Mehreen Aftab

Background Breast cancer, the most common malignancy among women worldwide, involves disrupted autophagy pathways contributing to tumor progression. The LC3B–p62–Nrf2 feedback loop is vital in maintaining cellular homeostasis, with dysfunction promoting cancer survival and therapy resistance. Phytochemicals hold promise in cancer treatment by restoring autophagic flux. This study explores the phytochemical 6,6'-dihydroxythiobinupharidine (DTBN) in modulating Nrf2 and autophagy markers p62 and LC3B across breast cancer cell lines with varying Tp53 status. Methodology To achieve the study's objectives, we conducted molecular experiments using breast cancer cell lines with varying Tp53 statuses, treating them with DTBN while concurrently inhibiting Nrf2 activity. Additionally, we analyzed TCGA and GEO datasets to delineate the correlations among Nrf2, p62, LC3B, and Tp53 expression. Results Our findings indicate that the phytochemical DTBN induces LC3B-mediated autophagy and activates the Nrf2 pathway in breast cancer cells. We evaluated autophagy markers p62 and LC3B to test this hypothesis while inhibiting Nrf2 with brusatol in breast cancer cell lines with different TP53 statuses. Results revealed that brusatol-enhanced NRF2 inhibition significantly amplified DTBN-induced cell death and autophagy, marked by decreased p62 and increased LC3B expression. Notably, DTBN and brusatol acted synergistically to promote cell death and autophagy. Additionally, analysis of TCGA and GEO datasets validated a positive correlation between NRF2 and autophagic genes in diverse TP53 contexts, furthering therapeutic potential. Conclusion In conclusion, these findings underline the potential risks of persistent Nrf2 activation in breast cancer cells. The study highlights a critical interplay between persistent Nrf2 activation, autophagy induction, and cell death modulation by DTBN and brusatol co-treatment. The synergistic effects suggest that pharmacological inhibition of Nrf2 in combination with DTBN treatment represents a promising strategy to enhance autophagy, providing novel therapeutic opportunities for breast cancer.

Background: As per recent scenarios, drug resistance is a significant challenge in treating breast cancer for several reasons, such as genetic mutations, altered signaling pathways, and tumor microenvironment. Endocrine resistance is one of the biggest significant barriers to treatment, particularly in hormone receptor-positive (HR+) breast cancers, which depends on estrogen or progesterone signaling for growth. While therapies such as tamoxifen, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) have effectively targeted these pathways, many patients develop resistance, rendering them less effective over time, which is driving a need for innovative therapeutics to treat breast cancer and overcome drug resistance and better treatment outcomes. Recent studies suggest that combining the different therapies, including immunotherapy, targeted therapy, chemotherapy, etc., with endocrine therapy, may bypass the endocrine resistance. Methodology: We conducted a comprehensive systematic review and meta-analysis examining the molecular mechanisms of endocrine resistance and evaluating randomized clinical trial outcomes, overall survival and progression-free survival in endocrine-resistant breast cancer patients treated with endocrine therapy, targeted therapy, immunotherapy, or chemotherapy. Results: We have analyzed 35 randomized clinical trial studies for different therapies along with combination therapy, and our results demonstrated that supplementary or additional therapies in endocrine resistance breast cancer patients have better progression-free and overall survival. Conclusions: The current study has demonstrated that combination therapies may have good survival results and patient outcomes in endocrine resistance. Also, This review sheds light on current challenges in drug resistance and the future direction of cancer treatment through a comprehensive analysis of these emerging treatment approaches to improve patient outcomes.

It is a well-known fact that following a proper routine light/dark or diurnal rhythm controls almost all biological processes. With the introduction of modern lighting and artificial illumination systems, continuous exposure to light at night may lead to the disruption of diurnal rhythm. However, the effect of light during the night on brain anatomy, physiology, and human body functions is less explored and poorly understood. In this study, we have evaluated the effect of exposure to dim light (5 lux) at night (dLAN) on Swiss Albino mice over a duration of three consecutive weeks. Results have revealed that exposure to dLAN led to an impairment of cognitive and non-cognitive behaviour, oxidative stress–mediated elevation of lipid peroxidation, and reduction of superoxide dismutase and catalase activity. It also led to the downregulation of hippocampal proteins (BDNF, Synapsin II and DCX) at both protein and mRNA level. Additionally, there was downregulation of CREB and SIRT1 mRNAs and neurodegeneration-associated miRNA21a-5p and miRNA34a-5p. The pyramidal and cortical neurons started showing pyknotic and chromatolysis characteristics. However, a dose of curcumin administered to the mice positively modulated these parameters in our experimental animals. We proposed the modulatory role of curcumin in addressing the deleterious effects of dLAN.