Exosomes secreted by mesenchymal stem cells delay brain aging by upregulating SIRT1 expression.

The increase in the aging population has seriously affected our society. Neurodegenerative diseases caused by aging of the brain significantly impact the normal life of the elderly, and delaying brain aging is currently the focus of research. SIRT1 is a viable therapeutic target, and there is mounting evidence that it plays a significant role in the aging process. Mesenchymal stem cell-derived exosomes (MSC-Exos) have gained widespread interest as nanotherapeutic agents because of their ability to be injected at high doses to reduce the immune response. The present study focused on the ameliorative effect of MSC-Exos on aging mice and the potential mechanisms of this effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effects of MSC-Exos in vitro on H2O2-induced oxidative damage in BV2 cells. An in vivo SAMP8 rapid senescence mouse model showed that MSC-Exos significantly increased SIRT1 gene expression in senescent mice. In addition, MSC-Exos also had an anti-apoptotic effect and reduced oxidative stress in the brains of SAMP8 senescent mice. In conclusion, MSC-Exos may exert neuroprotective effects and help prevent brain senescence in SAMP8 mice by activating the SIRT1 signaling pathway.

Depletion of gut microbiota resistance in 5×FAD mice enhances the therapeutic effect of mesenchymal stem cell-derived exosomes.

Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer's disease (AD) by promoting amyloid-ß (Aß) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the therapy of MSCs-exo, and the application of antibiotics would improve the therapy. METHODS: In this original research study, we used MSCs-exo to treat 5 ×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice's feces were collected to investigate alterations in the microbiota and metabolites. RESULTS: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. CONCLUSIONS: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD.

Effects of magnetically targeted iron oxide@polydopamine-labeled human umbilical cord mesenchymal stem cells in cerebral infarction in mice.

Mesenchymal stem cells are a potential therapeutic candidate for cerebral infarction due to their anti-inflammatory proprieties. However, ensuring the engraftment of sufficient cells into the affected brain area remains a challenge. Herein, magnetic targeting techniques were used for the transplantation of a large number of cells noninvasively. Mice subjected to pMCAO surgery were administered MSCs labeled or not with iron oxide@polydopamine nanoparticles by tail vein injection. Iron oxide@polydopamine particles were characterized by transmission electron microscopy, and labeled MSCs were characterized by flow cytometry and their differentiation potential was assessed in vitro. Following the systemic injection of iron oxide@polydopamine-labeled MSCs into pMCAO-induced mices, magnetic navigation increased the MSCs localization to the brain lesion site and reduced the lesion volume. Treatment with iron oxide@polydopamine-labeled MSCs also significantly inhibited M1 microglia polarization and increased M2 microglia cell infiltration. Furthermore, western blotting and immunohistochemical analysis demonstrated that microtubule-associated protein 2 and NeuN levels were upregulated the brain tissue of mice treated with iron oxide@polydopamine-labeled MSCs. Thus, iron oxide@polydopamine-labeled MSCs attenuated brain injury and protected neurons by preventing pro-inflammatory microglia activation. Overall, the proposed iron oxide@polydopamine-labeled MSCs approach may overcome the major drawback of the conventional MSCs therapy for the treatment of cerebral infarction.

Synergistic treatment of osteosarcoma with biomimetic nanoparticles transporting doxorubicin and siRNA.

Introduction: Osteosarcoma tumors are the most common malignant bone tumors in children and adolescents. Their treatment usually requires surgical removal of all detectable cancerous tissue and multidrug chemotherapy; however, the prognosis for patients with unresectable or recurrent osteosarcoma is unfavorable. To make chemotherapy safer and more effective for osteosarcoma patients, biomimetic nanoparticles (NPs) camouflaged by mesenchymal stem cell membranes (MSCMs) were synthesized to induce osteosarcoma cell apoptosis by co-delivering the anticancer drug doxorubicin hydrochloride(DOX) and a small interfering RNA (siRNA). Importantly, these NPs have high biocompatibility and tumor-homing ability. This study aimed to improve the efficacy of osteosarcoma therapy by using the synergistic combination of DOX and an siRNA targeting the apoptosis suppressor gene survivin. Methods: Biomimetic NPs (DOX/siSUR-PLGA@MSCM NPs) were synthesized by coloading DOX and survivin siRNA (siSUR) into poly (lactide-co-glycolide acid) (PLGA) via a double-emulsion solvent evaporation method. The NPs were camouflaged by MSCMs to deliver both DOX and survivin-targeting siRNA and characterized and evaluated in terms of cellular uptake, in vitro release, in vitro and in vivo antitumor effects, and biosafety. Results: DOX/siSUR-PLGA@MSCM NPs had good tumor-homing ability due to the MSCMs modification. The drug-laden biomimetic NPs had good antitumor effects in homozygous MG63 tumor-bearing mice due to the synergistic effect of the drug combination. Conclusion: DOX/siSUR-PLGA@MSCM NPs can show improved therapeutic effects in osteosarcoma patients due to the combination of a chemotherapeutic drug and gene therapy based on their good tumor targeting and biosafety.

