Scientific context: This article presents the results described in the cited publications. Cell and animal studies do not confirm the effectiveness of the treatment in humans. The mentioned concentrations, doses, and dosing regimens are solely for research protocols and do not constitute medical recommendations or instructions for self-administration. The cited references come from the source material and have not been independently verified.
Thymosin beta-4 (Tβ4), also known as timbetazin, β-tyminol is a small protein composed of 43 amino acids. It occurs naturally in the bodies of humans and mice. Scientists have also developed its synthetic and recombinant versions used in laboratory research and in early stages of clinical trials. The sumary structure of β-tyminol is C₂₁₂H₃₅₀N₅₆O₇₈S, and the molecular mass is approximately 4963 Da [1].
Thymosin β4 has attracted the interest of researchers due to its involvement in tissue repair, cell migration, and the regulation of inflammatory signaling. In experimental studies, its effects on wound closure, angiogenesis, fibrosis, and tissue damage have been described. However, these observations do not confirm its clinical efficacy in all the organs studied.
The peptide is involved in the processes of cell migration to damaged sites and in the regulation of natural repair signals, including VEGF via HIF-1α. Changes associated with the protection of heart, lung, liver and bone tissues were also observed in the studies. Thymosin β4 may also influence autophagy, a cellular process that enables the removal of damaged cellular components.
Amino acids in the structure of thymine beta-4 [1]
Based on the results of experimental studies, scientists analyzed various potential clinical applications of thymoquinone β4, ranging from heart damage and circulatory disorders to skin regeneration. One of the formulated products tested, RGN-259, is being developed as an eye drop intended for research on corneal surface diseases. A safety study was also conducted in healthy volunteers. This shows that interest in this peptide extends to both its basic biological functions and possible medical applications.
Thymosin β4: safety and pharmacokinetics in a clinical study
In the first clinical study involving humans, Wang and colleagues (2021) evaluated recombinant thymosin β4, labeled as NL005, in healthy adult volunteers in China [2].
The study consisted of two parts. In the first, participants received a single intravenous dose of 0.05 to 25.0 µg/kg. In the second, daily intravenous doses of 0.5, 2.0, or 5.0 µg/kg were administered for 10 days.
The preparation was well tolerated in both parts of the study. No severe adverse reactions or problems limiting the dose increase were reported. In the group receiving a single dose, approximately 57% participants reported mild or moderate adverse reactions, while in the placebo group this percentage was 70%. In the part involving multiple administrations, mild adverse reactions occurred in 67% people receiving NL005 and 83% people receiving placebo.
Most of the observed changes were transient and included minor deviations in laboratory test results, ECG recordings, or markers of cancer.
The pharmacokinetics of the drug were relatively predictable. After a single administration, the maximum blood concentration increased with the dose, from 1.99 ng/ml at the lowest dose to 230.07 ng/ml at the highest dose. Total exposure to the substance also increased proportionally.
The half-life increased slightly with higher doses and was approximately 0.5–2.1 hours. During ten-day administration, no significant accumulation of the substance was observed in the body. Clearance and volume of distribution remained stable.
The immune response to the preparation was detected in a small number of participants: one person in the single-dose group and two people in the multiple-dose group. These reactions were transient.
Within the limits of a small Phase I study, the results indicated good tolerability, low observed immunogenicity, and relatively stable pharmacokinetics. However, they do not confirm long-term safety or efficacy in patients with cardiovascular diseases.
Eye drops containing β4-thymozine in a study of severe dry eye syndrome
The phase II study evaluated whether eye drops containing timozine β4 can improve the symptoms and condition of the eye surface in people with severe dry eye syndrome.
Sosne and colleagues (2015) studied RGN-259 drops containing 0.1% thymozines β4, also in patients with ocular dryness associated with host-versus-host graft-versus-host disease (GVHD) [3].
The participants applied the drops six times a day for 28 days, followed by another 28-day period without treatment.
By day 56, in the RGN-259 group, a reduction in eye discomfort of 35.1% and signs of eye surface damage of 59.1% were observed compared to placebo.
Other parameters were also improved, including the stability of the tear film and the volume of tears. No significant safety issues were observed, and the preparation was well tolerated.
The preliminary results justified further studies of RGN-259, but they were not sufficient to confirm its routine clinical use.
Intravenous thymosine β4: early safety data
In an early intravenous study, the tolerance of thymosine β4 was evaluated in healthy volunteers at various doses.
Ruff and colleagues (2010) studied synthetic thymozine β4 using four intravenous doses: 42, 140, 420, and 1260 mg [4]. After an initial safety assessment, the same doses were administered once daily for 14 days.
The preparation was well tolerated in both phases. The reported adverse reactions were mild or moderate in severity and no severe reactions were observed.
The systemic exposure increased proportionally with the dose, and the duration of substance retention in the body lengthened at higher doses.
The results supported further research into tozumycin β4 in conditions associated with blood flow disorders, such as stroke or heart attack. However, they did not confirm its effectiveness in these conditions.
Local thymosine β4 in chronic venous ulcers of the lower limbs
In the Phase II study, a gel containing tymozine β4 was evaluated as an experimental adjunct to the standard treatment for chronic venous leg ulcers.
Guarnera and colleagues (2010) conducted a study in eight European centers involving 73 patients with chronic ulcers associated with venous stasis [5].
Different concentrations of gel were tested, including 0.03%. The preparation was used in conjunction with standard care, which included, among other things, compression bandages and wound cleansing.
The most favorable results were observed for the gel with a concentration of 0.03%. In about 25% patients, the wound healed completely within three months, especially in cases of mild or moderate severity lesions.
The preparation was well tolerated and no severe adverse reactions were reported.
The observations were consistent with previous laboratory studies indicating the involvement of thymosin β4 in skin cell migration, collagen production, and the formation of new blood vessels.
Study of moderate dry eye syndrome: partially positive results
In a Phase II clinical study by Sosne and Ousler (2015), RGN-259 drops containing 0.1% thymozine β4 were evaluated in 72 adults with moderate or severe dry eye syndrome [6].
The study was conducted in one center, with randomization, double-blinded design, and placebo control. The Controlled Adverse Environment (CAE™) model was used, which allows evaluating the eye surface response to specific conditions.
The study lasted 28 days, and during the 32 days six follow-up visits were scheduled. The participants were randomly assigned to the RGN-259 or placebo group.
The two main endpoints, namely reducing eye discomfort and reducing staining of the lower part of the cornea, showed no statistically significant improvement in the planned measurement on the 29th day.
