Tara Vinyette Saco

Role of epigenetics in pulmonary hypertension.

A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.

Benralizumab for the treatment of asthma

ABSTRACT Introduction: The classification of asthma into phenotypes and endotoypes allows for the use of targeted therapies, including three biologics which target interleukin 5 (IL-5) signaling in eosinophilic asthma. Areas covered: As of December 2016, two monoclonal antibodies, mepolizumab and reslizumab, are approved by U.S. Food and Drug Administration and one, benralizumab, is in clinical development. Two phase 3 trials for benralizumab, SIROCCO and CALIMA, were published in September 2016. Although there are no direct comparisons among these three anti-IL-5 therapies, the goal of this review is to summarize the current data and discuss their potential similarities and differences, with a focus on benralizumab. Expert commentary: Compared to mepolizumab and reslizumab, the possible advantages of benralizumab are less frequent dosing and a potential to reduce exacerbations irrespective of the blood eosinophil count. Some improvements in asthma symptom scores and quality of life occur with all three biologics, but the clinical meaningfulness of these improvements is less clear. A more defined reference range for eosinophil levels is necessary to determine which subjects will best benefit from these medications. Until quality randomized controlled trials directly compare the three, choosing among them for the treatment of eosinophilic asthma remains difficult.

Inflammasome: a new trigger of Alzheimer's disease

Alzheimers disease is an insidious and dementing illness currently affecting approximately 5 million Americans over the age of 65, and today, someone in the US develops Alzheimers disease every 68 s which is expected to drop to 33 s in the year 2050 (Thies and Bleiler, 2013). Although the scientific community has learned much about the pathogenesis of Alzheimers disease in recent years, treatments to prevent progression and reverse the effects of this disease have yet to be developed. Current therapies are primarily indicated for symptomatic control, but they do not have the capacity to inhibit or lead to regression of the pathologic changes contributing to Alzheimers disease. Therefore, current research into this condition is primarily focused on developing targeted therapies against genes involved in the development of Alzheimers disease. Currently, an avenue that is being focused on and should be given further attention is the epigenetic mechanisms contributing to the pathophysiology of Alzheimers disease. The main contributing factor in the development of Alzheimers disease is the deposition of β-amyloid in the brain, especially in the hippocampus (Heneka et al., 2013). Previous research which focused on chronic medical conditions involving β-amyloid pathology has shown that inflammatory mechanisms may be stimulated by β-amyloid deposition (Halle et al., 2008). Formation of β-amyloid plaques stimulates the production of inactive IL-1β, an inflammatory cytokine (Prinz et al., 2011). However, the mechanism that initiates inactive IL-1β processing in Alzheimers disease is not clearly defined. It was recently reported that caspase-1-mediated processing of IL-1β is mediated by inflammasomes in various pathological conditions (Kolliputi et al., 2010, 2012; Fukumoto et al., 2013). Inflammasomes, such as the NLRP3 inflammasome, detect the inflammatory aggregates of β-amyloid and inactive IL-1β, and respond by secreting caspase-1 (Casp-1) to activate IL-1β (Heneka et al., 2013; Qazi et al., 2013). This leads to the creation of an inflammatory environment around the plaque, which downregulates amyloid precursor protein (APP) degradation, as well as decreased destruction of β-amyloid plaques by microglia (Figure ​(Figure1).1). Although it can be surmised that this mechanism may contribute to the development of Alzheimers disease, its involvement has not been experimentally demonstrated (Heneka et al., 2013). NLRP3 inflammasome activation by β-amyloid in microglia is necessary for maturation of IL-1β and subsequent inflammatory events; however, the role of NLRP3 activation in Alzheimers disease in vivo is still unknown (Heneka et al., 2013). A recent study by Heneka et al. suggests that the NLRP3 inflammasome has a role in Alzheimers disease by demonstrating increased caspase-1 expression levels in brains with Alzheimers disease. Figure 1 The diagram is a schematic representation of the role of NLRP3 inflammasome in Alzheimers disease. Recently, Heneka et al. conducted a study to determine whether or not NLRP3 inflammasome activation contributes to the pathogenesis of Alzheimers disease. APP/Presenilin-1 (PS1) mice, which develop symptoms similar to Alzheimers disease, were crossed with NLRP3−/− or Casp-1−/− mice. The quantity of cleaved Casp-1 in the brains of the offspring was then measured in comparison to the APP/PS1 mice. The researchers also examined the differences in the level of spatial memory impairment between these groups and found that in APP/PS1/NLRP3−/− and APP/PS1/Casp-1−/− mice, the level of cleaved Casp-1 was markedly decreased when compared to APP/PS1 mice, while IL-1β levels were consistent between the groups (Heneka et al., 2013). This diminished Casp-1 level correlated with preserved spatial memory function in the APP/PS1/NLRP3−/− and APP/PS1/Casp-1−/− mice, as opposed to the significant spatial memory impairment seen in the APP/PS1 mice (Heneka et al., 2013). The researchers also compared the level of long-term potentiation (LTP), which is analogous to synaptic plasticity, in the hippocampi of these mice. The APP/PS1 mice were found to have decreased hippocampal synaptic plasticity, while the hippocampal synaptic plasticity in the APP/PS1/NLRP3−/− and APP/PS1/Casp-1−/− mice was preserved (Heneka et al., 2013). The role of the NLRP3 inflammasome in behavioral changes and cognitive deficiencies associated with Alzheimers disease was also examined in the study by Heneka et al. APP/PS1 underwent behavioral analysis and were found to have delayed habituation and increased psychomotor agitation. Conversely, APP/PS1/NLRP3−/− mice exhibited decreased locomotion and behavioral changes, further supporting the fact that the NLRP3 inflammasome places a large part in the development of cognitive and behavioral symptoms seen in Alzheimers patients. The study by Heneka et al. also assessed the effect of the NLRP3 inflammasome on the phagocytic activity of microglia. Studies have shown that large numbers of microglia surround β-amyloid plaques in Alzheimers patients. However, it is also well known that inflammatory cytokines inhibit microglial phagocytosis. Thus, Heneka et al. suggested that the NLRP3 inflammasome contributes to ineffective microglial phagocytosis by leading to increased expression of inflammatory cytokines. After isolating microglia from the APP/PS1 mice, APP/PS1/NLRP3−/− mice, and APP/PS1/Casp-1−/− mice, Heneka et al. found that microglial phagocytosis of β-amyloid was more efficient as it doubled in APP/PS1/NLRP3−/− mice and APP/PS1/Casp-1−/− mice when compared to APP/PS1. The deficiency in the NLRP3 inflammasome or Casp-1 did not change the overall amounts of APP but rather reduced the levels of β-amyloid aggregates. These results provide additional evidence that the NLRP3 inflammasome leads to pathologic deposition and ineffective clearing of β-amyloid in Alzheimers patients. Based on these results, the authors conclude that introducing therapeutic treatments targeting the NLRP3 inflammasome may have a beneficial effect on patients with Alzheimers disease as NLRP3 activation may contribute to the pathogenesis of Alzheimers disease in humans. The authors also suggest that activation of NLRP3 enhances Alzheimers disease and may be involved in synaptic dysfunction, cognitive impairment, and the restriction of microglial clearance functions (Heneka et al., 2013). Therefore, human trials should be conducted to determine the validity of this hypothesis. The experiment by Heneka et al. provides an excellent model for the development of possible future therapies for Alzheimers patients. Animal and human studies examining the safety and effectiveness of targeted NLRP3 or Casp-1 inhibitors should be further pursued as the results reveal an important role of the inflammatory activators NLRP3 inflammasome/caspase-1 in Alzheimers disease pathogenesis and could represent improved therapeutic treatments for millions of Alzheimers disease patients.

