Genomic and Non-genomic Action of Neurosteroids in the Peripheral Nervous System

Since the former evidence of biologic actions of neurosteroids in the central nervous system, also the peripheral nervous system (PNS) was reported as a structure affected by these substances. Indeed, neurosteroids are synthesized and active in the PNS, exerting many important actions on the different cell types of this system. PNS is a target for neurosteroids, in their native form or as metabolites. In particular, old and recent evidence indicates that the progesterone metabolite allopregnanolone possesses important functions in the PNS, thus contributing to its physiologic processes. In this review, we will survey the more recent findings on the genomic and non-genomic actions of neurosteroids in nerves, ganglia, and cells forming the PNS, focusing on the mechanisms regulating the peripheral neuron-glial crosstalk. Then, we will refer to the physiopathological significance of the neurosteroid signaling disturbances in the PNS, in to identify new molecular targets for promising pharmacotherapeutic approaches

Popular orange-fleshed sweetpotato products in Rwanda: Biscuits and doughnuts

Golden Power Biscuits and mandazi (fried doughnuts) have emerged as the top products made with freshly prepared orange-fleshed sweetpotato (OFSP) puree at Urwibutso Enterprises. This flyer shares the process and recipe or preparing these popular products

Neurosteroids involvement in the epigenetic control of memory formation and storage

Memory is our ability to store and remember past experiences; it is the result of changes in neuronal circuits of specific brain areas as the hippocampus. During memory formation, neurons integrate their functions and increase the strength of their connections, so that synaptic plasticity is improved and consolidated. All these processes recruit several proteins at the synapses, whose expression is highly regulated by DNA methylation and histone tails posttranslational modifications. Steroids are known to influence memory process, and, among them, neurosteroids are implicated in neurodegenerative disease related to memory loss and cognitive impairment. The epigenetic control of neurosteroids involvement in memory formation and maintenance could represent the basis for neuroregenerative therapies

Regulation of Schwann cells oncotransformation by changes in Nf2/merlin expression, Hippo/YAP signaling and DNA methylation

Schwann cell (SC) express the Neurofibromin type 2 gene (Nf2), encoding the tumor suppressor protein merlin, a cytoskeleton-associated protein regulating cell proliferation and survival. Nf2/merlin inactivation causes protein loss and leads to SC transformation into a form of benign tumor called schwannoma. Moreover, Nf2/merlin is mutated in an autosomal dominant multiple syndrome, called neurofibromatosis type 2. In line with observation that physio/mechanical cues, such as environmental challenges, may be pathogenetically relevant for SC oncotransformation, we recently showed that the exposure to electromagnetic fields (EMFs) causes changes in SC Nf2/merlin expression, cell migration, chemotactic responsivity and cytoskeleton reorganization. We showed a downstream MAPK/Erk activation, involved in SC proliferation, as well as activation of Hippo/YAP signalling commonly altered during tumorigenesis. We also showed that some genes, known to be upstream or downstream mediators of Hippo (Amotl2, Dchs, Fat, Wnt1) were changed. Further studies on rat SC oncotransformation following acute EMF exposure (0.1 T, 50 Hz, 10 min) demonstrated that the number of cells in G1 phase was increased. Focus forming analysis, after repeated exposures, showed an increase in 3D SC growth. EMF affects also the SC epigenome, as total DNA methylation, de novo DNMT and HDAC were reduced. Furthermore, RT2-profile assay evidenced that genes crucial for SCs are upregulated in EMF exposed cells. Overall, we identified some mechanisms responsible of environmental-induced SC changes toward a proliferative/migrating state, which may be pathologically relevant for nerve tumor development

Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons

Protein kinase type C-\u3b5 (PKC\u3b5) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKC\u3b5 is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKC\u3b5, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKC\u3b5 via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain

Establishment and genomic characterization of the new chordoma cell line Chor-IN-1

Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor "brachyury" represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine kinase receptors are also expressed, but so far kinase inhibitors have not shown clear clinical efficacy in chordoma patients. The need for effective therapies is extremely high, but the paucity of established chordoma cell lines has limited preclinical research. Here we describe the isolation of the new Chor-IN-1 cell line from a recurrent sacral chordoma and its characterization as compared to other chordoma cell lines. Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers. Chor-IN-1 gene variants, copy number alterations and kinome gene expression were analyzed in comparison to other four chordoma cell lines, generating large scale DNA and mRNA genomic data that can be exploited for the identification of novel pharmacological targets and candidate predictive biomarkers of drug sensitivity in chordoma. The establishment of this new, well characterized chordoma cell line provides a useful tool for the identification of drugs active in chordoma

Tumor suppressor Nf2/merlin drives Schwann cell changes following electromagnetic field exposure through Hippo-dependent mechanisms

Previous evidence showed mutations of the neurofibromin type 2 gene (Nf2), encoding the tumor suppressor protein merlin, in sporadic and vestibular schwannomas affecting Schwann cells (SC). Accordingly, efforts have been addressed to identify possible factors, even environmental, that may regulate neurofibromas growth. In this context, we investigated the exposure of SC to an electromagnetic field (EMF), which is an environmental issue modulating biological processes. Here we show that SC exposed to 50 Hz EMFs change their morphology, proliferation, migration and myelinating capability. In these cells merlin is downregulated, leading to activation of two intracellular signaling pathways, ERK/AKT and Hippo. Interestingly, SC change their phenotype toward a proliferative/migrating state, which in principle may be pathologically relevant for schwannoma development

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors