Peroxisome Proliferator-activated Receptor-α Research Articles

Selective Peroxisome Proliferator-Activated Receptor-α Modulator K-877 Stimulated the Expression of ABCA1 in Pancreatic Beta Cells in a Glucotoxic State

Selective Peroxisome Proliferator-Activated Receptor-α Modulator K-877 Stimulated the Expression of ABCA1 in Pancreatic Beta Cells in a Glucotoxic State

Anti-obesity potentiality of Lactiplantibacillus plantarum E2_MCCKT isolated from a fermented beverage, haria: a high fat diet-induced obese mice model study.

Obesity is a growing epidemic worldwide. Several pharmacologic drugs are being used to treat obesity but these medicines exhibit side effects. To find out the alternatives of these drugs, we aimed to assess the probiotic properties and anti-obesity potentiality of a lactic acid bacterium E2_MCCKT, isolated from a traditional fermented rice beverage, haria. Based on the 16S rRNA sequencing, the bacterium was identified as Lactiplantibacillus plantarum E2_MCCKT. The bacterium exhibited in vitro probiotic activity in terms of high survivability in an acidic environment and 2% bile salt, moderate auto-aggregation, and hydrophobicity. Later, E2_MCCKT was applied to obese mice to prove its anti-obesity potentiality. Adult male mice (15.39 ± 0.19g) were randomly divided into three groups (n = 5) according to the type of diet: normal diet (ND), high-fat diet (HFD), and HFD supplemented with E2_MCCKT (HFT). After four weeks of bacterial treatment on the obese mice, a significant reduction of body weight, triglyceride, and cholesterol levels, whereas, improvements in serum glucose levels were observed. The bacterial therapy led to mRNA up-regulation of lipolytic transcription factors such as peroxisome proliferator-activated receptor-α which may increase the expression of fatty acid oxidation-related genes such as acyl-CoA oxidase and carnitine palmitoyl-transferase-1. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol-regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase genes. In protein expression study, E2_MCCKT significantly increased IL-10 expression while decreasing pro-inflammatory cytokine (IL-1Ra and TNF-α) expression. In conclusion, the probiotic Lp. plantarum E2_MCCKT might have significant anti-obesity effects on mice.

NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice

Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b+ cells – monocytes, macrophages, and neutrophils – were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.

Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease.

Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD.

Effects of Clostridium tyrobutyricum on Lipid Metabolism, Intestinal Barrier Function, and Gut Microbiota in Obese Mice Induced by High-Fat Diet.

Obesity and its complications constitute a main threat to global human health. The purpose of this investigation was to explore the influences of Clostridium tyrobutyricum (Ct) on lipid metabolism, intestinal barrier function, and intestinal microbiome in obese mice induced by a high-fat diet (HFD). After establishing the obesity model, 107 CFU/mL and 108 CFU/mL C. tyrobutyricum were used to intervene in HFD-fed mice by gavage for six weeks, and indexes related to obesity were measured. In the liver of HFD-fed mice, the results revealed that C. tyrobutyricum reduced liver weight and the levels of triglyceride (TG), total cholesterol (TC), and nonesterified fatty acid (NEFA), along with decreasing red lipid droplets and fat vacuoles. After C. tyrobutyricum intervention, the mRNA expression of peroxisome proliferator-activated receptor-γ (PPARγ) was downregulated, and AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPARα), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) were upregulated in the liver. Additionally, C. tyrobutyricum alleviated intestinal morphology injury caused by HFD, decreased the expression of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-1β in the colon, and upregulated tight junction protein expression. In addition, 16S rRNA sequencing revealed that C. tyrobutyricum increases the diversity of intestinal microbiota. Overall, C. tyrobutyricum improved HFD-induced lipid metabolism disorders, preserved the intestinal barrier's integrity, and modulated the structure of the intestinal microbiome. These findings provide a novel insight into the role of C. tyrobutyricum as a probiotic in regulating lipid metabolism.

