Ningye Ma

Curcumin (Cur), a natural bioactive compound extracted from Curcuma longa, has garnered extensive interest due to its modulation of inflammation, antioxidant, and anti-tumor properties. However, its therapeutic translation remains constrained by limited systemic bioavailability. Triple-negative breast cancer (TNBC), an aggressive variant of breast malignancies, exhibits strong resistance to conventional therapies and poor prognosis. The present study was designed to clarify the mechanism through which NGR-modified nanovesicles loaded with Cur (NGR-NVs@Cur) reverse immunotherapy resistance in TNBC. Using transcriptomic and network pharmacology analysis, we identified key genes involved in TNBC development and immunotherapy resistance to determine the targets of Cur. In vitro experiments, including SA-β-gal staining, flow cytometry, and glycolysis analysis, validated that TNBC cells induce glycolysis and CD8⁺ T cell senescence. NGR-NVs@Cur were successfully constructed and marked by transmission electron microscopy (TEM), dynamic light scattering (DLS), pH-responsive release, and cellular uptake assays. Further cell-based studies demonstrated that NGR-NVs@Cur suppressed TNBC cell proliferation, migration, glycolysis, and reversed CD8⁺ T cell senescence. In vivo, both subcutaneous xenograft and adoptive T cell transfer models were developed to evaluate the therapeutic effects of NGR-NVs@Cur in combination with immune checkpoint inhibitors (ICIs, e.g., J43). The results revealed that Cur inhibited TNBC cell glycolysis and T cell senescence by activating TLR9 and suppressing the mTOR pathway, and that NGR-NVs@Cur enhanced targeted Cur delivery and effectively reversed immunotherapy resistance. This study demonstrated a novel strategy by which Cur, delivered via tumor-targeted nanovesicles, modulates glycolysis and CD8⁺ T cell senescence through the TLR9–mTOR axis, offering promising insights into overcoming immune resistance in TNBC.

Triple-negative breast cancer (TNBC) poses as a daunting and intricate manifestation of breast cancer, highlighted by few treatment options and a poor outlook. The crucial element in fostering tumor growth and immune resistance is the polarization of tumor-associated macrophages (TAMs) into the M2 state within the tumor microenvironment (TME). To address this, we developed M2 targeting peptide-chitosan-curcumin nanoparticles (M2pep-Cs-Cur NPs), a targeted delivery system utilizing chitosan (Cs) as a carrier, curcumin (Cur) as a therapeutic agent, and targeting peptides for specificity. These NPs effectively inhibited TNBC cell proliferation (~ 70%) and invasion (~ 70%), while increasing the responsiveness of tumors to anti-PD-L1 treatment (~ 50% survival enhancement) in vitro and in vivo. Bioinformatics analysis suggested that Cur modulates TAM polarization by influencing key genes such as COX-2, offering insights into its underlying mechanisms. This study highlights the potential of M2pep-Cs-Cur NPs to reverse M2 polarization in TAMs, providing a promising targeted therapeutic strategy to overcome immunotherapy resistance and improve TNBC outcomes.

Circular RNAs (circRNAs) have garnered substantial attention due to their distinctive circular structure and gene regulatory functions, establishing them as a significant class of functional non-coding RNAs in eukaryotes. Studies have demonstrated that circRNAs can interact with RNA-binding proteins (RBPs), which play crucial roles in tumorigenesis, metastasis, and drug response in cancer by influencing gene expression and altering the processes of tumor initiation and progression. This review aims to summarize the recent advances in research on circRNA-protein interactions (CPIs) and discuss the functions and mode of action of CPIs at various stages of gene expression, including transcription, splicing, translation, and post-translational modifications in the context of cancer. Additionally, we explore the role of CPIs in tumor drug resistance to gain a deeper understanding of their potential applications in the development of new anti-cancer therapeutic approaches.

Background: The association between a diverse array of environmental risk factors and the risk of endometriosis is contradictory.Objective: To summarize the evidence of associations between environmental risk factors and the risk of endometriosis.Methods: Databases such as PubMed, EMBASE, Web of Science, and ClinicalTrial.gov were systematically searched in June 2020. Meta-analyses of observational studies investigated any environmental exposure (non-genetic) and endometriosis risk. For each article, we estimated the summary effect size, 95% CIs, and the 95% prediction interval (PI). We also estimated the between-study heterogeneity expressed by I², evidence for small-study effects, and evidence of excess significance bias.Results: About 12 eligible articles (featuring 143,422 cases and 5,112,967 participants) yielded data on 40 unique environmental risk factors, including life styles (n = 16), reproductive factors (n = 3), early life factors (n = 4), and a range of other risk factors [e.g., phthalate metabolites, endocrine-disrupting chemicals, and body mass index (BMI)]. About 25 of these 40 associations (62.5%) were statistically significant (p < 0.05) under random-effects models. Evidence for an association was indicated for alcohol intake [relative risk (RR): 1.25; 95% CI: 1.11–1.41] and the exposure to endocrine disruptor chemicals (EDCs) (RR: 1.41; 95% CI: 1.23–1.60) while 15 associations presented only weak evidence.Conclusions: Our analyses showed that alcohol intake and exposure to endocrine-disrupting chemicals may be potential risk factors for endometriosis and supported by suggestive epidemiological evidence. However, it was evident that there was substantial heterogeneity and/or bias between the different studies featured in various meta-analyses included in this review; therefore, the outcomes of our analysis should be interpreted cautiously.

Purpose Circular RNAs (circRNAs) constitute a class of regulatory RNAs that are thought to play important roles in tumor initiation and progression. Several studies have reported that circRNAs may be involved in various biological processes via networks of competing endogenous RNAs (ceRNAs). However, the regulatory roles and underlying mechanisms of circRNAs in cervical cancer (CC) still largely remain to be resolved. Methods CircNFATC3 (hsa_circ_0005615) expression was assessed in CC cell lines (SiHa, H8) using circRNA microarray analysis, whereas qRT-PCR was used to detect circNFATC3 and miR-9-5p expression in primary human CC tissues and cell lines. The tumor promoting role of circNFATC3 was verified in CC cells using a series of functional assays, and interactions between circNFATC3, miR-9-5p and syndecan-2 (SDC2) were investigated using dual-luciferase reporter assays. SDC2 protein expression was detected using Western blotting and immunohistochemistry. The tumor promoting role of circNFATC3 was confirmed in vivo using a CC xenograft model. Results We found that circNFATC3 expression was upregulated in primary CC tissues and positively correlated with CC tumor size and stromal invasion. In addition, we found that exogenous circNFATC3 overexpression enhanced the proliferation, migration and invasion of HeLa cells, while its knockdown reduced the malignancy of SiHa cells. We also found that circNFATC3 may act directly as a miR-9-5p sponge to regulate SDC2 expression and its downstream signaling pathways, thereby enhancing CC development. Conclusion Our data indicate that circNFATC3 sponges miR-9-5p to regulate SDC2 expression and, thereby, to promote CC tumor development.