In vivo treatment of rats with phenobarbital (PB) induces liver enzyme induction associated with hepatocyte hypertrophy. In the present study we used a novel microTMA technology coupled with artificial intelligence (AI) driven image analysis and proteomics analysis to test the hypothesis that PB treatment of rat and human liver microtissues could recapitulate hepatocyte hypertrophy in vitro. Human and rat liver microtissues were treated with PB over a range of concentrations (500 uM - 2000 uM). Fixed liver microtissues were embedded in paraffin in a microTMA mold, sectioned and stained on parallel microTMA sections with H&E and cell type specific markers, respectively. An AI algorithm was trained to identify and measure changes in hepatocyte cytoplasmic area on images of H&E stained microtissue sections. Image analysis with this algorithm showed that treatment of human and rat liver microtissues with PB (500 uM) for 96 h caused significant increases (p ≤ 0.08- p < 0.01) in hepatocyte cytoplasmic area, a hallmark of hypertrophy. Proteomics analysis of control and PB treated liver microtissue samples confirmed this treatment also caused phase1 and phase 2 enzyme induction in both human and rat samples. In conclusion AI driven image analysis of H&E stained liver microtissue FFPE sections shows that this model can recapitulate a PB-induced hypertrophy response.

Background: Extra pulmonary tuberculosis (EPTB) accounts for a significant proportion of tuberculosis (TB), a devastating disease of public health concern. The complexity of the cases, the involvement of many organs, resource constraints, and concerns regarding drug resistance make disease diagnosis and treatment difficult. This study aimed to determine the burden of tuberculosis and associated factors among presumptive EPTB patients in selected hospitals in Addis Ababa.Material and methods: A cross-sectional study was conducted from February to August 2022 in selected public hospitals in Addis Ababa. Those who attended the hospitals and were presumptively diagnosed as EPTB patient were included in the study. Sociodemographic and clinical data were collected using a semistructured questionnaire. The GeneXpert MTB/RIF assay, Mycobacterium Growth Indicator Tube (MGIT) culture, and solid culture using Lowenstein-Jensen (LJ) medium were used. The data were entered and analyzed using SPSS version 23, and a p-value <= 0.05 was considered as statistically significant.Results: From a total of 308 participants enrolled in this study, the measured burdens of extrapulmonary tuberculosis using the Xpert MTB/RIF assay, liquid culture, and solid culture were 54 (17.5%), 45 (14.6%), and 39 (12.7%), respectively. In this study, sex, contact history with known TB cases, having a purulent type of aspirate, and being HIV positive had statistically significant associations with EPTB.Conclusions: The burden of extrapulmonary tuberculosis among presumptive extrapulmonary tuberculosis cases was found to be significant. Sex, contact history with a known TB case, having apurulent type of aspirate, and being HIV positive were found to be associated with extrapulmonary tuberculosis infection. Strict adherence to the national tuberculosis diagnosis and treatment guidelines is important, while the true burden of the disease should be ascertained using standard diagnostic tests for better prevention and control interventions.