Valerenic acid attenuates pathological myocardial hypertrophy by promoting the utilization of multiple substrates in the mitochondrial energy metabolism

IntroductionValerenic acid (VA) is a unique and biologically active component in Valeriana officinalis L., which has been reported to have a regulatory effect on the cardiovascular system. However, its therapeutic effects on pathological myocardial hypertrophy (PMH) and the underlying mechanisms are undefined. ObjectivesOur study aims to elucidate how VA improves PMH, and preliminarily discuss its mechanism. MethodsThe efficacy of VA on PMH was confirmed by in vivo and in vitro experiments and the underlying mechanism was investigated by molecular dynamics (MD) simulations and specific siRNA interference. ResultsVA enhanced cardiomyocyte fatty acid oxidation (FAO), inhibited hyper-activated glycolysis, and improved the unbalanced pyruvate-lactate axis. VA could significantly improve impaired mitochondrial function and reduce the triglyceride (TG) in the hypertrophic myocardium while reducing the lactate (LD) content. Molecular mechanistic studies showed that VA up-regulated the expression of peroxisome proliferator-activated receptor-α (PPARα) and downstream FAO-related genes including CD36, CPT1A, EHHADH, and MCAD. VA reduced the expression of ENO1 and PDK4, the key enzymes in glycolysis. Meanwhile, VA improved the pyruvate-lactate axis and promoted the aerobic oxidation of pyruvate by inhibiting LDAH and MCT4. MD simulations confirmed that VA can bind with the F273 site of PPARα, which proposes VA as a potential activator of the PPARα. ConclusionOur results demonstrated that VA might be a potent activator for the PPARα-mediated pathway. VA directly targets the PPARα and subsequently promotes energy metabolism to attenuate PMH, which can be applied as a potentially effective drug for the treatment of HF.

Gut-liver axis calibrates intestinal stem cell fitness

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/β-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.

Cornelian Cherry (Cornus mas L.) Fruit Extract Lowers SREBP-1c and C/EBPα in Liver and Alters Various PPAR-α, PPAR-γ, LXR-α Target Genes in Cholesterol-Rich Diet Rabbit Model.

Cornelian cherry (Cornus mas L.) fruits, abundant in iridoids and anthocyanins, are natural products with proven beneficial impacts on the functions of the cardiovascular system and the liver. This study aims to assess and compare whether and to what extent two different doses of resin-purified cornelian cherry extract (10 mg/kg b.w. or 50 mg/kg b.w.) applied in a cholesterol-rich diet rabbit model affect the levels of sterol regulatory element-binding protein 1c (SREBP-1c) and CCAAT/enhancer binding protein α (C/EBPα), and various liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor-α (PPAR-α), and peroxisome proliferator-activated receptor-γ (PPAR-γ) target genes. Moreover, the aim is to evaluate the resistive index (RI) of common carotid arteries (CCAs) and aortas, and histopathological changes in CCAs. For this purpose, the levels of SREBP-1c, C/EBPα, ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), fatty acid synthase (FAS), endothelial lipase (LIPG), carnitine palmitoyltransferase 1A (CPT1A), and adiponectin receptor 2 (AdipoR2) in liver tissue were measured. Also, the levels of lipoprotein lipase (LPL), visceral adipose tissue-derived serine protease inhibitor (Vaspin), and retinol-binding protein 4 (RBP4) in visceral adipose tissue were measured. The RI of CCAs and aortas, and histopathological changes in CCAs, were indicated. The oral administration of the cornelian cherry extract decreased the SREBP-1c and C/EBPα in both doses. The dose of 10 mg/kg b.w. increased ABCA1 and decreased FAS, CPT1A, and RBP4, and the dose of 50 mg/kg b.w. enhanced ABCG1 and AdipoR2. Mitigations in atheromatous changes in rabbits' CCAs were also observed. The obtained outcomes were compared to the results of our previous works. The beneficial results confirm that cornelian cherry fruit extract may constitute a potentially effective product in the prevention and treatment of obesity-related disorders.

Inflammaging and fatty acid oxidation in monocytes and macrophages.

Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5' AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.

Tyrosol regulates hepatic lipid metabolism in high-fat diet-induced NAFLD mice.

This study aimed to elucidate the effect of tyrosol (TYR) on the amelioration of nonalcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.025% (w/w) TYR (TYR) for 16 weeks. Following a 16-week intervention, the TYR cohort exhibited diminished final body weight and hepatic lipid accumulation, compared to HFD fed mice. Liver metabolomics analysis revealed that TYR increased the hepatic levels of spermidine, taurine, linoleic acid, malic acid and eicosapentaenoic acid (EPA), indicating the beneficial effect of TYR on lipid homeostasis. Using molecular docking analysis and the luciferase assay, we found that TYR acts as a ligand and binds with peroxisome proliferator-activated receptor-α (PPARα), which plays a pivotal role in the modulation of hepatic lipid metabolism, thereby activating the transcription of downstream genes. Our results suggest that TYR alleviates NAFLD in HFD-fed mice probably by the modulation of the PPARα signaling pathway.

