Identification of a novel histone H2A mono-ubiquitination-inhibiting cell-active small molecule.

Histone H2A mono-ubiquitination plays important roles in epigenetic gene expression and is also involved in tumorigenesis. Small molecules controlling H2A ubiquitination are of interest as potential chemical tools and anticancer drugs. To identify novel small molecule inhibitors of H2A ubiquitination, we synthesized and evaluated several compounds designed based on PRT4165 (1), which is a reported histone ubiquitin ligase RING1A inhibitor. We found that compound 11b strongly inhibited the viability and reduced histone H2A mono-ubiquitination in human osteosarcoma U2OS cells. Therefore, compound 11b is a promising lead compound for the development of H2A histone ubiquitination-inhibiting small molecules.

ß-aminoisobutyric acid protects against vascular inflammation through PGC-1ß-induced antioxidative properties.

BACKGROUD: Among various myocyte-derived bioactive molecules (myokines), ß-aminoisobutyric acid (BAIBA) is a unique myokine that attenuates skeletal muscle insulin resistance and inflammation, increases browning of white adipose tissue, and enhances hepatic fatty acid oxidation, resulting in upregulated energy expenditure of the whole body. In the present study, we investigated the effects of BAIBA on the vascular endothelial cell function. METHODS: The mRNA levels of proinflammatory molecules, antioxidants, and their related transcription regulators were examined by quantitative RT-PCR in BAIBA-treated human aortic or umbilical vein endothelial cells (HAEC or HUVEC, respectively), with or without tumor necrosis factor (TNF)-α stimulation. The protein expression and phosphorylation of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) were determined by Western blot analysis. RESULTS: BAIBA pretreatment significantly suppressed the mRNA levels of the adhesion molecules in the TNF-α-stimulated HAEC and HUVEC. BAIBA treatment significantly increased the mRNA levels of antioxidant molecules, catalase, superoxide dismutases, thioredoxin, and gamma-glutamylcysteine ligases, together with mitochondrial biogenesis-related molecules, nuclear respiratory factor 1, and mitochondrial transcription factor A. In addition, BAIBA treatment significantly increased the transcription factors that regulated these genes [i.e., peroxisome proliferator-activated receptor (PPAR)-δ, PPAR-γ, estrogen-related receptor α (ERRα), and peroxisome proliferator-activated receptor gamma coactivator (PGC)-1ß]. Adenovirus-mediated PGC-1ß overexpression significantly increased the mRNA levels of all antioxidant molecules. The phosphorylation levels of AMPK and eNOS were unaltered by BAIBA. CONCLUSIONS: In vascular endothelial cells, BAIBA had antiatherogenic effects through the PGC-1ß-ERRα/PPAR-δ and PPAR-γ pathway. This can explain the beneficial effects of exercise on vascular endothelial function.

ERRα Attenuates Vascular Inflammation via Enhanced NFκB Degradation Pathway.

We have previously reported that ß-aminoisobutyric acid (BAIBA), a muscle-derived exercise mimetic, had anti-inflammatory and reactive oxygen species (ROS) scavenging effects in vascular endothelial cells through the enhanced expression of peroxisome proliferator-activated receptor gamma coactivator-1ß (PGC-1ß). Although BAIBA also increased the expression of estrogen-related receptor α (ERRα), the roles of ERRα in vascular endothelial cells have yet to be fully elucidated. Here, we found that human aortic endothelial cells (HAECs) infected with ERRα-expressing adenovirus had significantly decreased mRNA levels of tumor necrosis factor α-stimulated proinflammatory molecules. However, ERRα overexpression had little effect on the mRNA levels of PGC-1ß, peroxisome proliferator-activated receptors, and almost all ROS scavenging molecules, except for superoxide dismutase 2. ERRα expression significantly decreased NFκB reporter activities in a dose-dependent manner with unaltered IκBα phosphorylation levels but with a significant increase in the mRNA levels of PDZ and LIM domain protein 2 (PDLIM2) and copper metabolism gene MURR1 domain-containing protein (COMMD1), which enhance the ubiquitination and degradation of NFκB. Also, PDLIM2 and COMMD1 mRNA levels were upregulated in BAIBA-treated HAECs. Finally, we identified the ERRα-response element in the COMMD1 promoter region (-283 to -29 bp). These results indicated that ERRα exerted anti-inflammatory effects in vascular endothelial cells through COMMD1-mediated attenuation of NFκB activity, which could be an atheroprotective mechanism of physical exercise.

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome.

The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.