Modification of Modeling Method of Toxic Dystrophy of Liver in Rats

The liver is the largest digestive gland that plays an important role in providing homeostasis of the internal environment of the body and in the development of adaptive reactions, which is due to its participation in many metabolic processes, anatomical, and functional connections with other organs and systems of the body. Recently, the risk of developing hepatopathy is increasingly associated with irrational pharmacotherapy of the underlying disease

Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers

<p>Abstract</p> <p>Background</p> <p>Insulin resistance (IR) is accompanied by chronic low grade systemic inflammation, obesity, and deregulation of total body energy homeostasis. We induced inflammation in adipose and liver tissues <it>in vitro </it>in order to mimic inflammation <it>in vivo </it>with the aim to identify tissue-specific processes implicated in IR and to find biomarkers indicative for tissue-specific IR.</p> <p>Methods</p> <p>Human adipose and liver tissues were cultured in the absence or presence of LPS and DNA Microarray Technology was applied for their transcriptome analysis. Gene Ontology (GO), gene functional analysis, and prediction of genes encoding for secretome were performed using publicly available bioinformatics tools (DAVID, STRING, SecretomeP). The transcriptome data were validated by proteomics analysis of the inflamed adipose tissue secretome.</p> <p>Results</p> <p>LPS treatment significantly affected 667 and 483 genes in adipose and liver tissues respectively. The GO analysis revealed that during inflammation adipose tissue, compared to liver tissue, had more significantly upregulated genes, GO terms, and functional clusters related to inflammation and angiogenesis. The secretome prediction led to identification of 399 and 236 genes in adipose and liver tissue respectively. The secretomes of both tissues shared 66 genes and the remaining genes were the differential candidate biomarkers indicative for inflamed adipose or liver tissue. The transcriptome data of the inflamed adipose tissue secretome showed excellent correlation with the proteomics data.</p> <p>Conclusions</p> <p>The higher number of altered proinflammatory genes, GO processes, and genes encoding for secretome during inflammation in adipose tissue compared to liver tissue, suggests that adipose tissue is the major organ contributing to the development of systemic inflammation observed in IR. The identified tissue-specific functional clusters and biomarkers might be used in a strategy for the development of tissue-targeted treatment of insulin resistance in patients.</p

Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices

This SuperSeries is composed of the SubSeries listed below

Transcriptomic signatures of peroxisome proliferator-activated receptor a (PPARa) in different mouse liver models identify novel aspects of its biology

Background The peroxisome proliferator-activated receptor alpha (PPARa) is a ligand-activated transcription factor that regulates lipid catabolism and inflammation and is hepatocarcinogenic in rodents. It is presumed that the functions of PPARa in liver depend on cross-talk between parenchymal (hepatocytes) and non-parenchymal (Kupffer and endothelial cells) fractions as well as inter-organ interactions. In order to determine how cellular composition and inter-organ interactions influence gene expression upon pharmacological activation of PPARa, we performed a meta-analysis of transcriptomics data obtained from mouse hepatocytes (containing only the parenchymal fraction), mouse liver slices (containing both fractions), and mouse livers exposed to a PPARa agonist. The aim was to obtain a comprehensive view of common and model-specific PPARa-dependent genes and biological processes to understand the impact of cross-talk between parenchymal and non-parenchymal fractions as well as the effect of inter-organ interactions on the hepatic PPARa transcriptome. To this end we analyzed microarray data of experiments performed in mouse primary hepatocytes treated with the PPARa agonist Wy14643 for 6 or 24 h (in vitro), mouse precision cut liver slices treated with Wy14643 for 24 h (ex vivo), and livers of wild type and Ppara knockout mice treated with Wy14643 for 6 h or 5 days (in vivo). Results In all models, activation of PPARa significantly altered processes related to various aspects of lipid metabolism. In ex vivo and in vivo models, PPARa activation significantly regulated processes involved in inflammation; these processes were unaffected in hepatocytes. Only in vivo models showed significant regulation of genes involved in coagulation, carcinogenesis, as well as vesicular trafficking and extracellular matrix. Conclusions PPARa-dependent regulation of genes/processes involved in lipid metabolism is mostly independent of the presence of non-parenchymal cells or systemic factors, as it was observed in all liver models. PPARa-dependent regulation of inflammatory genes requires the presence of non-parenchymal cells, as it was observed only ex vivo and in vivo. However, the full spectrum of PPARa biology at the level of lipid metabolism, immunity, carcinogenesis, as well as novel aspects of PPARa signaling such as coagulation, vesicular trafficking and the extracellular matrix, seems to require systemic factors, as it was observed exclusively in vivo