Integrated metabolomics and network pharmacology to reveal the lipid-lowering mechanisms of Qizha Shuangye granules in hyperlipidemic rats.

Qizha Shuangye granules (QSG) comprise six traditional Chinese herbal medicines (TCHMs), which have a long history of treating hyperlipidemia (HLP) in China. This study aimed to evaluate the potential lipid-lowering effects of QSG in an HLP rat model and investigate possible mechanisms. The HLP rat model was induced by a high-fat diet. Lipid-related indicators in serum were detected. Serum and liver metabolites were investigated using a liquid chromatography-mass spectrometry-based metabolomics approach. A herb-compound-target-metabolite (H-C-T-M) network was further constructed to reveal the possible molecular mechanism of QSG to alleviate HLP. The administration of QSG inhibited the HLP-induced changes in total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-esterified fatty acid (NEFA) levels. Additionally, QSG significantly attenuated the liver histopathological changes induced by HLP. Metabolomic analysis showed the serum and liver metabolic disorders presented in HLP rats. QSG can reverse the abnormal metabolism caused by HLP. Through network pharmacology analysis, key proteins such as androgen receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and peroxisome proliferator-activated receptor-α were screened out, and they were speculated to be possible therapeutic targets for QSG to treat HLP. The present study integrated metabolomics and network pharmacology analysis to reveal the efficacy and possible mechanism of QSG in treating HLP, which provides a new reference for the research and development of QSG as a functional food. © 2023 Society of Chemical Industry.

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

AimsAlcoholic 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 methodsThe 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 findingsHub genes identified, including monooxygenase DBH-like 1 (MOXD1), PDZK1-interacting protein 1 (PDZK1IP1) and solute carrier 51 β (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. SignificanceMOXD1 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.

Lead exposure induced lipid metabolism disorders by regulating the lipophagy process in microglia.

Environmental lead (Pb) pollution is a worldwide public health problem and causes various diseases, especially neurodegenerative diseases. It is increasingly recognized that microglia-mediated neuroinflammation plays a crucial role in lead neurotoxicity, but the underlying mechanisms remain to be further explored. Recent studies indicated that cell metabolism, especially lipid metabolism, regulates many microglial functions, including cytokine secretion and phagocytosis. Whether lipid metabolism is involved in Pb-induced neuroinflammation is still unknown. In the current studies, we investigated the effects of Pb on microglial lipid metabolism by utilizing lipidomics. Histochemistry staining and oxygen consumption rate (OCR) were used to validate lipidomics results. Fenofibrate (FEN), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, was applied to investigate whether lipid metabolism regulation mitigated Pb's neuroinflammatory response. Microglial autophagic proteins were detected to investigate the role of lipophagy in Pb's effect on lipid metabolism. Our results showed that Pb exposure increased concentrations of various lipid metabolites and induced lipid metabolism disorders, especially in fatty acid metabolism. Pb caused lipid droplet (LD) accumulation and slightly enhanced fatty acid oxidation (FAO) in microglia. FEN pretreatment markedly inhibited Pb's effects on LDs and further mitigated Pb-induced inflammatory response by reducing pro-cytokines' expression and enhancing phagocytosis function. FEN intervention also inhibited Pb's neurotoxicity by improving cognition-related behaviors. Pb exposure induced an abnormal increase of autophagic proteins, but the FEN addition partially neutralized Pb's effects on autophagy. Our data indicate that the Pb-induced neuroinflammation is regulated by fatty acid metabolism via the lipophagy process. Therapies focusing on lipid metabolism regulation are powerful tactics in Pb toxicity prevention and treatment.

Repurposing of monacolin K decorated BN nanoparticle on inhibition of HMG-CoA reductase: In silico approach

