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

Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

Dietary polyphenols and the prevention of diseases

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.

/pdf/erk-and-p38-mapk-activated-protein-kinases-a-family-of-xi88207cal.pdf

Erk and p38 mapk-activated protein kinases: a family of protein kinases with diverse biological functions

SUMMARY The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.

Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

1. beta-Amyloid peptide (A beta), a 39 -- 43 amino acid peptide, is believed to induce oxidative stress and inflammation in the brain, which are postulated to play important roles in the pathogenesis of Alzheimer's disease. Ferulic acid is an antioxidant and anti-inflammatory agent derived from plants; therefore, the potential protective activity of ferulic acid against A beta toxicity in vivo was examined. 2. Mice were allowed free access to drinking water (control) or water containing ferulic acid (0.006%). After 4 weeks, A beta 1-42 (410 pmol) was administered via intracerebroventricular injection. 3. Injection of control mice with A beta 1-42 impaired performance on the passive avoidance test (35% decrease in step-through latency), the Y-maze test (19% decrease in alternation behaviour), and the water maze test (32% decrease in percentage time in platform-quadrant). In contrast, mice treated with ferulic acid prior to A beta 1-42 administration were protected from these changes (9% decrease in step-through latency; no decrease in alternation behaviour; 14% decrease in percentage time in platform-quadrant). A beta 1-42 induced 31% decrease in acetylcholine level in the cortex, which was tended to be ameliorated by ferulic acid. 4. In addition, A beta 1-42 increased immunoreactivities of the astrocyte marker glial fibrillary acidic protein (GFAP) and interleukin-1 beta (IL-1 beta) in the hippocampus, effects also suppressed by pretreatment with ferulic acid. 5. Administration of ferulic acid per se unexpectedly induced a transient and slight increase in GFAP and IL-1 beta immunoreactivity in the hippocampus on day 14, which returned to basal levels on day 28. A slight (8%) decrease in alternation behaviour was observed on day 14. 6. These results demonstrate that long-term administration of ferulic acid induces resistance to A beta 1-42 toxicity in the brain, and suggest that ferulic acid may be a useful chemopreventive agent against Alzheimer's disease.

https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1038/sj.bjp.0704047

Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.

Therapeutic effects of lysophosphatidylcholine in experimental sepsis.

Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures

Flavonoids and monophenolic compounds have been well described in recent years as antioxidants and scavengers of reactive oxygen and nitrogen species. In the present study, we aimed to characterize the effects of long-term administration of ferulic acid on the centrally administered β-amyloid peptide (Aβ)1—42-induced activation of microglial cells in mice. Aβ1—42 increased the immunoreactivity of OX-42, a microglial marker, and interferon-γ in the hippocampus at 8 h after the intracerebroventricular injection. The effects were suppressed by long-term (4-week) pretreatment with ferulic acid. This inhibition of microglial cell activation may underlie the beneficial effects of long-term administration of ferulic acid on Aβ1—42-induced toxicity in vivo.

Inhibitory Effects of Long-Term Administration of Ferulic Acid on Microglial Activation Induced by Intracerebroventricular Injection of β-Amyloid Peptide (1—42) in Mice

Hong-Won Suh

Papers

Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid

Therapeutic effects of lysophosphatidylcholine in experimental sepsis.

Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures

Inhibitory Effects of Long-Term Administration of Ferulic Acid on Microglial Activation Induced by Intracerebroventricular Injection of β-Amyloid Peptide (1—42) in Mice

Antinociceptive mechanisms of orally administered decursinol in the mouse.