Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation.

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.

Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model.

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.

Task-Specific Neural Representations of Generalizable Metacognitive Control Signals in the Human Dorsal Anterior Cingulate Cortex.

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.

Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor.

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.

Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress.

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.

Clinical features and recurrence of Corynebacterium kroppenstedtii infection in patients with mastitis.

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.

Effect of vitamin C supplement on lead bioaccessibility in contaminated soils using multiple in vitro gastrointestinal assays: Mechanisms and health risks.

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.

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets.

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.

The Role of CaMKII and ERK Signaling in Addiction.

Nicotine is the predominant addictive compound of tobacco and causes the acquisition of dependence through its interactions with nicotinic acetylcholine receptors and various neurotransmitter releases in the central nervous system. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) play a pivotal role in synaptic plasticity in the hippocampus. CaMKII is involved in long-term potentiation induction, which underlies the consolidation of learning and memory; however, the roles of CaMKII in nicotine and other psychostimulant-induced addiction still require further investigation. This article reviews the molecular mechanisms and crucial roles of CaMKII and ERK in nicotine and other stimulant drug-induced addiction. We also discuss dopamine (DA) receptor signaling involved in nicotine-induced addiction in the brain reward circuitry. In the last section, we introduce the association of polyunsaturated fatty acids and cellular chaperones of fatty acid-binding protein 3 in the context of nicotine-induced addiction in the mouse nucleus accumbens and provide a novel target for the treatment of drug abuse affecting dopaminergic systems.

Disruptions of frontoparietal control network and default mode network linking the metacognitive deficits with clinical symptoms in schizophrenia.

The metacognitive deficit in awareness of one's own mental states is a core feature of schizophrenia (SZ). The previous studies suggested that the metacognitive deficit associates with clinical symptoms. However, the neural mechanisms underlying the relationship remain largely unknown. We here investigated the neural activities associated with the metacognitive deficit and the neural signatures associated with clinical symptoms in 38 patients with SZ using functional magnetic resonance imaging with a perceptual decision-making task accompanied with metacognition, in comparison to 38 age, gender, and education matched healthy control subjects. The metacognitive deficit in patients with SZ was associated with reduced regional activity in both the frontoparietal control network (FPCN) and the default mode network. Critically, the anticorrelational balance between the two disrupted networks was substantially altered during metacognition, and the extent of alteration positively scaled with negative symptoms. Conversely, decoupling between the two networks was impaired when metacognitive monitoring was not required, and the strength of excessive neural activity positively scaled with positive symptoms. Thus, disruptions of the FPCN and the default mode network underlie the metacognitive deficit, and alternations of network balance between the two networks correlate with clinical symptoms in SZ. These findings implicate that rebalancing these networks holds important clinical potential in developing more efficacious therapeutic treatments.

MCPIP1 regulates RORα expression to protect against liver injury induced by lipopolysaccharide via modulation of miR-155.

Liver injury plays vital roles in the development of inflammation and organ dysfunction during sepsis. MCP-1-induced protein 1 (MCPIP1), as an endoribonuclease, is a critical regulator for the maintenance of immune homeostasis. However, whether MCPIP1 participates in the septic liver injury remains unknown. The aim of this study was to investigate the role of MCPIP1 in lipopolysaccharides-induced liver injury and the underlying modulatory mechanisms. Quantitative real-time polymerase chain reaction and immunoblotting were used to determine proinflammatory cytokines, MCPIP1, retinoid-related orphan receptor α (RORα), miR-155, and related protein from nuclear factor-κB (NF-κB) pathway expression. Dual luciferase reporter assay was used to analyze whether miR-155 regulates RORα transcription. Secretion of inflammatory cytokines into sera in mice were measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, alanine aminotransferase, and aspartate transaminase, assay were used to evaluate liver function. We found that MCPIP1 expression was notably upregulated and significantly downregulated inflammatory cytokine secretion and NF-κB signaling activation in macrophages following exposure to lipopolysaccharide. Moreover, miR-155, lowered by MCPIP1, directly targeted on 3'-untranslated region of RORα to activate an inflammatory response. Importantly, MCPIP1 overexpression in mice alleviated septic liver injury symptoms following lipopolysaccharides stimulation. Collectively, these data highlight MCPIP1/miR-155/RORα axis as a novel modulation of inflammation in liver injury and potential therapeutic target for future research.

