scholarly journals New Therapeutic Targets for Mood Disorders

2010 ◽  
Vol 10 ◽  
pp. 713-726 ◽  
Author(s):  
Rodrigo Machado-Vieira ◽  
Giacomo Salvadore ◽  
Nancy DiazGranados ◽  
Lobna Ibrahim ◽  
David Latov ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Histone Deacetylases ◽  
Glycogen Synthase ◽  
Pharmacological Treatments ◽  
Novel Treatments ◽  
Kinase C ◽  
Targeted Treatments ◽  
Antidepressant Effects ◽  
Preclinical Animal Models ◽  
New Compounds

Existing pharmacological treatments for bipolar disorder (BPD) and major depressive disorder (MDD) are often insufficient for many patients. Here we describe a number of targets/compounds that clinical and preclinical studies suggest could result in putative novel treatments for mood disorders. These include: (1) glycogen synthase kinase-3 (GSK-3) and protein kinase C (PKC), (2) the purinergic system, (3) histone deacetylases (HDACs), (4) the melatonergic system, (5) the tachykinin neuropeptides system, (6) the glutamatergic system, and (7) oxidative stress and bioenergetics. The paper reviews data on new compounds that have shown antimanic or antidepressant effects in subjects with mood disorders, or similar effects in preclinical animal models. Overall, an improved understanding of the neurobiological underpinnings of mood disorders is critical in order to develop targeted treatments that are more effective, act more rapidly, and are better tolerated than currently available therapies.

A common mechanism links activities of butyrate in the colon

2017 ◽  
Author(s):  
Mohit S. Verma ◽  
Michael J. Fink ◽  
Gabriel L Salmon ◽  
Nadine Fornelos ◽  
Takahiro E. Ohara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Short Chain Fatty Acids ◽  
Common Mechanism ◽  
Epithelial Stem Cells ◽  
Degree Of Unsaturation ◽  
Structure Activity ◽  
Starting Point ◽  
New Compounds

Two biological activities of butyrate in the colon (suppression of proliferation of colonic epithelial stem cells and inflammation) correlate with inhibition of histone deacetylases. Cellular and biochemical studies of molecules similar in structure to butyrate, but different in molecular details (functional groups, chain-length, deuteration, oxidation level, fluorination, or degree of unsaturation) demonstrated that these activities were sensitive to molecular structure, and were compatible with the hypothesis that butyrate acts by binding to the Zn<sup>2+</sup> in the catalytic site of histone deacetylases. Structure-activity relationships drawn from a set of 36 compounds offer a starting point for the design of new compounds targeting the inhibition of histone deacetylases. The observation that butyrate was more potent than other short-chain fatty acids is compatible with the hypothesis that crypts evolved (at least in part), to separate stem cells at the base of crypts from butyrate produced by commensal bacteria.

scholarly journals Bioinformatic and experimental survey of 14-3-3-binding sites

2010 ◽  
Vol 427 (1) ◽  
pp. 69-78 ◽  
Author(s):  
Catherine Johnson ◽  
Sandra Crowther ◽  
Margaret J. Stafford ◽  
David G. Campbell ◽  
Rachel Toth ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Binding Sites ◽  
Histone Deacetylases ◽  
Cognitive Disorders ◽  
Logic Gates ◽  
Protein Families ◽  
Kinase C ◽  
Dependent Protein ◽  
Physiological Demands

