Non-pathological cognitive decline is a neurodegenerative condition associated with brain aging owing to epigenetic changes, telomere shortening, stem cells exhaustion, or altered differentiation. Human umbilical cord mesenchymal stem cells (hUCMSCs) have shown excellent therapeutic prospects on the hallmarks of aging. In this study, we aimed to elucidate the role of hUCMSCs with down-regulated miRNA-206 (hUCMSCs anti-miR-206) on cognitive decline and the underlying mechanism.

Alopecia areata (AA) is a common autoimmune hair loss disease with increasing incidence. Corticosteroids are the most widely used for hair loss treatment; however, long-term usage of hormonal drugs is associated with various side effects. Mesenchymal stem cells (MSCs) therapy has been studied extensively to curb autoimmune diseases without affecting immunity against diseases.

Defects in ataxin-3 proteins and CAG repeat expansions in its coding gene ATXN3 cause Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph disease (MJD) polyglutamine neurodegenerative disease. The mutant proteins aggregate as inclusion bodies in cells and compete with wild-type ataxin-3, which leads to neuronal dysfunction or death and impairs Beclin1-mediated autophagy. It has been reported that Mesenchymal stem cells (MSCs) can reliably treat several neurodegenerative diseases. Herein, we used a Transcription Factor EB (TFEB) nuclear translocation-mediated MSCs co-culture approach to reconstitute autophagy and lysosomal biogenesis, and reduce SCA3-like behaviors in induced pluripotent stem cells (iPSCs)-derived neuron cells models. Our iPSCs model showed enhanced expression of autophagy proteins, attenuated the expression and toxic effects of mutant ataxin-3 on neurons, and alleviated the effects of ataxin-3 on autophagy. Therefore, MSCs are associated with autophagy-inducing therapy and compared to animal models, our MSCs co-culture could be used as a novel and potential therapeutic approach to study SCA3 disease and other neurodegenerative diseases.

Methadone maintenance treatment (MMT) is recognized as one of the most effective treatments for heroin addiction but its effect is dimmed by the high incidence of heroin relapse. However, underlying neurobiology mechanism of heroin relapse under MMT is still largely unknown. Here, we took advantage of a resting-state fMRI technique by analysis of regional homogeneity (ReHo), and tried to explore the difference of brain function between heroin relapsers and non-relapsers in MMT.

Ginkgo biloba extract (GBE) contains diterpene ginkgolides (DGs), which have been shown to have neuroprotective effects by a number of previous studies. We previously demonstrated part of the action of DG. However, the impact of DG on the prefrontal cortex (PFC) remains unclear. Here, we evaluated the effects of DG and venlafaxine (for comparison) on behavioral and metabolite changes in the PFC using mice models and gas chromatography-mass spectrometry-based metabolomics.

Given the increased incidence of Parkinson's disease (PD) and the lack of accurate early diagnosis of PD with cognitive impairment (PD-CI), we compared the serum metabolomes and proteomes of 26 patients with PD without cognitive impairment (PD-N) and 31 patients with PD-CI by combining grade-dependent proteomics and metabolomics analyses.

Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson's disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson's disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson's disease. We then established a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson's disease.

Glioblastoma multiforme (GBM) is a highly proliferative cancer with generally poor prognosis and accumulating evidence has highlighted the potential of long noncoding RNAs (lncRNAs) in the biological behaviors of glioma cells. This study focused on the identification of lncRNAs to identify targets for possible GBM prognosis. Microarray expression profiling found that 1,759 lncRNAs and 3,026 messenger RNAs (mRNAs) were upregulated, and 1932s lncRNA and 2,979 mRNAs were downregulated in GBM. Bioinformatics analysis and experimental verification identified TCONS_00020456 (TCON) for further analysis. In situ hybridization, along with immunohistochemical and receiver operating characteristic analysis determined TCON (truncation value = 3.5) as highly sensitive and specific in GBM. Grade IV patients with glioma life span with different lncRNA staining scores were analyzed. TCON staining scores below 3.5 indicated poor prognosis (life span ranging from 0.25 to 7 months), even if the glioma was surgically removed. TCON decreased significantly in GBM, and showed a coexpressional relationship with Smad2 and protein kinase C α (PKCα). Overexpression of TCON reduced the proliferation on one hand and migration, invasion on the other. TCON also inhibited epithelial-mesenchymal transformation and glioma progression in vivo, based on a nude mouse tumorigenicity assay. In addition, we predicted a potential binding site and intersection that microRNAs targeting Smad2, PKCα, and TCON through RACE pretest and bioinformatics analysis. Taken together, TCON, regarded as oncosuppressor, targeting the Smad2/PKCα axis plays a novel role in inhibiting the malignant progression of glioma. Moreover, it also demonstrates that the level of TCON can be used as a prognostic and diagnostic biomarker for GBM.

