Fufang Xueshuantong alleviates diabetic retinopathy by activating the PPAR signalling pathway and complement and coagulation cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.

O-Methyl Phytocannabinoids: Semi-synthesis, Analysis in Cannabis Flowerheads, and Biological Activity.

A general protocol for the selective mono-O-methylation of resorcinyl phytocannabinoids was developed. The availability of semisynthetic monomethyl analogues of cannabigerol, cannabidiol, and cannabidivarin (1A: -3A: , respectively) made it possible to quantify these minor phytocannabinoids in about 40 different chemotypes of fiber hemp. No chemotype significantly accumulated mono-O-methyl cannabidiol (2B: ) or its lower homologue (3B: ), while at least three chemotypes containing consistent amounts (≥ 400 mg/kg) of O-methylcannabigerol (1B: ) were identified. O-Methylation of alkyl phytocannabinoids (1B: -3B: ) does not significantly change the activity on peroxisome proliferator-activated receptors in contrast to what was reported for phenethyl analogues.

Phytol: A review of biomedical activities.

Phytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of biological effects. PYT is a valuable essential oil (EO) used as a fragrance and a potential candidate for a broad range of applications in the pharmaceutical and biotechnological industry. There is ample evidence that PA may play a crucial role in the development of pathophysiological states. Focusing on PYT and some of its most relevant derivatives, here we present a systematic review of reported biological activities, along with their underlying mechanism of action. Recent investigations with PYT demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. PPARs- and NF-κB-mediated activities are also discussed as mechanisms responsible for some of the bioactivities of PYT. The overall goal of this review is to discuss recent findings pertaining to PYT biological activities and its possible applications.

Ginseng on Nuclear Hormone Receptors.

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

Natural Products for the Treatment of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus is a metabolic disease characterized by persistent hyperglycemia. High blood sugar can produce long-term complications such as cardiovascular and renal disorders, retinopathy, and poor blood flow. Its development can be prevented or delayed in people with impaired glucose tolerance by implementing lifestyle changes or the use of therapeutic agents. Some of these drugs have been obtained from plants or have a microbial origin, such as galegine isolated from Galega officinalis, which has a great similarity to the antidiabetic drug metformin. Picnogenol, acarbose, miglitol, and voglibose are other antidiabetic products of natural origin. This review compiles the principal articles on medicinal plants used for treating diabetes and its comorbidities, as well as mechanisms of natural products as antidiabetic agents. Inhibition of α-glucosidase and α-amylase, effects on glucose uptake and glucose transporters, modification of mechanisms mediated by the peroxisome proliferator-activated receptor, inhibition of protein tyrosine phosphatase 1B activity, modification of gene expression, and activities of hormones involved in glucose homeostasis such as adiponectin, resistin, and incretin, and reduction of oxidative stress are some of the mechanisms in which natural products are involved. We also review the most relevant clinical trials performed with medicinal plants and natural products such as aloe, banaba, bitter melon, caper, cinnamon, cocoa, coffee, fenugreek, garlic, guava, gymnema, nettle, sage, soybean, green and black tea, turmeric, walnut, and yerba mate. Compounds of high interest as potential antidiabetics are: fukugetin, palmatine, berberine, honokiol, amorfrutins, trigonelline, gymnemic acids, gurmarin, and phlorizin.

Effects of maternal dietary olive oil on pathways involved in diabetic embryopathy.

Maternal diabetes induces a pro-oxidant/pro-inflammatory intrauterine environment related to the induction of congenital anomalies. Peroxisome proliferator activated receptors (PPARs) are transcription factors that regulate antioxidant and anti-inflammatory pathways. We investigated whether maternal diets supplemented with olive oil, enriched in oleic acid, a PPAR agonist, can regulate the expression of PPAR system genes, levels of lipoperoxidation and activity of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in embryos and decidua from diabetic rats. The embryos and decidua from diabetic rats showed reduced expression of PPARs and increased concentration of lipoperoxidation, MMPs and TIMPs, whereas the maternal treatments enriched in olive oil increased PPARδ in embryos and PPARγ and PPARγ-coactivator-1α expression in decidua, and increased TIMPs concentrations and decreased lipoperoxidation and MMPs activity in both tissues. Thus, maternal diets enriched in olive oil can regulate embryonic and decidual PPAR system genes expression and reduce the pro-oxidant/pro-inflammatory environment during rat early organogenesis.

