NMN partially rescues cuproptosis by upregulating sirt2 to increase intracellular NADPH.

Cuproptosis is characterized by lipoylated protein aggregation and loss of iron-sulfur (Fe-S) proteins, which are crucial for a wide range of important cellular functions, including DNA replication and damage repair. Sirt2 and sirt4 are lipoamidases that remove the lipoyl moiety from lipoylated proteins using nicotinamide adenine dinucleotide (NAD+) as a cofactor. However, to date, it is not clear whether nicotinamide mononucleotide (NMN), a precursor of NAD+, affects cellular sensitivity to cuproptosis. Therefore, in the current study, cuproptosis was induced by the copper (Cu) ionophore elesclomol (Es) in HeLa cells. It was also found that Es/Cu treatment increased cellular DNA damage level. On the other hand, NMN treatment partially rescued cuproptosis in a dose-dependent manner, as well as reduced cellular DNA damage level. In addition, NMN upregulated the expression of Fe-S protein POLD1, without affecting the aggregation of lipoylated proteins. Mechanistic study revealed that NMN increased the expression of sirt2 and cellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) level. Overexpression of sirt2 and sirt4 did not change the aggregation of lipoylated proteins, however, sirt2, but not sirt4, increased cellular NADPH levels and partially rescued cuproptosis. Inhibition of NAD+ kinase (NADK), which is responsible for generating NADPH, abolished the rescuing function of NMN and sirt2 for Es/Cu induced cell death. Taken together, our results suggested that DNA damage is a characteristic feature of cuproptosis. NMN can partially rescue cuproptosis by upregulating sirt2, increase intracellular NADPH content and maintain the level of Fe-S proteins, independent of the lipoamidase activity of sirt2.

Efficacy of Lenvatinib in Combination With PD-1 Monoclonal Antibody and Interventional Treatment for Intermediate-Stage Hepatocellular Carcinoma: Impact on Serum Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 Levels: A Retrospective Study.

Objectives: To scrutinize the therapeutic efficiency and safety profile of lenvatinib, accompanied by the programmed cell death protein-1 (PD-1) monoclonal antibody, and interventional treatment in managing intermediate-stage hepatocellular carcinoma. Methods: Retrospective analysis was performed on clinical data from 93 patients suffering from intermediate to advanced hepatocellular carcinoma, treated at our institution from May 2018 to April 2020. Patients were divided based on the therapeutic regimen: 43 cases constituted the control group receiving lenvatinib plus transhepatic artery chemoembolization (TACE), while the remaining 50 cases in the study group were managed with lenvatinib, PD-1 monoclonal antibody, and TACE. Outcome measures included therapeutic efficacy, tumor markers (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], α-L-fucosidase [AFU], carbohydrate antigen 199 [CA199]), immune response indices (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), pertinent cytokine levels (vascular endothelial growth factor [VEGF], matrix metalloproteinase-9 [MMP-9], basic fibroblast growth factor [aFGF], acidic fibroblast growth factor [bFGF]), quality of life (as per Quality of Life Assessment Scale for Cancer Patients [QOL-LC] scores), adverse effects, and survival rates. Results: The study group exhibited a significantly enhanced total effective rate compared to the control group (74.00% vs 53.49%, P < .05). Post-treatment levels of CEA, AFP, AFU, CA199, CD8+, VEGF, MMP-9, aFGF, and bFGF were notably lower in both groups, particularly in the study group. Contrastingly, CD3+, CD4+, CD4+/CD8+ratios, and QOL-LC scores were substantially elevated in the study group (P < .05). Adverse reaction prevalence was analogous between 2 groups (27.91% vs 26.00%; P > .05). Moreover, the study group reported significantly higher 1-, 2-, and 3-year survival rates than the control group (P < .05). Conclusion: The combined use of lenvatinib, PD-1 monoclonal antibody, and interventional treatment for intermediate to advanced hepatocellular carcinoma may have a definitive therapeutic efficacy. This regimen is effective in reducing tumor marker levels, enhancing immune function, modulating VEGF, MMP-9, and other related cytokine levels, and improving patients' quality of life without significantly augmenting adverse effects. This treatment paradigm also contributes to increased survival rates and promises favorable prognosis.

Comparison of protective effects of nicotinamide mononucleotide and nicotinamide riboside on DNA damage induced by cisplatin in HeLa cells.

Background: Previous studies have shown that the nicotinamide adenine dinucleotide (NAD+) precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), protect against endogenously or exogenously induced DNA damage. However, whether the two compounds have the same or different efficacy against DNA damage is not clear. In the current study, we systematically compared the effects of NMN and NR on cisplatin-induced DNA damage in HeLa cells. Methods: To evaluate the protective effects of NMN or NR, HeLa cells were pretreated with different doses of NMN or NR followed with 10 µM of cisplatin treatment. Cell viability was examined by Trypan blue staining assay. For observing the DNA damage repair process, HeLa cells were treated with 10 µM of cisplatin for 12 h, followed with 10 mM NMN or NR treatment for another 8, 16, 24, or 32 h, DNA damage levels were assessed for each time point by immunofluorescent staining against phosphor-H2AX (γH2AX) and alkaline comet assay. The effects of NMN and NR on intracellular NAD+ and reactive oxygen species (ROS) levels were also determined. Results: NMN and NR treatment alone did not have any significant effects on cell viability, however, both can protect HeLa cells from cisplatin-induced decrease of cell viability with similar efficacy in a dose-dependent manner. On the other hand, while both can reduce the DNA damage levels in cisplatin-treated cells, NR exhibited better protective effect. However, both appeared to boost the DNA damage repair process with similar efficacy. NMN or NR treatment alone could increase cellular NAD+ levels, and both can reverse cisplatin-induced decrease of NAD+ levels. Finally, while neither NMN nor NR affected cellular ROS levels, both inhibited cisplatin-induced increase of ROS with no significant difference between them. Conclusion: NR have a better protective effect against cisplatin-induced DNA damage than NMN.

