Connexin-dependent neuroglial networking as a new therapeutic target

Astrocytes and neurons dynamically interact during physiological processes, and it is now widely accepted that they are both organized in plastic and tightly regulated networks. Astrocytes are connected through connexin-based gap junction channels, with brain region specificities, and those networks modulate neuronal activities, such as those involved in sleep-wake cycle, cognitive, or sensory functions. Additionally, astrocyte domains have been involved in neurogenesis and neuronal differentiation during development; they participate in the "tripartite synapse" with both pre-synaptic and post-synaptic neurons by tuning down or up neuronal activities through the control of neuronal synaptic strength. Connexin-based hemichannels are also involved in those regulations of neuronal activities, however, this feature will not be considered in the present review. Furthermore, neuronal processes, transmitting electrical signals to chemical synapses, stringently control astroglial connexin expression, and channel functions. Long-range energy trafficking toward neurons through connexin-coupled astrocytes and plasticity of those networks are hence largely dependent on neuronal activity. Such reciprocal interactions between neurons and astrocyte networks involve neurotransmitters, cytokines, endogenous lipids, and peptides released by neurons but also other brain cell types, including microglial and endothelial cells. Over the past 10 years, knowledge about neuroglial interactions has widened and now includes effects of CNS-targeting drugs such as antidepressants, antipsychotics, psychostimulants, or sedatives drugs as potential modulators of connexin function and thus astrocyte networking activity. In physiological situations, neuroglial networking is consequently resulting from a two-way interaction between astrocyte gap junction-mediated networks and those made by neurons. As both cell types are modulated by CNS drugs we postulate that neuroglial networking may emerge as new therapeutic targets in neurological and psychiatric disorders

Connexin-Based Channels and RhoA/ROCK Pathway in Angiotensin II-Induced Kidney Damage

The incidence of chronic kidney diseases is increasing worldwide, and there is no efficient therapy to reduce this phenomenon. The main therapies currently available focus on the control of blood pressure and the optimization of the blockade of the renin-angiotensin system (RAS). In addition, it is known that in several models of kidney damage, the amounts of connexins are altered. On the other hand, fasudil, a selective ROCK blocker, has shown renoprotective effects. The beneficial effects of blocking the RhoA/ROCK pathway in renal function may be related to its action of reducing macrophage infiltration, inflammation, and oxidative stress (OS), its expression of extracellular matrix genes and proteinuria, or to its effects on connexin abundance. Even though a correlation has been found between renal damage, caused by an increase in the RAS activity, connexins, and the RhoA/ROCK signaling pathway, it has not yet been possible to clearly determine its functional significance. Moreover, it has not been possible to identify the preponderance of this signaling pathway in the development of chronic kidney diseases. Here, we describe the advances in this subject

Glial connexin expression and function in the context of Alzheimer's disease

AbstractA hallmark of neurodegenerative diseases is the reactive gliosis characterized by a phenotypic change in astrocytes and microglia. This glial response is associated with modifications in the expression and function of connexins (Cxs), the proteins forming gap junction channels and hemichannels. Increased Cx expression is detected in most reactive astrocytes located at amyloid plaques, the histopathological lesions typically present in the brain of Alzheimer's patients and animal models of the disease. The activity of Cx channels analyzed in vivo as well as in vitro after treatment with the amyloid β peptide is also modified and, in particular, hemichannel activation may contribute to neuronal damage. In this review, we summarize and discuss recent data that suggest glial Cx channels participate in the neurodegenerative process of Alzheimer's disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics

Involvement of Gap Junction Proteins in Infectious Diseases Caused by Parasites

Parasitic diseases affect low-income nations with health consequences that affect the economy of these countries. Research aimed at understanding their biology and identification of potential targets for drug development is of the highest priority. Inhibitors of channels formed by proteins of the gap junction family such as suramin and probenecid are currently used for treatment of parasitic diseases caused by pathogenic protozoan. Gap junction proteins are present in both vertebrates and invertebrates permitting direct and indirect cellular communication. These cellular specializations are formed by two protein families corresponding to connexins (vertebrates) and innexins (invertebrates). In addition, a third protein family composed by proteins denominated pannexins is present in vertebrates and shows primary sequence homology to innexins. Channels formed by these proteins are essential in many biological processes. Recent evidences suggest that gap junction proteins play a critical role in bacterial and viral infections. Nonetheless, little is known about the role of these channels in parasitic infections. In this chapter, we summarized the current knowledge about the role of gap junction family proteins and channels in parasitic infections

Stability metrics for multi-source biomedical data based on simplicial projections from probability distribution distances