Green tea catechins prevent obesity through modulation of peroxisome proliferator-activated receptors.

Epidemiological evidence and experimental studies suggest that drinking green tea is associated with a lower risk of obesity and related diseases. However, the mechanisms of these effects are not clear. In the present study, we investigated the anti-obesity mechanisms of green tea catechins (GTCs) through modulation of peroxisome proliferator activated-receptor (PPAR) pathways in high-fat diet-induced obesity in rats. GTC supplementation significantly attenuated the increased body and liver weights and the elevated serum and liver triglyceride levels. Meanwhile, GTCs increased the PPARγ levels in subcutaneous white adipose tissue (SWAT) and decreased the PPARγ levels in visceral white adipose tissue (VWAT). In addition, GTC treatment up-regulated the levels of PPARδ in SWAT, VWAT, and brown adipose tissue and increased the expression of genes involved in fatty acid oxidation in brown adipose tissue. Our results suggest that GTCs exert their anti-obesity mechanism in part by modulating PPAR signaling pathways.

Toxicogenomic analysis of the gene expression changes in rat liver after a 28-day oral Tripterygium wilfordii multiglycoside exposure.

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii multiglycoside (GTW), which is an extract derived from Tripterygium wilfordii Hook.f., has been used for the treatment of rheumatoid arthritis and other immune diseases in China. However, its potential hepatotoxicity has not been completely investigated. THE AIM OF THE STUDY: The aim of the study was to determine the hepatotoxicity of GTW in Wistar rats and to investigate the underlying cellular mechanism further by microarray analysis. MATERIALS AND METHODS: Doses of GTW at 60, 100 and 120mg/kg/day were administered by oral gavage for subchronic toxicity in Wistar rats. Changes in the hepatic gene expression were identified with oligonucleotide microarrays at the 100-mg/kg/day dose level to study the hepatotoxic mechanism of GTW. RESULTS AND CONCLUSIONS: A number of changes in the body weight and food consumption, absolute and relative liver weight, biochemical analysis and histopathology were observed after the subacute exposure to GTW, and a dose-dependent hepatotoxicity was observed. A total of 1312 genes were found to be significantly altered (2-fold, P<0.05), including 582 up-regulated genes and 730 down-regulated genes. According to our biological pathway analysis, the GTW resulted in aberrant gene expression in metabolic pathways and the peroxisome proliferator-activated receptor (PPAR) signaling pathway and cellular stress. Real-time PCR analyses of several genes verified these results. Consequently, our gene expression microarray study will be useful for future GTW hepatotoxicity studies.

Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats.

Metabolic syndrome can precede the development of type 2 diabetes and cardiovascular disease and includes phenotypes such as obesity, systemic inflammation, insulin resistance, and hyperlipidemia. A recent epidemiological study indicated that blueberry intake reduced cardiovascular mortality in humans, but the possible genetic mechanisms of this effect are unknown. Blueberries are a rich source of anthocyanins, and anthocyanins can alter the activity of peroxisome proliferator-activated receptors (PPARs), which affect energy substrate metabolism. The effect of blueberry intake was assessed in obesity-prone rats. Zucker Fatty and Zucker Lean rats were fed a higher-fat diet (45% of kcal) or a lower-fat diet (10% of kcal) containing 2% (wt/wt) freeze-dried whole highbush blueberry powder or added sugars to match macronutrient and calorie content. In Zucker Fatty rats fed a high-fat diet, the addition of blueberry reduced triglycerides, fasting insulin, homeostasis model index of insulin resistance, and glucose area under the curve. Blueberry intake also reduced abdominal fat mass, increased adipose and skeletal muscle PPAR activity, and affected PPAR transcripts involved in fat oxidation and glucose uptake/oxidation. In Zucker Fatty rats fed a low-fat diet, the addition of blueberry also significantly reduced liver weight, body weight, and total fat mass. Finally, Zucker Lean rats fed blueberry had higher body weight and reduced triglycerides, but all other measures were unaffected. In conclusion, whole blueberry intake reduced phenotypes of metabolic syndrome in obesity-prone rats and affected PPAR gene transcripts in adipose and muscle tissue involved in fat and glucose metabolism.

