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Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (αSyn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced αSyn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated αSyn-associated pathological processes in PLP-hαSyn transgenic mice (PLP-αSyn mice), a wildly used MSA mouse model with overexpressing αSyn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-αSyn mice were orally administered MF6 (0.1, 1 mg ·kg-1 ·d-1) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced αSyn aggregation levels in both cerebellum and basal ganglia of PLP-αSyn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and αSyn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced αSyn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting αSyn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.
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Atrofia de Múltiples Sistemas , Ratones , Animales , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Atrofia de Múltiples Sistemas/metabolismo , Atrofia de Múltiples Sistemas/patología , alfa-Sinucleína/metabolismo , Proteína de Unión a los Ácidos Grasos 7/metabolismo , Ratones Transgénicos , Oligodendroglía/metabolismo , Cerebelo/metabolismo , Cerebelo/patología , Modelos Animales de EnfermedadRESUMEN
In the context of building Child-Friendly Cities in China, child-friendly school environments are considered as having a profound impact on children's development and growth. This study presents the development and validation of the Child-Friendly School Environment Questionnaire for assessing a child-friendly school environment. Utilizing open-ended questions and interviews, an initial questionnaire on the child-friendly school environment was compiled. An exploratory factor analysis of the preliminary test results with 696 primary school children in grades three to six was conducted to refine the questionnaire into a formal 19-item questionnaire. Subsequently, a confirmatory factor analysis was performed to analyze the evaluation results of 807 primary school children in grades three to six. The results indicated that a child-friendly school environment is a multi-dimensional construct encompassing Environment Friendly, Teaching Friendly, Peer Friendly, and Children Participation, with good reliability and validity. The promising outcomes of this study suggest that the Child-Friendly School Environment Questionnaire can be widely used as a powerful evaluation tool for the child-friendly school education practice in the future.
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Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.
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Dolor Crónico , Habénula , Ratones , Animales , Depresión/metabolismo , Neuronas/metabolismo , Habénula/fisiología , Núcleos TalámicosRESUMEN
Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRNâDAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN â DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN â DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN â DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN â DAVTA â D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.
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Dolor Crónico , Neuralgia , Humanos , Área Tegmental Ventral , Núcleo Dorsal del Rafe , Anhedonia , Neuronas Dopaminérgicas , Ácido GlutámicoRESUMEN
Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.
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Habénula , Ratones , Animales , Histamina , Emociones , Sensación , PruritoRESUMEN
Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) and myelin disruption. However, the mechanism underlying αSyn accumulation in MSA brains remains unclear. Here, we aimed to identify epsin-2 as a potential regulator of αSyn propagation in MSA brains. In the MSA mouse model, PLP-hαSyn mice, and FABP7/αSyn hetero-aggregate-injected mice, we initially discovered that fatty acid-binding protein 7 (FABP7) is related to MSA development and forms hetero-aggregates with αSyn, which exhibit stronger toxicity than αSyn aggregates. Moreover, the injected FABP7/αSyn hetero-aggregates in mice selectively accumulated only in oligodendrocytes and Purkinje neurons, causing cerebellar dysfunction. Furthermore, bioinformatic analyses of whole blood from MSA patients and FABP7 knockdown mice revealed that epsin-2, a protein expressed in both oligodendrocytes and Purkinje cells, could potentially regulate FABP7/αSyn hetero-aggregate propagation via clathrin-dependent endocytosis. Lastly, adeno-associated virus type 5-dependent epsin-2 knockdown mice exhibited decreased levels of αSyn aggregate accumulation in Purkinje neurons and oligodendrocytes, as well as improved myelin levels and Purkinje neuron function in the cerebellum and motor performance. These findings suggest that epsin-2 plays a significant role in αSyn accumulation in MSA, and we propose epsin-2 as a novel therapeutic target for MSA.
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Atrofia de Múltiples Sistemas , Ratones , Animales , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteína de Unión a los Ácidos Grasos 7/metabolismo , Ratones Transgénicos , Oligodendroglía/metabolismo , Encéfalo/metabolismoRESUMEN
We previously demonstrated that fatty acid-binding protein 3 null (FABP3-/-) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Nicotina , Ratones , Animales , Nicotina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Núcleo Accumbens/metabolismo , Transducción de Señal , Ratones Noqueados , Proteína 3 de Unión a Ácidos Grasos/metabolismoRESUMEN
AIMS: We previously found that a decoy peptide derived from the C-terminal sequence of α-Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid-binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn-derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)-injected mouse model of Parkinson's disease (PD). METHODS: Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2-week intervals post-injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co-immunoprecipitation. RESULTS: αSyn PFF-injected mice showed significant memory loss but no motor function impairment. Long-term nasal treatment with peptides effectively prevented memory impairment. In peptide-treated αSyn PFF-injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn-FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3. CONCLUSIONS: Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn-FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.
