Chrysin attenuates estradiol-induced endometrial hyperplasia in rats via enhancing PPARα activity.

Endometrial hyperplasia (EH) is a complex condition that commonly affects women after menopause. Since the current available treatments for EH are mainly invasive, there is a need for developing new treatment modalities. Chrysin (Ch) is a dihydroxyflavone with numerous promising therapeutic potentials. In this study, Ch's protective effects on estradiol (E2)-induced EH were studied in rats. Animals were allocated randomly to five groups and were treated for 4 weeks as follows: Group 1, control: received the vehicle; group 2, Ch: received Ch 25 mg/kg; group 3, estradiol (E2): received E2 (3 mg/kg) 3 × weekly subcutaneously and the vehicle. Group 4, E2 + Ch 10 mg/kg and group 5, E2 + Ch 25 mg/kg: Ch was given once daily at 10 mg/kg or 25 mg/kg, respectively. In addition, E2 was administered 3 × weekly (3 mg/kg) in groups 4 and 5. Ch inhibited the E2-induced increase in uterine weights and histopathological changes. Ch lowered the cyclin D1 expression. Ch raised the caspase-3 content and Bax mRNA expression. Furthermore, it corrected the raised Bcl2 mRNA expression due to E2. Ch inhibited MDA accumulation and GSH depletion. It also prevents E2-induced SOD and GPx exhaustion. It also ameliorated the rise in NFκB, TNF-α, and IL-6 expression. These effects were correlated with an enhanced PPARα activity ratio relative to the E2 group. This suggests that Ch attenuates EH in this model by exerting anti-proliferative, anti-oxidant, and anti-inflammatory effects partially through increasing PPARα activity.

The anti-aging effect of velvet antler polypeptide is dependent on modulation of the gut microbiota and regulation of the PPARα/APOE4 pathway.

We investigated the anti-aging effects of velvet antler polypeptide on D-galactose (D-gal)-induced aging mice. D-gal-induced aging mice were established and randomly divided into five groups, the control, model, vitamin E (VE), velvet antler polypeptide low-dose and velvet antler polypeptide high-dose groups. The Morris water maze test was used to evaluate the learning and memory abilities of aging mice. Hippocampal neurons were observed via hematoxylin-eosin staining and transmission electron microscopy. Biochemical methods were used to detect the activities of superoxide dismutase, malonaldehyde and other enzymes and evaluate the influence of velvet antler polypeptide on the antioxidant capacity of aging mice. Using 16S rRNA gene sequencing and meristem technology, we assessed the effect of velvet antler polypeptide on aging mice's intestinal flora and fatty acid metabolism. The experimental results showed that velvet antler polypeptide could significantly improve aging mice's learning and cognitive abilities, increase the activities of superoxide dismutase, glutathione peroxidase, and catalase in the serum decrease the malonaldehyde content. Intestinal microecological analysis showed that velvet antler polypeptide could significantly increase the beneficial bacterial genus Lactobacillus abundance. Western blot analysis further demonstrated that velvet antler polypeptide could promote fatty acid metabolism by activating peroxisome proliferator-activated receptor α (PPARα) and upregulating the expression of the downstream enzymes carnitine-palmitoyl transferase-1 A and acyl-CoA oxidase 1 while downregulating that of apolipoprotein E4 (APOE4), thereby reducing fatty acid accumulation and increasing adenosine-triphosphate (ATP) production. Therefore, velvet antler polypeptide improves the intestinal microecology and activates the PPARα/APOE4 pathway to regulate fatty acid metabolism.

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism.

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Nanoparticle conjugation of ginsenoside Rb3 inhibits myocardial fibrosis by regulating PPARα pathway.

BACKGROUND: Cardiac fibrosis occurs in ischemic and non-ischemic heart failure, hereditary cardiomyopathy, diabetes and aging. Energy metabolism, which serves a crucial function in the course and treatment of cardiovascular diseases, might have therapeutic benefits for myocardial fibrosis. Ginsenoside Rb3 (G-Rb3) is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases. Therefore, the study investigated the effect of chitosan (CS) @ sodium tripolyphosphate (TPP) nanoparticles conjugation with ginsenoside Rb3 (NpRb3) on myocardial fibrosis and studied its possible mechanisms. The results showed that NpRb3 directly participates in the remodeling of myocardial energy metabolism and the regulation of perixisome proliferation-activated receptor alpha (PPARα), thereby improving the degree of myocardial fibrosis. The study also verifies the protective effect of NpRb3 on energy metabolism and mitochondrial function by targeting the PPARα pathway. Therefore, the prepared nanodrug carrier may be a potential solution for the delivery of G-Rb3, which is a promising platform for oral treatment of myocardial fibrosis.

MiR-21 promotes calcium oxalate-induced renal tubular cell injury by targeting PPARA.