Anti-diabetic effects of lemon balm ( Melissa officinalis) essential oil on glucose- and lipid-regulating enzymes in type 2 diabetic mice.

The antioxidant activity of lemon balm (Melissa officinalis) essential oil (LBEO) on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and its hypoglycaemic effect in db/db mice were investigated. LBEO scavenged 97 % of DPPH radicals at a 270-fold dilution. Mice administered LBEO (0.015 mg/d) for 6 weeks showed significantly reduced blood glucose (65 %; P < 0.05) and TAG concentrations, improved glucose tolerance, as assessed by an oral glucose tolerance test, and significantly higher serum insulin levels, compared with the control group. The hypoglycaemic mechanism of LBEO was further explored via gene and protein expression analyses using RT-PCR and Western blotting, respectively. Among all glucose metabolism-related genes studied, hepatic glucokinase and GLUT4, as well as adipocyte GLUT4, PPAR-gamma, PPAR-alpha and SREBP-1c expression, were significantly up-regulated, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression was down-regulated in the livers of the LBEO group. The results further suggest that LBEO administered at low concentrations is an efficient hypoglycaemic agent, probably due to enhanced glucose uptake and metabolism in the liver and adipose tissue and the inhibition of gluconeogenesis in the liver.

Tocotrienol enriched palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferators-activated receptors.

Palm oil is enriched in vitamin E in the form of alpha-, gamma-, and delta-tocotrienols. Dietary tocotrienol supplements have been shown to prevent atherosclerosis development in patients and preclinical animal models. However, the mechanistic basis for this health beneficial effect is not well established. Peroxisome proliferator-activated receptors alpha, gamma, and delta (PPARalpha, PPARgamma, and PPARdelta) are ligand regulated transcription factors that play essential preventive roles in the development of atherosclerosis through regulating energy metabolism and inflammation. In this study, we presented data that the tocotrienol rich fraction (TRF) of palm oil activated PPARalpha, PPARgamma, and PPARdelta in reporter based assays. Importantly, TRF attenuated the development of atherosclerosis in ApoE-/- mice through inducing PPAR target gene liver X receptor alpha (LXRalpha) and its down-stream target genes apolipoproteins and cholesterol transporters, suggesting that modulating the activities of PPARs is a key aspect of the in vivo action of tocotrienols.

Comparison of hormonal activity of isoflavone-containing supplements used to treat menopausal complaints.

OBJECTIVES: The isoflavones present in red clover and soy are used as an alternative treatment for menopausal complaints and are commercially available as high-dose food supplements. These preparations contain varying amounts of active ingredients, often without detailed specifications. Thus, it is difficult to derive a recommended daily dose, and the reliability of these products is rather low. METHODS: We quantified the isoflavone content of 19 different isoflavone-containing preparations and compared their binding and transactivational activities with regard to estrogen receptor alpha, estrogen receptor beta, androgen receptor, progesterone receptor, peroxisome-proliferator-activated receptor, and aryl hydrocarbon receptor. RESULTS: The food supplements that we tested bound to and transactivated both the estrogen receptors and the other receptors. After comparing the isoflavone content quantified by us with the isoflavone content specified on the package labels, we found that at least the specified isoflavone content or more could be detected in only 5 of the 19 food supplements that we tested. CONCLUSIONS: Preparations containing isoflavones should be standardized for the isoflavone aglycone content to facilitate the prediction of theoretical hormonal activity, facilitate the intake of a controlled amount of isoflavones, and ensure greater product reliability.

Anticancer actions of omega-3 fatty acids--current state and future perspectives.