How to create public acceptance for wind power projects : Communication and dialogue with the public

Sveriges regering har tagit fram en nationell planeringsram för vindkraft som inkluderar 30 TWh installerad effekt år 2020. Negativa attityder mot vindkraft kan dock bromsa upp och hindra specifika vindkraftsprojekt, vilket skapar en utmaning för att uppnå målen. En problematik för vindkrafts­projektörer i Sverige är att även om majoriteten av lokalbefolkningen är positivt inställda till en etablering, kan det vara tillräckligt att en person agerar rättsligt för att ett projekt ska fördröjas eller hindras. Motstånd mot vindkraft baseras ofta på subjektiva uppfattningar, vilket innebär att det är svårt att hitta en generell lösning för att öka acceptansen bland lokalbefolkningen. Ibland baseras motståndet på den lokala påverkan en vindkraftsanläggning förväntas medföra medan det i andra fall snarare är ett motstånd mot de som driver ett projekt eller det sätt projektet genomförs på. Denna studie syftar till att kvalitativt undersöka hur lokalbefolkningens acceptans till vindkraftsprojekt påverkas av kommunikationen i planerings- och prövningsprocessen, samt identifiera åtgärder som kan öka acceptansen för nyetableringar av vindkraft. Detta har utförts med hjälp av intervjuer med projektörer, myndigheter och konsulter som delgivit sina tidigare erfarenheter från olika vindkrafts­projekt. Informationen har sammanställts och kopplats till teorier kring attityder och kommunikation för att sedan resultera i en rekommendation för projektörers framtida arbete. Studien har resulterat i bland annat ett antal faktorer som kan påverka acceptansnivån och attityderna hos lokalbefolkningen, som därmed är viktiga för projektören att ta hänsyn till i kommunikationen med de närboende. En vindkraftsetablering innebär för många en förändring av närområdet och kan skapa en känsla av oro för hur etableringen ska påverka människor och miljö. En etablering kan även skapa en känsla hos de närboende av att de inte har kontroll och bestämmanderätt över sin närmaste omgivning och livssituation. Oro samt känslan av att sakna kontroll kan skapa negativa attityder och bör därför fokuseras på under projektet. Ett sätt att erbjuda lokalbefolkningen kontroll är att involvera dem i projektet samt förklara samråds- och tillståndsprocessen. Ett sätt att stilla oro är att delge de närboende saklig och korrekt information kontinuerligt under hela projektet. Det är viktigt att involvera lokalbefolkningen för att de inte ska känna sig åsidosatta, men om lokalbefolkningen involveras är det viktigt att deras åsikter har en reell effekt på etableringen. Människor litar på information de får från en tillitsfull person. Därför är det viktigt att projektören inger förtroende och vinner tillit från lokalbefolkningen. Detta kan fås genom att ha en ärlig, öppen och respektfull kommunikation. Det är även viktigt att projektörer visar att de tar hänsyn till och lyssnar på lokalbefolkningens åsikter och oro, oavsett om dessa är relevanta för tillståndsprövningen eller inte. Det är viktigt med en tidig och proaktiv kommunikation då studiens resultat påvisat att det är svårt att förändra negativa attityder. Om människor bygger en negativ attityd på felaktig information, rykten eller spekulationer är det svårt att ändra dessa attityder i efterhand. Därför är det viktigt att aktivt informera människor tidigt i processen. Projektören bör tidigt i processen kartlägga intressenter och deras eventuella oro i syfte att sammanställa en kommunikationsplan. Resultaten visar tydligt att ett utställningssamråd har större förutsättningar att skapa en lokal förankring för ett projekt än ett presentationssamråd. Vid ett presentationssamråd är det svårt för alla människor att komma till tals och ställa sina frågor eller lämna synpunkter. Vid en utställning sker en dialog mellan projektörer och närboende, vilket innebär att samtalet kan fokusera på den enskilde individens oro. Risken för feltolkningar och missförstånd minskar då projektören kan anpassa dialogen till den närboende. Övriga åtgärder som kan öka acceptansen för vindkraftsprojekt är bland annat ekonomisk ersättning och fältbesök. Ekonomisk ersättning kan ge en individuell tillfredställelse. Fältbesök och liknande åtgärder kan ge de närboende nya erfarenheter av vindkraft, vilka kan stilla lokalbefolkningens oro och därmed påverka attityden mot specifika vindkraftsetableringar positivt.The Swedish government has established a national planning framework for wind power, including a goal of 30 TWh of installed capacity by 2020. It has however been proven difficult to reach these goals since negative attitudes towards wind power projects can hinder the development. One main issue is that even though the majority of the local community is positive to a wind power establishment, it can be enough that one person take legal action against it for the project to be interrupted. Resistance towards wind power is often subjective which means that it is difficult to find a general solution to increase the acceptance among the local community. People often resist the local impact wind turbines might cause, but the resistance could also be towards those who carry out the project or how the project is conducted. This study aims to qualitatively investigate how communication throughout the planning- and permission process affect the level of acceptance among the local community, as well as to identify measures which can raise the acceptance for wind power projects. Interviews have been conducted with project planners, authorities and consultants in order to gather their experiences from previous projects. This information has been related to theories regarding attitudes and communication and has resulted in a recommendation of how future projects should be conducted in order to raise the local acceptance. The study results in several factors that affect the level of acceptance and the attitudes among the local community. These factors are important for the project planner to take into account when communicating with the public. A wind power establishment is for many people a huge change in the surroundings, and can create a feeling of worry and anxiety related to how the establishment will affect humans and the environment. A project might also cause a feeling of not being in control. These two feelings can create negative attitudes towards a project. One way to create a feeling of control is to involve the local community in the project and to explain for them the process of planning a project and applying for permission. In order to ease worries, the project planner should share objective and accurate information. People tend to trust the information they receive from a person they consider trustworthy. Therefore it is important for the project planner to act in a trustworthy manner, for example by being honest and to use a transparent and respectful communication. It is also important that the project planner listen to the public’s opinions and worries, even though they are not relevant for the permission process. The study proves the difficulty of changing already negative attitudes, which emphasise the importance of an early and proactive communication. If people create a negative attitude based on false information, rumours or speculations, it is hard to change their attitudes afterwards. Therefore it is important to map actors in the community and their potential worries, with the purpose to construct a communication plan. The results clearly indicate that a consultation meeting in the shape of an exhibition instead of a presentation has a higher potential for creating a local acceptance towards a project. With only a presentation not everyone will have their saying. An exhibition enables a dialogue between the project planner and individual inhabitants where opinions and questions can be more easily communicated between the parties. The project planner can also easily adapt the dialogue to decrease the risk of misperceptions and confusions. Other measures that can increase the level of acceptance are economical compensation as well as field trips, where the inhabitants can create their own opinion of the impact from wind turbines. It can ease worries and thereby create positive attitudes towards wind power projects

Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes

Background Unexpected cholestasis substantially contributes to drug failure in clinical trials. Current models used for safety assessment in drug development do not accurately predict cholestasis in humans. Therefore, it is of relevance to develop new screening models that allow identifying drugs with cholestatic properties. Methods We employed mouse precision cut liver slices (PCLS), which were incubated 24 h with two model cholestatic compounds: cyclosporin A (CsA) and chlorpromazine (CPZ). Subsequently, transcriptome analysis using DNA microarrays and q-PCR were performed to identify relevant biological processes and biomarkers. Additionally, histology was carried out and levels of triglycerides (TG) and bile acids (BA) were measured. To verify the ex vivo mouse data, these were compared with publically available human data relevant for cholestasis. Results Whole genome gene expression analysis showed that CsA up-regulated pathways related to NF-¿B, ER stress and inflammation. Both CsA and CPZ down-regulated processes related to extracellular matrix (ECM) remodelling, BA homeostasis, Fxr signalling, and energy metabolism. The differential expression of a number of characteristic genes (e.g. Abcg5, Abcg8, Klf15, and Baat) could be confirmed by q-PCR. Histology revealed that CsA but not CPZ induced “ballooning” of hepatocytes. No effects on TG and BA levels were observed after incubation of PCLS with CsA and CPZ. A substantial number of processes altered in CsA- and CPZ-treated mouse PCLS ex vivo was also found to be affected in liver biopsies of cholestatic patients. Conclusion The present study demonstrated that mouse PCLS can be used as a tool to identify mechanisms of action of cholestatic model compounds. The induction of general stress responses and down-regulated Fxr signalling could play a role in the development of drug induced cholestasis. Importantly, comparative data analysis showed that the ex vivo mouse findings are also relevant for human pathology. Moreover, this work provides a set of genes that are potentially useful to assess drugs for cholestatic properties