Lyonlindholm3457

Background Injections of osmolytes are promising immunomodulatory treatments for medical benefit, although the rationale and underlying mechanisms are often lacking. The goals of the present study were twofold (1) to clarify the anti-inflammatory role of the potassium ion and (2) to begin to decouple the effects that ionic strength, ionic species, and osmolarity have on macrophage biology. Materials and Methods RAW 264.7 murine macrophages were encapsulated in three-dimensional, poly(ethylene glycol) diacrylate hydrogels and activated with interferon-gamma to yield M(IFN). Gene and protein profiles were made of M(IFN) exposed to different hyperosmolar treatments (80 mM potassium gluconate, 80 mM sodium gluconate, and 160 mM sucrose). Results Relative to M(IFN), all hyperosmolar treatments suppressed expression of pro-inflammatory markers (nitric oxide synthase-2 [NOS-2], tumor necrosis factor-alpha, monocyte chemoattractant protein-1 [MCP-1]) and increased messenger RNA (mRNA) expression of the pleiotropic and angiogenic markers interleukin-6 (IL-6) and vascular endothelial growth factor-A (VEGF), respectively. Ionic osmolytes also demonstrated a greater level of change compared to the nonionic treatments, with mRNA levels of IL-6 the most significantly affected. M(IFN) exposed to K+ exhibited the lowest levels of NOS-2 and MCP-1, and this ion limited IL-6 release induced by osmolarity. Conclusion Cumulatively, these data suggest that osmolyte composition, ionic strength, and osmolarity are all parameters that can influence therapeutic outcomes. Future work is necessary to further decouple and mechanistically understand the influence that these biophysical parameters have on cell biology, including their impact on other macrophage functions, intracellular osmolyte composition, and cellular and organellular membrane potentials. Copyright 2020, Mary Ann Liebert, Inc., publishers.Background Human mesenchymal stem cells (hMSCs) are utilized preclinically and clinically as a candidate cell therapy for a wide range of inflammatory and degenerative diseases. Despite promising results in early clinical trials, consistent outcomes with hMSC-based therapies have proven elusive in many of these applications. In this work, we attempt to address this limitation through the design of a stem cell therapy to enrich hMSCs for desired electrical and ionic properties with enhanced stemness and immunomodulatory/regenerative capacity. Materials and Methods In this study, we sought to develop initial protocols to achieve electrically enriched hMSCs (EE-hMSCs) with distinct electrical states and assess the potential relationship with respect to hMSC state and function. We sorted hMSCs based on fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE) and investigated phenotypic differences between the sorted populations. Results Subpopulations of EE-hMSCs exhibit differential expression of genes associated with senescence, stemness, immunomodulation, and autophagy. EE-hMSCs with low levels of TMRE, indicative of depolarized membrane potential, have reduced mRNA expression of senescence-associated markers, and increased mRNA expression of autophagy and immunomodulatory markers relative to EE-hMSCs with high levels of TMRE (hyperpolarized). Conclusions This work suggests that the utilization of EE-hMSCs may provide a novel strategy for cell therapies, enabling live cell enrichment for distinct phenotypes that can be exploited for different therapeutic outcomes. Copyright 2020, Mary Ann Liebert, Inc., publishers.As the leading cause of death in cancer, there is an urgent need to develop treatments to target the dissemination of primary tumor cells to secondary organs, known as metastasis. Bioelectric signaling has emerged in the last century as an important controller of cell growth, and with the development of current molecular tools we are now beginning to identify its role in driving cell migration and metastasis in a variety of cancer types. This review summarizes the currently available research for bioelectric signaling in solid tumor metastasis. We review the steps of metastasis and discuss how these can be controlled by bioelectric cues at the level of a cell, a population of cells, and the tissue. The role of ion channel, pump, and exchanger activity and ion flux is discussed, along with the importance of the membrane potential and the relationship between ion flux and membrane potential. We also provide an overview of the evidence for control of metastasis by external electric fields (EFs) and draw from examples in embryogenesis and regeneration to discuss the implications for endogenous EFs. By increasing our understanding of the dynamic properties of bioelectric signaling, we can develop new strategies that target metastasis to be translated into the clinic. Copyright 2019, Mary Ann Liebert, Inc., publishers.Background Prescriptive and illicit amphetamine (AMPH) use continues to increase along with the likelihood that during an individual's lifetime, the drug deleteriously influences the growth and connectivity of behavior circuits necessary for survival. A-1331852 supplier Throughout ontogeny, neural circuits underlying these behaviors grow in complexity, gradually integrating many sensory inputs that trigger higher order coordinated motor responses. In the present study, we examine how AMPH disrupts the establishment of these circuits at critical neurodevelopmental periods, as well as the communication among established survival circuits. Materials and Methods Zebrafish embryos (from 1 hpf) were raised in AMPH solutions, growth parameters and escape behavior were assessed at 24 and 48 hpf, and spinal cord tissues analyzed for differences in excitatory-inhibitory signaling balance among treatments. Adult fish were fed an acute dosage of AMPH over an 11-day conditioned place preference (PP) paradigm during which behaviors were recorded and brain tissues analyzed for alterations in dopaminergic signaling. Results AMPH negatively affects embryonic growth and slows the execution of escape behavior, suggesting an imbalance in locomotor signaling. Although local spinal circuits provide primary escape modulation, no differences in inhibitory glycinergic, and excitatory glutamatergic signaling were measured among spinal neurons. AMPH also influenced place preference in adult zebrafish and resulted in the increased expression of dopamine signaling proteins (DRD1) in brain areas governing survival behaviors. Copyright 2019, Mary Ann Liebert, Inc., publishers.