TY  - JOUR
AB  - Glucocorticoids (GCs) are a class of steroid hormones that regulate key physiological processes such as metabolism, immune function, and stress responses. The effects of GCs are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor that activates or represses the expression of hundreds to thousands of genes in a tissue- and physiological state-specific manner. The activity of GR is modulated by numerous coregulator proteins that interact with GR in response to different stimuli assembling into a multitude of DNA-protein complexes and facilitate the integration of these signals, helping GR to communicate with basal transcriptional machinery and chromatin. Here, we provide a brief overview of the physiological and molecular functions of GR, and discuss the roles of GR coregulators in the immune system, key metabolic tissues and the central nervous system. We also present an analysis of the GR interactome in different cells and tissues, which suggests tissue-specific utilization of GR coregulators, despite widespread functions shared by some of them.
AU  - Fadel, L.
AU  - Dacic, M.*
AU  - Fonda, V.
AU  - Sokolsky, B.A.*
AU  - Quagliarini, F.
AU  - Rogatsky, I.*
AU  - Uhlenhaut, N.H.
C1  - 68209
C2  - 54793
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
TI  - Modulating glucocorticoid receptor actions in physiology and pathology: Insights from coregulators.
JO  - Pharmacol. Ther.
VL  - 251
PB  - Pergamon-elsevier Science Ltd
PY  - 2023
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, survival and function. The term "proteasome" embraces a whole family of distinct complexes, which share a common proteolytic core, the 20S proteasome, but differ by their attached proteasome activators. Each of these proteasome complexes plays specific roles in the control of cellular function. In addition, distinct proteasome interacting proteins regulate proteasome activity in subcellular compartments and in response to cellular signals. Proteasome activators and regulators may thus serve as building blocks to fine-tune proteasome function in the cell according to cellular needs.Inhibitors of the proteasome, e.g. the FDA approved drugs Velcade (TM), Kyprolis (TM), Ninlaro (TM), inactivate the catalytic 20S core and effectively block protein degradation of all proteasome complexes in the cell resulting in inhibition of cell growth and induction of apoptosis. Efficacy of these inhibitors, however, is hampered by their pronounced cytotoxic side-effects as well as by the emerging development of resistance to catalytic proteasome inhibitors. Targeted inhibition of distinct buiding blocks of the proteasome system, i.e. proteasome activators or regulators, represents an alternative strategy to overcome these limitations.In this review, we stress the importance of the diversity of the proteasome complexes constituting an entire proteasome system. Our building block concept provides a rationale for the defined targeting of distinct proteasome super-complexes in disease. We thereby aim to stimulate the development of innovative therapeutic approaches beyond broad catalytic proteasome inhibition.
AU  - Wang, X.
AU  - Meul, T.
AU  - Meiners, S.
C1  - 58751
C2  - 48581
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
TI  - Exploring the proteasome system: A novel concept of proteasome inhibition and regulation.
JO  - Pharmacol. Ther.
VL  - 211
PB  - Pergamon-elsevier Science Ltd
PY  - 2020
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - Despite significant therapeutic advances in heart failure (HF) therapy, the morbidity and mortality associated with this disease remains unacceptably high. The concept of metabolic dysfunction as an important underlying mechanism in HF is well established.Cardiac function is inextricably linked to metabolism, with dysregulation of cardiac metabolism pathways implicated in a range of cardiac complications, including HF. Modulation of cardiac metabolism has therefore become an attractive clinical target. Cardiac metabolism is based on the integration of adenosine triphosphate (ATP) production and utilization pathways. ATP itself impacts the heart not only by providing energy, but also represents a central element in the purinergic signaling pathway, which has received considerable attention in recent years. Furthermore, novel drugs that have received interest in HF include angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors, whose favorable cardiovascular profile has been at least partly attributed to their effects on metabolism.This review, describes the major metabolic pathways and concepts of the healthy heart (including fatty acid oxidation, glycolysis, Krebs cycle, Randle cycle, and purinergic signaling) and their dysregulation in the progression to HF (including ketone and amino acid metabolism). The cardiac implications of HF comorbidities, including metabolic syndrome, diabetes mellitus and cachexia are also discussed. Finally, the impact of current HF and diabetes therapies on cardiac metabolism pathways and the relevance of this knowledge for current clinical practice is discussed. Targeting cardiac metabolism may have utility for the future treatment of patients with HF, complementing current approaches. (C) 2018 Published by Elsevier Inc.
AU  - Birkenfeld, A.L.
AU  - Jordan, J.*
AU  - Dworak, M.*
AU  - Merkel, T.*
AU  - Burnstock, G.*
C1  - 54191
C2  - 45427
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
SP  - 132-144
TI  - Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts.
JO  - Pharmacol. Ther.
