Neural stem cell-derived exosomes-loaded adhesive hydrogel controlled-release promotes cerebral angiogenesis and neurological function in ischemic stroke.

OBJECTIVE: Ischemic stroke has become one of the leading diseases for international death, which brings burden to the economy and society. Exosomes (Exos) derived following neural stem cells (NSCs) stimulation promote neurogenesis and migration of NSCs. However, Exos themselves are easily to be removed in vivo. Our study is to investigate whether adhesive hyaluronic acid (HAD) hydrogel loading NSCs-derived-Exo (HAD-Exo) would promote the recovery of ischemic stroke. METHODS: A mouse model of middle cerebral artery occlusion (MCAO) was established. PBS, Exo, HAD, and HAD-Exo groups were independently stereotactically injected in mice, respectively. The modified neurological severity score scale and behaviour tests were used to evaluate neurological improvement. Neuroimagings were used to observe the improvement of cerebral infarct volume and vessels. Immunofluorescence staining was used to verify the expression of vascular and cell proliferation-related proteins. RESULTS: The structural and mechanical property of HAD and HAD-Exo were detected. Behavioral results showed that HAD-Exo significantly improved neurological functions, especially motor function. Neuroimagings showed that HAD-Exo significantly promoted infarct volume and angiogenesis. Immunofluorescence staining showed that HAD-Exo significantly promoted the cerebral angiogenesis and anti-inflammation. CONCLUSION: NSCs derived exosomes-loaded adhesive HAD hydrogel controlled-release could promote cerebral angiogenesis and neurological function for ischemic stroke.

New Insights into Molecular Mechanisms Underlying Neurodegenerative Disorders.

As a large and heterogeneous group of disorders, neurodegenerative diseases are characterized by the progressive loss of structure or function in neurons, finally leading to neuronal death. Neurodegenerative diseases cause serious threat to a patient's quality of life and the most common are Alzheimer's disease and Parkinson's disease. Currently, little is known of the detailed etiology of these disorders; as such, there are no effective treatments available. Furthermore, the lack of targeted, effective, and resolvable therapy for neurodegenerative diseases, represents an expanding research field for the discovery of new therapeutic strategies. Investigations of the potential pathogenesis of neurodegenerative diseases will become the basis of preventing the occurrence and development of neurodegenerative diseases and finding effective therapies. Existing theories and mechanisms, such as genetic and environmental factors, abnormal protein accumulation, and oxidative stress, are intricately associated with each other. However, there is no molecular theory that can entirely explain the pathological processes underlying neurodegenerative diseases. Due to the development of experimental technology and the support of multidisciplinary integration, it has been possible to perform more in-depth research on potential targets for neurodegenerative diseases and there have been many exciting discoveries in terms of original theories and underlying mechanisms. With this review, we intend to review the existing literature and provide new insights into the molecular mechanisms underlying neurodegenerative diseases.

Timeless-Stimulated miR-5188-FOXO1/ß-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of ß-Catenin in Breast Cancer.

MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with ß-catenin in the cytoplasm, facilitated ß-catenin degradation, and impaired the nuclear accumulation of ß-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/ß-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/ß-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.