Peroxisome Proliferator-activated Receptor-α Research Articles

Effects of Enterococcus faecalis Supplementation on Growth Performance, Hepatic Lipid Metabolism, and mRNA Expression of Lipid Metabolism Genes and Intestinal Flora in Geese.

The effects of Enterococcus faecalis (E. faecalis) at a concentration of 1.0 × 108 CFU/mL on growth performance, hepatic lipid metabolism, and mRNA expression related to lipid metabolism, intestinal morphology, and intestinal flora were investigated in geese. A total of 60 male geese, aged 30 days and of similar weight, were randomly assigned to 2 groups. Each group was divided into six replicates, with five geese per replicate. During the 45-day experiment, the control group received a basal diet, while the experimental group was provided with the same basal diet supplemented with E. faecalis in drinking water at a concentration of 1.0 × 108 CFU/mL. E. faecalis significantly increased the half-eviscerated weight of geese and improved ileal intestinal morphology (p < 0.05). Serum triglyceride (TG) levels were significantly reduced on day 5, while serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased on day 25 (p < 0.05). By day 45, serum TG and free fatty acid (FFA) levels were also significantly reduced (p < 0.05). Additionally, E. faecalis significantly increased the HDL/LDL ratio and serum high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05). Serum insulin levels were significantly elevated on day 25, and glucagon-like peptide-1 (GLP-1) levels were significantly increased on day 45 (p < 0.05). On day 25 of the trial, hepatic TG levels, FFA levels, and Oil Red O-stained areas in the liver were significantly reduced (p < 0.05), accompanied by significantly decreased mRNA expression of hepatic acetyl-CoA carboxylase (ACCA) (p < 0.05). Conversely, the mRNA expression levels of fatty acid synthase (FASN), farnesoid X receptor (FXR), sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor-α (PPARα) were significantly elevated (p < 0.05). A 16S rRNA diversity analysis of ileal contents on day 25 revealed significant differences in intestinal flora composition between the control and E. faecalis groups. The 16S rRNA data demonstrated a strong correlation between microbial communities and lipid-related physiological and biochemical indicators (p < 0.05). In conclusion, E. faecalis supplementation promoted fatty acid oxidation, reduced blood lipid levels, alleviated hepatic lipid accumulation, and improved ileal morphology and intestinal flora diversity, thereby enhancing growth performance and lipid metabolism in geese. These findings suggest that E. faecalis is a promising probiotic candidate for development as a feed additive.

Effects of radiotherapy on the hippocampus and hippocampal neurogenesis: asystematic review of preclinical studies.

Acomprehensive literature review was undertaken to understand the effects and underlying mechanisms of cranial radiotherapy (RT) on the hippocampus and hippocampal neurogenesis as well as to explore protective factors and treatments that might mitigate these effects in preclinical studies. PubMed/MEDLINE, Web of Science, and Embase were queried for studies involving the effects of radiation on the hippocampus and hippocampal neurogenesis. Data extraction followed the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines, and arisk of bias assessment was conducted for the included animal studies using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool. Ninety studies were included, with 48assessing radiation-induced changes and 42examining possible interventions. The majority of studies (97.8%) used experimental animal models. Studies demonstrated that cranial irradiation reduces hippocampal neurogenesis, particularly in the neurogenic niches of the dentate gyrus; causes alterations in gene expression and enzymatic activity; induces inflammation; promotes apoptosis; and often results in cognitive impairment. Potential protective strategies include pharmacological agents like metformin and peroxisome proliferator-activated receptor-α (PPAR-α) agonists or behavioral interventions like voluntary running. In arisk of bias assessment, many studies were rated as having an unclear risk of bias. Radiotherapy, while essential for managing brain tumors, can have adverse effects on hippocampal function and structure in animal models. These effects manifest in reduced neurogenesis, molecular alterations, and increased inflammation, leading to cognitive deficits. Further research is needed to identify and improve interventions and develop comprehensive therapeutic approaches that balance effective tumor control with the preservation of cognitive health.

