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.

Moving Targets: Recent Advances in Lipid-Lowering Therapies

Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in the field of genomics have revolutionized drug discovery and development and have revealed novel therapeutic targets to lower low-density lipoprotein cholesterol (LDL-C), as well as other detrimental lipids and lipoproteins. Therapeutic LDL-C lowering prevents atherosclerotic cardiovascular disease with an effect size proportional to absolute LDL-C reductions and time of exposure. This understanding supports the notion that reducing cumulative LDL-C exposure should be a key therapeutic target. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibiting monoclonal antibodies provides the possibility of reducing LDL-C to very low levels. Novel therapeutic platforms such as RNA inhibition present opportunities to combine robust lipid lowering with infrequent dosing regimens, introducing therapies with vaccine-like properties. The position of lipid-lowering therapies with targets other than LDL-C, such as Lp(a) [lipoprotein(a)], TRL (triglyceride-rich lipoproteins), and remnant cholesterol, will likely be determined by the results of ongoing clinical trials. Current evidence suggests that reducing Lp(a) or TRLs could attenuate atherosclerotic cardiovascular disease risk in specific categories of patients. This review provides an overview of the latest therapeutic developments, focusing on their mechanisms, efficacy, and safety.

The role of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptors-α in mediating the antinociceptive effects of palmitoylethanolamine in rats.

Palmitoylethanolamine (PEA) is a ligand at peroxisome proliferator-activated receptors-α (PPARα), a nuclear receptor that has anti-inflammatory effects. Herein, complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats and in-vitro calcium imaging studies were used to evaluate the mechanisms that underlie the antinociceptive effects of PEA, including modulating the activity of the transient receptor potential vanilloid receptor 1, which is a key receptor involved in the development of inflammatory pain. Adult male Sprague-Dawley rats (180-250 g) received subcutaneous injections of CFA (0.1 ml) into the plantar surface of the left hind paw. Von Frey filaments were used to determine the paw withdrawal threshold. PEA (50 µg), WY14643 (50 µg, a selective PPARα agonist) were injected into the plantar surface of the left hind paw at day 7 after CFA injection, and behavioral tests were repeated 6 h after drug administration. Rats were killed and dorsal root ganglia neurons were dissected and prepared for calcium imaging. Neurons were loaded with the calcium-sensitive ratiometric dye Fura-2AM. Changes in [Ca]i were measured as ratios of peak florescence at excitation wavelengths of 340 and 380 nm and expressed as a percentage of the KCl (60 mM) response. Both PEA and WY14643 significantly restored the paw withdrawal threshold in a PPARα-dependent fashion (P<0.01). Capsaicin of 15 nM produced 63.9±13.4% of KCl response. Preincubation of dorsal root ganglia neurons with PEA 6 h before stimulation with capsaicin, significantly reduce capsaicin-evoked calcium responses (42.9±6.4% of KCl response, n=54, P<0.001). In conclusion, modulating transient receptor potential vanilloid receptor 1 activity could provide the mechanism that underlies PEA antinociceptive effects observed in vivo.

Novel Anti-Obesity Properties of Palmaria mollis in Zebrafish and Mouse Models.

(1) Background: The red seaweed Palmaria mollis (PM), which has a bacon-like taste, is increasingly being included in Western diets. In this study, we evaluate anti-obesity effects of PM using diet-induced obese (DIO) zebrafish and mice models. (2) Methods: We fed PM-containing feed to DIO-zebrafish and mice, and evaluated the anti-obesity effects We also analyzed gene expression changes in their liver and visceral adipose tissues (VAT). (3) Results: PM ameliorated several anti-obesity traits in both animals, including dyslipidaemia, hepatic steatosis, and visceral adiposity. In liver tissues of DIO-zebrafish and mice, PM upregulated gene expressions involved in peroxisome proliferator-activated receptor alpha (PPARA) pathways, and downregulated peroxisome proliferator-activated receptor gamma (PPARG) pathways, suggesting that the lipid-lowering effect of PM might be caused by activation of beta-oxidation and inhibition of lipogenesis. In VAT, PM downregulated genes involved in early and late adipocyte differentiation in zebrafish, but not in mice. (4) Conclusions: We have demonstrated that PM can prevent hepatic steatosis and visceral adiposity for the first time. Dietary supplementation of PM as a functional food may be suitable for obesity prevention and reduction in the prevalence of obesity-related diseases.

Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: A clinical trial.

Obesity is a crucial public health problem worldwide and is considered as the main cause of many chronic diseases. The present study evaluated the effects of Oleoylethanolamide (OEA) supplementation on proximal proliferator-activated receptor-α (PPAR-α) gene expression, appetite sensations, and anthropometric measurements in obese people. This randomized, double-blind, placebo-controlled clinical trial was carried out on 60 healthy obese people in Tabriz, Iran, in 2016. The eligible subjects were divided into an intervention group (who received two 125 mg OEA capsules daily) and a placebo group (who received the same amount of starches) and treated for 60 days. Anthropometric measurements and body composition were assessed in a fasting state at baseline and at the end of the study. The visual analogue scales (VAS) were used to assess appetite sensations. Quantitative real-time PCR analysis targeting the 16S rRNA gene of PPAR-α was done. Analysis was done on 56 participants who continued intervention until the end of the study. A significant increase in PPAR-α gene expression was observed in the intervention group (p < 0.001). Weight, body mass index, waist circumference, and fat percent decreased significantly at the end of the study in the intervention group (all p < 0.01). Hunger, the desire to eat, and cravings for sweet foods decreased significantly and fullness increased significantly by the end of study in the intervention group at the end of study (all p < 0.01). The fullness item increased significantly by the end of study in the intervention group (p < 0.001). Use of OEA as a complementary approach could be effective in suppressing appetite and modulating energy balance in obese people.

[Effects of perfluorooctanoic acid on oxidative stress and PPARα and its related CYP4A1 gene expression in rat liver].

OBJECTIVE: To study the effects on oxidative stress and the expression of PPARα-related genes and protein in the liver of rats induced by pentadecafluorooctanoic acid( PFOA). METHODS: A total of 28 male SD rats were randomly divided into four groups: control group: double distilled water, low dose group: PFOA 1 mg/( kg·d), middle dose group: PFOA 5 mg/( kg·d), high dose group: PFOA 25 mg/( kg·d), and were administrated by gavage once a day for 14 days take the organization after anesthesia, according to the follow-up experiments need treatment. The activity of oxidative stressrelated enzymes and the content of malondialdehyde( MDA) in liver tissue were detected. The mRNA levels of peroxisome proliferators-activited receptors α( PPARα) and cytochrome P4504A1( CYP4A1) were detected by real-time PCR. The protein expression of PPARα was detected by Western blot. RESULTS: There was significant difference between high dose group and control group of the body weight( P < 0. 05). The liver weight and relative liver weight of the middle and high dose groups were significantly higher than those of the control group( P < 0. 05). The activity of superoxide dismutase( SOD) and glutathione peroxidase( GSH-Px) in the liver of the low dose group were significantly higher than that of the control group( P < 0. 05). The content of MDA in liver of middle and high dose groups were increased by 2. 5 times and 3. 5 times compared with that of control group( P < 0. 05). The expression of PPARα and its regulated CYP4A1 mRNA were significantly increased in low, middle and high dose groups. The expression of PPARα protein in the low, middle and high dose groups were up-regulated. CONCLUSION: PFOA exposure can lead to oxidative stress in rat liver, resulting in antioxidant enzymes SOD and GSH-Px and MDA changes. At the same time, PFOA exposure induced up regulation of PPARα and CYP4A1 in the liver of rats to enhance theß-oxidation of fatty acids, leading to lipid peroxidation, which has obvious toxic effects on rat liver.