To identify a novel inhibitor of 3‑hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the current perspective has shifted toward a B12N12 nanocage that also has cardioprotective properties. Therefore, this study identified the bioactive complexes derived from monacolin K and BN nanoparticle and determines their potential for inhibiting HMG-CoA reductase, hypolipidemic activity, and anti-apoptotic properties via molecular docking. A molecular docking study was conducted with the Auto Dock Vina software on a complex of monacolin K and the B12N12 fullerene using an in silico docking approach. The protein structures of selective HMG-COA reductase, as well as peroxisome proliferator-activated receptor-α (PPAR-α) and others, were obtained from Protein Data Bank (PDB). The binding affinity between key residues involved in the binding mode of the targets and selective complexes is identified via in silico molecular docking. A further evaluation of the ADMET properties of the selective complexes has also been carried out. B12N12 nanoparticles and monacolin K complex (A) showed higher inhibitory potential for HMG-CoA reductase than monacolin K alone. These complexes seemed to be selective to the PPAR-α and caspase3 domains. Meanwhile, complex B had the highest binding affinity to the active site of SGK, TNF- α, NF-Kβ and AMPK receptors. Furthermore, both complex A and B could inhibit inflammatory targets more efficiently. The selective B12N12 nanoparticles were assessed for their drug-likeness and ADMET analysis, confirming that the selective B12N12 nanoparticles met the Lipinski and drug-likeness criteria. It was revealed that B12N12 fullerene and monacolin K complexes have potential inhibitory HMG-COA reductase and anti-apoptotic properties, as well as activating PPAR-α and AMPK. Consequently, these cardioprotective effects lead to improved cardiovascular health.

Abstract 14039: Therapeutic Potential of Beta Hydroxybutyrate in Nonalcoholic Fatty Liver Disease (NAFLD)-Induced Cardiovascular Disease

Background: Cardiovascular disease (CVD) is the leading cause of mortality in non-alcoholic fatty liver disease (NAFLD). Beta hydroxybutyrate (BHOB), a liver metabolite, is the major ketone that serves as an alternative fuel source in the body. Our previous studies show that hepatocyte peroxisome proliferator activator receptor-α knockout (Ppara HEPKO ) mice, model of NAFLD-induced CVD, exhibit reduced circulating levels of BHOB. Hypothesis: We hypothesized that restoring plasma BHOB levels will improve cardiovascular function in Ppara HEPKO mice. Aims: To determine the therapeutic role of BHOB in NAFLD-induced CVD. Methods: 30 weeks old male Ppara HEPKO mice were given 1,3 butanediol (20% in drinking water) (Ppara HEPKO + BHOB) or vehicle (Ppara HEPKO ) (n=6) for 6 weeks. Plasma BHOB was measured at baseline and after treatment. Cardiac structure and function were measured by high resolution ultrasound echocardiography (VEVO 3100), using the B-mode, M-mode, pulse wave and tissue doppler at baseline and after treatment. Mean arterial blood pressure was measured by radiotelemetry. Liver fat was determined by EchoMRI, Oil Red O staining and hepatic triglyceride levels. Results: After 6 weeks of BHOB treatment, Ppara HEPKO exhibit increased plasma BHOB compared to baseline (0.5 ± 0.01 vs. 0.2 ± 0.02mmol/L), attenuated arterial blood pressure compared to control (109 ± 3 vs. 121 ± 4mmHg), improved systolic function: cardiac output (13.8 ± 0.8 vs. 11.1 ± 0.7ml/min), stroke volume (31.1 ± 2.1 vs. 23.4 ± 1.3ml/min), improved diastolic function: isovolumic relaxation time (18.7 ± 0.8 vs. 20.6 ± 0.9m/sec), E/e’ (-29.6 ± 0.9 vs. -32.4 ± 1.4), and attenuated vascular stiffness. Interestingly, BHOB did not alleviate hepatic fat compared to control as demonstrated by EchoMRI (0.8 ± 0.3 vs. 0.7 ± 0.3), hepatic triglyceride (1.4 ± 0.3 vs. 1.3 ± 0.2mM) and Oil Red O staining. Conclusion: Our findings indicate that BHOB treatment improves arterial blood pressure, systolic, diastolic, and vascular function in, Ppara HEPKO knockout mice. However, BHOB did not alleviate hepatic steatosis suggesting that BHOB improves cardiovascular function in Ppara HEPKO mice independent of changes in hepatic fat content.

Impact of Pemafibrate Therapy on Reducing Small Dense Low-Density-Lipoprotein-Cholesterol Levels in Patients with Hypertriglyceridemia.