The PPAR-α selective agonist WY14643 improves lupus nephritis via the downregulation of the RORγT/STAT3 signaling pathway in MRL/lpr mice.

Systemic lupus erythematosus (SLE) is a classic autoimmune disorder that mostly affects young women and involves various organs, such as the skin, joints, central nervous system, and kidneys. WY14643, a selective agonist of peroxisome proliferator-activated receptor-α, has previously shown anti-inflammatory effects in various disease models. However, its effects on lupus nephritis are yet to be explored. Therefore, the efficacy of WY14643 on renal biomarkers and lupus nephritis was assessed in MRL/lpr mice. Flow cytometry was used to examinethe effects of WY14643 on the expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in splenic CD4+ T cells. We further investigated the impact of WY14643 on the mRNA expression of IL-17A, STAT3, RORγT, IL-21, IL-21R, IL-22, and TNF-α in kidney tissue via RT-PCR analysis. The administration of WY14643 effectively improved the symptoms of lupus nephritis in MRL/lpr mice. The administration of WY14643 decreased serum albumin, urine protein, serum creatinine, and blood urea nitrogen levels in MRL/lpr mice. WY14643 reduced the levels of inflammatory markers, including CD4+IL-17A+, CD4+STAT3+, CD4+RORγT+, CD4+IL-21+, CD4+IL-21R+, CD4+IL-22+, and CD4+TNF-α+, in the spleen cells of MRL/lpr mice. Additionally, we discovered that the administration of WY14643 resulted in the suppression of mRNA levels of IL-17A, STAT3, RORγT, IL-21, IL-22, and TNF-α. The current work shows that the suppression of inflammatory cells by WY14643 may effectively reduce autoimmune characteristics, such as renal inflammation, in lupus-prone MRL/lpr mice. Therefore, WY14643, being a specific PPAR-α agonist, shows significant potential as a novel therapeutic option for treatingnephritis associated with SLE, offering hope for future treatments in this challenging field.

Peroxisome Proliferator Activator α Agonist Clofibrate Induces Pexophagy in Coconut Oil-Based High-Fat Diet-Fed Rats.

Peroxisomes are crucial for fatty acid β-oxidation in steatosis, but the role of pexophagy-the selective autophagy of peroxisomes-remains unclear. This study investigated the effects of the peroxisome proliferator-activated receptor-α (PPARα) agonist clofibrate on pexophagy in a coconut oil-based high-fat diet (HFD)-induced hepatocarcinogenesis model. Rats were divided into four groups: control, clofibrate, HFD, and HFD with clofibrate. The HFD induced steatosis, along with a 2.4-fold increase in pexophagy receptor NBR1-positive granules in hepatocytes. Clofibrate significantly inhibited HFD-induced steatosis, increasing p62-, LAMP2-, and Pex5-positive granules by 7.5-, 7.2-, and 71.4-fold, respectively, while decreasing NBR1 expression. The effects were associated with peroxisome proliferation and pexophagy in ultrastructural observations and increased levels of Lc3, p62, Pex2, Pex14, Acox1, and Scd1 in gene expression analysis. The results suggested that clofibrate effectively reduced steatosis through combined peroxisome proliferation and pexophagy, though it had a marginal impact on hepatocarcinogenesis in coconut oil-based HFD-fed rats. These findings highlight the utility of PPARα agonists in studying mammalian pexophagy.

Fenofibrate attenuates renal lipotoxicity in uninephrectomized mice with high-fat diet-induced obesity.

