The small screw-apex distance is potentially associated with femoral head osteonecrosis in adults with femoral neck fractures treated by closed reduction and percutaneous 3 parallel cannulated screws.

OBJECTIVE: Femoral neck fractures (FNFs) are among the most common fractures in elderly individuals. Surgery is the main treatment for FNFs, and osteonecrosis of the femoral head (ONFH) is one of the unacceptable complications. This study aimed to assess both the clinical and radiological outcomes in patients with FNFs treated with three parallel cannulated screws and to identify relationship between screws position and ONFH. PATIENTS AND METHODS: A total of 100 patients who were treated with closed reduction and fixed with 3 parallel cannulated screws met the inclusion criteria between January 2014 and December 2020 at authors' institution. The follow-up duration, age, sex, affected side, and injury-to-surgery interval were collected; the neck-shaft angle of both hips, screw-apex distance (SAD) and the tip-apex distance (TAD)were measured; and the Garden classification, quality of reduction and presence of ONFH were evaluated. RESULTS: The sample consisted of 37 males and 63 females, with 60 left and 40 right hips affected. The mean age of patients was 54.93 ± 12.24 years, and the mean follow-up was 56.3 ± 13.38 months. The overall incidence of ONFH was 13%. No significant difference was observed in the incidence of ONFH by affected side, age, fracture displacement, injury-to-surgery interval, neck-shaft angle deviation, or reduction quality. The SAD was significantly shorter in ONFH patients than in normal patients for all three screws (p = 0.02, 0.02, and 0.01, respectively). CONCLUSIONS: The short SAD of all screws is associated with femoral head necrosis of FNFs treated with 3 cannulated screws. The short SAD indicated that screws malpositioning in the weight-bearing area of the femoral head, potentially harming the blood supply and compromising the anchorage of the primary compressive trabeculae in this region.

Complicated Treatment Course of Severe Asymptomatic Hypertriglyceridemia: A Case Report and Literature Review.

BACKGROUND Close observation, statins, fibrate treatment, and lifestyle changes can safely manage asymptomatic individuals with severe hypertriglyceridemia (HTG) and minimal risk of symptom development. However, the risk of medication-induced liver injury in patients taking statin-fibrate makes management more challenging, and may require hospital admission and close monitoring with follow-up. CASE REPORT We present a rare case of a 43-year-old man with asymptomatic severe HTG exceeding 11.370 mg/dL with mixed hyperlipidemia, managed initially with high-intensity statins and fibrate. However, due to the concurrent use of statin and fibrates, the patient subsequently developed an acute liver injury. Hence, the oral medications had to be stopped, and the patient was admitted to the hospital for an insulin drip. Even during the hospital course, the patient's triglyceride (TG) levels showed resistance to the recommended dose of insulin and he required a higher insulin dose. He was discharged on fenofibrate and subcutaneous insulin to keep the TG level under 500. Fibrate was stopped, and high-intensity statin was used as primary prevention with lifestyle modifications. CONCLUSIONS This instance highlights the necessity of increased cognizance and cooperative endeavors in handling severe asymptomatic HTG. Our results highlight the significance of further research into the management of severe asymptomatic HTG in cases of injury to the liver. This work adds essential knowledge to the ongoing discussion about managing a rare case complicated by acute liver injury.

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid-Liquid Phase Separation.

