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://e-lactancia.org/media/papers/ComposicionBF-PedCliMA2013.pdf

Human milk composition: nutrients and bioactive factors

Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".

Curcumin: The Indian solid gold

OVERVIEW The GRA Marketing Internship Program is offered to students who are interested in gaining valuable work experience through efforts in marketing, membership, sales, and events. Interns work directly to assist the Director of Marketing and Communications on various tasks relating to upcoming GRA events. During this internship, students will work a minimum of 10 hours a week and a maximum of 20 hours a week. Students are encouraged to earn credit for their internship, however this is a paid internship. Students interested in obtaining credit for their internship must consult their academic advisor or the intern coordinator at their academic unit.

Role of WHO.

Introduction
Liver microcirculation disturbances are a cause of hepatic failure in sepsis. Increased leukocyte-endothelial interaction, platelet adherence and impaired microperfusion cause hepatocellular damage. The time course and reciprocal influences of ongoing microcirculatory events during endotoxemia have not been clarified.

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Hepatic platelet and leukocyte adherence during endotoxemia

A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo. Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106-125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.

/pdf/cold-inducible-rna-binding-protein-cirp-triggers-1upb70vnvi.pdf

Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis

Curcumin, the phytochemical component in turmeric, is used as a dietary spice and a topical ointment for the treatment of inflammation in India for centuries. Curcumin (diferuloylmethane) is relatively insoluble in water, but dissolves in acetone, dimethylsulphoxide, and ethanol. Commercial grade curcumin contains 10–20% curcuminoids, desmethoxycurcumin, and bisdesmethoxycurcumin and they are as effective as pure curcumin. Based on a number of clinical studies in carcinogenesis, a daily oral dose of 3.6 g curcumin has been efficacious for colorectal cancer and advocates its advancement into Phase II clinical studies. In addition to the anticancer effects, curcumin has been effective against a variety of disease conditions in both in vitro and in vivo preclinical studies. The present review highlights the importance of curcumin as an anti-inflammatory agent and suggests that the beneficial effect of curcumin is mediated by the upregulation of peroxisome proliferator-activated receptor-γ (PPAR-γ) activation.

/pdf/mechanism-of-the-anti-inflammatory-effect-of-curcumin-ppar-g-37hdov59s0.pdf

Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-γ Activation

Rationale: Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-κB–dependent pathway. However, it remains unknown whether ghrelin has any protective effects on severe sepsis–induced acute lung injury (ALI) and, if so, whether inhibition of NF-κB plays any role in it.

Objectives: To test the hypothesis that ghrelin reduces severe sepsis–induced ALI and mortality through inhibition of NF-κB.

Methods: Sepsis was induced in rats by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by continuous infusion of 12 nmol of ghrelin via a minipump for 15 hours. Samples were harvested 20 hours post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinflammatory cytokines were measured by ELISA. NF-κB p65 and IκBα expression and NF-κB activity were measured by Western blot analysis and ELISA, respectively. Pulmonary blood flow was measured with radioactive microspheres. In additional animals, the necrotic cecum was excised 20 hours post-CLP and 10-day survival was recorded.

Measurements and Main Results: Pulmonary levels of ghrelin decreased significantly 20 hours post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-κB activation, and improved survival in sepsis. Administration of a specific ghrelin receptor antagonist worsened the survival rate after CLP and cecal excision.

Conclusions: Ghrelin can be developed as a novel treatment for severe sepsis–induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-κB.

/pdf/ghrelin-attenuates-sepsis-induced-acute-lung-injury-and-di4ri5cwk6.pdf

Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats.

