Effects of Bone Marrow Mesenchymal Stem Cell-Derived Exosomes in Central Nervous System Diseases.

Central nervous system (CNS) diseases are one of the diseases that threaten human health. The delivery of drugs targeting the CNS has always been a significant challenge; the blood-brain barrier (BBB) is the main obstacle that must be overcome. The rise of bone marrow mesenchymal stem cell (BMSC) therapy has brought hope for the treatment of CNS diseases. However, the problems of low homing rate, susceptibility differentiation into astrocytes, immune rejection, and formation of iatrogenic tumors of transplanted BMSCs limit their clinical application. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have become a hot research topic in the treatment of CNS diseases in recent years because of their excellent histocompatibility, low immunogenicity, ease of crossing the BBB, and their ability to serve as natural carriers for treatment. This article reviews the mechanisms of BMSC-Exos in CNS diseases and provides direction for further research.

Tumor-derived extracellular vesicles: how they mediate glioma immunosuppression.

Gliomas, the most common malignant brain tumor, present a grim prognosis despite available treatments such as surgical resection, temozolomide (TMZ) therapy, and radiation therapy. This is due to their aggressive growth, high level of immunosuppression, and the blood-brain barrier (BBB), which obstruct the effective exchange of therapeutic drugs. Gliomas can significantly affect differentiation and function of immune cells by releasing extracellular vesicles (EVs), resulting in a systemic immunosuppressive state and a highly immunosuppressive microenvironment. In the tumor immune microenvironment (TIME), the primary immune cells are regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). In particular, glioma-associated TAMs are chiefly composed of monocyte-derived macrophages and brain-resident microglia. These cells partially exhibit characteristics of a pro-tumorigenic, anti-inflammatory M2-type. Glioma-derived EVs can hijack TAMs to differentiate into tumor-supporting phenotypes or directly affect the maturation of peripheral blood monocytes (PBMCs) and promote the activation of MDSCs. In addition, EVs impair the ability of dendritic cells (DCs) to process antigens, subsequently hindering the activation of lymphocytes. EVs also impact the proliferation, differentiation, and activation of lymphocytes. This is primarily evident in the overall reduction of CD4 + helper T cells and CD8 + T cells, coupled with a relative increase in Tregs, which possess immunosuppressive characteristics. This study investigates thoroughly how tumor-derived EVs impair the function of immune cells and enhance immunosuppression in gliomas, shedding light on their potential implications for immunotherapy strategies in glioma treatment.

The role of integrin αvß3 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction.

Calcium phosphate ceramics-based biomaterials were reported to have good biocompatibility and osteoinductivity and have been widely applied for bone defect repair and regeneration. However, the mechanism of their osteoinductivity is still unclear. In our study, we established an ectopic bone formation in vivo model and an in vitro macrophage cell co-culture system with calcium phosphate ceramics to investigate the effect of biphasic calcium phosphate on osteogenesis via regulating macrophage M1/M2 polarization. Our micro-CT data suggested that biphasic calcium phosphate had significant osteoinductivity, and the fluorescence co-localization detection found increased F4/80+/integrin αvß3+ macrophages surrounding the biphasic calcium phosphate scaffolds. Besides, our study also revealed that biphasic calcium phosphate promoted M2 polarization of macrophages via upregulating integrin αvß3 expression compared to tricalcium phosphate, and the increased M2 macrophages could subsequently augment the osteogenic differentiation of MSCs in a TGFß mediated manner. In conclusion, we demonstrated that macrophages subjected to biphasic calcium phosphate could polarize toward M2 phenotype via triggering integrin αvß3 and secrete TGFß to increase the osteogenesis of MSCs, which subsequently enhances bone regeneration.

Characterization of upper airway and analysis of potential risk factor associated with OSA in patients with unilateral temporomandibular ankylosis and micrognathia deformities.

