[Screening of place cell and analysis of its influencing factors for pigeons].

Place cell with location tuning characteristics play an important role in brain spatial cognition and navigation, but there is relatively little research on place cell screening and its influencing factors. Taking pigeons as model animals, the screening process of pigeon place cell was given by using the spike signal in pigeon hippocampus under free activity. The effects of grid number and filter kernel size on the place field of place cells during the screening process were analyzed. The results from the real and simulation data showed that the proposed place cell screening method presented in this study could effectively screen out place cell, and the research found that the size of place field was basically inversely proportional to the number of grids divided, and was basically proportional to the size of Gaussian filter kernel in the overall trend. This result will not only help to determine the appropriate parameters in the place cell screening process, but also promote the research on the neural mechanism of spatial cognition and navigation of birds such as pigeons.

The effects of microgravity on stem cells and the new insights it brings to tissue engineering and regenerative medicine.

Conventional two-dimensional (2D) cell culture techniques may undergo modifications in the future, as life scientists have widely acknowledged the ability of three-dimensional (3D) in vitro culture systems to accurately simulate in vivo biology. In recent years, researchers have discovered that microgravity devices can address many challenges associated with 3D cell culture. Stem cells, being pluripotent cells, are regarded as a promising resource for regenerative medicine. Recent studies have demonstrated that 3D culture in microgravity devices can effectively guide stem cells towards differentiation and facilitate the formation of functional tissue, thereby exhibiting advantages within the field of tissue engineering and regenerative medicine. Furthermore, We delineate the impact of microgravity on the biological behavior of various types of stem cells, while elucidating the underlying mechanisms governing these alterations. These findings offer exciting prospects for diverse applications.

Simulated microgravity altered the gene expression profiles and inhibited the proliferation of Kupffer cells in the early phase by downregulating LMO2 and EZH2.

Microgravity is a primary challenge that need to overcome, when human travel to space. Our study provided evidence that Kupffer cells (KCs) are sensitive to simulated microgravity (SMG), and no similar research report has been found in the literature. Using transcriptome sequencing technology, it was showed that 631 genes were upregulated and 801 genes were downregulated in KCs after treatment under SMG for 3 days. The GO analysis indicated that the proliferation of KCs was affected when exposed to SMG for 3 days. CCK-8 assay confirmed that the proliferation of KCs was inhibited in the third day under the environment of SMG. Furthermore, we identified 8 key genes that affect the proliferation of KCs and predicted 2 transcription factors (TFs) that regulate the 8 key genes. Significantly, we found that microgravity could affect the expression of LMO2 and EZH2 to reduce the transcription of Racgap1, Ccna2, Nek2, Aurka, Plk1, Haus4, Cdc20, Bub1b, which resulting in the reduction in KCs proliferation. These finding suggested that the inhibition of KCs proliferation under microgravity may influence the homeostasis of liver, and LMO2 and EZH2 can be the targets in management of KCs' disturbance in the future practice of space medicine.

GRP94 in cerebrospinal fluid may contribute to a potential biomarker of depression: Based on proteomics.

The present study was designed to investigate potential biomarkers of depression and targets of antidepressants from the perspective of hippocampal endoplasmic reticulum stress (ERS) based on cerebrospinal fluid (CSF) proteomics. Firstly, a six-week depression model was established and treated with fluoxetine (FLX). We found antidepressant-FLX could ameliorate depression-like behaviors and cognition in depressed rats caused by chronic unpredictable mild stress (CUMS). FLX significantly increased neuronal numbers in dentate gyrus (DG) and CA3 regions of hippocampus. CSF proteome data revealed thirty-seven differentially expressed proteins (DEPs) co-regulated by CUMS and FLX, including GRP94 and EIF2α. Results of Gene Oncology (GO) annotation and KEGG pathway enrichment for DEPs mainly included PERK-mediated unfolded protein response, endoplasmic reticulum, and translational initiation. The expression levels of GRP94, p-PERK, p-EIF2α, CHOP and Caspase-12 were increased in hippocampus of CUMS rats, and FLX worked the opposite way. FLX had strong affinity and binding activity with GRP94 protein, and four key proteins on the PERK pathway (PERK, EIF2α, p-EIF2α, CHOP). We proposed that FLX may exert antidepressant effects and neuroprotective action by alleviating excessive activation of the hippocampal PERK pathway and reducing neuronal deficits in depressed rats. PERK, EIF2α, p-EIF2α, and CHOP may be potential targets for antidepressant-FLX. GRP94 in CSF may be a potential biomarker of depression and the therapeutic effects of antidepressants.

