Shuchin 3

Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-α receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and activating (signal 2) signals of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of signal 1, sterol regulatory element-binding protein 2 transactivates TIFA, which in turn induces NF-κB activation and augments the transcription of NLRP3 inflammasome components. For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting signals 1 and 2.

Vascular endothelial cells (ECs) play significant roles in regulating circulatory functions. Mechanical stimuli, including the stretch and shear stress resulting from circulatory pressure and flow, modulate EC functions by activating mechanosensors, signaling pathways, and gene and protein expressions. Mechanical forces with a clear direction (e.g., the pulsatile shear stress and the uniaxial circumferential stretch existing in the straight part of the arterial tree) cause only transient molecular signaling of pro-inflammatory and proliferative pathways, which become downregulated when such directed mechanical forces are sustained. In contrast, mechanical forces without a definitive direction (e.g., disturbed flow and relatively undirected stretch seen at branch points and other regions of complex geometry) cause sustained molecular signaling of pro-inflammatory and proliferative pathways. The EC responses to directed mechanical stimuli involve the remodeling of EC structure to minimize alterations in intracellular stress/strain and elicit adaptive changes in EC signaling in the face of sustained stimuli; these cellular events constitute a feedback control mechanism to maintain vascular homeostasis and are atheroprotective. Such a feedback mechanism does not operate effectively in regions of complex geometry, where the mechanical stimuli do not have clear directions, thus placing these areas at risk for atherogenesis. The mechanotransduction-induced EC adaptive processes in the straight part of the aorta represent a case of the "Wisdom of the Cell," as a part of the more general concept of the "Wisdom of the Body" promulgated by Cannon, to maintain cellular homeostasis in the face of external perturbations.

Marine ecosystems are rich in "omega-3" long-chain (C20-24) polyunsaturated fatty acids (LC-PUFA). Their production has been historically accepted to derive mostly from marine microbes. This long-standing dogma has been challenged recently by the discovery that numerous invertebrates, mostly with an aquatic life-style, have the enzyme machinery necessary for the de novo biosynthesis of polyunsaturated fatty acids (PUFA) and, from them, LC-PUFA. The key breakthrough was the detection in these animals of enzymes called "methyl-end desaturases" enabling PUFA de novo biosynthesis. Moreover, other enzymes with pivotal roles in LC-PUFA biosynthesis, including front-end desaturases and elongation of very long- chain fatty acids proteins, have been characterised in several non-vertebrate animal phyla. This review provides a comprehensive overview of the complement and functions of these gene/protein families in aquatic animals, particularly invertebrates and fish. Therefore, we expand and re-define our previous revision of the LC-PUFA biosynthetic enzymes present in chordates to animals as a whole, discussing how key genomic events have determined the diversity and distribution of desaturase and elongase genes in different taxa. We conclude that both invertebrates and fish display active, but markedly different, LC-PUFA biosynthetic gene networks that result from a complex evolutionary path combined with functional diversification and plasticity.