OBJECTIVE: To ascertain the airway characteristics in patients with unilateral temporomandibular joint ankylosis and maxilla-mandibular deformities (UTMAMD) and investigate the potential risk factors associated with obstructive sleep apnea (OSA) among UTMAMD patients. METHODS: Authors conducted a retrospective single-center study to assess and compare study group consisting of a cohort of 32 patients diagnosed with UTMAMD between January 2011 and July 2022 with control group including 54 participants. The study group was further divided into two subgroups based on the presence or absence of OSA in patients. Parameters related to the upper airway were measured and analyzed using three-dimensional reconstruction of computed tomographic scans. The measurements of airway parameters were compared between study group and control group and between two subgroups. Pearson correlation analysis was used to identify the factors associated with the presence of OSA, and a multiple variable regression model was used to identify risk factors for OSA. RESULTS: Airway volume (VOL), Minimum cross-section area (min CSA), mean CSA, tilt in sagittal plane (TS), and tilt in sagittal plane (TC) in velopharynx; VOL, airway length (AL), min CSA, mean CSA, TS, TC, and airway deviation (AD) in glossopharynx; min CSA, TS, and AD in hypopharynx were found difference with significance between study group and control group. Lateral dimension/anterior-posterior dimension (LAT/AP) ratio in velopharynx and min CSA, TC, and LAT/AP ratio in glossopharynx were significant different between patients with UTMAMD with OSA and without OSA. CONCLUSIONS: The upper airway of patients with UTMAMD exhibits significant narrowing and distortion, rendering them susceptible to suffer from OSA. Patients with UTMAMD and OSA demonstrate more elliptical airways, and the glossopharyngeal LAT/AP ratio is a predictive indicator for the occurrence of OSA.

Mechanism of ligusticum cycloprolactam against neuroinflammation based on network pharmacology and experimental verification.

Ligustilide, a natural phthalide mainly derived from chuanxiong rhizomes and Angelica Sinensis roots, possesses anti-inflammatory activity, particularly in the context of the nervous system. However, its application is limited because of its unstable chemical properties. To overcome this limitation, ligusticum cycloprolactam (LIGc) was synthesized through structural modification of ligustilide. In this study, we combined network pharmacological methods with experimental verification to investigate the anti-neuroinflammatory effects and mechanisms of ligustilide and LIGc. Based on our network pharmacology analysis, we identified four key targets of ligustilide involved in exerting an anti-inflammatory effect, with the nuclear factor (NF)-κB signal pathway suggested as the main signalling pathway. To verify these results, we examined the expression of inflammatory cytokines and inflammation-related proteins, analysed the phosphorylation level of NF-κB, inhibitor of κBα (IκBα) and inhibitor of κB kinase α and ß (IKKα+ß), and evaluated the effect of BV2 cell-conditioned medium on HT22 cells in vitro. Our results, demonstrate for the first time that LIGc can downregulate the activation of the NF-κB signal pathway in BV2 cells induced by lipopolysaccharide, suppress the production of inflammatory cytokines and reduce nerve injury in HT22 cells mediated by BV2 cells. These findings suggest that LIGc inhibits the neuroinflammatory response mediated by BV2 cells, providing strong scientific support for the development of anti-inflammatory drugs based on natural ligustilide or its derivatives. However, there are some limitations to our current study. In the future, further experiments using in vivo models may provide additional evidence to support our findings.

Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppression Mediated Through the PI3K/Akt/mTOR Axis.

Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 µg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI.

Prenatally VPA exposure is likely to cause autistic-like behavior in the rats offspring via TREM2 down-regulation to affect the microglial activation and synapse alterations.

Microglial dysfunction has been reported in the valproic acid (VPA)-induced autism spectrum disorder (ASD) rat models. However, how does prenatal VPA exposure affect microglia remains to be elucidated. The triggering receptor expressed on myeloid cells 2 (TREM2) is revealed to be implicated in a range of microglia functions. However, reports on the association between TREM2 and VPA-induced ASD rat models are scarce. Our results showed that prenatal VPA exposure induced autistic-like behaviors, downregulated the levels of TREM2, up-regulated microglial activation, dysregulated microglial polarization, and altered synapse in offspring. TREM2 overexpression partly ameliorated microglia dysfunction and autistic-like behaviors in prenatal VPA-exposed rats. Our findings demonstrated that prenatally VPA exposure is likely to cause autistic-like behavior in the rat offspring via TREM2 down-regulation to affect the microglial activation, microglial polarization and synaptic pruning of microglia for the first time.