Drug-rich droplets formed through liquid-liquid phase separation (LLPS) have the potential to enhance the oral absorption of drugs. This can be attributed to the diffusion of these droplets into the unstirred water layer (UWL) of the gastrointestinal tract and their reservoir effects on maintaining drug supersaturation. However, a quantitative understanding of the effect of drug-rich droplets on intestinal drug absorption is still lacking. In this study, the enhancement of intestinal drug absorption through the formation of drug-rich droplets was quantitatively evaluated on a mechanistic basis. To obtain fenofibrate (FFB)-rich droplets, an amorphous solid dispersion (ASD) of FFB/hypromellose (HPMC) was dispersed in an aqueous medium. Physicochemical characterization confirmed the presence of nanosized FFB-rich droplets in the supercooled liquid state within the FFB/HPMC ASD dispersion. An in situ single-pass intestinal perfusion (SPIP) assay in rats demonstrated that increased quantities of FFB-rich nanodroplets enhanced the intestinal absorption of FFB. The effective diffusion of FFB-rich nanodroplets through UWL would partially contribute to the improved FFB absorption. Additionally, confocal laser scanning microscopy (CLSM) of cross sections of the rat intestine after the administration of fluorescently labeled FFB-rich nanodroplets showed that these nanodroplets were directly taken up by small intestinal epithelial cells. Therefore, the direct uptake of drug-rich nanodroplets by the small intestine is a potential mechanism for improving FFB absorption in the intestine. To quantitatively evaluate the impact of FFB-rich droplets on the FFB absorption enhancement, we determined the apparent permeabilities of the FFB-rich nanodroplets and dissolved FFB based on the SPIP results. The apparent permeability of the FFB-rich nanodroplets was 110-130 times lower than that of dissolved FFB. However, when the FFB-rich nanodroplet concentration was several hundred times higher than that of dissolved FFB, the FFB-rich nanodroplets contributed significantly to FFB absorption improvement. The present study highlights that drug-rich nanodroplets play a direct role in enhancing drug absorption in the gastrointestinal tract, indicating their potential for further improvement of oral absorption from ASD formulations.

High-Dose Fenofibrate Stimulates Multiple Cellular Stress Pathways in the Kidney of Old Rats.

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.

Kallistatin leads to cognition impairment via downregulating glutamine synthetase.

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

Not enough known about fenofibrate's kidney effects in people with Type 2 diabetes.

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data.

Disturbed brain energy metabolism in a rodent model of DYT-TOR1A dystonia.

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.

Role of fenofibrate in multiple sclerosis.

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the destruction of myelin sheath by immune cells. The formation of myelin plaques, inflammation, and injury of neuronal myelin sheath characterizes its neuropathology. MS plaques are multiple focal regions of demyelination disseminated in the brain's white matter, spinal cords, deep grey matter, and cerebral cortex. Fenofibrate is a peroxisome proliferative activated receptor alpha (PPAR-α) that attenuates the inflammatory reactions in MS. Fenofibrate inhibits differentiation of Th17 by inhibiting the expression of pro-inflammatory signaling. According to these findings, this review intended to illuminate the mechanistic immunoinflammatory role of fenofibrate in mitigating MS neuropathology. In conclusion, fenofibrate can attenuate MS neuropathology by modulating different pathways, including oxidative stress, autophagy, mitochondrial dysfunction, inflammatory-signaling pathways, and neuroinflammation.

Fenofibrate Recognition and Gq Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1.

The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-Gi complexes in synthetic agonist-bound forms have been resolved to date. However, the commercial drug recognition and Gq coupling mechanisms of CB1 remain elusive. Herein, the cryo-electron microscopy (cryo-EM) structure of CB1-Gq complex, in fenofibrate-bound form, at near-atomic resolution, is reported. The structure elucidates the delicate mechanisms of the precise fenofibrate recognition and Gq protein coupling by CB1 and will facilitate future drug discovery and design.

Shen-Shuai-II-Recipe inhibits tubular inflammation by PPARα-mediated fatty acid oxidation to attenuate fibroblast activation in fibrotic kidneys.

