Hao Wang

Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion (I/R) injury. However, whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown. Here, we show that the downregulation of serum Wnt2 levels in acute myocardial infarction (AMI) patients following reperfusion therapy, and Wnt2 levels are inversely correlated with the levels of myocardial injury markers (cTnT and CK-MB). Therapeutic administration of recombinant Wnt2 protein (rbWnt2) alleviates cardiac I/R injury and improves cardiac function by suppressing ROS levels and cardiomyocyte death in mice. Further analysis revealed that rbWnt2 downregulated Nap1L1 to reactivate the transcription of antioxidant genes (SOD, GPX, and UCP3) to reduce ROS levels and subsequently inhibit cardiomyocyte apoptosis and ferroptosis during the I/R process. Cardiac-specific Nap1L1 knockdown attenuated I/R injury, whereas overexpression of Nap1L1 partly abolished the cardiac protection mediated by rbWnt2 administration in the I/R model. Mechanistically, Wnt2 promoted Nap1L1 ubiquitination and degradation to restore ROS scavenging systems via Lrp6-mediated recruitment of the E3 ligase Trim11 in I/R hearts. Nap1L1 suppression plays a critical role in mediating the cardioprotective effects of rbWnt2. These findings establish Wnt2 as a therapeutic agent that targets compartmentalized oxidative damage, suggesting a novel strategy to mitigate I/R injury through the Lrp6/Trim11/Nap1L1 axis.

Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper‐dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinoma (HCC). In this study, PLB showed HCC‐suppressive activities and caused representative molecular phenotypes of cuproptosis, whereas tetrathiomolybdate, an inhibitor of cuproptosis, could alleviate these effects the most. The mRNA and protein expression levels of the primary hepatic copper exporter, ATPase copper transporting beta (ATP7B), decreased in PLB‐treated HCC cells, which might cause the accumulation of intracellular copper and trigger cuproptosis. An upstream ATP7B‐regulatory microRNA, microRNA‐302a‐3p (miR‐302a‐3p), was identified by quantification and validated by the overexpression/inhibition experiment and luciferase reporter assay. Moreover, PLB was found to reduce the protein level of DNA‐methyltransferase 1 (DNMT1), thereby enhancing the promoter hypomethylation and the expression of miR‐302a‐3p. Gene manipulation experiments further demonstrated that ATP7B, miR‐302a‐3p, and DNMT1 mediated PLB‐induced cuproptosis. Preliminary clinical analyses showed that low ATP7B expression levels were associated with better prognosis, supporting the importance of ATP7B‐lowering therapeutic strategies in HCC. Together, our results indicate that PLB triggers HCC cuproptosis via the DNMT1/miR‐302a‐3p/ATP7B axis, providing a potential therapeutic strategy for HCC.