Retinoic acid administration normalizes aberrant microglial activation via regulating TREM2 transcription in the PFC of valproic acid induced autism rat.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with an unclear underlying pathogenesis. Disruption of retinoic acid (RA)-retinoic acid receptor α (RARα) signaling and aberrant microglial activation were reported to be involved in the pathogenesis of ASD. However, the effect of RA-RARα signaling on microglial activation in ASD and the underlying mechanisms are unknown. Herein, we found inhibited RA-RARα signaling and increased microglial activation in valproic acid (VPA)-induced autism rats. Furthermore, we administered RA to VPA rats and found that RA ameliorated autism-like behaviors, inhibited microglial activation and normalized microglial polarization in VPA rats. Additionally, the expression levels of RARα and triggering receptor expressed on myeloid cells 2 (TREM2) were increased in the prefrontal cortex (PFC) of VPA rats given RA. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays confirmed that RARα can regulate the transcriptional activity of the TREM2 gene by binding to its promoter. We conclude that RA administration ameliorates autism-like behaviors in VPA rats by inhibiting microglial activation and normalizing microglial polarization through the regulation of TREM2 transcription by RARα.

Emission characteristics, environmental impact assessment and priority control strategies derived from VOCs speciation sourcely through measurement for wooden furniture-manufacturing industry in China.

Volatile organic compounds (VOCs) from wooden furniture-manufacturing industry is an important emission source. The VOC content levels, source profiles, emission factors and inventories, O3 and SOA formation, and priority control strategies were investigated from the source. One hundred sixty-eight representative woodenware coatings were sampled, and VOC species and contents were determined. The VOC, O3 and SOA emission factors per gram of coatings for three types of woodenware coatings were quantified. The total VOC, O3 and SOA emissions from wooden furniture-manufacturing industry in 2019 were 976,976 t/a, 2,840,282 t/a, 24,970 t/a, and solvent-based coatings accounted for 98.53 %, 99.17 % and 99.6 % of the total VOC, O3 and SOA emissions, respectively. Aromatics and esters were major organic groups, contributing 49.80 % and 36.03 % to total VOC emissions, respectively. Aromatics contributed 86.14 % and 100 % to total O3 and SOA emissions, respectively. The top 10 species contributing to VOC, O3 and SOA had been identified. Four benzene series, including o-Xylene, m-Xylene, toluene and ethylbenzene, were ranked as the first-class priority control species, accounting for 85.90 % and 99.89 % of the total O3 and SOA, respectively. Priority should be given to solvent-based coatings, aromatics and four benzene series for future O3 and SOA reduction for wooden furniture-manufacturing industry.

Early life exposure to triclosan from antimicrobial daily necessities may increase the potential risk of autism spectrum disorder: A multicenter study in China.

BACKGROUND: Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders with unclear etiologies. Our recent work indicated that maternal exposure to triclosan (TCS) significantly increased the autistic-like behavior in rats, possibly through disrupting neuronal retinoic acid signaling. Although environmental endocrine disruptors (EEDs) have been associated with autism in humans, the relationship between TCS, one of the EEDs found in antibacterial daily necessities, and autism has received little attention. OBJECTIVE: The aims of this multicenter study were to evaluate TCS concentrations in typically developing (TD) children and ASD children, and to determine the relationship between TCS levels and the core symptoms of ASD children. METHODS: A total of 1345 children with ASD and 1183 TD children were enrolled from 13 cities in China. Ages ranged between 2 and 7 years. A questionnaire was used to investigate the maternal use of antibacterial daily necessities (UADN) during pregnancy. The core symptoms of ASD were evaluated using the Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), Social Response Scale (SRS), and the Children Neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016). The TCS concentration was measured using LC-MS/MS. RESULTS: Maternal UADN during pregnancy may be an unrecognized potential environmental risk factor for ASD (OR=1.267, P = 0.023). Maternal UADN during pregnancy strongly correlated with TCS levels in the offspring (Adjusted ß = 0.277, P < 0.001). TCS concentration was higher in ASD children (P = 0.005), and positively correlated with ABC (Sensory subscales: P = 0.03; Social self-help subscales: P = 0.011) and SRS scale scores (Social awareness subscales: P = 0.045; Social communication subscales: P = 0.001; Autism behavior mannerisms subscales: P = 0.006; SRS total score: P = 0.003) in ASD children. This association was more pronounced in boys than in girls. CONCLUSION: To our knowledge, this is the first case-control study to examine the correlation between TCS and ASD. Our results suggest that maternal UADN during pregnancy may be a potential risk of ASD in offspring. Further detection of TCS levels showed that maternal UADN during pregnancy may be associated with excessive TCS exposure. In addition, the level of TCS in children with ASD is higher than TD children. The higher levels of TCS in children with ASD may be significantly associated with more pronounced core symptoms, and this association was more significant in male children with ASD.