Effects of preoperative carbohydrate loading on recovery after elective surgery: A systematic review and Bayesian network meta-analysis of randomized controlled trials.

Background: Preoperative carbohydrate loading is an important element of the enhanced recovery after surgery (ERAS) paradigm in adult patients undergoing elective surgery. However, preoperative carbohydrate loading remains controversial in terms of improvement in postoperative outcomes and safety. We conducted a Bayesian network meta-analysis to evaluate the effects and safety of different doses of preoperative carbohydrates administrated in adult patients after elective surgery. Methods: MEDLINE (PubMed), Web of Science, EMBASE, EBSCO, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure (CNKI) were searched to identify eligible trials until 16 September 2022. Outcomes included postoperative insulin resistance, residual gastric volume (RGV) during the surgery, insulin sensitivity, fasting plasma glucose (FPG), fasting serum insulin (Fin) level, the serum levels of C-reactive protein (CRP), postoperative scores of pain, patients' satisfaction, thirst, hunger, anxiety, nausea and vomit, fatigue, and weakness within the first 24 h after surgery and the occurrences of postoperative infection. The effect sizes were estimated using posterior mean difference (continuous variables) or odds ratios (dichotomous variables) and 95 credible intervals (CrIs) with the change from baseline in a Bayesian network meta-analysis with random effect. Results: Fifty-eight articles (N = 4936 patients) fulfilled the eligibility criteria and were included in the meta-analysis. Both preoperative oral low-dose carbohydrate loading (MD: -3.25, 95% CrI: -5.27 to -1.24) and oral high-dose carbohydrate loading (MD: -2.57, 95% CrI: -4.33 to -0.78) were associated with postoperative insulin resistance compared to placebo/water. When trials at high risk of bias were excluded, association with insulin resistance was found for oral low-dose carbohydrate loading compared with placebo/water (MD: -1.29, 95%CrI: -2.26 to -0.27) and overnight fasting (MD: -1.17, 95%CrI: -1.88 to -0.43). So, there was large uncertainty for all estimates vs. control groups. In terms of safety, oral low-dose carbohydrate administration was associated with the occurrences of postoperative infection compared with fasting by 0.42 (95%Crl: 0.20-0.81). In the other outcomes, there was no significant difference between the carbohydrate and control groups. Conclusion: Although preoperative carbohydrate loading was associated with postoperative insulin resistance and the occurrences of postoperative infection, there is no evidence that preoperative carbohydrate administration alleviates patients' discomfort. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022312944].

Evaluation of short-term effects of drug-loaded microspheres and traditional transcatheter arterial chemoembolization in the treatment of advanced liver cancer.

BACKGROUND: Liver cancer is a malignant tumor with high morbidity and mortality. Transcatheter arterial chemoembolization (TACE) is the main method for surgically unresectable liver cancer. In recent years, drug-loaded microspheres have been gradually applied in TACE technology. There are some controversies about the therapeutic effects of drug-loaded microspheres TACE (D-TACE) and traditional TACE. AIM: To explore the short-term efficacy of D-TACE and traditional TACE in the treatment of advanced liver cancer. METHODS: The clinical data of 73 patients with advanced liver cancer admitted to the First and Sixth Medical Centers of Chinese PLA General Hospital from January 2017 to October 2019 were retrospectively analyzed. Among them, 15 patients were treated with D-TACE, and 58 patients were treated with traditional TACE. Clinical baseline characteristics, perioperative laboratory indices, postoperative adverse reactions and postoperative complications were compared between the two groups. RESULTS: There was no statistical difference between the two groups for the postoperative response: The highest postoperative body temperature of the drug-loaded microsphere group was 38.0 ± 0.9℃ and the postoperative highest body temperature of the traditional TACE group was 38.3 ± 0.7℃ (t = -1.414, P = 0.162). For the 24 h postoperative nausea and vomiting after surgery in terms of scoring and postoperative pain scores, the traditional TACE group was higher than the drug-loaded microsphere group (χ 2 = 14.33, P = 0.014; χ 2 = 32.967, P = 0.000) and the two groups had significant statistical differences. The disease control rate at 3 mo after treatment in the drug-loaded microsphere group was 60% and the disease control rate at 3 mo after treatment in the traditional TACE group was 75.9% (χ 2 = 4.091, P = 0.252). There was no statistical difference between the two groups of data. During the follow-up period, the number of interventional treatments received was once in the drug-loaded microsphere group and the traditional TACE group received an average of 1.48 treatments (χ 2 = 10.444 P = 0.005). There was a statistical difference between the two groups. CONCLUSION: Compared with traditional TACE, D-TACE may have some advantages in the treatment of advanced hepatocellular carcinoma with a large tumor load in the short term, but the long-term clinical efficacy needs additional follow-up studies. In addition, compared with the traditional group, the patients in the drug-loaded microsphere group had better subjective tolerance and could reduce the number of interventional treatments. Therefore, D-TACE is worthy of clinical promotion.