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Enfermedad de Parkinson , alfa-Sinucleína , Ratones , Animales , alfa-Sinucleína/metabolismo , Neuronas/metabolismo , Encéfalo/metabolismo , Amnesia/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Trastornos de la Memoria/metabolismoRESUMEN
We have previously shown that a fatty acid-binding protein7 (FABP7) inhibitor ameliorates cerebral ischemia-reperfusion injury in mice, suggesting an association between FABPs and ischemic neuronal injury. However, the precise role of FABPs in ischemic neuronal injury remains unclear. In this study, we investigated the role of FABPs in ischemia-reperfusion neuronal injury. FABP3, FABP5, and FABP7 were upregulated in the ischemic penumbra regions in mice. However, only FABP3 and FABP5 were expressed in injured neurons. Furthermore, FABP3 and FABP5 accumulated in the mitochondria of ischemic neurons. Overexpressing either FABP3 or FABP5 aggravated the reduced mitochondrial membrane potential and induced cell death in human neuroblastoma SH-SY5Y cells during oxidative stress. This damage was mediated by the formation of BAX-containing pores in the mitochondrial membrane. Moreover, FABP5 mediates lipid peroxidation and generates toxic by-products (i.e., 4-HNE) in SH-SY5Y cells. HY11-08 (HY08), a novel FABP3 and 5 inhibitor that does not act on FABP7, significantly reduced cerebral infarct volume and blocked FABP3/5-induced mitochondrial damage, including lipid peroxidation and BAX-related apoptotic signaling. Thus, FABP3 and FABP5 are key players in triggering mitochondrial damage in ischemic neurons. In addition, the novel FABP inhibitor, HY08, may be a potential neuroprotective treatment for ischemic stroke.
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Neuroblastoma , Daño por Reperfusión , Animales , Humanos , Ratones , Proteína X Asociada a bcl-2/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Isquemia/metabolismo , Neuroblastoma/metabolismo , Neuronas/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Neonatal hypoxic-ischemic encephalopathy (HIE) refers to nervous system damage caused by perinatal hypoxia, which is the major cause of long-term neuro-developmental disorders in surviving infants. However, the mechanisms still require further investigation. In this study, we found that the butanoate metabolism pathway exhibited significantly decreased and short chain fatty acid (SCFAs)-producing bacteria, especially butyrate-producing bacteria, were significantly decreased in fecal of neonatal hypoxic-ischemic brain damage (HIBD) rats. Surprisingly, Sodium butyrate (SB) treatment could ameliorate pathological damage both in the cerebral cortex and hippocampus and facilitate recovery of SCFAs-producing bacteria related to metabolic pathways in neonatal HIBD rats. Moreover, we found that in samples from SB treatment neonatal HIBD rats cortex with high levels of butyrate acid along with aberrant key crotonyl-CoA-producing enzymes ACADS levels were observed compared HIBD rats. We also demonstrated that a decrease in histone 3-lysine 9-crotonylation (H3K9cr) downregulated expression of the HIE-related neurotrophic genes Bdnf, Gdnf, Cdnf, and Manf in HIBD rats. Furthermore, SB restored H3K9cr binding to HIE-related neurotrophic genes. Collectively, our results indicate that SB contributes to ameliorate pathology of HIBD by altering gut microbiota and brain SCFAs levels subsequently affecting histone crotonylation-mediated neurotrophic-related genes expression. This may be a novel microbiological approach for preventing and treating HIE.
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Stroke is among the leading causes of death and disability worldwide. However, despite long-term research yielding numerous candidate neuroprotective drugs, there remains a lack of effective neuroprotective therapies for ischemic stroke patients. Among the factors contributing to this deficiency could be that single-target therapy is insufficient in addressing the complex and extensive mechanistic basis of ischemic brain injury. In this context, lipids serve as an essential component of multiple biological processes and play important roles in the pathogenesis of numerous common neurological diseases. Moreover, in recent years, fatty acid-binding proteins (FABPs), a family of lipid chaperone proteins, have been discovered to be involved in the onset or development of several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. However, comparatively little attention has focused on the roles played by FABPs in ischemic stroke. We have recently demonstrated that neural tissue-associated FABPs are involved in the pathological mechanism of ischemic brain injury in mice. Here, we review the literature published in the past decade that has reported on the associations between FABPs and ischemia and summarize the relevant regulatory mechanisms of FABPs implicated in ischemic injury. We also propose candidate FABPs that could serve as potential therapeutic targets for ischemic stroke.