Molecular Mechanism of the Protective Effects of M2 Microglia on Neurons: A Review Focused on Exosomes and Secretory Proteins.

Microglia, as innate immune cells in the brain, closely monitor changes in the internal environment and participate in the maintenance of homeostasis in the central nervous system (CNS). Microglia can be polarized to the M1 or M2 phenotype in response to various stimuli in vivo or in vitro, affecting the functions of peripheral neurons. M2 microglia have attracted increasing attention in recent years owing to their beneficial effects on various diseases and injuries of the CNS, such as traumatic brain injury, stroke, Alzheimer's disease and multiple sclerosis. They exert neuroprotective effects by various mechanisms, e.g., suppressing inflammation, promoting the degradation of misfolded and aggregated proteins, promoting neurite growth, enhancing neurogenesis, inhibiting autophagy and apoptosis, promoting myelination, maintaining blood-brain barrier integrity, and enhancing phagocytic activity.This review summarizes the molecular mechanisms by which M2 microglia exert protective effects on neurons and provides a reference for the selection of therapeutic targets for CNS diseases.

Involvement of retinoic acid receptor α in the autistic-like behavior of rats with vitamin A deficiency by regulating neurexin 1 in the visual cortex: a mechanism study. / è§†é»„é ¸å—ä½“α通过调控视皮质轴突蛋白1å‚ä¸Žç»´ç”Ÿç´ Aç¼ºä¹å¤§é¼ å­¤ç‹¬ç—‡æ ·è¡Œä¸ºçš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To study the mechanism of retinoic acid receptor α (RARα) signal change to regulate neurexin 1 (NRXN1) in the visual cortex and participate in the autistic-like behavior in rats with vitamin A deficiency (VAD). METHODS: The models of vitamin A normal (VAN) and VAD pregnant rats were established, and some VAD maternal and offspring rats were given vitamin A supplement (VAS) in the early postnatal period. Behavioral tests were performed on 20 offspring rats in each group at the age of 6 weeks. The three-chamber test and the open-field test were used to observe social behavior and repetitive stereotyped behavior. High-performance liquid chromatography was used to measure the serum level of retinol in the offspring rats in each group. Electrophysiological experiments were used to measure the long-term potentiation (LTP) level of the visual cortex in the offspring rats. Quantitative real-time PCR and Western blot were used to measure the expression levels of RARα, NRXN1, and N-methyl-D-aspartate receptor 1 (NMDAR1). Chromatin co-immunoprecipitation was used to measure the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene. RESULTS: The offspring rats in the VAD group had autistic-like behaviors such as impaired social interactions and repetitive stereotypical behaviors, and VAS started immediately after birth improved most of the behavioral deficits in offspring rats. The offspring rats in the VAD group had a significantly lower serum level of retinol than those in the VAN and VAS groups (P<0.05). Compared with the offspring rats in the VAN and VAS groups, the offspring rats in the VAD group had significant reductions in the mRNA and protein expression levels of NMDAR1, RARα, and NRXN1 and the LTP level of the visual cortex (P<0.05). The offspring rats in the VAD group had a significant reduction in the enrichment of RARα transcription factor in the promoter region of the NRXN1 gene in the visual cortex compared with those in the VAN and VAS groups (P<0.05). CONCLUSIONS: RARα affects the synaptic plasticity of the visual cortex in VAD rats by regulating NRXN1, thereby participating in the formation of autistic-like behaviors in VAD rats.