At the same time, beneficial changes were observed in several secondary parameters. On the 28th day, the discomfort caused by the CAE™ exposure was 27% less than in the placebo group. A significant improvement in the condition of the middle and upper parts of the cornea was also observed.
Some of the indicators of eye redness, tear film stability, and daily recorded symptoms also improved.
No adverse reactions related to the investigated product were reported, nor were any problems noted in ocular safety assessments.
Although the study did not achieve the planned primary endpoints, the secondary results warranted further studies, including the evaluation of larger groups of patients and the appropriate time for measurements.
Thymosin β4 in chronic corneal ulcers
Dunn and colleagues (2010) described a series of four cases of patients aged 47 to 84 years with long-standing neurotrophic corneal ulcers [7].
The causes of the injuries included retinal detachment and diabetes. Previous treatment, which included antibiotics, moisturizing preparations, steroid drops, and protective lenses, did not bring the expected improvement.
The patients received drops of tymozine β4 supplied by RegeneRx Biopharmaceuticals four times a day for four weeks.
In one patient, the corneal defect completely healed within 25 days and remained closed until the 56th day. In another, the surface area of the injury was significantly reduced by day 28. In a third patient, healing progressed more slowly but continued until day 70. In a fourth patient, the cornea healed by day 42 and the achieved effect persisted.
None of the patients reported any pain or adverse reactions. All of them experienced an improvement in comfort and a reduction in redness.
A small series of cases suggested the possibility of further studies on tozines β4 in difficult-to-treat corneal lesions, but did not allow for unequivocal conclusions regarding efficacy to be drawn.
Wound closure and healing time: results of studies in animals and humans
Animal studies and early clinical trials indicated that thymozine β4 may affect the rate of wound healing and the time required for their complete closure.
In full-thickness skin wounds in healthy rats, diabetic mice, rats receiving steroids, and older mice, faster healing was observed in the groups receiving thymozine β4 [9].
In clinical studies involving venous ulcers and bedsores, patients who experienced wound healing after using timozine β4 achieved this result on average about a month earlier than those receiving placebo.
Animal studies focused primarily on the speed of wound closure, whereas clinical studies evaluated the time until complete healing.
The proposed mechanisms include stimulating cell migration, the participation of stem cells in tissue repair, reducing inflammation, protecting cells from damage, and potentially reducing the risk of infections.
The results suggest activity at different stages of healing, however, larger studies are necessary to confirm the benefits, determine the appropriate formulations, and identify groups of patients.
Gel containing β4-thymosin in venous ulcers of the lower leg
Guarnera and colleagues (2007) designed a European study on thymidine β4 in venous ulcers, conducted in ten hospitals in Italy and Poland [10].
The study was randomized, double-blinded, and placebo-controlled. It included three dose groups, with 24 participants in each, with three-quarters of the participants receiving timozine β4.
All patients also received standard wound care, which included compression therapy and wound cleansing.
For 84 days, gel containing β4-thymozine or placebo was applied to the wounds, followed by an additional 14-day observation period.
The main parameters evaluated were the percentage of completely healed ulcers by day 84 and the average healing time.
Safety was also monitored, the concentration of thymozine β4 in the blood and the results of weekly laboratory tests.
At the time of publication, the study was still ongoing, and 21 people were included in the first group receiving the lowest dose.
The project’s strengths were strict blinding, detailed monitoring, and accurate measurements of wound surface area. Limitations included the planned small number of participants, 72 people, and the lack of final results at the time of publication.
Skin regeneration: results of a review of studies
Kleinman and Sosne (2016) presented a review of laboratory and clinical studies regarding the effect of thymozine β4 on skin healing [8].
The peptide occurs naturally in human tissues and blood platelets. It has been studied in various forms, including topical gels, injection preparations, and synthetic and dimeric variants of the molecule.
In animal models, thymozine β4 accelerated wound healing even under conditions that hinder regeneration, such as aging, diabetes, the use of steroids, and limited blood flow.
The intensification of angiogenesis, migration of skin cells, and a more orderly structure of collagen were observed, as well as a reduction in scarring.
In models of ischemia, the peptide increased the survival of skin flaps and improved regeneration after ischemia of the limbs, especially when using controlled-release systems.
In animal studies, dimeric forms of thymidine β4 showed slightly greater wound-healing-related activity than the simple monomeric form.
In clinical trials, early safety assessments did not reveal significant adverse effects or measurable concentrations of the substance in the blood after topical application.
Three small phase II studies concerning chronic wounds such as bedsores, venous and bullous skin separations, indicated faster healing when using gels containing 0.02–0.03% thymozines β4, especially between the fourth and ninth week [8].
Lower and higher concentrations did not show equally beneficial results, which highlights the importance of the relationship between concentration and biological response.
The mechanisms included the inhibition of inflammation and cell damage, the regulation of harmful molecules, the support of migration and growth of skin and blood vessel cells, as well as the possible activation of stem cells and hair follicles.
These effects were associated with specific peptide fragments and signaling pathways, including ATP receptors, PI3K/AKT, and heat shock proteins.
The review discussed experimental gels with concentrations of 0.02–0.03%, used in studies lasting approximately 8–12 weeks. These parameters relate to the study protocols, not to established clinical recommendations.
According to a review, tymozine β4 was evaluated for safety in approximately 200 patients in Phase I and II studies. No severe adverse reactions were reported even in studies with high intravenous doses [8].
Since thymoquinone β4 is involved in cell migration and angiogenesis, processes that may also be important for the development of tumors, the issue of oncological safety requires special attention.
Skin studies did not show any activity that would favor the development of tumors, and some results even suggested anti-tumor activity in certain models, such as multiple myeloma.
However, the authors emphasized the need for further research into molecular mechanisms, the selection of parameters for the type of wounds, and more advanced formulations, including dimers and active peptide fragments.
Thymosin β4 in epithelial vesicle secretion (EB)
Timozine β4 was also studied in epithelial vesicle secretion (Epidermolysis bullosa, EB) and other severe skin injuries.
EB is a rare genetic disease causing significant skin fragility and frequent blistering. It is associated with pain, increased risk of infections, scarring, disability, and in some cases skin cancers. The literature describes the treatment as largely supportive, with limited effectiveness [11].
Thymosin β4 occurs naturally in most tissues and body fluids, including wound fluid. It is involved in regulating inflammation, cell survival, angiogenesis, and the organization of extracellular matrix.
Different fragments of the peptide are responsible for different biological activities. Some are involved in reducing inflammation and fibrosis, others support cell survival, migration, vessel formation, or repair processes in the heart muscle.
