Aaron L. Hilliard

Breast cancer remains a formidable global health challenge, with triple-negative breast cancer (TNBC) posing unique clinical complexities. Characterized by its aggressive nature and limited number of specific therapeutic targets, this breast cancer subtype disproportionately affects African American women, highlighting critical disparities in care. The tumor immune microenvironment (TIME) plays a critical role in breast cancer development and response to immunotherapy, and it is essential in fostering an immunosuppressive and pro-inflammatory niche. Inflammation, primarily mediated by the NF-κB signaling pathway and chemokine signaling, particularly involving CCL2, plays a pivotal role in TNBC progression and therapy resistance. This review describes some of the molecular mechanisms of polyphenols, which are naturally occurring compounds abundant in various dietary sources, and their potential use as therapeutic agents in the management of TNBC. Polyphenolic compounds have been described as modulating the TIME through the inhibition of tumor progression, immune evasion, and therapy resistance, due to their diverse bioactivities, including anti-inflammatory, antioxidant, and anticancer properties, making them attractive candidates for combating the aggressiveness of TNBC and addressing treatment disparities. Polyphenols, such as curcumin, gossypol, butein, epigallocatechin gallate, cardamonin, and resveratrol, have demonstrated efficacy in modulating several signaling pathways within the TIME, which are implicated in the progression of TNBC. This review highlights the potential effects of polyphenols on inflammatory cytokine release, programmed cell death ligand 1 (PD-L1) expression, which is associated with immune evasion by the host cell, and various intracellular signaling cascades, demonstrating their potential use in personalized therapeutic interventions for TNBC. This study also describes differential responses of TNBC cell lines to polyphenol treatment, highlighting the importance of considering genetic variability in therapeutic strategies, as well as the importance of the interaction of polyphenols with the gut microbiome, which may establish the bioavailability and effectiveness of these compounds toward therapeutic outcomes. Further preclinical and clinical studies are warranted to fully elucidate the therapeutic potential of polyphenols and translate these findings into clinical practice, thereby improving outcomes for patients with TNBC worldwide.

Cataracts account for over half of global blindness. Cataracts formations occur mainly due to aging and to the direct insults of oxidative stress and inflammation to the eye lens. The nuclear factor-erythroid-2-related factor 2 (Nrf2), a transcriptional factor for cell cytoprotection, is known as the master regulator of redox homeostasis. Nrf2 regulates nearly 600 genes involved in cellular protection against contributing factors of oxidative stress, including aging, disease, and inflammation. Nrf2 was reported to disrupt the oxidative stress that activates Nuclear factor-κB (NFκB) and proinflammatory cytokines. One of these cytokines is matrix metalloproteinase 9 (MMP-9), which participates in the decomposition of lens epithelial cells (LECs) extracellular matrix and has been correlated with cataract development. Thus, during inflammatory processes, MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFκB pathway activation. Moreover, plant-based polyphenols have garnered attention due to their presumed safety and efficacy, nutritional, and antioxidant effects. Polyphenol compounds can activate Nrf2 and inhibit MMP-9. Therefore, this review focuses on discussing Nrf2’s role in oxidative stress and cataract formation, epigenetic effect in Nrf2 activity, and the association between Nrf2 and MMP-9 in cataract development. Moreover, we describe the protective role of flavonoids in cataract formation, targeting Nrf2 activation and MMP-9 synthesis inhibition as potential molecular targets in preventing cataracts.

Heart disease continues to be the leading cause of death in the United States, with approximately 805 000 cumulative deaths from myocardial infarctions (MI) from 2005 to 2014. Gender and racial/ethnic disparities in MI diagnoses are becoming more evident in quality review audits. Although recent changes in diagnostic codes provided an improved framework, clinically distinguishing types of MI remains a challenge. MI misdiagnoses and health disparities contribute to adverse outcomes in cardiac medicine. We conducted a literature review of relevant biomedical sources related to the classification of MI and disparities in cardiovascular care and outcomes. From the studies analyzed, African Americans and women have higher rates of mortality from MI, are more probably to be younger and present with other comorbidities and are less probably to receive novel therapies with respect to type of MI. As high‐sensitivity troponin assays are adopted in the United States, implementation should account for how race and sex differences have been demonstrated in the reference range and diagnostic threshold of the newer assays. More research is needed to assess how the complexity of health disparities contributes to adverse cardiovascular outcomes. Creating dedicated medical quality teams (physicians, nurses, clinical documentation improvement specialists, and medical coders) and incorporating a plan‐do‐check‐adjust quality improvement model are strategies that could potentially help better define and diagnose MI, reduce financial burdens due to MI misdiagnoses, reduce cardiovascular‐related health disparities, and ultimately improve and save lives.

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a −3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.