More than 200 phosphorylated 14-3-3-binding sites in the literature were analysed to define 14-3-3 specificities, identify relevant protein kinases, and give insights into how cellular 14-3-3/phosphoprotein networks work. Mode I RXX(pS/pT)XP motifs dominate, although the +2 proline residue occurs in less than half, and LX(R/K)SX(pS/pT)XP is prominent in plant 14-3-3-binding sites. Proline at +1 is rarely reported, and such motifs did not stand up to experimental reanalysis of human Ndel1. Instead, we discovered that 14-3-3 interacts with two residues that are phosphorylated by basophilic kinases and located in the DISC1 (disrupted-in-schizophrenia 1)-interacting region of Ndel1 that is implicated in cognitive disorders. These data conform with the general findings that there are different subtypes of 14-3-3-binding sites that overlap with the specificities of different basophilic AGC (protein kinase A/protein kinase G/protein kinase C family) and CaMK (Ca2+/calmodulin-dependent protein kinase) protein kinases, and a 14-3-3 dimer often engages with two tandem phosphorylated sites, which is a configuration with special signalling, mechanical and evolutionary properties. Thus 14-3-3 dimers can be digital logic gates that integrate more than one input to generate an action, and coincidence detectors when the two binding sites are phosphorylated by different protein kinases. Paired sites are generally located within disordered regions and/or straddle either side of functional domains, indicating how 14-3-3 dimers modulate the conformations and/or interactions of their targets. Finally, 14-3-3 proteins bind to members of several multi-protein families. Two 14-3-3-binding sites are conserved across the class IIa histone deacetylases, whereas other protein families display differential regulation by 14-3-3s. We speculate that 14-3-3 dimers may have contributed to the evolution of such families, tailoring regulatory inputs to different physiological demands.

Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases

2011 ◽  
Vol 39 (4) ◽  
pp. 1092-1095 ◽  
Author(s):  
Alexander J.P. Edwards ◽  
Sylvia L.F. Pender
Keyword(s):  
Gene Transcription ◽  
Inflammatory Bowel Diseases ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Novel Treatments ◽  
Bowel Diseases ◽  
Normal Gene ◽  
Inflammatory Bowel

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

scholarly journals The regulatory domain of protein kinase C delta positively regulates insulin receptor signaling

2009 ◽  
Vol 44 (3) ◽  
pp. 155-169 ◽  
Author(s):  
Avraham I Jacob ◽  
Miriam Horovitz-Fried ◽  
Shlomit Aga-Mizrachi ◽  
Tamar Brutman-Barazani ◽  
Hana Okhrimenko ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Regulatory Domain ◽  
Protein Kinase C Delta ◽  
Kinase C ◽  
Regulatory Effects ◽  
In Cells

Protein kinase C delta (PKCδ) is induced by insulin to rapidly associate with insulin receptor (IR) and upregulates insulin signaling. We utilized specific JM and CT receptor domains and chimeras of PKCα and PKCδ regulatory and catalytic domains to elucidate which components of PKCδ are responsible for positive regulatory effects of PKCδ on IR signaling. Studies were performed on L6 and L8 skeletal muscle myoblasts and myotubes. PKCδ was preferentially bound to the JM domain of IR, and insulin stimulation increased this binding. Both PKCδ/α and PKCα/δ chimeras (regulatory/catalytic) were bound preferentially to the JM but not to the CT domain of IR. Although IR–PKCδ binding was higher in cells expressing either the PKCδ/α or PKCα/δ chimera than in control cells, upregulation of IR signaling was observed only in PKCδ/α cells. Thus, in response to insulin increases in tyrosine phosphorylation of IR and insulin receptor substrate-1, downstream signaling to protein kinase B and glycogen synthase kinase 3 (GSK3) and glucose uptake were greater in cells overexpressing PKCδ/α and the PKCδ/δ domains than in cells expressing the PKCα/δ domains. Basal binding of Src to PKCδ was higher in both PKCδ/α- and PKCα/δ-expressing cells compared to control. Binding of Src to IR was decreased in PKCα/δ cells but remained elevated in the PKCδ/α cells in response to insulin. Finally, insulin increased Src activity in PKCδ/α-expressing cells but decreased it in PKCα/δ-expressing cells. Thus, the regulatory domain of PKCδ via interaction with Src appears to determine the role of PKCδ as a positive regulator of IR signaling in skeletal muscle.

Thiazolidinediones: novel treatments for cognitive deficits in mood disorders?

2007 ◽  
Vol 8 (11) ◽  
pp. 1615-1628 ◽  
Author(s):  
Roger S McIntyre ◽  
Joanna K Soczynska ◽  
Hanna O Woldeyohannes ◽  
Gary F Lewis ◽  
Lawrence A Leiter ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Cognitive Deficits ◽  
Novel Treatments
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