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Lesiones Encefálicas , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Encéfalo/metabolismo , Lesiones Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Ratones , Accidente Cerebrovascular/metabolismoRESUMEN
Effects of vitamin C supplementation on the oral bioaccessibility of lead (Pb) present in contaminated soils were examined using a number of in vitro assays (PBET, SBRC, UBM and IVG). In the presence of vitamin C, an increase in Pb bioaccessibility was observed in the gastric phase by 1.3-fold (30.5%-85.5%) and in the intestinal phase by 3.1-fold (0.9%-58.9%). Lead mobilization was regulated by reductive dissolution of Fe(III) and sequestration of Pb on secondary Fe minerals. Sequential extraction by the Bureau Community of Reference (BCR) provided more evidence that reducible fraction and residual fraction were major contributor of gastric Pb bioaccessibility, as well as reduced fractions in intestinal Pb bioaccessibility. In addition, higher non-carcinogenic risks may occur based on target hazard quotient (THQ ≥ 1). For people exposed to Pb present in soil, the management of vitamin C supplements is of serious concern.
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Contaminantes del Suelo , Ácido Ascórbico , Disponibilidad Biológica , Suplementos Dietéticos , Compuestos Férricos , Humanos , Plomo/toxicidad , Suelo , Contaminantes del Suelo/análisisRESUMEN
BACKGROUND: Few studies have investigated the differences in clinical features of patients with mastitis following Corynebacterium kroppenstedtii infection, and most focused on the bacterial antimicrobial susceptibility, detection methods and therapy. METHODOLOGY: There were 133 patients with mastitis infected by C. kroppenstedtii between August 2016 and September 2019. C. kroppenstedtii was identified using mass spectrometry. The demographics, clinical diagnosis, laboratory test results of different types of mastitis combined with bacillus infection, and the effects of different treatments in reducing recurrence were compared. RESULTS: The incidence of pus following C. kroppenstedtii infection was higher in patients with non-granulomatous lobular mastitis (NGLM; 56.6%) than in those with granulomatous lobular mastitis (GLM; 33.3%; χ2 = 7.072, p = 0.008). While C-reactive protein (CRP) was higher in the GLM group (12.50 mg/L) than in the NGLM group (6.05 mg/L; Z = - 2.187, p = 0.029). Treatment with local lavage (triamcinolone acetonide) and antibiotics (cefuroxime) showed a recurrent rate of 25.9% in C. kroppenstedtii infection. CONCLUSION: Increased pus, large masses, and an elevated CRP level may occur in patients with mastitis infected by C.kroppenstedtii. These clinical features may guide the determination of the bacterial infection in patients with mastitis. Combining an antibiotic with a triamcinolone acetonide lavage, preferably cefuroxime, may reduce the recurrence.
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Infecciones por Corynebacterium , Mastitis Granulomatosa , Antibacterianos/uso terapéutico , Cefuroxima/uso terapéutico , Corynebacterium , Infecciones por Corynebacterium/diagnóstico , Infecciones por Corynebacterium/tratamiento farmacológico , Infecciones por Corynebacterium/microbiología , Femenino , Mastitis Granulomatosa/tratamiento farmacológico , Humanos , Supuración/tratamiento farmacológico , Triamcinolona Acetonida/uso terapéuticoRESUMEN
The dorsal anterior cingulate cortex (dACC) plays a critical role in cognitive control over different domains of tasks. The dACC activities uniformly represent task-generic intensities of control signals across different tasks. However, it remains unclear whether the dACC activities could also encode task identities of control signals across different tasks. If so, how the two types of control information are coherently organized in the dACC? Decision uncertainty is an internally-generated control signal by retrospective monitoring, namely, metacognition, even with no external feedback. We here investigated neural representations of decision uncertainty accompanying three decision-making tasks in the domains of perception, rule-based inference, and memory using trial-by-trial univariate and multivariate analyses on functional magnetic resonance imaging (fMRI) data acquired on human male and female healthy subjects. Our results demonstrated that the dACC represented decision uncertainty commonly across the three decision-making tasks. Further, the multivariate fMRI analyses revealed a mosaic form of neural representations of decision uncertainty across tasks in the dACC. The identity and intensity information was separately represented in two dissociable components, the high-dimensional pattern and the scalar magnitude, of the dACC multivoxel fMRI activities. Lastly, a follow-up behavioral experiment confirmed that this mosaic form of neural representations of parallelly existing decision uncertainty across different tasks should lead to mutual interferences more on the intensity, but less on the identity of control signals. Thus, our findings suggest that the dACC with the mosaic form of neural representations could provide task-generic and task-specific metacognitive control signals to guide appropriate control on different decision-making tasks.SIGNIFICANCE STATEMENT Metacognition is a form of cognitive control using internally generated decision uncertainty to guide behavior adjustment with no needs of external feedback. Decision uncertainty as a generalizable control signal is commonly encoded in the human dorsal anterior cingulate cortex (dACC) accompanying different decision-making tasks. It remains unknown whether or not the task-specific control information is represented in the dACC. We here revealed that multivoxel functional magnetic resonance imaging (fMRI) activities associated with decision uncertainty in the dACC concurrently represented the identity and intensity information. The mixtures of neural representations of decision uncertainty across different tasks should cause specific interferences on each other. Hence, the neural representations of control signals in the human dACC should be task-generic and task-specific.