Background:Drug resistance in tuberculosis poses challenges to both the control and prevention of the disease. The extent of resistance is not well known in developing countries, including Ethiopia. This study was conducted to determine the drug resistance patterns and mutation characteristics of Mycobacterium tuberculosis among extra pulmonary tuberculosis patients in selected health facilities in Addis Ababa.Material and Methods:A cross-sectional study was conducted from February 2022 to August 2022 in selected hospitals in Addis Ababa. Socio-demographic and clinical data were collected using structured questionnaire. Mycobacterium tuberculosis complex (MTBC) isolates were tested for phenotypic drug susceptibility patterns using the Mycobacterium growth indicator tube (MGIT) method for first-line drugs and mutation characteristics using the Line Probe Assay (LPA) method. The data were analyzed using: SPSS version 23, and a P-value ≤ 0.05 was considered statistically significant.Results:From a total of 308 patient samples from presumptive extra pulmonary patients, 44 (14.3%) were positive for MTBC. Any drug resistance was discovered in 25% of 44 MTBC isolates evaluated for five first-line drugs phenotypically, with isoniazid (INH) and pyrazinamide (PZA) resistance accounting for a greater proportion with 13.6% and 11.4% of the isolates, respectively. Two (4.5%) of the isolates were MDR-TB. Out of 44 isolates tested using the Geno Type MTBDRplus assay, 5 (11.4%) showed mutations at katG and 2 (4.5%) showed mutations in the rpoB genes.Conclusion:Both the phenotypic and genotypic drug susceptibility test results showed a high proportion of INH resistance. All INH resistance-conferring mutations were identified from katG gene. The overall prevalence of MDR-TB was also high. For early case detection and treatment, expanding diagnostic capacity for first-line DST is a vital step to limit further spread of drug resistant TB strains in the study area.

Veterinary RecordVolume 188, Issue 1 p. 37-38 Animal Welfare Regulating research on client-owned animals Jodi Ware, Corresponding Author Jodi Ware pharmacist jodiware@mac.com J Ware Consulting LLC, Kingwood, Texas, USASearch for more papers by this authorEddie Clutton, Eddie Clutton professor in anaesthesiology Wellcome Trust Critical Care Laboratory for Large Animals, Roslin Institute, Easter Bush, Midlothian, EH25 9RGSearch for more papers by this authorNgaire Dennison, Ngaire Dennison named veterinary surgeon Biological Services, University of Dundee, MSI/WTB/JBC Complex, Dow Street, Dundee, DD1 5EHSearch for more papers by this authorKathy Murphy, Kathy Murphy director Comparative Biology Centre, Newcastle University, Newcastle upon Tyne, NE2 4HHSearch for more papers by this authorGabrielle C Musk, Gabrielle C Musk senior lecturer Animal Care Services, University of Western Australia, M720, Perth, WA, 6009 AustraliaSearch for more papers by this authorPolly Taylor, Polly Taylor specialist in anaesthesia and analgesia Taylor Monroe, Gravel Head Farm, Little Downham, Ely, Cambridgeshire, CB6 2TYSearch for more papers by this authorSarah Wolfensohn, Sarah Wolfensohn professor of animal welfare School of Veterinary Medicine, University of Surrey, Stags Hill, Guildford, Surrey, GU2 7TESearch for more papers by this authorJayne Wright, Jayne Wright pathologist Jayne Wright Ltd, Underhill House, Putley, Herefordshire, HR8 2QRSearch for more papers by this author Jodi Ware, Corresponding Author Jodi Ware pharmacist jodiware@mac.com J Ware Consulting LLC, Kingwood, Texas, USASearch for more papers by this authorEddie Clutton, Eddie Clutton professor in anaesthesiology Wellcome Trust Critical Care Laboratory for Large Animals, Roslin Institute, Easter Bush, Midlothian, EH25 9RGSearch for more papers by this authorNgaire Dennison, Ngaire Dennison named veterinary surgeon Biological Services, University of Dundee, MSI/WTB/JBC Complex, Dow Street, Dundee, DD1 5EHSearch for more papers by this authorKathy Murphy, Kathy Murphy director Comparative Biology Centre, Newcastle University, Newcastle upon Tyne, NE2 4HHSearch for more papers by this authorGabrielle C Musk, Gabrielle C Musk senior lecturer Animal Care Services, University of Western Australia, M720, Perth, WA, 6009 AustraliaSearch for more papers by this authorPolly Taylor, Polly Taylor specialist in anaesthesia and analgesia Taylor Monroe, Gravel Head Farm, Little Downham, Ely, Cambridgeshire, CB6 2TYSearch for more papers by this authorSarah Wolfensohn, Sarah Wolfensohn professor of animal welfare School of Veterinary Medicine, University of Surrey, Stags Hill, Guildford, Surrey, GU2 7TESearch for more papers by this authorJayne Wright, Jayne Wright pathologist Jayne Wright Ltd, Underhill House, Putley, Herefordshire, HR8 2QRSearch for more papers by this author First published: 16 January 2021 https://doi.org/10.1002/vetr.65Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume188, Issue1January 2021Pages 37-38 RelatedInformation

