Copper (Cu) is an essential micronutrient required for the activity of redox‐active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu ⁺ ‐transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.

Background: Mesenchymal stem cell-derived neural progenitor cell (MSC-NP) therapy is an experimental approach to treat multiple sclerosis. The influence of MSC-NPs on microglial activation was inve... Graphical abstract Plain language summary Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and spinal cord that leads to neuronal damage and neurological disability. A novel cell therapy has bee... Tweetable abstract MSC-NP cell therapy for multiple sclerosis found to target proinflammatory microglia through secreted factors including TGF-β.

Mesenchymal stem cell-neural progenitors (MSC-NP) are a neural derivative of MSCs that are being investigated in clinical trials as an autologous intrathecal cell therapy to treat patients with secondary progressive (SP) or primary progressive (PP) multiple sclerosis (MS). MSC-NPs promote tissue repair through paracrine mechanisms, however which secreted factors mediate the therapeutic potential of MSC-NPs and how this cell population differs from MSCs remain poorly understood. The objective of this study was to define the transcriptional profile of MSCs and MSC-NPs from MS and non-MS donors to better characterize each cell population. MSCs derived from SPMS, PPMS, or non-MS bone marrow donors demonstrated minimal differential gene expression, despite differences in disease status. MSC-NPs from both MS and non-MS-donors exhibited significant differential gene expression compared to MSCs, with 2,156 and 1,467 genes upregulated and downregulated, respectively. Gene ontology analysis demonstrated pronounced downregulation of cell cycle genes in MSC-NPs compared to MSC consistent with reduced proliferation of MSC-NPs in vitro. In addition, MSC-NPs demonstrated significant enrichment of genes involved in cell signaling, cell communication, neuronal differentiation, chemotaxis, migration, and complement activation. These findings suggest that increased cell signaling and chemotactic capability of MSC-NPs may support their therapeutic potential in MS.

Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis. Human cancer research in general requires refined models to bridge the gap between basic science research and meaningful clinical trials. Classic studies in cultured cancer cell lines and animal models such as mice and rats often present caveats when extended to humans due to inherent genetic and physiological differences. However, larger animal models such as pigs are emerging as more appropriate tools for translational research as they present more similarities with humans in terms of genetics, anatomical structures, organ sizes, and pathological manifestations of diseases like cancer. These similarities make porcine models well-suited for addressing long standing questions in cancer biology as well as in the arena of novel drug and therapeutic development against human cancers. With the emergent roles of Cu in human health and pathology, the pig presents an emerging and valuable model to further investigate the contributions of this metal to human cancers. The Oncopig Cancer Model is a transgenic swine model that recapitulates human cancer through development of site and cell specific tumors. In this review, we briefly outline the relationship between Cu and cancer, and how the novel Oncopig Cancer Model may be used to provide a better understanding of the mechanisms and causal relationships between Cu and molecular targets involved in cancer.

Zinc (Zn) is the second most abundant and essential trace element for all organisms. Under physiological conditions, Zn exists as a non‐redox active divalent cation (Zn ²⁺ ). Zn is part of several biological processes, including transcriptional regulation, signaling, catalysis, and as a structural component of proteins. A complex subcellular network of Zn transporters is indispensable to ensure the adequate distribution of Zn and to maintain homeostasis. Among these, the family of importers Zrt/Irt‐like protein (ZIP) constitutes 14 members (ZIP1‐ZIP14) that mobilize Zn into the cytosol. Some ZIP proteins can also transport iron, manganese, and cadmium. Research has shown that the expression of these transporters varies among tissues and during the different developmental stages. The presence of ZIP transporters at various cellular locations is essential for defining the net cellular transport of Zn. In cells, about 50% of Zn is cytosolic, 30‐40% localizes in the nucleus, and 10% in the membrane. Normally, the ion is bound to proteins or sequestered in organelles and vesicles. Extensive research has focused on Zn internalization in mammalian cells. However, little attention has been given to the mobilization of the ion within the cells and the organelles, including the nucleus. In this regard, ZIP11 is the only ZIP transporter localized in the nucleus of mammalian cells. Sequence analyses indicated that Zip11 expression is responsive to Zn. However, the cellular role and the mechanism and direction of transport of ZIP11 are not defined yet. Therefore, we hypothesized that ZIP11 is a nuclear Zn transporter essential to maintaining nuclear Zn homeostasis in mammalian cells. To test this idea, our laboratory is using a well‐established model of shRNA to knock‐down Zip11 in normal fibroblasts and the cancer cell line HeLa. Preliminary data shows that partial deletion of Zip11 significantly reduced the proliferation rate of HeLa cells, and when HeLa cells reached confluency, they acquired an epithelial morphology. Experiments to determine the expression of epithelial vs . cancer markers are in progress. We will also investigate the direction of transport of ZIP11 by measuring changes in nuclear and cytosolic Zn levels between wild type cells and cells with decreased expression of the transporter. Our work has the potential to discover a novel molecular mechanism where nuclear Zn homeostasis is an essential factor for cancer progression.