Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation.

The importance of Fbxo22 in carcinogenesis has been highly documented. Here, we discussed downstream regulatory factors of Fbxo22 in TNBC. RNA-sequencing was conducted for identifying differentially expressed genes, followed by construction of a regulatory network. Expression patterns of Fbxo22/KDM5A in TNBC were determined by their correlation with the prognosis analyzed. Then, regulation mechanisms between Fbxo22 and KDM5A as well as between KDM5A and H3K4me3 were assayed. After silencing and overexpression experiments, the significance of Fbxo22 in repressing tumorigenesis in vitro and in vivo was explored. Fbxo22 was poorly expressed, while KDM5A was highly expressed in TNBC. Patients with elevated Fbxo22, decreased KDM5A, or higher p16 had long overall survival. Fbxo22 reduced the levels of KDM5A by ubiquitination. KDM5A promoted histone H3K4me3 demethylation to downregulate p16 expression. Fbxo22 reduced KDM5A expression to enhance p16, thus inducing DNA damage as well as reducing tumorigenesis and metastasis in TNBC. Our study validated FBXO22 as a tumor suppressor in TNBC through ubiquitination of KDM5A and regulation of p16.

Exosomes derived from NGF-overexpressing bone marrow mesenchymal stem cell sheet promote spinal cord injury repair in a mouse model.

Cell transplantation has been an appealing way to improve the recovery of motor, sensory, and autonomic functions following spinal cord injury (SCI). Herein, we sought to elucidate the function of bone marrow mesenchymal stem cells (BMSCs) sheet in the progression of SCI and its underlying mechanism. BMSCs were extracted from bone marrow of femur and tibia collected from C57BL/6 mice, and the BMSC sheet was prepared when cells grew to 100% confluence after approximately 14 days. Exosomes (Exos) derived from BMSCs were isolated and characterized. The expression of NGF in the isolated Exos and neural stem cells (NSCs) was quantified. NSCs were co-cultured with Exos derived from the BMSC sheet that was treated with overexpressed NGF (oe-NGF) (Exos-oe-NGF). NSC differentiation, axonal regeneration and locomotor function were detected in vitro and in vivo. The BMSC sheet was successfully prepared and exerted a promoting effect on NSC differentiation into neuronal cells and axonal regeneration after SCI by releasing Exos. Co-culture data showed that NGF was highly expressed in the BMSC sheet-loaded Exos and facilitated neuronal differentiation of NSCs and axonal regeneration. In vivo experimental results unveiled that transplantation of BMSC sheet-loaded Exos-oe-NGF into SCI mice displayed enhanced functional recovery. Collectively, Exo-oe-NGF loaded on the BMSC sheet can accelerate NSC differentiation, axonal regeneration and SCI repair, therefore offering us with a potential therapeutic target for treating SCI.

Adipose mesenchymal stem cell sheets-derived extracellular vesicles-microRNA-10b promote skin wound healing by elevating expression of CDK6.

Application of adipose-derived mesenchymal stromal cells (AMSCs)-derived extracellular vesicles (EVs) in skin wound healing has been documented. In this study, we investigated the therapeutic potential of AMSCs-derived EVs in skin wound healing through delivery of microRNA-10b (miR-10b). HaCaT cells were treated with H2O2 to establish the skin wound cell models. Next, the binding affinity between miR-194, PEA15, and CDK6 was identified. Additionally, EVs were isolated from the culture medium of AMSC sheets, followed by incubation with H2O2-treated HaCaT cells to detect cell proliferation, migration, and apoptosis using gain- or loss-of-function experiments. Lastly, the mice skin wound models were also established to assess skin wound healing ability. miR-10b was down-regulated in the skin trauma models and enriched in the EVs of AMSC sheets. Moreover, miR-10b derived from EVs targeted PEA15 to promote CDK6 expression, thereby stimulating the proliferation and migration of H2O2-damaged HaCaT cells but inhibiting apoptosis. In vivo experiments further ascertained the therapeutic functionality of AMSC sheets-derived EVs-miR-10b. In summary, AMSC sheets-derived EVs carrying miR-10b promoted CDK6 expression to intensify skin wound healing by regulating PEA15.

Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis.

As a severe neurological deficit, intracerebral hemorrhage (ICH) is associated with overwhelming mortality. Subsequent oxidative stress and neurological dysfunction are likely to cause secondary brain injury. Therefore, this study sought to define the role of Krüppel-like factor 6 (KLF6) and underlying mechanism in oxidative stress and neurological dysfunction following ICH. An in vivo model of ICH was established in rats by injection of autologous blood, and an in vitro ICH cell model was developed in hippocampal neurons by oxyhemoglobin (OxyHb) exposure. Next, gain- and loss-of-function assays were performed in vivo and in vitro to clarify the effect of KLF6 on neurological dysfunction and oxidative stress in ICH rats and neuronal apoptosis and mitochondrial reactive oxygen species in OxyHb-induced hippocampal neurons. KLF6, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were highly expressed in hippocampal tissues of ICH rats, whereas sirtuin 5 (SIRT5) presented a poor expression. Mechanistically, KLF6 bound to the SIRT5 promoter and transcriptionally repressed SIRT5 to activate the Nrf2/HO-1 signaling pathway. KLF6 silencing alleviated neurological dysfunction and oxidative stress in ICH rats and diminished oxidative stress and neuronal apoptosis in OxyHb-induced neurons, whereas SIRT5 overexpression negated its effect. To sum up, KLF6 silencing elevated SIRT5 expression to inactivate the Nrf2/HO-1 signaling pathway, thus attenuating oxidative stress and neurological dysfunction after ICH.