The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.

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Materials with three-dimensional micro- and nanoarchitectures exhibit many beneficial mechanical, energy conversion and optical properties. However, these three-dimensional microarchitectures are significantly limited by their scalability. Efforts have only been successful only in demonstrating overall structure sizes of hundreds of micrometres, or contain size-scale gaps of several orders of magnitude. This results in degraded mechanical properties at the macroscale. Here we demonstrate hierarchical metamaterials with disparate three-dimensional features spanning seven orders of magnitude, from nanometres to centimetres. At the macroscale they achieve high tensile elasticity (>20%) not found in their brittle-like metallic constituents, and a near-constant specific strength. Creation of these materials is enabled by a high-resolution, large-area additive manufacturing technique with scalability not achievable by two-photon polymerization or traditional stereolithography. With overall part sizes approaching tens of centimetres, these unique nanostructured metamaterials might find use in a broad array of applications.

Prostanoids are local hormones formed from arachidonic acid that coordinate responses to circulating hormones which elicit prostanoid synthesis. For example, in the kidney, prostaglandin (PG) E2 synthesized by collecting tubule epithelia in response to arginine vasopressin (AVP) acts on the parent collecting tubule as well as the neighboring thick limb to modulate NaCl and water reabsorption occurring in response to AVP. Studies performed over the last 15 years have defined the major cellular and subcellular sites of PG synthesis in the kidney. In addition, it is now recognized that the multiple cellular actions of prostanoids in the kidney are mediated through receptors coupled to guanine nucleotide regulatory proteins. The goal of this review is to summarize recent biochemical and molecular biological studies on prostanoid biosynthetic enzymes and on prostanoid receptors. The major topics to be addressed are 1) phospholipid precursors of arachidonate, 2) membrane-associated and cytosolic phospholipase A2s, 3) PG endoperoxide (PGH) synthase isozymes, 4) thromboxane A (TxA) synthase, and 5) TxA/PGH and PGE receptors.

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Prostaglandins and their precursorsSince the discovery in 1991 of a second isoform of prostaglandin endoperoxide H synthase (PGHS, or cyclooxygenase), there has been considerable interest in the question of why two isoforms of this enzyme are necessary and what roles they might play. PGHS-1-deficient (1) and PGHS-2-deficient (2, 3) mice and isoform-specific inhibitors have been developed and used to investigate the physiological functions of PGHS-1 and PGHS-2. These studies suggest that there are processes in which each isozyme is uniquely involved (e.g., platelet aggregation for PGHS-1, ovulation for PGHS-2) and others in which both isozymes function coordinately (e.g., carcinogenesis, inflammation). There are also physiological events in which one PGHS isozyme normally functions but for which the other can compensate when the first is lacking (e.g., parturition and remodeling of the ductus arteriosus). Biochemical studies indicate that each isoform can function independently; namely, that there are distinct PGHS-1 and PGHS-2 prostanoid biosynthetic pathways. Thus, the unique physiological roles for each isozyme can be rationalized by what is known about the biochemistry of the enzymes.To facilitate discussion of the physiological functions of PGHS-1 and PGHS-2 and to point out those functions for which PGHS-1 and PGHS-2 can substitute for one another, we describe the following in sequence: (a) physiological processes that depend solely or primarily on PGHS-1, (b) physiological processes that depend solely or primarily on PGHS-2, and (c) processes in which both PGHS-1 and PGHS-2 are involved and act coordinately. We then summarize the biochemical evidence for distinct PGHS-1 and PGHS-2 biosynthetic pathways.

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