S-Nitrosylation
of DNA methyltransferase (DNMT) inhibits its enzymatic activity, resulting in
DNA hypomethylation and aberrant gene expression related to its pathogenesis.
The authors demonstrated that nitric oxide epigenetically induces CA9
expression in human small airway epithelial cells through pharmacological
evaluation using DBIC, a specific inhibitor of DNMT3B S-nitrosylation. Hypoxia-inducible
factor 1 alpha (HIF1α) is recruited to the CA9 promoter region via
nitric oxide-induced epigenetic regulation. These findings indicate that nitric
oxide is a key epigenetic regulator in normal human cells.
Transcriptional
activation of endogenous genes using clustered regularly interspaced short
palindromic repeats activation (CRISPRa) is an excellent tool not only for biological
research but also for treatment of diseases. The authors have successfully upregulated
three endogenous genes encoding phosphoinositide phosphatases using the CRISPRa
system targeting multiple promoter sites. The effects of gene upregulation on
autophagy, a potential therapeutic target for various diseases, were investigated.
The results showed that TMEM55A/PIP4P2, a phosphatidylinositol-4,5-bisphosphate
4-phosphatase, promotes autophagosome formation. It was also revealed that TMEM55B/PIP4P1
and SAC1 are involved in autolysosome formation.
The increasing
number of patients with depressive disorder is a serious socioeconomic problem
worldwide, and effectiveness of several therapeutic agents used clinically is
insufficient and thus discovery of novel therapeutic targets is desired. Focusing
on dysregulation of neuronal purinergic signaling in depressive-like behavior, Nishioka
et al. revealed that in astrocytes derived from cerebral cortex of
chronic social defeat stress-susceptible mice, the expression levels of mRNAs
for connexin 43 and P2X7 receptors were inversely correlated with mouse
sociability. Together with recent findings, it is suggested that ATP channels
expressed by cortical astrocytes might be potential therapeutic targets for
depressive disorder.
[Highlighted Paper selected
by Editor-in-Chief]
This
study revealed the gene
expression profiles of bicellular and tricellular tight junction components in
different segments of the human intestinal tract. Claudin-8, angulin-1
and -2 could be potential targets for intestinal permeation enhancers in the
rectum. Claudin-2 and -15 may serve as targets for drug absorption enhancers in
the upper intestine. Claudin-7, occludin, and tricellulin appear to be suitable
targets for enhancing drug absorption throughout all intestinal segments.
Furthermore, claudin-3, -4, and -7 modulators seem to be the most potent
intestinal permeation enhancers. Thus, this study provides valuable insights
for the development of intestinal drug permeation enhancers.
Understanding the
mechanisms behind the induction or inhibition of CYP enzymes, which are pivotal
for drug metabolism, is essential for predicting drug-drug interactions (DDI). In
this study, the authors demonstrate that omeprazole, a well-known inducer of
CYP1A2, not only increased CYP1A2 mRNA expression but also
elevated CYP3A4 mRNA levels. However,
omeprazole treatment did not lead to an increase in CYP3A4 protein levels
because it caused the CYP3A4 protein to degrade more quickly. These
findings suggest that evaluating CYP protein degradation, in addition to CYP
induction and inhibition, is crucial for more accurate DDI predictions.