Small dense LDL-cholesterol is a recently discovered cardiovascular risk factor beyond LDL-cholesterol. Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator that reduces triglyceride levels. Given the significant association between triglycerides and small dense LDL-cholesterol levels, pemafibrate may reduce the levels of small dense LDL-cholesterol. Patients with hypertriglyceridemia who started pemafibrate therapy and continued it for >3 months between 2018 and 2022 were included in this retrospective study. The levels of small dense LDL-cholesterol, which was estimated using Sampson's equation, consisting of the LDL-cholesterol and triglyceride levels, were compared between baseline and 3-month follow-up. A total of 98 patients receiving pemafibrate therapy (median age: 63 years, 69 male) were eligible, including 33 patients (34%) who received concomitant statins. Small dense LDL-cholesterol levels decreased significantly during the course of 3-month pemafibrate therapy from 48.9 (IQR: 35.7, 57.9) mg/dL to 38.8 (IQR: 30.0, 45.1) mg/dL, regardless of the concomitant administration of statins (p < 0.001). The rate of cardiovascular events decreased significantly from the pre-treatment 1-year period to the treatment 1-year period (from 13 to 2 events, from 0.133 to 0.021 events per year, incidence rate ratio: 0.16, 95% confidence interval: 0.14-0.17, p < 0.001). Pemafibrate therapy may mitigate the concentrations of small dense LDL-cholesterol autonomously in patients manifesting hypertriglyceridemia within the authentic clinical milieu. The clinical importance of the diminishment in small dense LDL-cholesterol instigated via pemafibrate merits further scrutiny.

Effects of Fenofibrate and Gemfibrozil on Kynurenic Acid Production in Rat Kidneys In Vitro: Old Drugs, New Properties.

Kidney dysfunction significantly increases the cardiovascular risk, even in cases of minor functional declines. Hypertriglyceridemia is the most common lipid abnormality reported in patients with kidney disorders. PPAR-α (peroxisome proliferator-activated receptor-α) agonists called fibrates are the main agents used to lower triglyceride levels. Kynurenic acid (KYNA) is a tryptophan (Trp) derivative directly formed from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KYNA is classified as a uremic toxin, the level of which is correlated with kidney function impairments and lipid abnormalities. The aim of this study was to analyze the effect of the most commonly used triglyceride-lowering drugs, fenofibrate and gemfibrozil, on KYNA production and KAT activity in rat kidneys in vitro. The influence of fenofibrate and gemfibrozil on KYNA formation and KAT activity was tested in rat kidney homogenates in vitro. Fenofibrate and gemfibrozil at 100 µM-1 mM significantly inhibited KYNA synthesis in rat kidney homogenates. Both fibrates directly affected the KAT I and KAT II isoenzyme activities in a dose-dependent manner at similar concentrations. The presented results reveal the novel mechanism of action of fibrates in the kidneys and suggest their potential role in kidney function protection beyond the well-known anti-hyperlipidemic effect.

A practical guide to machine-learning scoring for structure-based virtual screening.

Structure-based virtual screening (SBVS) via docking has been used to discover active molecules for a range of therapeutic targets. Chemical and protein data sets that contain integrated bioactivity information have increased both in number and in size. Artificial intelligence and, more concretely, its machine-learning (ML) branch, including deep learning, have effectively exploited these data sets to build scoring functions (SFs) for SBVS against targets with an atomic-resolution 3D model (e.g., generated by X-ray crystallography or predicted by AlphaFold2). Often outperforming their generic and non-ML counterparts, target-specific ML-based SFs represent the state of the art for SBVS. Here, we present a comprehensive and user-friendly protocol to build and rigorously evaluate these new SFs for SBVS. This protocol is organized into four sections: (i) using a public benchmark of a given target to evaluate an existing generic SF; (ii) preparing experimental data for a target from public repositories; (iii) partitioning data into a training set and a test set for subsequent target-specific ML modeling; and (iv) generating and evaluating target-specific ML SFs by using the prepared training-test partitions. All necessary code and input/output data related to three example targets (acetylcholinesterase, HMG-CoA reductase, and peroxisome proliferator-activated receptor-α) are available at https://github.com/vktrannguyen/MLSF-protocol , can be run by using a single computer within 1 week and make use of easily accessible software/programs (e.g., Smina, CNN-Score, RF-Score-VS and DeepCoy) and web resources. Our aim is to provide practical guidance on how to augment training data to enhance SBVS performance, how to identify the most suitable supervised learning algorithm for a data set, and how to build an SF with the highest likelihood of discovering target-active molecules within a given compound library.