The objective of this study was to investigate the role of fenofibrate, a peroxisome proliferator-activated receptor-α agonist, in obesity-induced kidney damage (lipotoxicity) in mice with uninephrectomy. C57BL/6 mice underwent uninephrectomy and sham surgeries and were fed normocaloric or high-fat diets. After 10 weeks, obese mice were administered 0.02% fenofibrate for 10 weeks. Kidney function and morphology were evaluated, as well as levels of inflammatory and fibrotic mediators and lipid metabolism markers. High-fat diet-fed mice developed characteristic obesity and hyperlipidemia, with subsequent renal lipid accumulation and damage, including mesangial expansion, interstitial fibrosis, inflammation, and proteinuria. These changes were greater in obese uninephrectomy mice than in obese sham mice. Fenofibrate treatment prevented hyperlipidemia and glomerular lesions, lowered lipid accumulation, ameliorated renal dysfunction, and attenuated inflammation and renal fibrosis. Furthermore, fenofibrate treatment downregulated renal tissue expression of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and local expression of fibroblast growth factor-21. Peroxisome proliferator-activated receptor-α activation by fenofibrate, with subsequent lipolysis, attenuated glomerular and tubulointerstitial lesions induced by renal lipotoxicity, thus protecting the kidneys of uninephrectomy mice from obesity-induced lesions. The study findings suggest a pathway in the pharmacological action of fenofibrate, providing insight into the mechanisms involved in kidney damage caused by obesity in kidney donors.

Selective peroxisome proliferator-activated receptor-α modulator improves hypertriglyceridemia and muscle quality in patients with chronic kidney disease: A retrospective observational study

Background & AimsPatients with chronic kidney disease (CKD) often have additional health problems, including sarcopenia and sarcopenic obesity. These conditions involve ectopic fat accumulation within muscles. This ectopic fat deposition reduces muscle quality, leading to weaker muscle strength and poorer physical performance. Persistent hypertriglyceridemia contributes to ectopic fat accumulation. Metabolic abnormalities, including dyslipidemia, are major factors in CKD development. Triglycerides (TG) and muscle quality are thus important factors in CKD management. Recently developed selective peroxisome proliferator-activated receptor α modulator (SPPARMα) hold promises for improving hypertriglyceridemia. However, their effectiveness and impact on muscle quality in CKD patients remain unclear. This study aimed to evaluate the effect of SPPARMα on muscle quality and its efficacy in CKD patients. MethodsThis retrospective observational study involved CKD patients with dyslipidemia. We included patients who initiated medications for hypertriglyceridemia. We compared changes in lipid profiles, renal function, and muscle quality, assessed by phase angle, over six months between two groups: those receiving this type of medication and those receiving conventional treatment. ResultsAmong 245 patients diagnosed with CKD and hypertriglyceridemia, 52 started medications for hypertriglyceridemia. Of these, 26 received SPPARMα, and 26 received conventional lipid-lowering medications (statins, ezetimibe, eicosapentaenoic acid, and fibrates). SPPARMα significantly reduced TG (from 296.8 ± 106.1 to 153.0 ± 86.1, p <0.001) without affecting glomerular filtration rate or urinary protein levels. Conventional treatment also improved TG (from 261.6 ± 89.5 to 173.6 ± 81.3, p <0.001). Only patients treated with SPPARMα showed significant improvement in muscle quality. Their phase angle increased from 5.41 ± 0.6 to 5.55 ± 0.6 after six months of treatment (p <0.05). ConclusionsOur study demonstrates that the newly developed SPPARMα significantly lowers TG levels in CKD patients without harming their kidneys. Additionally, only patients treated with SPPARMα showed improvement in muscle quality. These findings suggest that SPPARMα may be a valuable treatment option for CKD patients with dyslipidemia, particularly those with low muscle quality.

Andrographolide Attenuates Myocardial Ischemia-Reperfusion Injury in Mice by Up-Regulating PPAR-α.

Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6J mice were pre-treated orally with AGP (25mg/kg) for six days. After 30min of the left anterior descending coronary artery occlusion followed by 24h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.

Dual-edged role of SIRT1 in energy metabolism and cardiovascular disease.