The proposed mechanisms include inhibition of NF-κB signaling, protection of skin cells from damage, increased nutrient supply through angiogenesis, improved cell migration and adhesion, and more orderly deposition of collagen.
Antimicrobial and antioxidant properties that may be involved in limiting infections and oxidative damage have also been described [11].
In a phase II study involving approximately 30 patients with EB, three concentrations of the local preparation were evaluated.
The main goal of completely healing the wounds by day 56 was not achieved. However, on the 14th day, the area of the wounds was smaller in the group receiving timozine β4 than in the placebo group.
The source material notes that the US FDA no longer requires complete wound closure as the sole primary endpoint in EB studies, making a partial improvement also a significant study outcome.
Preliminary observations regarding the surface of wounds encouraged further research, especially since modern gene therapies remain complex and expensive.
Previous dermatological studies indicated a favorable tolerance profile, including in elderly patients, patients with diabetes, and people with EB. However, the small number of participants limits the ability to draw conclusions about rare and long-term adverse effects.
Other experimental results from animal and laboratory studies
Regulation of glucose and insulin sensitivity
In studies in mice with diabetes, thymozine β4 influenced glycemic control and muscle sensitivity to insulin.
Zhu and colleagues (2012) administered thymozine β4 to mice with diabetes for 12 weeks [12]. The KK Cg-Ay/J strain was used, and the experimental dose was 100 ng per 10 g of body weight, administered as injections.
Compared to untreated diabetic mice, the animals receiving the peptide showed better results in glucose tolerance tests, had lower levels of HbA1c and triglycerides, and higher levels of adiponectin, a hormone involved in regulating insulin sensitivity.
The response of muscle cells to insulin also improved, accompanied by an increase in the level of phosphorylated AKT.
No similar changes were observed in healthy mice, which suggests a relationship between the effect and the metabolic conditions present in diabetes.
Restoring blood flow and nerve function in diabetic neuropathy
Wang and colleagues (2012) studied β4-tyrosine in mice with type 2 diabetes and diabetic neuropathy [13].
In the model under study, an improvement in blood flow and an increase in the density of blood vessels in the sciatic nerve, one of the main nerves of the lower limb, were observed.
The parameters of the nerve functions also improved.
In damaged nerves, the level of angiopoietin-1 (Ang1), a protein involved in the stabilization of blood vessels, increased, while the level of angiopoietin-2 (Ang2), associated with disorders of blood vessel function, decreased.
Changes were observed in endothelial cells and Schwann cells, which support the proper functioning of nerves.
In laboratory experiments on human cells, thymosine β4 also supported processes related to angiogenesis under conditions of high glucose concentration.
The mechanism was associated with the PI3K/AKT pathway, which is important for the stability and function of blood vessels.
Improvement of vascular cell function derived from patients with diabetes
Su and colleagues (2022) analyzed the effect of thymozine β4 on endothelial cells of blood vessels obtained from induced pluripotent stem cells of patients with diabetes, referred to as dia-hiPSC-ECs [14].
These cells usually exhibit functional abnormalities.
After exposure to 600 ng/ml thymidine β4, greater survival, faster growth, and slower cellular aging were observed.
Production of endothelial-1 (ET-1), associated with vessel constriction, and MMP-1, an enzyme involved in tissue degradation, also decreased.
Not all disorders have been corrected. Among other things, the proper level of cellular energy and some other metabolic parameters have not been restored.
When cells treated with thymozine β4 were transplanted into mice with diabetes and circulatory disorders in the limbs, blood flow in the limbs improved significantly.
The authors linked the results to the activation of AKT signaling and the reduction of harmful inflammatory mediators.
Skin regeneration in mice with diabetes and in older animals
Philp and colleagues (2003) studied β4-thymozine in db/db mice with diabetes and in very old mice aged 26 months, in which deep skin wounds were produced [15].
The preparation was applied topically in a PBS or hydrogel solution.
In mice with diabetes, thymozine β4 increased wound healing and the production of collagen, which is involved in skin repair.
By the eighth day, all the diabetic mice showed complete skin wound coverage, therefore no significant differences in keratinocyte migration were observed.
In older mice, where the healing processes naturally progress more slowly, thymozine β4 significantly accelerated wound closure, improved keratinocyte migration, and increased both wound contraction and collagen content.
The type of formulation, PBS or hydrogel, did not significantly affect the results.
The researchers also evaluated a short fragment of thymine β4 composed of seven amino acids, LKKTETQ.
In older mice, this fragment showed activity similar to that of the full molecule. This suggested that an important part of the wound-healing activity may result from this fragment, which influences cell migration and collagen remodeling through the regulation of the actin cytoskeleton.
Healing of skin burns in diabetes
Kim and Kwon (2014) studied β4-thymozine in mice with diabetes and severe skin burns [16].
Burns were induced with hot water over an area of 10 mm in size. The β4-thymosin was administered as injections near the wound at a dose of 5 mg/kg twice a week for two weeks.
Compared to untreated mice, the animals receiving the peptide showed faster healing, a greater amount of new granulation tissue, and stronger development of blood vessels within the wound.
The level of the protein RAGE also decreased; its increased activity in diabetes is associated with chronic inflammation and impaired wound healing.
Restricting RAGE signaling could reduce the adverse inflammatory response and promote the restoration of normal circulation in damaged skin.
Wound healing in various disease states
Studies on thymozine β4 included burns, diabetic wounds, venous leg ulcers, bedsores, and vesicular peeling of the epidermis.
The available evidence comes from animal studies and relatively small early clinical trials, which differ in methodology and the results assessed.
Gao and colleagues (2022) reviewed the studies and indicated that local concentrations of about 0.02–0.03% showed the most favorable results in terms of efficacy and tolerance in the analyzed protocols [17].
Thymosin β4 occurs naturally in the blood platelets and flows from wounds. It participates in the regulation of inflammation, angiogenesis, migration of skin cells, and the reduction of scarring.
In burn models in rodents, subcutaneous administration of 30 mg/kg twice weekly significantly accelerated healing, especially in combination with other growth factors such as bFGF.
In diabetic wound studies in older mice, topical preparations containing 0.01–0.03% thymozines β4 improved skin repair, vessel development, and reduced inflammation.
In a phase II study involving 72 people with leg ulcers, a gel containing 0.02% thymozines β4 accelerated healing between the fourth and ninth week.
In the case of venous ulcers, the gel with a concentration of 0.03% was associated with complete wound closure in 33.3% patients, compared with 17.6% in the placebo group.
