Exosomes from Hypoxia-treated Mesenchymal Stem Cells: Promoting Neuroprotection in Ischemic Stroke Through miR-214-3p/PTEN Mechanism.

Stroke stands as the second leading cause of death globally, surpassed only by ischemic heart disease. It accounts for 9% of total worldwide deaths. Given the swiftly evolving landscape, medical professionals and researchers are devoting increased attention to identifying more effective and safer treatments. Recent years have witnessed a focus on exosomes derived from mesenchymal stem cells cultivated under hypoxic conditions, referred to as Hypo-Exo. These specialized exosomes contain an abundance of components that facilitate the restoration of ischemic tissue, surpassing the content found in normal exosomes. Despite advancements, the precise role of Hypo-Exo in cases of cerebral ischemia remains enigmatic. Therefore, this study was designed to shed light on the potential efficacy of Hypo-Exo in stroke treatment. Our investigations unveiled promising outcomes, as the administration of Hypo-Exo led to improved behavioral deficits and reduced infarct areas in mice affected by ischemic conditions. Notably, these positive effects were hindered when Hypo-Exo loaded with anti-miR-214-3p were introduced, implying that the neuroprotective attributes of Hypo-Exo are reliant on miR-214-3p. This conclusion was substantiated by the high levels of miR-214-3p detected within Hypo-Exo. Furthermore, our examination of the ischemic penumbra zone revealed a gradual and sustained escalation in PTEN expression, a phenomenon effectively countered by Hypo-Exo treatment. Collectively, our findings suggest the existence of a regulatory pathway centered on miR-214-3p within Hypo-Exo. This pathway exerts a downregulating influence on the PTEN/Akt signaling pathway, thereby contributing to the amelioration of neurological function subsequent to ischemia-reperfusion events.

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis.

Sepsis is a major global health problem, causing a significant burden of disease and death worldwide. Risk stratification of sepsis patients, identification of severe patients and timely initiation of treatment can effectively improve the prognosis of sepsis patients. We procured gene expression datasets for sepsis (GSE54514, GSE65682, GSE95233) from the Gene Expression Omnibus and performed normalization to mitigate batch effects. Subsequently, we applied weighted gene co-expression network analysis to categorize genes into modules that exhibit correlation with macrophage activity. To pinpoint macrophage-associated genes (MAAGs), we executed differential expression analysis and single sample gene set enrichment analysis. We then established a prognostic model derived from four MAAGs that were significantly differentially expressed. Functional enrichment analysis and immune infiltration assessments were instrumental in deciphering the biological mechanisms involved. Furthermore, we employed principal component analysis and conducted survival outcome analyses to delineate molecular subgroups within sepsis. Four novel MAAGs-CD160, CX3CR1, DENND2D, and FAM43A-were validated and used to create a prognostic model. Subgroup classification revealed distinct molecular profiles and a correlation with 28-day survival outcomes. The MAAGs risk score was developed through univariate Cox, LASSO, and multivariate Cox analyses to predict patient prognosis. Validation of the risk score upheld its prognostic significance. Functional enrichment implicated ribonucleoprotein complex biogenesis, mitochondrial matrix, and transcription coregulator activity in sepsis, with an immune infiltration analysis indicating an association between MAAGs risk score and immune cell populations. The four MAAGs exhibited strong diagnostic capabilities for sepsis. The research successfully developed a MAAG-based prognostic model for sepsis, demonstrating that such genes can significantly stratify risk and reflect immune status. Although in-depth mechanistic studies are needed, these findings propose novel targets for therapy and provide a foundation for future precise clinical sepsis management.

Distribution characteristics of non-point source pollution of TP and identification of key source areas in Nanyi Lake (China) Basin: based on InVEST model and source list method.