Regulation of energy metabolism is pivotal in the development of cardiovascular diseases. Dysregulation in mitochondrial fatty acid oxidation has been linked to cardiac lipid accumulation and diabetic cardiomyopathy. Sirtuin 1 (SIRT1) is a deacetylase that regulates the acetylation of various proteins involved in mitochondrial energy metabolism. SIRT1 mediates energy metabolism by directly and indirectly affecting multiple aspects of mitochondrial processes, such as mitochondrial biogenesis. SIRT1 interacts with essential mitochondrial energy regulators such as peroxisome proliferator-activated receptor-α (PPARα), PPARγ coactivator-1α, estrogen-related receptor-α, and their downstream targets. Apart from that, SIRT1 regulates additional proteins, including forkhead box protein O1 and AMP-activated protein kinase in cardiac disease. Interestingly, studies have also shown that the expression of SIRT1 plays a dual-edged role in energy metabolism. Depending on the physiological state, SIRT1 expression can be detrimental or protective. This review focuses on the molecular pathways through which SIRT1 regulates energy metabolism in cardiovascular diseases. We will review SIRT1 and discuss its role in cardiac energy metabolism and its benefits and detrimental effects in heart disease.

The Effects of Warm Acupuncture on the Expression of AMPK in High-Fat Diet-Induced MAFLD Rats.

This study investigated the effects of acupuncture and warm acupuncture on the expression and mechanism of the AMP-activated protein kinase (AMPK) signalling pathway associated with lipid accumulation in the liver tissue of rats with metabolic dysfunction-associated fatty liver disease (MAFLD) induced by a high-fat diet. Sprague-Dawley rats were categorised into four groups: control (CON), untreated MAFLD (MAFLD), and two MAFLD groups treated with acupuncture (ACU) and warm acupuncture (WA). The treatment groups underwent 16 application sessions over 8 weeks at the SP9 and BL18 acupoints. We measured the expression levels of AMPK, sterol regulatory element-binding protein1 (SREBP1), acetyl-coenzyme A carboxylase (ACC), peroxisome proliferator-activated receptorα (PPARα), carnitine palmitoyltransferase1 (CPT1), and CPT2. AMPK was activated in both ACU and WA groups. WA downregulated both SREBP1 and ACC expression at the protein level, whereas the acupuncture treatment downregulated SREBP1 expression. Additionally, WA selectively induced the activation of signalling pathways related to AMPK, PPARα, CPT1, and CPT2 at the mRNA level. Histological observations confirmed that fat accumulation was reduced in both the ACU and the WA groups compared to the MAFLD group. The WA treatment-promoted amelioration of HFD-induced MAFLD may be related to the activation of the AMPK/SREBP1/ACC pathway in the liver.

Atractylodes Lancea and Its Constituent, Atractylodin, Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease via AMPK Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), which encompasses a spectrum of conditions ranging from simple steatosis to hepatocellular carcinoma, is a growing global health concern associated with insulin resistance. Since there are limited treatment options for MASLD, this study investigated the therapeutic potential of Atractylodes lancea, a traditional herbal remedy for digestive disorders in East Asia, and its principal component, atractylodin, in treating MASLD. Following 8 weeks of high-fat diet (HFD) feeding, mice received oral doses of 30, 60, or 120 mg/kg of Atractylodes lancea. In HFD-fed mice, Atractylodes lancea treatment reduced the body weight; serum triglyceride, total cholesterol, and alanine aminotransferase levels; and hepatic lipid content. Furthermore, Atractylodes lancea significantly ameliorated fasting serum glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance levels in response to HFD. Additionally, a glucose tolerance test demonstrated improved glucose homeostasis. Treatment with 5 or 10 mg/kg atractylodin also resulted in anti-obesity, anti-steatosis, and glucose-lowering effects. Atractylodin treatment resulted in the downregulation of key lipogenic genes (Srebf1, Fasn, Scd2, and Dgat2) and the upregulation of genes regulated by peroxisome proliferator-activated receptor-α. Notably, the molecular docking model suggested a robust binding affinity between atractylodin and AMP-activated protein kinase (AMPK). Atractylodin activated AMPK, which contributed to SREBP1c regulation. In conclusion, our results revealed that Atractylodes lancea and atractylodin activated the AMPK signaling pathway, leading to improvements in HFD-induced obesity, fatty liver, and glucose intolerance. This study suggests that the phytochemical, atractylodin, can be a treatment option for MASLD.

Trophoblast-specific overexpression of adiponectin receptor 2 causes fetal growth restriction in pregnant mice.