Microalgal Oil from Schizochytrium sp. Prevents HFD-Induced Abdominal Fat Accumulation in Mice.

OBJECTIVE: Dietary n-3 polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acids (EPA) and docosahexaenoic acid (DHA), are proved to be effective in obesity reduction. Microalgal oil (MO) is an important alternative source of n-3 PUFAs that effectively alleviates obesity. The aim of the present study was to explore the anti-obesity effects of microalgal oil from Schizochytrium sp. (SMO) and to compare the effects of 2 SMOs (SMO1 and SMO2) with different levels of purity of n-3 PUFAs on high fat diet (HFD)-induced obesity in male C57BL/6J mice. METHODS: Mice were randomly divided into 5 groups: (1) regular chow (RC); (2) HFD; (3) HFD + fish oil (FO); (4) HFD + SMO1; and (5) HFD + SMO2. Body weight and food intake were weekly monitored. After 16 weeks of treatment, a glucose tolerance test (GTT) and an insulin tolerance test (ITT) were performed. Serum lipid profile, morphological changes in the liver and epididymal white adipose tissue (eWAT), and the mRNA expression of lipid metabolism-related genes were also examined. RESULTS: SMO treatment significantly decreased HFD-induced abdominal fat accumulation, lowered the levels of triglycerides, cholesterol, and low-density lipoprotein, as did the positive control treated with FO. Morphological examination revealed a remarkable reduction in lipid droplet formation in the liver tissue and the particle size of eWAT. An alleviation of inflammation infiltration in eWAT caused by a high-fat diet was also observed. Real-time reverse transcription-polymerase chain reaction analysis examination confirmed that microalgal oil inhibited the gene expression of fatty acid synthase, sterol responsive element-binding protein-1c, and acetyl-CoA carboxylase but promoted that of hormone-sensitive lipase and lipoprotein lipase, carnitine palmitoyltransferase-1, and uncoupling proteins in the liver and eWAT. Moreover, similar anti-obesity effects were obtained with the same dosage but different purity of n-3 PUFAs. CONCLUSIONS: As an alternative n-3 PUFAs resource, dietary intake of SMO might be beneficial to prevent HFD-induced abdominal fat accumulation.

Disruption of cortical integration during midazolam-induced light sedation.

This work examines the effect of midazolam-induced light sedation on intrinsic functional connectivity of human brain, using a randomized, double-blind, placebo-controlled, cross-over, within-subject design. Fourteen healthy young subjects were enrolled and midazolam (0.03 mg/kg of the participant's body mass, to a maximum of 2.5 mg) or saline were administrated with an interval of one week. Resting-state fMRI was conducted before and after administration for each subject. We focus on two types of networks: sensory related lower-level functional networks and higher-order functions related ones. Independent component analysis (ICA) was used to identify these resting-state functional networks. We hypothesize that the sensory (visual, auditory, and sensorimotor) related networks will be intact under midazolam-induced light sedation while the higher-order (default mode, executive control, salience networks, etc.) networks will be functionally disconnected. It was found that the functional integrity of the lower-level networks was maintained, while that of the higher-level networks was significantly disrupted by light sedation. The within-network connectivity of the two types of networks was differently affected in terms of direction and extent. These findings provide direct evidence that higher-order cognitive functions including memory, attention, executive function, and language were impaired prior to lower-level sensory responses during sedation. Our result also lends support to the information integration model of consciousness.

Acute downregulation of miR-155 at wound sites leads to a reduced fibrosis through attenuating inflammatory response.