In patients with EB, all tested concentrations, ranging from 0.01% to 0.10%, showed signs of wound healing-related activity, however, the limited number of participants did not allow obtaining statistical significance.
Mechanistically, β4-thymozine can participate in all phases of healing.
In the early phase, it affects the stabilization of clots and the reduction of oxidative damage associated with ROS and NO.
In the proliferative phase, it can stimulate angiogenesis through VEGF, PI3K/AKT and related pathways.
In later stages, it participates in the reconstruction of the skin barrier and the regulation of excessive accumulation of collagen and fibroblasts.
Unlike some growth factors, thymosin β4 can diffuse through tissues and modulate natural repair responses without the need to directly induce excessive cell proliferation.
The authors of the review also drew attention to the importance of the formulation. After intravenous administration, thiosynin β4 has a relatively short half-life, approximately 2.1 hours.
Advanced systems, such as collagen-chitozan sponges and etosomal gels, can prolong the time of their local action.
Local gels with concentrations of 0.02–0.03% showed favorable results, but the dose-response relationship resembled a bell curve. This means that increasing the concentration does not necessarily lead to stronger action.
In studies of healthy volunteers, no serious safety issues were observed even at high intravenous doses of up to 1260 mg. However, the authors recommended caution in interpreting data regarding individuals with active cancer disease, due to the involvement of thymidine β4 in cell growth and migration processes.
The discussed concentrations and controlled-release systems remain research questions, rather than confirmed clinical recommendations [17].
Regeneration of nerves in diabetic neuropathy
Wang and colleagues (2019) studied β4-thymozine in mice with diabetes and peripheral nerve damage [18].
After four weeks, improvements in nerve conduction and temperature sensitivity were observed, an increase in the number of small blood vessels in the sciatic nerve, and better maintenance of protective nerve barriers.
The researchers analyzed the angiopoietin-1 pathway and the Tie2 receptor.
When the Tie2 receptor was blocked, the effect of thymozine β4 disappeared. This indicated the key role of the Ang1/Tie2 signaling in the observed changes affecting nerve regeneration.
Regeneration of nerves without lowering glycemia
In a separate 16-week study, Wang and colleagues (2015) demonstrated that thymozine β4 improved nerve function despite no reduction in blood glucose levels [19].
More favorable nerve conduction was observed, sensory improvement and better preserved axon and myelin structure were observed.
In laboratory experiments, the peptide increased the growth of neurons, or nerve cell protrusions.
This effect disappeared after the blocking of Tie2, which again indicated the involvement of the Ang1/Tie2 pathway.
Overall, studies in mice suggest that changes in blood flow and nerve structure can occur independently of glycemic control. The clinical significance of this mechanism in humans remains unknown.
Bone healing and structural strength in mice
Brady and colleagues (2014) investigated the effect of thymoquinone β4 on the healing of the femoral bone after surgical intervention in mice [20].
The animals received either physiological salt or thymozine β4 at a dose of 6 mg/kg in a systemic injection.
On the 21st day, the bones in the thymosin β4 group showed 41% more strength needed to break them and 25% more stiffness than in the control group.
Imaging studies showed an additional 18% new formed mineralized bone tissue and 26% more strongly mineralized, mature bone.
At the same time, the volume of bone was 23% lower. It contained 47% less old bone tissue and 31% more new spongy tissue.
The results suggest a more efficient bone remodeling and better mechanical properties of the healing tissue in this model.
Regeneration of ligaments and mechanical strength
Xu and colleagues (2013) studied mice with surgically repaired patellar ligament (MCL), one of the main ligaments stabilizing the knee joint [21].
A small amount of gel containing 1 µg of thymozine β4 was placed directly at the site of the damage.
After four weeks, the regenerating ligaments in the thymosin β4 group showed a more organized collagen structure and thicker and stronger fibers.
These changes resulted in greater mechanical strength during tests.
The results were consistent with the involvement of thymosin β4 in cell migration, angiogenesis, and collagen production, processes essential for tendon repair.
Reduction of inflammation and bone loss in models of periodontal diseases
Lee and colleagues (2016) investigated the effect of thymozine β4 on cells involved in gum inflammation and bone tissue loss [22].
In human periodontal ligament cells (PDLCs) subjected to oxidative stress caused by hydrogen peroxide, the natural level of thymine β4 decreased.
After the addition of the peptide, the levels of inflammatory mediators such as nitric oxide (NO), prostaglandin E₂ (PGE₂), TNF-α and cytokines of the interleukin family decreased.
The ratio of RANKL to OPG, which is important for regulating bone resorption, was also improving.
In the bone marrow cells of mice induced to differentiate into osteoclasts, thymosin β4 inhibited the formation of these cells and the activity of genes related to bone breakdown.
The mechanism involved a weakening of MAPK and NF-κB signaling.
The Wnt5a pathway was also important. Blocking it intensified the effect of thymozine β4, whereas adding the Wnt5a peptide weakened the observed effects.
The results indicate complex relationships between signaling pathways regulating inflammation and bone metabolism.
Development of the fetus and organs during pregnancy in mice
Faa and colleagues (2021) studied β4-thymozine in pregnant mice [23].
The animals were administered 6 mg/kg of peptide in injections on the 14th and 17th day of gestation.
The offspring of females receiving thymosin β4 had longer body lengths and more developed organs than the control animals.
The changes concerned, among others, the lungs, the heart, the kidneys, the brain, including the cerebral cortex, and the spinal cord.
The results suggest a possible role of thymine β4 in angiogenesis, migration, and cell differentiation during mouse embryonic development.
However, they do not confirm the benefits or safety of use in pregnant women or premature infants.
Mortality and inflammation in models of severe sepsis
Badamchian and colleagues (2003) studied β4 thymosin in a mouse model of sepsis caused by lipopolysaccharide (LPS), a potent activator of the immune response [24].
After exposure to LPS, the level of thymidine β4 decreased in animals.
Similar changes were observed in human volunteers and patients with septic shock, suggesting a reduction in the availability of thymidine β4 during severe inflammation.
Mice receiving 100 µg of thymosin β4 0, 2 and 4 hours after LPS administration showed lower mortality and lower levels of inflammatory mediators such as IL-1β and 6-keto-PGF1α.
The results suggested a reduction in excessive immune response and possible protection against severe inflammatory effects in this model.
Pulmonary fibrosis and respiratory function
Yu and colleagues (2025) studied recombinant human thymosin β4 (rhTβ4) in a mouse model of bleomycin-induced lung injury [25].
The peptide was administered at an early, intermediate or late stage of the development of the damage.