Maternal obesity in pregnancy is strongly associated with complications such as fetal overgrowth and infants of obese mothers have an increased risk to develop obesity, diabetes, and cardiovascular disease later in life. However, the underlying mechanisms are not well established. Circulating levels of adiponectin are low in obese pregnant women and maternal circulating adiponectin is negatively associated with birth weight. We have reported that normalizing maternal adiponectin in obese pregnant mice prevents placental dysfunction, fetal overgrowth, and programming of offspring cardio-metabolic disease. However, the mechanistic link between maternal adiponectin, placental function, and fetal growth remains to be established. We hypothesized that trophoblast-specific overexpression of the adiponectin receptor 2 (Adipor2) in healthy pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Using lentiviral transduction of blastocysts with a mammalian gene expression lentiviral vector for up-regulation of Adipor2 (Adipor2-OX), we achieved a ~ 3-fold increase in placenta Adipor2 mRNA levels and a 2-fold increase of the ADIPOR2 protein in the trophoblast plasma membrane. Placenta-specific Adipor2-OX increased placental peroxisome proliferator-activated receptor-α phosphorylation, ceramide synthase expression and ceramide concentrations. Furthermore, Adipor2-OX inhibited placental mTORC1 signaling and reduced invivo placental transport of glucose and amino acids. Lastly, Adipor2-OX reduced fetal weight by 11%. These data provide mechanistic evidence that placental Adipor2 signaling directly affects fetal growth. We propose that low circulating adiponectin in maternal obesity causes fetal overgrowth and programs the offspring for cardio-metabolic disease mediated by a direct effect on placental function.

Impact of Conversion from Conventional Pemafibrate to Novel Pemafibrate XR on Hypertriglyceridemia: An Observational Retrospective Study

Background: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator, which was demonstrated to reduce serum triglyceride levels with few drug-related adverse events in several clinical studies, as well as phase II and III clinical trials. One of the limitations of this medicine was the requirement of twice-daily oral administration, resulting in reduced medication adherence, particularly in elderly patients, who are rather good targets for this medicine. Recently, a once-daily extended-release (XR) tablet has been introduced. Given an improvement in medication adherence, the therapeutic efficacy of pemafibrate may be enhanced. Methods: Patients with hypertriglyceridemia, in whom conventional twice-daily immediate-release (IR) pemafibrate was converted to pemafibrate XR between 2023 and 2024, were eligible. Each type of tablet was prescribed for three months, respectively. A dose change was not attempted. The serum triglyceride levels were compared between 3 months pre-conversion and 3 months post-conversion using a Friedman test and a post hoc Wilcoxon signed-rank test. Results: A total of 46 patients were included. The median age was 62 years, and 29 were men. IR was continued for 698 (280, 1183) days before the conversion. During the last 3-month IR therapy, serum triglyceride levels remained unchanged from 171 (138, 239) mg/dL to 181 (123, 245) mg/dL (p = 0.78). Following the conversion, no patients had drug-related adverse events, and all patients completed 3-month XR therapy. At three months after the conversion, the serum triglyceride levels decreased significantly from 181 (123, 245) mg/dL to 146 (107, 184) mg/dL (p &lt; 0.001). Conclusions: Pemafibrate XR might be a more promising medication than conventional IR in improving hypertriglyceridemia, probably due to improved medication adherence.

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

Discovering the lipid metabolism-related hub genes of HCC-treated samples with PPARα agonist through weighted correlation network analysis

Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy.

Dietary supplementation with 25-hydroxyvitamin D3 regulates productive performance, lipid metabolism and gut microbiota in aged laying ducks

