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Thymosin B4 Reduces Inflammation by Upregulating MicroRNA-146a and Promotes Myelin
"Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury... TB4-mediated oligodendrogenesis results from [up-regulating] miR-146a [causing the] suppression [of] the TLR proinflammatory pathway and modulation of the p38 MAPK pathway." (8)
"By targeting IRAK1 and TRAF6, miR-146 inhibits NF-κB activation. We therefore hypothesized that TB4 regulates the TLR proinflammatory signaling pathway by specifically regulating miR-146a to promote differentiation of OPCs [oligodendrocyte progenitor cells] to mature myelin basic protein (MBP)-expressing OLs [oligodendrocytes]... transfection with anti-miR-146a inhibitor nucleotides significantly inhibited the expression of MBP and phosphorylation of p38 MAPK." (8)
Thymosin B4 Affects Immune System and Protects Hippocampus After Brain Injury
"...recombinant human IL-18 (rhIL-18) enhanced the endogenous level of TB4 through p38MAPK and JNK signaling pathway in the human NK cell line, NK-92MI. Overexpression of endogeneous TB4 stimulated IFN-y expression and secretion... data indicated that TB4 is regulated by IL-18 and is involved in IL-18-enhanced IFN-y secretion in NK cells. (12)
"Compared with saline administration, TB4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus." (14) "Treatment of traumatic brain injury with thymosin B4 in rats: Compared with the saline treatment, delayed TB4 treatment did not affect lesion volume but significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, increased oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning." (15)
Thymosin B4 Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice
"TB4 is a potent angiogenic factor and regulates angiogenesis and vasculogenesis during development by promoting progenitor cell differentiation and by directing endothelial cell migration... Our data that blockage of Tie2 with a neutralizing antibody suppressed the effect of TB4 on in vitro angiogenesis implicates the Ang/Tie2 signaling pathway in mediating TB4-improved vascular function observed in vivo... The Ang/Tie2 signaling pathway regulates vascular homeostasis."
"Hyperglycemia downregulates Ang1 and upregulates Ang2... Increases in Ang1 levels normalize diabetes induced immature vasculature. Ang1 by increasing angiogenesis reduces myocardial infarction, whereas an elevation of Ang2 levels exacerbates the infarction in diabetic rats. Patients with diabetic peripheral neuropathy have significantly elevated levels of circulating Ang2. Our data show that hyperglycemia downregulated Ang1 and upregulated Ang2 on endothelial cells and Schwann cells, whereas TB4 reversed expression of Ang1 and Ang2." (1)
Benefit of Thymosin B4 Treatment Is Independent of Blood Glucose Level in Mice With Diabetic Peripheral Neuropathy: "Treatment with TB4 significantly increased intraepidermal nerve fiber density. Furthermore, TB4 counteracted the diabetes-induced axon diameter and myelin thickness reductions and the g-ratio increase in sciatic nerve. In vitro, compared with dorsal root ganglia (DRG) neurons derived from nondiabetic mice, DRG neurons derived from diabetic mice exhibited significantly decreased neurite outgrowth, whereas TB4 promoted neurite growth in these diabetic DRG neurons. Our data demonstrate that extended TB4 treatment ameliorates diabetic-induced axonal degeneration and demyelination, which likely contribute to therapeutic effect of TB4 on diabetic neuropathy. Blockage of the Ang1/Tie2 signaling pathway with a neutralized antibody against Tie2 abolished TB4-increased neurite outgrowth... The Ang1/Tie2 pathway may mediate TB4-induced axonal remodeling." (2)
Thymosin Beta 4 Eye Drops Significantly Improve Signs and Symptoms of Severe Dry Eye in a Physician-Sponsored Phase 2 Clinical Trial
"Of particular note at Day 56, the follow-up period, were the differences between TB4 and vehicle control. The TB4-treated group (12 eyes) had a 35.1% reduction of ocular discomfort compared to vehicle control (6 eyes) (p=0.0141), and a 59.1% reduction of total corneal fluorescein staining compared to vehicle control (p=0.0108). Other improvements seen in the TB4-treated patients included tear film breakup time and increased tear volume production." (14)
"Tbeta4 treatment decreases corneal inflammation and modulates the MMP/TIMP balance and thereby promotes corneal wound repair and clarity after alkali injury. These results suggest that Tbeta4 may be useful clinically to treat severe inflammation-mediated corneal injuries." (13)
Thymosin Beta-4 activates phagocytosis (phagocytosis clears senescent cells after being activated by resistance exercise.)
