Thymosin β4 as a restorative/regenerative therapy for neurological injury and neurodegenerative diseases

Chopp, Michael; Zhang, Zheng G ang

doi:10.1517/14712598.2015.1005596

Cited by 20 publications

(21 citation statements)

References 15 publications

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“…MicroRNAs, small 22-25 nucleotide noncoding RNAs, have the ability to affect the translation of many proteins and are involved in mediating microglia activation [31]. Consistent with previous observations, miRNA-339-5p was found to be upregulated in mouse alcohol-induced brain damage [32].…”

Section: Discussionsupporting

confidence: 85%

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Zhang¹,

Wu²,

Zeng³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Neuroinflammation mediated by activated microglia may play a pivotal role in a variety of central nervous system (CNS) pathologic conditions, including ethanolinduced neurotoxicity. The purpose of this study was to investigate the function of Tβ4 in ethanol-induced microglia activation. Methods: Quantitative real-time PCR was conducted to assess the expression of Tβ4 and miR-339-5p. Western blot analysis was used to measure the expression of Tβ4, phosphorylated p38, ERK, JNK, Akt, and NF-κB p65. The concentration of TNF-α and IL-1β was determined using ELISA. NO concentration was measured using a nitric oxide colorimetric BioAssay Kit. Double immunofluorescence was performed to determine Tβ4 expression, in order to assess microglial activation in neonatal mouse FASD model. Results: Increased Tβ4 expression was observed in ethanol treated microglia. Knockdown of Tβ4 enhanced ethanol-induced inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and nitric oxide (NO) in BV-2 cells was performed. Exogenous Tβ4 treatment significantly inhibited expression and secretion of these inflammatory mediators. Tβ4 treatment attenuated p38, ERK MAPKs, and nuclear factor-kappa B (NF-κB) pathway activation, and enhanced miR-339-5p expression induced by ethanol exposure in microglia. A neonatal mouse fetal alcohol spectrum disorders (FASD) model showed that Tβ4 expression in the microglia of the hippocampus was markedly enhanced, while Tβ4 treatment effectively blocked the ethanol-induced increase in inflammatory mediators, to the level expressed in vehicle-treated control animals. Conclusion: This study is the first to demonstrate the function of Tβ4 in ethanol-induced microglia activation, thus contributing to a more robust understanding of the role of Tβ4 treatment in CNS disease.

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Section: Discussionsupporting

confidence: 85%

Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Zhang¹,

Wu²,

Zeng³

et al. 2016

Cell Physiol Biochem

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“…), regeneration (Lopez‐Verrilli et al . ; Chopp & Zhang ; de Rivero Vaccari et al . ) and other functions (Emmanouilidou et al .…”

Section: Discussionmentioning

confidence: 99%

Secretome analysis to elucidate metalloprotease‐dependent ectodomain shedding of glycoproteins during neuronal differentiation

et al. 2017

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Many membrane proteins are subjected to limited proteolyses at their juxtamembrane regions, processes referred to as ectodomain shedding. Shedding ectodomains of membrane-bound ligands results in activation of downstream signaling pathways, whereas shedding those of cell adhesion molecules causes loss of cell-cell contacts. Secreted proteomics (secretomics) using high-resolution mass spectrometry would be strong tools for both comprehensive identification and quantitative measurement of membrane proteins that undergo ectodomain shedding. In this study, to elucidate the ectodomain shedding events that occur during neuronal differentiation, we establish a strategy for quantitative secretomics of glycoproteins released from differentiating neuroblastoma cells into culture medium with or without GM6001, a broadspectrum metalloprotease inhibitor. Considering that most of transmembrane and secreted proteins are N-glycosylated, we include a process of N-glycosylated peptides enrichment as well as isotope tagging in our secretomics workflow. Our results show that differentiating N1E-115 neurons secrete numerous glycosylated polypeptides in metalloprotease-dependent manners. They are derived from cell adhesion molecules such as NCAM1, CADM1, L1CAM, various transporters and receptor proteins. These results show the landscape of ectodomain shedding and other secretory events in differentiating neurons and/or during axon elongation, which should help elucidate the mechanism of neurogenesis and the pathogenesis of neurological disorders.

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“…Indeed, therapeutic benefits were observed in the damaged CNS of neurological disorders, including MS, when the synthetic form of thymosin β4 (Tβ4), a single peptide purified from thymosin fraction V able to pass the blood brain barrier (Mora et al, 1997), was exogenously administered. Using animal models of neurological injury, studies have demonstrated that Tβ4 can target multiple neural cells (including neurons, oligodendrocytes and microglia) and can also provide neuroprotection, immunosuppression, and neurorestoration, including remyelination, synaptogenesis, and axon growth (Zhang et al, 2016a,b;Chopp and Zhang, 2015;Santra et al, 2012;Santra et al, 2016;Wang et al, 2015;Wang et al, 2012;Cheng et al, 2014).…”

Section: The Use Of Thymosins In Msmentioning

confidence: 99%

“…Tβ4 is the major G-actin-sequestering molecule, and its primary physiological function is to regulate cell motility (Bock-Marquette et al, 2004). During (Chopp and Zhang, 2015;Kuzan, 2016;Goldstein and Kleinman, 2015) THYMOSIN-β10 (Tβ−10) rat, mice, humans, cattle, cytoskeleton organization and morphology, proliferation, motility, anti-inflammatory effects, insulin secretion (Sribenja et al, 2009;Zhang et al, 2017b) THYMOSIN-β15 (Tβ−15) rat, mice, human motility, progression and metastatis of non-small cell lung cancer (Banyard et al, 2007) development of CNS, Tβ4 regulates neurogenesis, tangential expansion, tissue growth and hemisphere folding (Lever et al, 2017;Wirsching et al, 2012Wirsching et al, , 2014. Tβ4 was initially employed as an anti-inflammatory agent (Badamchian et al, 2003;Girardi et al, 2003) and, subsequently, to inhibit proliferation and induce differentiation and apoptosis of leukemic cells (Huang et al, 2006).…”

Section: Thymosins: the Old And The Newmentioning

confidence: 99%

“…Tβ4 was initially employed as an anti-inflammatory agent (Badamchian et al, 2003;Girardi et al, 2003) and, subsequently, to inhibit proliferation and induce differentiation and apoptosis of leukemic cells (Huang et al, 2006). Recently, Tβ4 healing properties were described in skin, cornea and cardiac repair (Zhang et al, 2016a;Chopp and Zhang, 2015;Bock-Marquette et al, 2004;Badamchian et al, 2007;Li et al, 2017;Kim et al, 2017;Goldstein et al, 2012).…”

Section: Thymosins: the Old And The Newmentioning

confidence: 99%

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