JAC4 Protects from X-ray Radiation-Induced Intestinal Injury by JWA-Mediated Anti-Oxidation/Inflammation Signaling

Abstract

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.

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease

“…JAC4, a compound synthesized by our collaborator Prof. Zhou in his laboratory to increase JWA expression [ 21 ], demonstrated a dose-dependent upregulation of JWA expression in primary neurons ( Fig. 5 A–C).…”

“…To evaluate the potential of JWA as a therapeutic target for PD, we employed JAC4, a compound designed to activate JWA by enhancing its expression [ 21 ]. JAC4 treatment demonstrated effectiveness in elevating JWA expression across various tissues, encompassing the intestine, lung, and brain [ 21 , 38 , 39 ].…”

“…To evaluate the potential of JWA as a therapeutic target for PD, we employed JAC4, a compound designed to activate JWA by enhancing its expression [ 21 ]. JAC4 treatment demonstrated effectiveness in elevating JWA expression across various tissues, encompassing the intestine, lung, and brain [ 21 , 38 , 39 ]. In line with these observations, our study revealed a significant increase in JWA expression in primary neurons and the midbrain of mice upon JAC4 treatment.…”

“…After a 1-week rest, motor symptom evaluation through behavioral tests was conducted, and samples were collected. JAC4 was provided by our collaborator, Prof Jianwei Zhou [ 21 ]. Throughout this period, JAC4 was administered intragastrically at doses of 25, 50, and 100 mg/kg per day.…”

JAC4 Inhibits EGFR-Driven Lung Adenocarcinoma Growth and Metastasis through CTBP1-Mediated JWA/AMPK/NEDD4L/EGFR Axis

“…To determine whether the agonists of the JWA gene can selectively activate the expression of JWA in lung-cancer cells, two small-molecular compound agonists, JAC1 [30] and JAC4 [31] (Figure S2A), were used in experimental models. Considering the tumor heterogeneity and drug sensitivity, the subcutaneous tumor-bearing model was first constructed to screen for a better tumor-inhibition effect in lung cancer.…”