The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex. To date, most in vitro BBB models utilize endothelial cells, pericytes and astrocytes. We report a 3D spheroid model of the BBB comprising all major cell types, including neurons, microglia and oligodendrocytes, to recapitulate more closely normal human brain tissue. Spheroids show expression of tight junctions, adherens junctions, adherens junction-associated proteins and cell specific markers. Functional assessment using MPTP, MPP+ and mercury chloride indicate charge selectivity through the barrier. Junctional protein distribution was altered under hypoxic conditions. Our spheroid model may have potential applications in drug discovery, disease modeling, neurotoxicity and cytotoxicity testing.
Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O
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supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.
The immune response to ischemic stroke is an area of study that is at the forefront of stroke research and presents promising new avenues for treatment development. Upon cerebral vessel occlusion, the innate immune system is activated by danger-associated molecular signals from stressed and dying neurons. Microglia, an immune cell population within the central nervous system which phagocytose cell debris and modulate the immune response via cytokine signaling, are the first cell population to become activated. Soon after, monocytes arrive from the peripheral immune system, differentiate into macrophages, and further aid in the immune response. Upon activation, both microglia and monocyte-derived macrophages are capable of polarizing into phenotypes which can either promote or attenuate the inflammatory response. Phenotypes which promote the inflammatory response are hypothesized to increase neuronal damage and impair recovery of neuronal function during the later phases of ischemic stroke. Therefore, modulating neuroimmune cells to adopt an anti-inflammatory response post ischemic stroke is an area of current research interest and potential treatment development. In this review, we outline the biology of microglia and monocyte-derived macrophages, further explain their roles in the acute, subacute, and chronic stages of ischemic stroke, and highlight current treatment development efforts which target these cells in the context of ischemic stroke.
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