Depression is a severe and chronic mental disorder, affecting about 322 million individuals worldwide. A recent study showed that diterpene ginkgolides (DG) have antidepressant-like effects on baseline behaviours in mice. Here, we examined the effects of DG and venlafaxine (VLX) in a chronic social defeat stress model of depression. Both DG and VLX attenuated stress-induced social deficits, despair behaviour and exploratory behaviour. To elucidate the metabolic changes underlying the antidepressive effects of DG and VLX, we investigated candidate functional pathways in the prefrontal cortex using a GC-MS-based metabolomics approach. Metabolic functions and pathways analysis revealed that DG and VLX affect protein biosynthesis and nucleotide metabolism to enhance cell proliferation, with DG having a weaker impact than VLX. Glutamate and aspartate metabolism played important roles in the antidepressant effects of DG and VLX. Tyrosine degradation and cell-to-cell signaling and interaction helped discriminate the two antidepressants. L-glutamic acid was negatively correlated, while hypoxanthine was positively correlated, with the social interaction ratio. Understanding the metabolic changes produced by DG and VLX should provide insight into the mechanisms of action of these drugs and aid in the development of novel therapies for depression.

Background: There is a continued debate and inconsistent findings in previous literature about the relationship of catechol-O-methyltransferase (COMT) and Parkinson's disease (PD) susceptibility as well as cognitive dysfunction. To substantiate this existing gap, we comprehensively examine COMT genotype effects on the development of PD and test the hypothesis that the Met158 allele of the COMT gene is associated with cognitive dysfunction by conducting a meta-analysis review. Methods: PubMed/MEDLINE, Embase, Cochrane databases search (18/30/08) yielded 49 included studies. Data were extracted by two reviewers and included COMT genotype, publication year, diagnostic status, ancestry, the proportion of male participants, and whether genotype frequencies were consistent with Hardy-Weinberg equilibrium. Unadjusted odds ratios (ORs) were used to derive pooled estimates of PD risk overall and in subgroups defined by ethnicity, gender, and onset of disease. Moreover, the association of certain cognitive domains in PD and COMT gene type was explored. Meta-analyses were performed using random-effect models and p value-based methods. All statistical tests were two-sided. The present study was registered with PROSPERO (CRD42018087323). Results: In the current studies, we found no association between COMT Val158/108Met polymorphism and PD susceptibility. However, the gender-stratified analyses revealed marginally significant effects in heterozygote model analyses in women (P = 0.053). In addition, stratification according to onset of PD also shows significant effects of COMT Val158/108Met polymorphism on late-onset population both in recessive (P = 0.017) and allelic (P = 0.017) genetic models. For the intelligence quotient (IQ) score and Unified Parkinson Disease Rating Scale III (UPDRS III), there was no evidence for genetic association, except in subgroup analyses in Asian populations (IQ score, P = 0.016; UPDRS III, P < 0.001). Conclusion: The COMT Val158/108Met polymorphism is associated with the risk for PD in female or late-onset PD. Methionine/methionine carriers of Asian population performed significantly worse than the valine allele carriers in IQ score and UPDRS III.

Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. For decades, the unilateral 6‑hydroxydopamine (6‑OHDA) rat model has been employed to investigate the pathogenesis and therapy of PD. However, the behavior and associated pathological features of the model long term have not previously been described dynamically. In the present study, the unilateral model was established by 6‑OHDA injection in the striatum. The PD rat model was determined 2 weeks following surgery, according to the apomorphine (APO)‑induced rotations, cylinder, rotarod and open field tests. TH‑positive neurons and fibers in the substantia nigra pars compacta (SNpc) and striatum, respectively, and glial activation in the SNpc, determined by glial fibrillary acidic protein (GFAP) expression for astrocytes and CD11b (Mac1) expression for microglia, were detected by immunohistological staining. Correlation analysis was performed to understand the association between PD‑associated behavior and pathology. The behavioral impairment progressively deteriorated during the process of experiment. In addition, the decrease in TH‑positive neurons was associated with an increase in GFAP‑ and Mac1‑positive cells in the SNpc. Linear regression analysis indicated the association between behavioral and pathological changes. The results of the present study indicate that the APO‑induced rotation, cylinder and rotarod tests are all sensitive and reliable strategies to predict the loss of TH+ neurons. These results provide a potential intervention time‑point and a comprehensive evaluation index system for assessment of PD therapeutic strategies using the hemiparkinsonian rat.