The aim of this study was to investigate the effect of dietary supplementation with 25-hydroxyvitamin D3 (25(OH)D3) on productive performance, lipid metabolism and gut microbiota in aged laying ducks. A total of 432 healthy Longyan ducks at 60-week of age were randomly allotted to 6 groups, each with 6 replicates of 12 ducks. Ducks were given a basal diet (without added 25(OH)D3) or that diet supplemented with 800, 1600, 2400, 3200, or 4000 IU/kg 25(OH)D3 for a total of 16 wk. Dietary supplementation with 25(OH)D3 improved egg production, egg mass and average daily feed intake, and decreased the feed conversion ratio (FCR) of ducks during the whole trial period (linear, quadratic; P < 0.05). Supplementation with 25(OH)D3 decreased very low-density lipoprotein (VLDL) content in yolk (P = 0.008), decreased high-density lipoprotein and low-density lipoprotein (LDL) content in plasma (P = 0.002). Hepatic index, VLDL, LDL, triglyceride and total cholesterol content in liver, nonalcoholic fatty liver activity score of liver and alanine aminotransferase activity in plasma were decreased with supplementation of 25(OH)D3 (linear or quadratic; P < 0.05). The decreased hepatic apolipoprotein B 100 and lipoprotein lipase expression, and increased hepatic peroxisome proliferator-activated receptor-α and sterol regulatory element binding protein-1 expression resulted from 25(OH)D3 supplementation (linear, quadratic; P < 0.05). Moreover, 25(OH)D3 supplementation increased the villus/crypt ratio (linear, quadratic; P < 0.05) and expression of zonula occludens protein 1 and nuclear factor-κ-gene binding in duodenum (P < 0.05). The supplementation of 25(OH)D3 reduced the abundance of Wittenberg polluted soil-2 bacteria, Synergistota, Bacteroidales, Colidextribacter, Eggerthellaceae, Oscillospira, Oscillibacter, UCG-009, Barnesiellaceae and Lachnospiraceae_UCG-010 in cecal contents (P < 0.05). Dietary requirements for 25(OH)D3 for ducks (60 to 76 wk), were estimated to be 3377 IU/kg for egg production, 3434 IU/kg for egg mass, and 3256 IU/kg for FCR. In summary, dietary 25(OH)D3 supplementation improved productive performance and influenced liver and plasma lipid homeostasis in aged laying ducks, which may be associated with the reduction of bacteria involved in carbohydrate metabolism in the cecum. Supplementing the basal diet with 3250 to 3450 IU/kg 25(OH)D3 is recommended for aged laying ducks (60 to 76 wk).

Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

Endogenous activation of peroxisome proliferator-activated receptor-α in proximal tubule cells in counteracting phosphate toxicity.

Increased dietary phosphate consumption intensifies renal phosphate burden. Several mechanisms for phosphate-induced renal tubulointerstitial fibrosis have been reported. Considering the dual nature of phosphate as both a potential renal toxin and an essential nutrient for the body, kidneys may possess inherent protective mechanisms against phosphate overload, rather than succumbing solely to injury. However, there is limited understanding of such mechanisms. To identify these mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) analysis of the kidneys of control and dietary phosphate-loaded (Phos) mice at a time point when the Phos group had not yet developed tubulointerstitial fibrosis. scRNA-seq analysis identified the highest number of differentially expressed genes in the clusters belonging to proximal tubular epithelial cells (PTECs). Based on these differentially expressed genes, in silico analyses suggested that the Phos group activated peroxisome proliferator-activated receptor-α (PPAR-α) and fatty acid β-oxidation (FAO) in the PTECs. This activation was further substantiated through various experiments, including the use of an FAO activity visualization probe. Compared with wild-type mice, Ppara knockout mice exhibited exacerbated tubulointerstitial fibrosis in response to phosphate overload. Experiments conducted with cultured PTECs demonstrated that activation of the PPAR-α/FAO pathway leads to improved cellular viability under high-phosphate conditions. The Phos group mice showed a decreased serum concentration of free fatty acids, which are endogenous PPAR-α agonists. Instead, experiments using cultured PTECs revealed that phosphate directly activates the PPAR-α/FAO pathway. These findings indicate that noncanonical metabolic reprogramming via endogenous activation of the PPAR-α/FAO pathway in PTECs is essential to counteract phosphate toxicity.NEW & NOTEWORTHY This study revealed the activation of peroxisome proliferator-activated receptor-α and fatty acid β-oxidation in proximal tubular epithelial cells as an endogenous mechanism to protect the kidney from phosphate toxicity. These findings highlight noncanonical metabolic reprogramming as a potential target for suppressing phosphate toxicity in the kidneys.