[EN] Biomedical data may be composed of individuals generated from distinct, meaningful sources. Due to possible contextual biases in the processes that generate data, there may exist an undesirable and unexpected variability among the probability distribution functions (PDFs) of the source subsamples, which, when uncontrolled, may lead to inaccurate or unreproducible research results. Classical statistical methods may have difficulties to undercover such variabilities when dealing with multi-modal, multi-type, multi-variate data. This work proposes two metrics for the analysis of stability among multiple data sources, robust to the aforementioned conditions, and defined in the context of data quality assessment. Specifically, a global probabilistic deviation (GPD) and a source probabilistic outlyingness (SPO) metrics are proposed. The first provides a bounded degree of the global multi-source variability, designed as an estimator equivalent to the notion of normalized standard deviation of PDFs. The second provides a bounded degree of the dissimilarity of each source to a latent central distribution. The metrics are based on the projection of a simplex geometrical structure constructed from the Jensen-Shannon distances among the sources PDFs. The metrics have been evaluated and demonstrated their correct behaviour on a simulated benchmark and with real multi-source biomedical data using the UCI Heart Disease dataset. The biomedical data quality assessment based on the proposed stability metrics may improve the efficiency and effectiveness of biomedical data exploitation and research.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by own IBIME funds under the UPV project Servicio de evaluacion y rating de la calidad de repositorios de datos biomedicos [UPV-2014-872] and the EU FP7 Project Help4Mood - A Computational Distributed System to Support the Treatment of Patients with Major Depression [ICT-248765].Sáez Silvestre, C.; Robles Viejo, M.; García Gómez, JM. (2014). Stability metrics for multi-source biomedical data based on simplicial projections from probability distribution distances. Statistical Methods in Medical Research. 1-25. https://doi.org/10.1177/0962280214545122S12

Possible Role of Gap Junction Channels and Non-Junctional Channels in the Infection Caused by <em>Trypanosoma cruzi</em>

Chagas disease affects low-income nations with health consequences that impact the economy of those countries. Interestingly, inhibitors of channels formed by proteins of the gap junction family, such as suramin and boldine, exhibit trypanocidal activity. Gap junction proteins are integral membrane proteins present in both vertebrates and invertebrates that participate in cellular communication. These proteins form gap junction channels, which connect the cytoplasm of neighboring cells or non-junctional channels that connect the intra- and extracellular milieu. Interestingly, Trypanosoma cruzi modulates the expression of proteins of the gap junction family or modify the activity of the channels formed by these proteins in host cells. Moreover, Lucifer yellow microinjected into fibroblast was incorporated into associated trypanosomes of Trypanosoma musculi, suggesting the possibility of direct communication via gap junction channels between them. In this chapter, we summarized the current knowledge about the possible roles of gap junction family proteins in Chagas disease

Relation of surface and underground waters in Chungará and Cotacotani lake districts, northern Chile: an isotopic study.

Lake Chungará and Cotacotani lake districts are surface water bodies located to the northwest of Lauca Basin in the northern Chilean Altiplano. Surface and underground waters show low to moderate saline content and an electrical conductivity in the range of 48.7 to 3090 μS/cm. The lakes are related to a system of aquifers on the nearby volcano flanks and debris avalanche deposits of Parinacota volcano. On the basis of δ18O and δD isotopic composition and its correlation with the chloride content in Chungará and Cotacotani lake, spring, and Chungará river waters it is demonstrated that: a. Lake Chungará's waters show vertical and horizontal homogeneous isotopic composition, which indicates a good mixture of waters in the lake; b. an important part of the Cotacotani lake recharge feeding come from Lake Chungará, that flows laterally as groundwater; c. the groundwater that feeds the springs of the area has its main recharge in the spring-summer (October-March) precipitation. The high content of tritium (3H) measured in spring waters of the area suggested a very recent recharge (last decades) of the aquifer system. The application of lumped parameter models to interpret the water residence time in the aquifer indicates that the piston flow model shows the best fit to the isotopic composition of Chungará-Cotacotani groundwater

Connexins and Pannexins in Bone and Skeletal Muscle

PURPOSE OF REVIEW: To discuss current knowledge on the role of connexins and pannexins in the musculoskeletal system. RECENT FINDINGS: Connexins and pannexins are crucial for the development and maintenance of both bone and skeletal muscle. In bone, the presence of connexin and more recently of pannexin channels in osteoblasts, osteoclasts, and osteocytes has been described and shown to be essential for normal skeletal development and bone adaptation. In skeletal muscles, connexins and pannexins play important roles during development and regeneration through coordinated regulation of metabolic functions via cell-to-cell communication. Further, under pathological conditions, altered expression of these proteins can promote muscle atrophy and degeneration by stimulating inflammasome activity. In this review, we highlight the important roles of connexins and pannexins in the development, maintenance, and regeneration of musculoskeletal tissues, with emphasis on the mechanisms by which these molecules mediate chemical (e.g., ATP and prostaglandin E2) and physical (e.g., mechanical stimulation) stimuli that target the musculoskeletal system and their involvement in the pathophysiological changes in both genetic and acquired diseases