Enhancement of the Wear Resistance and Corrosion Resistance of Electroplated Ni-W-B Coatings Using PDA-Functionalized VC.

In this study, vanadium carbide (VC) was used as the raw material to synthesize PDA-functionalized VC (P-VC). VC and P-VC were added as nanoreinforced materials to the Ni-W-B coating. The effects of the two nanomaterials on the morphology, wear resistance, and corrosion resistance of the Ni-W-B coatings were investigated and compared. The experimental results show that the surface of the Ni-W-B/P-VC coating is denser and more uniform than that of the Ni-W-B and Ni-W-B/VC coatings, and there are no obvious defects on the surface. According to the hardness test, the Ni-W-B/P-VC coating reaches the highest microhardness of 887.1 HV. According to the friction and wear tests, the Ni-W-B/P-VC coating has the shallowest scratches, the lowest average friction coefficient (COF = 0.274), and the lowest wear rate (9.578 × 10-8 mm2/N). The corrosion resistance is the best, the corrosion rate is 0.0456 mm/y, and the impedance value Rt reaches 14,501 Ω·cm2.

Enhancement of Corrosion and Wear Resistance of Ni-P Coatings Stems from the Synergistic Effects of Cr3C2 and Heat Treatment.

This study describes the preparation of Ni-P-Cr3C2 composite coatings using pulsed electrodeposition, with varying Cr3C2 concentrations (0, 1, 2, 3, 4, and 5 g/L). Subsequently, the Ni-P-Cr3C2 composite coatings are heat-treated at different temperatures (200, 400, and 600 °C) using the characteristic of Cr3C2 oxidizing to Cr2O3 at high temperatures. The Ni-P coatings, Ni-P-Cr3C2 composite coatings, and heat-treated-state Ni-P-Cr3C2 composite coatings are compared and discussed. The results show that the hardness, wear resistance, and corrosion resistance of the composite coatings are optimized when the Cr3C2 content is 3 g/L and the heat-treatment temperature is 400 °C. This is due to the presence of oxides such as Cr2O3 on the surface of the composite coatings after heat treatment at 400 °C. By efficiently enhancing the coating's densification to the substrate, these oxides raise the composite coating's resistance to corrosion and wear. The Ni-P-Cr3C2 composite coating in its heat-treated makeup at 400 °C is found to have long-term corrosion resistance in the 3.5 wt % NaCl solution immersion test. This study provides a new idea in the field of corrosion.

Eukaryotic initiation factor 6 repression mitigates atherosclerosis progression by inhibiting macrophages expressing Fasn.

Atherosclerosis, a chronic inflammatory disease that often leads to myocardial infarction and stroke, is mainly caused by lipid accumulation. Eukaryotic initiation factor 6 (Eif6) is a rate-limiting factor in protein translation of transcription factors necessary for lipogenesis. To determine whether Eif6 affects atherosclerosis, Eif6+/- mice were crossed into Apoe-/- background. Apoe-/-/Eif6+/- mice on high fat diet showed significant reduction in atherosclerotic lesions and necrotic core content in aortic root sections in comparison with Apoe-/- mice. RNA-Seq was used to investigate the effect of Eif6 in aorta. Deficiency of Eif6 shows broad effect on cell metabolism. Expression of genes for fatty acid synthesis including Fatty acid synthase (Fasn), Elovl3, Elovl6 and Acaca are down-regulated in aortas. Importantly, Fasn is decreased in macrophages. Results suggest that Eif6 deficiency may decrease atherosclerosis through inhibition of Fasn and lipids metabolism in macrophages.

RHDV 3C protein antagonizes type I interferon signaling by cleaving interferon promoter stimulated 1 protein.

The host innate immune response to viral infection often involves the activation of type I interferons. Not surprisingly, many viruses have evolved various mechanisms to disable the interferon pathway and evade the antiviral response involving innate immunity. Rabbit hemorrhagic disease (RHD) is caused by RHD virus (RHDV), but whether it can antagonize the production of host interferon to establish infection has not been investigated. In this study, we found that during RHDV infection, the expressions of interferon and the interferon-stimulated gene were not activated. We constructed eukaryotic expression plasmids of all RHDV proteins, and found that RHDV 3C protein inhibited poly(I:C)-induced interferon expressions. Using siRNA to interfere with the expressions of TLR3 and MDA5, we found that the MDA5 signal pathway was used by the 3C protein to inhibit poly(I:C)-induced interferon expression. This effect was mediated by cleaving the interferon promoter stimulated 1 (IPS-1) protein. Finally, our study showed that interferon was effective against RHDV infection. In summary, our findings showed that the RHDV 3C protein was a new interferon antagonist. These results increase our understanding of the escape mechanism from innate immunity mediated by the RHDV 3C protein.