Lactobacillus rhamnosus NKU FL1-8 Isolated from Infant Feces Ameliorates the Alcoholic Liver Damage by Regulating the Gut Microbiota and Intestinal Barrier in C57BL/6J Mice.

Alcoholic liver damage is caused by long-term or heavy drinking, and it may further progress into alcoholic liver diseases (ALD). Probiotic supplements have been suggested for the prevention or improvement of liver damage. This study was designed to consider the ameliorative effects of Lactobacillus rhamnosus NKU FL1-8 isolated from infant feces against alcoholic liver damage. The mice were gavaged with a 50% ethanol solution and treated with 109 CFU of L. rhamnosus NKU FL1-8 suspension. The factors for liver function, oxidative stress, inflammation, gut microbiota composition, and intestinal barrier integrity were measured. The results showed that L. rhamnosus NKU FL1-8 could decrease the levels of aspartate aminotransferase (AST) to 61% and alanine aminotransferase (ALT) to 50% compared with ethanol given by gavage. It could inhibit the expression level of malondialdehyde (MDA), increase superoxide dismutase (SOD), glutathione (GSH) to relieve oxidative stress, and down-regulate the cytokines to decrease hepatic inflammation. After treatment, the level of triglycerides was reduced, and the expression levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and the peroxisome proliferators-activated receptor-α (PPAR-α) pathway were up-regulated. Additionally, the 16S rRNA sequencing analysis showed that L. rhamnosus NKU FL1-8 increased the relative abundance of Lactobacillus, Ruminococcaceae, etc. At the same time, L. rhamnosus NKU FL1-8 could significantly reduce lipopolysaccharides (LPS) and enhance intestinal tight junction proteins. These results demonstrated that L. rhamnosus NKU FL1-8 could reduce the level of oxidative stress, fat accumulation, and liver inflammation caused by alcohol in the host. The underlying mechanism could be that L. rhamnosus NKU FL1-8 inhibits LPS by regulating the gut microbiota and repairing the intestinal barrier. Thereby, these findings support L. rhamnosus NKU FL1-8 as a potential functional food for the relief of ALD.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Effect of fructose on anthracycline and HER-2 blocking agent mediated cardiotoxicity through NLRP3 and MyD88 mediated pathways: New roles of sweeteners in cardio-oncology.

e24020 Background: Combinatorial therapy based on anthracyclines and HER-2 blocking agents increases the risk of cardiomyopathy in women with breast cancer. Fructose is a monosaccharide associated with high risk of diabetes, non-alcoholic fatty liver disease, atherosclerosis and visceral obesity. A high fructose diet is a potential cardiometabolic risk factor and may increase cardiac risk in women with breast cancer treated with cardiotoxic drugs. In this study, we highlighted the role of sweeteners fructose in the worsening of cardiotoxicity induced by combinatorial therapy anthracycline-HER2-blocking agents. Methods: Human cardiomyocytes were pre-exposed with doxorubicin combined to trastuzumab (at 300 and 1000 nM) for 48 and 72h alone or combined to fructose at 0.25, 1 and 2.5 mM. After the incubation period, we performed the following tests: determination of cell viability, through mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6, CXCL-12). Results: High fructose increases significantly cell mortality of cardiomyocytes exposed to doxorubicin and trastuzumab through the activation of NLRP-3 and Myd-88 expression. Intracellular Ca++ levels were also increased of 4 times compared to non-fructose exposed cardiomyocytes; MDA and 4-HNA levels were increased of 48,3 and 51,2 % compared to non-fructose exposed cells (p&lt;0.001). Fructose increases IL-1, IL-6 and CXCL-12 expression in cardiomyocytes in a concentration dependent manner, compared to doxorubicin-trastuzumab group (p&lt;0.05). Conclusions: Data of the present study indicate that fructose induces a pro-inflammatory phenotype in human cardiac cells exposed to anticancer cardiotoxic drugs, providing even more data on the harmful role of fructose as a key player of cardiotoxic phenomena.