The Nanyi Lake basin, located in the middle and lower reaches of the Yangtze River, is a crucial component of the Yangtze River ecosystem. Excessive phosphorus levels lead to eutrophication in rivers and lakes. This study aims to enhance the identification efficiency of key source areas for non-point source pollution of total phosphorus (TP) in the Nanyi Lake Basin and improve decision-making regarding the treatment of these areas. The study employs the InVEST model and utilizes GIS spatial hot spot analysis to identify key source areas of agricultural TP non-point source pollution. The accuracy of the InVEST model's simulation results was verified using the source list method. The findings indicate that paddy fields serve as the primary pollution source. TP non-point source pollution in Nanyi Lake is influenced by pollution sources, pollution load filtration rate, and potential TP runoff mass concentration. Different pollution sources correspond to distinct key source areas, and the pollution generated by these sources in different administrative regions, ultimately affecting the lake, varies as well. The InVEST model demonstrates great applicability in regions where agricultural TP is the primary pollution source. For the Nanyi Lake basin, which predominantly experiences agricultural TP non-point source pollution, a combination of the InVEST model and the source list method is recommended. The InVEST model serves as the primary tool, while the source list method supplements it. This approach not only compensates for any limitations of the InVEST model's simulation results but also avoids unnecessary economic waste. The outcomes of this study contribute to a deeper scientific understanding of TP pollution in the Nanyi Lake Basin. They also aid in effectively identifying key source areas and formulating appropriate measures based on the pollution characteristics, thereby providing guidance for non-point source pollution control in the basin.

The role of molecular subtypes and immune infiltration characteristics based on disulfidptosis-associated genes in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer which accounts for about 40% of all lung cancers. Early detection, risk stratification and treatment are important for improving outcomes for LUAD. Recent studies have found that abnormal accumulation of cystine and other disulfide occurs in the cell under glucose starvation, which induces disulfide stress and increases the content of disulfide bond in actin cytoskeleton, resulting in cell death, which is defined as disulfidptosis. Because the study of disulfidptosis is in its infancy, its role in disease progression is still unclear. In this study, we detected the expression and mutation of disulfidptosis genes in LUAD using a public database. Clustering analysis based on disulfidptosis gene was performed and differential genes of disulfidptosis subtype were analyzed. 7 differential genes of disulfidptosis subtype were used to construct a prognostic risk model, and the causes of prognostic differences were investigated by immune-infiltration analysis, immune checkpoint analysis, and drug sensitivity analysis. qPCR was used to verify the expression of 7 key genes in lung cancer cell line (A549) and normal bronchial epithelial cell line (BEAS-2B). Since G6PD had the highest risk factor of lung cancer, we further verified the protein expression of G6PD in lung cancer cells by western blot, and confirmed through colony formation experiment that interference with G6PD was able to significantly inhibit the proliferation ability of lung cancer cells. Our results provide evidence for the role of disulfidptosis in LUAD and provide new ideas for individualized precision therapy of LUAD.

The deficiency of Maged1 attenuates Parkinson's disease progression in mice.

Melanoma-associated antigen D1 (Maged1) has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, and drug addiction. However, the role of Maged1 in Parkinson's disease (PD) remains unclear. In this study, we observed that Maged1 was expressed in the dopaminergic (DA) neurons of the substantia nigra in mice and humans, which could be upregulated by the in vivo or in vitro treatment with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-Methyl-4-phenylpyridinium iodide (MPP+). Genetic ablation of Maged1 in mice attenuated motor deficits, the loss of DA neurons, and disease progression induced by MPTP. Moreover, Maged1 deficiency protected DA neurons against MPP+-induced toxicity in primary cultured cells. Mechanistically, loss of Maged1 upregulated the Akt signaling pathway and downregulated the mTOR signaling pathway in SH-SY5Y cells, which may in turn attenuate the cell apoptosis and impairment of autophagy. Consistent with it, the degeneration of midbrain and striatum among elderly Maged1 knockout mice was relatively mild compared to those in wild-type mice under physiological conditions. Taken together, this study suggested that Maged1 deficiency inhibited apoptosis and enhanced autophagy, which may provide a new potential target for the therapy of PD.

Protein phosphatase 2A deficiency in hippocampal CA1 inhibits priming effect of morphine on conditioned place preference in mice.

