Biological function molecular pathways and druggability of DNMT2/TRDMT1.

5-methylcytosine (m5C) is among the most common epigenetic modification in DNA and RNA molecules, and plays an important role in the animal development and disease pathogenesis. Interestingly, unlike other m5C DNA methyltransferases (DNMTs), DNMT2/TRDMT1 has the double-substrate specificity and adopts a DNMT-similar catalytic mechanism to methylate RNA. Moreover, it is widely involved in a variety of physiological regulatory processes, such as the gene expression, precise protein synthesis, immune response, and disease occurrence. Thus, comprehending the epigenetic mechanism and function of DNMT2/TRDMT1 will probably provide new strategies to treat some refractory diseases. Here, we discuss recent studies on the spatiotemporal expression pattern and post-translational modifications of DNMT2/TRDMT1, and summarize the research advances in substrate characteristics, catalytic recognition mechanism, DNMT2/TRDMT1-related genes or proteins, pharmacological application, and inhibitor development. This review will shed light on the pharmacological design by targeting DNMT2/TRDMT1 to treat parasitic, viral and oncologic diseases.

LAMP1 controls CXCL10-CXCR3 axis mediated inflammatory regulation of macrophage polarization during inflammatory stimulation.

Increased expression of CXCL10 and its receptor CXCR3 represents an inflammatory response in cells and tissues. Macrophage polarization and autophagy are major functions in inflammatory macrophages; however, the cellular functions of the CXCL10-CXCR3 axis in macrophages are not well understood. Here, we examined the role of CXCL10-CXCR3-axis-regulated autophagy in macrophage polarization. First, in non-inflammatory macrophages, whereas CXCL10 promotes M2 polarization and inhibits M1 polarization, CXCR3 antagonist AMG487 induces the opposite macrophage polarization. Next, CXCL10 promotes the expression of autophagy proteins (Atg5-Atg12 complex, p62, LC3-II, and LAMP1) and AMG487 inhibits their expression. Knockdown of LAMP1 by short interfering RNA switches the CXCL10-induced polarization from M2 to M1 in non-inflammatory macrophages. Furthermore, in inflammatory macrophages stimulated by poly(I:C), CXCL10 induces M1 polarization and AMG487 induces M2 polarization in association with a decrease in LAMP1. Finally, AMG487 alleviates lung injury after poly(I:C) treatment in mice. In conclusion, CXCL10-CXCR3 axis differentially directs macrophage polarization in inflammatory and non-inflammatory states, and autophagy protein LAMP1 acts as the switch controlling the direction of macrophage polarization by CXCL10-CXCR3.

ACE2 improves endothelial cell function and reduces acute lung injury by downregulating FAK expression.

Endothelial cell (EC) barrier dysfunction and increased adhesion of immune inflammatory cells to ECs crucially contribute to acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2) is an essential regulator of the renin-angiotensin system (RAS) and exerts characteristic vasodilatory and anti-inflammatory effects. SARS-COV-2 infects the lungs by binding to ACE2, which can lead to dysregulation of ACE2 expression, further leading to ALI with predominantly vascular inflammation and eventually to more severe acute respiratory distress syndrome (ARDS). Therefore, restoration of ACE2 expression represents a valuable therapeutic approach for SARS-COV-2-related ALI/ARDS. In this study, we used polyinosinic-polycytidylic acid (Poly(I:C)), a double-stranded RNA analog, to construct a mouse ALI model that mimics virus infection. After Poly(I:C) exposure, ACE2 was downregulated in mouse lung tissues and in cultured ECs. Treatment with DIZE, an ACE2-activating compound, upregulated ACE2 expression and relieved ALI in mice. DIZE also improved barrier function and reduced the number of THP-1 monocytes adhering to cultured ECs. Focal adhesion kinase (FAK) and phosphorylated FAK (p-FAK) levels were increased in lung tissues of ALI mice as well as in Poly(I:C)-treated ECs in vitro. Both DIZE and the FAK inhibitor PF562271 decreased FAK/p-FAK expression in both ALI models, attenuating ALI severity in vivo and increasing barrier function and reducing monocyte adhesion in cultured ECs. Furthermore, in vivo experiments using ANG 1-7 and the MAS inhibitor A779 corroborated that DIZE-mediated ACE2 activation stimulated the activity of the ANG 1-7/MAS axis, which inhibited FAK/p-FAK expression in the mouse lung. These findings provide further evidence that activation of ACE2 in ECs may be a valuable therapeutic strategy for ALI.