Pharmacology & therapeutics
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Hypoxia inducible factor (HIF) is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia. This is achieved through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Under conditions of normoxia, the hydroxylation of HIF by prolyl hydroxylase domain-containing (PHD) enzymes targets it for polyubiquitination and proteosomal degradation by the von Hippel-Lindau protein (VHL). ⋯ Experimental studies suggest that HIF may act as a mediator of ischemic preconditioning, and that the genetic or pharmacological stabilization of HIF under normoxic conditions, may protect the heart against the detrimental effects of acute ischemia-reperfusion injury. The mechanisms underlying the cardioprotective effect of HIF are unclear, but it may be attributed to the transcriptional activation of genes associated with cardioprotection such as erythropoietin, heme oxygenase-1, and inducible nitric oxide synthase or it may be due to reprogramming of cell metabolism. In this review article, we highlight the role of HIF in mediating both adaptive and pathological processes in the heart, as well as focusing on the therapeutic potential of the HIF-signaling pathway as a target for cardioprotection.
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Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, activates the innate immunity system through a receptor complex of myeloid differentiation 2 (MD-2) and toll-like receptor 4 (TLR4). MD-2 directly recognizes the lipid A domain of LPS, which triggers MD-2/TLR4-mediated cellular response aimed at eliminating the invaded pathogen. ⋯ In particular, eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site, and it ameliorates various inflammatory conditions due to infection or sterile organ injury. In this review, we outline the recent advances in the structure biology of ligand interaction with MD-2/TLR4, and highlight the MD-2-directed LPS antagonists, which are natural and synthetic chemicals, under development to treat inflammatory diseases.
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The necessity of safe and effective treatments for chronic pain has intensified the search for new analgesic drugs. In the last few years, members of a closely-related family of ion channels, called transient receptor potential (TRP) have been identified in different cell types and their functions in physiological and pathological conditions have been characterized. The transient receptor potential ankyrin 1 (TRPA1), originally called ANKTM1 (ankyrin-like with transmembrane domains protein 1), is a molecule that has been conserved in different species during evolution; TRPA1 is a cation channel that functions as a cellular sensor, detecting mechanical, chemical and thermal stimuli, being a component of neuronal, epithelial, blood and smooth muscle tissues. ⋯ However, its participation in cold sensation has not been agreed in different studies. In this review, we focus on data that support the relevance of the activation and blockade of TRPA1 in pain transmission, as well as the mechanisms underlying its activation and modulation by exogenous and endogenous stimuli. We also discuss recent advances in the search for new analgesic medicines targeting the TRPA1 channel.
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Selective thyromimetics are synthetic analogs of thyroid hormones with tissue-specific thyroid hormone actions. Tissue selectivity is partly mediated by selectivity for the thyroid hormone receptor-β isoform, but is also enhanced by tissue-selective uptake. Several preclinical animal models and recent human clinical trials have provided sound evidence that thyromimetics can serve as pharmacological tools to improve serum lipids without affecting heart rate. ⋯ Animal data have further suggested that thyromimetics might be useful in the treatment of obesity, hepatic steatosis and atherosclerosis. However, only long-term phase III clinical trials will tell if the observed lipid lowering effects of thyromimetics will improve cardiovascular outcome in humans, too. At the moment, the treatment of dyslipidemia seems to be the major indication for the therapeutic use of thyromimetics, which are now rapidly moving from bench to bed-side.
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The chronic inflammatory response within the airways of asthmatics is associated with structural changes termed airway remodeling. This remodeling process is a key feature of severe asthma. The 5-10% of patients with a severe form of the disease account for the higher morbidity and health costs related to asthma. ⋯ Additionally, aberrant communication between an injured airway epithelium and ASM could also contribute to disease severity. Airway remodeling is insensitive to corticosteroids and anti-leukotrienes whereas the effect of monoclonal antibodies (the anti-IgE omalizumab, the anti-interleukin-5 mepolizumab or anti-tumor necrosis factor-alpha) remains to be investigated. This review focuses on potential new therapeutic strategies targeting ASM cells, especially Ca(2+) and mitochondria-dependent pathways.