BACKGROUND: The effectiveness and safety of opioid-free anesthesia (OFA) regimens in distinct types of surgeries remain controversial. In this study, we investigated whether OFA could reduce the occurrence of chronic postoperative pain in patients receiving video-assisted thoracoscopic surgery (VATS). METHODS: We conducted a 2-center, randomized, controlled trial from September 2021 to January 2022. A total of 162 lung tumor patients scheduled to undergo VATS were randomly divided into an opioid-based anesthesia (OA) group and an OFA group. The OA group received general anesthesia combined with thoracic epidural block using morphine, while the OFA group received general anesthesia combined with thoracic epidural block using esketamine. Patient-controlled epidural analgesia (PCEA) was used after surgery (ropivacaine and morphine for the OA group versus ropivacaine and esketamine for the OFA group). The primary end point was chronic pain rates at 3 months after VATS, which were analyzed using a logistic regression model. The secondary end points were chronic pain rates at 6 months, acute pain rates at 24 hours and 48 hours postoperatively, postoperative side effects, and perioperative variables. RESULTS: The final analysis included 159 patients. Acute postoperative pain at 24 hours occurred in 0 of the 79 (0%) patients in the OA group and 10 of the 80 (17.5%) patients in the OFA group (odds ratio, 52.14; 95% confidence interval [CI], 6.47–420.10; P < .001). Acute postoperative pain at 48 hours occurred in 3 of the 79 (3.8%) patients in the OA group and 2 of the 80 (2.5%) patients in the OFA group (odds ratio, 2.07; 95% CI, 0.99–4.32; P = .053). In this study, none of the patients had moderate or severe pain in either group at 3 and 6 months postsurgically. Mild chronic postoperative pain at 3 months occurred in 27 of the 79 (34.2%) patients in the OA group and 14 of the 80 (17.5%) patients in the OFA group (odds ratio, 3.52; 95% CI, 1.49–8.31; P = .004). At 6 months, mild chronic pain still occurred in 23 of the 79 (29.1%) patients in the OA group and 9 of the 80 (11.3%) patients in the OFA group (odds ratio, 5.55; 95% CI, 2.01–15.33; P = .001). In addition, the OFA group included fewer patients with side effects, including nausea, vomiting, and pruritus, within 48 hours after surgery. CONCLUSIONS: Replacement of opioids by esketamine, intraoperatively as intravenous injection and epidural infusion and postoperatively as epidural infusion, reduces the incidence of mild chronic postoperative pain and side effects in patients after VATS.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide. Ferroptosis is emerging as an effective target for tumor treatment as it has been shown to potentiate cell death in some malignancies. However, it remains unclear whether histone phosphorylation events, an epigenetic mechanism that regulates transcriptional expression, are involved in ferroptosis. Our study found that supplementation with anisomycin, an agonist of p38 mitogen‐activated protein kinase (MAPK), induced ferroptosis in HCC cells, and the phosphorylation of histone H3 on serine 10 (p‐H3S10) was participated in anisomycin‐induced ferroptosis. To investigate the anticancer effects of anisomycin‐activated p38 MAPK in HCC, we analyzed cell viability, colony formation, cell death, and cell migration in Hep3B and HCCLM3 cells. The results showed that anisomycin could significantly suppress HCC cell colony formation and migration and induce HCC cell death. The hallmarks of ferroptosis, such as abnormal accumulation of iron and elevated levels of lipid peroxidation and malondialdehyde, were detected to confirm the ability of anisomycin to promote ferroptosis. Furthermore, coincubation with SB203580, an inhibitor of activated p38 MAPK, partially rescued anisomycin‐induced ferroptosis. And the levels of p‐p38 MAPK and p‐H3S10 were successively increased by anisomycin treatment. The relationship between p‐H3S10 and ferroptosis was revealed by ChIP sequencing. The reverse transcription PCR and immunofluorescence results showed that NCOA4 was upregulated both in mRNA and protein levels after anisomycin treatment. And by C11‐BODIPY staining, we found that anisomycin‐induced lipid reactive oxygen species was reduced after NCOA4 knockdown. In conclusion, the anisomycin‐activated p38 MAPK promoted ferroptosis of HCC cells through H3S10 phosphorylation.

Rationale: Accumulating evidence shows that Rho-GTPase-activating proteins (RhoGAPs) exert suppressive roles in cancer cell proliferation and metastasis. However, no study has systematically investigated the clinical significance of RhoGAPs and analyzed the functions of ARHGAP24 in hepatocellular carcinoma (HCC).

Background: The purpose of this randomized controlled trial was to determine if enhanced recovery after surgery (ERAS) would improve outcomes for three-stage minimally invasive esophagectomy (MIE). Methods: Patients with esophageal cancer undergoing MIE between March 2016 and August 2018 were consecutively enrolled, and were randomly divided into 2 groups: ERAS+group that received a guideline-based ERAS protocol, and ERAS- group that received standard care. The primary endpoint was morbidity after MIE. The secondary endpoints were the length of stay (LOS) and time to ambulation after the surgery. The perioperative results including the Surgical Apgar Score (SAS) and Visualized Analgesia Score (VAS) were also collected and compared. Results: A total of 60 patients in the ERAS+ group and 58 patients in the ERAS- group were included. Postoperatively, lower morbidity and pulmonary complication rate were recorded in the ERAS+ group (33.3% vs. 51.7%; p = 0.04, 16.7% vs. 32.8%; p = 0.04), while the incidence of anastomotic leakage remained comparable (11.7% vs. 15.5%; p = 0.54). There was an earlier ambulation (3 [2–3] days vs. 3 [3–4] days, p = 0.001), but comparable LOS (10 [9–11.25] days vs. 10 [9–13] days; p = 0.165) recorded in ERAS+ group. The ERAS protocol led to close scores in both SAS (7.80 ± 1.03 vs. 8.07 ± 0.89, p = 0.21) and VAS (1.74 ± 0.85 vs. 1.78 ± 1.06, p = 0.84). Conclusions: Implementation of an ERAS protocol for patients undergoing MIE resulted in earlier ambulation and lower pulmonary complications, without a change in anastomotic leakage or length of hospital stay. Further studies on minimizing leakage should be addressed in ERAS for MIE.