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16 pages, 3054 KiB

Open AccessArticle

Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts

by Tahereh Gharbi, Chang Liu, Haroon Khan, Zhijun Zhang, Guo-Yuan Yang and Yaohui Tang

Curr. Issues Mol. Biol. 2023, 45(3), 1982-1997; https://doi.org/10.3390/cimb45030127 - 1 Mar 2023

Cited by 2 | Viewed by 1738

Abstract

Hypoxic preconditioning has been demonstrated to increase the resistance of neural stem cells (NSCs) to hypoxic conditions, as well as to improve their capacity for differentiation and neurogenesis. Extracellular vesicles (EVs) have recently emerged as critical mediators of cell–cell communication, but their role [...] Read more.

Hypoxic preconditioning has been demonstrated to increase the resistance of neural stem cells (NSCs) to hypoxic conditions, as well as to improve their capacity for differentiation and neurogenesis. Extracellular vesicles (EVs) have recently emerged as critical mediators of cell–cell communication, but their role in this hypoxic conditioning is presently unknown. Here, we demonstrated that three hours of hypoxic preconditioning triggers significant neural stem cell EV release. Proteomic profiling of EVs from normal and hypoxic preconditioned neural stem cells identified 20 proteins that were upregulated and 22 proteins that were downregulated after hypoxic preconditioning. We also found an upregulation of some of these proteins by qPCR, thus indicating differences also at the transcript level within the EVs. Among the upregulated proteins are CNP, Cyfip1, CASK, and TUBB5, which are well known to exhibit significant beneficial effects on neural stem cells. Thus, our results not only show a significant difference of protein cargo in EVs consequent to hypoxic exposure, but identify several candidate proteins that might play a pivotal role in the cell-to-cell mediated communication underlying neuronal differentiation, protection, maturation, and survival following exposure to hypoxic conditions. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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19 pages, 5065 KiB

Open AccessArticle

Effects of Scrophularia buergeriana Extract (Brainon^®) on Aging-Induced Memory Impairment in SAMP8 Mice

by Hae Lim Kim, Sung Kwon Lee, Da Eun Min, Tonking Bastola, Bo Yoon Chang, Jin Hye Bae and Dong Ryung Lee

Curr. Issues Mol. Biol. 2023, 45(2), 1287-1305; https://doi.org/10.3390/cimb45020084 - 3 Feb 2023

Cited by 3 | Viewed by 1841

Abstract

Alzheimer’s disease (AD) is a worldwide problem. Currently, there are no effective drugs for AD treatment. Scrophularia buergeriana Miquel (SB) is a traditional herbal medicine used in Korea to treat various diseases. Our previous studies have shown that ethanol extract of SB roots [...] Read more.

Alzheimer’s disease (AD) is a worldwide problem. Currently, there are no effective drugs for AD treatment. Scrophularia buergeriana Miquel (SB) is a traditional herbal medicine used in Korea to treat various diseases. Our previous studies have shown that ethanol extract of SB roots (SBE, Brainon^®) exhibits potent anti-amnesic effects in Aβ_1–42- or scopolamine-treated memory impairment mice model and neuroprotective effects in a glutamate-induced SH-SY5Y cell model. In this study, we evaluated the therapeutic effects of Brainon^® and its mechanism of action in senescence-accelerated mouse prone 8 (SAMP8) mice. Brainon^® (30 or 100 mg/kg/day) was orally treated to six-month-old SAMP8 mice for 12 weeks. Results revealed that Brainon^® administration effectually ameliorated cognitive deficits in Y-maze and passive avoidance tests. Following the completion of behavioral testing, western blotting was performed using the cerebral cortex. Results revealed that Brainon^® suppressed Aβ_1–42 accumulation, Tau hyperphosphorylation, oxidative stress, and inflammation and alleviated apoptosis in SAMP8 mice. Brainon^® also promoted synaptic function by downregulating the expression of AChE and upregulating the expression of p-CREB/CREB and BDNF. Furthermore, Brainon^® restored SAMP8-reduced expression of ChAT and -dephosphorylated of ERK and also decreased AChE expression in the hippocampus. Furthermore, Brainon^® alleviated AD progression by promoting mitophagy/autophagy to maintain normal cellular function as a novel finding of this study. Our data suggest that Brainon^® can remarkably improve cognitive deficiency with the potential to be utilized in functional food for improving brain health. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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10 pages, 463 KiB

Open AccessArticle

Effect of Long-Term Adaptation to Cold and Short-Term Cooling on the Expression of the TRPM2 Ion Channel Gene in the Hypothalamus of Rats

by Anna A. Evtushenko, Irina P. Voronova and Tamara V. Kozyreva

Curr. Issues Mol. Biol. 2023, 45(2), 1002-1011; https://doi.org/10.3390/cimb45020065 - 20 Jan 2023

Cited by 3 | Viewed by 1357

Abstract

The present study is aimed to elucidate the possible involvement of the thermosensitive TRPM2 ion channel in changing of the temperature sensitivity of the hypothalamus after different cold exposures—long-term adaptation to cold and short-term cooling. Quantitative RT-PCR was used to study the expression [...] Read more.