Omega-3 fatty acids (omega3-FA) were shown to attenuate growth and induce apoptosis in a variety of human cancer cell lines derived from colonic, pancreatic, prostate, and breast cancer. In addition, recent findings indicate that omega3-FA act synergistically with chemotherapeutic agents and may also be used to enhance tumour radiosensitivity. The mechanisms underlying the anti-tumour effects of omega3-FA are complex. Incorporation of omega3-FA in biological membranes alters the profile of lipid mediators generated during inflammatory reactions. Furthermore, omega3-FA act as ligands of nuclear peroxisome proliferator-activated receptors that attenuate transcription of NF-kappaB-dependent genes. Thereby, the cyclooxygenase-2/prostaglandin E(2)-dependent production of pro-angiogenic vascular endothelial growth factor and levels of anti-apoptotic bcl-2 and bcl-X(L) are decreased. Eicosanoid-independent pro-apoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis and enhanced production of reactive oxygen species as well as activation of p53. This review article will give a comprehensive overview over the pleiotropic actions of omega3-FA and will discuss the potential of omega3-FA and derivatives like conjugated eicosapentaenoic acid as important nutritional adjuvant therapeutics in the management of various human cancer diseases and the impact of nutritional omega-3 FA on cancer prevention.

Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation.

The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB(1) and CB(2) cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB(1) and/or CB(2) receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.

Expression of human peroxisome proliferator-activated receptors ligand binding domain-maltose binding protein fusion protein in Escherichia coli: a convenient and reliable method for preparing receptor for screening ligands.

Human peroxisome proliferator-activated receptors (hPPARs) are ligand-activated transcription factors and are the target for the treatment of many diseases. Screening of their ligands is mainly based on assays of ligand binding to the ligand binding domain (LBD) of hPPARs.However, such assays are difficult because of the preparation of hPPARs LBD. In order to yield functional hPPARs LBD for screening ligands, hPPARs LBD was fused with maltose-binding protein(MBP) using the pMAL-p2x expression system through the gene engineering technique. The radioligand binding assay showed that MBP did not affect ligand binding with hPPARs LBD in the fusion proteins, which means that MBP-hPPARs LBD can be used instead of hPPARs LBD in ligand screening work. The results show that the new strategy using MBP as a fusion tag for preparing hPPARs LBD for screening ligands is a convenient and reliable method. It may be used to easily obtain the other nuclear receptors.

Peroxisome proliferator-activated receptors: a therapeutic target in COPD?

Extrapulmonary pathology significantly impairs clinical outcome in chronic obstructive pulmonary disease (COPD). The peroxisome proliferator-activated receptors (PPARs) are implicated in the regulation of several hallmarks of systemic COPD pathology, including cachexia, decreased oxidative muscle metabolism, oxidative stress and systemic inflammation. Recently, expression of PPARs and related cofactors was shown to be reduced in peripheral skeletal muscle of patients with moderate-to-severe COPD and muscle weakness. The current authors hypothesise that impaired peroxisome proliferator-activated receptor signalling may underlie some of the muscular disturbances in chronic obstructive pulmonary disease. Proposed mechanisms will be outlined in the present article, as well as the therapeutic potential of peroxisome proliferator-activated receptor modulation in the treatment of skeletal muscle dysfunction.

Investigational therapies in the treatment of obesity.

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.

An aqueous extract of the popular Chinese nutraceutical Kwei Ling Ko (Tortoise shell-Rhizome jelly) activates the PPARgamma pathway and down-regulates the NFkappaB activity.