Hypodermin A improves survival of skin allografts.

BACKGROUND: Hypodermin A (HA) is a serine esterase that degrades complement, a key element of the innate immune system. Immunosuppressive properties of HA have previously been studied in vitro. However, such properties have not been fully demonstrated in vivo. The aim of this study was to evaluate the effect of HA in inhibiting allograft rejection in an HA transgenic mouse model. METHODS: FVB (HA transgenic mice or wild-type mice) to BALB/c mice skin transplantation model were used. Skin grafts were analyzed by histology, immunohistochemistry, and Western blotting. RESULTS: HA overexpression resulted in significantly prolonged skin allograft survival. Histologic changes in the skin allografts paralleled the gross appearance of rejection. ELISA and Western blotting showed that HA significantly reduced the content of complement C3 and C9 in HA skin allografts. The expressions of CD4, B7-2, and MHC class II were all significantly suppressed in HA skin allografts compared with the control group. CONCLUSIONS: These findings suggest that HA effectively prolongs skin allograft survival. The study results provide insight into a promising strategy to improve the survival of grafts in humans.

Early Pregnancy Factor Enhances the Generation and Function of CD4+CD25+ Regulatory T Cells.

The mechanisms of fetal semi-allograft acceptance by the mother's immune system have been the target of many immunological studies. Early pregnancy factor (EPF) is a molecule present in the serum of pregnant mammals soon after conception that has been reported to have immunomodulatory effects. In the present study, we aimed to determine whether immune cells such as CD4+CD25+ regulatory T cells (Tregs) are involved in the suppressive mechanism of EPF. Accordingly, CD4+CD25- T cells were isolated from spleens of female C57BL/6 mice and stimulated with anti-CD3 antibody, anti-CD28 antibody and IL-2 in the presence or absence of EPF. Flow cytometry was used to analyze the differentiation of CD4+CD25- T cells to CD4+CD25+ Tregs. We thus found a remarkable rise in the Treg ratio in the EPF-treated cells. Higher mRNA and protein levels of fork head box P3 (Foxp3), a marker of the Treg lineage, were also observed in cells treated with EPF. Furthermore, the effect of EPF on Treg immunosuppressive capacity was evaluated. EPF treatment induced the expression of interleukin-10 and transforming growth factor ß1 in Tregs. The suppressive capacity of Tregs was further measured by their capability to inhibit T cell receptor-mediated proliferation of CD4+CD25- T cells. We thus found that EPF exposure can enhance the immunosuppressive functions of Tregs. Overall, our data suggest that EPF induces the differentiation of Tregs and increases their immunosuppressive activities, which might be an important mechanism to inhibit immune responses during pregnancy.

Copper/Guanidine-Catalyzed Asymmetric Alkynylation of Isatins.

The highly enantioselective alkynylation of isatins, catalyzed by a bifunctional guanidine/CuI catalyst under mild reaction conditions, is described. The reaction is broad in scope with respect to alkyl/aryl-substituted terminal alkynes and substituted isatins, thus affording bioactive propargylic alcohols in excellent yields and enantioselectivities.

Direct Synthesis of Chiral Allenoates from the Asymmetric C-H Insertion of α-Diazoesters into Terminal Alkynes.

The asymmetric C-H insertion of α-diazoesters into 1-alkynes was achieved using chiral cationic guanidinium salts and copper(I) complexes. Optically active 2,4-disubstituted allenoates were generated under mild reaction conditions from various α-diazoesters and 1-alkynes in high yield (up to 99%) and enantioselectivity (up to 97:3 e.r.). Control experiments excluded the possibility of an asymmetric isomerization of alkynoates.

Molecular cloning, functional characterization and antiviral activity of porcine DDX3X.

