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.
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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.
Since the first report of epidermal growth
factor (EGF) in 1962, research on intracellular signaling through its receptor
EGFR has greatly advanced. While the canonical activation of EGFR via tyrosine
phosphorylation is well understood, the existence of a non-canonical activation
via p38-dependent phosphorylation of serine/threonine residues has recently
attracted attention. The authors have found that both of these mechanisms occur
in parallel and are now analyzing them as a dual-mode activation model. This
review summarizes new advances in EGFR signaling research and the latest status
of EGFR inhibitor development for molecular targeted therapy of lung cancer.
Human
immunodeficiency virus type 1 (HIV-1) hijacks various cellular machinery to
achieve efficient replication. HIV-1 infection induces a metabolic shift towards
aerobic glycolysis as a cellular response to maintain homeostasis, yet the
virus continues to replicate efficiently under these conditions. In this
review, the authors introduce the regulatory role of glycolytic enzymes in
HIV-1 replication and the impact of aerobic glycolysis on viral infection. In
addition, the authors propose a novel strategy to eradicate latently
HIV-1-infected cells.
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Nonalcoholic steatohepatitis (NASH)
is a serious form of nonalcoholic fatty liver disease (NAFLD) that can lead to
liver damage and inflammation. In this study, the authors focused on the
therapeutic effects of emodin succinyl ethyl ester (ESEE) on NASH using a
murine model induced by Special tailored diet. After four weeks of ESEE
treatment, researchers observed significant improvements in glycolipid
metabolism disorders, liver injury, and histopathological features of
NAFLD/NASH. ESEE showed effectiveness in reducing cellular steatosis,
inflammation, fat deposition in hepatocytes, and liver fibrosis in the model
mice. These findings suggest that ESEE could serve as a novel therapeutic agent
for NASH, providing protection against diet-induced liver abnormalities and
injuries.
Exposure
of animals to the enriched environments improves memory consolidation that
requires extracellular ripples generated in the hippocampus during sleep.
Natural sleep and general anesthesia are similar in terms of extracellular
oscillations. However, whether the preexposure of animals to the enriched
environment modulates neural activity in the hippocampus under subsequent
anesthesia is not fully understood. The authors allowed mice to explore the
enriched or standard environment, anesthetized them, and recorded local field
potentials in the hippocampus, demonstrating that the amplitude of ripples and
the number of successive ripples were larger in the novel enriched environment
group.
Carbon monoxide (CO) exhibits versatile bioactivities; its preventive effect on the progression of ischemia-reperfusion injury in various organs has been reported. The authors developed CO-bound red blood cells (CO-RBC) as a bioinspired CO delivery donor and investigated the therapeutic potential of CO-RBC against ischemia-reperfusion injury in the hind limbs of rats. As a result, CO-RBC alleviated the skeletal muscle injury and systemic inflammation following ischemia-reperfusion in the rat model. The present study significantly contributes to the advancement of CO-based therapeutic strategies for treating skeletal muscle ischemia-reperfusion injury.
HER2 overexpression is observed in 15-20% of breast cancers and is associated with an aggressive phenotype and poor prognosis. Trastuzumab is the primary treatment for HER2-positive breast cancers. However, trastuzumab resistance is often observed, highlighting the need for novel therapeutic approaches to improve clinical benefits. This study showed that Maitake beta-glucan MD-Fraction enhanced the therapeutic effect of trastuzumab in HER2-positive xenograft models. MD-Fraction enhances trastuzumab-induced antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. These findings suggest that the combination of trastuzumab and MD-Fraction could be beneficial for the treatment of HER2-positive breast cancer.
Lactate transport via monocarboxylate transporters (MCTs) in the central nervous system is crucial for the memory formation. The present study aimed to identify transporters that contribute to lactate transport in differentiated human neuroblastoma SH-SY5Y cells, which are used as a model for neurons. Kinetic analysis suggested that lactate transport was biphasic. Selective inhibitors for MCT1 and MCT2 significantly inhibited lactate transport. Therefore, the authors found that MCT1 and MCT2 are major contributors to lactate transport in differentiated SH-SY5Y cells. These results lead to a better understanding of the involvement of MCTs in the memory formation and central nervous system disease.