Spinal cord injury (SCI) can cause a variety of cells apoptosis, neurodegeneration, and eventually permanent paralysis. This study aimed to examine whether transplanting human umbilical cord mesenchymal stem cells (hucMSCs) can promote locomotor function recovery, reduce apoptosis and inhibit demyelination in SCI models.

NeuroD plays a key regulatory effect on differentiation of neural stem cells into mature neurons in the brain. Thus, we assumed that electroacupuncture at Baihui (DU20) acupoint in newborn rats exposed to in utero fetal distress would influence expression of NeuroD. Electroacupuncture at Baihui was performed for 20 minutes on 3-day-old (Day 3) newborn Sprague-Dawley rats exposed to in utero fetal distress; electroacupuncture parameters consisted of sparse and dense waves at a frequency of 2-10 Hz. Real-time fluorescent quantitative PCR results demonstrated that mRNA expression of NeuroD, a molecule that indicates NeuroD, increased with prolonged time in brains of newborn rats, and peaked on Day 22. The level of mRNA expression was similar between Day 16 and Day 35. These findings suggest that electro acupuncture at Baihui acupoint could effectively increase mRNA expression of molecules involved in NeuroD in the brains of newborn rats exposed to in utero fetal distress.

Inflammation of the surrounding environment is a major reason causing loss or injury of oligodendrocyte precursor cells (OPCs) in myelin-associated diseases. Lipopolysaccharide-activated microglia can release various inflammatory factors such as tumor necrosis factor-α (TNF-α). One of the ways of OPC death is necroptosis, which can be triggered by TNF-α, a death receptor ligand, by activating receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) signaling pathway. This study investigated whether inhibiting microglia ferroptosis can decrease TNF-α release to alleviate OPC necroptosis.

To plan experiments, a biologist needs to evaluate a growing set of empirical findings and hypothetical assertions from diverse fields that use increasingly complex techniques. To address this problem, we operationalized principles (e.g., convergence and consistency) that biologists use to test causal relations and evaluate experimental evidence. With the framework we derived, we then created a free, open-source web application that allows biologists to create research maps, graph-based representations of empirical evidence and hypothetical assertions found in research articles, reviews, and other sources. With our ResearchMaps web application, biologists can systematically reason through the research that is most important to them, as well as evaluate and plan experiments with a breadth and precision that are unlikely without such a tool.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Promising therapies for PD still need to be explored. Immune dysfunction has been found to be involved in PD pathogenesis. Here, a novel immunosuppressor, (5R)-5-hydroxytriptolide (LLDT8), was used to treat 6-hydroxydopamine (6-OHDA)-induced hemiparkinson rats. We found that oral administration of LLDT8 significantly alleviated apomorphine-induced rotations at a dose of 125 µg/kg, and improved performance in cylinder and rotarod tests at a lower dose of 31.25 µg/kg, in 6-OHDA hemiparkinsonian rats. Moreover, loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the 6-OHDA rat was attenuated in response to LLDT8 treatment in a dose-dependent manner. In addition, inflammatory factors IL-1β, IL-6 and TNF-α, were significantly inhibited in LLDT8-treated hemiparkisonian rats, compared with vehicle. Notably, the level of dopamine (DA) in the striatum of PD rats was restored by LLDT8 treatment. Furthermore, we also detected that the disequilibrium of peripheral lymphocytes was reversed by LLDT8 administration. Taken together, the results imply that the immunosuppressor, LLDT8, can rescue dopaminergic neurodegeneration in 6-OHDA hemiparkinsonian rats, thus providing a potential therapeutic strategy for PD.

