In recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.

The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo . Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy.

The polyphenolic extract of Ilex latifolia (PEIL) exhibits a variety of biological activities. An evaluation of the parameters influencing the ultrasonic extraction process and the assessment of PEIL antioxidant activity are presented herein. Response surface methodology (RSM) was used to optimize the experimental conditions for the polyphenols ultrasonic-assisted extraction (UAE) from the leaves of Ilex latifolia. We identified the following optimal conditions of PEIL: ethanol concentration of 53%, extraction temperature of 60 °C, extraction time of 26 min and liquid–solid ratio of 60 mL/g. Using these parameters, the UAE had a yield of 35.77 ± 0.26 mg GAE/g, similar to the value we predicted using RSM (35.864 mg GAE/g). The antioxidant activity of PEIL was assessed in vitro, using various assays, as well as in vivo. We tested the effects of various doses of PEIL on D-galactose induced aging. Vitamin C (Vc) was used as positive control. After 21 days of administration, we measured superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, malondialdehyde (MDA) levels in mouse serum and liver tissue. The results demonstrated that the PEIL exhibits potent radical scavenging activity against 1,1-diphenyl-2-picrythydrazyl (DPPH∙), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS+), and hydroxyl (∙OH) radicals. The serum concentrations of SOD and GSH-Px were higher, and MDA levels were lower, in the medium- and high-dose PEIL-treated groups than those in the aging group (p < 0.01), and the activity of MDA was lower than those of the model group (p < 0.01). The liver concentrations of SOD and GSH-Px were higher (p < 0.05), and MDA levels were lower, in the medium- and high-dose PEIL-treated groups than those in the aging control group (p < 0.01). These results suggest that optimizing the conditions of UAE using RSM could significantly increase the yield of PEIL extraction. PEIL possesses strong antioxidant activity and use as a medicine or functional food could be further investigated.

With the development of marine business, the diversification of marine business has produced more and more delay-sensitive and computing-intensive tasks, and the demand for marine communication is becoming more and more obvious. Establish a task offloading model between ship users, select offload nodes based on the connectivity probability between ship users, in order to alleviate the problem of data congestion during transmission, use orthogonal frequency division multiple access technology to divide channels, and propose subtasks and Algorithm for subchannel matching. Ship users use solar energy to supply energy, and propose a penalty strategy for insufficient energy collection and a penalty strategy for task delay, so that the system can minimize the actual energy consumption and establish an objective function under the condition of satisfying the delay constraint. The local transmit power is optimized, and the gray wolf optimization algorithm is improved to obtain a better data offloading ratio. The simulation results of EdgeCloudSim show that, compared with other methods, the proposed method can achieve the best performance while guaranteeing the delay.

N-methyladenosine (m6A) is the abundant RNA modification in colorectal cancer. However, the biological significance of m6A methylation of LncRNA CARMN remains unknown in colorectal cancer, especially for mutant p53 Gain-of-function. Here, we found that CARMN reduced in the colorectal cancer patients with mutant p53, due to its rich m6A methylation, which promotes cancer proliferation, invasion, and metastasis in vitro and in vivo. Deeper investigation illustrates that ALKBH5 directly demethylated m6A level of CARMN at 477 sites, which maintains CARMN with a higher expression level. However, mutant p53 binds to the promoter of ALKBH5 to prevent its transcription, results in the high level m6A methylation of CARMN, subsequently read by YTHDF2/YTHDF3 and degraded. Meantime, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. In addition, miR-5683 was identified as a direct downstream target of LncRNA CARMN, which plays anti-tumor effect through cooperating with CARMN to down-regulate FGF2 expression. Our study revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, which may highlight a demethylation-based approach for the diagnosis and therapy of cancer.