The accuracy of virtual surgical planning in segmental Le Fort I surgery: A comparison of planned and actual outcome.

Segmental Le Fort I surgery is an effective technique to correct complicated dentomaxillofacial deformities. This retrospective study evaluated the accuracy of segmental Le Fort I surgery under the guidance of virtual surgical planning (VSP). A total of 129 patients who accepted segmental Le Fort I surgery were investigated in this study. VSP was transferred to segmental surgery with different pieces precisely with the aid of 3D-printed surgical templates and splints. The surgical result was evaluated by postoperative complications, color distance maps, and quantitative accuracy analysis. Outcomes showed that the VSP was successfully transferred to actual surgery with high accuracy. The overall mean linear difference was 1.28 mm, and the overall mean angular difference was 2.4°. Except for one case of root injury, there was no serious complication recorded. The results suggested that VSP was a reliable assistance for segmental Le Fort I surgery.

Loading of erythropoietin on biphasic calcium phosphate bioceramics promotes osteogenesis and angiogenesis by regulating EphB4/EphrinB2 molecules.

Improving osteogenesis and angiogenesis using different cells and drugs is critical in the field of bone tissue engineering. Recent research has found that erythropoietin (EPO) plays an important role in both osteogenesis and angiogenesis. In this study, we grafted polydopamine and EPO onto the surface of biphasic calcium phosphate. The characterization and release property of the modified bioceramics were assessed. Cell proliferation, expression of osteoblastic and endothelial markers, and EphB4/EphrinB2 molecules were investigated while employing co-cultures of two different cells [rat vein endothelial cells (VECs) and rat bone marrow mesenchymal stromal cells (BMSCs)]. The modified bioceramics were finally implanted into the SD rats' femurs and followed by investigating the bone defect repair efficacy and the expression of EphB4/EphrinB2 molecules in vivo. The results indicated that the modified bioceramics could control the release of EPO continuously. The osteogenesis and angiogenesis were improved along with the increased expression of EphB4/EphrinB2 molecules. The expression of EphB4/EphrinB2 molecules was also significantly increased in vivo and the bone defect was repaired effectively. Overall, our findings demonstrated that EPO loading on biphasic calcium phosphate bioceramics could promote both osteogenesis and angiogenesis. The results suggest that EphB4/EphrinB2 may be crucial in the process. Graphical abstract.

eIF2α-ATF4 Pathway Activated by a Change in the Calcium Environment Participates in BCP-Mediated Bone Regeneration.

Biphasic calcium phosphate (BCP) ceramic is a classic bone void filler and a common basis of new materials for bone defect repair. However, the specific mechanism of BCP in osteogenesis has not been fully elucidated. Endoplasmic reticulum stress (ERs) and the subsequent PERK-eIF2α-ATF4 pathway can be activated by various factors, including trauma and intracellular calcium changes, and therefore worth exploring as a potential mechanism in BCP-mediated bone repair. Herein, a rat lateral femoral epicondyle defect model in vivo and a simulated BCP-mediated calcium environment in vitro were constructed for the analysis of BCP-related osteogenesis and the activation of ERs and the eIF2α-ATF4 pathway. An inhibitor of eIF2α dephosphorylation (salubrinal) was also used to explore the effect of the eIF2α-ATF4 pathway on BCP-mediated bone regeneration. The results showed that the ERs and eIF2α-ATF4 pathway activation were observed during 4 weeks of bone repair, with a rapid but brief increase immediately after artificial defect surgery and a re-increase after 4 weeks with the resorption of BCP materials. Mild ERs and the activated eIF2α induced by the calcium changes mediated by BCP regulated the expression of osteogenic-related proteins and had an important role during the defect repair. In conclusion, the eIF2α-ATF4 pathway activated by a change in the calcium environment participates in BCP-mediated bone regeneration. eIF2α-ATF4 and ERs could provide new directions for further studies on new materials in bone tissue engineering.