Dietary umbelliferone attenuates alcohol-induced fatty liver via regulation of PPARα and SREBP-1c in rats.

This study investigated the effects of umbelliferone (UF) on alcoholic fatty liver and its underlying mechanism. Rats were fed a Lieber-DeCarli liquid diet with 36% of calories as alcohol with or without UF (0.05 g/L) for 8 weeks. Pair-fed rats received an isocaloric carbohydrate liquid diet. UF significantly reduced the severity of alcohol-induced body weight loss, hepatic lipid accumulation and droplet formation, and dyslipidemia. UF decreased plasma AST, ALT, and γGTP activity. UF significantly reduced hepatic cytochrome P450 2E1 activities and increased alcohol dehydrogenase and aldehyde dehydrogenase 2 activities compared to the alcohol control group, which resulted in a lower plasma acetaldehyde level in the rats that received UF. Chronic alcohol exposure inhibited hepatic AMPK activation compared to the pair-fed rats, which was reversed by UF supplementation. UF also significantly suppressed the lipogenic gene expression (SREBP-1c, SREBP-2, FAS, CIDEA, and PPARγ) and elevated the fatty acid oxidation gene expression (PPARα, Acsl1, CPT, Acox, and Acaa1a) compared to the alcohol control group, which could lead to inhibition of FAS activity and stimulation of CPT and fatty acid ß-oxidation activities in the liver of chronic alcohol-fed rats. These results indicated that UF attenuated alcoholic steatosis through down-regulation of SREBP-1c-mediated lipogenesis and up-regulation of PPARα-mediated fatty acid oxidation. Therefore, UF may provide a promising natural therapeutic strategy against alcoholic fatty liver.

Screening of medicinal plants for PPARα and PPARγ activation and evaluation of their effects on glucose uptake and 3T3-L1 adipogenesis.

Medicinal plants are a rich source of ligands for nuclear receptors. The present study was aimed to screen a collection of plant extracts for PPARα/γ-activating properties and identify the active extract that can stimulate cellular glucose uptake without enhancing the adipogenesis. A reporter gene assay was performed to screen ethanolic extracts of 263 plant species, belonging to 94 families, for activation of PPARα and PPARγ. Eight extracts showed activation of PPARγ, while 22 extracts showed activation of PPARα. The extracts of five plants (Daphne gnidium, Illicium anisatum, Juniperus virginiana, Terminalia chebula, and Thymelaea hirsuta) showed activation of both PPARα and PPARγ and out of them, D. gnidium and T. hirsuta markedly increased PPARα/γ protein expression. All five extracts showed an increase in cellular glucose uptake. Of the five dual agonists, T. chebula and T. hirsuta did not show any increase in differentiation of 3T3-L1 preadipocytes, but I. anisatum caused an increase in adipogenesis, while D. gnidium and J. virginiana were toxic to adipocytes. The adipogenic effect of rosiglitazone was antagonized by T. chebula and T. hirsuta. It was concluded that T. hirsuta and T. chebula retain the property of elevating glucose uptake as PPARα/γ dual agonists without the undesired side effect of adipogenesis. This is the first report to reveal the PPARα/γ dual agonistic action and glucose uptake enhancing property of T. hirsuta and T. chebula.

Protective effects of gypenosides against fatty liver disease induced by high fat and cholesterol diet and alcohol in rats.