In all the studied periods, smaller lung fibrosis was observed, lower collagen content and more favorable respiratory function parameters.
In laboratory experiments, thymozine β4 limited the proliferation and migration of fibroblasts involved in the formation of fibrous tissue.
It also reduced adverse changes in the epithelial cells of the lung and regulated the activity of TGF-β1, one of the main mediators of fibrosis.
The results indicate activity at different stages of experimental lung damage.
Protection of the heart and lungs in models of pulmonary hypertension
Wei and colleagues (2014) studied β4-thymosin in animals with pulmonary hypertension caused by monochlorotane [26].
In mice receiving the peptide, lower pulmonary vascular pressure and smaller hypertrophy of the right ventricle of the heart were observed.
Molecular analyses revealed changes in the Notch3–Col3A1–CTGF pathway, which is involved in the remodeling of blood vessels and tissues.
The results suggest the possibility of limiting adverse vascular and structural changes in experimental pulmonary hypertension.
Repair of tissues of many organs: review of animal studies
Philp and Kleinman (2010) reviewed studies on thymoquinone β4 in various organs [27].
In models of corneal damage, local application of 5 µg in 5 µl twice daily accelerated the healing of corneal burns without causing unwanted angiogenesis.
In skin studies in animals with diabetes and in older individuals, the peptide promoted cell migration, collagen production, and the development of new blood vessels.
The effect on hair growth through the activation of the hair follicles was also observed.
In heart studies, thymozine β4 was evaluated in both small animals, for example mice receiving 400 ng, and larger animals, such as pigs receiving 15 mg.
In these models, the limitations of tissue damage, increased survival of heart cells, and less scarring after injury were described.
In models of LPS-induced sepsis, a weaker inflammatory response and greater survival were observed.
In brain and central nervous system research, thymozine β4 limited neuronal damage and supported the development of oligodendrocytes, which are cells that produce the myelin that surrounds nerve fibers.
The proposed mechanisms included inhibition of inflammatory mediators, regulation of matrix metalloproteinases (MMP), modulation of NF-κB and Akt signaling, and activation of stem cells.
The review also described the tolerance results in rats and monkeys at the tested doses. However, toxicological data from animals do not allow for a broad safety margin to be determined for humans on its own.
Protection of the lungs from reperfusion damage after aortic closure
Yaman and colleagues (2019) studied β4 thymosin in a rat model of ischemia and reperfusion of the aorta [28].
The animals were given 10 mg/kg of peptide an hour before the closure of the aorta or 15 minutes before the return of blood flow.
Both timeframes yielded similar results.
Thymosin β4 reduced oxidative stress, lowered inflammatory cytokine levels, improved antioxidant parameters in the lungs and blood, and reduced tissue damage.
The results indicate a possible protection against acute lung injury associated with disruption and restoration of blood flow, for example in experimental models of surgical procedures and injuries.
Reducing esophageal scarring after surgical treatment
Wang and colleagues (2019) studied the local zymosin β4 gel in eight pigs undergoing endoscopic retrograde diversion of the esophageal sphincter (ESD) [29].
This procedure is associated with the risk of developing esophageal strictures.
Four pigs received a local gel containing thymozine β4, and the other four formed the control group.
In all animals, narrowing occurred, but in the thymosin β4 group it was less severe.
Animals receiving the peptide required fewer balloon dilation procedures (p = 0.002), and healing occurred more quickly (p = 0.012).
The authors linked the effects to a reduction in the formation of scar tissue, an improvement in cell migration, and a reduction in excessive accumulation of collagen.
No adverse reactions have been reported.
Maintenance of vascular structure and development of aortic aneurysms
Munshaw and colleagues (2021) studied mice lacking thymidine β4 [30].
In these animals, the blood vessel walls were weaker and aortic aneurysms developed more frequently, especially after exposure to angiotensin II.
In the absence of thymosin β4, vascular smooth muscle cells (VSMCs) more frequently changed their phenotype towards an unfavorable remodeling and fiberization pattern.
This phenomenon was associated with excessive recycling of the PDGFRβ receptor, whose activity under normal conditions is regulated by thymosin β4.
The use of imatinib, a drug that inhibits PDGFRβ, reduced the damage to blood vessels in mice lacking thymidine β4.
The results suggest that natural thymoquinone β4 participates in maintaining proper vascular remodeling by regulating growth signals.
Intestinal barrier and inflammation in models of chronic atrophic enteropathy
Renga and colleagues (2019) studied thymosin β4 in models of chronic granulomatous disease (CGD), a genetic disorder of immune system function [31].
The experiments included human and mouse immune cells as well as mice with CGD.
Thymosin β4 restored the activity of the protective protein HIF-1α and stimulated noncanonical autophagy via DAPK1.
These changes improved the function of the intestinal barrier, reduced inflammation and the formation of granulomas, and increased the survival of the animals.
The results suggest the involvement of thymoquinone β4 in the regulation of inflammatory responses and processes of removing damaged cellular components in the intestines.
Cardiovascular disease and vascular stability
Munshaw and colleagues (2023) studied thymozine β4 in ApoE⁻/⁻ mice predisposed to the development of atherosclerosis [32].
Animals with proper expression of thymosin β4 were compared with mice lacking this protein.
In mice without thymosin β4, larger atherosclerotic plaques developed, stronger damage to the middle layer of the blood vessel wall was observed, and smooth muscle cells lost their normal properties.
In healthy vessels, thymosin β4 was present in cells involved in maintaining their tension and function, while its level decreased in cells that were clinically altered.
The absence of thymidine β4 led to excessive PDGFRβ activity due to impaired receptor regulation, which exacerbated the adverse remodeling of the vessels.
The results suggest a protective role of endogenous thymidine β4 in maintaining arterial stability.
Stability of vessels and survival in sepsis models
Bongiovanni and colleagues (2015) applied a gene therapy method to increase the expression of thymosin β4 in mice two weeks before inducing sepsis with LPS [33].
Animals with elevated expression of thymosin β4 showed milder disease symptoms, better blood pressure values, and less vascular permeability.
Greater survival and better preservation of pericytes, the supporting cells surrounding the tiny blood vessels in the heart and muscles, were also observed.
The results suggest that thymosin β4 is involved in maintaining the integrity of the vascular barrier and limiting excessive fluid leakage from the vessels during severe inflammation.
Pulmonary fibrosis and cellular damage in inflammatory models
Tian and colleagues (2022) used gene therapy to deliver thymidine β4 to mice in a model of LPS-induced lung injury [34].