The present study is aimed to elucidate the possible involvement of the thermosensitive TRPM2 ion channel in changing of the temperature sensitivity of the hypothalamus after different cold exposures—long-term adaptation to cold and short-term cooling. Quantitative RT-PCR was used to study the expression of the gene of thermosensitive TRPM2 ion channel in the hypothalamus in the groups of control (kept for 5 weeks at +20 to +22 °C) and cold-adapted (5 weeks at +4 to +6 °C) rats, as well as in the groups of animals which were subjected to acute cooling (rapid or slow) with subsequent restoration of body temperature to the initial level. It has been shown that after long-term adaptation to cold, the decrease in the Trpm2 gene expression was observed in the hypothalamus, while a short-term cooling does not affect the expression of the gene of this ion channel. Thus, long-term adaptation to cold results in the decrease in the activity not only of the TRPV3 ion channel gene, as shown earlier, but also of the Trpm2 gene in the hypothalamus. The overlapping temperature ranges of the functioning of these ion channels and their unidirectional changes during the adaptation of the homoeothermic organism to cold suggest their functional interaction. The decrease in the Trpm2 gene expression may indicate the participation of this ion channel in adaptive changes in hypothalamic thermosensitivity, but only as a result of long-term cold exposure and not of a short-term cooling. These processes occurring at the genomic level are one of the molecular mechanisms of the adaptive changes. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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17 pages, 8068 KiB

Open AccessArticle

1,2-¹³C₂-Glucose Tracing Approach to Assess Metabolic Alterations of Human Monocytes under Neuroinflammatory Conditions

by Ginevra Giacomello, Carolin Otto, Josef Priller, Klemens Ruprecht, Chotima Böttcher and Maria Kristina Parr

Curr. Issues Mol. Biol. 2023, 45(1), 765-781; https://doi.org/10.3390/cimb45010051 - 16 Jan 2023

Cited by 1 | Viewed by 1942

Abstract

Neuroinflammation is one of the common features in most neurological diseases including multiple sclerosis (MScl) and neurodegenerative diseases such as Alzheimer’s disease (AD). It is associated with local brain inflammation, microglial activation, and infiltration of peripheral immune cells into cerebrospinal fluid (CSF) and [...] Read more.

Neuroinflammation is one of the common features in most neurological diseases including multiple sclerosis (MScl) and neurodegenerative diseases such as Alzheimer’s disease (AD). It is associated with local brain inflammation, microglial activation, and infiltration of peripheral immune cells into cerebrospinal fluid (CSF) and the central nervous system (CNS). It has been shown that the diversity of phenotypic changes in monocytes in CSF relates to neuroinflammation. It remains to be investigated whether these phenotypic changes are associated with functional or metabolic alteration, which may give a hint to their function or changes in cell states, e.g., cell activation. In this article, we investigate whether major metabolic pathways of blood monocytes alter after exposure to CSF of healthy individuals or patients with AD or MScl. Our findings show a significant alteration of the metabolism of monocytes treated with CSF from patients and healthy donors, including higher production of citric acid and glutamine, suggesting a more active glycolysis and tricarboxylic acid (TCA) cycle and reduced production of glycine and serine. These alterations suggest metabolic reprogramming of monocytes, possibly related to the change of compartment (from blood to CSF) and/or disease-related. Moreover, the levels of serine differ between AD and MScl, suggesting different phenotypic alterations between diseases. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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25 pages, 1707 KiB

Open AccessArticle

Transcriptomic Analysis of the Effect of Metformin against Cisplatin-Induced Ototoxicity: A Potential Mechanism of Metformin-Mediated Inhibition of Thioredoxin-Interacting Protein (Txnip) Gene Expression

by Sehee Lee, Sun Choi, Seok Hyun Park, Gi Jung Im and Jiwon Chang

Curr. Issues Mol. Biol. 2023, 45(1), 286-310; https://doi.org/10.3390/cimb45010021 - 31 Dec 2022

Viewed by 1418

Abstract

Ototoxicity is the drug-induced damage of the inner ear, causing bilateral irreversible sensorineural hearing loss. Cisplatin is a widely used chemotherapeutic agent which causes ototoxicity as its side effect. Pretreatment with metformin prior to the application of cisplatin significantly decreased the late apoptosis [...] Read more.

