The role of NLRP3 inflammasome in aging and age-related diseases.

The gradual aging of the global population has led to a surge in age-related diseases, which seriously threaten human health. Researchers are dedicated to understanding and coping with the complexities of aging, constantly uncovering the substances and mechanism related to aging like chronic low-grade inflammation. The NOD-like receptor protein 3 (NLRP3), a key regulator of the innate immune response, recognizes molecular patterns associated with pathogens and injury, initiating an intrinsic inflammatory immune response. Dysfunctional NLRP3 is linked to the onset of related diseases, particularly in the context of aging. Therefore, a profound comprehension of the regulatory mechanisms of the NLRP3 inflammasome in aging-related diseases holds the potential to enhance treatment strategies for these conditions. In this article, we review the significance of the NLRP3 inflammasome in the initiation and progression of diverse aging-related diseases. Furthermore, we explore preventive and therapeutic strategies for aging and related diseases by manipulating the NLRP3 inflammasome, along with its upstream and downstream mechanisms.

Association between serum copper levels and stroke in the general population: A nationally representative study.

OBJECTIVES: The objective was to explore the association between serum copper levels and the prevalence of stroke. METHODS: Data were obtained from 3 consecutive National Health and Nutrition Examination Survey (NHANES) cycles (2011-2016). Weighted multivariable logistic regression analysis was conducted to evaluate the association between serum copper levels and self-reported stroke. RESULTS: A total of 5,151 adults met the inclusion criteria. A total of 181 (3.51%) stroke patients were identified. In comparison to individuals with serum copper levels in the lowest tertile (<16.4 µmol/l), those with levels in the middle tertile (16.4-19.8 µmol/l) had an odds ratio (OR) of 0.99 (95% confidence interval [CI]: 0.44-2.25), while those with levels in the highest tertile (>19.8 µmol/l) had an OR of 2.36 (95% CI: 1.01-5.52). Furthermore, each standard deviation (SD) increase in serum copper was found to be positively associated with the prevalence of stroke, with an OR of 1.44 (95% CI: 1.11-1.86). Dose‒response analysis showed a positive linear association between serum copper levels and stroke (Pnonlinearity=0.554). CONCLUSIONS: This cross-sectional study suggested a positive association between serum copper levels and stroke among American adults.

Tunable composite lattice structure for low-frequency and ultra-broadband underwater sound absorption.

The underwater sound absorption technique in low-frequency and broadband has far-reaching prospects since it is essential for noise reduction of deep-sea operation requirements and evading advanced underwater target detection. Here, we propose an underwater sound-absorbing composite lattice with low-frequency and ultra-broadband characteristics. The composite lattice is constructed by regular spatially stacking cells with different sizes of metallic core spheres. All the core spheres are coated with silicon rubbers, and cells are embedded in the rubber matrix. In the composite lattice stereostructure, the lattice cells convert incident longitudinal waves into transverse waves through multiple local resonance coupling and multiple scattering. The energy is localized and dissipated in the composite lattice. We analyze the relationship among the corresponding absorption spectrums, the displacement clouds, and the resonance modes of lattice cells. Then, we construct a composite lattice and realize low-frequency broadband absorption from 693 to 1106 Hz with absorptance above 0.8. Further, our investigation demonstrates that the absorption bandwidth can be extended to ultra-broadband from 1077 to 10 000 Hz, where the thickness of the composite lattice is λ/17.05. The proposed composite lattice provides a practical approach to designing ultrathin low-frequency and ultra-broadband acoustic absorption coating for underwater noise suppression.

Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression.

Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.

Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum.

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson's disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H4R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H4R was in the top functional category for PD treatment targets. Interestingly, the H4R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H4R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology.

A new sulfated triterpene glycoside from the sea cucumber Colochirus quadrangularis, and evaluation of its antifungal, antitumor and immunomodulatory activities.

Our continuing search for marine bioactive secondary metabolites led to the screening of crude extracts of sea cucumbers by the model of Pyricularia oryzae. A new sulfated triterpene glycoside, coloquadranoside A (1), together with four known triterpene glycosides, philinopside A, B, E and pentactaside B (2-5) were isolated from the sea cucumber Colochirus quadrangularis, and their structures were elucidated using extensive spectroscope analysis (ESI-MS, 1D and 2D NMR) and chemical methods. Coloquadranoside A possesses a 16-acetyloxy group in the holostane-type triterpene aglycone with a 7(8)-double bond, a double bond (25,26) at its side chain, and two ß-d-xylose in the carbohydrate chain. Coloquadranoside A exhibits in vitro some antifungus, considerable cytotoxicity (IC50 of 0.46-2.03 µM) against eight human tumor cell lines, in vivo antitumor, and immunomodulatory activity.

Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy.

While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.

Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior.

Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all-trans retinoic acid (RA) potently activated the hypothalamus-pituitary-adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive-like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor-α (RAR-α) protein expression in the hippocampus, suggesting an activation of RA-induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders. © 2016 Wiley Periodicals, Inc.

Abnormal retinoid and TrkB signaling in the prefrontal cortex in mood disorders.

The prefrontal cortex shows structural and functional alterations in mood disorders. Retinoid signaling, brain-derived neurotrophic factor (BDNF), and its receptor TrkB are reported to be involved in depression. Here, we found that mRNA levels of key elements of retinoid signaling were significantly reduced in the postmortem dorsolateral prefrontal cortex/anterior cingulate cortex (ACC) from elderly depressed patients who did not die from suicide. Decreased mRNA levels of BDNF and TrkB isoforms were also found. Similar alterations were observed in rats subjected to chronic unpredictable mild stress. Along with neurons immunopositive for both retinoic acid receptor-α (RARα) and TrkB, a positive correlation between mRNA levels of the 2 receptors was found in the ACC of control subjects but not of depressed patients. In vitro studies showed that RARα was able to bind to and transactivate the TrkB promoter via a putative RA response element within the TrkB promoter. In conclusion, the retinoid and BDNF-TrkB signaling in the prefrontal cortex are compromised in mood disorders, and the transcriptional upregulation of TrkB by RARα provide a possible mechanism for their interaction. The retinoid signaling pathway that may activate TrkB expression will be an alternative novel target for BDNF-based antidepressant treatment.

Decreased NOS1 expression in the anterior cingulate cortex in depression.

Decreased function of the anterior cingulate cortex (ACC) is crucially involved in the pathogenesis of depression. A key role of nitric oxide (NO) has also been proposed. We aimed to determine the NO content in the cerebrospinal fluid (CSF) and the expression of NO synthase (NOS) isoforms, that is, NOS1, NOS2, and NOS3 in the ACC in depression. In depressive patients, CSF-NOx levels (the levels of the NO metabolites nitrite and nitrate) were significantly decreased (P = 0.007), indicating a more general decrease of NO production in this disorder. This agreed with a trend toward lower NOS1-mRNA levels (P = 0.083) and a significant decrease of NOS1-immunoreactivity (ir) (P = 0.043) in ACC. In controls, there was a significant positive correlation between ACC-NOS1-ir cell densities and their CSF-NOx levels. Furthermore, both localization of NOS1 in pyramidal neurons that are known to be glutamatergic and co-localization between NOS1 and GABAergic neurons were observed in human ACC. The diminished ACC-NOS1 expression and decreased CSF-NOx levels may be involved in the alterations of ACC activity in depression, possibly by affecting glutamatergic and GABAergic neurotransmission.

Serum copper and obesity among healthy adults in the National Health and Nutrition Examination Survey.

BACKGROUND: Copper (Cu) homeostasis are important processes in the cause of metabolic diseases, but the association between Cu and obesity remains unclear. METHODS: Participants were drawn from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression assessed the associations of serum Cu concentrations (tertiles) with obesity and central obesity in individuals without comorbidities. Obesity was defined as a BMI ≥30.0 kg/m2, and central obesity was defined as a waist circumference ≥80 cm for women and ≥95 cm for men. RESULTS: This cross-sectional study included 1,665 adults without comorbidities, representing 24,744,034 people (mean age 35.1 years, 48.5% female). High serum Cu levels (tertile 3: ≥19.19 µmol/L) were associated with higher odds of obesity (adjusted odds ratio [OR]: 4.48, 95% CI[confidence interval]: 2.44-8.32) and central obesity (OR: 2.36, 95% CI: 1.19-4.66) compared to low serum Cu levels (tertile 1: ≤15.64 µmol/L). The dose-response curve showed a nonlinear association between Cu levels and obesity (P-nonlinear = 0.02) and a linear association with central obesity (P-nonlinear = 0.21). CONCLUSION: This study suggests that higher serum Cu levels are associated with increased odds of obesity in healthy American adults.

Multi-objective optimization of hydrogen production system based on the combined supercritical cycle and gas turbine plant.

In this paper, considering the hydrogen production cycle coupled with the supercritical CO2 cycle, hydrogen is produced as a clean fuel along with power and heat production. Also, the world's need for clean energy doubles the solutions to achieve clean hydrogen energy. The investigated cycle has a supercritical CO2 cycle with a combustion chamber where enriched fuel is introduced. Combustion products produce work in the gas turbine, and further hydrogen separation is formed with the help of water gas shift reaction and hydrogen separation membrane. In the thermodynamic analysis, combustion chamber known as the most irreversible member of set, where the most exergy is lost. The energy and exergy efficiency for whole set are 64.82%, 52.46% respectively. Produced hydrogen mass flow rate calculated 46.8 kg/h. Also, multi-objective optimization based on genetic algorithm were done and the results were reported. All calculation and optimization method has been done in MATLAB software.

Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors.

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.

Technical Success after Transcatheter Aortic Valve Replacement for Bicuspid versus Tricuspid Aortic Stenosis.

Background: Comparative data of the Valve Academic Research Consortium (VARC-3)-defined technical success between bicuspid versus tricuspid aortic stenosis (AS) remain lacking. Aims: We sought to compare the technical success and other clinical outcomes between patients with bicuspid and tricuspid AS receiving transcatheter aortic valve replacement. Methods: A registration-based analysis was performed for 402 patients (211 and 191 cases of bicuspid and tricuspid AS, respectively). The primary outcome was VARC-3-defined technical success. Additional analysis was performed to assess outcomes for up to one year between the two groups. Results: Bicuspid AS patients tended to be younger (74 years vs. 77 years; p < 0.001) with a lower Society of Thoracic Surgeons score (4.4% vs. 5.4%; p = 0.003). Bicuspid AS patients showed a lower prevalence of hypertension and peripheral vascular diseases. Technical failure was encountered in 17.7% of these patients, driven primarily by the high incidence of second valve implantation. The technical success rates were comparable between the bicuspid and tricuspid AS groups (82.5% vs. 82.2%, p = 0.944). Chronic kidney disease (CKD) and larger sinotubular junctional diameter (STJ) were identified as predictors of technical failure, whereas CKD, impaired left ventricular ejection fraction (LVEF), along with larger STJ, were predictors of cardiac technical failure. Technical failure was associated with an increased risk of all-cause mortality at 30 days and 1 year, as evidenced by the Cox multivariable analysis. Conclusions: No significant differences were observed in the technical success rates and most clinical outcomes between the bicuspid and tricuspid AS groups. Technical failure conferred an increased risk for both 30-day and 1-year all-cause mortalities.

Multifaceted roles of T cells in obesity and obesity-related complications: A narrative review.

Obesity is characterized by chronic low-grade inflammatory responses in the adipose tissue, accompanied by pronounced insulin resistance and metabolic anomalies. It affects almost all body organs and eventually leads to diseases such as fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Recently, T cells have emerged as interesting therapeutic targets because the dysfunction of T cells and their cytokines in the adipose tissue is implicated in obesity-induced inflammation and their complicated onset. Although several recent narrative reviews have provided a brief overview of related evidence in this area, they have mainly focused on either obesity-associated T cell metabolism or modulation of T cell activation in obesity. Moreover, at present, no published review has reported on the multifaceted roles of T cells in obesity and obesity-related complications, even though there has been a significant increase in studies on this topic since 2019. Therefore, this narrative review aims to comprehensively summarize current advances in the mechanistic roles of T cells in the development of obesity and its related complications. Further, we aim to discuss relevant drugs for weight loss as well as the contradictory role of T cells in the same disease so as to highlight key findings regarding this topic and provide a valid basis for future treatment strategies.

Changes in the Mitochondria-Related Nuclear Gene Expression Profile during Human Oocyte Maturation by the IVM Technique.

To address which mitochondria-related nuclear differentially expressed genes (DEGs) and related pathways are altered during human oocyte maturation, single-cell analysis was performed in three oocyte states: in vivo matured (M-IVO), in vitro matured (M-IVT), and failed to mature in vitro (IM-IVT). There were 691 DEGs and 16 mitochondria-related DEGs in the comparison of M-IVT vs. IM-IVT oocytes, and 2281 DEGs and 160 mitochondria-related DEGs in the comparison of M-IVT vs. M-IVO oocytes, respectively. The GO and KEGG analyses showed that most of them were involved in pathways such as oxidative phosphorylation, pyruvate metabolism, peroxisome, and amino acid metabolism, i.e., valine, leucine, isoleucine, glycine, serine, and threonine metabolism or degradation. During the progress of oocyte maturation, the metabolic pathway, which derives the main source of ATP, shifted from glucose metabolism to pyruvate and fatty acid oxidation in order to maintain a low level of damaging reactive oxygen species (ROS) production. Although the immature oocytes could be cultured to a mature stage by an in vitro technique (IVM), there were still some differences in mitochondria-related regulations, which showed that the mitochondria were regulated by nuclear genes to compensate for their developmental needs. Meanwhile, the results indicated that the current IVM culture medium should be optimized to compensate for the special need for further development according to this disclosure, as it was a latent strategy to improve the effectiveness of the IVM procedure.

