Search Results (6)

Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., “gliopathy”. However, the role of SGCs in neuropathic pain is not simply as “peripheral astrocytes”. We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain. Full article

The β-Coronavirus mouse hepatitis virus (MHV-A59)-RSA59 has a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) in the S2 domain of the Spike protein. Our previous studies compared the PP-containing fusogenic-demyelinating strain RSA59(PP) to its one proline-deleted mutant strain RSA59(P) and one proline-containing non-fusogenic non-demyelinating parental strain RSMHV2(P) to its one proline inserted mutant strain RSMHV2(PP). These studies highlighted the crucial role of PP in fusogenicity, hepato-neuropathogenesis, and demyelination. Computational studies combined with biophysical data indicate that PP at the center of the FP provides local rigidity while imparting global fluctuation to the Spike protein that enhances the fusogenic properties of RSA59(PP) and RSMHV2(PP). To elaborate on the understanding of the role of PP in the FP of MHV, the differential neuroglial tropism of the PP and P mutant strains was investigated. Comparative studies demonstrated that PP significantly enhances the viral tropism for neurons, microglia, and oligodendrocytes. PP, however, is not essential for viral tropism for either astroglial or oligodendroglial precursors or the infection of meningeal fibroblasts in the blood–brain and blood–CSF barriers. PP in the fusion domain is critical for promoting gliopathy, making it a potential region for designing antivirals for neuro-COVID therapy. Full article

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) accumulation and cognitive mental decline. Epidemiological studies have suggested an association between low serum vitamin D levels and an increased risk of AD. Vitamin D regulates gene expression via the vitamin D receptor, a nuclear ligand-dependent transcription factor. However, the molecular mechanism underlying the pathogenic and therapeutic effects of vitamin D on AD is not fully understood yet. To better understand how vitamin D regulates the expression of genes related to AD pathology, first, we induced vitamin D deficiency in 5xFAD mice by providing a vitamin-D-deficient diet and observed the changes in the mRNA level of genes related to Aβ processing, which resulted in an increase in the Aβ load in the brain. The vitamin D-deficient diet also suppressed the expression of genes for microglial Aβ phagocytosis. Interestingly, vitamin D deficiency in the early stage of AD resulted in earlier memory impairment. In addition, we administered vitamin D intraperitoneally to 5xFAD mice with a normal diet and found lower Aβ levels with the suppressed expression of genes for Aβ generation and observed improved memory function, which may be potentially associated with reduced MAO-B expression. These findings strongly suggest the role of vitamin D as a crucial disease-modifying factor that may modulate the amyloid pathology with regard to reducing AD symptoms. Full article

Until recently, glia were considered to be a structural support for neurons, however further investigations showed that glial cells are equally as important as neurons. Among many different types of glia, enteric glial cells (EGCs) found in the gastrointestinal tract, have been significantly underestimated, but proved to play an essential role in neuroprotection, immune system modulation and many other functions. They are also said to be remarkably altered in different physiopathological conditions. A nutraceutical is defined as any food substance or part of a food that provides medical or health benefits, including prevention and treatment of the disease. Following the description of these interesting peripheral glial cells and highlighting their role in physiological and pathological changes, this article reviews all the studies on the effects of nutraceuticals as modulators of their functions. Currently there are only a few studies available concerning the effects of nutraceuticals on EGCs. Most of them evaluated molecules with antioxidant properties in systemic conditions, whereas only a few studies have been performed using models of gastrointestinal disorders. Despite the scarcity of studies on the topic, all agree that nutraceuticals have the potential to be an interesting alternative in the prevention and/or treatment of enteric gliopathies (of systemic or local etiology) and their associated gastrointestinal conditions. Full article

Cisplatin is a chemotherapeutic agent widely used for the treatment of solid cancers. Its administration is commonly associated with acute and chronic gastrointestinal dysfunctions, likely related to mucosal and enteric nervous system (ENS) injuries, respectively. Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone exerting trophic/reparative activities on the intestine, via antiapoptotic and pro-proliferating pathways, to guarantee mucosal integrity, energy absorption and motility. Further, it possesses anti-inflammatory properties. Presently, cisplatin acute and chronic damages and GLP-2 protective effects were investigated in the mouse distal colon using histological, immunohistochemical and biochemical techniques. The mice received cisplatin and the degradation-resistant GLP-2 analog ([Gly2]GLP-2) for 4 weeks. Cisplatin-treated mice showed mucosal damage, inflammation, IL-1β and IL-10 increase; decreased number of total neurons, ChAT- and nNOS-immunoreactive (IR) neurons; loss of SOX-10-IR cells and reduced expression of GFAP- and S100β-glial markers in the myenteric plexus. [Gly2]GLP-2 co-treatment partially prevented mucosal damage and counteracted the increase in cytokines and the loss of nNOS-IR and SOX-10-IR cells but not that of ChAT-IR neurons. Our data demonstrate that cisplatin causes mucosal injuries, neuropathy and gliopathy and that [Gly2]GLP-2 prevents these injuries, partially reducing mucosal inflammation and inducing ENS remodeling. Hence, this analog could represent an effective strategy to overcome colonic injures induced by cisplatin. Full article

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease–dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen–nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis—vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow. Full article