Polychlorinated biphenyl 153 exacerbates nonalcoholic fatty liver disease in C57BL/6 mice.

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants which are detectable in the serum of all American adults. Amongst PCB congeners, PCB 153 has the highest serum level. PCBs have been dose-dependently associated with suspected nonalcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome in epidemiological studies. The purpose of this study is to determine if PCB 153 induces NAFLD in mice fed a control diet (CD), and exacerbates NAFLD in mice fed a high fat diet (HFD). C57BL6/J mice were fed either control or 42% milk fat diet for 12 weeks with or without PCB 153 coexposure (50 mg/kg i.p. x 4). Glucose tolerance tests were performed, and plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression microarrays. In mice fed CD, the addition of PCB 153 had little to no effect on any of the measured parameters. In contrast, PCB 153 co-exposure in high fat-fed mice was associated with dramatically increased visceral adiposity, hepatic steatosis and increased plasma adipokines including adiponectin, leptin, resistin and plasminogen activator inhibitor-1 levels. Likewise, co-exposure reduced expression of hepatic genes implicated in ~oxidation while increasing the expression of genes associated with lipid biosynthesis. Regardless of diet, PCB 153 had no effect on insulin resistance or tumor necrosis factor alpha levels. However, HFD+PCB 153 appeared to induce an endoplasmic reticulum (ER) stress response. Therefore, PCB 153 is an obesogen which exacerbates hepatic steatosis; alters adipocytokines; and disrupts normal hepatic lipid metabolism when administered with HFD. Because all U.S. adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts on the progression of human NAFLD

Evaluating the effects of aroclor 1260 in non-alcoholic fatty liver disease : the role of xenobiotic receptors.

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of US adults and dose-dependently associated with nonalcoholic fatty liver disease (NAFLD) in epidemiologic studies. PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), liver-X-receptor and farnesoid-X-receptor. This study evaluated the hepatic effects of the PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity. Male C57Bl/6J mice were fed a control or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 or 200 mg/kg in corn oil) for 12 weeks. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice. Aroclor 1260+HFD co-exposed mice demonstrated increased inflammatory foci at both doses while serum cytokines and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg. Aroclor 1260 induced hepatic Cyp3a11 (PXR target) and Cyp2b10 (CAR target) expression but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (AhR target) was induced only at 200 mg/kg. In PXR-/- and CAR-/- mice, Aroclor 1260 exposure resulted in steatohepatitis with increased basal hepatic TNFα and IL-6 expression. PXR-/- mice had increased % body fat and liver to body weight ratio regardless of exposure. HOMA-IR decreased in all groups following Aroclor 1260 exposure. PXR-/- mice exposed to Aroclor 1260 showed impaired glucose uptake, increased hepatic gluconeogenic and lipogenic gene expression. The knockout groups demonstrated increased basal mTOR1 activity while Aroclor 1260 exposure increased AMPKα activity. Thus, PXR and CAR participate in hepatic energy metabolism and are protective in Aroclor 1260-induced liver injury. The study further evaluated Aroclor 1260 and selected congeners as potential ligands for human receptors utilizing HepG2 and COS-1 cell lines; and primary human hepatocytes. The results suggested that Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2 and an antagonist for human PPARα. In summary, Aroclor 1260 worsened hepatic inflammation in diet-induced obesity. HFD decreased the protective CAR/PXR activation illustrating the importance of dietary co-exposures in PCB-mediated steatohepatitis

Evolution of holographic Fermi surface from non-minimal couplings

We study a holographic toy model by considering a probe fermion of finite charge density in an anisotropic background. By computing the fermionic spectral function numerically, we observed that the system exhibits some interesting behaviours in the nature of the Fermi surface (FS) and its evolution when tuning the controlling parameters. We introduced non-minimal interaction terms in the action for holographic fermions along with a complex scalar field but neglecting the backreaction of the fermion field on the background. Suppression in the spectral weight and deformation of FS is found out which are reminiscent of the results seen in various condensed matter experiments in real materials.Comment: 5 pages+references, 4 figure

Reactive oxygen species signaling influences feeding behaviour

Reactive Oxygen Species (ROS) are not just by products of substrate oxidation but also chemicals that are involved in intracellular signaling when they are generated transiently and moderately. This review explores the intracellular signaling aspects of reactive oxygen species in influencing feeding behaviour. Substrates like glucose and lipids stimulate generation of reactive oxygen species mainly through mitochondria and to some extent through the NADPH oxidases. The level of ROS generated in hypothalamic neurons like NPY/AgRP and POMC neurons, under the influence of substrate level, directly influences  the activity of these neurons and subsequently affect the downstream neurons located in other parts of the hypothalamus like the ventromedial nucleus (VMN), the paraventricular nucleus (PVN) and the lateral hypothalamus. Activation of POMC neuronal population is driven by increase ROS level whereas activation of NPY/AgRP neurons occurs when ROS level is reduced. The activation of these neurons will determine the feeding behaviour which will either be satiety if POMC neurons are activated or increase food intake if NPY/AgRP neurons are activated