Species differences in hepatic metabolism of thyroxine (T4) by uridine diphosphate glucuronosyl transferase (UGT) and susceptibility to thyroid hormone imbalance could underlie differences in thyroid carcinogenesis caused by hepatic enzyme inducers in rats and humans. To investigate this hypothesis we examined profiles of hepatic UGT induction by the prototypical CAR activator phenobarbital (PB) in rat and human liver 3D microtissues. The rationale for this approach was that 3D microtissues would generate data more relevant to humans. Rat and human liver 3D microtissues were exposed to PB over a range of concentrations (500 u M - 2000 u M) and times (24-96 hr). Microarray and proteomics analyses were performed on parallel samples to generate integrated differentially expressed gene (DEG) datasets. Bioinformatics analysis of DEG data, including CAR response element (CRE) sequence analysis of UGT promoters, was used to assess species differences in UGT induction relative to CAR-mediated transactivation potential. A higher proportion of human UGT promoters were found to contain consensus CREs compared to the rat homologs. UGTs 1a6, 2b17 and 2b37 were upregulated by PB in rat liver 3D microtissues, but unaltered in human liver 3D microtissues. By contrast, human UGTs 1A8, 1A10 and 2B10 showed higher levels of induction (RNA and /or protein) compared to the rat homologs. There was general concordance between the presence of CREs and the induction of UGT RNA. As UGT1A and 2B isoforms metabolise T4, these results suggest that differences in UGT induction could contribute to differential susceptibility to CAR-mediated thyroid carcinogenesis in rats and humans.

Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PKdata toman and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create amousemodel that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, togetherwith Car and Pxr, for humanCAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.

Characterisation of the mode of action (MOA) of constitutive androstane receptor (CAR)-mediated rodent liver tumours involves measurement 5 key events including activation of the CAR receptor, altered gene expression, hepatocellular proliferation, clonal expansion and increased hepatocellular adenomas/carcinomas. To test whether or not liver 3D microtissues (LiMTs) recapitulate CAR- mediated procarcinogenic key events in response to the prototypical CAR activator phenobarbital (PB) we performed hepatocyte proliferation (LI%) analysis in rat and human LiMTs using a microTMA technology in conjunction with integrated transcriptomics (microarray) and proteomics analysis. The rationale for this approach was that LiMTs containing parenchymal and non-parenchymal cells (NPCs) are more physiologically representative of liver and thus would generate data more relevant to the in vivo situation. Rat and human LiMTs were treated with PB over a range of concentrations (500 uM - 2000 uM) and times (24 h - 96 h) in a dose-response/time-course analysis. There was a dose-dependent induction of LI% in rat LiMTs, however there was little or no effect of PB on LI% in human LiMTs. ATP levels in the rat and human LiMTs were similar to control in all of the PB treatments. There was also a dose- and time-dependent PB-mediated RNA induction of CAR regulated genes CYP2B6/Cyp2b2, CYP3A7/Cyp3a9 and UGT1A6/Ugt1a6 in human and rat LiMTs, respectively. These CAR regulated genes were also upregulated at the protein level. Ingenuity pathways analysis (IPA) indicated that there was a significant (Z score > 2.0;-log p value >) activation of CAR by PB in both human and rat LiMTs. These results indicate that human and rat LiMTs showed the expected responses at the level of PB-induced hepatocyte proliferation and enzyme induction with rat LiMTs showing significant dose-dependent effects while human LiMTs showed no proliferation response but did show dose-dependent enzyme induction at the RNA and protein levels. In conclusion LiMTs serve as a model to provide mechanistic data for 3 of the 5 key events considered necessary to establish a CAR-mediated MOA for liver tumourigenesis and thus can potentially reduce the use of animals when compiling mechanistic data packages.