In the present study, the protective effects of gypenosides from Gynostemma pentaphyllum on fatty liver disease (FLD) were examined in rats treated with high fat and cholesterol diet and alcohol. Male SD rats were divided into seven groups: control, model, lovastatin, silymarin, gypenosides high-, medium- and low-treatment groups. The latter 6 groups were fed high-fat and cholesterol diet and administered alcohol intragastricly once a day. Body weight was measured every week for 10 weeks, and the hepatic index was measured after 10 weeks. Compared with model group, levels of serum triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), and low density lipoprotein cholesterol (LDL-C) level, malondialdehyde (MDA), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, and hepatocyte apoptosis were significantly decreased in gypenosides groups; while serum high density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD) activity in both serum and hepatic tissue and mRNA and protein level of peroxisome proliferator-activated receptor α (PPAR-α) were significantly increased. Moreover, hepatic steatosis and mitochondrial damage were improved. These results suggested that gypenosides could prevent liver fatty degeneration in fatty liver disease through modulating lipid metabolism, ameliorating liver dysfunction and reducing oxidative stress.

[Effects of ursolic acid in ameliorating insulin resistance in liver of KKAy mice via peroxisome proliferator-activated receptors α and γ].

OBJECTIVE: To explore the effects and mechanism of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes. METHODS: Thirty-five KKAy mice were divided into five groups according to the randomized block design, namely, control, rosiglitazone, fenofibrate, and high- and low-dose ursolic acid groups with seven mice in each group. C57BL/6J mice were used as the normal control group. At the end of the 4th week, free fatty acid (FFA), tumor necrosis factor-α (TNF-α) and adiponectin contents in serum were detected by enzyme-linked immunosorbent assay; the protein expressions of phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor substrate-2 (IRS-2) and glucose transport factor-2 (GLUT-2) were detected by Western blot method; the mRNA expressions of PEPCK, IRS-2 and GLUT-2 were detected by real-time polymerase chain reaction; the expressions of peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) in liver tissue were detected by immunohistochemical method. RESULTS: After four weeks of intervention, the contents of FFA, TNF-α and adiponectin in serum of the high-dose ursolic acid group had changed, showing statistically significant difference compared to those of the control group (P<0.01); high dose of ursolic acid had depressant effect on the expressions of PEPCK protein and PEPCK mRNA (P<0.01); low dose of ursolic acid depressed the expression of PEPCK mRNA and induced phosphorylation of IRS-2 in the liver (P<0.05); both high and low dose of ursolic acid improved the expression of PPARα in the liver (P<0.01). CONCLUSION: The effects of ursolic acid in improving hepatic insulin resistance in KKAy mice with spontaneous type 2 diabetes may be closely related to affecting the contents of FFA, TNF-α and adiponectin, improving the expression of PPARα protein, regulating transcription of PEPCK protein and inducing phosphorylation of IRS-2.

PPARα activation by culinary herbs and spices.

Hyper- and dyslipidemia are risk factors for cardiovascular disease, the primary cause of death in industrialized countries. Peroxisome proliferators-activated receptor (PPAR)α activation is involved in various mechanisms that improve the lipid profile. We tested various plant extracts and their compounds to determine whether they stimulated PPARα activity in vitro. Out of 34 tested plant extracts, nine exhibited low to moderate PPARα transactivation, including caraway, chili pepper, nutmeg, licorice, black and white pepper, paprika, coriander, saffron, and stevia tea. The active components of black pepper and chili pepper, piperine, and capsaicin exerted the highest transactivational activities with EC50 values of 84 µM and 49 µM, respectively. The chalcones, including 2-hydroxychalcone, 2'-hydroxychalcone, 4-hydroxychalcone, and 4-methoxychalcone, moderately transactivated PPARα. Resveratrol and apigenin only slightly transactivated PPARα. These results suggest that a diet rich in fruit, herbs, and spices provides a number of PPARα agonists that might contribute to an improved lipid profile.

Red clover extract: a source for substances that activate peroxisome proliferator-activated receptor alpha and ameliorate the cytokine secretion profile of lipopolysaccharide-stimulated macrophages.