Studies have shown that protein phosphorylation plays an important role in morphine abuse. However, the neurobiological mechanism of protein phosphatase 2A (PP2A) underlying the morphine-priming process is still unclear. Here we constructed T29-2-Cre; PP2Afl/fl conditional knockout mice (KO) and investigated the role of hippocampal PP2A in morphine priming. We observed that the deficit of PP2A inhibited the priming behavior of morphine and blocked the priming-induced long-term potentiation (LTP) in the hippocampus of KO mice. Moreover, the expression levels of Rack1 and the membrane GluN2B were significantly reduced in the nucleus accumbens of KO mice compared with those in the control mice, which may be attributed to the decreased HDAC4 in the hippocampus of KO mice. Consistent with it, the similar inhibited priming effects were also observed in the wild-type mice treated with sodium butyrate (NaB)-a nonspecific inhibitor of histone deacetylases-3 h after morphine administration. Taken together, our results suggest that hippocampal PP2A may be involved in morphine priming through the PP2A/HDAC4/Rack1 pathway.

Valproic acid enhances neurosphere formation in cultured rat embryonic cortical cells through TGFß1 signaling.

This study aimed to investigate the effect and mechanism of valproic acid (VPA) on the neurosphere formation in rat embryonic cortical cells. We used free-floating neurosphere formation as a model system to evaluate the VPA on the proliferation of neural stem cells (NSCs). We found a time- and dose-dependent increase in neurosphere formation and NSC proliferation after VPA treatment. Further RNA-seq analysis demonstrated that the upregulated TGFß1 signaling might attribute to the effect of VPA on the neurosphere formation and NSC proliferation. Consistently, the neurosphere formation and NSC proliferation were blocked by the treatment with SB431542, an inhibitor of TGFß1 receptor. Moreover, in a coculture system, NSCs treated with VPA significantly reduced the oxygen-glucose deprivation-induced neuronal apoptosis. Taken together, our results showed that VPA could enhance neurosphere formation and NSC proliferation by activating TGFß1, which might be a novel therapeutic strategy for neurological disorders.

[Spatial Distribution and Pollution Assessment of Dissolved Heavy Metals in Chaohu Lake Basin During the Wet Season].

The spatial distribution characteristics of the mass concentration of V, Cr, Mn, Ni, Cu, Zn, Pb, Cd, Fe, and Sb in the Chaohu Lake basin and ten surrounding rivers during the wet season were explored. The results showed that the average mass concentration of heavy metals in the western and northwestern Chaohu Lake surrounding rivers was higher than that in the central and eastern regions. The correlation analysis showed a significant positive correlation between the concentrations of Cu, Ni, Zn, Pb, and Cd, which indicated a similarity of spatial distribution among the five elements. The single-factor pollution index evaluation results classified Cr in the ten surrounding rivers as Grade I based on the Environmental Quality Standards for Surface Water. Pb was classified as Grade Ⅰ-Ⅱ; Cu and Zn as Grade Ⅰ-Ⅴ; Fe, Sb, and V were far below the standard limit; Ni slightly exceeded the standard at some sampling points of the Nanfei River; Mn slightly exceeded the standard at some points of the Shiwuli and Pai River; Cd exceeded the standard at some points of the Nanfei River. Except Mn at one point of the Tangxi River, V, Cr, Ni, Cu, Zn, Pb, and Fe were all<1, which indicated clean and pollution-free level. The integrated pollution index of the rivers surrounding the lake in the northwestern part was the highest compared to the southwestern, central, and eastern parts.

Dopamine agonist responsive burning mouth syndrome: Report of eight cases.

BACKGROUND: Burning mouth syndrome (BMS) is characterized by burning sensation of the oral mucosa. There is a lack of effective treatment. In recent years, a special subtype of BMS has been reported, in which oral burning sensation is alleviated after chewing, speaking, or dopaminergic drug delivery. Currently, there are few reports about the subtype of BMS in China. This study was a retrospective analysis of the clinical data of BMS patients sensitive to dopamine agonist at our hospital, aiming to improve the recognition on this disease. CASE SUMMARY: Eight patients diagnosed with dopamine agonist responsive BMS at the Liaocheng People's Hospital from January 1, 2017 to June 30, 2020 were recruited. The clinical manifestations, treatment, and prognosis were retrospectively analyzed. There were three male and five females in the eight patients. The median age was 56 years (range, 46-65 years). All the eight patients showed burning pain in the mouth. The symptoms were mild in the morning and severe in the evening, and alleviated after chewing, talking, and other oral activities. Four patients were accompanied by restless legs syndrome (RLS). Family history of RLS was positive in two patients. All patients were treated with pramipexol, and symptoms were basically relieved after 2-8 wk. CONCLUSION: Dopamine agonist responsive BMS is a special subtype of BMS, which is alleviated after oral activities. Dopamine receptor agonist is an effective treatment.

ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal-Oral Routes.

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly transfers from human to human via respiratory and gastrointestinal routes. The S-glycoprotein in the virus is the key factor for the entry of SARS-CoV-2 into the cell, which contains two functional domains: S1 is an angiotensin-converting enzyme 2 (ACE2) receptor binding domain, and S2 is necessary for fusion of the coronavirus and cell membranes. Moreover, it has been reported that ACE2 is likely to be the receptor for SARS-CoV-2. In addition, mRNA level expression of Furin enzyme and ACE2 receptor had been reported in airway epithelia, cardiac tissue, and enteric canals. However, the expression patterns of ACE2 and Furin in different cell types of oral tissues are still unclear. Methods: In order to investigate the potential infective channel of the new coronavirus via the oropharyngeal cavity, we analyze the expression of ACE2 and Furin in human oral mucosa using the public single-cell sequence datasets. Furthermore, immunohistochemistry was performed in mucosal tissue from different oral anatomical sites to confirm the expression of ACE2 and Furin at the protein level. Results: The bioinformatics results indicated the differential expression of ACE2 and Furin on epithelial cells from different oral anatomical sites. Immunohistochemistry results revealed that both the ACE2-positive and Furin-positive cells in the target tissues were mainly positioned in the epithelial layers, partly expressed in fibroblasts, further confirming the bioinformatics results. Conclusions: Based on these findings, we speculated that SARS-CoV-2 could invade oral mucosal cells through two possible routes: binding to the ACE2 receptor and fusion with cell membrane activated by Furin protease. Our results indicated that oral mucosa tissues are susceptible to SARS-CoV-2 that could facilitate COVID-19 infection via respiratory and fecal-oral routes.

Erratum: Andrographolide Suppress Tumor Growth by Inhibiting TLR4/NF-κB Signaling Activation in Insulinoma: Erratum.

[This corrects the article DOI: 10.7150/ijbs.7723.].

Acupuncture for Hormone Therapy-Related Side Effects in Breast Cancer Patients: A GRADE-Assessed Systematic Review and Updated Meta-Analysis.

Purpose: To determine the efficacy of acupuncture on the management of hormone therapy-related side effects in breast cancer patients. Methods: Randomized controlled trials of acupuncture versus a control or placebo in breast cancer patients that examined reductions in therapy-related side effects were retrieved from PubMed, EMBASE, Web of Science, and the Cochrane Library through April 2020. Data on patient symptoms (hot flashes, fatigue, pain, stiffness, and gastrointestinal symptoms), physical capacity, cytokines, and general psychosomatic well-being were analyzed. We evaluated and analyzed the quality of all included studies with the 5.2 Cochrane Handbook standards using Stata software (version 10.0) and Revman software (version 5.2), respectively. We assessed the risk of bias using the Cochrane Risk of Bias tool and evaluated the quality of evidence using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach. Results: The pooled results suggested that acupuncture led to moderate improvements in hot flashes, fatigue, and stiffness. No significant differences were observed in pain, gastrointestinal symptoms, Kupperman index scores, Overall quality of life, tumor necrosis factor levels, and interleukin levels. Conclusions: Evidence for outcome indicators of symptom management were downgraded by the GRADE system for inconsistency, indirectness, and imprecision in the included RCTs. Nonetheless, acupuncture is a moderately appropriate alternative therapy for hormone therapy-related side effects in breast cancer patients. However, it still lacks large-sample, multicenter, prospective RCTs. Future research should focus on standardizing comparison groups and treatment methods, be at least single-blinded, assess biologic mechanisms, have adequate statistical power, and involve multiple acupuncturists.