Human DDX3X is a newly discovered DEAD-box RNA helicase. In addition to involvement of eukaryotic gene expression regulation, human DDX3X has recently been demonstrated to be a critical molecule in innate immune signaling pathways and to contribute to type I interferon (IFN) induction. In the present study, porcine DDX3X was cloned by RT-PCR from PK-15 cells and its function in regulating IFN-ß was characterized. The putative porcine DDX3X ORF encodes 662 amino acids possessing several conserved motifs. Sequence alignments indicated that porcine DDX3X has high identity at the amino acid level to those of horse (96.7%), mouse (97.6%), cattle (98.5%), dog (98.6%) and human (98.9%). Ectopic expression of porcine DDX3X significantly activated IFN-ß expression, whereas knockdown of porcine DDX3X inhibited dsRNA- or Sendai virus (SeV)-induced IFN-ß. Furthermore, porcine DDX3X co-localized with IPS-1, TBK1 and IKKε, and enhanced IFN-ß promoter activation induced by these molecules. We also investigated the role of porcine DDX3X during porcine reproductive and respiratory syndrome virus (PRRSV) infection and found that overexpression of DDX3X significantly inhibited PRRSV replication, indicating that DDX3X is a potential antiviral agent.

PRRSV infection facilitates the shedding of soluble CD163 to induce inflammatory responses.

Porcine reproductive and respiratory syndrome (PRRS), which poses substantial threats to the global pig industry, is primarily characterized by interstitial pneumonia. Cluster of differentiation 163 (CD163) is the essential receptor for PRRSV infection. Metalloproteinase-mediated cleavage of CD163 leads to the shedding of soluble CD163 (sCD163), thereby inhibiting PRRSV proliferation. However, the exact cleavage site in CD163 and the potential role of sCD163 in inflammatory responses during PRRSV infection remain unclear. Herein, we found that PRRSV infection increased sCD163 levels, as demonstrated in primary alveolar macrophages (PAMs), immortalized PAM (IPAM) cell lines, and sera from PRRSV-infected piglets. With LC-MS/MS, Arg-1041/Ser-1042 was identified as the cleavage site in porcine CD163, and an IPAM cell line with precise mutation at the cleavage site was constructed. Using the precisely mutated IPAM cells, we found that exogenous addition of sCD163 protein promoted inflammatory responses, while mutation at the CD163 cleavage site suppressed inflammatory responses. Consistently, inhibition of sCD163 using its neutralizing antibodies reduced PRRSV infection-triggered inflammatory responses. Importantly, sCD163 promoted cell polarization from M2 to M1 phenotype, which in turn facilitated inflammatory responses. Taken together, our findings identify sCD163 as a novel proinflammatory mediator and provide valuable insights into the mechanisms underlying the induction of inflammatory responses by PRRSV infection.

The prognostic value of bioinformatics analysis of ECM receptor signaling pathways and LAMB1 identification as a promising prognostic biomarker of lung adenocarcinoma.

The extracellular matrix (ECM) is a complex and dynamic network of cross-linked proteins and a fundamental building block in multicellular organisms. Our study investigates the impact of genes related to the ECM receptor interaction pathway on immune-targeted therapy and lung adenocarcinoma (LUAD) prognosis. This study obtained LUAD chip data (GSE68465, GSE31210, and GSE116959) from NCBI GEO. Moreover, the gene data associated with the ECM receptor interaction pathway was downloaded from the Molecular Signature Database. Differentially expressed genes were identified using GEO2R, followed by analyzing their correlation with immune cell infiltration. Univariate Cox regression analysis screened out ECM-related genes significantly related to the survival prognosis of LUAD patients. Additionally, Lasso regression and multivariate Cox regression analysis helped construct a prognostic model. Patients were stratified by risk score and survival analyses. The prognostic models were evaluated using receiver operating characteristic curves, and risk scores and prognosis associations were analyzed using univariate and multivariate Cox regression analyses. A core gene was selected for gene set enrichment analysis and CIBERSORT analysis to determine its function and tumor-infiltrating immune cell proportion, respectively. The results revealed that the most abundant pathways among differentially expressed genes in LUAD primarily involved the cell cycle, ECM receptor interaction, protein digestion and absorption, p53 signaling pathway, complement and coagulation cascade, and tyrosine metabolism. Two ECM-associated subtypes were identified by consensus clustering. Besides, an ECM-related prognostic model was validated to predict LUAD survival, and it was associated with the tumor immune microenvironment. Additional cross-analysis screened laminin subunit beta 1 (LAMB1) for further research. The survival time of LUAD patients with elevated LAMB1 expression was longer than those with low LAMB1 expression. Gene set enrichment analysis and CIBERSORT analyses revealed that LAMB1 expression correlated with tumor immune microenvironment. In conclusion, a prognostic model of LUAD patients depending on the ECM receptor interaction pathway was constructed. Screening out LAMB1 can become a prognostic risk factor for LUAD patients or a potential target during LUAD treatment.