BACKGROUND: Shen Shuai Ⅱ Recipe (SSR) is clinically used to treat chronic kidney diseases (CKDs) with remarkable efficacy and safety. In earlier research, we found the anti-inflammatory, antioxidant, and mitochondrial protective properties of SSR in hypoxic kidney injury model, which is closely related to its renal protection. Further work is needed to understand the underlying molecular mechanisms. PURPOSE: Further investigation of the mechanisms of action of SSR against renal interstitial fibrosis (RIF) building on previous research leads. METHODS: Rats receiving CKD model surgery were given with Fenofibrate or SSR once a day for eight weeks. In vitro, the NRK-52E cells were treated with SSR in the presence or absence of 10 µM Sc75741, 0.5 µM PMA, or 1 µM fenofibrate under 1% O2. The effects of SSR on NF-κB/NLRP3 inflammatory cascade, secretion of pro-inflammatory cytokines, fatty acid oxidation (FAO), and renal tubular injury were determined by immunoblotting, luminex liquid suspension chip assay, transmission electron microscopy, and Oil red O staining. Next, we delivered PPARα-interfering sequences to kidney tissue and NRK-52E cells by adeno-associated virus (AAV) injection and siRNA transfection methods. Finally, we evaluated the effect of renal tubular cells on fibroblast activation by co-culture method. RESULTS: SSR attenuated the release of IL-18, VEGF, and MCP1 cytokines, inhibited the activation of NF-κB/NLRP3 cascade, increased the PPARα, CPT-1α, CPT-2, ACADL, and MCAD protein expression, and improved the lipid accumulation. Further studies have demonstrated that one of the ways in which SSR suppresses the inflammatory response to protect renal tubular cells is through the restoration of PPARα-mediated FAO. In addition, by means of co-culture ways, the results demonstrated that SSR attenuated secretion of inflammatory mediators in NRK-52E cells by PPARα/NF-κB/NLRP3 pathway, thereby inhibiting renal fibroblast activation. CONCLUSION: SSR inhibits RIF by suppressing inflammatory response of hypoxia-exposed RTECs through PPARα-mediated FAO.

Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Prolonged Remission Induced by FENofibrate in children with newly diagnosed type 1 diabetes (PRIFEN): protocol of a randomised controlled trial.

INTRODUCTION: Sphingolipids regulate proinsulin folding, insulin secretion and control beta cells apoptosis. Recent evidence has demonstrated that, among other factors, reduced amounts of sulfatide may be relevant in the development of type 1 diabetes (T1D). Thus, fenofibrate, which activates sulfatide biosynthesis, may prolong remission in subjects with T1D. The aim of the study is to evaluate clinical efficacy of fenofibrate on the maintenance of residual beta-cell function in children with newly diagnosed T1D. METHODS AND ANALYSIS: A total of 102 children aged 10-17 years with newly diagnosed T1D will be enrolled in a double-blind, two-centre randomised, non-commercial, placebo-controlled trial. Subjects who will meet all inclusion criteria will be randomly assigned to receive fenofibrate at a dose of 160 mg or an identically appearing placebo, orally, once daily, for 12 months. The primary endpoint will be the area under the curve of the C-peptide level during 2-hour responses to a mixed-meal tolerance test (MMTT). Secondary endpoints include fasting and maximum C-peptide concentration in the MMTT, parameters of diabetes control and glucose fluctuations, daily insulin requirement, inflammation markers, genetic analysis, safety and tolerance of the fenofibrate ETHICS AND DISSEMINATION: The study protocol was approved by the Bioethics Committee. The results of this study will be submitted to a peer-reviewed diabetic journal. Abstracts will be submitted to international and national conferences. TRIAL REGISTRATION NUMBER: EnduraCT 2020-003916-28.

Fenofibrate alleviates NAFLD by enhancing the PPARα/PGC-1α signaling pathway coupling mitochondrial function.

BACKGROUND: To comprehend the influences of fenofibrate on hepatic lipid accumulation and mitochondrial function-related signaling pathways in mice with non-alcoholic fatty liver disease (NAFLD) secondary to high-fat diets together with free fatty acids-influenced HepG2 cells model. MATERIALS AND METHODS: A random allocation of male 6-week C57BL/6J mice into three groups was done, including controls, model (14 weeks of a high-fat diet), and fenofibrate [similar to the model one with administered 0.04 g/(kg.d) fenofibrate by gavage at 11 weeks for 4 weeks] groups, which contained 10 mice each. This study verified NAFLD pathogenesis via mitochondrial functions in hepatic pathological abnormalities, liver index and weight, body weight, serum biochemical indexes, oxidative stress indicators, mitochondrial function indexes, and related signaling pathways. The effect of fenofibrate intervention was investigated in NAFLD model mice. In vitro, four groups based on HepG2 cells were generated, including controls, the FFA model (1.5 mmol/L FFA incubation for 24 h), LV-PGC-1α intervention (similar to the FFA model one after PPARGC1A lentivirus transfection), and LV control intervention (similar to the FFA model one after negative control lentivirus transfection) groups. The study investigated the mechanism of PGC-1α related to lipid decomposition and mitochondrial biosynthesis by Oil red O staining, colorimetry and western blot. RESULTS: In vivo experiments, a high-fat diet achieved remarkable changes regarding liver weight, liver index, serum biochemical indicators, oxidative stress indicators, liver pathological changes, mitochondrial function indicators, and body weight of the NAFLD model mice while fenofibrate improved the objective indicators. In the HepG2 cells model, the lipid accumulation increased significantly within the FFA model group, together with aggravated hepatocytic damage and boosted oxidative stress levels. Moreover, FFA induced excessive mitosis into fragmented in mitochondrial morphology, ATP content in cells decreased, mtDNA replication fold decreased, the expression of lipid decomposition protein PPARα reduced, mitochondrial biosynthesis related protein PGC-1α, NRF-1 and TFAM decreased. PGC-1α overexpression inhibited lipid deposition by improving mitochondrial biosynthesis and lipid decomposition. CONCLUSION: Fenofibrate up-regulated PPARα/PGC-1α signaling pathway, promoted mitochondrial ß-oxidation, reduced oxidative stress damage and lipid accumulation of liver. PGC-1α overexpression enhanced mitochondrial biosynthesis and ATP production, and reduced HepG2 intracellular accumulation of lipids and oxidative stress.

