Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain ω-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (ω-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are required.

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.

Vertebrate muscle arises sequentially from embryonic, fetal, and adult myoblasts. Although functionally distinct, it is unclear whether these myoblast classes develop from common or different progenitors. Pax3 and Pax7 are expressed by somitic myogenic progenitors and are critical myogenic determinants. and Pax7 + cells contribute differentially to embryonic and fetal limb myogenesis. To investigate whether embryonic and fetal limb myogenic cells have different genetic requirements we conditionally inactivated or activated b-catenin, an important regulator of myogenesis, in Pax3-or Pax7-derived cells. b-Catenin is necessary within the somite for dermomyotome and myotome formation and delamination of limb myogenic progenitors. In the limb, b-catenin is not required for embryonic myoblast specification or myofiber differentiation but is critical for determining fetal progenitor number and myofiber number and type. Together, these studies demonstrate that limb embryonic and fetal myogenic cells develop from distinct, but related progenitors and have different cellautonomous requirements for b-catenin.[Keywords: Pax3; Pax7; b-catenin; limb; myogenesis] Supplemental material is available at http://www.genesdev.org.

Some strains of human immunodeficiency virus type 1 (HIV-1) can infect primary monocytes and monocyte-derived macrophages in vitro. In this report, the effect of cytokines on the production of one of these strains that shows a tropism for mononuclear phagocytes, designated HIV-1JR-FL, was studied. Primary peripheral blood mononuclear phagocytes infected with HIV-1JR-FL were treated with the hematopoietic factors: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), macrophage colony-stimulating factor (M-CSF), and gamma-interferon (gamma-IFN). The M-CSF, GM-CSF, IL-3, and gamma-IFN were able to alter HIV-1 production under different conditions.

There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death. As this is the only detectable site of vascular abnormality in the mutant embryos, and because the phenotype cannot be rescued by a wild-type trophectoderm, we propose that UNC5B-mediated signaling is a specific and autonomous component of fetal-placental angiogenesis. Disruption of UNC5B represents a unique example of a mutation that acts solely within the fetal-placental vasculature and one that faithfully recapitulates the structural and physiological characteristics of clinical uteroplacental insufficiency. This pro-angiogenic, but spatially restricted requirement for UNC5B is not unique to murine development, as the knock-down of the Unc5b ortholog in zebrafish similarly results in the specific and highly penetrant absence of the parachordal vessel, the precursor to the lymphatic system.

Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.

Macrophage polarization is implicated in the inflammation in obesity. The aim of the present study was to examine the anti-inflammatory activities of botanical triterpene celastrol against diet-induced obesity. We treated diet-induced obese C57BL/6N male mice with celastrol (5, 7.5 mg/kg/d) for 3 weeks, and investigated macrophage M1/M2 polarization in adipose and hepatic tissues. Celastrol reduced fat accumulation and ameliorated glucose tolerance and insulin sensitivity. Celastrol down-regulated the mRNA levels of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in cell culture and in mice. The underlying mechanisms were investigated in murine macrophage RAW264.7 cells. Our results demonstrated that celastrol might control macrophage polarization through modulating the cross-talk between the following three mechanisms: 1) suppressing LPS-induced activation of MAP kinases (e.g., ERK1/2, p38, JNK) in a concentration dependent manner; 2) attenuating LPS-induced nuclear translocation of NF-κB p65 subunit in a time dependent manner; 3) activating Nrf2 and subsequently inducing HO-1 expression. HO-1 inhibitor SnPP diminished the inhibitory effects of celastrol on the activation of NF-κB pathway and the pro-inflammatory M1 macrophage polarization. Taken together, celastrol exhibited anti-obesity effects via suppressing pro-inflammatory M1 macrophage polarization. Thus, our results provide new evidence for the potential of celastrol in the treatment of obesity.

Aging is associated with a pro-oxidant state and a decline in endothelial function. Whether acute, enteral antioxidant treatment can reverse this decrement in vascular function is not well known. Flow-mediated vasodilation and reactive hyperemia were evaluated following consumption of either placebo or an oral antioxidant cocktail (Vitamin C, 1000mg; Vitamin E, 600 I.U.; Alpha-lipoic acid, 600 mg) in 87 healthy volunteers (42 young, 25 ± 1 yrs; 45 older, 71 ± 1 yrs) using a double-blind, crossover design. Blood velocity and brachial artery diameter (ultrasound Doppler) were assessed before and after 5-min forearm circulatory arrest. Serum markers of lipid peroxidation, total antioxidant capacity, endogenous antioxidant activity, and Vitamin C were assayed, and plasma nitrate, nitrite, and 3-nitrotyrosine were determined. In the placebo trial, an age-related reduction in brachial artery vasodilation was evident (young: 7.4 ± 0.6 %; older: 5.2 ± 0.4 %). Following antioxidant consumption, flow-mediated vasodilation improved in older subjects (5.2 ± 0.4 %, placebo: 8.2 ± 0.6 %, antioxidant) but declined in the young (7.4 ± 0.6 %, placebo; 5.8 ± 0.6 %, antioxidant). Reactive hyperemia was reduced with age, but antioxidant administration did not alter the response in either group. Together, these data demonstrate that antioxidant consumption acutely restores endothelial function in the elderly, while disrupting normal endothelium-dependent vasodilation in the young, and suggest that this age-related impairment is due, at least in part, to free radicals.