To study the structure-function relationship of the oxidative-damage effect of ascorbic acid, we have focused on the interaction between plasmid DNA pUC19 and a series of ascorbic acid derivatives modified on different OH groups in the presence of transition metal ions. Some ascorbic acid derivatives can selectively cleave plasmid DNA from Form I to Form II in the presence of low concentration of Cu2+ just like ascorbic acid itself, while other derivatives oxidatively damage plasmid DNA slightly. We found that those derivatives with unattached 2-OH and 3-OH groups retain the ability to cleave the plasmid DNA. The derivatives that have been methylated on 2-OH or 3-OH can only cleave plasmid DNA softly, and those derivatives that have been protected on both 2-OH and 3-OH can hardly exert an oxidative damage on plasmid DNA under the same condition. Form these results, we can draw the conclusion that 2-OH and 3-OH groups of the ascorbic acid molecule contribute most to this biological activity.

Diabetes mellitus in early pregnancy causes birth defects, including neural tube defects (NTDs). Hyperglycemia increases production of nitric oxide (NO) through NO synthase 2 (Nos2) and reactive oxygen species (ROS), generating nitrosative and oxidative stress conditions in the embryo. The present study aimed to target nitrosative stress using a naturally occurring Nos2 inhibitor, quercetin, to prevent NTDs in the embryos of diabetic mice. Daily administration of quercetin to diabetic pregnant mice during the hyperglycemia-susceptible period of organogenesis significantly reduced NTDs and cell apoptosis in the embryos, compared with those of vehicle-treated diabetic pregnant mice. Using HPLC-coupled ESI-MS/MS, quercetin metabolites, including methylated and sulfonylated derivatives, were detected in the conceptuses. The methylated metabolite, 3-O-methylquercetin, was shown to reduce ROS level in embryonic stem cells cultured in high glucose. Quercetin treatment decreased the levels of Nos2 expression, protein nitrosylation, and protein nitration, alleviating nitrosative stress. Quercetin increased the expression of superoxide dismutase 1 and 2, and reduced the levels of oxidative stress markers. Expression of genes of redox regulating enzymes and DNA damage repair factors was upregulated. Our study demonstrates that quercetin ameliorates intracellular stresses, regulates gene expression, and reduces embryonic malformations in diabetic pregnancy.

BackgroundHonokiol is a bioactive lignanoid and has been utilized in traditional Chinese medicine for a long time. It exhibits several pharmacological properties, such as anticancer effects, anti-inflammatory effects, and antianxiety effects. However, the poor aqueous solubility of honokiol has impeded clinical applications.Materials and methodsIn the present study, we adopted the liquid antisolvent precipitation (LAP) technique to prepare nanoparticles of honokiol for enhancement of solubility and bioavailability. Moreover, the honokiol nanoparticles obtained were investigated and evaluated in terms of morphology, physicochemical properties, saturation solubility, dissolution in vitro, bioavailability in vivo, toxicity, and the inhibitory effect on growth of HepG2 cells.ResultsThe obtained honokiol nanoparticles existed nearly in spherical shape and could be turned into amorphous structure by the LAP method. Moreover, the solubility of the honokiol nanoparticles was extremely higher than that of free honokiol, and the nanoparticle dissolution rate was also higher than that of free honokiol, which was about 20.41 times and 26.2 times than that of free honokiol in artificial gastric juice and in artificial intestinal juice. The area under the curve [AUC(0–t)] value of honokiol nanoparticles was about 6.52 times greater than that of free honokiol; therefore, the honokiol nanoparticles had a higher bioavailability than free honokiol but were innoxious to the organs of rats. Additionally, the honokiol nanoparticles exhibited a higher inhibition of HepG2 cells due to their lower IC50 compared to free honokiol.ConclusionHonokiol nanoparticles have high solubility and bioavailability, and can become a new oral drug formulation and produce a better response for its clinical applications.

Intratumoral copper levels are closely associated with immune escape from diverse cancers. Cuproptosis-related lncRNAs (CRLs), however, have an unclear relationship with hepatocellular carcinoma (HCC). Gene expression data from 51 normal tissues and 373 liver cancer tissues from the Cancer Genome Atlas (TCGA) database were collected and analyzed. To identify CRLs, we employed differentially expressed protein-coding genes (DE-PCGs)/ lncRNAs (DE-lncRNAs) analysis, Kaplan-Meier (K-M) analysis, and univariate regression. By univariate and Lasso Cox regression analyses, we screened 10 prognosis-related lncRNAs. Subsequently, five CRLs were identified by multivariable Cox regression analysis to construct the prognosis model. This feature is an independent prognostic indicator to forecast overall survival. According to Gene Set Variation Analysis (GSVA) and Gene Ontology (GO), both immune-related biological processes (BPS) and pathways have CRL participation. In addition, we found that the characteristics of CRLs were associated with the expression of the tumor microenvironment (TME) and crucial immune checkpoints. CRLs could predict the clinical response to immunotherapy based on the studies of tumor immune dysfunction and rejection (TIDE) analysis. Additionally, it was verified that tumor mutational burden survival and prognosis were greatly different between high-risk and low-risk groups. Finally, we screened potential sensitive drugs for HCC. In conclusion, this study provides insight into the TME status in patients with HCC and lays a basis for immunotherapy and the selection of sensitive drugs.

NF-kB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-kB, IKKb, in prostate cancer has neither been fully documented nor are there any effective IKKb inhibitors used in clinical settings.