Macroautophagy/autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that autophagy is impaired during cerebral ischemia, contributing to neuronal dysfunction and neurodegeneration. However, the outcomes after transient modification in autophagy machinery are not fully understood. This study investigated the effects of ischemic stress on autophagy and synaptic structures using a rat model of oxygen-glucose deprivation (OGD) in hippocampal neurons and a mouse model of middle cerebral artery occlusion (MCAO). Upon acute ischemia, an initial autophagy modification occurred in an upregulation manner. Following, the number of lysosomes increased, as well as lysosomal volume, indicating dysfunctional lysosomal storage. These changes were prevented by inhibiting autophagy via 3-methyladenine (3-MA) treatment or ATG7 (autophagy related 7) knockdown, or were mimicked by rapamycin (RAPA), a known activator of autophagy. This suggests that dysfunctional lysosomal storage is associated with the early burst of autophagy. Dysfunctional lysosomal storage contributed to autophagy dysfunction because the basal level of MTOR-dependent lysosomal biogenesis in the reperfusion was not sufficient to clear undegraded cargoes after transient autophagy upregulation. Further investigation revealed that impairment of synaptic ultra-structures, accompanied by dysfunctional lysosomal storage, may result from a failure in dynamic turnover of synaptic proteins. This indicates a vital role of autophagy-lysosomal machinery in the maintenance of synaptic structures. This study supports previous evidence that dysfunctional lysosomal storage may occur following the upregulation of autophagy in neurons. Appropriate autophagosome-lysosomal functioning is vital for maintenance of neuronal synaptic function and impacts more than the few known synaptic proteins.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALR: autophagic lysosome reformation; ATG7: autophagy related 7; CTSB: cathepsin B; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HPCA: hippocalcin; i.c.v: intracerebroventricular; KEGG: kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; LSDs: lysosomal storage disorders; MAP2: microtubule-associated protein 2; MCAO: middle cerebral artery occlusion; mCTSB: mature CTSB; mCTSD: mature CTSD; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; OGD/R: oxygen-glucose deprivation/reoxygenation; PBS: phosphate-buffered saline; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; proCTSD: pro-cathepsin D; RAPA: rapamycin; RNA-seq: RNA sequencing; RPS6KB/p70S6K: ribosomal protein S6 kinase; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SIM: Structured Illumination Microscopy; SNAP25: synaptosomal-associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYT1: synaptotagmin I; TBST: tris-buffered saline Tween-20; TEM: transmission electron microscopy; TFEB: transcription factor EB; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; TUBB3: tubulin, beta 3 class III.

Lipotoxicity contributes to diabetic myocardial disease. In this study, we investigated the lipid species contributing to lipotoxicity and the relationship with peroxisomal β-oxidation in the heart of diabetic mice.

Background: Poststroke cognitive impairments are common in stroke survivors, and pose a high risk of incident dementia. However, the cause of these cognitive impairments is obscure and required an investigation. Methods: Oxygen-glucose deprivation (OGD) model and middle cerebral artery occlusion (MCAO) model were used to imitate in vitro or in vivo acute cerebral ischemia, respectively. The differentially expressed synaptosome associated protein 29 (SNAP29)-interacting proteins upon ischemia and reperfusion were analyzed with bioinformatics analysis and the results indicated that the changes of SNAP29 after acute ischemia were mainly involved in the synaptic functions. The outcomes of SNAP29 reduction were assessed with SNAP29 knockdown, which mimicked the distribution of SNAP29 along neuronal processes after acute ischemia. Using the whole-cell patch clamp recording method and transmission electron microscope, the pre-synaptic function and readily releasable pool (RRP) were observed after SNAP29 knock down. Using photogenetic manipulations and behavioral tests, the neuronal projection and cognitive functions of mice with SNAP29 knock down in hippocampus CA1 region were evaluated. Results: It was found that SNAP29 protein levels decreased in both in vitro and in vivo ischemic models. Further, the SNAP29 reduction wasn't associated with impaired autophagy flux and neuronal survival. When SNAP29 was knocked down in primary cortical neurons, the frequency of AMPARs-mediated mEPSCs, but not the amplitude, significantly decreased. Meanwhile, the mice with SNAP29 knockdown at CA1 region of hippocampus developed an impairment in hippocampus-mPFC (middle prefrontal cortex) circuit and behavioral dysfunctions. Moreover, the size of RRP at presynaptic sites was diminished. Conclusion: Since SNAP29 protein levels didn't significantly influence the neuronal survival and its decrease was sufficient to disturb the neural circuit via a presynaptic manner, the SNAP29-associated strategies may be an efficient target against poststroke synaptic dysfunction and cognitive deficits.