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Depression is a heterogeneous disorder and, similar to other spectrum disorders, its manifestation varies by age of onset, severity, comorbidity, treatment responsiveness, and other factors. A laboratory blood test based on specific biomarkers for major depressive disorder (MDD) and its subgroups could increase diagnostic accuracy and expedite the initiation of treatment. We identified candidate blood biomarkers by examining genome-wide expression differences in the blood of animal models representing both the genetic and environmental/stress etiologies of depression. Human orthologs of the resulting transcript panel were tested in pilot studies. Transcript abundance of 11 blood markers differentiated adolescent subjects with early-onset MDD from adolescents with no disorder (ND). A set of partly overlapping transcripts distinguished adolescent patients who had comorbid anxiety disorders from those with only MDD. In adults, blood levels of nine transcripts discerned subjects with MDD from ND controls. Even though cognitive behavioral therapy (CBT) resulted in remission of some patients, the levels of three transcripts consistently signaled prior MDD status. A coexpression network of transcripts seems to predict responsiveness to CBT. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for different manifestations of MDD, potentially reducing diagnostic heterogeneity and advancing individualized treatment strategies. [ABSTRACT FROM AUTHOR]

The chemopreventive agent sulforaphane is an isothiocyanate derived from cruciferous vegetables. Transcriptional activation of antioxidant response element (ARE)-regulated phase II detoxification and antioxidant genes through the induction of transcription factor NF-E2-related factor-2 (Nrf2) is considered as the prime mechanism of its chemopreventive action. Cellular level of Nrf2 is tightly regulated by proteolysis through Cullin3 (Cul3)/Kelch-like ECH-associated protein 1 (Keap1)-dependent polyubiquitination. Sulforaphane is an electrophile that can react with protein thiols to form thionoacyl adducts and is believed to affect the Cys residues in Keap1 protein. In addition, sulforaphane might affect the activity of a variety of intracellular kinases to phosphorylate Nrf2 proteins, which dictates the nucleocytoplasmic trafficking of Nrf2 or modulates the Nrf2 protein stability. This review is designed to briefly account for the regulatory mechanism of Nrf2 protein expression by Cul3/Keap1 E3 ligase and for the possible roles of posttranslational modifications of cellular Keap1 or Nrf2 proteins by sulforphane in the regulation of ARE-dependent gene activation. [ABSTRACT FROM AUTHOR]

Thioaptamers offer advantages over normal phosphate ester backbone aptamers due to their enhanced affinity, specificity, and higher stability, largely due to the properties of the sulfur backbone modifications. Over the past several years, in vitro thioaptamer selection and bead-based thioaptamer selection techniques have been developed in our laboratory. Furthermore, several thioaptamers targeting specific proteins such as transcription factor NF-κB and AP-1 proteins have been identified. Selected thioaptamers have been shown diagnostic promise in proteome screens. Moreover, some promising thioaptamers have been shown in preliminary animal therapeutic dosing to increase survival in animal models of infection with West Nile virus. [ABSTRACT FROM AUTHOR]

The transcription factor, nuclear factor-κB (NF-κB), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF-κB in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF-κB has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF-κB in broader pathophysiological contexts. From such studies, it has become quite clear that NF-κB plays unique and distinct functions in different cell types. Because of the importance of NF-κB in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small-molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF-κB as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF-κB activity, we suggest that there are certain niche indications for blocking NF-κB in inflammatory bowel disease that offer particular promise. [ABSTRACT FROM AUTHOR]

Transcription factor proteins regulate gene expression via binding to specific DNA sequences found in the promoter/enhancer regions of the genes they control. Although most transcription factor binding has been associated with an increase in gene expression, gene suppression has also been described. Transcription factor decoys are molecules that mimic the binding sites for transcription factor proteins, and compete with promoter regions to absorb this binding activity in the cell nucleus. By blocking transcription factor-chromosomal DNA interaction, these molecules provide a powerful means to manipulate the regulation of gene expression, particularly as transcription factors are increasingly understood to alter gene activation during the course of normal and pathologic processes in cell biology. As methods for cellular and nuclear delivery of these agents improve, the increasing use of transcription factor decoys, both as investigative and therapeutic tools, promises to have a significant impact on our understanding of and ability to treat human disease. [ABSTRACT FROM AUTHOR]

Owing to improving preventative, diagnostic, and therapeutic measures for cardiovascular disease and a variety of cancers, the average ages of North Americans and Europeans continue to rise. Regrettably, accompanying this increase in life span, there has been an increase in the number of individuals afflicted with age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and stroke. Although different cell types and brain areas are vulnerable among these, each disorder likely develops from activation of a common final cascade of biochemical and cellular events that eventually lead to neuronal dysfunction and death. In this regard, different triggers, including oxidative damage to DNA, the overactivation of glutamate receptors, and disruption of cellular calcium homeostasis, albeit initiated by different genetic and/or environmental factors, can instigate a cascade of intracellular events that induce apoptosis. To forestall the neurodegenerative process, we have chosen specific targets to inhibit that are at pivotal rate-limiting steps within the pathological cascade. Such targets include TNF-α, p53, and GLP-1 receptor. The cytokine TNF-α is elevated in Alzheimer's disease, Parkinson's disease, stroke, and amyotrophic lateral sclerosis. Its synthesis can be reduced via posttranscriptional mechanisms with novel analogues of the classic drug, thalidomide. The intracellular protein and transcription factor, p53, is activated by the Alzheimer's disease toxic peptide, Aβ, as well as by excess glutamate and hypoxia to trigger neural cell death. It is inactivated by novel tetrahydrobenzothiazole and -oxazole analogues to rescue cells from lethal insults. Stimulation of the glucagon-like peptide-1 receptor (GLP-1R) in brain is associated with neurotrophic functions that, additionally, can protect cells against excess glutamate and other toxic insults. [ABSTRACT FROM AUTHOR]