PDK1 Regulates the Maintenance of Cell Body and the Development of Dendrites of Purkinje Cells by pS6 and PKCγ.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a critical role in the development of mammalian brain. Here, we investigated the role of PDK1 in Purkinje cells (PCs) by generating the PDK1-conditional knock-out mice (cKO) through crossing PV-cre or Pcp2-cre mice with Pdk1fl/fl mice. The male mice were used in the behavioral testing, and the other experiments were performed on mice of both sexes. These PDK1-cKO mice displayed decreased cerebellar size and impaired motor balance and coordination. By the electrophysiological recording, we observed the reduced spontaneous firing of PCs from the cerebellar slices of the PDK1-cKO mice. Moreover, the cell body size of PCs in the PDK1-cKO mice was time dependently reduced compared with that in the control mice. And the morphologic complexity of PCs was also decreased after PDK1 deletion. These effects may have contributed to the reduction of the rpS6 (reduced ribosomal protein S6) phosphorylation and the PKCγ expression in PDK1-cKO mice since the upregulation of pS6 by treatment of 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1, the agonist of mTOR1, partly rescued the reduction in the cell body size of the PCs, and the delivery of recombinant adeno-associated virus-PKCγ through cerebellar injection rescued the reduced complexity of the dendritic arbor in PDK1-cKO mice. Together, our data suggest that PDK1, by regulating rpS6 phosphorylation and PKCγ expression, controls the cell body maintenance and the dendritic development in PCs and is critical for cerebellar motor coordination.SIGNIFICANCE STATEMENT Here, we show the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in Purkinje cells (PCs). The ablation of PDK1 in PCs resulted in a reduction of cell body size, and dendritic complexity and abnormal spontaneous firing, which attributes to the motor defects in PDK1-conditional knock-out (cKO) mice. Moreover, the ribosomal protein S6 (rpS6) phosphorylation and the expression of PKCγ are downregulated after the ablation of PDK1. Additionally, upregulation of rpS6 phosphorylation by3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1 partly rescued the reduction in cell body size of PCs, and the overexpression of PKCγ in PDK1-KO PCs rescued the reduction in the dendritic complexity. These findings indicate that PDK1 contributes to the maintenance of the cell body and the dendritic development of PCs by regulating rpS6 phosphorylation and PKCγ expression.

Colorimetric determination of ascorbic acid using a polyallylamine-stabilized IrO2/graphene oxide nanozyme as a peroxidase mimic.

The authors describe a peroxidase-mimicking nanozyme composed of IrO2 and graphene oxide (GO). It was synthesized from monodisperse IrO2 nanoparticles with an average diameter of 1.7 ± 0.3 nm that were prepared by pulsed laser ablation in ethanol. The nanoparticles were then placed on polyallylamine-modified GO nanosheets through electrostatic interaction. The peroxidase-like activity of the resulting nanocomposites was evaluated by catalytic oxidation of 3,3',5,5'-tetramethylbenzidine in the presence of H2O2. Kinetic results demonstrated that the catalytic behavior of the nanocomposites follows Michaelis-Menten kinetics. Experiments performed with terephthalic acid and cytochrome C confirmed that the peroxidase-like activity originated from the electron transfer mechanism rather than from generation of hydroxy radicals. The peroxidase-like activity is inhibited in the presence of ascorbic acid (AA). Based on this property, a colorimetric assay was developed for the determination of AA by exploiting the peroxidase-like activity of IrO2/GO nanocomposites. The linear relationship between absorbance at 652 nm and the concentration of AA was acquired. The limit of detection for AA is 324 nM. Further applications of the method for AA detection in real samples were also successfully demonstrated. Graphical abstractSchematic of the preparation of polyallylamine (PAH)-stabilized IrO2/GO nanocomposites and the colorimetric detection of AA based on the peroxidase-like activity of IrO2/GO nanocomposites.

Facile synthesis of IrO2/rGO nanocomposites with high peroxidase-like activity for sensitive colorimetric detection of low weight biothiols.