A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

In silico analysis reveals PRR11 as a prognostic and oncogenic marker in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common lung cancer. Although there are various treatments for LUAD, its prognosis remains poor. Therefore, it is imperative to identify new targets and develop novel therapeutic strategies. In this study, we analyze the expression of proline rich 11 (PRR11) in pan cancer based on The Cancer Genome Atlas (TCGA) database, and explore the prognostic value of PRR11 in LUAD by GEPIA2 (Gene Expression Profiling Interactive Analysis, version 2) database. In addition, the relationship between PRR11 and the clinicopathological features of LUAD was analyzed using UALCAN database. The association between PRR11 expression and immune infiltration was accessed. The PRR11 related genes were screened using LinkOmics and GEPIA2. Gene Ontology Term Enrichment (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed by David database. The results suggested that the expression of PRR11 in most tumor tissues was significantly higher than that in normal tissues. In LUAD patients, high expression of PRR11 was associated with shortened first progression survival (FPS), overall survival (OS) and post progression survival (PPS), and correlated with individual cancer stage, race, gender, smoking habit, and tissue subtype. Besides, the high expression of PRR11 was accompanied by a relatively higher infiltration level of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cell (MDSC), and decreased infiltration level of CD8+ T cells in the tumor microenvironment. GO analyses showed that PRR11 participated in biological processes such as cell division and cell cycle, and was involved in protein binding and microtubule binding functions. KEGG analyses revealed that PRR11 was implicated in p53 signaling pathway. All the results indicated that PRR11 might be an independent prognostic biomarker and therapeutic target for LUAD.

Conditional Knockout of IL-1R1 in Endothelial Cells Attenuates Seizures and Neurodegeneration via Inhibiting Neuroinflammation Mediated by Nrf2/HO-1/NLRP3 Signaling in Status Epilepticus Model.

Studies on the bench and at bedside have demonstrated that the process of epileptogenesis is involved in neuroinflammatory responses. As the receptor of proinflammatory cytokine IL-1ß, IL-1ß type 1 receptor (IL-1R1) is reported to express abundantly in the endothelial cells in epileptic brains, which is deemed to be implicated in the epileptogenic process. However, whether and how endothelial IL-1R1 modulates neuroinflammatory responses in the pathological process of epileptic seizures and/or status epilepticus (SE) remains obscure. Here, we indicated endothelial IL-1R1 is involved in neuroinflammation, facilitating epilepsy progress via Nrf2/HO-1/NLRP3. In vitro, we observed upregulation of inflammatory cytokines in co-culture model under IL-1ß challenge, as well as in BV2 cells after stimulation with conditional medium (CM) from IL-1ß-stimulated bEnd.3 cells. In vivo, mice with conditional knockout of endothelial IL-1R1 (IL-1R1-CKO) were generated by hybrid IL-1R1flox/flox mice with Tek-Cre mice. IL-1R1-CKO reduced seizure susceptibility in kainic acid (KA)-induced SE model. In addition, IL-1R1-CKO KA mice exhibited lessened hippocampal neuroinflammation, mitigated neuronal damage, and decreased abnormal neurogenesis. In cognitive behavioral tests, IL-1R1-CKO KA mice presented improvement in learning and memory. Furthermore, we also indicated blockage of endothelial IL-1R1 downregulated the expressions of Nrf2/HO-1/NLRP3 pathway-related proteins. Nrf2-siRNA reversed the downregulation of HO-1, NLRP3, caspase-1, and IL-1ß. These results demonstrated CKO of endothelial IL-1R1 reduces seizure susceptibility and attenuates SE-related neurobehavioral damage by suppressing hippocampal neuroinflammation via Nrf2/HO-1/NLRP3.