Remarkably, TB4 was thus associated with microglia and macrophages, the differentiated phagocytic cells residing in every tissue. Motility and phagocytosis, two important activities of macrophages, depend on actin, which can explain the presence of TB4 in these cells. (5) "Rapid senescent cell clearance of human skeletal muscle during resistance exercise seems to associate with enhanced in situ phagocytosis." (4)
"Senescent endothelial progenitor cells (p16Ink4a+/CD34+) in human skeletal muscle after resistance exercise. Senescent endothelial progenitor cells decreased in human skeletal muscle after a single bout of resistance exercise, and to a greater extends under low protein supplemented condition" (5):
An external file that holds a picture, illustration, etc.
Object name is aging-10-101472-g002.jpg
Thymosin B4 reduces senescence of endothelial progenitor cells and boosts telomerase
"We previously demonstrated that thymosin B4 (TB4) regulates a variety of endothelial progenitor cell (EPC) functions, including cell migration, proliferation, survival and angiogenesis... TB4 inhibited EPC senescence in a concentration‑dependent manner. In addition, TB4 increased telomerase activity and expression of telomerase reverse transcriptase mRNA in EPCs. TB4 also regulated the expression of p21, p27 and cyclin D1. The effects of TB4 on EPC senescence were eliminated by the phosphoinositide 3'-kinase (PI3K) inhibitor, wortmannin and the endothelial nitric oxide synthase inhibitor, L‑nitroarginine methyl ester hydrochloride (L-NAME). In conclusion, the inhibitory effect on EPC senescence mediated by TB4 may be attributed, at least in part, to activation of the PI3K-Akt-eNOS signaling pathway." (3)
TB4 decreased senescence of endothelial progenitor cells in a dose-dependent manner:
Incubation of endothelial progenitor cells with TB4 was identified to result in a significant increase in telomerase activity (P<0.05):
Thymosin 4 increases hair growth by activation of hair follicle stem cells
"The results of depilation indicated that hair re-growth was faster in TB4-overexpressing mice, but slower in knockout mice." (6)
Fig 2
Fig 3
"Expression and secretion of the extracellular matrix-degrading enzyme matrix metalloproteinase-2 were increased by thymosin beta4… thymosin beta4 accelerates hair growth, in part, due to its effect on critical events in the active phase of the hair follicle cycle, including promoting the migration of stem cells and their immediate progeny to the base of the follicle, differentiation, and extracellular matrix remodeling." (7)
Thymosin B4 reduces lung, liver, and renal fibrosis via TGF-beta and epigenetics.
"It also prevented ethanol- and LPS-mediated increase in oxidative stress by decreasing ROS and lipid peroxidation and increasing the antioxidants, reduced glutathione and manganese-dependent superoxide dismutase. It also prevented the activation of nuclear factor kappa B by blocking the phosphorylation of the inhibitory protein, IkB, thereby prevented proinflammatory cytokine production. Moreover, TB4 prevented fibrogenesis by suppressing the epigenetic repressor, methyl-CpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-y and downregulated fibrogenic genes, platelet-derived growth factor-B receptor, a-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that TB4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury." (16)
"TB4 treatment improved the apoptosis of In vitro tubular epithelial cells compared with pure TGF-B stimulation, and equally, the decrease of apoptosis was more apparent in the TGF-B + high-dose TB4 group. TB4 treatment might alleviate the renal fibrosis and apoptosis of tubular epithelial cells through TGF-B pathway inhibition in UUO rats with CRTIF." (17)
"TB4 possesses anti-fibrotic activity in the liver, which is attributable, at least partly, to down-regulating TGF-BRII and thereby blunting TGF-B1‐mediated fibrogenetic signaling in both HSCs and hepatocytes." (18)
Thymosin beta 4 improves left ventricular function after heart injury but excess administration may promote overly thick epicardium.
"Treatment improved left ventricular function and reduced cardiac remodeling. After myocardial injury it improves cell survival, reduces inflammation and activates epicardial progenitor cells. (9)
Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes: "Here we tested if TB4 treatment after MI could reprogram epicardium into cardiomyocytes and augment the epicardium's injury response. Using epicardium genetic lineage trace line Wt1CreERT2/+ and double reporter line Rosa26mTmG/+, we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density." (10)
"Our data revealed for the first time that TB4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced [pulmonary hypertension] and [right ventricle hypertrophy]." (11)
TB4 was shown to repair left ventricular after injury, but prolonged administration may enlarge its epicardial layer. Studies reveal TB4 reduces cardiac injury, pulmonary hypertension, and right ventricular hypertrophy/enlargement:
Sourced Studies:
(1) 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, www.ncbi.nlm.nih.gov/pmc/articles/PMC3533234/, 10.1016/j.nbd.2012.08.002.
(2) 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/.
"Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury... TB4-mediated oligodendrogenesis results from [up-regulating] miR-146a [causing the] suppression [of] the TLR proinflammatory pathway and modulation of the p38 MAPK pathway." (8)
"By targeting IRAK1 and TRAF6, miR-146 inhibits NF-κB activation. We therefore hypothesized that TB4 regulates the TLR proinflammatory signaling pathway by specifically regulating miR-146a to promote differentiation of OPCs [oligodendrocyte progenitor cells] to mature myelin basic protein (MBP)-expressing OLs [oligodendrocytes]... transfection with anti-miR-146a inhibitor nucleotides significantly inhibited the expression of MBP and phosphorylation of p38 MAPK." (8)
Thymosin B4 Affects Immune System and Protects Hippocampus After Brain Injury
"...recombinant human IL-18 (rhIL-18) enhanced the endogenous level of TB4 through p38MAPK and JNK signaling pathway in the human NK cell line, NK-92MI. Overexpression of endogeneous TB4 stimulated IFN-y expression and secretion... data indicated that TB4 is regulated by IL-18 and is involved in IL-18-enhanced IFN-y secretion in NK cells. (12)
"Compared with saline administration, TB4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus." (14) "Treatment of traumatic brain injury with thymosin B4 in rats: Compared with the saline treatment, delayed TB4 treatment did not affect lesion volume but significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, increased oligodendrogenesis in the CA3 region, and significantly improved sensorimotor functional recovery and spatial learning." (15)
Thymosin B4 Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice
"TB4 is a potent angiogenic factor and regulates angiogenesis and vasculogenesis during development by promoting progenitor cell differentiation and by directing endothelial cell migration... Our data that blockage of Tie2 with a neutralizing antibody suppressed the effect of TB4 on in vitro angiogenesis implicates the Ang/Tie2 signaling pathway in mediating TB4-improved vascular function observed in vivo... The Ang/Tie2 signaling pathway regulates vascular homeostasis."
"Hyperglycemia downregulates Ang1 and upregulates Ang2... Increases in Ang1 levels normalize diabetes induced immature vasculature. Ang1 by increasing angiogenesis reduces myocardial infarction, whereas an elevation of Ang2 levels exacerbates the infarction in diabetic rats. Patients with diabetic peripheral neuropathy have significantly elevated levels of circulating Ang2. Our data show that hyperglycemia downregulated Ang1 and upregulated Ang2 on endothelial cells and Schwann cells, whereas TB4 reversed expression of Ang1 and Ang2." (1)
Benefit of Thymosin B4 Treatment Is Independent of Blood Glucose Level in Mice With Diabetic Peripheral Neuropathy: "Treatment with TB4 significantly increased intraepidermal nerve fiber density. Furthermore, TB4 counteracted the diabetes-induced axon diameter and myelin thickness reductions and the g-ratio increase in sciatic nerve. In vitro, compared with dorsal root ganglia (DRG) neurons derived from nondiabetic mice, DRG neurons derived from diabetic mice exhibited significantly decreased neurite outgrowth, whereas TB4 promoted neurite growth in these diabetic DRG neurons. Our data demonstrate that extended TB4 treatment ameliorates diabetic-induced axonal degeneration and demyelination, which likely contribute to therapeutic effect of TB4 on diabetic neuropathy. Blockage of the Ang1/Tie2 signaling pathway with a neutralized antibody against Tie2 abolished TB4-increased neurite outgrowth... The Ang1/Tie2 pathway may mediate TB4-induced axonal remodeling." (2)
Thymosin Beta 4 Eye Drops Significantly Improve Signs and Symptoms of Severe Dry Eye in a Physician-Sponsored Phase 2 Clinical Trial
"Of particular note at Day 56, the follow-up period, were the differences between TB4 and vehicle control. The TB4-treated group (12 eyes) had a 35.1% reduction of ocular discomfort compared to vehicle control (6 eyes) (p=0.0141), and a 59.1% reduction of total corneal fluorescein staining compared to vehicle control (p=0.0108). Other improvements seen in the TB4-treated patients included tear film breakup time and increased tear volume production." (14)
"Tbeta4 treatment decreases corneal inflammation and modulates the MMP/TIMP balance and thereby promotes corneal wound repair and clarity after alkali injury. These results suggest that Tbeta4 may be useful clinically to treat severe inflammation-mediated corneal injuries." (13)
Thymosin Beta-4 activates phagocytosis (phagocytosis clears senescent cells after being activated by resistance exercise.)
Remarkably, TB4 was thus associated with microglia and macrophages, the differentiated phagocytic cells residing in every tissue. Motility and phagocytosis, two important activities of macrophages, depend on actin, which can explain the presence of TB4 in these cells. (5) "Rapid senescent cell clearance of human skeletal muscle during resistance exercise seems to associate with enhanced in situ phagocytosis." (4)
"Senescent endothelial progenitor cells (p16Ink4a+/CD34+) in human skeletal muscle after resistance exercise. Senescent endothelial progenitor cells decreased in human skeletal muscle after a single bout of resistance exercise, and to a greater extends under low protein supplemented condition" (5):
An external file that holds a picture, illustration, etc.
Object name is aging-10-101472-g002.jpg
Thymosin B4 reduces senescence of endothelial progenitor cells and boosts telomerase
"We previously demonstrated that thymosin B4 (TB4) regulates a variety of endothelial progenitor cell (EPC) functions, including cell migration, proliferation, survival and angiogenesis... TB4 inhibited EPC senescence in a concentration‑dependent manner. In addition, TB4 increased telomerase activity and expression of telomerase reverse transcriptase mRNA in EPCs. TB4 also regulated the expression of p21, p27 and cyclin D1. The effects of TB4 on EPC senescence were eliminated by the phosphoinositide 3'-kinase (PI3K) inhibitor, wortmannin and the endothelial nitric oxide synthase inhibitor, L‑nitroarginine methyl ester hydrochloride (L-NAME). In conclusion, the inhibitory effect on EPC senescence mediated by TB4 may be attributed, at least in part, to activation of the PI3K-Akt-eNOS signaling pathway." (3)
TB4 decreased senescence of endothelial progenitor cells in a dose-dependent manner:
Incubation of endothelial progenitor cells with TB4 was identified to result in a significant increase in telomerase activity (P<0.05):
Thymosin 4 increases hair growth by activation of hair follicle stem cells
"The results of depilation indicated that hair re-growth was faster in TB4-overexpressing mice, but slower in knockout mice." (6)
Fig 2
Fig 3
"Expression and secretion of the extracellular matrix-degrading enzyme matrix metalloproteinase-2 were increased by thymosin beta4… thymosin beta4 accelerates hair growth, in part, due to its effect on critical events in the active phase of the hair follicle cycle, including promoting the migration of stem cells and their immediate progeny to the base of the follicle, differentiation, and extracellular matrix remodeling." (7)
Thymosin B4 reduces lung, liver, and renal fibrosis via TGF-beta and epigenetics.
"It also prevented ethanol- and LPS-mediated increase in oxidative stress by decreasing ROS and lipid peroxidation and increasing the antioxidants, reduced glutathione and manganese-dependent superoxide dismutase. It also prevented the activation of nuclear factor kappa B by blocking the phosphorylation of the inhibitory protein, IkB, thereby prevented proinflammatory cytokine production. Moreover, TB4 prevented fibrogenesis by suppressing the epigenetic repressor, methyl-CpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-y and downregulated fibrogenic genes, platelet-derived growth factor-B receptor, a-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that TB4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury." (16)
"TB4 treatment improved the apoptosis of In vitro tubular epithelial cells compared with pure TGF-B stimulation, and equally, the decrease of apoptosis was more apparent in the TGF-B + high-dose TB4 group. TB4 treatment might alleviate the renal fibrosis and apoptosis of tubular epithelial cells through TGF-B pathway inhibition in UUO rats with CRTIF." (17)
"TB4 possesses anti-fibrotic activity in the liver, which is attributable, at least partly, to down-regulating TGF-BRII and thereby blunting TGF-B1‐mediated fibrogenetic signaling in both HSCs and hepatocytes." (18)
Thymosin beta 4 improves left ventricular function after heart injury but excess administration may promote overly thick epicardium.
"Treatment improved left ventricular function and reduced cardiac remodeling. After myocardial injury it improves cell survival, reduces inflammation and activates epicardial progenitor cells. (9)
Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes: "Here we tested if TB4 treatment after MI could reprogram epicardium into cardiomyocytes and augment the epicardium's injury response. Using epicardium genetic lineage trace line Wt1CreERT2/+ and double reporter line Rosa26mTmG/+, we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density." (10)
"Our data revealed for the first time that TB4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced [pulmonary hypertension] and [right ventricle hypertrophy]." (11)
TB4 was shown to repair left ventricular after injury, but prolonged administration may enlarge its epicardial layer. Studies reveal TB4 reduces cardiac injury, pulmonary hypertension, and right ventricular hypertrophy/enlargement:
Sourced Studies:
(1) 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, www.ncbi.nlm.nih.gov/pmc/articles/PMC3533234/, 10.1016/j.nbd.2012.08.002.
(2) 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/.