OBJECTIVE: Inflammation and hyperlipidemia or dyslipidemia contribute to an increased risk of atherosclerosis and cardiovascular disease. Cardiovascular disease represents one of the major causes of premature death worldwide. The activation of peroxisome proliferator-activated receptor (PPAR) alpha, a drug target for hyperlipidemia and dyslipidemia, leads to an improved blood lipid profile. In this study, we determined the putative anti-inflammatory and PPARalpha stimulatory activities of red clover, an alternative to the classic hormone therapy used currently to treat menopausal symptoms. METHODS: Lipopolysaccharide-induced macrophages were used as a model for anti-inflammatory activity, and a chimeric GAL4-PPARalpha system was used as a model for putative hypolipidemic activity. RESULTS: Red clover extract and the isoflavones genistein and biochanin A were moderate PPARalpha activators. Daidzein only slightly activated PPARalpha, but its metabolite 6-hydroxydaidzein exerted a much higher PPARalpha activity. Similarly, the metabolite 3'-hydroxygenistein achieved higher activation efficiency than its precursor, genistein, did. In lipopolysaccharide-stimulated macrophages, red clover extract and its compounds reduced the secretion of proinflammatory cytokines, interleukin-6 and tumor necrosis factor alpha, increased the secretion of the anti-inflammatory interleukin-10, and/or reduced the expression of nuclear factor-kappaB, inducible nitric oxide synthase, and/or cyclooxygenase 2. Tumor necrosis factor alpha production was most efficiently reduced by biochanin A and genistein. Interleukin-6 levels were most efficiently reduced by genistein and equol. CONCLUSIONS: Owing to its PPARalpha activation and modulation of the secreted cytokine profile, red clover extract is a putative candidate for preventing atherosclerosis and, thus, cardiovascular disease.

Iridoids from Fraxinus excelsior with adipocyte differentiation-inhibitory and PPARalpha activation activity.

Two new secoiridoid glucosides, excelsides A (1) and B (2), were isolated from the seeds of Fraxinus excelsior. Their structures were elucidated as (2S,4S,3E)-methyl 3-ethylidene-4-(2-methoxy-2-oxoethyl)-2-[(6-O-beta-D-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate and (2S,4S,3E)-methyl 3-ethylidene-4-{2-[2-(4-hydroxyphenyl)ethyl]oxy-2-oxoethyl}-2-[(6-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate, respectively, on the basis of NMR and MS data. Eight known compounds were identified as nuzhenide (3), GI3 (4), GI5 (5), ligstroside (6), oleoside 11-methyl ester (7), oleoside dimethyl ester (8), 1'''-O-beta-D-glucosylformoside (9), and salidroside (10). Compounds 1-9 inhibited adipocyte differentiation in 3T3-L1 cells. Dilutions of the aqueous extract of F. excelsior (1:10,000) as well as compounds 2, 3, 4, 5, and 8 activated the peroxisome proliferator-mediated receptor-alpha (PPARalpha) reporter cell system in the range of 10(-4) M, compared to 10(-7)-10(-8) M for the synthetic PPARalpha activator, WY14,643. Both biological activity profiles support the hypothesis that inhibition of adipocyte differentiation and PPARalpha-mediated mechanisms might be relevant pathways for the antidiabetic activity of F. excelsior extract.

Pomegranate flower ameliorates fatty liver in an animal model of type 2 diabetes and obesity.

AIMS OF THE STUDY: Fatty liver is the most common cause of abnormal liver function tests. We investigated the effect and its underlying mechanism of pomegranate flower (PGF), a traditional antidiabetic medicine, on fatty liver. MATERIALS AND METHODS: At the endpoint of treatment of male Zucker diabetic fatty (ZDF) rats with PGF extract (500 mg/kg, p.o. x 6 weeks), liver weight index, hepatic lipid contents (enzymatic colorimetric methods) and droplet accumulation (Oil Red O staining) were determined. Gene profiles (RT-PCR) were analyzed in the liver of ZDF rats and in human liver-derived HepG2 cell line. RESULTS: PGF-treated ZDF rats showed reduced ratio of liver weight to tibia length, hepatic triglyceride contents and lipid droplets. These effects were accompanied by enhanced hepatic gene expression of peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase (ACO), and reduced stearoyl-CoA desaturase-1. In contrast, PGF showed minimal effects on expression of genes responsible for synthesis, hydrolysis or uptake of fatty acid and triglycerides. PGF treatment also increased PPAR-alpha and ACO mRNA levels in HepG2 cells. CONCLUSION: Our findings suggest that this Unani medicine ameliorates diabetes and obesity-associated fatty liver, at least in part, by activating hepatic expression of genes responsible for fatty acid oxidation.