Comprehensive analysis identifies DNA damage repair-related gene HCLS1 associated with good prognosis in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-associated mortality. Lung adenocarcinoma (LUAD) amounts to more than 40% of all lung malignancies. Therefore, developing clinically useful biomarkers for this disease is critical. DNA damage repair (DDR) is a complicated signal transduction process that ensures genomic stability. DDR should be comprehensively analyzed to elucidate their clinical significance and tumor immune microenvironment interactions. Methods: In this study, DDR-related genes (DRGs) were selected to investigate their prognostic impact on LUAD. A regression-based prognostic model was established based on The Cancer Genome Atlas (TCGA)-LUAD cohort and three external Gene Expression Omnibus (GEO) validation cohorts (GSE31210, GSE68465, and GSE72094). The robust, established model could independently predict the clinical outcomes in patients. Then, the prognostic performance of risk profiles was assessed using a time-dependent receiver operating characteristic (ROC) curve, Cox regression, nomogram, and Kaplan-Meier analyses. Furthermore, the potential biological functions and infiltration status of DRGs in LUAD were investigated with ESTIMATE and CIBERSORT. Finally, the effects of HCLS1 on the clinical features, prognosis, biological function, immune infiltration, and treatment response in LUAD were systematically analyzed. Results: Eleven DRGs were constructed to categorize patients into high- and low-risk groups. The risk score was an independent predictor of overall survival (OS). HCLS1 expression was downregulated in LUAD samples and linked with clinicopathological features. Multivariate Cox regression analysis using the Kaplan-Meier plotter revealed that low HCLS1 expression was independently associated with poor OS. Moreover, the HCLS1 high-expression group had higher immune-related gene expression and ESTIMATE scores. It was positively correlated with the infiltration of M1 macrophages, activated memory CD4 T cells, CD8 T cells, memory B cells, resting dendritic cells, and memory CD4 T cells, Tregs, and neutrophils. Conclusions: A new classification system was developed for LUAD according to DDR characteristics. This stratification has important clinical values, reliable prognosis, and immunotherapy in patients with LUAD. Moreover, HCLS1 is a potential prognostic biomarker of LUAD that correlates with the extent of immune cell infiltration in the tumor microenvironment (TME).

Comprehensive characterization of MUC16 mutations in lung adenocarcinoma for immunotherapies and prognosis: An observational study.

Lung adenocarcinoma (LUAD) is a non-small-cell lung cancer and is the leading cause of cancer-related deaths worldwide. Immunotherapy is a promising candidate for LUAD, and tumor mutation burden (TMB) could be a new biomarker to monitor the response of cancer patients to immunotherapy. It is known that the mucin 16 (MUC16) mutation is the most common and affects the progression and prognosis of several cancers. However, whether MUC16 mutations are associated with TMB and tumor-infiltrating immune cells in LUAD is not fully elucidated. All the data were obtained from the cancer genome atlas database to assess the prognostic value and potential mechanism of MUC16 in LUAD. An immune prognostic model (IPM) was developed based on immune-related genes that could be differentially expressed between MUC16MUT and MUC16WT LUAD patients. Later, the IPM effect on the prognosis and immunotherapy of LUAD was comprehensively evaluated. MUC16 was frequently mutated in LUAD, with a mutational frequency of 43.4%, significantly associated with higher TMB and better clinical prognosis. Based on 436 patients with LUAD, an IPM was established and validated to differentiate patients with a low or high risk of poor survival. The univariate and multivariate Cox regression analyses demonstrated that the IPM was an independent prognostic indicator for LUAD patients. Elevated expressions of PD-L1, LAG3, PDCD1, and SIGLEC15, and most of the T-effector and interferon-γ gene signatures, were depicted in the high-risk group. Moreover, the nomogram using the IPM and clinical prognostic factors also predicted the overall survival and clinical utility. Our project developed a robust risk signature depending on the MUC16 status and provided novel insights for individualized treatment options for LUAD patients.

Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.

Heme-heme oxygenase-2 reduces the atherosclerosis by preventing inflammation.