Mechanism of autophagy mediated by IGF-1 signaling pathway in the neurotoxicity of lead in pubertal rats.

Lead can damage neuron synapses in the hippocampus and cause synaptic plasticity losses, and learning, memory, and intelligence impairments. Previous studies have focused on the functional and structural plasticity of hippocampal synapses; however, the specific molecular mechanisms behind such impairments are not fully understood. This study aimed to elucidate the molecular mechanisms of cognitive impairment in rats following chronic lead exposure and mitigate or prevent lead toxicity in the central nervous system. We found that lead exposure caused significant damage to rat nervous systems, that is, compared with the control group, the lead treatment group had more autophagosomes in their hippocampal neurons; lower serum and hippocampal IGF-1 levels; lower hippocampal IGF-1, IGF-1R, PI3K, Akt, and mTOR gene expression; and upregulated hippocampal autophagy-associated proteins levels. Brain stereotactic technology was used to conduct autophagy inhibitor in vivo intervention experiments, and the results of these experiments suggest that the autophagy inhibitor DC661 inhibited lead-exposure-induced autophagy and autophagy-related gene expression in the rat hippocampus, possibly through activation of the IGF-1 pathway. Overall, our findings suggest that lead might activate hippocampal autophagy through the IGF-1/PI3K/Akt/mTOR signaling pathway. Therefore, this study provides a novel molecular mechanism underlying developmental toxicity in pubertal rats induced by lead exposure and provides a new target for anticipation and reversal of such neurotoxicity.

Mesenchymal stem cells and exosomes improve cognitive function in the aging brain by promoting neurogenesis.

Biologically speaking, normal aging is a spontaneous and inevitable process of organisms over time. It is a complex natural phenomenon that manifests itself in the form of degenerative changes in structures and the decline of functions, with diminished adaptability and resistance. Brain aging is one of the most critical biological processes that affect the physiological balance between health and disease. Age-related brain dysfunction is a severe health problem that contributes to the current aging society, and so far, there is no good way to slow down aging. Mesenchymal stem cells (MSCs) have inflammation-inhibiting and proliferation-promoting functions. At the same time, their secreted exosomes inherit the regulatory and therapeutic procedures of MSCs with small diameters, allowing high-dose injections and improved therapeutic efficiency. This manuscript describes how MSCs and their derived exosomes promote brain neurogenesis and thereby delay aging by improving brain inflammation.

Identification of Potential Biomarkers and Metabolic Profiling of Serum in Ovarian Cancer Patients Using UPLC/Q-TOF MS.

BACKGROUND/AIMS: Ovarian cancer (OC) is a malignant neoplasm of the female reproductive system with a high mortality rate. Identifying useful biomarkers and clarifying the molecular pathogenesis of OC are critical for early diagnosis and treatment. The aim of the study was to identify candidate biomarkers and explore metabolic changes of OC. METHODS: A two-stage design was used in our study, with a discovery cohort of OC cases (n = 30) and controls (n = 30) and an independent cohort of cases (n = 17) and controls (n = 18) for validation. The serum metabolic profiling was investigated by ultra-performance liquid chromatography and quadrupole time-of-fight mass spectrometry with positive electrospray ionization. RESULTS: A total of 18 metabolites closely related to OC were identified in the discovery stage, of which 12 were confirmed in the validation cohort. Metabolic pathways in OC related to these biomarkers included fatty acid ß-oxidation, phospholipid metabolism, and bile acid metabolism, which are closely related to the proliferation, invasion, and metastasis of cancer cells. Multiple logistic regression analysis of these metabolites showed that 2-piperidinone and 1-heptadecanoylglycerophosphoethanolamine were potential biomarkers of OC, with high sensitivity (96.7%), specificity (66.7%), and area under the receiver operating characteristic curve value (0.894). CONCLUSION: These findings provide insight into the pathogenesis pathogenesis of OC and may be useful for clinical diagnosis and treatment.