Ototoxicity is the drug-induced damage of the inner ear, causing bilateral irreversible sensorineural hearing loss. Cisplatin is a widely used chemotherapeutic agent which causes ototoxicity as its side effect. Pretreatment with metformin prior to the application of cisplatin significantly decreased the late apoptosis and attenuated the cisplatin-induced increase in ROS. To understand the molecular mechanisms that are involved in the preventive effect of metformin, we evaluated the change of gene expression induced by cisplatin at several different time points (0 h, 6 h, 15 h, 24 h and 48 h) and the alteration of gene expression according to pretreatment with metformin in HEI-OC1 cells through microarray analysis. Cisplatin exposure induced a total of 89 DEGs (differentially expressed genes) after 6 h, with a total of 433 DEGs after 15 h, a total of 941 DEGs after 24 h, and a total of 2764 DEGs after 48 h. When cells were pretreated with metformin for 24 h, we identified a total of 105 DEGs after 6 h of cisplatin exposure, a total of 257 DEGs after 15 h, a total of 1450 DEGs after 24 h, and a total of 1463 DEGs after 48 h. The analysis was performed based on the gene expression, network analyses, and qRT-PCR, and we identified several genes (CSF2, FOS, JUN, TNFα, NFκB, Txnip, ASK1, TXN2, ATF3, TP53, IL6, and IGF1) as metformin-related preventive biomarkers in cisplatin ototoxicity. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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12 pages, 4387 KiB

Open AccessArticle

miR-92a-2-5p Regulates the Proliferation and Differentiation of ASD-Derived Neural Progenitor Cells

by Wenting Zhuang, Hui Liu, Zhize He, Jielan Ju, Qiuxia Gao, Zhiyan Shan and Lei Lei

Curr. Issues Mol. Biol. 2022, 44(6), 2431-2442; https://doi.org/10.3390/cimb44060166 - 24 May 2022

Cited by 2 | Viewed by 1959

Abstract

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with abnormal behavior. However, the pathogenesis of ASD remains to be clarified. It has been demonstrated that miRNAs are essential regulators of ASD. However, it is still unclear how miR-92a-2-5p acts on [...] Read more.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with abnormal behavior. However, the pathogenesis of ASD remains to be clarified. It has been demonstrated that miRNAs are essential regulators of ASD. However, it is still unclear how miR-92a-2-5p acts on the developing brain and the cell types directly. In this study, we used neural progenitor cells (NPCs) derived from ASD-hiPSCs as well as from neurotypical controls to examine the effects of miR-92a-2-5p on ASD-NPCs proliferation and neuronal differentiation, and whether miR-92a-2-5p could interact with genetic risk factor, DLG3 for ASD. We observed that miR-92a-2-5p upregulated in ASD-NPCs results in decreased proliferation and neuronal differentiation. Inhibition of miR-92a-2-5p could promote proliferation and neuronal differentiation of ASD-NPCs. DLG3 was negatively regulated by miR-92a-2-5p in NPCs. Our results suggest that miR-92a-2-5p is a strong risk factor for ASD and potentially contributes to neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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10 pages, 901 KiB

Open AccessArticle

The Selective Agonist for Sphingosine-1-Phosphate Receptors Siponimod Increases the Expression Level of NR4A Genes in Microglia Cell Line

by Francesca Montarolo, Serena Martire, Fabiana Marnetto, Paola Valentino, Sabdi Valverde, Marco Alfonso Capobianco and Antonio Bertolotto

Curr. Issues Mol. Biol. 2022, 44(3), 1247-1256; https://doi.org/10.3390/cimb44030083 - 7 Mar 2022

Cited by 4 | Viewed by 2670

Abstract

Fingolimod (FTY720) and siponimod (BAF312) are selective agonists for sphingosine-1-phosphate (S1P) receptors approved for the treatment of relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), respectively. BAF312 exerts pro-myelination and neuro-protective functions on CNS resident cells, although the underlying molecular mechanism is [...] Read more.

