Progress in molecular biology and translational science
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Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) efficacy, coupled with the phenomenon of orthosteric ligand "bias," offers the prospect of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. As the best-studied non-G protein effectors, arrestins have been shown to mediate a wide range of GPCR signals, and arrestin pathway-selective ligands have been identified for several receptors. ⋯ Yet, when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. While some widely conserved arrestin-regulated biological processes are becoming apparent, what is lacking at present is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will aid drug discovery programs in identifying "biased" ligands with the desired biological effects.
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Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition. It is classified into several types according to the cerebrovascular amyloid proteins involved [amyloid β-protein (Aβ), cystatin C (ACys), prion protein (APrP), transthyretin (ATTR), gelsolin (AGel), ABri/ADan, and AL]. Sporadic Aβ-type CAA is commonly found in elderly individuals and patients with Alzheimer's disease (AD). ⋯ It has been proposed that cerebrovascular Aβ originates mainly from the brain and is transported to the vascular wall through a perivascular drainage pathway, where it polymerizes into fibrils on vascular basement membrane through interactions with extracellular components. CAA would be promoted by overproduction of Aβ40 (a major molecular species of cerebrovascular Aβ), a decrease of Aβ degradation, or reduction of Aβ clearance due to impairment of perivascular drainage pathway. Further understanding of the molecular pathogenesis of CAA would lead to development of disease-modifying therapies for CAA and CAA-related disorders.
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Prog Mol Biol Transl Sci · Jan 2012
ReviewMembrane pores in the pathogenesis of neurodegenerative disease.
The neurodegenerative diseases described in this volume, as well as many nonneurodegenerative diseases, are characterized by deposits known as amyloid. Amyloid has long been associated with these various diseases as a pathological marker and has been implicated directly in the molecular pathogenesis of disease. However, increasing evidence suggests that these proteinaceous Congo red staining deposits may not be toxic or destructive of tissue. ⋯ These include irreversible insertion of the pores in lipid membranes, formation of heterodisperse pore sizes, inhibition by Congo red of pore formation, blockade of pores by zinc, and a relative lack of ion selectivity and voltage dependence. Although there exists some information about the physical structure of these pores, molecular modeling suggests that 4-6-mer amyloid subunits may assemble into 24-mer pore-forming aggregates. The molecular structure of these pores may resemble the β-barrel structure of the toxics pore formed by bacterial toxins, such as staphylococcal α-hemolysin, anthrax toxin, and Clostridium perfringolysin.
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Prog Mol Biol Transl Sci · Jan 2011
ReviewTherapeutic targets for neuroprotection and/or enhancement of functional recovery following traumatic brain injury.
Traumatic brain injury (TBI) is a significant public health concern. The number of injuries that occur each year, the cost of care, and the disabilities that can lower the victim's quality of life are all driving factors for the development of therapy. ⋯ This cascade of molecular, cellular, and systemwide changes involves plasticity in many different neurochemical systems, which represent putative targets for remediation or attenuation of neuronal injury. The purpose of this chapter is to highlight some of the promising molecular and cellular targets that have been identified and to provide an up-to-date summary of the development of therapeutic compounds for those targets.
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Heparin is frequently used in the treatment of cancer-associated thromboembolism. Accumulating clinical evidence indicates that cancer patients treated with unfractionated and low-molecular weight heparin (LMWH) survive longer than patients treated by other anticoagulants, especially patients in the early stage of the disease. ⋯ The non-anticoagulant activity of heparin on metastasis includes the ability to inhibit cell-cell-interaction through blocking of P- and L-selectin, to inhibit extracellular matrix protease heparanase, and to inhibit angiogenesis. This chapter summarizes current experimental evidence on the biology of heparin during cancer progression, with the focus on potential mechanism of heparin antimetastatic activity.