VL  - 194
PB  - Pergamon-elsevier Science Ltd
PY  - 2019
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - Synaptic transmission is a fundamental neurobiological process enabling exchange of signals between neurons as well as neurons and their non-neuronal effectors. The complex molecular machinery of the synaptic vesicle cycle and transmitter release has emerged and developed in the course of the evolutionary race, to ensure adaptive gain and survival of the fittest. In parallel, a generous arsenal of biomolecules and neuroactive peptides have co-evolved, which selectively target the transmitter release machinery, with the aim of subduing natural rivals or neutralizing prey. With advances in neuropharmacology and quantitative biology, neurotoxins targeting pre synaptic mechanisms have attracted major interest, revealing considerable potential as carriers of molecular cargo and probes for meddling synaptic transmission mechanisms for research and medical benefit. In this review, we investigate and discuss key facets employed by the most prominent bacterial and animal toxins targeting the presynaptic secretory machinery. We explore the cellular basis and molecular grounds for their tremendous potency and selectivity, with effects on a wide range of neural functions. Finally, we consider the emerging preclinical and clinical data advocating the use of active ingredients of neurotoxins for the advancement of molecular medicine and development of restorative therapies. (C) 2018 Elsevier Inc. All rights reserved.
AU  - Ovsepian, S.V.
AU  - O'Leary, V.B.*
AU  - Ayvazyan, N.M.*
AU  - Al-Sabi, A.*
AU  - Ntziachristos, V.
AU  - Oliver Dolly, J.*
C1  - 54190
C2  - 45266
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
SP  - 135-155
TI  - Neurobiology and therapeutic applications of neurotoxins targeting transmitter release.
JO  - Pharmacol. Ther.
VL  - 193
PB  - Pergamon-elsevier Science Ltd
PY  - 2019
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - The WNT signalling cascades have emerged as critical regulators of a wide variety of biological aspects involved in lung development as well as in physiological and pathophysiological processes in the adult lung. WNTs (secreted glycoproteins) interact with various transmembrane receptors and co-receptors to activate signalling pathways that regulate transcriptional as well as non-transcriptional responses within cells. In physiological conditions, the majority of WNT receptors and co-receptors can be detected in the adult lung. However, dysregulation of WNT signalling pathways contributes to the development and progression of chronic lung pathologies, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. The interaction between a WNT and the (co-)receptor(s) present at the cell surface is the initial step in transducing an extracellular signal into an intracellular response. This proximal event in WNT signal transduction with (cell-specific) ligand-receptor interactions is of great interest as a potential target for pharmacological intervention. In this review we highlight the diverse expression of various WNT receptors and co-receptors in the aforementioned chronic lung diseases and discuss the currently available biologicals and pharmacological tools to modify proximal WNT signalling.
AU  - Skronska-Wasek, W.
AU  - Gosens, R.*
AU  - Königshoff, M.
AU  - Baarsma, H.A.
C1  - 52999
C2  - 44720
SP  - 150-166
TI  - WNT receptor signalling in lung physiology and pathology.
JO  - Pharmacol. Ther.
VL  - 187
PY  - 2018
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - The regulation of metabolic processes by the Indy (I'm Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an 'ideal target for the treatment of metabolic disease'. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease.
AU  - Willmes, D.M.
AU  - Kurzbach, A.
AU  - Henke, C.
AU  - Zahn, G.*
AU  - Heifetz, A.*
AU  - Jordan, J.*
AU  - Helfand, S.L.*
AU  - Birkenfeld, A.L.
C1  - 52075
C2  - 43710
TI  - The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target.
JO  - Pharmacol. Ther.
PY  - 2017
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - The diversity of pore-forming subunits of KV1 channels (KV1.1-KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletions of corresponding kcna2 gene in mouse models precipitate symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insight towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions.
AU  - Ovsepian, S.V.
AU  - LeBerre, M.*
AU  - Steuber, V.*
AU  - O'Leary, V.B.
AU  - Leibold, C.*
AU  - Dolly, J.O.*
C1  - 47791
C2  - 39475
CY  - Oxford
SP  - 93-101
TI  - Distinctive role of KV1.1 subunit in the biology and functions of low threshold K+ channels with implications for neurological disease.
JO  - Pharmacol. Ther.
VL  - 159
PB  - Pergamon-elsevier Science Ltd
PY  - 2016
SN  - 0163-7258
ER  - 

TY  - JOUR
AB  - Wingless/integrase-1 (WNT) signaling is a key pathway regulating various aspects of embryonic development; however it also underlies several pathological conditions in man, including various cancers and fibroproliferative diseases in several organs. Investigating the molecular processes involved in (canonical) WNT signaling will open new avenues for generating new therapeutics to specifically target diseases in which WNT signaling is aberrantly regulated. Here we describe the complexity of WNT signal transduction starting from the processes involved in WNT ligand biogenesis and secretion by WNT producing cells followed by a comprehensive overview of the molecular signaling events ultimately resulting in enhanced transcription of specific genes in WNT receiving cells. Finally, the possible targets for therapeutic intervention and the available pharmacological inhibitors for this complex signaling pathway are discussed.
AU  - Baarsma, H.A.
AU  - Königshoff, M.
AU  - Gosens, R.*
C1  - 23925
C2  - 31304
SP  - 66-83
TI  - The WNT signaling pathway from ligand secretion to gene transcription: Molecular mechanisms and pharmacological targets.
JO  - Pharmacol. Ther.
VL  - 138
IS  - 1
PB  - Pergamon-Elsevier Science
PY  - 2013
SN  - 0163-7258
ER  -