Luteolin alleviates depression-like behavior by modulating glycerophospholipid metabolism in the hippocampus and prefrontal cortex of LOD rats.

BACKGROUND: Late-onset depression (LOD) is defined as primary depression that first manifests after the age of 65. Luteolin (LUT) is a natural flavonoid that has shown promising antidepressant effects and improvement in neurological function in previous studies. AIMS: In this study, we utilized UPLC-MS/MS non-targeted metabolomics techniques, along with molecular docking technology and experimental validation, to explore the mechanism of LUT in treating LOD from a metabolomics perspective. RESULTS: The behavioral results of our study demonstrate that LUT significantly ameliorated anxiety and depression-like behaviors while enhancing cognitive function in LOD rats. Metabolomic analysis revealed that the effects of LUT on LOD rats were primarily mediated through the glycerophospholipid metabolic pathway in the hippocampus and prefrontal cortex. The levels of key lipid metabolites, phosphatidylserine (PS), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), in the glycerophospholipid metabolic pathway were significantly altered by LUT treatment, with PC and PE showing significant correlations with behavioral indices. Molecular docking analysis indicated that LUT had strong binding activity with phosphatidylserine synthase 1 (PTDSS1), phosphatidylserine synthase 2 (PTDSS2), and phosphatidylserine decarboxylase (PISD), which are involved in the transformation and synthesis of PC, PE, and PS. Lastly, our study explored the reasons for the opposing trends of PC, PE, and PS in the hippocampus and prefrontal cortex from the perspective of autophagy, which may be attributable to the bidirectional regulation of autophagy in distinct brain regions. CONCLUSIONS: Our results revealed significant alterations in the glycerophospholipid metabolism pathways in both the hippocampus and prefrontal cortex of LOD rats. Moreover, LUT appears to regulate autophagy disorders by specifically modulating glycerophospholipid metabolism in different brain regions of LOD rats, consequently alleviating depression-like behavior in these animals.

Multi-channel data transmission through a multimode fiber based on OAM phase encoding.

Data transmission based on the transmission matrix method has realized the multiplexing of a large number of orbital angular momentum (OAM) modes under scattering, which encodes the data by modulating the amplitude of the OAM modes. However, this amplitude modulation (amplitude encoding) method has obvious cross talk when the number of output modes is small, resulting in a non-negligible bit error rate. Here, a multi-channel data transmission method based on OAM phase modulation (phase encoding) under scattering is proposed. This method can resist the multiple-scattering effect of multimode fibers and realize accurate data transmission with very few rows of camera pixels for output mode measurement, which is suitable for high-speed data transmission under scattering. Experimentally, we have achieved a bit error rate of less than 0.005% in the data transmission of a color image through a 60 m multimode fiber with only 2 rows of camera pixels for output mode measurement. Experiments also showed that the proposed method has a higher stability than amplitude encoding when the proportion of "1" or "0" in the code changes.

Constructing ROS-Responsive Supramolecular Gel with Innate Antibacterial Properties.