Fibrosis, tightly associated with wound healing, is a significant symptomatic clinical problem. Inflammatory response was reported to be one of the reasons. MiR-155 is relatively related with the development and requirement of inflammatory cells, so we thought reduce the expression of miR-155 in wound sites could improve the quality of healing through reduce inflammatory response. To test this hypothesis, locally antagonizing miR-155 by directly injecting antagomir to wound edge was used to reduce the expression of miR-155. We found wounds treated with miR-155 antagomir had an obvious defect in immune cells requirements, pro-inflammatory factors IL-1ß and TNF-α reduced while anti-inflammatory factor IL-10 increased. With treatment of miR-155 antagomir, the expression of α-smooth muscle actin (α-SMA), Col1 and Col3 at wound sites all reduced both from mRNA levels and protein expressions. Wounds injected with antagomir resulted in the structure improvement of collagen, the collagen fibers were more regularly arranged. Meanwhile the rate of healing did not change significantly. These results provide direct evidences that miR-155 play an important role in the pathogenesis of fibrosis and show that miR-155 antagomir has the potential therapy in prevention and reduction of skin fibrosis.

Barbital-derived chelating ligands for interface regulation and stabilization of Zn metal anodes for aqueous zinc-ion batteries.

Aqueous zinc-ion batteries (AZIBs) have inherent merits, such as a low price, good safety and high volumetric capacity, and have promising potential for widespread applications. However, the unexpected issues posed by both water-induced side reactions and the uncontrollable growth of zinc dendrites on the zinc anode-electrolyte interface have significantly hindered the widespread application of AZIBs. In this work, barbital (Bb), which has two amide groups, was introduced into a ZnSO4 electrolyte to create a Bb@ZnSO4 electrolyte. The hydrolysis of the amide groups resulted in the formation of strong polar groups (carboxyl and amino), which could efficiently anchor zinc ions. Specifically, through the derivation of Bb, it was possible to adjust the Zn2+ solvation structure, decreasing the coordinated active SO42-/H2O and promoting the anchoring of these species on the surface of the zinc anode. This process provided electrostatic shielding and isolates the SO42-/H2O, demonstrating an interface regulating effect and synergistic solvation. Therefore, Bb could mitigate electrochemical corrosion and facilitate dendrite-free homogeneous zinc deposition. As a consequence, the assembled asymmetric Zn∥V2O5 full cell utilizing the Bb@ZnSO4 electrolyte showed highest specific capacities of 294.9 and 92.7 mA h g-1 at 0.1 and 1 A g-1, much higher than the Zn∥V2O5 full cell with the ZnSO4 electrolyte, which delivered specific capacities of 161.1 and 3.0 mA h g-1 at the same current densities. These findings promise to realize the practical application of Bb as an efficient additive in high-performance AZIBs.

Effect of Different Slow-Release Urea on the Production Performance, Rumen Fermentation, and Blood Parameter of Angus Heifer.

This study investigated the effect of replacing part of the dietary soybean meal with either polymer-coated urea or gelatinized starch urea on the production performance, blood indexes, and ruminal fermentation of Angus heifers. A total of 210 purebred Angus cattle (BW = 314.26 kg) were divided into three groups: the no urea group (CON), the polymer-coated urea group (PCU), and the gelatinized starch urea group (GSU); 20 g/kg polymer-coated urea or 25 g/kg gelatinized starch urea was used to replace part of soybean meal in the concentrate feed, according to the principle of isometabolic energy and isonitrogenous. The result showed that the PCU group had higher ADG and ADF apparent digestibility, while it had a lower feed-weight ratio. On the 86th day, the serum albumin (ALB) content in the PCU group was significantly higher than that in the CON group. In rumen, compared with the CON group, the contents of acetic acid and total volatile fatty acid were significantly higher in the PCU group, whereas butyric acid and propionic acid were significantly higher in the PCU group and GSU group. Ruminal bacterial diversity analysis found that the abundance of Firmicutes was higher in the PCU group at the phylum level, and an inverse result was observed in Bacteroidetes. The abundance of Paraprevotella was higher in the PCU group, whereas higher abundance of Prevotella was found in the GSU group at the genus level. These results indicate that slow-release urea can replace part of soybean meal in the diet, and the amount of substitution in this trial had no diverse effect on the performance of Angus heifers.

Development and validation of Child-Friendly School Environment Questionnaire from Chinese culture.

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.

Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons.

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.

α-Synuclein decoy peptide protects mice against α-synuclein-induced memory loss.

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.

The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain.

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.