Restoring normal neurological function is considered to require controlling the inflammatory response, which develops in injured tissues. A part of the innate immune response system controls tissue damage via the Toll-like receptor (TLR) proinflammatory signaling pathway. Studies suggest that in TB4-mediated oligodendrogenesis, the p38 MAPK pathway is modulated, and the TLR proinflammatory pathway is suppressed due to the up-regulation of miR-146a.
Inhibiting NF-κB activation is accomplished by miR-146 by targeting IRAK1 and TRAF6. Therefore, researchers postulated that TB4 may control the TLR proinflammatory signaling pathway by modulating miR-146a, which in turn may promote oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes (OLs) expressing myelin basic protein (MBP). Researchers suggested that transfection with anti-miR-146a inhibitor nucleotides may greatly reduce MBP expression and phosphorylation of p38 MAPK.
Thymosin Beta-4 and the Immune System
NK-92MI, an NK cell line, was induced to produce more TB4 when exposed to recombinant IL-18 (rhIL-18) via the p38MAPK and JNK signaling pathways. Results suggested that TB4 is IL-18 regulated and involved in NK cell IL-18 increased IFN-y secretion; overexpression of endogenous TB4 has been hypothesized to promote IFN-y expression and secretion.
After 6 hours of damage, TB4 peptide appeared to considerably improve sensorimotor functional recovery and spatial learning compared to saline presentation. It also seemed to decrease the extent of cortical lesions and hippocampal cell death and promoted cell development and neurogenesis in the injured hippocampus. Researchers commented that “Thymosin B4 in traumatic brain injury in rats: compared to saline treatment, delayed TB4 treatment substantially lowered hippocampal cell loss, enhanced angiogenesis, and neurogenesis in the injured cortex and hippocampus, elevated oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning.”
Thymosin Beta-4 and Peripheral Neuropathy
Research suggests that TB4 may promote progenitor cell differentiation and direct endothelial cell migration; it has been theorized to be a powerful angiogenic factor that may control angiogenesis and vasculogenesis throughout development. Researchers’ findings suggest that the Ang/Tie2 signaling pathway may be responsible for the TB4-improved vascular function speculated in vitro since blocking Tie2 using a neutralizing antibody seemed to reduce TB4’s influence on in vitro angiogenesis. The Ang/Tie2 signaling pathway controls the homeostasis of the blood vessels.
Hyperglycemia decreases Ang1 expression while increasing Ang2 expression. Elevated Ang1 levels restore normalcy to the immature vasculature caused by diabetes. Elevated Ang2 levels worsen myocardial infarction in diabetic rats, but Ang1 levels decrease it via boosting angiogenesis. Circulating Ang 2 levels are much higher in research models of diabetic peripheral neuropathy. The results imply that endothelial and Schwann cells have Ang1 downregulated, Ang2 increased by hyperglycemia, and TB4 may have had the opposite effect.
Investigations purport that the density of intraepidermal nerve fibers seemed considerably elevated after TB4 presentation. Additionally, TB4 appeared to reverse the decreases in axon diameter and myelin thickness and the rise in g-ratio in sciatic nerve caused by diabetes. Dorsal root ganglia (DRG) neurons from diabetes mice showed lower neurite outgrowth in vitro compared to nondiabetic animals, although TB4 may have stimulated neurite development in these diabetic neurons. Findings imply that axonal degeneration and demyelination caused by diabetes may be facilitated by prolonged TB4 presentation. This presumably contributes to the potential impact of TB4 on diabetic neuropathy. Neurite outgrowth that TB4 was theorized to have enhanced appeared to be reduced when the Ang1/Tie2 signaling pathway was blocked with a neutralizing antibody against Tie2.
Thymosin Beta-4 and Telomerase Activity
“Previous research has shown that thymosin B4 (TB4) controls many EPC activities, including migration, proliferation, survival, and angiogenesis. TB4 suppressed EPC senescence in a way that was dependent on concentration” wrote one research team. Furthermore, TB4 has been hypothesized to enhance EPC telomerase reverse transcriptase mRNA expression and telomerase activity. Studies suggest that TB4 may also control cyclin D1 and p21/p27 expression.
Wortmannin, an inhibitor of phosphoinositide 3′-kinase (PI3K), and L-nitroarginine methyl ester hydrochloride (L-NAME), an inhibitor of endothelial nitric oxide synthase, have been speculated to abolish the effects of TB4 on EPC senescence. Research suggests that activation of the PI3K-Akt-eNOS signaling pathway may account, at least in part, for the inhibitory impact on EPC senescence mediated by TB4.
Investigations purport that Thymosin beta 4 may have enhanced the extracellular matrix-degrading enzyme matrix metalloproteinase-2 activity and its secretion. The active stage of the hair follicle process is when Thymosin beta 4 is theorized to have a significant impact, speeding up follicle development by, among other things, encouraging stem cell migration and their immediate descendants to the follicle base, differentiation, and remodeling of the extracellular matrix.
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References
[i] Wang, Lei, et al. “Thymosin B4 Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice.” Neurobiology of Disease, vol. 48, no. 3, 1 Dec. 2012, pp. 546–555, httpS://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533234/, 10.1016/j.nbd.2012.08.002.
[ii] L, Wang, et al. “Therapeutic Benefit of Extended Thymosin B4 Treatment Is Independent of Blood Glucose Level in Mice With Diabetic Peripheral Neuropathy.” Journal of Diabetes Research, 2015, pubmed.ncbi.nlm.nih.gov/25945352/.
[iii] Li, Juan, et al. “Thymosin B4 Reduces Senescence of Endothelial Progenitor Cells via the PI3K/Akt/ENOS Signal Transduction Pathway.” Molecular Medicine Reports, vol. 7, no. 2, 1 Feb. 2013, pp. 598–602, https://www.ncbi.nlm.nih.gov/pubmed/23151623, 10.3892/mmr.2012.1180.
[iv] Yang, Chi, et al. “Aged Cells in Human Skeletal Muscle after Resistance Exercise.” Aging (Albany NY), vol. 10, no. 6, 27 June 2018, pp. 1356–1365, www.ncbi.nlm.nih.gov/pmc/articles/PMC6046228, 10.18632/aging.101472.
[v] Paulussen, Melissa, et al. “Thymosin Beta 4 MRNA and Peptide Expression in Phagocytic Cells of Different Mouse Tissues.” Peptides, vol. 30, no. 10, 1 Oct. 2009, pp. 1822–1832, https://www.sciencedirect.com/science/article/abs/pii/S0196978109003015, 10.1016/j.peptides.2009.07.010.
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