Bacterial infections, especially antibiotic-resistant bacterial infections, pose a significant threat to human health. Supramolecular gel with innate antibacterial properties is an advanced material for the treatment of bacterial infections, which have attracted great attention. Herein, a reactive oxygen species (ROS)-responsive innate antibacterial supramolecular gel is developed by a bottom-up approach based on phenylalanine and hydrazide with innate antibacterial properties. The structure of gelators and intermediate products was characterized by proton nuclear magnetic resonance (1H NMR) and a high-resolution mass spectrum (HRMS). The results of 1H NMR and the Fourier transform infrared spectrum (FT-IR) experiment disclosed that hydrogen bonding and the π-π stacking force are the important self-assembly driving forces of gelators. The microstructure and mechanical properties of gel were studied by Scanning electron microscope (SEM) and Rheometer, respectively. An in vitro degradation experiment proved that the gelator has ROS-responsive degradation properties. The in vitro drug release experiment further manifested that antibiotic-loaded gel has ROS-responsive drug-release performances. An in vitro cytotoxicity experiment showed that the supramolecular gel has good biocompatibility and could promote cell proliferation. The in vitro antibacterial experiment proved that the supramolecular gel has excellent inherent antibacterial properties, and the antibacterial rate against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was 98.6% and 99.1%, respectively. The ROS-responsive supramolecular gel as a novel antibacterial agent has great application prospects in treating antibiotic-resistant bacterial-infected wounds and preventing the development of bacterial resistance.

Simulated microgravity altered the proliferation, apoptosis, and extracellular matrix formation of L929 fibroblasts and the transforming growth factor-ß1/Smad3 signaling pathway.

Exposure to microgravity can adversely affect the fitness of astronauts. The integrity of the skin plays a crucial role in protecting against mechanical forces and infections, fluid imbalance, and thermal dysregulation. In brief, the skin wound may cause unknown challenges to the implementation of space missions. Wound healing is a physiological process that relies on the synergistic action of inflammatory cells, extracellular matrix (ECM), and various growth factors to maintain the integrity of skin after trauma. Fibroblasts are present almost throughout the entire process of wound repair, especially in the scar formation at the endpoint of wound healing. However, there is limited knowledge about the extent to which fibroblasts are affected by the lack of gravity during wound healing. In this study, we utilized the rotary cell culture system, a ground-based facility that mimics the weightless condition, to study the alterations of L929 fibroblast cells under simulated microgravity (SMG). Our results demonstrated that the SM condition exerted negative influences on the proliferation and ECM formation of the L929 fibroblast. Whereas, the apoptosis of fibroblast was significantly upregulated upon exposure to SMG conditions. Moreover, the transforming growth factor-ß1/Smad3 (TGF-ß1/smad3) signaling pathway of L929 fibroblast related to wound repair was also altered significantly under a weightless environment. Overall, our study provided evidence that fibroblasts are strongly sensitive to SMG and elucidated the potential value of the TGF-ß1/Smad3 signaling pathway modulating wound healing in the future practice of space medicine.

[Development of a flexible embedded neurostimulator for animal robots].

The neural stimulator is a core component of animal robots. While the control effect of animal robots is influenced by various factors, the performance of the neural stimulator plays a decisive role in regulating animal robots. In order to optimize animal robots, embedded neural stimulators had been developed using flexible printed circuit board technology. This innovation not only enabled the stimulator to generate parameter-adjustable biphasic current pulses through control signals, but also optimized its carrying mode, material, and size, overcoming the disadvantages of traditional backpack or head-inserted stimulators, which have poor concealment and are prone to infection. Static, in vitro, and in vivo performance tests of the stimulator demonstrated that it not only had precise pulse waveform output capability, but also was lightweight and small in size. It had excellent in vivo performance in both laboratory and outdoor environments. Our study has high practical significance for the application of animal robots.

Super-resolution orbital angular momentum holography.

