Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.

Along with an increase in overweight and obesity among all age groups, the development of efficacious and safe anti-obesity strategies for patients, as well as health systems, is critical. Oleoylethanolamide (OEA), a high-affinity endogenous ligand of nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), plays important physiological and metabolic actions. OEA is derived from oleic acid, a monounsaturated fatty acid, which has beneficial effects on body composition and regional fat distribution. The role of OEA in the modulation of food consumption and weight management makes it an attractive molecule requiring further exploration in obesogenic environments. This systematic review was conducted to assess the effects of OEA on the obesity management, with emphasizing on its physiological roles and possible mechanisms of action in energy homeostasis. We searched PubMed/Medline, Google Scholar, ScienceDirect, Scopus, ProQuest, and EMBASE up until September 2019. Out of 712 records screened, 30 articles met the study criteria. The evidence reviewed here indicates that OEA, an endocannabinoid-like compound, leads to satiation or meal termination through PPAR-α activation and fatty acid translocase (FAT)/CD36. Additionally, the lipid-amide OEA stimulates fatty acid uptake, lipolysis, and beta-oxidation, and also promotes food intake control. OEA also exerts satiety-inducing effects by activating the hedonic dopamine pathways and increasing homeostatic oxytocin and brain histamine. In conclusion, OEA may be a key component of the physiological system involved in the regulation of dietary fat consumption and energy homeostasis; therefore, it is suggested as a possible therapeutic agent for the management of obesity.

Introduction: Peroxisome proliferator-activated receptors (PPARs), PPARα, PPARδ, and PPARγ, play an important role in the regulation of various physiological processes, specifically lipid and energy metabolism and immunity. PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism but PPARδ-acting drugs are not yet available. Many synthetic ligands for PPARs have been developed to expand their therapeutic applications.Areas covered: The authors searched recent patent activity regarding PPAR ligands. Novel PPARα agonists, PPARδ agonists, PPARγ agonists, PPARα/γ dual agonists, and PPARγ antagonists have been claimed for the treatment of metabolic disease and inflammatory disease. Methods for the combination of PPAR ligands with other drugs and expanded application of PPAR agonists for bone and neurological disease have been also claimed.Expert opinion: Novel PPAR ligands and the combination of PPAR ligands with other drugs have been claimed for the treatment of mitochondrial disease, inflammatory/autoimmune disease, neurological disease, and cancer in addition to metabolic diseases including dyslipidemia and type 2 diabetes. Selective therapeutic actions of PPAR ligands should be exploited to avoid adverse effects. More basic studies are needed to elucidate the molecular mechanisms of selective actions.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.

With great changes in people\'s lifestyles, the incidence of hyperlipidaemia has dramatically increased in recent years. Numerous studies have demonstrated that natural polysaccharides have lipid lowering effects. In this review, the causes and mechanisms of hyperlipidaemia are discussed in order to better understand how polysaccharides alleviate hyperlipidaemia. Natural polysaccharides reduce triglyceride levels through ATGL-(PPAR-α)/(PGC-1α), (SREBP-1c)-ACC/FAS and ACC-CPT1 signal pathways, and exert cholesterol lowering effects via (SREBP-2)-HMGCR and bile acid biosynthesis pathways. Activation of adenosine monophosphate-activated protein kinase (AMPK) is the key factor that mediated the simultaneous regulation of both glucose and lipid metabolism by polysaccharides. The new discovery of polysaccharides increasing the production of endogenous H2S, an important physiological gaseous signaling molecule, is also discussed. Collectively, the current available data suggest that natural polysaccharides could be potentially developed as new and safe lipid-lowering drugs; yet further mechanistic and clinical studies are required during this long-term process.