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Toma de Decisiones/fisiología , Giro del Cíngulo/fisiología , Metacognición/fisiología , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
We previously show that fatty acid-binding protein 3 (FABP3) triggers α-synuclein (Syn) accumulation and induces dopamine neuronal cell death in Parkinson disease mouse model. But the role of fatty acid-binding protein 7 (FABP7) in the brain remains unclear. In this study we investigated whether FABP7 was involved in synucleinopathies. We showed that FABP7 was co-localized and formed a complex with Syn in Syn-transfected U251 human glioblastoma cells, and treatment with arachidonic acid (100 M) significantly promoted FABP7-induced Syn aggregation, which was associated with cell death. We demonstrated that synthetic FABP7 ligand 6 displayed a high affinity against FABP7 with Kd value of 209 nM assessed in 8-anilinonaphthalene-1-sulfonic acid (ANS) assay; ligand 6 improved U251 cell survival via disrupting the FABP7-Syn interaction. We showed that activation of phospholipase A2 (PLA2) by psychosine (10 M) triggered oligomerization of endogenous Syn and FABP7, and induced cell death in both KG-1C human oligodendroglia cells and oligodendrocyte precursor cells (OPCs). FABP7 ligand 6 (1 M) significantly decreased Syn oligomerization and aggregation thereby prevented KG-1C and OPC cell death. This study demonstrates that FABP7 triggers α-synuclein oligomerization through oxidative stress, while FABP7 ligand 6 can inhibit FABP7-induced Syn oligomerization and aggregation, thereby rescuing glial cells and oligodendrocytes from cell death.
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Proteína de Unión a los Ácidos Grasos 7/metabolismo , Neuroglía/metabolismo , Oligodendroglía/metabolismo , Estrés Oxidativo/fisiología , alfa-Sinucleína/metabolismo , Animales , Ácido Araquidónico/farmacología , Muerte Celular/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Fosfolipasas A2/efectos de los fármacos , Unión Proteica/fisiología , Psicosina/farmacologíaRESUMEN
BACKGROUND: MicroRNA-101 (miR-101) is a tumor suppressor microRNA (miRNA) and its loss is associated with the occurrence and progression of various diseases. However, the biological function and target of miR-101 in the pathogenesis of hypertrophic scars (HS) remains unknown. METHODS: We harvested HS and paired normal skin (NS) tissue samples from patients and cultured their fibroblasts (HSF and NSF, respectively). We used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assays (ELISA) and Western blot analyses to measure mRNA levels and protein expression of miR-101, enhancer of zeste homolog 2 (EZH2), collagen 1 and 3 (Col1 and Col3) and α-smooth muscle actin (α-SMA) in different in vitro conditions. We also used RNA sequencing to evaluate the relevant signaling pathways and bioinformatics analysis and dual-luciferase reporter assays to predict miR-101 targets. We utilized a bleomycin-induced fibrosis mouse model in which we injected miR-101 mimics to evaluate collagen deposition in vivo. RESULTS: We found low expression of miR-101 in HS and HSF compared to NS and NSF. Overexpressing miR-101 decreased Col1, Col3 and α-SMA expression in HSF. We detected high expression of EZH2 in HS and HSF. Knockdown of EZH2 decreased Col1, Col3 and α-SMA in HSF. Mechanistically, miR-101 targeted the 3'-untranslated region (3'UTR) of EZH2, as indicated by the decreased expression of EZH2. Overexpressing EZH2 rescued miR-101-induced collagen repression. MiR-101 mimics effectively suppressed collagen deposition in the bleomycin-induced fibrosis mouse model. CONCLUSIONS: Our data reveal that miR-101 targets EZH2 in HS collagen production, providing new insight into the pathological mechanisms underlying HS formation.