A veterinary pioneer and a pathfinder in One Health, he enjoyed teaching and never lost enthusiasm for his research projects; he was also well versed in the arts.

An increased incidence of liver tumours in the long term rodent bioassay is not an uncommon finding, invariably as a result of a non-genotoxic mode of action. Non-genotoxic liver carcinogenesis has been found to involve activation of certain nuclear hormone receptors (NHR) including the constitutive androstane receptor (CAR), peroxisome proliferator activated receptor alpha (PPARalpha) and arylhydrocarbon receptor (AHR) and more recently the induction of specific microRNAs (miRs), has also been demonstrated following CAR activation in studies up to 90 days (Koufaris et al., 2012). The stable induction of these tissue specific miRs, namely miR200a, 200b and 429, by liver non-genotoxic carcinogens may serve as early predictors (biomarkers) of heptocarcinogenic potential. To test this hypothesis we used RT-PCR to measure the levels of these miRs in the livers from Wistar rats treated with two rat hepatocarcinogenic and one non hepatocarcinogenic pyrazole carboxamide succinate dehydrogenase inhibitors, Isopyrazam, Sedaxane and Benzovindiflupyr, respectively. The miRs were quantified by RT-PCR in liver RNA samples from three 90 day repeat dose toxicity studies performed at the low, mid and high doses relative to control. In Isopyrazam treated rats a statistically significant (p < 0.01) dose-dependent increase in miR 200a, 220b and 429 in both males and females was observed, whilst for Sedaxane a significant (p < 0.05) increase in miR200b in males and females at the high dose was seen. Benzovindiflupyr treatment did not cause any dose related changes in miR 200a, 200b and 429 relative to control. Our results suggest that assessment of miR 200a/200b/429 levels has potential as a biomarker of the perturbation of pathways involved in hepatocarcinogenesis in Wistar rats. Further work is required to establish the possible relationship between miR200 cluster induction and CAR-mediated hepatocarcinogenesis in a more diverse range of compounds.

There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored using in vitro L6 metabolic models. These models demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle models to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.

The coronary vasculature is an essential vessel network providing the blood supply to the heart. Disruptions in coronary blood flow contribute to cardiac disease, a major cause of premature death worldwide. The generation of treatments for cardiovascular disease will be aided by a deeper understanding of the developmental processes that underpin coronary vessel formation. From an ENU mutagenesis screen, we have isolated a mouse mutant displaying embryonic hydrocephalus and cardiac defects (EHC). Positional cloning and candidate gene analysis revealed that the EHC phenotype results from a point mutation in a splice donor site of the Myh10 gene, which encodes NMHC IIB. Complementation testing confirmed that the Myh10 mutation causes the EHC phenotype. Characterisation of the EHC cardiac defects revealed abnormalities in myocardial development, consistent with observations from previously generated NMHC IIB null mouse lines. Analysis of the EHC mutant hearts also identified defects in the formation of the coronary vasculature. We attribute the coronary vessel abnormalities to defective epicardial cell function, as the EHC epicardium displays an abnormal cell morphology, reduced capacity to undergo epithelial-mesenchymal transition (EMT), and impaired migration of epicardial-derived cells (EPDCs) into the myocardium. Our studies on the EHC mutant demonstrate a requirement for NMHC IIB in epicardial function and coronary vessel formation, highlighting the importance of this protein in cardiac development and ultimately, embryonic survival.