Valproic Acid Induces Autism-Like Synaptic and Behavioral Deficits by Disrupting Histone Acetylation of Prefrontal Cortex ALDH1A1 in Rats.

OBJECTIVES: This study aimed to investigate the impact of valproic acid (VPA) on the histone acetylation of acetaldehyde dehydrogenase 1A1 (ALDH1A1) and the mechanism underlying VPA-induced autism-like behavior. METHODS: Female Sprague-Dawley rats were intraperitoneally injected with VPA during gestation to establish an autism model in their offspring. Some offspring prenatally exposed to VPA were randomly treated with MS-275, one histone deacetylase (HDAC) inhibitor, or retinoic acid (RA) after birth. Behavioral tests were conducted on the offspring 6 weeks after birth. Electrophysiological experiments were performed to investigate long-term potentiation (LTP) in the prefrontal cortex (PFC). The expression levels of AMPA receptors (GluA1 and 2), NMDA receptors (GluN1 and 2), synapsin 1 (SYN1), HDAC, acetylated histone 3 (AcH3), RA receptor alpha (RARα), and ALDH1A1 in the PFC were measured by Western blotting and quantitative polymerase chain reaction. ALDH enzyme activity in PFC tissue was detected using a Micro ALDH Assay Kit. The RA level in the PFC was measured using ultrahigh-performance liquid chromatography/tandem mass spectrometry. A chromatin immunoprecipitation (ChIP) experiment explored the interaction between the ALDH1A1 gene and AcH3. RESULTS: Offspring prenatally exposed to VPA showed autism-like behavior, upregulated the levels of LTP and GluN2A, GluA1, and SYN1 proteins relevant to synaptic plasticity in the PFC. The expression levels of HDAC3 mRNA and protein were increased. On the other hand, there was a significant reduction in the levels of AcH3, RARα, RA, ALDH1A1 mRNA and protein, the level of ALDH activity and AcH3 enrichment in the ALDH1A1 promoter region in VPA-induced offspring. Administration of MS-275 in VPA offspring significantly elevated the levels of AcH3, ALDH1A1 mRNA and protein, ALDH activity, RA, the level of RARα protein and the binding of AcH3 to the ALDH1A1 promoter. In addition, the GluA1 protein level and LTP were reduced, and most behavioral deficits were reversed. After RA supplementation in the VPA-treated offspring, the RA and RARα protein levels were significantly upregulated, GluA1 protein and LTP were downregulated, and most autism-like behavioral deficits were effectively reversed. CONCLUSION: These findings suggest that VPA impairs histoneacetylation of ALDH1A1 and downregulates the RA-RARα pathway. Such epigenetic modification of ALDH1A1 by VPA leads to autism-like synaptic and behavioral deficits.

Multifunctional DNA dendrimer nanostructures for biomedical applications.

DNA nanomaterials have attracted ever-increasing attention over the past decades due to their incomparable programmability and multifunctionality. In particular, DNA dendrimer nanostructures, as a major research focus, have been applied in the fields of biosensing, therapeutics, and protein engineering, benefiting from their highly branched configuration. With the aid of specific recognition probes and inherent signal amplification, DNA dendrimers can achieve ultrasensitive detection of nucleic acids, proteins, cells, and other substances, such as lipopolysaccharides (LPS), adenosine triphosphate (ATP), and exosomes. By virtue of their void-containing structures and biocompatibility, DNA dendrimers can deliver drugs or functional nucleic acids into target cells in chemotherapy, immunotherapy, and gene therapy. Furthermore, DNA dendrimers are being applied in protein engineering for efficient directed evolution of proteins. This review summarizes the main research progress of DNA dendrimers, concerning their assembly methods and biomedical applications as well as the emerging challenges and perspectives for future research.

Vitamin A supplementation ameliorates motor incoordination via modulating RORα in the cerebellum in a valproic acid-treated rat autism model with vitamin A deficiency.

