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Hydrogen has been used to suppress tumor growth with considerable efficacy. Inhalation of hydrogen gas and oral ingestion of hydrogen-rich saline are two common systemic routes of hydrogen administration. We have developed a topical delivery method of hydrogen at targeted sites through the degradation of magnesium-based biomaterials. However, the underlying mechanism of hydrogen's role in cancer treatment remains ambiguous. Here, we investigate the mechanism of tumor cell apoptosis triggered by the hydrogen released from magnesium-based biomaterials. We find that the localized release of hydrogen increases the expression level of P53 tumor suppressor proteins, as demonstrated by the in vitro RNA sequencing and protein expression analysis. Then, the P53 proteins disrupt the membrane potential of mitochondria, activate autophagy, suppress the reactive oxygen species in cancer cells, and finally result in tumor suppression. The anti-tumor efficacy of magnesium-based biomaterials is further validated in vivo by inserting magnesium wire into the subcutaneous tumor in a mouse. We also discovered that the minimal hydrogen concentration from magnesium wires to trigger substantial tumor apoptosis is 91.2 μL/mm3 per day, which is much lower than that required for hydrogen inhalation. Taken together, these findings reveal the release of H2 from magnesium-based biomaterial exerts its anti-tumoral activity by activating the P53-mediated lysosome-mitochondria apoptosis signaling pathway, which strengthens the therapeutic potential of this biomaterial as localized anti-tumor treatment., Graphical abstract Image 1, Highlights • The feasibility of using Mg implants is explored for localized delivery of hydrogen against colorectal tumors. • This approach is advantageous over conventional chemotherapy/H2 inhalation due to the portability, high H2-loading capacity and efficient delivery of H2 gas to tumors. • We provide a molecularly detailed and mechanistic understanding of how H2 could activate the antitumor pathway above certain threshold concentrations of H2, which inspires more effective therapy against tumors.

Little attention has been paid to the biocompatibility and biological effects of zinc as a material. Here, we therefore investigated the biocompatibility and anti-inflammatory and collagen-promoting effects of pure zinc material in the colorectum. Our in vitro results indicated that zinc toxicity and concentration were closely related. Low concentrations of zinc ions and pure zinc material extract had only minor effects on the viability of primary rectal mucosal epithelial cells; however, cytotoxicity was observed at concentrations greater than 0.017 μg/μL and 60%, respectively. In vivo experiments demonstrated that zinc pins degraded slowly in the colorectum (their volume decreasing by approximately 7.79% over 1 month) and did not cause serious adverse reactions. Pure zinc material was found to inhibit acute inflammation through increased expression of ENA-78 and F4/80. Moreover, zinc material heightened expression of collagen and VEGF, factors conducive to wound healing, in surrounding colorectal tissues. These preliminary results suggest that zinc shows great promise as an implant material for medical applications involving colorectal surgery.

Hao Wang,1,2,* Xuhui Ge,1,3,* Huiheng Qu,1,2,* Ning Wang,1,2 Jiawen Zhou,4 Wenjing Xu,1,2 Jingjing Xie,1,2 Yongping Zhou,1,2 Liqing Shi,1 Zhongke Qin,1 Zhuang Jiang,1,2 Wenjie Yin,1 Jiazeng Xia1,2 1Department of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu, People’s Republic of China; 2Department of General Surgery, Wuxi Clinical College Affiliated to Nantong University, Wuxi 214002, Jiangsu, People’s Republic of China; 3Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China; 4The State Key Laboratory of Reproductive Medicine; Key Laboratory for Aging & Disease, Research Centre for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiazeng XiaDepartment of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, 68, Zhong Shan Road, Wuxi 214002, Jiangsu, People’s Republic of ChinaEmail jiazengxia@yahoo.comPurpose: Glycyrrhizic acid (GA) is the main active ingredient extracted from Chinese herb licorice root, and it shows anti-tumor effects in many cancer types, while its role in gastric cancer (GC) is still unknown. In this study, we evaluated the effects of GA on GC cells and explored the underlying mechanisms.Methods: The anti-proliferation effect of GA on GC cells was assessed by CCK-8, colony formation, and EdU assay. The effects of GA on cell cycle and apoptosis were detected by flow cytometer. Western blotting was performed to explore the underlying mechanisms.Results: Our results showed thatGA had a time- and dose-dependent inhibitory effect on proliferation of GC cells. Flow cytometer analysis demonstrated thatGA would lead to G1/S-phase arrest and apoptosis. GA treatment down-regulated the levels of G1 phase-related proteins, including cyclin D1, D2, D3, E1, and E2. In terms of apoptosis, GA treatment up-regulated thelevels of Bax, cleaved PARP, and pro-caspase-3, -8, -9, but did not influence their cleavage patterns. The expression of Bcl-2, survivin and p65 was attenuated after treatment. Besides, GA would down-regulate the phosphorylation of PI3K/AKT pathway.Conclusion: This study focused on inhibitory effect of GA on GC cells by inducing cell cycle arrest and apoptosis. Several important cyclins- and apoptosis-related proteins were involved in the regulation of GA to GC cells, and phosphorylated PI3K and AKT were attenuated. The results of this study indicated that GA is a potential and promising anti-cancer drug for GC.Keywords: glycyrrhizic acid, gastric cancer, cell cycle, apoptosis, PI3K/AKT pathway

Background: UCH-L1 has been implicated to playing a potential role in cancer development and progression. However, UCH-L1’s role in hilar cholangiocarcinoma remains unclear. Methods: The function of UCH-L1 in hilar cholangiocarcinoma was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. Results: In the present study, UCH-L1 was overexpressed in 62.1% of patients with primary hilar cholangiocarcinoma. Overexpression of UCH-L1 is associated with large tumor size, advanced tumor stage, lymph node metastasis, advanced TNM stage, and high CA19-9 levels, and is also correlated with poor survival rates. Silencing of UCH-L1 inhibited proliferation, colony formation of hilar cholangiocarcinoma cells in vitro and suppressed tumor growth of hilar cholangiocarcinoma cells in vivo. We also observed that silencing of UCH-L1 decreased the phosphorylation level of Akt and PCNA in the xenograft experiments. Discussion: Taken together, these findings suggest that UCH-L1 functions as an oncogene in the development and progression of hilar cholangiocarcinoma. UCH-L1 can serve as an independent prognostic factor and maybe a potential therapeutic target for patients with hilar cholangiocarcinoma.