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

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.

/pdf/the-regulation-of-il-10-production-by-immune-cells-2viwsmf2ls.pdf

The regulation of IL-10 production by immune cells

Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2003

Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases

Peroxynitrite: biochemistry, pathophysiology and development of therapeutics

Immunoglobulins on the surface of lymphocytes in autoimmune diseases.

The enzymes of glycogen metabolism are regulated by interconversion between phosphorylated and dephosphorylated forms. In contrast with our well-defined knowledge of the phosphorylation processes of different enzymes and their role in glycogen breakdown and synthesis, the phosphatases catalysing the reverse processes are only now being understood. The regulation of dephosphorylation reactions is still unclear. Phosphorylase phosphatase converts active phosphorylase a (EC 2.4.1 . l) into inactive phosphorylase b by cleavage of the phosphate groups from the serine residues. For the control of phosphorylase phosphatase (EC 3.1.3.17) some mechanisms are possible, namely ligands that affect the substrate phosphorylase a or phosphatase; proteins that affect phosphorylase a (or phosphatase); or enzymic modification of phosphatase. It is known that different proteins can influence the phosphorylase phosphatase reaction. The activation of phosphorylase with synchronous inhibition of phosphorylase phosphatase was observed in the protein-glycogen complex isolated from rabbit skeletal muscle (Haschke et af., 1970). No clear explanation has been offered for the transient inhibition of phosphorylase phosphatase during the ‘flash activation’. Haschke et af. (1972) attributed the inhibition to a protein-protein interaction caused by an unknown protein component of the complex. This assumption was supported by frontal gel filtration of muscle extract and purified enzymes showing a strong association between phosphorylase, phosphorylase kinase and phosphatase (Gergely et al., 1974, 1975). A heat-stable protein isolated from different mammalian tissues also inhibits the phosphatase reaction (Brandt et af., 1974, 1975~). This heat-stable inhibitor protein is phosphorylated by cyclic AMP-dependent protein kinase (Cohen rt al., 1977). Toth et al. (1977) demonstrated the reversible phosphorylation and dephosphorylation of this heat-stable inhibitor protein in vivo. Huang & Glinsmann (1975, 1976a,h) demonstrated the existence of two heat-stable inhibitor proteins for phosphatase. In the present study the effect of phosphorylase kinase and cyclic AMP-dependent protein kinase on the regulation of phosphorylase phosphatase has been investigated. Rabbit skeletal-muscle phosphorylase a was prepared and assayed as previously described (Bot et al., 1977). The specific activity of phosphorylase a was 55 units/mg in the presence of 0.016~-gh1cose 1-phosphate and in the absence of AMP. Non-activated phosphorylase kinase was prepared from rabbit skeletal muscle, and its activity was measured, as described by Cohen (1973). Thiophosphate-activated phosphorylase kinase was prepared by the method of Gergely et al. (1976). Cyclic AMP-dependent protein kinase was prepared from rabbit skeletal muscle by the method of Beavo e ta / . (1974). The separation of regulatory and catalytic subunits of protein kinase was carried out on a Blue Dextran/Sepharose column (Witt & Roskoski, 1975). The isolated protein kinase holoenzyme, the separated regulatory and catalytic subunits, phosphorylase a and phosphorylase kinase were homogeneous by sodium dodecyl sulphate (0.1 %)/ polyacrylamide-gel (7.5 %) electrophoresis. The gel-electrophoresis experiments were carried out as described by Weber & Osborn (1969). Phosphorylase phosphatase was prepared by method of Brandt et a/. (197%). Inhibition of the phosphorylase phosphatase reaction by phosphorylase kinase and cyclic AMP-dependent protein kinase was assayed in the following manner. Phosphorylase a (1 .Omg/ml) was incubated in 0.04~-Tris/2m~-EDTA/O.5m~-dithiothreito~ buffer (pH7.4) with phosphorylase phosphatase in the presence of various concentrations of phosphorylase kinase or cyclic AMP-dependent protein kinase or its regulatory/ catalytic subunit. The reaction mixtures were incubated at 30T , portions (50~1) were removed at various times, and the reaction was stopped by the addition of 0.1 M-NaF/

Role of phosphorylase kinase and cyclic AMP-dependent protein kinase in the regulation of phosphorylase phosphatase.

Regulatory effect of ligands on the activity of purified and crude phosphoprotein phosphatase preparations.

The effect of agents influencing intracellular cyclic nucleotide levels and that of exogenous cAMP was studied on the cytotoxicity of normal human peripheral blood mononuclear cells on antibody coated human and chicken erythrocytes. Elevation of the cAMP level resulted in a marked decrease in cytotoxicity, while basically similar in the allogeneic and the xenogeneic test systems, but more expressed in the allogeneic system.

Pál Gergely

Papers

Immunoglobulins on the surface of lymphocytes in autoimmune diseases.

Role of phosphorylase kinase and cyclic AMP-dependent protein kinase in the regulation of phosphorylase phosphatase.

Regulatory effect of ligands on the activity of purified and crude phosphoprotein phosphatase preparations.

Effect of changes in cyclic nucleotide levels on human antibody-dependent cellular cytotoxicity.

Identification of Arabidopsis mutants carrying T-DNA inserts in phosphoprotein phosphatase genes