Pharmacological Reviews current issue

[Note from the Editors] Sixty Years of Pharmacological Reviews: Has The Role of Review Articles in Biomedical Sciences Changed and, If So, How Does This Affect Pharmacological Reviews?

Brass, E. P., Feldman, R. D. — 2009-06-23

[IUPHAR Nomenclature Report] International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the Formyl Peptide Receptor (FPR) Family

2009-06-23

Formyl peptide receptors (FPRs) are a small group of seven-transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. The three human FPRs (FPR1, FPR2/ALX, and FPR3) share significant sequence homology and are encoded by clustered genes. Collectively, these receptors bind an extraordinarily numerous and structurally diverse group of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. N-formyl peptides, which are encoded in nature only by bacterial and mitochondrial genes and result from obligatory initiation of bacterial and mitochondrial protein synthesis with N-formylmethionine, is the only ligand class common to all three human receptors. Surprisingly, the endogenous anti-inflammatory peptide annexin 1 and its N-terminal fragments also bind human FPR1 and FPR2/ALX, and the anti-inflammatory eicosanoid lipoxin A4 is an agonist at FPR2/ALX. In comparison, fewer agonists have been identified for FPR3, the third member in this receptor family. Structural and functional studies of the FPRs have produced important information for understanding the general pharmacological principles governing all leukocyte chemoattractant receptors. This article aims to provide an overview of the discovery and pharmacological characterization of FPRs, to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature, and to discuss unmet challenges, including the mechanisms used by these receptors to bind diverse ligands and mediate different biological functions.

[Review Articles] Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System

Tsujino, N., Sakurai, T. — 2009-06-23

Recent studies have implicated the orexin system as a critical regulator of sleep/wake states as well as feeding behavior and reward processes. Orexin deficiency results in narcolepsy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. In addition, orexin deficiency also cause abnormalities in energy homeostasis and reward systems. Orexin activates waking active monoaminergic and cholinergic neurons in the hypothalamus and brainstem regions to maintain a long, consolidated waking period. Orexin neurons receive abundant input from the limbic system. Orexin neurons also have reciprocal links with the hypothalamic arcuate nucleus, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues, such as leptin and glucose, suggest that these neurons have important role as a link between the energy homeostasis and vigilance states. Orexin neurons also have a link with the dopaminergic reward system in the ventral tegmental nucleus. These findings suggest that the orexin system interacts with systems that regulate emotion, reward, and energy homeostasis to maintain proper vigilance states. Therefore, this system may be a potentially important therapeutic target for treatment of sleep disorder, obesity, emotional stress, and addiction.

[Review Articles] Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer

O'Neill, L. A. J., Bryant, C. E., Doyle, S. L. — 2009-06-23

Since first being described in the fruit fly Drosophila melanogaster, Toll-like receptors (TLRs) have proven to be of great interest to immunologists and investigators interested in the molecular basis to inflammation. They recognize pathogen-derived factors and also products of inflamed tissue, and trigger signaling pathways that lead to activation of transcription factors such as nuclear factor-B and the interferon regulatory factors. These in turn lead to induction of immune and inflammatory genes, including such important cytokines as tumor necrosis factor- and type I interferon. Much evidence points to a role for TLRs in immune and inflammatory diseases and increasingly in cancer. Examples include clear roles for TLR4 in sepsis, rheumatoid arthritis, ischemia/reperfusion injury, and allergy. TLR2 has been implicated in similar pathologic conditions and also in systemic lupus erythematosus (SLE) and tumor metastasis. TLR7 has also been shown to be important in SLE. TLR5 has been shown to be radioprotective. Recent advances in our understanding of signaling pathways activated by TLRs, structural insights into TLRs bound to their ligands and antagonists, and approaches to inhibit TLRs (including antibodies, peptides, and small molecules) are providing possiblemeans by which to interfere with TLRs clinically. Here we review these recent advances and speculate about whether manipulating TLRs is likely to be successful in fighting off different diseases.

[Review Articles] Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

Jarvelainen, H., Sainio, A., Koulu, M., Wight, T. N., Penttinen, R. — 2009-06-23

The extracellular matrix (ECM) consists of numerous macromolecules classified traditionally into collagens, elastin, and microfibrillar proteins, proteoglycans including hyaluronan, and noncollagenous glycoproteins. In addition to being necessary structural components, ECM molecules exhibit important functional roles in the control of key cellular events such as adhesion, migration, proliferation, differentiation, and survival. Any structural inherited or acquired defect and/or metabolic disturbance in the ECM may cause cellular and tissue alterations that can lead to the development or progression of disease. Consequently, ECM molecules are important targets for pharmacotherapy. Specific agents that prevent theexcess accumulation of ECM molecules in the vascular system, liver, kidney, skin, and lung; alternatively, agents that inhibit the degradation of the ECM in degenerative diseases such as osteoarthritis would be clinically beneficial. Unfortunately, until recently, the ECM in drug discovery has been largely ignored. However, several of today's drugs that act on various primary targets affect the ECM as a byproduct of the drugs' actions, and this activity may in part be beneficial to the drugs' disease-modifying properties. In the future, agents and compounds targeting directly the ECM will significantly advance the treatment of various human diseases, even those for which efficient therapies are not yet available.