Application of robot navigation system for insertion of femoral neck system in the treatment of femoral neck fracture.

PURPOSE: To evaluate the short-term clinical efficacy and advantages of surgery robot positioning system for insertion of Femoral Neck System (FNS) in the treatment of femoral neck fractures. METHODS: The clinical data of 52 patients with Femoral neck fracture (FNF) who had been treated with FNS between June 2020 and September 2021 were retrospectively analyzed. Among them, 26 patients were treated with traditional FNS (control group), while 26 additional patients were treated with FNS assisted by an orthopaedic robot positioning system (study group). The operation duration, frequency of key-guide needle placement, intraoperative blood loss, incision length, fracture healing rate, fracture healing time, and the Harris scores at the last follow-up were calculated and compared between the 2 groups. RESULTS: The study group had shorter operation duration, fewer numbers of placing the key-guide needle, less intraoperative blood loss, and smaller surgical incisions than the control group (all, P < 0.05). There was no significant difference in the rate of fracture healing rate between the 2 groups (P = 0.47), while the fracture healing duration of the study group was shorter than that of the control group (P = 0.03). At the last follow-up, compared with the control group, the Harris score and the number of excellent and good ratings were significantly higher in the study group (all, P < 0.05). CONCLUSIONS: Using orthopaedic surgery robot positioning system-assisted FNS in the treatment of FNFs can effectively improve the efficiency of surgery, shorten operation time, and reduce the number of placing the key-guide needle, intraoperative blood loss, and operative trauma. Simultaneously, it shortens the duration of fracture healing and improves the recovery of hip function.

Morphological characteristics of femoral neck fractures in young and middle-aged population: a retrospective descriptive study.

BACKGROUND: A understanding of morphological characteristics are important to femoral neck fractures (FNFs) resulting in high rates of complications in the young and middle-aged adults and the detailed data is lack in the literature. We aimed to report on the detailed morphological characteristics and the relationship between them in young and middle-aged adults with femoral neck fractures (FNFs). METHODS: The postoperative CT images of one hundred and fifty-two adults with FNFs were retrospectively reviewed. After image standardization, morphological characteristics including fracture orientation, cortex comminution, and intraosseous bone defects were measured and analyzed. Additionally, the distribution and correlation of these morphological features were analyzed using Pauwels classification, the right angle of the neck axis (VNA) classification, and the anteromedial oblique angle (AMA). RESULTS: Pauwels III fractures accounted for approximately half (55.2%) of the FNFs analyzed. Pauwels II and III could be detected in all four VNA types, and the distribution of the Pauwels types in VNA classification showed significant differences (χ2 = 106.363, p < 0.001). The VNA (9.0° ± 12.1) showed positive correlation with the neck-shaft angle (139.5° ± 6.3) and modified Pauwels angle (49.8° ± 10.6) (r = 0.441, r = 0.855, all p < 0.001). Cortical comminutions were commonly observed in the posterior (86.7%) and the inferior (80.7%). AMAs within the cases without posterior and inferior cortex comminutions were significantly larger than those with comminution (t = 2.594, 2.1196; p = 0.01, 0.036), but no difference could be detected after the AMA being divided into three groups (< 85°, 85°-95°, > 95°). The MPA, VNA and AMA of the group with an intraosseous defect were significantly different compared with those without (t = 2.847, 2.314, 2.268; p = 0.005, 0.022,0.025). The incidence of intraosseous defects within the groups with coronal and axial cortex comminutions were significantly higher than those within the groups without comminutions (χ2 = 34.87, 25.303; p < 0.001). CONCLUSIONS: The present study highlights the morphological diversity and complexity within FNFs in young and middle-aged adults, which allows for more accurate simulation of FNF patterns in the future biomechanical studies.