In animals with increased expression of thymosin β4, less oxidative damage, lower collagen deposition, and a weaker inflammatory response were observed.
In laboratory studies on human lung cells, thymozine β4 supported the repair of damaged mitochondria, limited the activation of inflammatory cells, and slowed down the cellular processes associated with fibrosis.
It also inhibited the proliferation of fibroblasts and the formation of scar tissue.
The results indicate the involvement of thymidine β4 in the regulation of several pathways leading to long-term lung damage.
Wound healing through the activation of tissue repair enzymes
Philp and colleagues (2006) studied thymosin β4 in skin wound models in mice and in human skin and immune cell cultures [35].
After the peptide was applied, the production of metalloproteinases MMP-1, MMP-2 and MMP-9, enzymes involved in the breakdown of damaged tissue components and the preparation of the site for new cells, increased.
Effects were observed in keratinocytes, fibroblasts, endothelial cells, and activated monocytes.
A small fragment of thymine β4 containing amino acids 17–23 was sufficient to trigger this response.
This suggests that the peptide is involved in wound healing not only by promoting cell migration and growth, but also by regulating the removal of damaged components and the remodeling of the extracellular matrix.
The results indicate a relationship between the regulation of the cellular cytoskeleton and the processes of cleansing and repairing damaged skin.
The doses and formulations described in the studies are not clinical recommendations.
In early clinical studies, various formulations and dosage ranges of thymozine β4 were evaluated.
The described protocols should not be interpreted as recommendations for self-administration. The available data do not allow determining a standard therapeutic dose.
In the first intravenous studies of recombinant thymosin β4, NL005, single doses of 0.05 to 25 µg/kg and daily infusions of 0.5 to 5 µg/kg were evaluated for ten days.
Blood concentrations increased proportionally to the dose, and the half-life was approximately two hours. No significant accumulation of the substance in the body was observed.
In an earlier study of synthetic thymozine β4, much higher intravenous doses were used, ranging from 42 to 1260 mg per day for two weeks, without reporting of severe adverse effects.
Ophthalmological studies evaluated the 0.1% solution of thymozine β4, corresponding to approximately 1 mg/ml, at various dosing schedules established in the individual protocols.
Some parameters improved, but at least one study did not achieve the previously established primary endpoints.
In three Phase II studies involving chronic skin wounds, the most beneficial results were obtained when using gels with concentrations of 0.02–0.03%, evaluated when administered once daily.
Both the lower concentration of 0.01% and the higher one of 0.1% showed less favorable results.
In a study in pigs, local administration of a gel at a concentration of 0.1% around the esophagus reduced scarring after surgical removal of the mucous membrane, indicating the possibility of further research on local delivery systems.
In the small early studies described above, tolerance was generally beneficial, but the available data are insufficient to assess long-term or rare adverse effects.
In the study of the recombinant preparation, mild and transient changes in laboratory test results or ECG occurred in just over half of the participants, with a frequency similar to that of placebo.
No severe adverse reactions or dose-limiting reactions were reported. The detected immune responses were mild and transient.
In a study of high intravenous doses of synthetic thymosine β4, only mild dizziness or discomfort at the injection site was reported, without signs of organ damage.
Eye drops and skin gels were also well tolerated. No eye irritation associated with the product was observed, and minor itching or redness of the skin after the gel occurred with a frequency similar to that of placebo.
In the healthy volunteer groups studied, repeated administration did not lead to significant accumulation, and the observed immunological reactions were limited.
However, these results cannot be generalized to other populations, longer periods of use, or people with serious illnesses.
Because clinical trials are still in an early stage, many safety issues require caution.
The source material indicated a contraindication related to hypersensitivity to the peptide or the components of the preparation.
Although an increased risk of cancer has not yet been confirmed, even in studies involving patients with EB, the ability of thymosin β4 to regulate cell migration and angiogenesis warrants particular caution in individuals with active cancer disease, preferably within the framework of controlled studies.
The safety of thymozine β4 during pregnancy and breastfeeding has not been established. There is also a lack of adequate pharmacokinetic and safety data in people with severe liver or kidney diseases.
The source studies do not specify the appropriate dosing regimen for these populations.
Applications
Early clinical and laboratory studies indicate that thymozine β4 participates in many processes related to tissue repair and generally exhibits favorable tolerability under the conditions evaluated to date.
Following intravenous administration, synthetic thymozine β4 and recombinant NL005 were well tolerated by healthy volunteers, even when administered repeatedly.
The pharmacokinetics were relatively predictable. The substance had a short half-life in the blood, showed no significant accumulation and only produced a few transient immune responses.
In ophthalmological studies, drops containing thymozine β4 showed promising results in diseases of the surface of the eye.
In phase II studies and case series, a reduction in symptoms, a reduction in damage to the surface of the eye assessed using staining methods, and an improvement in the parameters of the tear film were observed.
However, in one of the studies using the CAE™ model, two main endpoints were not achieved, despite beneficial changes in several secondary parameters.
In dermatological studies, gels containing approximately 0.02–0.03% thymozine β4 were associated with faster healing of leg ulcers and venous wounds in phase II studies.
These results were consistent with previous laboratory experiments indicating the involvement of thymosin β4 in keratinocyte migration, angiogenesis, organization of collagen fibers, and reduction of scarring.
Overall, available studies suggest that thymoquinone β4 is an important regulator of repair and inflammatory processes.
However, further studies are necessary regarding long-term safety, especially in people with an increased risk of cancer.
Researchers should also seek biomarkers that allow identifying patients who may benefit the most, and better determine the relationship between dose, formulation, and biological response.
If future studies confirm the current results, tymozine β4 may become the subject of further development in the treatment of superficial eye diseases and difficult-to-heal wounds.
However, possible systemic applications, including in acute cardiovascular and neurological disorders, remain research hypotheses and not confirmed clinical benefits.
Disclaimer: This article is for educational purposes only. It does not constitute medical advice or recommendations regarding the use, dosage, or administration of thymozine β4. The results of cell and animal studies are not equivalent to confirmation of safety or efficacy in humans.
