Radiation-induced intestinal injury is one of the major side effects in patients receiving radiation therapy. There is no specific treatment for radiation-induced enteritis in the clinic. We synthesized a compound, named JAC4, which is an agonist and can increase JWA protein expression. JWA has been shown to reduce oxidative stress, DNA damage, anti-apoptosis, and anti-inflammatory; in addition, the small intestine epithelium showed dysplasia in JWA knockout mice. We hypothesized that JAC4 might exert a protective effect against radiation-induced intestinal damage. Herein, X-ray radiation models were built both in mice and in intestinal crypt epithelial cells (IEC-6). C57BL/6J mice were treated with JAC4 by gavage before abdominal irradiation (ABI); the data showed that JAC4 significantly reduced radiation-induced intestinal mucosal damage and increased the survival rate. In addition, radiation-induced oxidative stress damage and systemic inflammatory response were also mitigated by JAC4 treatment. Moreover, JAC4 treatment alleviated DNA damage, decreased cell apoptosis, and maintained intestinal epithelial cell proliferation in mice. In vitro data showed that JAC4 treatment significantly inhibited ROS formation and cell apoptosis. Importantly, all the above protective effects of JAC4 on X-ray radiation-triggered intestinal injury were no longer determined in the intestinal epithelium of JWA knockout mice. Therefore, our results provide the first evidence that JAC4 protects the intestine from radiation-induced enteritis through JWA-mediated anti-oxidation/inflammation signaling.

The intestinal epithelium is a rapid self-renewal and regenerated tissue of which the structural integrity is beneficial for maintaining health. The integrity of intestinal epithelium depends on the balance of cell proliferation, differentiation, migration, and the function of intestinal stem cells, which declines due to genetic defect or aging. Jwa participates in multiple cellular processes; it also responds to oxidative stress and repairs DNA damage. However, whether Jwa plays a role in maintaining the homeostasis of intestinal renewal and regeneration is not clear. In the present study, we firstly described that the deletion of Jwa disturbed the homeostasis of intestinal epithelial renewal and regeneration. Jwa deficiency promoted NOTCH1 degradation in the ERK/FBXW7-mediated ubiquitin-proteasome pathway, thus disturbing the PPARγ/STAT5 axis. These mechanisms might partially contribute to the reduction of intestinal stem cell function and alteration of intestinal epithelial cell lineage distribution, finally suppressing the renewal and regeneration of intestinal epithelium. Moreover, our results also revealed that Jwa was a novel putative aging related gene.

Lung adenocarcinoma (LUAD) is the most common lung cancer, with high mortality. As a tumor-suppressor gene, JWA plays an important role in blocking pan-tumor progression. JAC4, a small molecular-compound agonist, transcriptionally activates JWA expression both in vivo and in vitro. However, the direct target and the anticancer mechanism of JAC4 in LUAD have not been elucidated. Public transcriptome and proteome data sets were used to analyze the relationship between JWA expression and patient survival in LUAD. The anticancer activities of JAC4 were determined through in vitro and in vivo assays. The molecular mechanism of JAC4 was assessed by Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), ubiquitination assay, co-immunoprecipitation, and mass spectrometry (MS). Cellular thermal shift and molecule-docking assays were used for confirmation of the interactions between JAC4/CTBP1 and AMPK/NEDD4L. JWA was downregulated in LUAD tissues. Higher expression of JWA was associated with a better prognosis of LUAD. JAC4 inhibited LUAD cell proliferation and migration in both in-vitro and in-vivo models. Mechanistically, JAC4 increased the stability of NEDD4L through AMPK-mediated phosphorylation at Thr367. The WW domain of NEDD4L, an E3 ubiquitin ligase, interacted with EGFR, thus promoting ubiquitination at K716 and the subsequent degradation of EGFR. Importantly, the combination of JAC4 and AZD9191 synergistically inhibited the growth and metastasis of EGFR-mutant lung cancer in both subcutaneous and orthotopic NSCLC xenografts. Furthermore, direct binding of JAC4 to CTBP1 blocked nuclear translocation of CTBP1 and then removed its transcriptional suppression on the JWA gene. The small-molecule JWA agonist JAC4 plays a therapeutic role in EGFR-driven LUAD growth and metastasis through the CTBP1-mediated JWA/AMPK/NEDD4L/EGFR axis.

Previous studies have reported the potential developmental neurobehavioral effects of decabrominated diphenyl ethers (BDE 209) on developing animals, but the effects on adult animals are rare or controversial and the mechanism is not fully understood. In the present study, male adult Sprague-Dawley rats performed poor spatial learning and memory in Morris water maze after exposure to BDE 209 by gavage for 30 days. The expression of hippocampal glutamate receptor subunits NR1, NR2B and GluR1, the phosphorylation of NR2B subunit at Ser1301 (p-NR2B Ser1303) and GluR1 subunit at Ser831 (p-GluR1 Ser831) were all decreased, and the phosphorylation ratio of NR2B revealed an increasing trend after BDE 209 exposure. The present study provided evidence that BDE 209 could induce spatial learning and memory deficits in adult rats, and further explored the potential mechanism.

Aging usually suppresses the renewal and regeneration of intestinal epithelium. The imbalance of intestinal epithelial homeostasis may also be a promoter for aging. JWA responds to oxidative stress and repairs damaged DNA; it participates in multiple cellular processes like cell proliferation and differentiation. Here we identified JWA as a new aging-associated gene, whose deletion-accelerated aging in mice was related to intestinal epithelium atrophy. We further knocked out intestinal epithelial JWA and found it disrupted intestinal epithelial homeostasis, thus promoting aging in mice. Mechanistically, we discovered that JWA deficiency promoted Notch1 ubiquitination degradation via ERK/Fbxw7 cascade and interfered with the PPARγ/Stat5 signal axis. This reduced the intestinal stem cell function and altered the intestinal epithelial cell lineage distribution, finally suppressing the renewal and regeneration of intestinal epithelium. Our results demonstrated that JWA is a new aging-associated gene essential for the renewal and regeneration of intestinal epithelium. We also provide a new idea that maintaining intestinal epithelial homeostasis may be a potential anti-aging strategy in humans or mammals.