The Korean traditional medicine Gyeongshingangjeehwan inhibits obesity through the regulation of leptin and PPARalpha action in OLETF rats.

Gyeongshingangjeehwan (GGEx), which comprises Liriope platyphylla F.T. Wang & T. Tang (Liliaceae), Platycodongrandiflorum A. DC. (Campanulaceae), Schisandrachinensis K. Koch (Magnoliaceae), and Ephedra sinica Stapf (Ephedraceae), has traditionally been used as an anti-obesity drug in Korean local clinics, although there is no evidence concerning the scientific analyses of its effects and mechanism(s) of action. Thus, we investigated the effects of GGEx on obesity, as well as the mechanism by which GGEx functions, in Otsuka Long-Evans Tokushima Fatty (OLETF) male rats. Compared with obese OLETF control rats, administration of GGEx for 8 weeks significantly decreased food intake and plasma leptin levels as well as body weight gain and abdominal fat in OLETF rats. GGEx treatment not only decreased circulating triglycerides, but also inhibited lipid accumulation in the liver. GGEx increased the hepatic mRNA levels of PPARalpha target genes responsible for fatty acid beta-oxidation. Consistent with the in vivo data, GGEx elevated PPARalpha reporter gene expression in NMu2Li liver cells. These results suggest that GGEx may effectively prevent obesity and hypertriglyceridemia in part through the inhibition of feeding and the activation of hepatic PPARalpha.

Regulation of obesity and lipid disorders by herbal extracts from Morus alba, Melissa officinalis, and Artemisia capillaris in high-fat diet-induced obese mice.

Melissa officinalis L. (Labiatae), Morus alba L. (Moraceae), and Artemisia capillaris Thunb. (Compositae) are suggested to be involved in the regulation of hyperlipidemia. We hypothesized that Ob-X, a mixture of three herbs, Morus alba, Melissa officinalis and Artemisia capillaris [corrected] improves lipid metabolism, body weight gain and adiposity and that peroxisome proliferator-activated receptor alpha (PPARalpha) is associated with these events. Mice fed a high-fat diet for 12 weeks exhibited increases in body weight gain and adipose tissue mass compared with mice fed a low fat diet. However, feeding a high-fat diet supplemented with Ob-X significantly reduced these effects. Ob-X treatment also decreased the circulating levels of triglycerides and total cholesterol, and inhibited hepatic lipid accumulation. Ob-X supplementation was found to increase the hepatic mRNA levels of PPARalpha target enzymes responsible for fatty acid beta-oxidation. Moreover, Ob-X elevated the endogenous expression of a luciferase reporter gene containing three copies of a PPAR response element (PPRE) in NMu2Li liver cells. These data demonstrate that Ob-X regulates body weight gain, adipose tissue mass, and lipid metabolism in part through changes in the expression of hepatic PPARalpha target genes.

Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-alpha/-gamma activator properties.

PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-alpha is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-gamma participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-alpha or PPAR-gamma agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-alpha and PPAR-gamma activators, as well as their potential to modulate vascular disease, combined PPAR-alpha/-gamma activation has recently emerged as a promising concept, leading to the development of mixed PPAR-alpha/-gamma activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-alpha and PPAR-gamma activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-alpha/-gamma activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications.