The scale of the problem is staggering. Diabetes affected about 463 million people, roughly 9.3 percent of the global population, as of 2019, and chronic hyperglycemia gradually damages nerves and blood vessels throughout the body. When peripheral nerves deteriorate, patients lose protective sensation in their feet; when blood vessels narrow, tissues are starved of oxygen and nutrients. The review notes that neuropathy is the primary cause of diabetic ulcers, with 18.7 percent of cases classified as hypoxic and 34.2 percent as neuro-hypoxic. Add in impaired immune responses, stem cell dysfunction, growth factor imbalances, and a heightened susceptibility to infection by organisms such as Staphylococcus aureus—including methicillin-resistant strains—and the result is a wound environment that stubbornly resists healing. Current treatments, from offloading pressure and wound care to growth factors, stem cell therapy, and bioengineered skin substitutes, often fail to address every stage of the healing cascade: coagulation, inflammation, proliferation, and remodelling.

Thymosin beta 4 is a compact, naturally occurring protein of just 43 amino acids, with a molecular weight of 4.9 kilodaltons, originally isolated from bovine thymus. It is highly conserved and water-soluble, found in nearly every tissue and cell type except erythrocytes. Upon injury, platelets, natural killer cells, and other cells release Tβ4, which protects against further damage, reduces programmed cell death, curbs microbial proliferation, and dampens inflammation. Mechanistically, the peptide interacts with actin to drive cell movement, promotes the differentiation of progenitor cells, epithelial cells, and keratinocytes, and stimulates the formation of new blood vessels. Crucially, it also reduces the accumulation of myofibroblasts at wound sites, which translates into less scar tissue and fibrosis. In diabetic models, Tβ4 treatment has improved motor and sensory nerve conduction velocities, accelerated re-epithelialization, increased vascularization, and enhanced cell viability through pathways including PI3K/AKT and vascular endothelial growth factor signalling.

The review details how Tβ4 manipulates several key signalling cascades relevant to diabetic wounds. It prevents the transcription factor NF-κB from entering the cell nucleus, thereby lowering production of pro-inflammatory molecules such as interleukin-8. It bolsters antioxidant defences by enhancing superoxide dismutase and catalase activity while suppressing tumor necrosis factor alpha and interleukin-6, partly through modulation of the NADPH oxidase system and activation of the Nrf2 pathway. It increases Angiopoietin-1 expression and stabilizes newly formed blood vessels via the Ang1/Tie2 axis, and it activates Wnt/β-catenin signalling to enhance endothelial cell migration, proliferation, and angiogenesis. Through PI3K/AKT signalling, Tβ4 stimulates endothelial nitric oxide synthase, boosting nitric oxide production, vasodilation, and blood flow to healing tissue. Studies in human umbilical vein endothelial cells have also shown that Tβ4 pretreatment reduces harmful reactive oxygen species, restores VEGF expression, and activates insulin-like growth factor 1 signalling, protecting cells from high-glucose toxicity.

Selenium, for its part, is an essential trace element with potent antioxidant, antibacterial, and anti-inflammatory properties. As a coenzyme component of glutathione peroxidase, it neutralizes reactive oxygen species, reduces lipid peroxidation, and lowers neutrophil infiltration into wounds—effects reflected in decreased malondialdehyde and myeloperoxidase levels. Selenium supplementation has been shown to restore extracellular superoxide dismutase and VEGF levels within diabetic ulcers, both essential for angiogenesis and oxidative stress control. Novel delivery platforms are extending these effects: selenium-treated exosomes derived from mesenchymal stem cells have reduced inflammation and enhanced pro-angiogenic activity in endothelial cells, while chitosan-nano selenium biofilms have improved full-thickness wound regeneration in diabetic models. Organo-selenium bandages have even been shown to inhibit bacterial biofilm formation, directly tackling one of the most stubborn obstacles to healing infected ulcers.