Motor dysfunctions are common comorbidities among autism spectrum disorder (ASD) patients. Abnormal cerebellar development throughout critical periods may have an effect on motor functions and result in motor impairments. Vitamin A (VA) plays a crucial role in the developing process of the nervous system. The correlation of VA deficiency (VAD) and ASD with motor dysfunctions, however, is not clear. Therefore, we built rat models with different VA levels based on the valproic acid (VPA)-treated autism model. ASD rats with VAD showed aggravated motor coordination abnormalities, Purkinje cell loss and impaired dendritic arborization of Purkinje cells compared to ASD rats with normal VA levels (VA normal, VAN). Additionally, the expression levels of retinoid-related orphan receptor α (RORα) and retinoic acid receptor α (RARα) were lower in the cerebellum of ASD rats with VAD than in those of ASD rats with VAN. VA supplementation (VAS) effectively improved motor coordination and cerebellar Purkinje cell abnormalities in ASD rats with VAD. Furthermore, the results of chromatin immunoprecipitation (ChIP) assays confirmed that the enrichment of RARα was detected on the RORα promoter in the cerebellum and that VAS could upregulate the binding capacity of RARα for RORα promoters. These results showed that VAD in autism might result in cerebellar impairments and be a factor aggravating a subtype of ASD with motor comorbidities. The therapeutic effect of VAS on motor deficits and Purkinje neuron impairments in autism might be due to the regulation of RORα by RARα.

A weekly vitamin A supplementary program alleviates social impairment in Chinese children with autism spectrum disorders and vitamin A deficiency.

BACKGROUND: Children in China with Autism Spectrum Disorders (ASD) are prone to vitamin A deficiency (VAD). The present study compared two vitamin A supplements (VAS) in two groups of children with ASD and VAD to explore a better VAS program for children with ASD. METHOD: A total of 138 3-8-year-old children with ASD (118 males and 20 females) were enrolled in this 6-month study. Of these 138 children, 82 who had VAD (ASD-VAD) were divided into two VAS groups that received the recommended VAS program (RNI-VAS) or a weekly dose of VAS (WD-VAS). The 56 children who had normal vitamin A levels (ASD-VAN) served as a control group. The Social Responsiveness Scale (SRS) was used to assess the severity of social impairment before and after the interventions. Their serum retinol (VA) and oxytocin (OXT) concentrations, the mRNA expression of retinoic acid receptors (RARs), and CD38 gene in peripheral blood was measured before and after the 6-month intervention. RESULTS: The WD-VAS program increased VA levels better than the RNI-VAS program did (P < 0.01), and it significantly decreased SRS scores (P < 0.05). In addition, the change in VA was positively correlated with the change in mRNA levels in RARß (r = 0.2441, P = 0.0092), the CD38 in PBMC (r = 0.2729, P = 0.0033), and the change in OXT concentration in serum (r = 0.3735, P < 0.0001). VA was also negatively correlated with changes in SRS scores across the three groups (r = -0.2615, P = 0.0026). CONCLUSION: The WD-VAS might be more suitable for children with ASD and VAD than other interventions to improve both VA and social functioning, which may be mediated through the RARß-CD38-OXT axis.

Rab11-mediated recycling endosome role in nervous system development and neurodegenerative diseases.

STUDY: Membrane trafficking process is significant for the complex and precise regulatory of the nervous system. Rab11, as a small GTPase of the Rab superfamily, controls endocytic vesicular trafficking to the cell surface after sorting in recycling endosome (RE), coordinating with its receptors to maintain neurological function. MATERIALS AND METHODS: This article reviewed the literature of Rab11 in nervous system. RESULTS: Rab11-positive vesicles targeted transport growth-related molecules, such as integrins, protrudin, tropomyosin receptor kinase (Trk) A/B receptor and AMPA receptor (AMPAR) to membrane surface to promote the regeneration capacity of axon and dendrites and maintain synaptic plasticity. In addition, many studies have shown that the expression of Rab11 is decreased in multiple neurodegenerative diseases, which is highly correlated with the process of production, transport and clearance of disease-related pathological proteins. And overexpression or increased activity of Rab11 can greatly improve the defect of membrane trafficking and slow down the disease process. CONCLUSION: With increasing research efforts on Rab11-dependent membrane trafficking mechanisms, a potential target for nerve regeneration and neurodegenerative diseases will be provided.