Objective: Heme oxygenase (HO) has been shown to have important antioxidant and anti-inflammatory properties, resulting in a vascular antitherogenic effect. This study was undertaken to evaluate the role of HO-2 in atherosclerosis. Method and results: The expression levels of HO-2 were evaluated in M1 and M2 bone marrow macrophage induced by LPS and IL4. The expression of HO-2 was significantly higher in M2 macrophage than in M1 macrophage. Western diet (WD) caused a significant increase in HO-2 expression in ApoE-/- mice. The adeno-associated viral (AAV) vectors expressing HO-2 was constructed, and the mice were received saline (ApoE-/-), AAV (ApoE-/-), AAV-HO-2 (ApoE-/-) on WD at 12 weeks and their plasma lipids, inflammatory cytokines, atherosclerosis were evaluated for 16 weeks. The results showed AAV-HO-2 was robust, with a significant decrease in the en face aortas, lipids levels, inflammatory cytokines and M1 macrophage content in AAV-HO-2 ApoE-/- compared to control AAV-ApoE-/-. Conclusion: HO-2 expression in macrophages plays an important role of the antiatherogenic effect, decreasing the inflammatory component of atherosclerotic lesions. These results suggest that HO-2 may be a novel therapeutic target for cardiovascular diseases.

Regulation of adipose tissue development and energy metabolism by VEGFB isoforms.

Obesity is caused by imbalanced energy intake and expenditure. Excessive energy intake and storage in adipose tissues are associated with many diseases. Several studies have demonstrated that vascular growth endothelial factor B (VEGFB) deficiency induces obese phenotypes. However, the roles of VEGFB isoforms VEGFB167 and VEGFB186 in adipose tissue development and function are still not clear. In this study, genetic mouse models of adipose-specific VEGFB167 and VEGFB186 overexpression (aP2-Vegfb167 tg/+and aP2-Vegfb186tg/+) were generated and their biologic roles were investigated. On regular chow, adipose-specific VEGFB186 is negatively associated with white adipose tissues (WATs) and positively regulates brown adipose tissues (BATs). VEGFB186 upregulates energy metabolism and metabolism-associated genes. In contrast, VEGFB167 has a nominal role in adipose development and function. On high-fat diet, VEGFB186 expression can reverse the phenotypes of VEGFB deletion. VEGFB186 overexpression upregulates BAT-associated genes and downregulates WAT-associated genes. VEGFB186 and VEGFB167 have very distinct roles in the regulation of adipose development and energy metabolism. As a key regulator of adipose tissue development and energy metabolism, VEGFB186 may be a target for obesity prevention and treatment.

Lipopolysaccharide (LPS) increases susceptibility to epilepsy via interleukin-1 type 1 receptor signaling.

Epilepsy is the most common disease of the nervous system, characterized by aberrant normal brain activity. Neuroinflammation is a prominent feature in the brain in epileptic humans and animal models of epilepsy. However, it remains elusive as to how peripheral inflammation affects epilepsy. Herein we demonstrated significantly greater seizure susceptibility and severity of epilepsy under kainic acid (KA) via intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) in mouse model of epilepsy. Nissl staining was employed for assessment of the neuronal damage, immunofluorescence for staining of the microglial cells and astrocytes in the mouse brain slices, and ELISA for detection of the changes of inflammatory factors. We observed a smaller population of viable neurons in CA1 and CA3 regions, a greater population of IBA-1-positive and GFAP-positive cells, with a significant upregulation of IL-1ß and IL-6 in hippocampus of epileptic mice when treated with LPS, indicating that LPS aggravates hippocampal neuron injury in epilepsy, and induces neuroinflammation in the hippocampus. In addition, we provide an evident increase in BrdU+/DCX+ and Nestin+ cell populations in dentate gyrus (DG) in LPS-treated group, versus saline group on epileptic mouse model, which demonstrated LPS treatment enhanced hippocampal neurogenesis. In order to investigate whether interleukin-1 type 1 (IL-1R1) signaling is involved in this process, we adopted IL-1R1 globally restored mice (IL-1R1GR/GR) as an IL-1R1 reporter to visualize labeling of IL-1R1 mRNA and protein by means of RFP staining. Strikingly, the RFP immunofluorescence revealed increased IL-1R1 expression in LPS-treated group, versus saline group. Further, blockage of central IL-1R1 alleviated seizure susceptibility and severity of epilepsy. In summary, our findings suggested that LPS could enhance central inflammatory response and aggravate the susceptibility to epileptic seizure, which we postulated to be mediated by IL-1R1.