The molecular logic of the proposed combination is where the review becomes particularly compelling. Both agents converge on the same central pathways. In the PI3K/AKT cascade, Tβ4 activates signalling to promote cell survival and migration, while selenium enhances Akt phosphorylation through selenoprotein-mediated redox regulation—together amplifying anti-apoptotic and pro-survival signals. On the inflammatory front, selenium-containing glutathione peroxidases suppress NF-κB activation through their antioxidant activity, complementing Tβ4’s direct inhibition of NF-κB nuclear translocation, potentially producing a stronger anti-inflammatory effect in the wound environment than either agent could achieve alone. In the JAK/STAT pathway, Tβ4 modulates STAT3 activation to influence cell proliferation and migration, while selenium affects JAK2/STAT3 signalling through redox-sensitive mechanisms. Both also touch the Wnt/β-catenin pathway, suggesting combined effects on stem cell activation, tissue regeneration, and wound re-epithelialization.

The synergy extends beyond pathway overlap. Tβ4 upregulates VEGF expression and promotes endothelial cell differentiation, while selenium protects those newly formed vessels from oxidative damage by activating Nrf2. Selenium’s ability to modulate matrix metalloproteinases may complement Tβ4’s regulation of actin cytoskeleton reorganization, potentially improving wound contraction and remodelling. The review also highlights metabolic benefits: Tβ4 treatment lowers total cholesterol, triglycerides, and LDL cholesterol while raising HDL cholesterol, and both agents have been linked to improved insulin sensitivity. Selenium supplementation in patients with type 2 diabetes has reduced oxidative stress markers and improved glucose homeostasis and lipid profiles, meaning the combination might address not just the wound but the underlying diabetic pathophysiology that keeps wounds from closing.

Safety data offer cautious encouragement. A phase 1 study of recombinant human thymosin beta 4 (NL005) in healthy volunteers found adverse events were generally mild to moderate, with no serious toxicities and dose-proportional plasma concentrations. Topical Tβ4 in patients with venous stasis ulcers was well tolerated at all doses, with a 0.03 percent concentration showing the highest healing rate and a significantly reduced median healing time compared with placebo. But selenium is a double-edged sword: the review notes that blood levels exceeding roughly 140 nanograms per millilitre are extremely toxic to humans, causing selenosis and potential neurological damage, and excessive doses can paradoxically elevate pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha, slowing healing. Individual variability in response to Tβ4 and concerns about long-term effects also warrant further study.

The authors are careful to stress that the synergy between Tβ4 and selenium remains theoretical; no study has yet directly tested the combination in diabetic ulcers. They propose a research roadmap beginning with in vitro experiments combining the two agents in cell cultures to assess effects on fibroblast migration, keratinocyte proliferation, and inflammatory markers, followed by animal studies in diabetic wound models measuring wound closure time, angiogenesis, inflammation resolution, and infection control. Only then would well-structured clinical trials establish safety, efficacy, and optimal dosing ratios in patients with chronic diabetic ulcers. Key challenges include defining the optimal Tβ4-to-selenium ratio, managing selenium toxicity—particularly in patients with compromised renal function—and developing delivery systems that maintain the stability and bioavailability of both compounds at the wound site. If those hurdles can be cleared, the reviewers argue, the combination could reduce amputation rates, accelerate healing, and ease the enormous economic burden of diabetic foot ulcers, offering a genuinely integrated attack on a wound that has defeated conventional medicine for decades.

Subject of Research: Combined therapeutic effects of thymosin beta 4 and selenium on diabetic ulcer wound healing

Article Title: The combined impact of thymosin beta 4 and selenium on diabetic ulcers: a comprehensive review

Article References: Srinivasan, K., Sureshkumar, R., Nellore, J., Muthaiah, B., Selvan Christyraj, J. R. S., & Chandrasekaran, V. N. (2025). The combined impact of thymosin beta 4 and selenium on diabetic ulcers: a comprehensive review. Discover Biotechnology, 2(1), Article 11. https://doi.org/10.1007/s44340-025-00015-0

Image Credits: AI Generated

DOI: 10.1007/s44340-025-00015-0

Keywords: thymosin beta 4, selenium, diabetic ulcers, wound healing, angiogenesis, oxidative stress, NF-kB, PI3K/AKT pathway, inflammation, insulin sensitivity, diabetic neuropathy, nanoparticles