Background: Parkinson's disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra and striatum of brain, seriously threatens human health, and is still lack of effective treatment. Dysregulation of N6-methyladenosine (m6A) modification has been implicated in PD pathogenesis. However, how m6A modification regulates dopaminergic neuronal death in PD remains elusive. Mesenchymal stem cell-derived exosomes (MSC-Exo) have been shown to be effective for treating central nervous disorders. We thus propose that the m6A demethylase FTO-targeted siRNAs (si-FTO) may be encapsulated in MSC-Exo (Exo-siFTO) as a synergistic therapy against dopaminergic neuronal death in PD. Methods: In this study, the effect of m6A demethylase FTO on dopaminergic neuronal death was evaluated both in vivo and in vitro using a MPTP-treated mice model and a MPP + -induced MN9D cellular model, respectively. The mechanism through which FTO influences dopaminergic neuronal death in PD was investigated with qRT-PCR, western blot, immumohistochemical staining, immunofluorescent staining and flow cytometry. The therapeutic roles of MSC-Exo containing si-FTO were examined in PD models in vivo and in vitro. Results: The total m6A level was significantly decreased and FTO expression was increased in PD models in vivo and in vitro. FTO was found to promote the expression of cellular death-related factor ataxia telangiectasia mutated (ATM) via m6A-dependent stabilization of ATM mRNA in dopaminergic neurons. Knockdown of FTO by si-FTO concomitantly suppressed upregulation of α-Synuclein (α-Syn) and downregulation of tyrosine hydroxylase (TH), and alleviated neuronal death in PD models. Moreover, MSC-Exo were utilized to successfully deliver si-FTO to the striatum of animal brain, resulting in the significant suppression of α-Syn expression and dopaminergic neuronal death, and recovery of TH expression in the brain of PD mice. Conclusions: MSC-Exo delivery of si-FTO synergistically alleviates dopaminergic neuronal death in PD via m6A-dependent regulation of ATM mRNA.

Atopic dermatitis (AD), characterized by severe pruritus, immune imbalance, and skin barrier dysfunction, has a high incidence worldwide. Recent evidence has shown that the modulation of gut microbiota is crucial for alleviating clinical symptoms of AD. Tremella fuciformis polysaccharides (TFPS) have been demonstrated to have a variety of biological activities such as immunomodulatory, anti-tumor, antioxidant, anti-inflammatory, neuroprotective, hypoglycemic and hypolipidemic effects. However, their effects on AD treatment have never been investigated. In this study, we compared the therapeutic effects of topical or oral administration of TFPS on AD in dinitrofluorobenzene (DNFB)-induced AD mice. Both topical application and oral administration of TFPS led to improvement on transdermal water loss, epidermal thickening, and ear edema in AD mice, but the oral administration showed significantly better efficacy than the topical application. The TFPS treatment increased the proportion of CD4 (+) CD25 (+) Foxp3 (+) regulatory T cells in mesenteric lymph nodes. Additionally, the non-targeted metabolomics and sequencing of 16S rDNA amplicons were performed, revealing metabolite modulation in feces and changed composition of gut microbiota in mice, which were induced for AD-like disorder and treated by oral administration of TFPS. Collectively, these data suggest that the oral administration of TFPS may constitute a novel effective therapy for AD, with underlying mechanisms associated with the regulation of immune response, and improvement of both metabolism and the composition of intestinal microbiota.

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.

Diabetes mellitus (DM) is characterized by prolonged hyperglycemia, impaired vascularization, and serious complications, such as blindness and chronic diabetic wounds. About 25% of patients with DM are estimated to encounter impaired healing of diabetic wounds, often leading to lower limb amputation. Multiple factors are attributed to the non-healing of diabetic wounds, including hyperglycaemia, chronic inflammation, and impaired angiogenesis. It is imperative to develop more efficient treatment strategies to tackle healing difficulties in diabetic wounds. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising for diabetic wound healing considering their anti-inflammatory, pro-angiogenic and pro-proliferative activities. A histone deacetylase 7 (HDAC7)-derived 7-amino-acid peptide (7A) was shown to be highly effective for angiogenesis. However, it has never been investigated whether MSC-EVs are synergistic with 7A for the healing of diabetic wounds. Herein, we propose that MSC-EVs can be combined with 7A to greatly promote diabetic wound healing. The combination of EVs and 7A significantly improved the migration and proliferation of skin fibroblasts. Moreover, EVs alone significantly suppressed LPS-induced inflammation in macrophages, and notably, the combination treatment showed an even better suppression effect. Importantly, the in vivo study revealed that the combination therapy consisting of EVs and 7A in an alginate hydrogel was more efficient for the healing of diabetic wounds in rats than monotherapy using either EV or 7A hydrogels. The underlying mechanisms include suppression of inflammation, improvement of skin cell proliferation and migration, and enhanced collagen fiber disposition and angiogenesis in wounds. In summary, the MSC-EV-7A hydrogel potentially constitutes a novel therapy for efficient healing of chronic diabetic wounds.