Exploring structural effects in a new class of NRF2 inhibitors.

NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. A new class of NRF2 inhibitors has been discovered with substituted nicotinonitriles, such as MSU38225. In this work, the effects on NRF2 inhibition with structural changes were explored. Through these studies, we identified a few compounds with as good or better activity than the initial hit but with greatly improved solubility. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated.

Assessing student desire for professional skills development within the undergraduate science curriculum: a focus on teamwork.

Professional skill development has emerged as an increasingly important facet of undergraduate training, specifically within science curricula. The primarily agreed on professional skills for a well-rounded scientist include teamwork, oral communication, written communication, and quantitative skills. The demand for these skills has been driven by employers and graduate/professional schools. To this end, instructors in higher education have begun to integrate professional skill development into their course design and student learning goals. However, the attitudes of students themselves toward the importance of different professional skills, the inclusion of these skills in their coursework, level of improvement, and end confidence has yet to be thoroughly characterized. It was the aim of this study to ascertain students' desire for the aforementioned professional skills within their undergraduate science programs by exploring student perceptions of professional skills inclusion, importance, improvement, and confidence and identify the local courses students recognize as utilizing "teamwork activities." Here we detail these attitudes in biomedical science undergraduates at Michigan State University. By using the Science Student Skills Inventory (SSSI), a previously validated assessment tool, we observed differences in student perceptions of professional skills when compared to previous SSSI studies. We also observed significant differences in attitudes between age groups in respect to writing and communication skills, differing perceptions of what constitutes teamwork, as well as gender differences in respect to attitudes around communication and ethical thinking skills. Our results give valuable insight into student perspectives on how professional skills are developed in their program. These data may be used to inform curriculum development within and across institutions.

Apigenin by targeting hnRNPA2 sensitizes triple-negative breast cancer spheroids to doxorubicin-induced apoptosis and regulates expression of ABCC4 and ABCG2 drug efflux transporters.

Acquired resistance to doxorubicin is a major hurdle in triple-negative breast cancer (TNBC) therapy, emphasizing the need to identify improved strategies. Apigenin and other structurally related dietary flavones are emerging as potential chemo-sensitizers, but their effect on three-dimensional TNBC spheroid models has not been investigated. We previously showed that apigenin associates with heterogeneous ribonuclear protein A2/B1 (hnRNPA2), an RNA-binding protein involved in mRNA and co-transcriptional regulation. However, the role of hnRNPA2 in apigenin chemo-sensitizing activity has not been investigated. Here, we show that apigenin induced apoptosis in TNBC spheroids more effectively than apigenin-glycoside, owing to higher cellular uptake. Moreover, apigenin inhibited the growth of TNBC patient-derived organoids at an in vivo achievable concentration. Apigenin sensitized spheroids to doxorubicin-induced DNA damage, triggering caspase-9-mediated intrinsic apoptotic pathway and caspase-3 activity. Silencing of hnRNPA2 decreased apigenin-induced sensitization to doxorubicin in spheroids by diminishing apoptosis and partly abrogated apigenin-mediated reduction of ABCC4 and ABCG2 efflux transporters. Together these findings provide novel insights into the critical role of hnRNPA2 in mediating apigenin-induced sensitization of TNBC spheroids to doxorubicin by increasing the expression of efflux transporters and apoptosis, underscoring the relevance of using dietary compounds as a chemotherapeutic adjuvant.

Therapeutic potential of targeting mixed lineage kinases in cancer and inflammation.

Dysregulation of intracellular signaling pathways is a key attribute of diseases associated with chronic inflammation, including cancer. Mitogen activated protein kinases have emerged as critical conduits of intracellular signal transmission, yet due to their ubiquitous roles in cellular processes, their direct inhibition may lead to undesired effects, thus limiting their usefulness as therapeutic targets. Mixed lineage kinases (MLKs) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that interact with scaffolding proteins and function upstream of p38, JNK, ERK, and NF-kappaB to mediate diverse cellular signals. Studies involving gene silencing, genetically engineered mouse models, and small molecule inhibitors suggest that MLKs are critical in tumor progression as well as in inflammatory processes. Recent advances indicate that they may be useful targets in some types of cancer and in diseases driven by chronic inflammation including neurodegenerative diseases and metabolic diseases such as nonalcoholic steatohepatitis. This review describes existing MLK inhibitors, the roles of MLKs in various aspects of tumor progression and in the control of inflammatory processes, and the potential for therapeutic targeting of MLKs.