Phenobarbital (PB) is known to produce species-specific effects in the rat and mouse, being carcinogenic in certain mouse strains, but only in rats if treated after a DNA damaging event. PB treatment in the rat and mouse also produces disparate effects on cell signalling and miRNA expression profiles. These responses are induced by short term and prolonged PB exposure, respectively, with the latter treatments being difficult to examine mechanistically in primary hepatocytes due to rapid loss of the original hepatic phenotype and limited sustainability in culture. Here we explore the rat hepatocyte-like B13/H cell line as a model for hepatic response to PB exposure in both short-term and longer duration treatments. We demonstrate that PB with Egf treatment in the B13/H cells resulted in a significant increase in Erk activation, as determined by the ratio of phospho-Erk to total Erk, compared to Egf alone. We also show that an extended treatment with PB in the B13/H cells produces a miRNA response similar to that seen in the rat in vivo, via the time-dependent induction of miR-182/96. Additionally, we confirm that B13/H cells respond to Car activators in a typical rat-specific manner. These data suggest that the B13/H cells produce temporal responses to PB that are comparable to those reported in short-term primary rat hepatocyte cultures and in the longer term are similar to those in the rat in vivo. Finally, we also show that Car-associated miR-122 expression is decreased by PB treatment in B13/H cells, a PB-induced response that is common to the rat, mouse and human. We conclude that the B13/H cell system produces a qualitative response comparable to the rat, which is different to the response in the mouse, and that this model could be a useful tool for exploring the functional consequences of PB-sensitive miRNA changes and resistance to PB-mediated tumours in the rat.

This article contains mass spectrometry (MS) data investigating small molecule changes as an effect of a triple peroxisome proliferator-activated receptor (PPAR-pan) agonist GW625019 in the liver as described in the manuscript (Ament et al., 2016) [1]. Samples were measured using gas chromatography-mass spectrometry (GC–MS) for total fatty acid content, and liquid chromatography-mass spectrometry (LC–MS) to measure intact lipids, carnitines and selected aqueous metabolites and eicosanoids. Data files comprise of Excel (Microsoft, WA, USA) spreadsheets of identified metabolites and their area ratio values for total fatty acids, carnitines, aqueous metabolites, and eicosanoids where the intensity of the analytes were normalised to the intensity of the internal standard. In the case of open profiling intact lipid data, the Excel file contains area ratio values of retention time and mass to charge ratio pairs; again, the area ratio values were calculated by normalising to the intensity of the internal standard. It should be noted that several metabolic changes are potentially indirect (secondary, tertiary and ensuing changes).

Primary mucosal malignant melanoma of the head and neck (HN-PMMM) is an aggressive and uncommon neoplasm. Herein, we present a series of 33 patients and the results of treatment, and aimed to determine prognostic factors in HN-PMMM.Patients who were diagnosed as having HN-PMMM in our reference hospital, between 2005 and 2014 were evaluated. Thirty-three of these patients who had follow-up data were included. Surgical margin status was extracted from the original pathology reports. Archived materials were retrieved for the histopathologic findings: ulceration, necrosis, lymphovascular invasion, perineural invasion, pigmentation, and presence of an in situ component. Mitotic activity was evaluated using phosphohistone H3 (PHH3) immunohistochemical staining.We found an association of PHH3 mitotic activity with overall survival in a univariate analysis and to our knowledge, this is the first report among the available case series of HN-PMMM to evaluate mitotic activity using immunohistochemical staining. We also investigated the relationship between multicentricity and locoregional recurrence, which the authors believe is also a first.PHH3 mitotic activity can be used a prognostic factor for head and neck mucosal malignant melanoma.