In this work, we reported a novel nanozyme synthesized by decorating highly dispersed ultrafine IrO2 nanoparticles on reduced graphene oxide (rGO) nanosheets via a simple hydrothermal method. The as-prepared IrO2/rGO nanocomposites exhibited intrinsic peroxidase-like activity and could catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to produce blue product in the presence of H2O2. Catalytic kinetic of IrO2/rGO nanocomposites followed Michaelis-Menten behavior, exhibiting a higher affinity to TMB than horseradish peroxidase (HRP) enzyme. Catalytic mechanism studies suggested that the peroxidase-like activity of IrO2/rGO nanocomposites originated from their ability of electron transfer between substrate and H2O2. On the basis of high peroxidase-like activity of IrO2/rGO nanocomposites, a colorimetric strategy for rapid and sensitive detection of low weight biothiols was developed. The colorimetric detection assays for low weight biothiols showed high selectivity against other amino acids. Therefore, the IrO2/rGO nanozyme is expected for promising potential applications in the biosensor, diagnostics and environment.

A protein phosphatase 2A deficit in the hippocampal CA1 area impairs memory extinction.

Protein phosphorylation plays an important role in learning and memory. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of neural synaptic plasticity. Here, to determine if PP2A is necessary for successful learning and memory, we have utilized a Tg (Camk2a-cre) T29-2Stl mice to specific knock down the expression of hippocampal PP2A in mice. By analysing behavioural, we observed that loss of PP2A in the hippocampal CA1 area did not affect the formation of memory but impaired contextual fear memory extinction. We use the electrophysiological recording to find the synaptic mechanisms. The results showed that the basic synapse transmission and synaptic plasticity of PP2A conditional knockout (CKO) mice were impaired. Moreover, PP2A CKO mice exhibited a saturating long-term potentiation inducted by strong theta burst stimulation but no depotentiation after low-frequency stimulation. Taken together, our results provide the evidence that PP2A is involved in synaptic transmission and hippocampus-dependent memory extinction.

MoO3-x nanodots with dual enzyme mimic activities as multifunctional modulators for amyloid assembly and neurotoxicity.

Development of effective inhibitors toward Aß aggregation and reactive oxygen species (ROS) scavengers are of crucial therapeutic implications for Alzheimer's disease (AD). Herein, a novel agent with dual enzyme mimic activities has been fabricated as a multifunctional Aß fibrillation modulator. MoO3-x nanodots were synthesized by pulsed laser ablation (PLA) method in MoS2 nanosheets solutions, which may act directly as numerous fine targets. MoO3-x nanodots showed a uniform and monodispersed morphology, and the tiny dots were around 3-5 nm with a narrow size distribution. Due to the efficient charge transition between Mo5+/Mo6+ on the dots surface, MoO3-x nanodots exhibited excellent catalase and SOD mimic activities, which were adopted to alleviate Aß-mediated oxidative stress. Moreover, MoO3-x nanodots can efficiently inhibit Aß aggregation and destabilize the preformed fibrils, and eventually protect neuronal cells from apoptosis induced by Aß. Taken together, MoO3-x nanodots with multifunctional roles can act as a potential therapeutic strategy for treatment of amyloid induced neurotoxicity.

PDK1 Deficit Impairs the Development of the Dentate Gyrus in Mice.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is crucial for the development of the dentate gyrus (DG), the first gateway receiving afferent inputs from the entorhinal cortex. However, the role of PDK1 in DG development is unclear. In the present study, by crossing Pdk1fl/fl mice with the Emx1-cre line, we identified that the ablation of PDK1 disrupted the development of DG via decreasing the proliferation, and increasing the differentiation of dentate neural progenitor cells, downregulating AKT activity and upregulating GSK3ß signaling. Moreover, PDK1 deletion disrupted the distribution of Reelin+ cells and decreased the level of Reelin mRNA which may contribute to the defective migration of progenitor cells and the disrupted radial glial scaffolds. Furthermore, the inhibition of GSK3ß activity partially restored the decreased proliferation of primary neural stem cells in vitro. Taken together, our data indicated that the ablation of PDK1 affected the proliferation and differentiation of dentate neural progenitor cells in mice.