https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

Pathogen Recognition and Innate Immunity

Several reactive oxygen species (ROS) are continuously produced in plants as byproducts of aerobic metabolism. Depending on the nature of the ROS species, some are highly toxic and rapidly detoxified by various cellular enzymatic and nonenzymatic mechanisms. Whereas plants are surfeited with mechanisms to combat increased ROS levels during abiotic stress conditions, in other circumstances plants appear to purposefully generate ROS as signaling molecules to control various processes including pathogen defense, programmed cell death, and stomatal behavior. This review describes the mechanisms of ROS generation and removal in plants during development and under biotic and abiotic stress conditions. New insights into the complexity and roles that ROS play in plants have come from genetic analyses of ROS detoxifying and signaling mutants. Considering recent ROS-induced genome-wide expression analyses, the possible functions and mechanisms for ROS sensing and signaling in plants are compared with those in animals and yeast.

REACTIVE OXYGEN SPECIES: Metabolism, Oxidative Stress, and Signal Transduction

https://www.cell.com/cancer-cell/pdf/S1535-6108(14)00375-4.pdf

Whipping NF-κB to Submission via GADD45 and MKK7

Tracking the Road from Inflammation to Cancer: the Critical Role of IκB Kinase (IKK)

The IκB kinase (IKK) is a tripartite signaling complex composed of two catalytic (protein kinase) subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ (a.k.a. NEMO). The major function of IKK is to connect pro-inflammatory stimuli and signals generated by pathogen-associated molecular patterns (PAMPs) to the activation of transcription factor NF-κB. This function is mainly dependent on the IKKβ catalytic subunit, whose activation requires the ubiquitination of IKKγ. IKKβ is the major kinase that leads to phosphorylation-induced degradation of IκBs, the inhibitors of NF-κB, and the consequent translocation of NF-κB dimers, containing RelA or c-Rel as activating subunits, to the nucleus. This results in induction of pro-inflammatory cytokines, chemokines, inhibitors of apoptosis, and other molecules required for a successful innate immune response. The function of IKKα in this pathway has been puzzling, but we recently found that IKKα serves an anti-inflammatory function by phosphorylating RelA and c-Rel at sites that accelerate their nuclear turnover. This seems to occur concomitantly with IκB phosphorylation by IKKβ. Thus, the IKK complex is responsible both for the onset of NF-κB activation and for the proper termination of this response. Another function unique for IKKα, which occurs independently of IKKβ and IKKγ, is the phosphorylation and processing of the NF-κB2/p100 protein, leading to specific activation of p52:RelB dimers. This response is critical for coupling innate immunity to certain adaptive responses involving B cells.

The IκB kinase (IKK) complex as a critical regulator of immune responses

Alcoholic liver disease (ALD) is major cause of chronic liver injury which results in liver fibrosis and cirrhosis. According to the surveillance report published by the National Institute on Alcohol Abuse and Alcoholism, liver cirrhosis is the 12th leading cause of death in the United States with 48 % of these deaths being attributed to excessive alcohol consumption. ALD includes a spectrum of disorders from simple steatosis to steatohepatitis, fibrosis, and hepatocellular carcinoma. Several mechanisms play a critical role in the pathogenesis of ALD. These include ethanol-induced oxidative stress and depletion of glutathione, pathological methionine metabolism, increased gut permeability and release of endotoxins into the portal blood, recruitment and activation of inflammatory cells including bone marrow-derived and liver resident macrophages (Kupffer cells). Chronic alcohol consumption results in liver damage and activation of hepatic stellate cells (HSCs) and myofibroblasts, leading to liver fibrosis. Here we discuss the current view on factors that are specific for different stages of ALD and those that regulate its progression, including cytokines and chemokines, alcohol-responsive intracellular signaling pathways, and transcriptional factors. We also review recent studies demonstrating that alcohol-mediated changes can be regulated on an epigenetic level, including microRNAs. Finally, we discuss the reversibility of liver fibrosis and inactivation of HSCs as a potential strategy for treating alcohol-induced liver damage.

/pdf/new-approaches-for-studying-alcoholic-liver-disease-58y2lg43di.pdf

Michael Karin

Papers

Whipping NF-κB to Submission via GADD45 and MKK7

Tracking the Road from Inflammation to Cancer: the Critical Role of IκB Kinase (IKK)

The IκB kinase (IKK) complex as a critical regulator of immune responses

New Approaches for Studying Alcoholic Liver Disease

Cellular and molecular biology of hepatocyte growth, regeneration and gene expression.