ABC transporters play an important role in the disposition of avermectins in several animal species. In this study the interactions of three key avermectins, abamectin, emamectin and ivermectin, with human and mouse homologues of MDR1 (ABCB1/Abcb1a) and MRP (ABCC/Abcc), transporters endogenously expressed by human SH-SY5Y and mouse N2a neuroblastoma cells were investigated. In both cell lines, retention of the fluorescent dye H33342 was found to be significantly increased in the presence of avermectins and cyclosporin A. These effects were shown to be unresponsive to the BCRP inhibitor Ko-143 and therefore MDR1/Mdr1-dependent. Avermectins inhibited MDR1/Mdr1a-mediated H33342 dye efflux, with apparent K-i values of 0.24 +/- 0.08 and 0.18 +/- 0.02 mu M (ivermectin); 0.60 +/- 0.07 and 0.56 + 0.02 mM (emamectin) and 0.95 + 0.08 and 0.77 + 0.25 mM (abamectin) in SH-SY5Y and N2a cells, respectively.There were some apparent affinity differences for MDR1 and Mdr1a within each cell line (affinity for ivermectin > emamectin >= abamectin, P < 0.05 by One-Way ANOVA), but importantly, the K-i values for individual avermectins for human MDR1 or mouse Mdr1a were not significantly different. MK571-sensitive retention of GSMF confirmed the expression of MRP/Mrp efflux transporters in both cell lines. Avermectins inhibited MRP/Mrp-mediated dye efflux with IC50 values of 1.58 +/- 0.51 and 1.94 +/- 0.72 mu M (ivermectin); 1.87 +/- 0.57 and 2.74 +/- 1.01 mu M (emamectin) and 2.25 +/- 0.01 and 1.68 +/- 0.63 mM (abamectin) in SH-SY5Y and N2a cells, respectively. There were no significant differences in IC50 values between individual avermectins or between human MRP and mouse Mrp.Kinetic data for endogenous human MDR1/MRP isoforms in SH-SY5Y cells and mouse Mdr1a/b/Mrp isoforms in N2a cells are comparable for the selected avermectins. All are effluxed at concentrations well above 0.05-0.1 mu M ivermectin detected in plasma (Ottesen and Campbell, 1994; Ottesen and Campbell, 1994) This is an important finding in the light of toxicity seen in the Mdr1-deficient animal models CF-1 mice, Mdr1ab (-/-) double knockout mice and Collie dogs. We also confirm MRP/Mrp-mediated avermectin transport in both N2a and SH-SY5Y cell lines. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARoc, gamma and delta) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects.In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-alpha,-gamma, and -delta), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n 3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. (C) 2015 The Authors. Published by Elsevier Inc.

To avoid breeding during unsuitable environmental or physiological circumstances, the reproductive axis adjusts its output in response to fluctuating internal and external conditions. The ability of the reproductive system to alter its activity appropriately in response to these cues has been well established. However, the means by which reproductively relevant cues are interpreted, integrated and relayed to the reproductive axis remain less well specified. The neuropeptide kisspeptin has been shown to be a potent positive stimulator of the hypothalamo–pituitary–gonadal (HPG) axis, suggesting a possible neural locus for the interpretation/integration of these cues. Because a failure to inhibit reproduction during winter would be maladaptive for short-lived female rodents, female Siberian hamsters (Phodopus sungorus) housed in long and short days were examined. In long "summer" photoperiods, kisspeptin is highly expressed in the anteroventral periventricular nucleus (AVPV), with low expression in the arcuate nucleus (Arc). A striking reversal in this pattern is observed in animals held in short, "winter" photoperiods, with negligible kisspeptin expression in the AVPV and marked staining in the Arc. Although all studies to date suggest that both populations act to stimulate the reproductive axis, these contrasting expression patterns of AVPV and Arc kisspeptin point to disparate roles for these two cell populations. Additionally, we found that the stimulatory actions of exogenous kisspeptin are blocked by acyline, a gonadotropin-releasing hormone (GnRH) receptor antagonist, suggesting an action of kisspeptin on the GnRH system rather than pituitary gonadotropes. Finally, females held in short day lengths exhibit a reduced response to exogenous kisspeptin treatment relative to long-day animals. Together, these findings indicate a role for kisspeptin in the AVPV and Arc as an upstream integration center for reproductively relevant stimuli and point to a dual mechanism of reproductive inhibition in which kisspeptin expression is reduced concomitant with reduced sensitivity of the HPG axis to this peptide.