Cell-cell communication is essential for tissue homeostasis, but its contribution to disease prevention remains to be understood. We demonstrate the involvement of connexin 43 (Cx43, also known as GJA1) and related gap junction in epithelial homeostasis, illustrated by polarity-mediated cell cycle entry and mitotic spindle orientation (MSO). Cx43 localization is restricted to the apicolateral membrane of phenotypically normal breast luminal epithelial cells in 3D culture and in vivo. Chemically induced blockade of gap junction intercellular communication (GJIC), as well as the absence of Cx43, disrupt the apicolateral distribution of polarity determinant tight junction marker ZO-1 (also known as TJP1) and lead to random MSO and cell multilayering. Induced expression of Cx43 in cells that normally lack this protein reestablishes polarity and proper MSO in 3D culture. Cx43-directed MSO implicates PI3K-aPKC signaling, and Cx43 coprecipitates with signaling node proteins β-catenin (CTNNB1) and ZO-2 (also known as TJP2) in the polarized epithelium. The distribution of Cx43 is altered by pro-inflammatory breast cancer risk factors such as leptin and high-fat diet, as shown in cell culture and on tissue biopsy sections. The control of polarity-mediated quiescence and MSO may contribute to the tumor-suppressive role of Cx43.

Co, Ni, Cu, Zn, Hg) and metalloids from group 13-16 of the periodic table (e.g., Al, Ga, As, Sn, Sb, Pb, Bi) have increasingly Copper (Cu) and its alloys have been shown to eradicate a wide range of multidrug-resistant microbes upon direct contact. In this study, a facile one-step laser texturing (LT) process is demonstrated to effectively enhance the bactericidal properties of copper surfaces via concurrent selective modification of surface topography and chemistry of laser textured copper (LT-Cu). Surface morphology and elemental composition are analyzed via field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), and Raman spectroscopy. Surface area and pore size of LT-Cu is determined by Barrett-Joyner-Halenda (BJH) and Brunauer-Emmett-Teller (BET) analysis. It reveals direct formation of mesoporous structures with higher surface oxide (Cu 2 O and CuO), which provide a highly stable superhydrophilic property to the LT-Cu surfaces. The antibacterial properties of LT-Cu are tested against pathogenic bacterial strains with different concentrations including Pseudomonas aeruginosa, and methicillinresistant Staphylococcus aureus (MRSA USA300) at 10 5 CFU mL −1 , and Escherichia coli and Staphylococcus aureus at high bacterial concentrations of 10 8 CFU mL −1 using standard contact killing tests. The analysis shows that LT-Cu needs 40, 90, 60, and 120 min to completely eradicate the respective bacterial strain. The LT-Cu causes membrane damage to the bacterial cells immediately after exposure. Furthermore, the biocompatibility of LT-Cu is investigated by in vitro immune-staining assays with mammary stromal fibroblasts and T4-2 cells.

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Three-dimensional cell culture has the potential to revolutionize toxicology studies by allowing human-based reproduction of essential elements of organs. Beyond the study of toxicants on the most susceptible organs such as liver, kidney, skin, lung, gastrointestinal tract, testis, heart and brain, carcinogenesis research will also greatly benefit from 3D cell culture models representing any normal tissue. No tissue function can be suitably reproduced without the appropriate tissue architecture whether mimicking acini, ducts or tubes, sheets of cells or more complex cellular organizations like hepatic cords. In this review, we illustrate the fundamental characteristics of polarity that is an essential architectural feature of organs for which different 3D cell culture models are available for toxicology studies in vitro. The value of tissue polarity for the development of more accurate carcinogenesis studies is also exemplified, and the concept of using extracellular gradients of gaseous or chemical substances produced with microfluidics in 3D cell culture is discussed. Indeed such gradients-on-a-chip might bring unprecedented information to better determine permissible exposure levels. Finally, the impact of tissue architecture, established via cell-matrix interactions, on the cell nucleus is emphasized in light of the importance in toxicology of morphological and epigenetic alterations of this organelle.