Cutting Edge: Hypoxia Sensing by the Histone Demethylase UTX (KDM6A) Limits Colitogenic CD4+ T Cells in Mucosal Inflammation.

Hypoxia is a hallmark of inflammatory conditions (e.g., inflammatory bowel disease [IBD]), and adaptive responses have consequently evolved to protect against hypoxia-associated tissue injury. Because augmenting hypoxia-induced protective responses is a promising therapeutic approach for IBD, a more complete understanding of these pathways is needed. Recent work has demonstrated that the histone demethylase UTX is oxygen-sensitive, but its role in IBD is unclear. In this study, we show that hypoxia-induced deactivation of UTX downregulates T cell responses in mucosal inflammation. Hypoxia results in decreased T cell proinflammatory cytokine production and increased immunosuppressive regulatory T cells, and these findings are recapitulated by UTX deficiency. Hypoxia leads to T cell accumulation of H3K27me3 histone modifications, suggesting that hypoxia impairs UTX's histone demethylase activity to dampen T cell colitogenic activity. Finally, T cell-specific UTX deletion ameliorates colonic inflammation in an IBD mouse model, implicating UTX's oxygen-sensitive demethylase activity in counteracting hypoxic inflammation.

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.

Arbuscular Mycorrhizal Fungi Improve Tolerance of the Medicinal Plant Eclipta prostrata (L.) and Induce Major Changes in Polyphenol Profiles Under Salt Stresses.

Eclipta prostrata (L.) is an important and well-known medicinal plant due to its valuable bioactive compounds. Microorganisms, including arbuscular mycorrhizal fungi (AMF), and salinity could directly impact plant metabolome, thus influencing their secondary metabolites and the efficacy of herbal medicine. In this study, the role of different single AMF species (Funneliformis mosseae, Septoglomus deserticola, Acaulospora lacunosa) and a mixture of six AMF species in plant growth and physio-biochemical characteristics of E. prostrata under non-saline conditions was investigated. Next, the most suitable AM treatment was chosen to examine the impact of AMF on physio-biochemical features and polyphenol profiles of E. prostrata under saline conditions (100 and 200 mM NaCl). The findings indicated that AMF mixture application resulted in more effective promotion on the aboveground part of non-saline plants than single AMF species. AM mixture application improved growth and salt tolerance of E. prostrata through increasing the activity of catalase, peroxidase (at 4 weeks), proline, and total phenolic content (at 8 weeks). Such benefits were not observed under high salinity, except for a higher total phenolic concentration in mycorrhizal plants at 8 weeks. Through high-performance liquid chromatography, 14 individual phenolic compounds were analyzed, with wedelolactone and/or 4,5-dicaffeoylquinic acid abundant in all treatments. Salinity and mycorrhizal inoculation sharply altered the polyphenol profiles of E. prostrata. Moderate salinity boosted phenolic compound production in non-AM plants at 4 weeks, while at 8 weeks, the decline in the content of phenolic compounds occurred in uncolonized plants subjected to both saline conditions. Mycorrhization augmented polyphenol concentration and yield under non-saline and saline conditions, depending on the growth stages and salt stress severity. Plant age influenced polyphenol profiles with usually a higher content of phenolic compounds in older plants and changed the production of individual polyphenols of both non-AM and AM plants under non-stress and salt stress conditions. A better understanding of factors (involving mycorrhiza and salinity) affecting the phenolic compounds of E. prostrata facilitates the optimization of individual polyphenol production in this medicinal plant.