Thymosin Beta-4

Seborrheic dermatitis (SD) is a recurrent common inflammatory skin disease that affects all ethnic groups in all regions worldwide. However, no specific treatment or preventive measure is yet available. Identifying effective treatments with acceptable safety and tolerability is desirable. In this study, scalp microbiota alterations were measured in SD, showing significantly greater abundance of Malassezia and Staphylococcus and diminished fungal and bacterial diversity compared with healthy controls. We investigated the benefit of a 4-week treatment with 0.5 mg ml-1 recombinant human thymosin β4 (rhTβ4) gel or 2% ketoconazole lotion on the scalp condition of 71 patients with SD compared with 21 healthy individuals. Clinical assessment (Adherent Scalp Flaking Score, and the Maximum Erythema Area) and physiological conditions (transepidermal water loss, hydration, and sebum secretion) were evaluated. The rhTβ4 treatment provided significantly greater efficacy than ketoconazole and a sustained effect in the treatment of scalp SD. More importantly, rhTβ4 dramatically improved the microbiome homeostasis and prompted a shift of scalp microflora towards healthy composition, helping symptoms and ameliorating physiological conditions more effectively and durably than ketoconazole. Our research demonstrated the scalp microbe dysbiosis of SD and highlighted rhTβ4 as a promising therapeutic strategy in the prevention and treatment of SD.

BACKGROUND: Sepsis is a systemic inflammatory response syndrome, associated with high risk of acute kidney injury (AKI) and in-hospital mortality. Thymosin beta-4 (Tβ4) is an actin-sequestering protein that can prevent inflammation in several tissues. Thus, we studied the role of Tβ4 in sepsis. METHODS: The Tβ4 concentrations were prospectively measured in 191 patients within 6 h of the intensive care units (ICU) admission with diagnosis of sepsis. The cohort was divided into Tβ4 concentration tertiles: 1.19-7.11 ng/ml (n = 64), 7.12-11.01 ng/ml (n = 64), and 11.02-28.10 ng/ml (n = 63). RESULTS: Of 191 patients, 92 patients developed AKI, 24 of whom received continuous renal replacement therapy (CRRT), 29 patients died within 7 days, and 53 patients died within 28 days. Lower Tβ4 stages were correlated with poor prognosis, including AKI(odds ratio [OR], 2.102 per stage lower; 95% confidence interval [CI], 1.448 to 3.050; P < 0.001), CRRT(OR, 2.346 per stage lower; 95% CI, 1.287 to 4.276; P = 0.005), 7-day mortality(OR, 1.755 per stage lower; 95% CI, 1.050 to 2.935; P = 0.032), and 28-day mortality(OR, 1.821 per stage lower; 95% CI, 1.209 to 2.743; P = 0.004). Kaplan-Meier analysis also demonstrated that patients with lower Tβ4 stages had a high risk of AKI and death. In addition, the area under the curve (AUC) of Tβ4 for predicting AKI, CRRT, 7-day mortality, and 28-day mortality were, respectively, 0.702 (95% CI 0.628-0.776), 0.717 (95% CI 0.592-0.842), 0.694 (95% CI 0.579-0.808), and 0.682 (95% CI 0.598-0.767). CONCLUSIONS: Lower Tβ4 stages are associated with higher odds of poor prognosis in ICU patients with sepsis.

BACKGROUND: Thymosin beta-4 (TB4) is an X-linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non-HF controls. METHODS AND RESULTS: TB4 was measured using a liquid chromatography and mass spectrometry assay in age- and sex-matched HFpEF (n=219), HFrEF (n=219) patients, and controls (n=219) from a prospective nationwide study. Additionally, a 92-marker multiplex proximity extension assay was measured to identify biomarker covariates. Compared with controls, plasma TB4 was elevated in HFpEF (985 [421-1723] ng/mL versus 1401 [720-2379] ng/mL, P<0.001), but not in HFrEF (1106 [556-1955] ng/mL, P=0.642). Stratifying by sex, only women (1623 [1040-2625] ng/mL versus 942 [386-1891] ng/mL, P<0.001), but not men (1238.5 [586-1967] ng/mL versus 1004 [451-1538] ng/mL, P=1.0), had significantly elevated TB4 in the setting of HFpEF. Adjusted for New York Heart Association class, N-terminal pro B-type natriuretic peptide, age, and myocardial infarction, hazard ratio to all-cause mortality is significantly higher in women with elevated TB4 (1.668, P=0.036), but not in men (0.791, P=0.456) with HF. TB4 is strongly correlated with a cluster of 7 markers from the proximity extension assay panel, which are either X-linked, regulated by sex hormones, or involved with NF-κB signaling. CONCLUSIONS: We show that plasma TB4 is elevated in women with HFpEF and has prognostic information. Because TB4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB4 to X chromosome biology and differential outcomes in female heart disease warrants further study.

Although a myocardial infarction occurs roughly every minute in the U.S. alone, medical research has yet to unlock the key to fully enabling post-hypoxic myocardial regeneration. Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future.

The present work was conducted to further examine the effects of thymosin beta-4 (Tbeta4) upregulation on the apoptosis of SW480 colon cancer cells induced by T cells and various chemotherapeutic agents because reduced susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) in Tbeta4-overexpressing cells has previously been reported by us. As expected, Tbeta4 overexpressers were also more resistant to the killing effect of FasL-bearing Jurkat T cells. On the other hand, pretreating these cells with an MMP inhibitor restored not only their Fas levels but also their sensitivity to CH-11, suggesting a pivotal role of MMP in downregulating Fas in Tbeta4 overexpressers. Interestingly, while the susceptibilities of Tbeta4 overexpressers to 5-FU and irinotecan remained unchanged, they were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspases 9 and 3 in Tbeta4 overexpressers by the two aforementioned topoisomerase II inhibitors was dramatically abrogated which could be accounted mainly by an increased expression of Survivin, a critical anti-apoptotic factor. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody. Thus, advantages such as immune evasion and resistance to anticancer drug-induced apoptosis acquired by colon cancer cells through Tbeta4 overexpression might facilitate their survival during metastasis and chemotherapy.

Thymosin beta-4 (TMSB4X) was recently identified as a differentially expressed gene between malignant and non-malignant thyroid cells via single-cell RNA sequencing. In the present study, we aimed to study the immunostaining pattern of TMSB4X in benign and malignant thyroid neoplasms. Immunohistochemical analysis revealed that normal thyroid tissue or benign thyroid disorders exhibited undetectable immunoreactivity against TMSB4X except for positive staining of inflammatory infiltrates and stromal cells associated with autoimmune thyroid disease. By contrast, overexpression of TMSB4X was observed in a variety of thyroid malignancies, including papillary, follicular, poorly differentiated, and undifferentiated thyroid cancer. Among 141 patients with differentiated thyroid cancer, higher TMSB4X expression was associated with papillary tumor type, extrathyroidal extension, lymph node metastasis, and BRAF V600E mutation. The results were consistent with those from the public transcriptomic datasets. In summary, TMSB4X expression was aberrantly increased in various types of thyroid cancer, and higher TMSB4X expression was correlated with advanced disease characteristics. Thymosin beta-4 may be a novel downstream effector of the BRAF V600E mutation.