ABSTRACT
Bromodomain and extra-terminal domain proteins (BET proteins) are epigenetic reader proteins that have been implicated in regulating gene expression through binding to chromatin and interaction with transcription factors. These proteins are located in the nucleus and are responsible for recognizing acetylated lysine residues on histones, reading epigenetic messages, recruiting key transcription factors, and thereby regulating gene expression. BET proteins control the transcription of genes responsible for maladaptive effects in inflammation, cancer, and renal and cardiovascular diseases. Given the multifaceted role of BET proteins in the pathogenesis of various diseases, several small molecule inhibitors of BET proteins have been developed as potential therapeutic targets for treating different diseases in recent years. However, while many nonselective BET inhibitors are indicated for the treatment of cancer, a selective BET inhibitor, apabetalone, is the only oral BET inhibitor in phase III clinical trials for the treatment of cardiovascular diseases and others. Thus, this review aims to present and discuss the preclinical and clinical evidence for the beneficial effects and mechanism of action of apabetalone for treating various diseases.
ABSTRACT
The pathophysiology of autism is influenced by a combination of environmental and genetic factors. Furthermore, individuals with autism appear to be at a higher risk of developing cancer. However, this is not fully understood. Aflatoxin B1 (AFB1) is a potent food pollutant carcinogen. The effects of AFB1 on genomic instability in autism have not yet been investigated. Hence, we have aimed to investigate whether repeated exposure to AFB1 causes alterations in genomic stability, a hallmark of cancer and apoptosis in the BTBR autism mouse model. The data revealed increased micronuclei generation, oxidative DNA strand breaks, and apoptosis in BTBR animals exposed to AFB1 when compared to unexposed animals. Lipid peroxidation in BTBR mice increased with a reduction in glutathione following AFB1 exposure, demonstrating an exacerbated redox imbalance. Furthermore, the expressions of some of DNA damage/repair- and apoptosis-related genes were also significantly dysregulated. Increases in the redox disturbance and dysregulation in the DNA damage/repair pathway are thus important determinants of susceptibility to AFB1-exacerbated genomic instability and apoptosis in BTBR mice. This investigation shows that AFB1-related genomic instability can accelerate the risk of cancer development. Moreover, approaches that ameliorate the redox balance and DNA damage/repair dysregulation may mitigate AFB1-caused genomic instability.
ABSTRACT
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by motor deficits, cognitive impairment, fatigue, pain, and sensory and visual dysfunction. CD40, highly expressed in B cells, plays a significant role in MS pathogenesis. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS has been well established, as well as its relevance in MS patients. This study aimed to evaluate the therapeutic potential of DAPTA, a selective C-C chemokine receptor 5 (CCR5) antagonist in the murine model of MS, and to expand the knowledge of its mechanism of action. Following the induction of EAE, DAPTA was administrated (0.01 mg/kg, i.p.) daily from day 14 to day 42. We investigated the effects of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α in CD40+ spleen B cells using flow cytometry. Furthermore, we also analyzed the effect of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α mRNA expression levels using qRT-PCR in brain tissue. EAE mice treated with DAPTA showed substantial reductions in NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α but an increase in the IκBα of CD40+ B lymphocytes. Moreover, EAE mice treated with DAPTA displayed decreased NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α and but showed increased IκBα mRNA expression levels. This study showed that DAPTA has significant neuroprotective potential in EAE via the downregulation of inflammatory mediators and NF-κB/Notch signaling. Collectively, DAPTA might have potential therapeutic targets for use in MS treatment.
