The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.

Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide‐I (AT-I), a novel TLR4-antagonizing agent, is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear.Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments.Results: We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit N-Nitroso-N-methylurea-induced rat mammary tumor progression through TLR4/NF-κB pathway.Conclusion: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are two of the most fatal respiratory diseases, seriously threatening human health and imposing a heavy burden on families and society. Although COPD is a significant independent risk factor for LC, it is still unclear how COPD affects the prognosis of LC patients, especially when LC patients with COPD receive immunotherapy. With the development of immune checkpoint inhibition (ICI) therapy, an increasing number of inhibitors of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) have been applied to the treatment of LC. Recent studies suggest that LC patients with COPD may benefit more from immunotherapy. In this review, we systematically summarized the outcomes of LC patients with COPD after anti-PD-1/PD-L1 treatment and discussed the tumor immune microenvironment (TIME) regulated by COPD in LC immunotherapy, which provides novel insights for the clinical treatment of LC patients with COPD.

Human cytosolic sulfotransferases (SULTs) regulate the activities of hundreds of signaling metabolites via transfer of the sulfuryl moiety (-SO₃) from activated sulfate (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and primary amines of xeno- and endobiotics. How SULTs select substrates from the scores of competing ligands present in a cytosolic milieu is an important issue in the field. Selectivity appears to be sterically controlled by a molecular pore that opens and closes in response to nucleotide binding. This point of view is fostered by structures showing nucleotide-dependent pore closure and the fact that nucleotide binding induces an isomerization that restricts access to the acceptor-binding pocket. Molecular dynamics models underscore the importance of pore isomerization in selectivity and predict that specific molecular linkages stabilize the closed pore in response to nucleotide binding. To test the pore model, these linkages were disrupted in SULT2A1 via mutagenesis, and the effects on selectivity were determined. The mutations uncoupled nucleotide binding from selectivity and produced enzymes that no longer discriminated between large and small substrates. The mutations did not affect the affinity or turnover of small substrates but resulted in a 183-fold gain in catalytic efficiently toward large substrates. Models predict that an 11-residue “flap” covering the acceptor-binding pocket can open and admit large substrates when nucleotide is bound; a mutant structure demonstrated that this is so. In summary, the model was shown to be a robust, accurate predictor of SULT structure and selectivity whose general features will likely apply to other members of the SULT family.

Dietary phytochemicals play chemopreventive roles in breast cancer by activating Nrf2 signaling pathway.

Aims of this study: This study aims to investigate the potential of Huangqin Tang (HQT), a traditional Chinese medicine formulation, in the treatment of breast cancer (BC) through a comprehensive approach integrating network pharmacology, molecular docking, and experimental validation. Methods: Chemical composition and target information of HQT were collected using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Disease-related target genes were obtained from the GeneCards database. Network pharmacological analysis, including construction of compound-disease-target networks and protein-protein interaction networks, was performed. Molecular docking simulations were conducted to evaluate the binding affinity between HQT components and key targets. Experimental validation was carried out using cell viability assays, clone formation assays, flow cytometry, Western blotting, and pathway analysis. Results: A total of 210 candidate targets were identified. Network analysis revealed STAT3, AKT1, MAPK3 etc. as central targets. Enrichment analysis suggested HQT may exert anti-tumor effects through regulating lipid metabolism and inflammation related pathways. Molecular docking showed that the key compounds baicalein, wogonin, kaempferol and quercetin all bound effectively to MAPK1. The binding of baicalein to IL6 and naringenin to TNF-α was also relatively stable. The experimental results demonstrated that HQT effectively inhibited the proliferation of breast cancer cells, with IC50 values of 2.334 mg/mL and 1.749 mg/mL in MCF-7 cells at 24 h and 48 h, and IC50 values of 1.286 mg/mL and 1.496 mg/mL in MDA-MB-231 cells at 24 h and 48 h, respectively. Furthermore, HQT induced cell cycle arrest at the G2/M phase in breast cancer cells and downregulated the expression of related proteins including CDK1, Cyclin B1, CDK2, and Cyclin E. Additionally, HQT promoted apoptosis in breast cancer cells by upregulating the expression of Bak and CC-3, while downregulating the expression of Bcl-2. Notably, HQT also exhibited regulatory effects on the HIF-1 signaling pathway. Conclusions: This study provides insights into the potential multi-component and multi-target mechanisms of HQT against BC, suggesting it may achieve therapeutic effects through regulating inflammatory response and cancer-related pathways via the identified active compounds and targets. The findings highlight the importance of integrating traditional medicine with modern approaches for the development of novel cancer therapies.