Lab-on-a-Chip Platforms as Tools for Drug Screening in Neuropathologies Associated with Blood-Brain Barrier Alterations.

Lab-on-a-chip (LOC) and organ-on-a-chip (OOC) devices are highly versatile platforms that enable miniaturization and advanced controlled laboratory functions (i.e., microfluidics, advanced optical or electrical recordings, high-throughput screening). The manufacturing advancements of LOCs/OOCs for biomedical applications and their current limitations are briefly discussed. Multiple studies have exploited the advantages of mimicking organs or tissues on a chip. Among these, we focused our attention on the brain-on-a-chip, blood-brain barrier (BBB)-on-a-chip, and neurovascular unit (NVU)-on-a-chip applications. Mainly, we review the latest developments of brain-on-a-chip, BBB-on-a-chip, and NVU-on-a-chip devices and their use as testing platforms for high-throughput pharmacological screening. In particular, we analyze the most important contributions of these studies in the field of neurodegenerative diseases and their relevance in translational personalized medicine.

Ca2+ homeostasis in brain microvascular endothelial cells.

Blood brain barrier (BBB) is formed by the brain microvascular endothelial cells (BMVECs) lining the wall of brain capillaries. Its integrity is regulated by multiple mechanisms, including up/downregulation of tight junction proteins or adhesion molecules, altered Ca2+ homeostasis, remodeling of cytoskeleton, that are confined at the level of BMVECs. Beside the contribution of BMVECs to BBB permeability changes, other cells, such as pericytes, astrocytes, microglia, leukocytes or neurons, etc. are also exerting direct or indirect modulatory effects on BBB. Alterations in BBB integrity play a key role in multiple brain pathologies, including neurological (e.g. epilepsy) and neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis etc.). In this review, the principal Ca2+ signaling pathways in brain microvascular endothelial cells are discussed and their contribution to BBB integrity is emphasized. Improving the knowledge of Ca2+ homeostasis alterations in BMVECa is fundamental to identify new possible drug targets that diminish/prevent BBB permeabilization in neurological and neurodegenerative disorders.

Altered Organelle Calcium Transport in Ovarian Physiology and Cancer.

Calcium levels have a huge impact on the physiology of the female reproductive system, in particular, of the ovaries. Cytosolic calcium levels are influenced by regulatory proteins (i.e., ion channels and pumps) localized in the plasmalemma and/or in the endomembranes of membrane-bound organelles. Imbalances between plasma membrane and organelle-based mechanisms for calcium regulation in different ovarian cell subtypes are contributing to ovarian pathologies, including ovarian cancer. In this review, we focused our attention on altered calcium transport and its role as a contributor to tumor progression in ovarian cancer. The most important proteins described as contributing to ovarian cancer progression are inositol trisphosphate receptors, ryanodine receptors, transient receptor potential channels, calcium ATPases, hormone receptors, G-protein-coupled receptors, and/or mitochondrial calcium uniporters. The involvement of mitochondrial and/or endoplasmic reticulum calcium imbalance in the development of resistance to chemotherapeutic drugs in ovarian cancer is also discussed, since Ca2+ channels and/or pumps are nowadays regarded as potential therapeutic targets and are even correlated with prognosis.

Role of microRNAs as Clinical Cancer Biomarkers for Ovarian Cancer: A Short Overview.

Ovarian cancer has the highest mortality rate among gynecological cancers. Early clinical signs are missing and there is an urgent need to establish early diagnosis biomarkers. MicroRNAs are promising biomarkers in this respect. In this paper, we review the most recent advances regarding the alterations of microRNAs in ovarian cancer. We have briefly described the contribution of miRNAs in the mechanisms of ovarian cancer invasion, metastasis, and chemotherapy sensitivity. We have also summarized the alterations underwent by microRNAs in solid ovarian tumors, in animal models for ovarian cancer, and in various ovarian cancer cell lines as compared to previous reviews that were only focused the circulating microRNAs as biomarkers. In this context, we consider that the biomarker screening should not be limited to circulating microRNAs per se, but rather to the simultaneous detection of the same microRNA alteration in solid tumors, in order to understand the differences between the detection of nucleic acids in early vs. late stages of cancer. Moreover, in vitro and in vivo models should also validate these microRNAs, which could be very helpful as preclinical testing platforms for pharmacological and/or molecular genetic approaches targeting microRNAs. The enormous quantity of data produced by preclinical and clinical studies regarding the role of microRNAs that act synergistically in tumorigenesis mechanisms that are associated with ovarian cancer subtypes, should be gathered, integrated, and compared by adequate methods, including molecular clustering. In this respect, molecular clustering analysis should contribute to the discovery of best biomarkers-based microRNAs assays that will enable rapid, efficient, and cost-effective detection of ovarian cancer in early stages. In conclusion, identifying the appropriate microRNAs as clinical biomarkers in ovarian cancer might improve the life quality of patients.