Fingolimod (FTY720) and siponimod (BAF312) are selective agonists for sphingosine-1-phosphate (S1P) receptors approved for the treatment of relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), respectively. BAF312 exerts pro-myelination and neuro-protective functions on CNS resident cells, although the underlying molecular mechanism is not yet fully understood. NR4A2 is an anti-inflammatory gene, belonging to the NR4A family, whose expression is reduced in blood from treatment-naïve patients with RRMS, but is restored in patients treated with FTY720 for more than two years. We performed an in vitro study to investigate the potential involvement of the NR4A genes in the protective and restorative effects of BAF312. We showed that BAF312 enhances the expression of NR4A1 and NR4A2 in the N9 microglial cell line, but has no effect in the peripheral blood mononuclear cells and oligodendrocytes. This study suggests a novel molecular mechanism of action for the selective agonists for S1P receptors within the CNS. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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19 pages, 3618 KiB

Open AccessArticle

Mesenchymal Stem Cells in the Treatment of Human Spinal Cord Injury: The Effect on Individual Values of pNF-H, GFAP, S100 Proteins and Selected Growth Factors, Cytokines and Chemokines

by Lucia Slovinska, Denisa Harvanova, Jana Janockova, Jana Matejova, Peter Cibur, Marko Moravek, Timea Spakova and Jan Rosocha

Curr. Issues Mol. Biol. 2022, 44(2), 578-596; https://doi.org/10.3390/cimb44020040 - 24 Jan 2022

Cited by 3 | Viewed by 2979

Abstract

At present, there is no effective way to treat the consequences of spinal cord injury (SCI). SCI leads to the death of neural and glial cells and widespread neuroinflammation with persisting for several weeks after the injury. Mesenchymal stem cells (MSCs) therapy is [...] Read more.

At present, there is no effective way to treat the consequences of spinal cord injury (SCI). SCI leads to the death of neural and glial cells and widespread neuroinflammation with persisting for several weeks after the injury. Mesenchymal stem cells (MSCs) therapy is one of the most promising approaches in the treatment of this injury. The aim of this study was to characterize the expression profile of multiple cytokines, chemokines, growth factors, and so-called neuromarkers in the serum of an SCI patient treated with autologous bone marrow-derived MSCs (BM-MSCs). SCI resulted in a significant increase in the levels of neuromarkers and proteins involved in the inflammatory process. BM-MSCs administration resulted in significant changes in the levels of neuromarkers (S100, GFAP, and pNF-H) as well as changes in the expression of proteins and growth factors involved in the inflammatory response following SCI in the serum of a patient with traumatic SCI. Our preliminary results encouraged that BM-MSCs with their neuroprotective and immunomodulatory effects could affect the repair process after injury. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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13 pages, 430 KiB

Open AccessBrief Report

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

by Danton H. O’Day

Curr. Issues Mol. Biol. 2022, 44(11), 5802-5814; https://doi.org/10.3390/cimb44110394 - 21 Nov 2022

Cited by 7 | Viewed by 1902

Abstract

Neurodegeneration leads to multiple early changes in cognitive, emotional, and social behaviours and ultimately progresses to dementia. The dysregulation of calcium is one of the earliest potentially initiating events in the development of neurodegenerative diseases. A primary neuronal target of calcium is the [...] Read more.

Neurodegeneration leads to multiple early changes in cognitive, emotional, and social behaviours and ultimately progresses to dementia. The dysregulation of calcium is one of the earliest potentially initiating events in the development of neurodegenerative diseases. A primary neuronal target of calcium is the small sensor and effector protein calmodulin that, in response to calcium levels, binds to and regulates hundreds of calmodulin binding proteins. The intimate and entangled relationship between calmodulin binding proteins and all phases of Alzheimer’s disease has been established, but the relationship to other neurodegenerative diseases is just beginning to be evaluated. Risk factors and hallmark proteins from Parkinson’s disease (PD; SNCA, Parkin, PINK1, LRRK2, PARK7), Huntington’s disease (HD; Htt, TGM1, TGM2), Lewy Body disease (LBD; TMEM175, GBA), and amyotrophic lateral sclerosis/frontotemporal disease (ALS/FTD; VCP, FUS, TDP-43, TBK1, C90rf72, SQSTM1, CHCHD10, SOD1) were scanned for the presence of calmodulin binding domains and, within them, appropriate binding motifs. Binding domains and motifs were identified in multiple risk proteins, some of which are involved in multiple neurodegenerative diseases. The potential calmodulin binding profiles for risk proteins involved in HD, PD, LBD, and ALS/FTD coupled with other studies on proven binding proteins supports the central and potentially critical role for calmodulin in neurodegenerative events. Full article

(This article belongs to the Special Issue Signaling Pathways, Development, and Biomarkers in Neuropathy)

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