenofibrate, insulin CRI, and manual TPE for treatment of severe hyperlipidemia in a dog. Detailed protocols for manual TPE and a novel insulin CRI are provided. A discussion of multiple spurious biochemical and hematologic errors associated with the severe hypertriglyceridemia is also provided. [ABSTRACT FROM AUTHOR]

Fenofibrate is a fibric acid derivative used as an antihyperlipidemic drug in humans. Its active metabolite, fenofibric acid, acts as an agonist to the peroxisome proliferator-activated receptor alpha (PPAR-α), a transcription factor involved in different metabolic pathways. Some studies have reported the potential protective role of this drug in cell lines and in vivo models against bacterial and viral infections. The aim of this study was to assess the in vitro effect of fenofibrate in the macrophage cell line J744A.1 against infections produced by Aeromonas, a pathogen for humans whose resistance to antibiotics has increased in recent decades. Macrophages were infected at MOI 10 with four strains of Aeromonas caviae and Aeromonas hydrophila isolated from human clinical samples and subsequently treated with fenofibrate. It was observed that fenofibrate-treated macrophages showed lower levels of cytotoxicity and intracellular bacteria compared to non-treated macrophages. In addition, the viability of treated macrophages was dependent on the dose of fenofibrate used. Furthermore, transcriptional analysis by RT-qPCR revealed significant differences in the expression of the PPAR-α gene and immune-related genes TNF-α, CCL3, and BAX in fenofibrate-treated macrophages compared to the macrophages without treatment. This study provides evidence that fenofibrate offered some protection in vitro in macrophages against Aeromonas infection. However, further studies are needed with other bacteria to determine its potential antibacterial effect and the route by which this protection is achieved.

Despite significant advancements in diabetes management, the prevalence of diabetic retinal disease remains a major public health concern. Diabetic retinopathy remains one of the leading causes of vision loss among adults with diabetes. Because current treatments primarily focus on advanced stages of diabetic retinopathy, there is a critical need for cost-effective therapies that can intervene earlier in disease development. An article about the LENS (Lowering Events in Non-proliferative Retinopathy in Scotland) trial, published in this issue of NEJM Evidence, offers a promising approach using fenofibrate, a lipid-lowering medication, to reduce the progression of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.

Improved oral bioavailability of lipophilic substances can be achieved using self-emulsifying drug delivery systems. However, because the properties of self-emulsifying are greatly influenced by surfactant amount and type, type of oil used, droplet size, charge, cosolvents, and physiological variables, the synthesis of self-emulsifying is highly complex; consequently, only a small number of excipient self-emulsifying formulations has been developed so far for clinical use. This study reports a highly effective procedure for developing self-emulsifying formulations using a novel approach based on the hydrophilic-lipophilic difference theory. Microemulsion characteristics, such as the constituents and amounts of oil and surfactant electrolyte concentration and temperature, were optimized to produce high-quality self-emulsifying drug delivery systems. Furthermore, in vitro lipolysis and in vivo bioavailability studies of fenofibrate, a highly lipophilic oral drug, loaded self-emulsifying dosage form were conducted. The self-emulsifying drug delivery system used in this study comprised soybean oil, water with a specific salinity, sodium dioctyl sulphosuccinate as a surfactant, and orlistat as a lipase inhibitor. The hydrophilic-lipophilic difference-based approach involved fewer experiments and allowed for the development of an efficient self-emulsifying dosage form with a relatively low surfactant concentration when compared to previous works. The salinity and equivalent alkane carbon number were optimized, with the proper selection of the type and amount of surfactant, to obtain a bicontinuous microemulsion (Winsor type III) that can be fully diluted with water. In vitro lipolysis was investigated in fasting and feeding settings, which showed a significant dosage form digestion by lipase enzyme; orlistat was successfully used to overcome dosage digestion and drug precipitation problem. In vivo experiments in rats involved oral gavage with a self-emulsifying dosage form containing fenofibrate (20 mg/kg). The pharmacokinetic profile of fenofibric acid showed remarkable enhancement in the bioavailability (F-95%). These findings demonstrate that the hydrophilic-lipophilic difference approach is a practical, scalable, and easy technique for self-emulsifying drug delivery system formulation development. [ABSTRACT FROM AUTHOR]