Cotadutide improves brown adipose tissue thermogenesis in obese mice

We studied the effect of cotadutide, a dual agonist glucagon-like peptide 1 (GLP1)/Glucagon, on interscapular brown adipose tissue (iBAT) remodeling and thermogenesis of obese mice. Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Then, animals were redivided, adding cotadutide treatment: C, CC, HF, and HFC for four additional weeks. The multilocular brown adipocyte structure showed fat conversion (whitening), hypertrophy, and structural disarray in the HF group, which was reverted in cotadutide-treated animals. Cotadutide enhances the body temperature, thermogenesis, and sympathetic innervation (peroxisome proliferator-activated receptor-α, β3 adrenergic receptor, interleukin 6, and uncoupled protein 1), reduces pro-inflammatory markers (disintegrin and metallopeptidase domain, morphogenetic protein 8a, and neuregulin 4), and improves angiogenesis (vascular endothelial growth factor A, and perlecan). In addition, cotadutide enhances lipolysis (perilipin and cell death-inducing DNA fragmentation factor α), mitochondrial biogenesis (nuclear respiratory factor 1, transcription factor A mitochondrial, mitochondrial dynamin-like GTPase, and peroxisome proliferator-activated receptor gamma coactivator 1α), and mitochondrial fusion/fission (dynamin-related protein 1, mitochondrial fission protein 1, and parkin RBR E3 ubiquitin protein ligase). Cotadutide reduces endoplasmic reticulum stress (activating transcription factor 4, C/EBP homologous protein, and growth arrest and DNA-damage inducible), and extracellular matrix markers (lysyl oxidase, collagen type I α1, collagen type VI α3, matrix metallopeptidases 2 and 9, and hyaluronan synthases 1 and 2). In conclusion, the experimental evidence is compelling in demonstrating cotadutide's thermogenic effect on obese mice's iBAT, contributing to unraveling its action mechanisms and the possible translational benefits.

Enhancing Immune-Mediated Radiotherapy Efficacy in Murine Models of Head and Neck Cancer through Peroxisome Proliferator-Activated Receptor Modulation

The tumor microenvironment (TME) in HPV-unrelated head and neck cancer (HNC) is considered to be immunologically "cold," and immunometabolic adaptations to radiotherapy (RT) can exacerbate these conditions and lead to radioresistance. Peroxisome proliferator-activated receptor-α (PPARα) agonism may improve the immune response to RT by reducing glucose scarcity through upregulation of fatty acid utilization in cancer cells. Our clinical trial data shows that high serum oleic acid (OA), a PPAR ligand, correlates with response to radioimmunotherapy. Orthotopic buccal tumor implantations of MOC2 and LY2 HNC cell lines were performed in C57BL/6 and BALB/c mice, respectively. Mice were placed on a high OA diet (38% kcal from OA) 3 weeks prior to tumor implantation. Control diet consisted of 1% kcal from OA. In vitro RT was performed to characterize the metabolic effects on the cancer cell lines. For in vivo studies, tumors were irradiated upon reaching 100 mm^3 with three 8 Gy fractions, given every 4-5 days. The PPARα agonist fenofibrate (FF, 100mg/kg/day) was given via oral gavage or intraperitoneal injection starting 5 days after RT. Tumor volume and overall survival were measured as objective outcomes, and flow cytometry was used to characterize the immune landscape of the tumor, blood, and lymph nodes. Mass spectrometry was employed for bulk proteomics and metabolomics on serum samples, and stable isotope labeling was performed on CD8 T cells from treated mice ex vivo. Extracellular flux analyses were performed on tumor cells and CD8 T cells to determine metabolic phenotypic changes. In vitro cytotoxicity was met for MOC2 and LY2 cancer cells in 100 uM FF and OA in comparison to solvent (p<0.01). Extracellular flux analyses show that RT upregulates the glycolytic phenotype of MOC2 and LY2 cancer cells; and that FF and/or OA decrease the glycolytic capacity of the cancer cells. Ex vivo extracellular flux analyses showed increased glycolytic capacity of CD8 T cells in mice treated with FF in comparison to RT alone. RT in combination with FF significantly improved tumor volume response in comparison to RT alone (mean 99.4 vs 182.7 mm^3, p = 0.001) and was comparable to combination radioimmunotherapy (with anti-PDL1 therapy; mean 99.4 vs. 132.3 mm^3). Unexpectedly, OA negated this improvement in efficacy in both MOC2 and LY2 tumor models; mice on the high OA diet had significantly higher average body weight (p<0.01). Significant changes in adaptive immune response were observed within the TME with the addition of FF. This was mirrored by changes in serum metabolomics. PPARα agonism improved the efficacy of RT in murine HNC models and could be considered in future translational clinical trial design.