References
- https://pubchem.ncbi.nlm.nih.gov/compound/Thymosin-beta4#section=NCI-Thesaurus-Tree
- Wang, X., Liu, L., Qi, L., Lei, C., Li, P., Wang, Y., Liu, C., Bai, H., Han, C., Sun, Y., & Liu, J. (2021). A first-in-human, randomized, double-blind, single- and multiple-dose, phase I study of recombinant human thymosin β4 in healthy Chinese volunteers. Clinical and Translational Science, 14(5), 1949–1962. https://doi.org/10.1111/cts.13050
- Sosne, G., Dunn, S. P., & Kim, C. (2015). Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. Cornea, 34(5), 491–496. https://doi.org/10.1097/ICO.0000000000000379
- Ruff, D., Crockford, D., Girardi, G., & Zhang, Y. (2010). A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers. Annals of the New York Academy of Sciences, 1194, 223–229. https://doi.org/10.1111/j.1749-6632.2010.05474.x
- Guarnera, G., DeRosa, A., & Camerini, R. (2010). The effect of thymosin treatment of venous ulcers. Annals of the New York Academy of Sciences, 1194, 207–212. https://doi.org/10.1111/j.1749-6632.2010.05490.x
- Sosne, G., & Ousler, G. W. (2015). Thymosin beta 4 ophthalmic solution for dry eye: A randomized, placebo‑controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE™) model. Clinical Ophthalmology, 9, 877-884. https://doi.org/10.2147/OPTH.S80954 https://www.tandfonline.com/doi/full/10.2147/OPTH.S80954
- Dunn, S. P., Heidemann, D. G., Chow, C. Y. C., Crockford, D., Turjman, N., Angel, J., Allan, C. B., & Sosne, G. (2010). Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta 4. Archives of Ophthalmology, 128(5), 636–638. https://doi.org/10.1001/archophthalmol.2010.71 https://pismin.com/10.1001/archophthalmol.2010.53
- Kleinman, H. K., & Sosne, G. (2016). Thymosin β4 Promotes Dermal Healing. In Vitamins and Hormones (Vol. 102, pp. 251–275). Elsevier. https://doi.org/10.1016/bs.vh.2016.04.005 https://pismin.com/10.1016/bs.vh.2016.04.005
- Treadwell, T., Kleinman, H. K., Crockford, D., Hardy, M. A., Guarnera, G. T., & Goldstein, A. L. (2012). The regenerative peptide thymosin β4 accelerates the rate of dermal healing in preclinical animal models and in patients. Annals of the New York Academy of Sciences, 1270, 37–44. https://doi.org/10.1111/j.1749-6632.2012.06717.x https://pubmed.ncbi.nlm.nih.gov/23050815/
- Guarnera, G., De Rosa, A., & Camerini, R. (2007). Thymosin β 4 and venous ulcers: Clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on healing. Annals of the New York Academy of Sciences, 1112, [pages pending]. https://doi.org/10.1196/annals.1415.003 https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1196/annals.1415.003
- Yang, W. S., Kang, S., Sung, J., & Kleinman, H. K. (2019). Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries. European Journal of Dermatology, 29(5), 459-467. https://doi.org/10.1684/ejd.2019.3642 https://stm.cairn.info/revue-european-journal-of-dermatology-2019-5-page-459?lang=en
- Zhu, J., Su, L.-P., Ye, L., Lee, K.-O., & Ma, J.-H. (2012). Thymosin beta 4 ameliorates hyperglycemia and improves insulin resistance of KK Cg-Ay/J mice. Diabetes Research and Clinical Practice, 96(1), 53-59. https://doi.org/10.1016/j.diabres.2011.12.009 https://pubmed.ncbi.nlm.nih.gov/22217673/
- Wang, L., Chopp, M., Szalad, A., Liu, Z., Lu, M., Zhang, L., Zhang, J., Zhang, R. L., Morris, D., & Zhang, Z. G. (2012). Thymosin β4 promotes the recovery of peripheral neuropathy in type II diabetic mice. Neurobiology of Disease, 48(3), 546–555. https://doi.org/10.1016/j.nbd.2012.08.002 https://pubmed.ncbi.nlm.nih.gov/22922221/
- Su, L., Kong, X., Loo, S., Gao, Y., Liu, B., Su, X., Dalan, R., Ma, J., & Ye, L. (2022). Thymosin beta‑4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient-induced pluripotent stem cells. Stem Cell Research & Therapy, 13(1), 13. https://doi.org/10.1186/s13287-021-02687-x https://pubmed.ncbi.nlm.nih.gov/35012642/
- Philp, D., Badamchian, M., Scheremeta, B., Nguyen, M., Goldstein, A. L., & Kleinman, H. K. (2003). Thymosin beta 4 and a synthetic peptide containing its actin‑binding domain promote dermal wound repair in db/db diabetic mice and in aged mice. Wound Repair and Regeneration, 11(1), 19–24. https://doi.org/10.1046/j.1524-475x.2003.11105.x https://pubmed.ncbi.nlm.nih.gov/12581423/
- Kim, S., & Kwon, J. (2014). Thymosin beta 4 improves dermal burn wound healing via downregulation of receptor of advanced glycation end products in db/db mice. Biochemistry and Biophysics Acta (BBA)–General Subjects, 1840(12), 3452-3459. https://doi.org/10.1016/j.bbagen.2014.09.013 https://pubmed.ncbi.nlm.nih.gov/25230158/
- Gao, Y. X., Wang, L. F., Ba, S. J., Cao, J. L., Li, F., Li, B., & Zhou, B. (2022). Zhonghua shao shang yu chuang mian xiu fu za zhi, 38(4), 378–384. https://doi.org/10.3760/cma.j.cn501120-20210221-00059 https://pmc.ncbi.nlm.nih.gov/articles/PMC11704510/
- Wang, L., Chopp, M., Szalad, A., Lu, X., Lu, M., Zhang, T., & Zhang, Z. G. (2019). The Angiopoietin-1/Tie2 signaling pathway contributes to the therapeutic effect of thymosin β4 on diabetic peripheral neuropathy. Neuroscience research, 147, 1-8. https://doi.org/10.1016/j.neures.2018.10.005 https://pubmed.ncbi.nlm.nih.gov/30326249/
- Wang, L., Chopp, M., Jia, L., Lu, X., Szalad, A., Zhang, Y., Zhang, R., & Zhang, Z. G. (2015). Therapeutic benefit of extended thymosin β4 treatment is independent of blood glucose level in mice with diabetic peripheral neuropathy. Journal of Diabetes Research, 2015, 173656. https://doi.org/10.1155/2015/173656 https://pubmed.ncbi.nlm.nih.gov/25945352/