Epigenetics of Mucus Hypersecretion in Chronic Respiratory Diseases

Abstract Asthma, chronic obstructive pulmonary disease, and cystic fibrosis are three chronic pulmonary diseases that affect an estimated 420 million individuals across the globe. A key factor contributing to each of these conditions is mucus hypersecretion. Although management of these diseases is vastly studied, researchers have only begun to scratch the surface of the mechanisms contributing to mucus hypersecretion. Epigenetic regulation of mucus hypersecretion, other than microRNA post‐translational modification, is even more scarcely researched. Detailed study of epigenetic mechanisms, such as DNA methylation and histone modification, could not only help to better the understanding of these respiratory conditions but also reveal new treatments for them. Because mucus hypersecretion is such a complex event, there are innumerable genes involved in the process, which are beyond the scope of a single review. Therefore, the purpose of this review is to narrow the focus and summarize specific epigenetic research that has been conducted on a few aspects of mucus hypersecretion in asthma, chronic obstructive pulmonary disease, cystic fibrosis, and some cancers. Specifically, this review emphasizes the contribution of DNA methylation and histone modification of particular genes involved in mucus hypersecretion to identify possible targets for the development of future therapies for these conditions. Elucidating the role of epigenetics in these respiratory diseases may provide a breath of fresh air to millions of affected individuals around the world.