It is generally believed that the popular nutraceutical 'Kwei Ling Ko' (KLK; Tortoise shell-Rhizome jelly) has antiinflammatory effects, but the mechanism by which its effects are manifested remains unknown. Peroxisome proliferation-activated receptors (PPARs) are members of the nuclear hormone receptor/transcription factor superfamily with multiple roles in adipocyte differentiation, glucose homeostasis, immunomodulation and antiinflammatory regulation. As PPAR is required for adipocyte induction, we used adipogenesis as a possible screen for the activation of the PPAR pathway. Interestingly, an aqueous extract of KLK (sKLK) was able to induce the adipocyte differentiation of fibroblast cell lines. Adipogenesis was confirmed by flow cytometric analysis using a fluorescent lipid stain. Up-regulation of PPARgamma transcripts during adipogenesis was also demonstrated by reverse transcription-polymerase chain reaction (RT-PCR). The sKLK-induced adipogenesis was similar to that elicited by insulin. The activity of nuclear factor-kappaB (NFkappaB), a transcription factor responsible for the regulation of proinflammatory genes, was also down-regulated in response to sKLK. Luciferase reporter gene assays further demonstrated that sKLK inhibited both basal and tumor necrosis factor-alpha-stimulated NFkappaB activation. The activities reported in this study support an immunomodulatory effect for sKLK. As activation of PPAR pathway has a dual role in adipogenesis and anti-inflammation, our observations are consistent with the notion that KLK possesses antiinflammatory properties.

Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. A review.

Consumption of soy has been demonstrated to reduce circulating cholesterol levels, most notably reducing low-density lipoprotein (LDL) cholesterol levels in hypercholesterolemic individuals. The component or components that might be responsible for this effect is still a matter of debate or controversy among many researchers. Candidate agents include an activity of soy protein itself, bioactive peptides produced during the digestive process, or the soy isoflavones. Although soy intake may provide other health benefits including preventative or remediative effects on cancer, osteoporosis and symptoms of menopause, this review will focus on isoflavones as agents affecting lipid metabolism. Isoflavones were first discovered as a bioactive agent disrupting estrogen action in female sheep, thereby earning the often-used term 'phytoestrogens'. Subsequent work confirmed the ability of isoflavones to bind to estrogen receptors. Along with the cholesterol-lowering effect of soy intake, research that is more recent has pointed to a beneficial antidiabetic effect of soy intake, perhaps mediated by soy isoflavones. The two common categories of antidiabetic drugs acting on nuclear receptors known as peroxisome proliferator activated receptors (PPARs) are the fibrates and glitazones. We and others have recently asked the research question 'do the soy isoflavones have activities as either "phytofibrates" or "phytoglitazones"?' Such an activity should be able to be confirmed both in vivo and in vitro. In both the in vivo and in vitro cases, this action has indeed been confirmed. Further work suggests a possible action of isoflavones similar to the nonestrogenic ligands that bind the estrogen-related receptors (ERRs). Recently, these receptors have been demonstrated to contribute to lipolytic processes. Finally, evaluation of receptor activation studies suggests that thyroid receptor activation may provide additional clues explaining the metabolic action of isoflavones. The recent advances in the discovery and evaluation of the promiscuous nuclear receptors that bind many different chemical ligands should prove to help explain some of the biological effects of soy isoflavones and other phytochemicals.

Immune-enhancing enteral nutrients differentially modulate the early proinflammatory transcription factors mediating gut ischemia/reperfusion.

BACKGROUND: Recent reports suggest that enteral diets enriched with arginine may be harmful by enhancing inflammation. This is consistent with our gut ischemia/reperfusion (I/R) model in which arginine induced the proinflammatory mediator inducible nitric oxide synthase and resulted in injury and inflammation whereas glutamine was protective. We now hypothesize that arginine and glutamine differentially modulate the early proinflammatory transcription factors activated by gut I/R. METHODS: At laparotomy, jejunal sacs were filled with either 60 mmol/L glutamine, arginine, or an iso-osmotic control followed by 60 minutes of superior mesenteric artery occlusion and 6 hours of reperfusion and compared with shams. Jejunum was harvested for nuclear factor (NF)-kappaB and activator protein-1 (AP-1) measured by electrophoretic mobility shift assay and c-jun and c-fos (AP-1 family) by supershift. RESULTS: Both NF-kappaB and AP-1 were activated by gut I/R. Arginine and glutamine had no differential effect on NF-kappaB, whereas AP-1 expression (c-jun but not c-fos) was markedly enhanced by arginine and significantly lessened by glutamine. CONCLUSION: Arginine enhanced expression of the early proinflammatory transcription factor AP-1 but not NF-kappaB. This represents a novel mechanism by which arginine may be harmful when administered to critically ill patients.