2LS: memory safety and non-termination (competition contribution)

2LS is a C program analyser built upon the CPROVER infrastructure. 2LS is bit-precise and it can verify and refute program assertions and termination. 2LS implements template-based synthesis techniques, e.g. to find invariants and ranking functions, and incremental loop unwinding techniques to find counterexamples and $k$-induction proofs. New features in this year's version are improved handling of heap-allocated data structures using a template domain for shape analysis and two approaches to prove program non-termination

GENERIC DRUG: PRESCRIBER’S PERSPECTIVE

Objective: Knowledge of doctors and their understanding of generic drugs could facilitate in recognizing potential barriers to larger generic medicine prescriptions. Hence, the primary objective of this study was focused to explore knowledge, attitude, and practice (KAP) of doctors toward generic medicines. Methods: It is a cross-sectional questionnaire-based study. The study participants are the doctors working in the hospital during the study period (2016–2017). The questionnaire designed for this study comprised of thirty-five questions related to the knowledge, attitude, and practice (KAP) of generic medicine and about demographic details of the participants. Results: A total of 86 questionnaires were distributed among the health care professionals and the response rate is 37%. The majority of doctors who participated in this survey perceived that generic medicine is effective, safe and need to have the same active component, dose and bioequivalent as the brand name medicines. Most of the doctors (72%) were of the view that generic drugs were manufactured in poor quality than branded medicines. More than three-quarters of doctors (78%) prescribed generic drugs. Conclusion: Majority of the participants had an honest angle about the efficaciousness and safety of generic and though they sometimes prescribe generic medicine, however a high range of doctors (72%) were of the opinion that generic was of poorer quality than brand medicine. To have a better understanding of the generic drug, the doctor must be well informed about the generics during their academic career resulting in savings to healthcare budgets

Comparative analysis of conventional and real time PCR for detection of haemoparasites in dogs

9-15Ehrlichiosis and babesiosis are the most pathogenic tick-borne diseases of dogs worldwide. The present study reports that the development of SYBR green based real time PCR (RT-PCR) protocols with novel primers targeting small subunit ribosomal RNA genes to detect natural infections of Ehrlichia canis, Babesia vogeli and B. gibsoni in dogs and its comparison with conventional PCR. Statistical analysis revealed that RT- PCR is more superior to conventional PCR assay to detect low level rickettsaemia (p < 0.05). The high prevalence of these pathogens in the study population also warrants immediate attention to the adoption of efficient and sustainable control strategies

A Compromised Liver Alters Polychlorinated Biphenyl-Mediated Toxicity

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9 mg/kg) or the PCB mixture, Arcolor1260 (20 mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases

Investigating the effects of long-term Aroclor 1260 exposure on fatty liver disease in a diet-induced obesity mouse model

IntroductionPolychlorinated biphenyls (PCBs) are persistent environmental toxicants that have been implicated in numerous health disorders including liver diseases such as non-alcoholic fatty liver disease (NAFLD). Toxicant-associated NAFLD, also known as toxicant-associated fatty liver disease (TAFLD), consists of a spectrum of disorders ranging from steatosis and steatohepatitis to fibrosis and hepatocellular carcinoma. Previously, our group demonstrated that 12-week exposure to the PCB mixture, Aroclor 1260, exacerbated steatohepatitis in high-fat diet (HFD)-fed mice; however, the longer-term effects of PCBs on TAFLD remain to be elucidated. This study aims to examine the longer-term effects of Aroclor 1260 (&gt;30 weeks) in a diet-induced obesity model to better understand how duration of exposure can impact TAFLD.MethodsMale C57BL/6 mice were exposed to Aroclor 1260 (20 mg/kg) or vehicle control by oral gavage at the beginning of the study period and fed either a low-fat diet (LFD) or HFD throughout the study period.ResultsAroclor 1260 exposure (&gt;30 weeks) led to steatohepatitis only in LFD-fed mice. Several Aroclor 1260 exposed LFD-fed mice also developed hepatocellular carcinoma (25%), which was absent in HFD-fed mice. The LFD+Aroclor1260 group also exhibited decreased hepatic Cyp7a1 expression and increased pro-fibrotic Acta2 expression. In contrast, longer term Aroclor 1260 exposure in conjunction with HFD did not exacerbate steatosis or inflammatory responses beyond those observed with HFD alone. Further, hepatic xenobiotic receptor activation by Aroclor 1260 was absent at 31 weeks post exposure, suggesting PCB redistribution to the adipose and other extra-hepatic tissues with time.DiscussionOverall, the results demonstrated that longer-term PCB exposure worsened TAFLD outcomes independent of HFD feeding and suggests altered energy metabolism as a potential mechanism fueling PCB mediated toxicity without dietary insult. Additional research exploring mechanisms for these longer-term PCB mediated toxicity in TAFLD is warranted