Computer-generated holograms are crucial for a wide range of applications such as 3D displays, information encryption, data storage, and opto-electronic computing. Orbital angular momentum (OAM), as a new degree of freedom with infinite orthogonal states, has been employed to expand the hologram bandwidth. However, in order to reduce strong multiplexing crosstalk, OAM holography suffers from a fundamental sampling criterion that the image sampling distance should be no less than the diameter of largest addressable OAM mode, which severely hinders the increase in resolution and capacity. Here we establish a comprehensive model on multiplexing crosstalk in OAM holography, propose a pseudo incoherent approach that is almost crosstalk-free, and demonstrate an analogous coherent solution by temporal multiplexing, which dramatically eliminates the crosstalk and largely relaxes the constraint upon sampling condition of OAM holography, exhibiting a remarkable resolution enhancement by several times, far beyond the conventional resolution limit of OAM holography, as well as a large scaling of OAM multiplexing capacity at fixed resolution. Our method enables OAM-multiplexed holographic reconstruction with high quality, high resolution, and high capacity, offering an efficient and practical route towards the future high-performance holographic systems.

Exploration of the Core Pathways and Potential Targets of Luteolin Treatment on Late-Onset Depression Based on Cerebrospinal Fluid Proteomics.

Cognitive deficiency is one of the fundamental characteristics of late-onset depression (LOD). Luteolin (LUT) possesses antidepressant, anti-aging, and neuroprotective properties, which can dramatically enhance cognition. The altered composition of cerebrospinal fluid (CSF), which is involved in neuronal plasticity and neurogenesis, directly reflects the physio-pathological status of the central nervous system. It is not well known whether the effect of LUT on LOD is in association with a changed CSF composition. Therefore, this study first established a rat model of LOD and then tested the therapeutic effects of LUT using several behavioral approaches. A gene set enrichment analysis (GSEA) was used to evaluate the CSF proteomics data for KEGG pathway enrichment and Gene Ontology annotation. We combined network pharmacology and differentially expressed proteins to screen for key GSEA-KEGG pathways as well as potential targets for LUT therapy for LOD. Molecular docking was adopted to verify the affinity and binding activity of LUT to these potential targets. The outcomes demonstrated that LUT improved the cognitive and depression-like behaviors in LOD rats. LUT may exert therapeutic effects on LOD through the axon guidance pathway. Five axon guidance molecules-EFNA5, EPHB4, EPHA4, SEMA7A, and NTNG-as well as UNC5B, L1CAM, and DCC, may be candidates for the LUT treatment of LOD.

Decline of stress resilience in aging rats: Focus on choroid plexus-cerebrospinal fluid-hippocampus.

OBJECTIVES: This study was designed to examine the mechanisms underlying decline of stress resilience in aged rats from the perspective of CP-CSF-hippocampus. METHODS: Male Wistar rats (7-8 weeks old or 20 months old) were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. The behavioral tests were conducted to assess anxiety, depression and cognitive function. Hippocampal neurogenesis, apoptosis and synaptic plasticity were detected by western blot (WB) and/or immunofluorescence (IF) assay. Differential expression of growth factors (GFs) and axon guidance proteins (AGPs) in CSF was analyzed using the quantitative proteomics approach. IF and WB were performed to detect expression of occludin-1, Ki-67/Transthyretin, and folate transporters in choroid plexus (CP). RESULTS: Decreased proliferation, impaired structure and transport function of CP were correlated with CSF composition alterations in stressed aging rats, including reduced 5-Methyltetrahydrofolate, growth factors and axon growth factors. Nutritional support of CSF upon hippocampus was attenuated, therefore affecting hippocampal plasticity. It has led to depression-like behaviors and cognitive deficits in stressful aged rats. CONCLUSIONS: Keeping normal structure and function of CP-CSF system may be a practical strategy for neuropsychological disorders in the elderly. This work provides evidential basis for CP transplant and CSF replacement therapy in future studies.

Mesoporous hierarchical NiCoSe2-NiO composite self-supported on carbon nanoarrays as synergistic electrocatalyst for flexible lithium-sulfur batteries.