Despite improvement in the management of septic patients with systemic antibiotics, surgical intervention, aggressive fluid resuscitation, and careful monitoring, sepsis continues to be one of the leading causes of death in intensive care units, and a large number of septic patients die of ensuing septic shock and multiple organ failure.1–4 The pathophysiologic sequelae of sepsis are caused by an overreaction of the immune system to microorganisms and their products. During sepsis, bacterial toxins activate macrophages/Kupffer cells to release proinflammatory cytokines and other mediators that initiate specific immune responses. A growing collection of experimental and clinical data has indicated that proinflammatory cytokines play a prominent role in sepsis-induced tissue injury.5,6 The kinetics and magnitude of cytokine release influence the development of sepsis.5,7

Ghrelin is a gastric hormone first identified in the rat stomach in 1999 as an endogenous ligand for the growth hormone secretagogue receptor (GHSR).8 Human ghrelin is a 28-amino acid peptide with an n-octanoyl group at Ser3, a modification essential for its activity.9,10 Rat ghrelin differs from human ghrelin by only 2 amino acids.10 The biologic effects of ghrelin are thought to be mediated through GHSR. Although a group of synthetic molecules featuring growth hormone secretagogue can bind to GHSR, ghrelin is the only identified endogenous ligand for this receptor. Ghrelin was originally reported to induce growth hormone release through pituitary GHSR stimulation. It has a strong stimulatory effect on growth hormone secretion.11–13 However, a large body of evidence has indicated physiologic functions of ghrelin mediated by the central and peripheral GHSR distribution.14 The wide distribution of GHSR suggests multiple paracrine, autocrine and endocrine roles of ghrelin.15–18 One recent study demonstrates the presence of GHSR in afferent neurons of the nodose ganglion, suggesting that ghrelin signals are transmitted to the brain via vagal afferent nerves.19 Moreover, central administration of ghrelin stimulates the vagal efferent nerve in anesthetized rats.20

The vagus nerve is an important link between the involuntary nervous system and proinflammation, which has been suggested for more than 70 years.21 This “parasympathetic” nerve emanates from the cranium and innervates all major organs in a subconscious way. It is finely branched and is composed of both sensory (input) and motor (output) fibers, suggesting that the vagus nerve can sense continuing inflammation and subsequently suppresses it. This mechanism is more efficient and rapid than other anti-inflammatory pathways. In addition, the vagus nerve has been shown to convey the immunologic state of the gastrointestinal tract to the hypothalamus. Thus, the vagus nerve provides the endogenous mechanism to regulate the magnitude of innate immune responses and attenuate inflammation. Activation of parasympathetic efferent nerves during systemic stress confers an additional protective advantage to the host by restraining a potentially adverse peripheral immune response. Tracey et al found that after administration of LPS in the rat, electrical stimulation of the vagus nerve via the activation of nicotinic acetylcholine receptors (α7 receptors), prevented both the release of TNF from macrophages and death.22–25 However, it remains unknown whether the novel peptide ghrelin plays any role in such an anti-inflammatory pathway.26

Circulating levels of ghrelin have been shown to decrease significantly in endotoxemia.27 Our recent studies also demonstrated that plasma levels of ghrelin decrease significantly in a rat model of polymicrobial sepsis induced by cecal ligation of puncture (CLP), raising the possibility of treating sepsis with ghrelin.28 In addition, recent studies have shown that treatment with ghrelin significantly down-regulates circulating levels of cytokines in a rat model of endotoxemia.29,30 However, it remained unknown whether ghrelin also decreases cytokine levels in polymicrobial sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by vagal nerve activation. The present study was conducted to test the hypothesis that administration of exogenous ghrelin attenuates the inflammatory response in sepsis through vagal nerve stimulation.

Ghrelin Down-regulates Proinflammatory Cytokines in Sepsis Through Activation of the Vagus Nerve

/pdf/reviewarticle-mechanism-of-the-anti-inflammatory-effect-of-bgp7ox4kfk.pdf

Mian Zhou

Papers

Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis

Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-γ Activation

Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats.

Ghrelin Down-regulates Proinflammatory Cytokines in Sepsis Through Activation of the Vagus Nerve

ReviewArticle Mechanism of the Anti-inflammatory Effect of Curcumin: PPAR-γ Activation