In this study, we investigated PFAS (per- and polyfluoroalkyl substances) binding potencies to nuclear hormone receptors (NHRs): peroxisome proliferator-activated receptors (PPARs) α, β, and γ and thyroid hormone receptors (TRs) α and β. We have simulated the docking scores of 43 perfluoroalkyl compounds and based on these data developed QSAR (Quantitative Structure-Activity Relationship) models for predicting the binding probability to five receptors. In the next step, we implemented the developed QSAR models for the screening approach of a large group of compounds (4464) from the NORMAN Database. The in silico analyses indicated that the probability of PFAS binding to the receptors depends on the chain length, the number of fluorine atoms, and the number of branches in the molecule. According to the findings, the considered PFAS group bind to the PPARα, β, and γ only with low or moderate probability, while in the case of TR α and β it is similar except that those chemicals with longer chains show a moderately high probability of binding.

OBJECTIVE: Palmitoylethanolamide is an endogenous fatty acid amide with neuroprotective and anti-inflammatory actions. We performed a randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy and safety of palmitoylethanolamide combination therapy in acute mania.
METHODS: Patients in the acute phase of mania were assigned into two parallel groups given either lithium (blood level of 0.8-1.1 mEq/L) and risperidone 3 mg plus palmitoylethanolamide 600 mg or placebo twice per day for 6 weeks. All participants were assessed with the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and Extrapyramidal Symptom Rating Scale (ESRS) at baseline and at weeks 1, 2, 4, and 6.
RESULTS: A total of 63 patients (32 in palmitoylethanolamide and 31 in placebo groups) completed the trial. We found a significant effect for time×treatment interaction on the YMRS score (F = 5.22, d.f. = 2.34, P= 0.004) from baseline to study end point. Results from independent t test showed a significantly greater decrease in YMRS scores in the palmitoylethanolamide group, compared with the placebo group, from baseline to weeks 4 and 6 (P= 0.018 and P= 0.002, respectively). There was no significant difference between palmitoylethanolamide and placebo groups based on ESRS scores or ESRS changes in scores (P>0.05).
CONCLUSIONS: Our findings provide preliminary evidence that palmitoylethanolamide is an effective adjunctive medication that improves manic symptoms and overall clinical status in acute episodes of mania. However, larger sample sizes and more extended follow-up therapy are needed in future studies to confirm our findings.

OBJECTIVE: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant.
METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16.
RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation.
CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS.
UNASSIGNED: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

So far, numerous meta-analyses have been published regarding the correlation between peroxisome proliferator-activated receptor gamma (PPARG) proline 12 alanine (Pro12Ala) gene polymorphism and chronic kidney disease (CKD); however, the results appear to be contradictory. Hence, this study is formulated with the objective of using existing meta-analysis data together with our research population to study the correlation between PPARG Pro12Ala gene polymorphism and CKD and evaluate whether an accurate result can be obtained.
First, literature related to CKD and PPARG Pro12Ala available on the PubMed and EMBASE databases up to December 2016 was gathered from 20 publications. Then, the gathered results were combined with our case-control study of 1693 enrolled subjects and a trial sequential analysis (TSA) was performed to verify existing evidence and determine whether a firm conclusion can be drawn.
The TSA results showed that the cumulative sample size for the Asian sample was 6078 and was sufficient to support a definite result. The results of this study confirmed that there is no obvious correlation between PPARG Pro12Ala and CKD for Asians (OR = 0.82 (95% CI = 0.66-1.02), I2 = 63.1%), but this was not confirmed for Caucasians. Furthermore, the case-control sample in our study was shown to be the key for reaching this conclusion.
The meta-analysis results of this study suggest no significant correlation between PPARG Pro12Ala gene polymorphism and CKD for Asians after adding our samples, but not for Caucasian.

The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar.
The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population.
Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC0-24 ) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively).
Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.

BACKGROUND: The thioredoxin system maintains redox balance through the action of thioredoxin and thioredoxin reductase. Thioredoxin regulates the activity of various substrates, including those that function to counteract cellular oxidative stress. These include the peroxiredoxins, methionine sulfoxide reductase A and specific transcription factors. Of particular relevance is Redox Factor-1, which in turn activates other redox-regulated transcription factors.
METHODS: Experimentally defined transcription factor binding sites in the human thioredoxin and thioredoxin reductase gene promoters together with promoters of the major thioredoxin system substrates involved in regulating cellular redox status are discussed. An in silico approach was used to identify potential putative binding sites for these transcription factors in all of these promoters.
CONCLUSIONS: Our analysis reveals that many redox gene promoters contain the same transcription factor binding sites. Several of these transcription factors are in turn redox regulated. The ARE is present in several of these promoters and is bound by Nrf2 during various oxidative stress stimuli to upregulate gene expression. Other transcription factors also bind to these promoters during the same oxidative stress stimuli, with this redundancy supporting the importance of the antioxidant response. Putative transcription factor sites were identified in silico, which in combination with specific regulatory knowledge for that gene promoter may inform future experiments.
CONCLUSIONS: Redox proteins are involved in many cellular signalling pathways and aberrant expression can lead to disease or other pathological conditions. Therefore understanding how their expression is regulated is relevant for developing therapeutic agents that target these pathways.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD.
METHODS: One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).
RESULTS: NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP.
CONCLUSIONS: We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.

The incomplete inhibition of platelet function by acetylsalicylic acid (ASA), despite the patients are receiving therapeutic doses of the drug (\'aspirin-resistance\'), is caused by numbers of risk factors. In this study we verified the idea that plasma homocysteine (Hcy) contributes to \'aspirin-resistance\' in patients with coronary artery disease (CAD) and with or without type 2 diabetes mellitus (T2DM). A cross-designed randomized controlled intervention study has been performed (126 CAD pts incl. 26 with T2DM) to determine whether increasing ASA dose from 75mg to 150mg daily may result in the increased antiplatelet effect, in the course of four-week treatment. Platelet response to collagen (coll) or arachidonic acid (AA) was monitored with whole blood aggregometry, plasma thromboxane (Tx), and Hcy levels were determined immunochemically. The ASA-mediated reductions in platelet response to coll (by 12±3%) or AA (by 10±3%) and in plasma Tx (by 20±9%; p<0.02 or less) were significantly greater for higher ASA dose and significantly correlated with plasma Hcy, which was significantly lower in \"good\" ASA responders compared to \"poor\" responders (p<0.001). Higher plasma Hcy appeared a significant risk factor for blood platelet refractoriness to low ASA dose (OR=1.11; ±95%CI: 1.02-1.20, p<0.02, adjusted to age, sex and CAD risk factors). Hcy diminished in vitro antiplatelet effect of low ASA concentration and augmented platelet aggregation (by up to 62% (p<0.005) for coll and up to 15% (p<0.005) for AA), whereas its acetyl derivative acted oppositely. Otherwise, Hcy intensified antiplatelet action of high ASA. Hyperhomocysteinaemia may be a novel risk factor for the suppressed blood platelet response to ASA, and homocysteine may act as a specific sensitizer of blood platelets to some agonists. While homocysteine per se acts as a proaggregatory agent to blood platelets, its acetylated form is able to reverse this effect. Thus, these findings reveal a possibly new challenging potential of the acetylating properties of ASA therapy.

An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.