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BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease characterised by the demyelination of mature oligodendrocytes in the central nervous system. Recently, several studies have indicated the vital roles of fatty acid-binding proteins (FABPs) 5 and 7 in regulating the immune response. METHODS: We assessed a novel FABP5/FABP7 inhibitor, FABP ligand 6 (MF 6), as a potential therapeutic for MS therapy. In vivo, we established MOG35-55-administered experimental autoimmune encephalomyelitis (EAE) mice as an MS mouse model, followed by prophylactic and symptomatic treatment with MF 6. The therapeutic effect of MF 6 was determined using behavioural and biochemical analyses. In vitro, MF 6 effects on astrocytes and oligodendrocytes were examined using both astrocyte primary culture and KG-1C cell lines. FINDINGS: Prophylactic and symptomatic MF 6 therapy reduced myelin loss and clinical EAE symptoms. Furthermore, oxidative stress levels and GFAP-positive and ionised calcium-binding adaptor protein-1-positive cells were reduced in the spinal cord of MF 6-treated mice. In addition, MF 6 attenuated lipopolysaccharide-stimulated interleukin-1ß and tumour necrosis factor-α accumulation in primary astrocyte culture. Moreover, MF 6 indicated a powerful protective function for the mitochondria in the oligodendrocytes of EAE mice via FABP5 inhibition. INTERPRETATIONS: MF 6 is a potent inhibitor of FABP5 and FABP7; targeted inhibition of the two proteins may confer potential therapeutic effects in MS via immune inhibition and oligodendrocyte protection. FUNDING: This work was supported by the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071).
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Proteína de Unión a los Ácidos Grasos 7/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismo , Esclerosis Múltiple/metabolismo , Proteínas de Neoplasias/metabolismo , Oligodendroglía/metabolismo , Animales , Astrocitos/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Synucleinopathies are diverse diseases with motor and cognitive dysfunction due to progressive neuronal loss or demyelination, due to oligodendrocyte loss in the brain. While the etiology of neurodegenerative disorders (NDDs) is likely multifactorial, mitochondrial injury is one of the most vital factors in neuronal loss and oligodendrocyte dysfunction, especially in Parkinson's disease, dementia with Lewy body, multiple system atrophy, and Krabbe disease. In recent years, the abnormal accumulation of highly neurotoxic α-synuclein in the mitochondrial membrane, which leads to mitochondrial dysfunction, was well studied. Furthermore, fatty acid-binding proteins (FABPs), which are members of a superfamily and are essential in fatty acid trafficking, were reported to trigger α-synuclein oligomerization in neurons and glial cells and to target the mitochondrial outer membrane, thereby causing mitochondrial loss. Here, we provide an updated overview of recent findings on FABP and α-synuclein interactions and mitochondrial injury in NDDs.
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INTRODUCTION: Spleen deficiency syndrome (SDS), a common clinical syndrome of traditional Chinese medicine, is manifested with digestive symptoms and cognitive impairments. However, the cognitive neural mechanism in brain networks of SDS still remained unclear. Our aim was to investigate the changes between the default mode, dorsal attention, and frontoparietal networks in SDS. METHODS: Twenty nonorganic gastrointestinal disorder (NOGD) patients with SDS and eighteen healthy controls were enrolled to attend functional magnetic resonance imaging scan and participated a continuous performance test (CPT) before scanning. RESULTS: Compared with healthy controls, NOGD patients with SDS showed the significantly increased functional connectivity (FC) between dorsal attention network (DAN) and left frontal-parietal control network (LFPN) and significantly decreased FC between LFPN and default mode network (DMN). The functional network connectivity analysis showed positive correlation coefficients between the DAN and LFPN and DAN and DMN as well as negative correlation between LFPN and DMN in NOGD patients with SDS compared with healthy controls. Correlation analysis revealed that the increased FC between LFPN and DAN was positively correlated with 4-digitnumber reaction time mean (RTM) and 3-digitnumber RTM. CONCLUSION: Our study may provide novel insights into the relationship among the DMN, DAN, and FPN in NOGD patients with SDS to deepen our understanding of the neuropsychological mechanisms of SDS.