FKBP51 is involved in LPS-induced microglial activation via NF-κB signaling to mediate neuroinflammation.

AIMS: FKBP5 encodes FKBP51, which has been implicated in stress-related psychiatric disorders, and its expression is often increased under chronic stress, contributing to mental dysfunctions. However, the precise role of FKBP51 in brain inflammation remains unclear. This study aimed to investigate the role of FKBP51 in microglia-mediated inflammatory responses in the central nervous system. MAIN METHODS: We employed a peripheral lipopolysaccharide (LPS) administration model to compare microglial activation and cytokine gene expression between Fkbp5 knockout (Fkbp5-KO) and wild-type (WT) male mice. Additionally, we used both BV2 and primary microglia in vitro to examine how Fkbp5 deletion influenced inflammation-related pathways and microglial functions. KEY FINDINGS: This study revealed that systemic LPS-induced microglial activation was significantly attenuated in Fkbp5-KO mice compared with WT mice. In Fkbp5-KO mice following the LPS challenge, there was a notable decrease in the expression of pro-inflammatory genes, coupled with an increase in the anti-inflammatory gene Arg1. Furthermore, Fkbp5 knockdown in BV2 microglial cells led to reduced expression of LPS-induced inflammatory markers, and targeted inhibition of NF-κB activation, while Akt signaling remained unaffected. Similar results were observed in Fkbp5-KO primary microglia, which exhibited not only decreased microglial activation but also a significant reduction in phagocytic activity in response to LPS stimulation. SIGNIFICANCE: This study highlights the critical role of FKBP51 in LPS-induced microglial activation and neuroinflammation. It shows that reducing FKBP51 levels attenuates inflammation through NF-κB signaling in microglia. This suggests that FKBP51 is a potential target for alleviating neuroinflammation-induced stress responses.

Toripalimab plus chemotherapy in American patients with recurrent or metastatic nasopharyngeal carcinoma: A cost-effectiveness analysis.

BACKGROUND: Toripalimab, combined with gemcitabine and cisplatin, has been approved as the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), representing a significant milestone as the first FDA-approved innovative therapy for this condition. Despite this achievement, there's a lack of data on the cost-effectiveness of toripalimab for RM-NPC patients in the American context. METHODS: To assess the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone, a 3-state partitioned survival model was constructed. The study involved participants with characteristics matching those in the JUPITER-02 trial. Cost and utility inputs were collected from literature. Main outcomes measured were quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Univariate and probabilistic sensitivity analyses, subgroup analyses, and scenario analyses were conducted to verify the robustness of results. RESULTS: The study found that the toripalimab regimen resulted in 4.390 QALYs at a cost of $361,813, while the chemotherapy-only regimen yielded 1.685 QALYs at a cost of $161,632. This translates to an ICER of $74,004/QALY, below the willingness-to-pay threshold of $150,000/QALY. Sensitivity analyses indicated that utility values, discount rate, and the price of toripalimab significantly impact INMB. With an 87.10% probability of being cost-effective at a $150,000/QALY threshold, the probabilistic sensitivity analysis supports toripalimab plus chemotherapy as a viable option. Scenario analysis showed that toripalimab remains cost-effective unless its price increases by 125%. Additionally, a simulated 15-year study period increases the ICER to $88,026/QALY. Subgroup analysis revealed ICERs of $76,538/QALY for PD-L1 positive and $70,158/QALY for PD-L1 negative groups. CONCLUSIONS: Toripalimab in combination with chemotherapy is likely to be a cost-effective alternative to standard chemotherapy for American patients with RM-NPC. This evidence can guide clinical and reimbursement decision-making in treating RM-NPC patients.

Reducing brain Aß burden ameliorates high-fat diet-induced fatty liver disease in APP/PS1 mice.

High-fat diet (HFD)-induced fatty liver disease is a deteriorating risk factor for Alzheimer's disease (AD). Mitigating fatty liver disease has been shown to attenuate AD-like pathology in animal models. However, it remains unclear whether enhancing Aß clearance through immunotherapy would in turn attenuate HFD-induced fatty liver or whether its efficacy would be compromised by long-term exposure to HFD. Here, the therapeutic potentials of an anti-Aß antibody, NP106, was investigated in APP/PS1 mice by HFD feeding for 44 weeks. The data demonstrate that NP106 treatment effectively reduced Aß burden and pro-inflammatory cytokines in HFD-fed APP/PS1 mice and ameliorated HFD-aggravated cognitive impairments during the final 18 weeks of the study. The rejuvenating characteristics of microglia were evident in APP/PS1 mice with NP106 treatment, namely enhanced microglial Aß phagocytosis and attenuated microglial lipid accumulation, which may explain the benefits of NP106. Surprisingly, NP106 also reduced HFD-induced hyperglycemia, fatty liver, liver fibrosis, and hepatic lipids, concomitant with modifications in the expressions of genes involved in hepatic lipogenesis and fatty acid oxidation. The data further reveal that brain Aß burden and behavioral deficits were positively correlated with the severity of fatty liver disease and fasting serum glucose levels. In conclusion, our study shows for the first time that anti-Aß immunotherapy using NP106, which alleviates AD-like disorders in APP/PS1 mice, ameliorates fatty liver disease. Minimizing AD-related pathology and symptoms may reduce the vicious interplay between central AD and peripheral fatty liver disease, thereby highlighting the importance of developing AD therapies from a systemic disease perspective.

