Douglas B Kell
For drug transport across (i.e., through) an intact biological membrane, two main routes are possible: drugs may cross (i) through the phospholipid bilayer portion of the membrane, and/or (ii) via proteinaceous pores or transporters. Perhaps surprisingly, there is in fact no direct scientific evidence that the first of these takes place at any significant rate because, in the experiments performed to date, it has neither been varied as an independent variable nor measured directly as a dependent variable. Using a standard hypothetico-deductive framework, I assess the intellectual and observable consequences of assuming that, for drugs, phospholipid bilayer diffusion is negligible - 'PBIN' - (i...
January 2015: Trends in Pharmacological Sciences
Takafumi Suzuki, Hozumi Motohashi, Masayuki Yamamoto
The Keap1-Nrf2 pathway plays a crucial role in determining the sensitivity of cells to chemical and/or oxidative insults by regulating the basal and inducible expression of detoxification and antioxidant enzymes, ABC transporters, and other stress response enzymes and/or proteins. Increasing attention has been focused on the roles that the Keap1-Nrf2 pathway plays in the protection of our body against drug toxicity and stress-induced diseases. Simultaneously, Nrf2 has been recognized to promote oncogenesis and resistance to chemotherapeutic drugs...
June 2013: Trends in Pharmacological Sciences
Andrew Whittle, Joana Relat-Pardo, Antonio Vidal-Puig
Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective...
June 2013: Trends in Pharmacological Sciences
Franz Hefti, William F Goure, Jasna Jerecic, Kent S Iverson, Patricia A Walicke, Grant A Krafft
Soluble Aβ oligomers are now widely recognized as key pathogenic structures in Alzheimer's disease. They inhibit synaptic function, leading to early memory deficits and synaptic degeneration, and they trigger the downstream neuronal signaling responsible for phospho-tau Alzheimer's pathology. The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques...
May 2013: Trends in Pharmacological Sciences
Natalia Novac
Drug repositioning is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. Several drugs have been successfully repositioned to a new indication, with the most prominent of them being viagra and thalidomide, which have generated historically high revenues. In line with these developments, most of the recent articles and reviews on repositioning are focused on success stories, leaving behind the challenges that repositioned compounds have on the way to the clinic...
May 2013: Trends in Pharmacological Sciences
Alan Wells, Jelena Grahovac, Sarah Wheeler, Bo Ma, Douglas Lauffenburger
Advances in diagnosis and treatment have rendered most solid tumors largely curable if they are diagnosed and treated before dissemination. However, once they spread beyond the initial primary location, these cancers are usually highly morbid, if not fatal. Thus, current efforts focus on both limiting initial dissemination and preventing secondary spread. There are two modes of tumor dissemination - invasion and metastasis - each leading to unique therapeutic challenges and likely to be driven by distinct mechanisms...
May 2013: Trends in Pharmacological Sciences
Alan V Smrcka
G-Protein-coupled receptors (GPCRs) signal through G protein α and βγ subunit families to regulate a wide range of physiological and pathophysiological processes. As such, GPCRs are major targets for therapeutic drugs. Downstream targets of GPCRs have also gained interest as a therapeutic approach to complex pathologies involving multiple GPCRs. One such approach involves targeting of the G proteins themselves. Several small molecule Gα and Gβγ modulators have been developed and been tested in various animal models of disease...
May 2013: Trends in Pharmacological Sciences
Antoine Dufour, Christopher M Overall
Matrix metalloproteinases (MMPs) are reputed to cause the inflammatory tissue destruction characterizing chronic inflammatory diseases and to degrade basement membrane collagen, thereby facilitating cancer cell metastasis. However, following the disappointing MMP drug cancer trials, recent studies using mouse models of disease coupled with high-throughput methods for substrate discovery have revealed surprising and unexpected new biological roles of MMPs in inflammatory diseases and cancer in vivo. Thus, MMPs modify signaling pathways and regulate the activity of whole families of cytokines of the immune response by precise proteolytic processing...
April 2013: Trends in Pharmacological Sciences
Laure B Bindels, Evelyne M Dewulf, Nathalie M Delzenne
Research interest in free fatty acid-binding receptors has been growing during the past decade, with an aim to better understand the modulation of host physiology in response to nutrition. G-protein-coupled receptor 43 (GPR43), also called free fatty acid receptor 2 (FFA2/FFAR2), binds short-chain fatty acids (SCFAs) produced by the microbial fermentation of carbohydrates and has shown promising therapeutic potential. This review presents current knowledge regarding the pharmacological properties of GPR43 and addresses its functions in selected organs (adipose tissue, intestine and immune cells)...
April 2013: Trends in Pharmacological Sciences
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