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Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia.
A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the effects of pemafibrate on lipid and glucose metabolism-related parameters in patients with dyslipidemia. For statistical analysis, standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random effect model.
Our search yielded seven RCTs (with a total of 1623 patients) that satisfied the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration significantly decreased in the pemafibrate group (SMD, - 1.38; 95% CI, - 1.63 to - 1.12; P < 0.001) than in the placebo group, with a reduction effect similar to that exhibited by fenofibrate. Compared with the placebo group, the pemafibrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafibrate group showed a significant decrease in hepatobiliary enzyme activity compared with the placebo and fenofibrate groups; and, total adverse events (AEs) were significantly lower in the pemafibrate group than in the fenofibrate group (OR, 0.60; 95% CI, 0.49-0.73; P < 0.001). In contrast, the low-density lipoprotein cholesterol level was significantly higher in the pemafibrate group than in the placebo (P = 0.006) and fenofibrate (P < 0.001) groups.
The lipid profile significantly improved in the pemafibrate group than in the placebo group. In addition to the pemafibrate group having an improved lipid profile, which was comparable with that of the fenofibrate group, the AEs were significantly lower than in the fenofibrate group and an improvement in hepatobiliary enzyme activity was also recognized. However, we believe that actual clinical data as well as long-term efficacy and safety need to be investigated in the future.

Obesity as a multifactorial disorder has been shown a dramatically growing trend recently. Besides genetic and environmental factors, dysregulation of the endocannabinoid system tone is involved in the pathogenesis of obesity. This study reviewed the potential efficacy of Oleoylethanolamide (OEA) as an endocannabinoid-like compound in the energy homeostasis and appetite control in people with obesity. OEA as a lipid mediator and bioactive endogenous ethanolamide fatty acid is structurally similar to the endocannabinoid system compounds; nevertheless, it is unable to induce to the cannabinoid receptors. Unlike endocannabinoids, OEA negatively acts on the food intake and suppress appetite via various mechanisms. Indeed, OEA as a ligand of PPAR-α, GPR-119, and TRPV1 receptors participates in the regulation of energy intake and energy expenditure, feeding behavior, and weight gain control. OEA delays meal initiation, reduces meal size, and increases intervals between meals. Considering side effects of some approaches used for the management of obesity such as antiobesity drugs and surgery as well as based on sufficient evidence about the protective effects of OEA in the improvement of common abnormalities in people with obese, its supplementation as a novel efficient and FDA approved pharmaceutical agent can be recommended.

To assess the effect of fibrates on circulating cystatin C levels.
Clinical studies evaluating the effect of a fibrate on circulating cystatin C levels were searched in PubMed-Medline, SCOPUS, Web of Science, and Google Scholar databases. A random-effect model and generic inverse variance method were used for quantitative data synthesis, sensitivity analysis conducted using the leave-one-out method, and weighted random-effects meta-regression performed to evaluate potential confounders on cystatin C levels.
This meta-analysis of data from nine published studies (16 treatment arms) involved a total of 2195 subjects. In a single-arm analysis of clinical trials (without control group; eight studies comprising 14 treatment arms), fibrate therapy increased circulating cystatin C concentrations (WMD: 0.07 mg/dL, 95% CI: 0.04, 0.10, p < .001; I2 = 82.66%). When the analysis was restricted to randomized controlled trials (four studies comprising six treatment arms), again elevation of circulating cystatin C levels was observed (WMD: 0.06 mg/L, 95% CI: 0.03, 0.09, p < .001; I2 = 42.98%). Elevated cystatin C levels were only seen with fenofibrate and not with other fibrates.
The results suggest that fenofibrate treatment adversely affects cystatin C levels and might partially explain the limited efficacy of fenofibrate in reducing cardiovascular events. Key message Fenofibrate treatment adversely affects cystatin C levels and might partially explain the limited efficacy of fenofibrate in reducing cardiovascular events.

BACKGROUND: Diabetic retinopathy is a significant cause of vision impairment, especially affecting those of working age. There are two large, randomised controlled trials examining the effect of fenofibrate on diabetic retinopathy.
OBJECTIVE: We summarise their findings, and report on the available safety data.
CONCLUSIONS: The FIELD study reported that patients treated with fenofibrate had a statistically significant relative risk reduction in the need for laser treatment for maculopathy and proliferative retinopathy. The ACCORD-Eye study reported a statistically significant reduction in diabetic retinopathy progression in patients treated with fenofibrate and statin combination therapy compared to statin therapy alone. There is firm evidence that fenofibrate slows the progression of diabetic retinopathy and the need for more invasive treatment modalities in patients with type 2 diabetes, especially those with pre-existing retinopathy. In October 2013, Australia became the first country in the world to approve the use of this medication for this specific indication.