The ZmNF-YC1-ZmAPRG pathway modulates low phosphorus tolerance in maize.

Phosphorus (P) is an essential nutrient for plant growth and yield. Low phosphate use efficiency makes it important to clarify the molecular mechanism of low P stress. In our previous studies, a P efficiency gene ZmAPRG was identified. Here, we further screened the upstream regulator ZmNF-YC1 of ZmAPRG by yeast one hybrid (Y1H) assay, and found it was a low inorganic phosphorus (Pi)-inducible gene. The results of dual luciferase assays, expression analysis, and ChIP-qPCR assays showed that ZmNF-YC1 is a positive regulator of ZmAPRG. Overexpression of ZmNF-YC1 improved low P tolerance, whereas knockout of ZmNF-YC1 decreased low P tolerance in maize. Bimolecular fluorescence complementation (BiFC), yeast two hybrid (Y2H) assay, and yeast three hybrid (Y3H) assay further showed that ZmNF-YC1 can interact with ZmNF-YB14, and recruit ZmNF-YA4/10 to form NF-Y complexes. Transcriptional activation assay confirmed that the NF-Y complexes can activate the promoters of ZmAPRG. Meanwhile, transcriptome and metabolome analyses indicated that overexpression of ZmAPRG improves low P tolerance by regulating lipid composition and photosynthetic capacity, and chlorophyll fluorescence parameters provided evidence in support of this hypothesis. Furthermore, overexpression of ZmAPRG increased grain yield in inbred and hybrid maize under low P conditions. Taken together, our research revealed a low P tolerance mechanism of the ZmNF-YC1-ZmAPRG pathway.

Salt Tolerant Gene 1 contributes to salt tolerance by maintaining photosystem II activity in maize.

Salt stress is a major environmental factor limiting crop growth and productivity. Here, we show that Salt-Tolerant Gene 1 (ZmSTG1) contributes to salt tolerance by maintaining photosystem activity in maize. ZmSTG1 encodes an endoplasmic reticulum localized protein and retrotransposon insertion in the promoter region causes differential expression levels in maize inbred lines. Overexpression of ZmSTG1 improved plant growth vigor, and knockout of ZmSTG1 weakened plant growth under normal and salt stress conditions. Transcriptome and metabolome analyses indicated that ZmSTG1 might regulate the expression of lipid trafficking-related genes dependent on the abscisic acid (ABA) signaling pathway, thereby increasing the galactolipids and phospholipid concentrations in the photosynthetic membrane under salt stress. Chlorophyll fluorescence parameters showed that the knockout of ZmSTG1 led to significant impairment of plant photosystem II (PSII) activity under normal and salt stress conditions, whereas overexpression of ZmSTG1 dramatically improved plant PSII activity under salt stress conditions. We also demonstrated that the application of the salt-tolerant locus could enhance salt tolerance in hybrid maize plants. Taken together, we propose that ZmSTG1 may modulate the lipid composition in the photosynthetic membrane by affecting the expression of lipid trafficking-related genes to maintain the photosynthetic activity of plants under salt stress.

Comprehensive transcriptomic analysis of immune-related eRNAs associated with prognosis and immune microenvironment in melanoma.

Background: Recent evidence suggests that enhancer RNAs (eRNAs) play key roles in cancers. Identification of immune-related eRNAs (ireRNAs) in melanoma can provide novel insights into the mechanisms underlying its genesis and progression, along with potential therapeutic targets. Aim: To establish an ireRNA-related prognostic signature for melanoma and identify potential drug candidates. Methods: The ireRNAs associated with the overall survival (OS-ireRNAs) of melanoma patients were screened using data from The Cancer Genome Atlas (TCGA) via WGCNA and univariate Cox analysis. A prognostic signature based on these OS-ireRNAs was then constructed by performing the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The immune landscape associated with the prognostic model was evaluated by the ESTIMATE algorithm and CIBERSORT method. Finally, the potential drug candidates for melanoma were screened through the cMap database. Results: A total of 24 OS-ireRNAs were obtained, of which 7 ireRNAs were used to construct a prognostic signature. The ireRNAs-related signature performed well in predicting the overall survival (OS) of melanoma patients. The risk score of the established signature was further verified as an independent risk factor, and was associated with the unique tumor microenvironment in melanoma. We also identified several potential anti-cancer drugs for melanoma, of which corticosterone ranked first. Conclusions: The ireRNA-related signature is an effective prognostic predictor and provides reliable information to better understand the mechanism of ireRNAs in the progression of melanoma.

FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus.

BACKGROUND: Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. METHODS: Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. RESULTS: LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. CONCLUSIONS: These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.

Identification of the RP11-21C4.1/SVEP1 gene pair associated with FAT2 mutations as a potential biomarker in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. Despite rapid advances in systemic therapy, GC remains the third leading cause of cancer-related deaths. We aimed to identify a novel prognostic signature associated with FAT2 mutations in GC. We analyzed the expression levels of FAT2-mutant and FAT2-wildtype GC samples obtained from The Cancer Genome Atlas (TCGA). The Kaplan-Meier survival curve showed that patients with FAT2 mutations showed better prognosis than those without the mutation. Sixteen long non-coding RNAs (lncRNAs) and 62 messenger RNAs (mRNAs) associated with FAT2 mutations were correlated with the prognosis of GC. We then constructed a 4-mRNA signature and a 5-lncRNA signature for GC. Finally, we identified the most relevant RP11-21 C4.1/SVEP1 gene pair as a prognostic signature of GC that exhibited superior predictive performance in comparison with the 4-mRNA or 5-lncRNA signature by weighted gene correlation network analysis (WGCNA) and Cox proportional hazards regression analysis. In this study, we constructed a prognostic signature of GC by integrative genomics analysis, which also provided insights into the molecular mechanisms linked to FAT2 mutations in GC.

Long noncoding RNA taurine-up regulated gene 1 for the prognosis of osteosarcoma: A protocol for meta-analysis and bioinformatics analysis.

BACKGROUND: In recent years, a variety of long noncoding RNA (lncRNA) has been confirmed to be involved in the initiation and progression of osteosarcoma. Taurine-up regulated gene 1 (TUG1) plays an important role in the formation, invasion, and metastasis of osteosarcoma. Therefore, perhaps TUG1 is a potential biomarker for the prognosis of patients suffering from osteosarcoma. In this study, meta-analysis and bioinformatics were adopted to further explore the effects of TUG1 on the prognosis of patients with osteosarcoma and its potential molecular mechanism. METHODS: Embase, PubMed, Sinomed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and Vip Journal Integration Platform were searched from inception to May 2021. The relationship between TUG1 expression and survival outcome was estimated by hazard ratio (HRs) and 95% confidence interval (CIs). Meta-analysis was conducted on the Stata 16.0. The differential expression of TUG1 in osteosarcoma was analyzed by using UALCAN database, and the survival of TUG1 was analyzed as well. The target genes of TUG1 were predicted by RegRNA2.0 biology software, HMDD, targetscan and microTCDS, and TUG1-micoRNAs-mRNAs regulatory network was constructed. The predicted target genes obtained GeneOntology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal transduction pathway enrichment analysis using FunRich platform. RESULTS: The results of this meta-analysis would be submitted to peer-reviewed journals for publication. CONCLUSION: This study will provide evidence-based medical evidence for the relationship between TUG1 and the prognosis of osteosarcoma. Furthermore, bioinformatics analysis will provide ideas for the exploration on osteosarcoma mechanism. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results will be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/CW4BF.

Correction to: Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid-Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis.

The original version of this article unfortunately contained a mistake. The authors observed inadvertent error in Fig. 7d, in which the image of the GFAP/DAPI in the WT saline treated mice was rotated left 90-degree by mistake. The corrected representative image is given below.

Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid-Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis.

Astrocytes play pivotal roles in regulating glutamate homeostasis at tripartite synapses. Inhibition of soluble epoxide hydrolase (sEHi) provides neuroprotection by blocking the degradation of 14,15-epoxyeicosatrienoic acid (14,15-EET), a lipid mediator whose synthesis can be activated downstream from group 1 metabotropic glutamate receptor (mGluR) signaling in astrocytes. However, it is unclear how sEHi regulates glutamate excitotoxicity. Here, we used three primary rat cortical culture systems, neuron-enriched (NE), astrocyte-enriched glia-neuron mix (GN), and purified astrocytes, to delineate the underlying mechanism by which sEHi and 14,15-EET attenuate excitotoxicity. We found that sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and 14,15-EET both attenuated N-methyl-D-aspartate (NMDA)-induced neurite damage and cell death in GN, not NE, cortical cultures. The anti-excitotoxic effects of 14,15-EET and AUDA were both blocked by the group 1 mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), as were their protective effects against NMDA-disrupted perineuronal astrocyte processes expressing glutamate transporter-1 (GLT-1) and subsequent glutamate uptake. Knockdown of sEH expression also attenuated NMDA neurotoxicity in mGluR5- and GLT-1-dependent manners. The 14,15-EET/AUDA-preserved astroglial integrity was confirmed in glutamate-stimulated primary astrocytes along with the reduction of the c-Jun N-terminal kinase 1 phosphorylation, in which the 14,15-EET effect is mGluR5-dependent. In vivo studies validated that sEHi and genetic deletion of sEH (Ephx2-KO) ameliorated excitotoxic kainic acid-induced seizure, memory impairment, and neuronal loss while preserving GLT-1-expressing perineuronal astrocytes in hippocampal CA3 subregions. These results suggest that 14,15-EET mediates mGluR5-dependent anti-excitotoxicity by protecting astrocytes to maintain glutamate homeostasis, which may account for the beneficial effect of sEH inhibition in excitotoxic brain injury and diseases.

Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels.

Mammalian Eag1 (Kv10.1) potassium (K+) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K+ channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner. Immunoprecipitation analyses confirmed the interaction between Cul7 and rEag1 in heterologous cells and neuronal tissues. Cul7 and rEag1 also exhibited significant co-localization at synaptic regions in neurons. Over-expression of Cul7 led to reduced protein level, enhanced ubiquitination, accelerated protein turn-over, and decreased current density of rEag1 channels. We provided further biochemical and morphological evidence suggesting that Cul7 targeted endoplasmic reticulum (ER)- and plasma membrane-localized rEag1 to the proteasome and the lysosome, respectively, for protein degradation. Cul7 also contributed to protein degradation of a disease-associated rEag1 mutant. Together, these results indicate that Cul7 mediates both proteasomal and lysosomal degradations of rEag1. Our findings provide a novel insight to the mechanisms underlying ER and peripheral protein quality controls of Eag1 channels.

Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia.

The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia-mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both anti-inflammatory and proinflammatory effects in lipopolysaccharide (LPS)-activated microglia. Activation of AhR by its ligands, formylindolo[3,2-b]carbazole (FICZ) or 3-methylcholanthrene (3MC), attenuated LPS-induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS-induced microglial immune responses and LPS-activated microglia-mediated neurotoxicity. Similarly, LPS-induced expressions of tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR-deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS-induced AhR activation, leading to suppression of LPS-induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS-FICZ co-treatment, but not LPS alone, not only resulted in co-recruitment of both AhR and NFκB onto the κB site of TNFα gene promoter but also reduced LPS-induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi-directional effects on the regulation of LPS-induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders.

The potential role of heat shock proteins in acute spinal cord injury.

PURPOSE: This study aims to investigate the differential expression proteins profile of spinal cord tissues after acute spinal cord injury (ASCI), provide preliminary results for further study and explore the secondary injury mechanisms underlying ASCI. METHODS: Using Allen's frame to establish ASCI model of Sprague-Dawley rats, then a stable isotope-labelled strategy using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional (2D) liquid chromatography tandem mass spectrometry (2D LC-MS/MS) was performed to separate and identify differentially expressed proteins. RESULTS: A total of 220 differentially expressed proteins were identified in the spinal cord tissues of H-8 group (acute spinal cord injury after 8 h) compared with H-0 group (acute spinal cord injury after 0 h); Up to 116 proteins were up-regulated, whereas 104 proteins were down-regulated in the spinal cord tissues. Three of the differentially expressed Heat shock proteins (HSPs) namely, Hsp90ab1, Hspa4 and Hspe1 were down-regulated. CONCLUSION: The differentially expressed proteins of spinal cord tissues after ASCI will provide scientific foundation for further study to explore the secondary injury mechanism of ASCI.

Diagnostic value of alpha-L-fucosidase for hepatocellular carcinoma: a meta-analysis.

Alpha-fetoprotein (AFP) is the primary marker for detecting hepatocellular carcinoma (HCC) and has been used widely in the clinic, but AFP is a biomarker characterized by poor sensitivity and specificity. Alpha-L-fucosidase (AFU) has been proposed as a tumor marker for diagnosis of HCC in many studies. However, conclusions of its diagnostic value are inconsistent. The current review aimed to evaluate the diagnostic value of AFU for HCC. After systematic review of 12 related studies, sensitivity, specificity, and diagnostic odds ratio (DOR) were pooled using random-effect models. Summary receiver operating characteristic (sROC) curve analysis was used to summarize the overall test performance. The pooled sensitivity for AFU was 0.72 (95% confidence interval (CI) 0.69-0.76), while the pooled specificity was 0.78 (95% CI 0.74-0.81). DOR was 10.26 (95% CI 5.99-17.59), and the area under the curve (AUC) was 0.8125. AFU had great value for the diagnosis of HCC as a serum marker.