Circulating extracellular vesicle-containing microRNAs reveal potential pathogenesis of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) remains unknown till today, hindering the research and development of AD therapeutics and diagnostics. Circulating extracellular vesicles (EVs) can be utilized as a new window to spy upon AD pathogenesis. Altered microRNA profiles were noted in both the cerebrospinal fluid (CSF)- and blood-isolated EVs of AD patients, implying the outstanding potential of circulating EV-containing miRNAs (CEmiRs) to serve as important regulators in AD pathogenesis. Although several CEmiRs were found to play a part in AD, the association of globally altered miRNA profiles in patients' serum-derived EVs with AD pathogenesis remains unclear. In this study, we first investigated the miRNA profile in serum-derived EVs from AD, mild cognitive impairment (MCI) patients, and healthy individuals. We observed differential expression patterns of CEmiRs and classified them into 10 clusters. We identified the predicted targets of these differentially expressed CEmiRs (DECEmiRs) and analyzed their biological functions and interactions. Our study revealed the temporal regulation of complex and precise signaling networks on AD pathogenesis, shedding light on the development of novel therapeutic strategies, including multi-target drug combination for AD treatment.

Cerebral Ischemic Lesions after Transcatheter Aortic Valve Implantation in Patients with Non-Calcific Aortic Stenosis.

Evidence for transcatheter aortic valve implantation (TAVI) is scarce among patients with non-calcific aortic stenosis, and it is not known whether aortic valve calcification is associated with new cerebral ischemic lesions (CILs) that are detected by diffusion-weighted magnetic resonance imaging. So, our study enrolled 328 patients who underwent transfemoral TAVI using a self-expanding valve between December 2016 and June 2021 from the TORCH registry (NCT02803294). A total of 34 patients were finally confirmed as non-calcific AS and the remaining 294 patients were included in the calcific AS group. Incidence of new CILs (70.6% vs. 85.7%, p = 0.022), number of lesions (2.0 vs. 3.0, p = 0.010), and lesions volume (105.0 mm3 vs. 200.0 mm3, p = 0.047) was significantly lower in the non-calcific AS group. However, the maximum and average lesion volumes were comparable between two groups. Non-calcific AS was associated with lower risk for developing new CILs by univariate logistic regression analysis [Odds ratio (OR): 0.040, 95% confident interval (CI): 0.18-0.90, p = 0.026] and multivariate analysis (OR: 0.031, 95% CI: 0.13-0.76, p = 0.010). In summary, non-calcific AS patients had a lower risk of developing new cerebral ischemic infarction after TAVI compared to calcific AS patients. However, new ischemic lesions were still found in over 70% of patients.

Dendritic cell nuclear protein-1, a novel depression-related protein, upregulates corticotropin-releasing hormone expression.

The recently discovered dendritic cell nuclear protein-1 is the product of a novel candidate gene for major depression. The A allele encodes full-length dendritic cell nuclear protein-1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5. In the present study we investigate whether the two forms of dendritic cell nuclear protein-1 might act on corticotropin-releasing hormone, which plays a crucial role in the stress response and in the pathogenesis of depression. The messenger RNA expression of dendritic cell nuclear protein-1 appeared to be increased in the laser micro-dissected paraventricular nucleus of patients with depression compared with control subjects. Dendritic cell nuclear protein-1 was also found to be co-localized with corticotropin-releasing hormone in paraventricular nucleus neurons. Moreover, full-length dendritic cell nucleus protein-1 bound to and transactivated the promoter of corticotropin-releasing hormone in human embryonic kidney 293 cells. We propose that full-length dendritic cell nucleus protein-1 may play a role in the pathogenesis of depressive disorders by enhancing corticotropin-releasing hormone expression in the hypothalamic paraventricular nucleus.

Neural Stem Cell-Derived Exosomes Regulate Neural Stem Cell Differentiation Through miR-9-Hes1 Axis.

Exosomes, a key element of the central nervous system microenvironment, mediate intercellular communication via horizontally transferring bioactive molecules. Emerging evidence has implicated exosomes in the regulation of neurogenesis. Recently, we compared the neurogenic potential of exosomes released from primary mouse embryonic neural stem cells (NSCs) and astrocyte-reprogrammed NSCs, and observed diverse neurogenic potential of those two exosome populations in vitro. However, the roles of NSC-derived exosomes on NSC differentiation and the underlying mechanisms remain largely unknown. In this study, we firstly demonstrated that NSC-derived exosomes facilitate the differentiation of NSCs and the maturation of both neuronal and glial cells in defined conditions. We then identified miR-9, a pro-neural miRNA, as the most abundantly expressed miRNA in NSC-derived exosomes. The silencing of miR-9 in exosomes abrogates the positive effects of NSC-derived exosomes on the differentiation of NSCs. We further identified Hes1 as miR-9 downstream target, as the transfection of Hes1 siRNA restored the differentiation promoting potential of NSC-derived exosomes after knocking down exosomal miR-9. Thus, our data indicate that NSC-derived exosomes facilitate the differentiation of NSCs via transferring miR-9, which sheds light on the development of cell-free therapeutic strategies for treating neurodegeneration.