This study examined the pathological mechanisms in the small intestine and the aging effects using a mouse model of type 2 diabetes (KK-Ay/TaJcl) aged 10 and 50 weeks. The results showed that Advanced glycation end products (AGEs) and mast cell expression increased, whereas diamine oxidase (DAO) decreased in the small intestine with age. Increased TNF-α and histamine levels occurred in plasma and the small intestine. The cell adhesion molecules ZO-1 and claudin-1 expression decreased in the small intestine. These findings may explain the pathological mechanisms and complications of type 2 diabetes.
[Highlighted Paper selected
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Angiotensin II is known to be an important factor
in the development of chronic heart failure. The authors showed that
angiotensin II is involved in the induction of necroptosis, a type of
programmed necrosis-like cell death, during the development of heart failure in
rats following myocardial infarction and in cultured cells. This finding
suggests a new mechanism of action for angiotensin II inhibitors and is
expected to contribute to a novel therapeutic strategy for heart failure by
targeting necroptosis.
[Highlighted Paper selected
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The study
examined which cells are responsible for
responding to the LNPs used in the approved COVID-19 mRNA vaccine. In this
study, the authors incubated immortalized
mouse lymphatic endothelial cells (mLECs) or professional antigen presenting
cells (APCs) such as RAW 264.7 monocyte/macrophage cells with SM-102 LNPs that contained no
mRNA. As a result, chemokines involved in the recruitment of
monocytes/neutrophils were produced only by the mLECs following the empty LNP
treatment. These findings indicate that LECs appear to serve as the cells that
send out initial signals to response LNPs.
Mitochondrial dysfunction is recognized as a key factor in the pathological progression of age-related macular degeneration (AMD) and can disrupt the balance of intracellular metabolic pathways (e.g., oxidative phosphorylation and glycolysis). The authors focused on oxidized low-density lipoprotein (ox-LDL), reported to a primary component accumulated in the retina of AMD patients, and elucidated its effect on metabolic alterations with increased mitochondrial reactive oxygen species production in retinal pigment epithelial cells. It was discovered that prolonged exposure to ox-LDL is crucial for the induction of these metabolic alterations. These significantly contribute to understanding the mechanisms underlying AMD metabolic alterations.
Management of chemotherapy-induced nausea and vomiting (CINV) after delayed periods presents a significant challenge in cancer chemotherapy. This study represents the first attempt to compare the administration of fosnetupitant (F-NTP), fosaprepitant (F-APR), or aprepitant (APR) from 0 to 168 hours following the initial doses of cisplatin-based regimens. The authors demonstrated that F-NTP was significantly more effective than F-APR and APR in reducing CINV after anticancer drug administration from 0 to 168 hours, without significant side effects. The efficacy of F-NTP was particularly effective in the beyond-delayed periods (120-168 hours), which is the focus of attention of the revised Japanese antiemetic guidelines.
The authors mainly investigated the risk factors and preventive strategies of cetuximab-induced hypomagnesemia in head and neck cancer (HNC) patients. Their results indicated that a low pre-treatment serum magnesium level emerges as the only risk factor, and this risk can be effectively mitigated through intravenous prophylactic magnesium sulfate administration from initiating cetuximab treatment. This preventive intervention exhibits minimal adverse events and is thus recommended for managing cetuximab-induced hypomagnesemia. Given that cetuximab interruption due to adverse events directly impacts prognosis, the insights gleaned from their study hold significant relevance for the optimal care of HNC patients undergoing cetuximab treatment.
Diabetes patients are well-known to exhibit alteration of taste sensitivity, but the alteration profiles have not been clarified in detail yet. In brief-access tests with a mixture of sucrose and quinine hydrochloride, the lick ratios of control, but not non-insulin-dependent diabetes mellitus (NIDDM)-model, rats for the mixture and quinine hydrochloride solutions decreased aging-dependently. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. These findings suggested that control, but not NIDDM-model, rats exhibited an aging-dependent increase of bitter taste sensitivity with alteration of gut microbiota.
(-)-Epigallocatechin-3-gallate (EGCg) is known to upregulate neprilysin, an Aβ-degrading enzyme. To clarify the mechanism underlying this process, the authors screened catechin-binding proteins by pull-down assay with magnetic beads and LC-tandem mass spectrometry and identified synaptic vesicle membrane protein VAT-1 homolog (VAT1). Surface plasmon resonance analysis revealed a direct binding of recombinant VAT1 protein to EGCg or its alkylated derivative NUP-15 with comparable affinity to the other EGCg binding proteins reported previously. Furthermore, the authors found that VAT1 prevented the upregulation of neprilysin by EGCg or NUP-15 through binding to and inactivating them in the cells overexpressing VAT1.