Lithium-sulfur batteries (LSBs) have enormous application potential in the flexible energy storage field due to their large theoretical specific capacities and high energy densities. However, lithium-sulfur batteries face a notorious shuttle effect problem. To address this challenge, this work reports a three-dimensional (3D) structure of binary transition metal selenides (B-TMSe) hierarchical composites (CC/NiCoSe2-NiO) on carbon cloth as a self-supporting sulfur host for flexible LSBs. According to the density functional theory (DFT) calculations, NiCoSe2can exert a synergetic effect of high affinity with Lithium polysulfides (LiPSs) and electrocatalytic activity to lower the adsorption energy barrier and accelerate the sluggish reaction kinetics of polysulfides. Consequently, the CC/NiCoSe2-NiO-based electrodes realize a large specific capacity of approximately 1363 mAh/g at a current density of 0.1C, excellent rate performance (454.66 mAh/g at 5C) and a reversible specific capacity of 978.9 mAh/g at 1C, along with impressive cycling stability with an attenuation rate of 0.038% per cycle for 1000 cycles. They also achieve a large reversible cycle capacity of 919.43 mAh/g at 0.2C even at a high sulfur loading (3.5 mg/cm2). With a lean electrolyte (E/S ratio 10 µL/mg) and a high sulfur loading of 2.65 mg/cm2, a large capacity of 934.1 mAh/g is retained after 150 cycles at 0.5C. The assembled pouch cells from S@CC/NiCoSe2-NiO electrodes show a high initial discharge capacity of 1039.5 mAh/g at 1C at a sulfur loading of 2.65 mg/cm2 and maintain strong stability under high twisting and buckling.

A moderate reduction in irrigation and nitrogen improves water-nitrogen use efficiency, productivity, and profit under new type of drip irrigated spring wheat system.

Rational irrigation and nitrogen management strategies are crucial for wheat growth. However, the optimal amount of water and nitrogen for the newly developed drip irrigated spring wheat system (TR6S, one drip tube service for six rows of wheat, with a row spacing of 10 cm and an inter-block space of 25 cm, saves drip tubes and obtains higher profits) in dry and semi-arid areas remains unclear. Therefore, a field experiment was conducted with four nitrogen levels (300, 270, 240, and 0 kg ha-1 referred N300, N270, N240, and N0) and four irrigation levels (4500, 4200, 3900, and 3600 m3 ha-1 referred I4500, I4200, I3900, and I3600) during the 2021-2022 and 2022-2023 spring wheat seasons to analyze the effects of irrigation (I) and nitrogen (N) levels on grain yield, water-nitrogen use efficiency, profit, biomass accumulation, and nitrogen nutrient absorption status under TR6S. Compared with the traditional irrigation and nitrogen management strategy (N300-I4500, as control), lesser irrigation and nitrogen supply (I<3979 m3 ha-1 and N<273 kg ha-1) saved cost but led to lower grain yield, water use efficiency (WUE), agronomic efficiency of nitrogen fertilizer (AEN), and profit. However, a moderate reduction in irrigation and nitrogen supply (4500 m3 ha-1>I>3979 m3 ha-1 and 300 kg ha-1 >N>273 kg ha-1) improved grain yield, WUE, AEN, and profit. The increase in grain yield was mainly related to the rise in 1000-grain weight and kernels per spike. Although the moderate reduction in irrigation lowered soil moisture status, the dry matter pre-stored in the vegetative organs before anthesis that gets redistributed into grains during grain filling was improved. Moreover, the moderate reduction in nitrogen supply resulted in a more reasonable nitrogen nutrition index (NNI) of wheat plant, which improved flag leaf area and chlorophyll relative content (SPAD) at the anthesis stage. This also played a positive role in biomass accumulation and redistributed, yield structure optimization. Considering comprehensively yield, WUE, AEN and profit, combination of 285 kg ha-1 N and 4170 m3 ha-1 I was optimal irrigation and nitrogen application pattern for TR6S. This strategy can be applied to other arid and semi-arid regions.

Mitochondria-Targeting Polymer Micelles in Stepwise Response Releasing Gemcitabine and Destroying the Mitochondria and Nucleus for Combined Antitumor Chemotherapy.

Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n (P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n (P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n (P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n (P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH/ROS dual-responsive GEM/P1 and GEM/P2 micelles have higher cumulative release than single-responsive GEM/P3 and GEM/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.

Transmission matrix-based phase correction for optical systems.

The demands in fields such as biology and communications are driving the development of structured light. However, the optical modulation devices which play an important role in generating structured light, often introduce phase distortion. Additional phase correction is required to obtain more precise modulation capabilities. In this Letter, we propose a transmission matrix (TM)-based phase correction method. With the measured TM, which establishes a link between the spatial light modulator (SLM) panel and the far-field distribution of the output, we can obtain the phase modulation achieving the ideal focus. The spatial distribution of the phase distortion can be extracted from the conjugate of this phase distribution. In our experiment, the sharpness metric of the focus dropped to about half. We further verified the availability of this method by correcting the phase distortion of Laguerre-Gaussian (LG) fields. We believe our method provides a simple way to achieve precise phase correction, which will be of interest in aspects of wavefront shaping and optical tweezers.

Data transmission under high scattering based on OAM-basis transmission matrix.

Multiplexing of orbital angular momentum (OAM) channels is an important method to increase the optical communication capacity at present, but the multiple scattering and distortion of long-distance optical communication greatly limit its application. Here, a data transmission method based on an OAM-basis transmission matrix (TM) under high scattering is proposed. In this method, OAM modes are directly encoded by the OAM-basis TM, and the incident power spectral distribution of OAM modes can be directly acquired by the intensity profile of the speckle field on the camera. This method can realize the multiplexing of a large number of OAM channels and is easy to perform. Experimentally, we have achieved a maximum of 800 OAM modes multiplexed, and a bit error rate of 0.01% in the data transmission of color images.

Correlation between T-Lymphocyte Subsets, Regulatory T Cells, and Hepatic Fibrosis in Patients with Nonalcoholic Fatty Liver.

Objective: The aim of this study is to assess the relationship between T-lymphocyte subsets, regulatory T cells (Treg), and hepatic fibrosis in patients with a nonalcoholic fatty liver disease (NAFLD). Methods: A retrospective analysis was conducted on 64 NAFLD patients (research group) and 73 healthy subjects (control group) in our hospital from January 2020 to December 2021. T-lymphocyte subsets (Th17) and Treg, liver function (alanine aminotransferase (ALT), aspartate aminotransferase (AST)), hepatic fibrosis indexes (type III procollagen (PCIII), type IV collagen (CIV), laminin (LN), hyaluronic acid (HA)), inflammatory factors (high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), interleukin-8 (IL-8)), and oxidative stress (OS) response ((superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA)) were tested. The relationship between Th17/Treg and the abovementioned indexes in NAFLD patients was analyzed. Results: In comparison to the control group, Th17 and Th17/Treg were higher in the research group (P < 0.05). In addition, liver function, liver fibrosis markers, inflammatory factors, and MDA were elevated, while SOD and GSH-PX decreased (P < 0.05). Subsequently, NAFLD patients were divided into groups A (Th17/Treg <1.15, n = 33) and B (Th17/Treg ≥1.15, n = 31) based on their median Th17/Treg levels. It was seen that liver injury, hepatic fibrosis, inflammation, and OS in group A were more severe (P < 0.05). The Pearson correlation coefficient revealed that Th17/Treg was positively correlated with AST, ALT, PCIII, MDA, and inflammatory factors but negatively correlated with SOD and GSH-PX (P < 0.05).

Luteolin Enhances Choroid Plexus 5-MTHF Brain Transport to Promote Hippocampal Neurogenesis in LOD Rats.

