Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets—“Sand Out and Gold Stays”

Abstract

To determine whether the expression of histone modification enzymes is regulated in physiological and pathological conditions, we took an experimental database mining approach pioneered in our labs to determine a panoramic expression profile of 164 enzymes in 19 human and 17 murine tissues. We have made the following significant findings: 1) Histone enzymes are differentially expressed in cardiovascular, immune and other tissues; 2) Our new pyramid model showed that heart and T cells are among a few tissues in which histone acetylation/deacetylation, histone methylation/demethylation are in the highest varieties; and 3) Histone enzymes are more downregulated than upregulated in metabolic diseases and Treg polarization/differentiation, but not in tumors. These results have demonstrated a new working model of “sand out and gold stays,” where more downregulation than upregulation of histone enzymes in metabolic diseases makes a few upregulated enzymes the potential novel therapeutic targets in metabolic diseases and Treg activity.

Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study

“…As shown in Table 8, analyzing of four microarray datasets revealed [44] that the ratios of downregulated caspase-1 substrates versus upregulated substrates were 5/2, 3/3, and 8/4, suggesting that the caspase-1 substrates downregulated in anti-inflammatory/immune suppressive Tregs [45] may be pro-inflammatory in the pathogenesis of coronary heart disease.…”

Low-Intensity Ultrasound-Induced Anti-inflammatory Effects Are Mediated by Several New Mechanisms Including Gene Induction, Immunosuppressor Cell Promotion, and Enhancement of Exosome Biogenesis and Docking

“…Determination of the novel molecular mechanisms underlying the anti-inflammatory properties of LIUS would significantly improve our understanding on this important issue and allow for the development of LIUS-based therapeutics. To fill in this important knowledge gap, in this study, we used cutting-edged molecular database mining approaches we pioneered in 2004 (Ng et al, 2004 ; Yin et al, 2009 ; Li et al, 2012 ; Shao et al, 2016 ). Our data analysis revealed the following significant findings which we have also elaborated in Figure 11 : (1) anti-inflammatory effects of LIUS are mediated by upregulation of anti-inflammatory gene expression; (2) LIUS upregulates the markers and master genes of immunosuppressor cells such as MDSCs, MSCs, B1-B cells and Treg; (3) LIUS not only can be used as novel therapeutic approaches to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4) LIUS induces the expression of extracellular vesicle/exosome biogenesis mediators and extracellular vesicle/exosome docking mediators; (5) The majority of top pathways are not shared between LIUS-induced anti-inflammatory genes and LIUS-induced immunosuppressor cell markers, suggesting that LIUS uses multiple cellular sensors-linked transcription pathways; and (6) anti-inflammatory cytokines and anti-inflammatory miRs in exosomes inhibit inflammation of target cells via multiple shared and specific pathways.…”

“…We have utilized a well-established data mining strategy that we originally reported in 2004 (Ng et al, 2004 ; Yin et al, 2009 ; Li et al, 2012 ; Shao et al, 2016 ) to identify the potential molecular mechanisms that are responsible for exerting anti-inflammatory effects of ultrasound (Figure 1 ).…”

Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells

“…We consolidated this working model by demonstrating that LPLs “transform” resting endothelial cells (ECs) to conditional innate immune cells 22 via caspase-1 activating-sirtuin 1 inhibiting pathway 23 . In addition, we found that in addition to post-translationally activating inflammasome, long-term low dose cardiovascular disease risk factors such as LPLs are required for transcriptionally upregulating low levels of or missing inflammasome components in order to elicit inflammatory responses 6 , presumably via histone modifications 24 and noncoding RNAs regulation 25, 26 .…”