Inhibition of tumor migration and invasion by fenofibrate via suppressing epithelial-mesenchymal transition in breast cancers.

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.

Role of Fenofibrate Use in Dyslipidemia and Related Comorbidities in the Asian Population: A Narrative Review.

Hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) persist despite statin therapy, contributing to residual atherosclerotic cardiovascular disease (ASCVD) risk. Asian subjects are metabolically more susceptible to hypertriglyceridemia than other ethnicities. Fenofibrate regulates hypertriglyceridemia, raises HDL-C levels, and is a recommended treatment for dyslipidemia. However, data on fenofibrate use across different Asian regions are limited. This narrative review summarizes the efficacy and safety data of fenofibrate in Asian subjects with dyslipidemia and related comorbidities (diabetes, metabolic syndrome, diabetic retinopathy, and diabetic nephropathy). Long-term fenofibrate use resulted in fewer cardiovascular (CV) events and reduced the composite of heart failure hospitalizations or CV mortality in type 2 diabetes mellitus. Fenofibrate plays a significant role in improving irisin resistance and microalbuminuria, inhibiting inflammatory responses, and reducing retinopathy incidence. Fenofibrate plus statin combination significantly reduced composite CV events risk in patients with metabolic syndrome and demonstrated decreased triglyceride and increased HDL-C levels with an acceptable safety profile in those with high CV or ASCVD risk. Nevertheless, care is necessary with fenofibrate use due to possible hepatic and renal toxicities in vulnerable individuals. Long-term trials and real-world studies are needed to confirm the clinical benefits of fenofibrate in the heterogeneous Asian population with dyslipidemia.

Compressive buttress compared with off-axial screw fixation for vertical femoral neck fractures in young adults: a prospective, randomized controlled trial.

BACKGROUND: To compare the clinical outcomes of compressive buttress screw (CBS) fixation, a novel screw fixation strategy, to off-axial screw fixation (off-axial partial threaded cannulated screw, OPTCS) for vertical femoral neck fractures (FNFs) in young adults. METHODS: A total of 146 adults younger than 55 years old with high-energy Pauwels type III FNFs were randomized to receive CBS fixation or OPTCS fixation. Primary outcomes were complication rates, including fixation failure, fracture nonunion, and avascular necrosis of the femoral head (ANFH) at 24 months after treatment. Fixation loosening, femoral neck shortening and varus collapse, patient function and quality of life using the Harris hip score (HHS), and EuroQol-5 dimensional-5 levels (EQ-5D-5L) questionnaire (including EQ-5D-5L and EQ-VAS) were assessed as secondary outcomes at 24 months. RESULTS: CBS and OPTCS fixation groups were similar with regard to demographics at baseline. At 24 months, patients in the CBS fixation cohort had a significantly lower rate of fixation failure (10.5% vs. 25.0%, p = 0.041) and fracture nonunion (1.8% vs. 18.3%, p = 0.003) compared with patients who received OPTCS fixation. There was no difference in rate of ANFH (7.0% vs. 11.7%, p = 0.389) between groups. Additionally, patients managed with CBS fixation showed significantly less fixation loosening (19.3% vs. 58.3%, p < 0.001), less severe femoral neck shortening and varus collapse (10.5% vs. 25.0%, p = 0.007), higher HHS (93 vs. 83, p = 0.001) and more excellent grade (68.4% vs. 36.7%, p = 0.008), higher EQ-5D-5L (0.814 vs, 0.581, p < 0.001) and EQ-VAS (85 vs. 80, p = 0.002). CONCLUSION: CBS screw fixation confers significantly lower complication rate in addition to higher functional and quality of life outcomes for young adults with high-energy FNF compared with OPTCS fixation. TRIAL REGISTRATION: This prospective, randomized controlled trial was approved by the institutional review board of our center, Ethics Committee of Shanghai sixth people's Hospital, and registered at www.chictr.org.cn (Approval Number: ChiCTR1900026283; Registered 29 September 2019-Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=43164 ).