Folates, provided by food, are commonly used antidepressant synergists in late-onset depression (LOD). However, increased intake of folic acid in the elderly population might lead to the accumulation of unmetabolized folic acid in the systemic circulation, leading to enhanced deterioration of the central nervous system function. In addition, folates cannot access the brain directly because of the blood-brain barrier. Choroid plexus (CP) 5-methyltetrahydrofolate (5-MTHF) brain transport plays a critical role in regulating the cerebrospinal fluid (CSF) 5-MTHF content. Luteolin is a natural flavonoid that has antidepressant effects and is involved in the anti-folate resistance pathway. It remains unclear whether the antidepressant effects of luteolin are associated with the CP 5-MTHF brain transport. In this study, 20-21-month-old Wistar rats were exposed to the chronic unpredictable mild stress (CUMS) protocol for 6 consecutive weeks to explore the long-term effects of luteolin on behavior, 5-MTHF levels, hippocampal neurogenesis, and folate brain transport of the CP. In vitro primary hippocampal neural stem cells (NSCs) cultured in media containing 10% CSF from each group of rats and choroid plexus epithelial cells (CPECs) cultured in media containing 20 µM luteolin were treated with 100 µM corticosterone and 40 mg/ml D-galactose. We found that aged rats exposed to CUMS showed a significantly reduced sucrose preference, decreased locomotion activity in the open field test and accuracy of the Morris water maze test, increased immobility time in the forced swimming test, accelerated dysfunctional neurogenesis and neuronal loss in the dentate gyrus of LOD rats, as well as decreased CSF and hippocampus 5-MTHF levels, and zona occludens protein 1 (ZO-1), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC) protein levels. In vitro assays showed media containing 10% aged CSF or LOD+ Luteolin-CSF significantly increased the viability of CORT + D-gal-injured NSCs and alleviated dysfunctional neurogenesis and neuronal loss compared with the CORT + D-gal medium. However, media containing 10% LOD-CSF had no such effect. In the meantime, induction of CORT + D-gal significantly decreased the ZO-1, PCFT, RFC, and folate receptor alpha (FR-α) protein levels and transepithelial electrical resistance in rat CPECs. As expected, luteolin treatment was effective in improving these abnormal changes. These findings suggested that luteolin could ameliorate CUMS-induced LOD-like behaviors by enhancing the folate brain transport.

[Effect of Dimethyl Fumarate (DMF) on T-cell Acute Lymphoblastic Leukemia].

OBJECTIVE: To explore the effect and possible mechanism of dimethyl fumarate (DMF) on T-cell acute lymphoblastic leukemia (T-ALL), and provide experimental and theoretical basis for the clinical treatment of T-ALL. METHODS: Jurkat cells were treated with different concentrations of DMF for 24 hours, and then the proportion and absolute count of Ki67-positive Jurkat cells were analyzed by flow cytometry. Meanwhile, the protein levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and E3 ubiquitin ligase HACE1 in Jurkat cells treated with DMF for 24 hours were evaluated by Western blot. Nrf2 proteins were co-immunoprecipitated in Jurkat cells, and then HACE1 protein was assessed by Western blot. Plasmids of Flag-Nrf2 and different gradients of Flag-HACE1 were transfected into HEK293T cells, and the levels of Flag-Nrf2 were detected by Western blot after 48 hours. RESULTS: DMF could significantly inhibit the proportion and absolute count of Ki67-positive Jurkat cells, and DMF inhibited the proliferation of Jurkat cells in a dose-dependent manner (r=0.9595, r=0.9054). DMF could significantly up-regulate the protein levels of Nrf2 and E3 ubiquitin ligase HACE1 in Jurkat cells (P<0.01, P<0.01). HACE1 physically interacted with Nrf2 in Jurkat cells. Overexpression of Flag-HACE1 significantly increased the protein level of Flag-Nrf2 in a dose-dependent manner (r=0.9771). CONCLUSION: DMF inhibits the proliferation of T-cell acute lymphoblastic leukemia cell. The mechanism may be that, DMF significantly up-regulates the protein levels of Nrf2 and E3 ubiquitin ligase HACE1, and HACE1 interacts with Nrf2 and positively regulates Nrf2 protein level.