- Brady, R. D., Grills, B. L., Schuijers, J. A., Ward, A. R., Tonkin, B. A., Walsh, N. C., & McDonald, S. J. (2014). Administration of thymosin β4 enhances fracture healing in mice. Journal of Orthopaedic Research, 32(10), 1277–1282. https://doi.org/10.1002/jor.22686 https://pubmed.ncbi.nlm.nih.gov/25042765/
- Xu, B., Yang, M., Li, Z., Zhang, Y., Jiang, Z., Guan, S., & Jiang, D. (2013). Thymosin β4 enhances the healing of medial collateral ligament injury in rats. Regulatory Peptides, 184, 1–5. https://doi.org/10.1016/j.regpep.2013.03.026 https://pubmed.ncbi.nlm.nih.gov/23523891/
- Lee, S. I., Yi, J. K., Bae, W. J., Lee, S., Cha, H. J., & Kim, E. C. (2016). Thymosin beta-4 suppresses osteoclastic differentiation and inflammatory responses in human periodontal ligament cells. PLoS ONE, 11(1), e0146708. https://doi.org/10.1371/journal.pone.0146708 https://pubmed.ncbi.nlm.nih.gov/26789270/
- Faa, G., Piras, M., Mancuso, L., Coni, P., Pichiri, G., Orrù, G., Fanni, D., Gerosa, C., Cao, G., Taibi, R., Pavone, P., & Castagnola, M. (2021). Prenatal administration of thymosin beta-4 improves fetal development and halts side effects due to preterm delivery. European Review for Medical and Pharmacological Sciences, 25(1), 431–437. https://doi.org/10.26355/eurrev_202101_24411 https://pubmed.ncbi.nlm.nih.gov/33506933/
- Badamchian, M., Fagarasan, M. O., Danner, R. L., Suffredini, A. F., Damavandy, H., & Goldstein, A. L. (2003). Thymosin beta(4) reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock. International Immunopharmacology, 3(8), 1225–1233. https://doi.org/10.1016/S1567-5769(03)00024-9 https://pubmed.ncbi.nlm.nih.gov/12860178/
- Yu, R., Li, S., Chen, L., Hu, E., Chai, D., Liu, Z., Zhang, Q., Mao, Y., Zhai, Y., Li, K., Liu, Y., Li, X., Zhou, H., Yang, C., & Xu, J. (2025). Inhaled exogenous thymosin beta 4 suppresses bleomycin-induced pulmonary fibrosis in mice via the TGF-β1 signaling pathway. Journal of Pharmacy and Pharmacology, 77(4), 582–592. https://doi.org/10.1093/jpp/rgae143 https://pubmed.ncbi.nlm.nih.gov/39579076/
- Wei, C., Kim, I. K., Li, L., Wu, L., & Gupta, S. (2014). Thymosin Beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. PLoS ONE, 9(11), e110598. https://doi.org/10.1371/journal.pone.0110598 https://pubmed.ncbi.nlm.nih.gov/25412097/
- Philp, D., & Kleinman, H. K. (2010). Animal studies with thymosin β4, a multifunctional tissue repair and regeneration peptide. Annals of the New York Academy of Sciences, 1194(1), 81–86. https://doi.org/10.1111/j.1749-6632.2010.05479.x https://pismin.com/10.1111/j.1749-6632.2010.05479.x
- Yaman, O. M., Guner, I., Guntas, G., Sonmez, O. F., Tanriverdi, G., Cakiris, A., Aksu, U., Akyol, S., Guzel, E., Uzun, H., Yelmen, N., & Sahin, G. (2019). Protective effect of thymosin β4 against abdominal aortic ischemia-reperfusion-induced acute lung injury in rats. Medicina (Kaunas), 55(5), 187. https://doi.org/10.3390/medicina55050187 https://pubmed.ncbi.nlm.nih.gov/31121838/
- Wang, H., Shuai, Q., Tang, J., Long, D., Xu, C., Liu, F., & Li, Z.-S. (2019). Local Thymosin β4 Gel Injection Prevents Esophageal Stricture after Circumferential Endoscopic Submucosal Dissection in a Porcine Model. Digestive Diseases, 37(2), 87–92. https://doi.org/10.1159/000492216 https://pubmed.ncbi.nlm.nih.gov/30428463/
- Munshaw, S., Bruche, S., Redpath, A. N., Jones, A., Patel, J., Dubé, K. N., Lee, R., Hester, S. S., Davies, R., Neal, G., Handa, A., Sattler, M., Fischer, R., Channon, K. M., & Smart, N. (2021). Thymosin β4 protects against aortic aneurysm via endocytic regulation of growth factor signaling. Journal of Clinical Investigation, 131(10), e127884. https://doi.org/10.1172/JCI127884 https://pubmed.ncbi.nlm.nih.gov/33784254/
- Renga, G., Oikonomou, V., Moretti, S., Stincardini, C., Bellet, M. M., Pariano, M., Bartoli, A., Brancorsini, S., Mosci, P., Finocchi, A., Rossi, P., Costantini, C., Goldstein, A. L., & Romani, L. (2019). Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease. Life Science Alliance, 2(6), e201900432. https://doi.org/10.26508/lsa.201900432 https://pubmed.ncbi.nlm.nih.gov/31719116/
- Munshaw, S., Redpath, A. N., Pike, B. T., & Smart, N. (2023). Thymosin β4 preserves vascular smooth muscle phenotype in atherosclerosis via regulation of low density lipoprotein-related protein 1 (LRP1). International Immunopharmacology, 115, 109702. https://doi.org/10.1016/j.intimp.2023.109702 https://pubmed.ncbi.nlm.nih.gov/37724952/
- Bongiovanni, D., Ziegler, T., D’Almeida, S., Zhang, T., Ng, J. K. M., Dietzel, S., Hinkel, R., & Kupatt, C. (2015). Thymosin β4 attenuates microcirculatory and hemodynamic destabilization in sepsis. Expert Opinion on Biological Therapy, 15(Suppl 1), S203–S210. https://doi.org/10.1517/14712598.2015.1006193 https://pubmed.ncbi.nlm.nih.gov/25604254/
- Tian, Z., Yao, N., Wang, F., & Ruan, L. (2022). Thymosin β4 suppresses LPS-induced murine lung fibrosis by attenuating oxidative injury and alleviating inflammation. Inflammation, 45(1), 59–73. https://doi.org/10.1007/s10753-021-01528-6 https://pubmed.ncbi.nlm.nih.gov/34414534/
- Philp, D., Scheremeta, B., Sibliss, K., Zhou, M., Fine, E. L., Nguyen, M., Wahl, L., Hoffman, M. P., & Kleinman, H. K. (2006). Thymosin beta4 promotes matrix metalloproteinase expression during wound repair. Journal of Cellular Physiology, 208(1), 195–200. https://doi.org/10.1002/jcp.20650 https://pubmed.ncbi.nlm.nih.gov/16607611/