Fenofibrate inhibits MOXD1 and PDZK1IP1 expression and improves lipid deposition and inflammation in mice with alcoholic fatty liver.

AIMS: Alcoholic liver disease (ALD) can develop into cirrhosis and hepatocellular carcinoma but no specific drugs are available. Fenofibrate is therapeutically effective in ALD, however, the exact mechanism remains unknown. We explored the hub genes of ALD and the role of fenofibrate in ALD. MAIN METHODS: The hub genes of ALD were screened by bioinformatics method, and their functional enrichment, signalling pathways, target genes and their correlation with immune microenvironment and pathogenic genes were analysed. We also analysed the binding affinity of fenofibrate to proteins of hub genes using molecular docking techniques, and the effects on hub gene expression, lipid deposition, oxidative stress and inflammation in the liver of National Institute on Alcohol Abuse and Alcoholism (NIAAA) model mice. The regulatory effects of fenofibrate on MOXD1 and PDZK1P1 were investigated after gene silencing of peroxisome proliferator-activated receptor-α (Ppar-α). KEY FINDINGS: Hub genes identified, including monooxygenase DBH-like 1 (MOXD1), PDZK1-interacting protein 1 (PDZK1IP1) and solute carrier 51 ß (SLC51B), are highly predictive for ALD. Hepatic MOXD1 and PDZK1IP1 expression was elevated in patients with ALD and NIAAA model mice, with no significant difference in SLC51B expression between the groups. Fenofibrate binds tightly to MOXD1 and PDZK1IP1, inhibits their hepatic expression independently of PPAR-α signalling, and ameliorates lipid deposition, oxidative stress and inflammatory responses in NIAAA model mice. SIGNIFICANCE: MOXD1 and PDZK1IP1 are key genes in ALD progression; fenofibrate improves liver damage in NIAAA model mice by downregulating their expression. Our findings provide insight for improving diagnostic and therapeutic strategies for ALD.

Associations of omega-3 fatty acids vs. fenofibrate with adverse cardiovascular outcomes in people with metabolic syndrome: propensity matched cohort study.

AIMS: Omega-3 fatty acids and fenofibrates have shown some beneficial cardiovascular effects; however, their efficacy has not been compared. This study aimed to compare the effectiveness of currently available omega-3 fatty acids and fenofibrate for reducing major adverse cardiovascular events (MACE). METHODS AND RESULTS: From a nationwide population-based cohort in South Korea (2008-2019), individuals with metabolic syndrome (≥30 years) who received statin with omega-3 fatty acids and those receiving statin with fenofibrate were matched by propensity score (n = 39 165 in both groups). The primary outcome was MACE, including ischaemic heart disease (IHD), ischaemic stroke (IS), and death from cardiovascular causes. The risk of MACE was lower [hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.74-0.83] in the fenofibrate group than in the omega-3 fatty acid group. Fenofibrate was associated with a lower incidence of IHD (HR, 0.72; 95% CI, 0.67-0.77) and hospitalization for heart failure (HR, 0.90; 95% CI, 0.82-0.97), but not IS (HR, 0.90; 95% CI, 0.81-1.00) nor death from cardiovascular causes (HR, 1.07; 95% CI, 0.97-1.17). The beneficial effect of fenofibrate compared to omega-3 fatty acids was prominent in patients with preexisting atherosclerotic cardiovascular disease and those receiving lower doses of omega-3 fatty acids (≤2 g per day). CONCLUSION: In a real-world setting, fenofibrate use was associated with a lower risk of MACE compared with low-dose omega-3 fatty acids when added to statins in people with metabolic syndrome.