The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. METHODS: In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. RESULTS: We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3ß signaling. CONCLUSION: MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

ß-Carotene synergistically enhances the anti-tumor effect of 5-fluorouracil on esophageal squamous cell carcinoma in vivo and in vitro.

Recently, we reported that ß-carotene exhibited anticancer activity against human esophageal squamous cell carcinoma cells in vitro. In the present study, we examined a novel therapeutic strategy by combining ß-carotene with 5-fluorouracil (5-FU) in human esophageal cancer in vitro and in vivo, and elucidated the underlying mechanisms. We found that the combination of 5-FU and ß-carotene displayed greater growth inhibitory effects than did either compound alone in esophageal squamous cell carcinoma (ESCC) cells. In addition, the combination of 5-FU and ß-carotene displayed greater tumor growth inhibition in an Eca109 xenograft mouse model than did a single agent with low systemic toxicity. ß-Carotene enhanced 5-FU-induced apoptosis. TUNEL staining revealed that the rate of TUNEL-positive cells was markedly increased in tumor tissues after treatment with 5-FU and ß-carotene. Western blotting and immunohistochemistry revealed the down-regulation of Bcl-2 and PCNA and the up-regulation of Bax and caspase-3 in tumor tissues. Further studies demonstrated that the combined administration of 5-FU and ß-carotene significantly down-regulated the protein levels of Cav-1, p-AKT, p-NF-κB, p-mTOR and p-p70S6K in Eca109 cells more effectively than did 5-FU alone. These data suggested that the combined therapy of 5-FU and ß-carotene exerted synergistic antitumor effects in vivo and in vitro and could constitute a novel therapeutic treatment for ESCC.

Resveratrol Exerts Dosage-Dependent Effects on the Self-Renewal and Neural Differentiation of hUC-MSCs.

Resveratrol (RES) plays a critical role in the fate of cells and longevity of animals via activation of the sirtuins1 (SIRT1) gene. In the present study, we intend to investigate whether RES could promote the self-renewal and neural-lineage differentiation in human umbilical cord derived MSCs (hUC-MSCs) in vitro at concentrations ranging from 0.1 to 10 µM, and whether it exerts the effects by modulating the SIRT1 signaling. Herein, we demonstrated that RES at the concentrations of 0.1, 1 and 2.5 µM could promote cell viability and proliferation, mitigate senescence and induce expression of SIRT1 and Proliferating Cell Nuclear Antigen (PCNA) while inhibit the expression of p53 and p16. However, the effects were reversed by 5 and 10 µM of RES. Furthermore, RES could promote neural differentiation in a dose-dependent manner as evidenced by morphological changes and expression of neural markers (Nestin, ßIII-tubulin and NSE), as well as pro-neural transcription factors Neurogenin (Ngn)1, Ngn2 and Mash1. Taken together, RES exerts a dosage-dependent effect on the self-renewal and neural differentiation of hUC-MSCs via SIRT1 signaling. The current study provides a new strategy to regulate the fate of hUC-MSCs and suggests a more favorable in vitro cell culture conditions for hUC-MSCs-based therapies for some intractable neurological disorders.

ß-Carotene Induces Apoptosis in Human Esophageal Squamous Cell Carcinoma Cell Lines via the Cav-1/AKT/NF-κB Signaling Pathway.

ß-carotene, a type of terpenoid, has many metabolic and physiological functions. In particular, ß-carotene has an antitumor effect. However, the efficacy of ß-carotene against esophageal squamous cell carcinoma (ESCC) remains unclear. In our study, ß-carotene inhibited the growth of ESCC cells and downregulated expression of the Caveolin-1 (Cav-1) protein. Cav-1 protein was expressed only in ESCC cells, not in Het-1A cells. Moreover, ß-carotene triggered apoptosis, induced cell cycle G0/G1 phase arrest, and inhibited cell migration. To explore the mechanism involved in these processes, we further examined the effect of ß-carotene on the Cav-1-mediated AKT/NF-κB pathway. The results showed that the level of AKT and NF-κB phosphorylation was dramatically inhibited, which led to an increase in the Bax/Bcl-2 ratio. Correspondingly, the activity of Caspase-3 was also enhanced. These data suggest that ß-carotene has an antiproliferative role in ESCC cells and may be a promising chemotherapeutic agent for use against ESCC cells.