[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

CA : A Cancer Journal for Clinicians

Conditioned place preference (CPP) continues to be one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. This is obvious from a steady year-to-year increase in the number of publications reporting the use this model. Since the compilation of the preceding review in 1998, more than 1000 new studies using place conditioning have been published, and the aim of the present review is to provide an overview of these recent publications. There are a number of trends and developments that are obvious in the literature of the last decade. First, as more and more knockout and transgenic animals become available, place conditioning is increasingly used to assess the motivational effects of drugs or non-drug rewards in genetically modified animals. Second, there is a still small but growing literature on the use of place conditioning to study the motivational aspects of pain, a field of pre-clinical research that has so far received little attention, because of the lack of appropriate animal models. Third, place conditioning continues to be widely used to study tolerance and sensitization to the rewarding effects of drugs induced by pre-treatment regimens. Fourth, extinction/reinstatement procedures in place conditioning are becoming increasingly popular. This interesting approach is thought to model certain aspects of relapse to addictive behavior and has previously almost exclusively been studied in drug self-administration paradigms. It has now also become established in the place conditioning literature and provides an additional and technically easy approach to this important phenomenon. The enormous number of studies to be covered in this review prevented in-depth discussion of many methodological, pharmacological or neurobiological aspects; to a large extent, the presentation of data had to be limited to a short and condensed summary of the most relevant findings.

Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade.

Histone deacetylases (HDACs) are a class of epigenetic enzymes that remove acetyl groups from lysine residues on histones and other proteins. In this Review, the authors highlight the role of HDACs in cancer, neurological diseases and immune disorders, and discuss the development of small-molecule inhibitors. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.

Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson's two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

/pdf/loss-of-tumor-suppressor-gene-function-in-human-cancer-an-4klojr4fde.pdf

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview.

In this study, the hepatoprotective effects of apple polyphenols (AP, Appjfnol) against CCl4-induced acute liver damage in Kunming mice as well as the possible mechanisms were investigated. Mice were treated with AP (200, 400, and 800 mg/kg, ig) for seven consecutive days prior to the administration of CCl4 (0.1%, intraperitoneally). The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in the hepatic homogenate, and histopathological changes in mouse liver sections were determined. Levels of ferrous sulfate-l-cysteine (FeSO4-l-Cys)-induced lipid peroxidation and 1,1-diphenyl-2-picrylhydrazyl (DPPH) were also determined in vitro. AP significantly prevented the increase in serum ALT and AST levels in acute liver injury induced by CCl4 and produced a marked amelioration in the histopathological hepatic lesions coupled to weight loss. The extent of MDA formation was reduced; ...

Hepatoprotective effects of apple polyphenols on CCl4-induced acute liver damage in mice.

Background: Ethanol abuse, especially binge drinking, can be toxic to human organs. However, there have been few studies on the genotoxicity induced by ethanol in human peripheral lymphocytes under binge drinking conditions. The purpose of this study was to investigate the oxidative DNA damage induced by ethanol in human peripheral lymphocytes in vitro and the possible mechanism associated with ethanol metabolism. The concentrations of ethanol investigated in this study were 50 and 100 mM, which are equal to the ethanol concentrations in blood after binge drinking. The maximum concentration we used was 150 mM although it is not the typical blood ethanol concentration seen during binge drinking, and most people may die at such a high concentration. The purpose of using this maximum concentration was to obtain more detailed evidence about the genotoxicity induced by ethanol. The DNA repair process was also studied.



Methods:  Peripheral lymphocytes were isolated from donors who were nonsmokers and not ethanol drinkers. Oxidative DNA damage, possible metabolic pathways of ethanol in human peripheral lymphocytes, and the repair system involved in the DNA auto-repair process were examined by comet assay, flow cytometry, time-of-flight mass spectrometry (TOF-MS), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting.



Results:  The results showed that ethanol at the concentrations of 50, 100, and 150 mM significantly induced the oxidative DNA damage in human peripheral lymphocytes in vitro, which was accompanied by a parallel increase in the generation of 8-OHdG, intracellular hydroxyl radical, and reactive oxygen species (iROS). The DNA damage induced by ethanol could be attenuated by alcohol dehydrogenase 1B (ADH1B) or acetaldehyde dehydrogenase 2 (ALDH2) inhibitor, and the mRNA expression levels of ADH1B and ALDH2 were increased markedly by ethanol. The inhibitor of cytochrome P450 2E1 (CYP2E1) had no effect on ethanol-induced DNA damage, and CYP2E1 mRNA expression was not affected by ethanol. Furthermore, ethanol-induced DNA damage could be auto-repaired by lymphocytes. The expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and the X-ray repair cross-complementation group 1 (XRCC1), 2 core enzymes in the base excision repair (BER) system, were increased in both of transcriptional and protein levels after ethanol treatment.



Conclusions: This study provides direct evidence that ethanol can induce oxidative DNA damage in human peripheral lymphocytes in vitro, and its mechanism may be associated with the metabolism of ethanol by the ADH1B/ALDH2 pathway. Moreover, ethanol-induced DNA damage can be auto-repaired by human peripheral lymphocytes possibly mediated by the BER system.

Possible metabolic pathways of ethanol responsible for oxidative DNA damage in human peripheral lymphocytes.

Activated microglia are implicated in cognitive deficits, neuronal death, and successful recovery following intermittent ethanol exposure.

Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement.

Chunfu Wu

Papers

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview.

Hepatoprotective effects of apple polyphenols on CCl4-induced acute liver damage in mice.

Possible metabolic pathways of ethanol responsible for oxidative DNA damage in human peripheral lymphocytes.

Activated microglia are implicated in cognitive deficits, neuronal death, and successful recovery following intermittent ethanol exposure.

Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement.