Navigating nonalcoholic fatty liver disease (NAFLD): Exploring the roles of estrogens, pharmacological and medical interventions, and life style.

The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition.

Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism.

The median overall survival of patients with metastatic breast cancer is only 2-3 years, and for patients with untreated liver metastasis, it is as short as 4-8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.

Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers.

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.