Micro RNAs: The Future of Idiopathic Pulmonary Fibrosis Therapy

Idiopathic pulmonary fibrosis (IPF) is a debilitating, chronically progressive lung disease that leads to significant morbidity and mortality [1]. Although it is a fairly uncommon disease, its incidence has been increasing over the past decade [2]. One of the key elements contributing to the development of IPF is the inability to halt the progression of damage to lung epithelial cells. The pathogenic mechanisms involved in this process include excessive inflammation, overactivity and hyperproliferation of fibroblasts, and inadequate repair of epithelial cell injury [3]. Currently, no treatment modality has been proven to be effective in preventing or reversing the parenchymal damage occurring in IPF. However, a surge in the amount of research pursuing future therapies has occurred in recent years. A field of study that appears to be particularly promising in the development of new IPF treatments is the study of epigenetic regulatory mechanisms involved in the pathogenesis of IPF. Epigenetic factors involved in the pathogenesis of IPF, including micro RNAs (miRNAs), may be the key to the development of future treatments for this disease [4]. miRNA expression can be controlled by the very epigenetic mechanisms they themselves regulate, including DNA methylation and histone modification. Thus, the number of ways they can be utilized in the development of targeted therapies for many diseases, including IPF, seems limitless [5]. Dakhlallah et al. recently demonstrated the role of epigenetic mechanisms in IPF [3]. This researchers investigated the role of miRNA-17~92 cluster (miR-17~92) in the development of IPF, which is presumed to inhibit specific pro-fibrotic genes, including transforming growth factor-β (TGF-β), metalloproteinases, and type 1 α1 collagen (COL1A1) [3]. This cluster is also involved with lung development, as evidenced by animal studies demonstrating death by asphyxiation in mice lacking the miR-17~92 cluster [6], and high proliferation rates of undifferentiated lung epithelial cells in mice overexpressing this cluster [7]. Expression of miR-17~92 is silenced by hypomethylation via DNA (cytosine-5)-methyltransferase 1 (DNMT-1), the DNMT that is most closely involved with cellular and tissue repair. Dakhlallah et al. demonstrated that lung fibroblasts and epithelial cells from IPF patients had increased DNMT-1 expression, leading to hypermethylation of and subsequently decreased levels of miR-17~92 expression [3]. This lead to upregulation of pro-fibrotic genes, especially TGF-β, which has been shown to lead to the overproduction of miRNA-21 (miR21), an miRNA that silences inhibitors of TGF-β expression, leading to a vicious cycle of unchecked fibrosis in IPF [8]. This is further supported by the fact that decreased miR-21 expression inhibits the pro-fibrotic effects of bleomycin in the lung parenchyma of mice [8]. In the study by Dakhlallah et al., administration of the chemotherapeutic demethylating agent, 5′-aza-2′-doxyctidine, in the IPF patients lead to upregulation of miR17~92, with a subsequent decrease in DNMT-1 levels and downregulation of genes involved in fibrosis. It can be eluded from these findings that the miR-17~92 cluster is vital to lung parenchymal repair in IPF [3]. This same mechanism was also seen in mice with pulmonary fibrosis induced by bleomycin. Dakhlallah et al. then went one step further by administering 5′-aza-2′-doxyctidine to see if subsequent upregulation of miR17~92 would lead to reversal of the pulmonary fibrosis in these mice. The mice treated with 5′-aza-2′-doxyctidine did not experience significant reversal of their pulmonary fibrosis because the 5′-aza-2′-doxyctidine did not lead to breakdown of collagen already present in the lung parenchyma. However, 5′-aza-2′-doxyctidine administration did prevent further production of collagen in the mice’s lungs, and thus slowed the progression of their IPF. These results are analogous to those obtained in a study conducted by Bechtel et al. revealing that 5′-aza-2′-doxyctidine decreased DNMT-1 methylation of RASAL1, an inhibitor of Ras expression, leading to slowed progression of renal fibrosis. Interestingly, other studies have shown that RASAL1 expression is not only controlled via DNMT-1, but also through TGF-β and many miRNA’s that make up the miR17~92 cluster [9]. The study by Dakhlallah et al. presents some compelling results that support conducting further human studies examining the efficaciousness of 5′-aza-2′-doxyctidine in IPF patients [3]. A side effect of the drug that could possibly limit its effectiveness is its tendency to lead to myelosuppression with subsequent pancytopenia. It can also be concluded from this study that direct DNMT-1 inhibitors may provide an alternative IPF therapy. Animal and human studies should be conducted to investigate the effectiveness of direct DNMT-1 inhibitors in the prevention of progression and possible reversal of IPF. Human trials examining the effect of exogenous administration of miR-17~92 on the progression of IPF pathology should also be pursued. In all, epigenetic therapies represent a versatile and promising new avenue for IPF treatment. Future studies should examine these possible therapies as they provide an arsenal of new weapons to be used in the battle against IPF.