Construction of charge-reversible coordination-crosslinked spherical nucleic acids to deliver dual anti-cancer genes and ferroptosis payloads.

Spherical nucleic acids (SNAs) are nanostructures with the DNA arranged radially on the surface, thus allowing specific binding with cancer cells expressing high levels of scavenger receptor-A to enhance cellular uptake. However, conventional carriers for SNAs are cytotoxic, not degradable and difficult to deliver multiple payloads. In this study, we developed charge-reversible coordination-crosslinked SNAs to deliver dual anti-cancer genes and ferroptosis payload for anti-cancer purposes. To this end, we modified poly(lactic acid) (PLA) with functionalized side chains to allow its binding with antisense oligonucleotides (ASOs) and siRNA, annealed two single-stranded RNAs to obtain double-stranded RNA, and introduced a polyethylene glycol (PEG) shell to enhance the circulation time. Additionally, the ferroptosis payload imidazole was coordinated with iron ions as a core-crosslinked group to enhance the stability of SNAs and efficiency to kill cancer cells. We demonstrated that this novel nanocomplex efficiently internalized and killed CT-26 cells in vitro. In vivo data confirmed that the dual gene delivery system successfully targeted CT-26 tumors in tumor-bearing BALB/c mice, and exhibited strong tumor suppression ability, without inducing adverse toxic effects. Taken together, our dual gene therapy system offered an enhanced anti-tumor solution by simultaneously delivering dual anti-cancer genes and ferroptosis payload in tumor microenvironment.

Dihydrotanshinone I reduces H9c2 cell damage by regulating AKT and MAPK signaling pathways.

Cardiovascular disease is the deadliest disease in the world. Previous studies have shown that Dihydrotanshinone I (DHT) can improve cardiac function after myocardial injury. This study aimed to observe the protective effect and mechanism of DHT on H9c2 cells by establishing an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model. By constructing OGD/R injury simulation of H9c2 cells in a myocardial injury model, the proliferation of H9c2 cells treated with DHT concentrations of 0.1 µmol/L were not affected at 24, 48, and 72 h. DHT can significantly reduce the apoptosis of H9c2 cells caused by OGD/R. Compared with the OGD/R group, DHT treatment significantly reduced the level of MDA and increased the level of SOD in cells. DHT treatment of cells can significantly reduce the levels of ROS and Superoxide in mitochondria in H9c2 cells caused by OGD/R and H2O2. DHT significantly reduced the phosphorylation levels of P38MAPK and ERK in H9c2 cells induced by OGD/R, and significantly increased the phosphorylation levels of AKT in H9c2 cells. DHT can significantly reduce the oxidative stress damage of H9c2 cells caused by H2O2 and OGD/R, thereby reducing the apoptosis of H9c2 cells. And this may be related to regulating the phosphorylation levels of AKT, ERK, and P38MAPK.

Short- and Long-Term Outcomes of the Minimal Proximal Resection Margin in Total Gastrectomy for Siewert II Adenocarcinoma of the Esophagogastric Junction.

OBJECTIVE: This study aimed to investigate the feasibility of the minimal proximal resection margin (PRM) in total gastrectomy (TG) for Siewert II adenocarcinoma of the esophagogastric junction (AEG). METHODS: This study finally included 178 Siewert II advanced AEG patients who underwent TG from January 2017 to September 2020. According to the PRM length, patients were divided into 20-25 mm group and 30-35 mm group. Intraoperative, short-, and long-term postoperative outcomes were compared between two groups. RESULTS: The PRM of the 20-25 mm group had significantly less operation time compared with the PRM of the 30-35 mm group (P < .001), but the amount of blood loss, management of the diaphragmatic crura, and the incidence of positive resection margin were not significantly different between two groups (P > .05). In short-term postoperative outcomes, first gas-passing time, gastric-tube removal time, start time of diet, hospitalization, postoperative complications, and body weight loss were similar between two groups (P > .05). During the follow-up, the 3-year overall survival rates and the recurrence rates were not significantly different between the PRM of 20-25 mm and 30-35 mm groups (81.2% vs 83.5%, P = .695; 18.8% vs 15.5%, P = .812, respectively). CONCLUSION: With less operation time and more preserved esophagus, the minimal PRM length of 20-25 mm could be an appropriate option in TG for patients with Siewert II advanced AEG.