Kidney stone disease is a crystal concretion formed in the kidneys that has been associated with an increased risk of chronic kidney disease. MicroRNAs are functionally involved in kidney injury. Data mining using a microRNA array database suggested that miR-21 may be associated with calcium oxalate monohydrate (COM)-induced renal tubular cell injury. Here, we confirmed that COM exposure significantly upregulated miR-21 expression, inhibited proliferation, promoted apoptosis, and caused lipid accumulation in an immortalized renal tubular cell line (HK-2). Moreover, inhibition of miR-21 enhanced proliferation and decreased apoptosis and lipid accumulation in HK-2 cells upon COM exposure. In a glyoxylate-induced mouse model of renal calcium oxalate deposition, increased miR-21 expression, lipid accumulation, and kidney injury were also observed. In silico analysis and subsequent experimental validation confirmed the peroxisome proliferator-activated receptor (PPAR)-α gene (PPARA) a key gene in fatty acid oxidation, as a direct miR-21 target. Suppression of miR-21 by miRNA antagomiR or activation of PPAR-α by its selective agonist fenofibrate significantly reduced renal lipid accumulation and protected against renal injury in vivo. In addition, miR-21 was significantly increased in urine samples from patients with calcium oxalate renal stones compared with healthy volunteers. In situ hybridization of biopsy samples from patients with nephrocalcinosis revealed that miR-21 was also significantly upregulated compared with normal kidney tissues from patients with renal cell carcinoma who underwent radical nephrectomy. These results suggested that miR-21 promoted calcium oxalate-induced renal tubular cell injury by targeting PPARA, indicating that miR-21 could be a potential therapeutic target and biomarker for nephrolithiasis.

The role of PPARα in autosomal dominant polycystic kidney disease.

PURPOSE OF REVIEW: Metabolic reprogramming is a prominent feature of cyst epithelial cells in autosomal dominant polycystic kidney disease (ADPKD). Peroxisome proliferator activated receptor alpha (PPARα) is a transcription factor that regulates many aspects of cellular metabolism. The purpose of this review is to understand the role of PPARα in ADPKD. RECENT FINDINGS: PPARα expression is reduced in ADPKD kidneys of mice and humans. This downregulation is in part secondary to microRNA mediated translational repression and leads to impairment of fatty acid metabolism. Genetic studies demonstrate that deletion of Pparα aggravates cyst growth in a slowly progressive mouse model of ADPKD. Recent studies also show that administration of Pparα agonists ameliorates cyst burden in mice. SUMMARY: Abnormal reduction of PPARα affects cellular metabolism in ADPKD. Pparα is a modulator of cyst progression in mouse models of ADPKD. These studies establish PPARα as an exciting new drug target for the treatment of individuals with ADPKD.

NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease.

Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro. PPARα agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPARα, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPARα and the phosphorylation of PPARα were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPARα, the main controller of fatty acid oxidation in the liver, because PPARα agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPARα. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPARα via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.

NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity.

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.

Hypolipidemic effect of pure total flavonoids from peel of Citrus (PTFC) on hamsters of hyperlipidemia and its potential mechanism.

Citrus is a group of popular fruit that includes oranges, lemons, limes and grapefruit but research of its peel on hyperlipidemia and its mechanism is rare reported. We examined the effect of pure total flavonoids from peel of Citrus (PTFC), an extract from the peel of Citrus Changshan-huyou which is a popular fruit in China, on hamsters with hyperlipoidemia induced by high-fat diet (HFD). We found that PTFC significantly reduced levels of serum cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c) and improved levels of alanine transaminase (ALT), aspartate transaminase (AST) and Alkaline phosphatase (ALP) which associated with liver function in golden hamsters. Liver pathological results confirmed that the liver pathological section of golden hamster treated with PTFC was significantly improved compared with that of HFD group. The content of main cholesterol metabolic enzymes Cholesterol 7a-hydroxylase (CYP7A1) in liver was obviously recovered with PTFC treatment. Further studies shown that PTFC attenuated oxidative stress and free radical damage through superoxide dismutase (SOD) and malonyldialdehyde (MDA) tests and inflammatory injury by levels of Tumor Necrosis Factor-alpha (TNF-α) and interleukin-6 (IL-6) both in serum and hepatocyte of golden hamsters. Moreover, PTFC increased levels of RNA and protein expression of Peroxisome proliferator-activated receptor-α (PPAR-α) and PPAR-γ in liver, fat and skeletal muscle of hyperlipidemia golden hamster, significantly. Our results suggested that PTFC could play a hypolipidemic role through improvement of liver function by antioxidant and anti-inflammatory effects in hyperlipoidemia hamsters, its mechanism of action may through activating of PPARα and PPARγ.

Activation of human nuclear receptors by perfluoroalkylated substances (PFAS).

Perfluoralkylated substances (PFAS) such as perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) are used to produce, e.g., surface coatings with water- and dirt-repellent properties. These substances have been shown to be hepatotoxic in rodents, and the mechanism of action is mostly attributed to the PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα). In the present study, we investigated by using luciferase-based reporter gene assays whether PFOA, PFOS and six alternative PFAS can activate, in addition to PPARα, eight other human nuclear receptors. All tested PFAS except for perfluorobutanesulfonic acid (PFBS) were able to activate human PPARα. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were weak agonists of human PPARγ. The other human nuclear receptors (PPARδ, CAR, PXR, FXR, LXRα, RXRα and RARα) were not affected by any PFAS tested in this study. Although PMOH was more effective than PFOA in stimulating PPARα in the transactivation assay, it was less effective in stimulating PPARα-dependent target gene expression in human HepG2 hepatocarcinoma cells. Notably, any effect observed in this in vitro study only occurred at concentrations higher than 10 µM of the respective PFAS which is in all cases several magnitudes above the average blood concentration in the Western population. Thus, the results suggest that nuclear receptor activation may only play a minor role in potential PFAS-mediated adverse effects in humans.