[Research Progress of Nrf2 and Ferroptosis in Tumor Drug Resistance].

Lung cancer is one of the most common cancers in the world, and its treatment strategy is mainly surgery combined with radiotherapy and chemotherapy. However, long-term chemotherapy will result in drug resistance, which is also one of the difficulties in the treatment of lung cancer. Ferroptosis is an iron-dependent and lipid peroxidation-driven non-apoptotic cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (Nrf2) is key for cellular antioxidant responses. Numerous studies suggest that Nrf2 assumes an extremely important role in regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. In this review, a brief overview of the research progress of ferroptosis over the past decade will be presented. In particular, the mechanism of ferroptosis and the regulation of ferroptosis by Nrf2 will be discussed, as well as the role of the Nrf2 pathway and ferroptosis in tumor drug resistance, which will provide new research directions for the treatment of drug-resistant lung cancer patients.
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High-throughput transcriptome sequencing reveals the protective role of adenosine receptor-related genes in paraquat-exposed Caenorhabditis elegans.

This study sought to identify the genes associated with adenosine's protective action against paraquat (PQ)-induced oxidative stress via the adenosine receptor (ADOR-1) in Caenorhabditis elegans (C. elegans). The C. elegans was divided into 3 groups-2 groups exposed to PQ, one in presence, and one in absence of adenosine-and a control group that was not treated. Each group's total RNA was extracted and sequenced. When the transcriptomes of these groups were analyzed, several genes were found to be differently expressed. These differentially expressed genes were significantly enriched in adenosine-response biological processes and pathways, including gene ontology terms related to neuropeptide and kyoto encyclopedia of genes and genomes pathways associated to cAMP pathway regulator activity. Quantitative reverse-transcription PCR confirmed that G-protein-coupled receptors signaling pathway involving dop-1, egl-30, unc-13, kin-1, and goa-1 genes may play crucial roles in modulating adenosine's protective action. Interestingly, there are no significant variations in the expression of the ador-1 gene across the 3 treatments, thereby indicating that adenosine receptor exerts a consistent and stable influence on its related pathways irrespective of the presence or absence of PQ. Furthermore, the wild-type group with ador-1 gene has higher survival rate than that of the ador-1-/RNA interference group while treated with PQ in the presence of adenosine. Conclusively, our study uncovered a number of novel PQ-response genes and adenosine receptor-related genes in C. elegans, which may function as major regulators of PQ-induced oxidative stress and indicate the possible protective effects of adenosine.

The NRF2 antagonist ML385 inhibits PI3K-mTOR signaling and growth of lung squamous cell carcinoma cells.

BACKGROUND: Lung squamous cell carcinoma (LUSC) currently has limited therapeutic options because of the relatively few validated targets and the lack of clinical drugs for some of these targets. Although NRF2/NFE2L2 pathway activation commonly occurs in LUSC, NRF2 has predominantly been studied in other cancer models. Here, we investigated the function of NRF2 in LUSC, including in organoid models, and we explored the activity of a small molecule NRF2 inhibitor ML385, which has not previously been investigated in LUSC. METHODS: We first explored the role of NRF2 signaling in LUSC cancer cell line and organoid proliferation through NRF2 knockdown or ML385 treatment, both in vivo and in vitro. Next, we performed Western blot and immunofluorescence assays to determine the effect of NRF2 inhibition on PI3K-mTOR signaling. Finally, we used cell viability and clonogenic assays to explore whether ML385 could sensitize LUSC cancer cells to PI3K inhibitors. RESULTS: We find that downregulation of NRF2 signaling inhibited proliferation of LUSC cancer cell lines and organoids, both in vivo and in vitro. We also demonstrate that inhibition of NRF2 reduces PI3K-mTOR signaling, with two potential mechanisms being involved. Although NRF2 promotes AKT phosphorylation, it also acts downstream of AKT to increase RagD protein expression and recruitment of mTOR to lysosomes after amino acid stimulation. We also find that ML385 potentiates LUSC growth inhibition by a pan-PI3K inhibitor, which correlates with stronger inhibition of PI3K-mTOR signaling. CONCLUSIONS: Our data provide additional support for NRF2 promoting LUSC growth through PI3K-mTOR activation and support development of NRF2 inhibitors for the treatment of LUSC.

[Progress of NRF2 Signaling Pathway in Promoting Proliferation 
of Non-small Cell Lung Cancer].

The morbidity and mortality of lung cancer ranks among the top cancers in the world. Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer, with limited treatment options and poor prognosis. The nuclear factor E2-related factor 2 (NRF2) signaling pathway is highly mutated and activated in NSCLC, and promotes the malignant progression of lung cancer through various mechanisms. NRF2-targeted therapy will provide new treatment strategies for patients with NSCLC. This article will review the basic structure and response pathways of the NRF2 pathway, the mechanism of NRF2 regulating lung cancer cell proliferation, and the research and development progress of NRF2 inhibitors.
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The Positive Influence of Polyphenols Extracted From Pueraria lobata Root on the Gut Microbiota and Its Antioxidant Capability.

Pueraria lobata, an edible food and medicinal plant, is a rich source of bioactive components. In this study, a polyphenol-rich extract was isolated from P. lobata. Puerarin was identified, and the high antioxidant bioactivity of the P. lobata extract was evaluated using the methods of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS), and hydroxyl free radical scavenging ratio. Additionally, the IC50 values of DPPH, ABTS, and hydroxyl radical scavenging activities were 50.8, 13.9, and 100.4 µg/ml, respectively. Then, the P. lobata extract was administered to C57Bl/6J mice and confirmed to have a superior effect on enhancing the antioxidant status including improving superoxide dismutase activity, glutathione peroxidase peroxide activity, total antioxidant capacity activity, and malondialdehyde contents in vivo. Furthermore, the P. lobata extract had beneficial and prebiotic effects on the composition and structure of gut microbiota. Results showed that the P. lobata extract significantly increased the abundance of beneficial bacteria, involving Lactobacillaceae and Bacteroidetes, and decreased the abundance of Ruminococcaceae, Prevotellaceae, and Burkholderiaceae. Overall, our results provided a basis for using the P. lobata extract as a promising and potential functional ingredient for the food industry.