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关键词： NMOSD   Microglia   IL-33   AQP4   ST2  

摘要： Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family. Its function in regulating microglial M1/ M2 polarization in neuromyelitis optica spectrum disorder (NMOSD) is still unelucidated. To evaluate the role of IL-33 in NMOSD, we constructed NMOSD mice model by injecting purified serum IgG from AQP4-IgG seropositive NMOSD patients into experimental autoimmune encephalomyelitis (EAE) mice, and IL-33 was intraperitoneally injected into NMOSD mice 3 d before the model induction. We found that pretreatment of the NMOSD mice with IL-33 relieved brain neuron loss, and demyelination and improved the structure of axons, astrocytes, and mitochondria. In the neuronal and microglial coculture system, pretreatment with IL-33 in microglia alleviated NMOSD serum-induced inflammation and damaged morphology in cultured neurons. IL-33 transformed microglia to the M2 phenotype, and NMOSD serum promoted microglia to the M1 phenotype in cultured BV2 cells. Moreover, IL-33 influenced microglial polarity via the IL-33/ST2 pathway. IL-33 may be a novel insight useful for further developing NMOSD-targeted therapy and drug development.

关键词： Baricitinib   TNF-alpha inhibitors   CDMARDs  

摘要： To evaluate the efficacy of baricitinib compared to TNF-alpha Inhibitors and conventional DMARDs (cDMARDs) in patients with RA. Our study included 334 RA patients classified into 3 groups: the first receiving baricitinib, the second receiving TNF-alpha Inhibitors, and the third receiving cDMARDs. Patients were evaluated at baseline, week 12, and week 24 using TJC, SJC, VAS, DAS28, CDAI, and HAQ-DI. Larsen score was measured at baseline and 24 weeks. The response to therapy was assessed at weeks 12 and 24 using ACR 20, ACR 50, and ACR 70 response criteria. Emerging treatment side effects were monitored. Patients receiving baricitinib showed significant improvement regarding all outcome measures at weeks 12 and 24. In addition, baricitinib was comparable to TNF Inhibitors in all outcome measures except the ACR 70 at week 12, which was higher in the baricitinib group. Furthermore, baricitinib group showed significantly better outcome measures and response to therapy in comparison to cDMARDs group. The most common side effects in the baricitinib group were infection, GIT, and CVS complications. The most common side effects in the TNF inhibitors group were infection and skin complications. The cDMARDs had the least side effects, mostly GIT complications. Baricitinib is an effective drug for treating RA refractory to cDMARDs, improving disease activity measures and functional status and reducing the progression of structural joint damage. It has a comparable efficacy and safety profile to TNF Inhibitors. Multicenter studies are recommended to support our results. Key Points center dot Baricitinib is an effective therapeutic choice for rheumatoid arthritis refractory to *** dot Patients treated with baricitinib showed improvement in all outcome measures and functional *** dot Bricitinib delayed the progression of radiographic joint damage more effectively than *** dot The efficacy and safety of baricitinib for treating rheumatoid arthritis i

关键词： Pluripotent stem cells (PSCs)   Mesoderm   Iinterleukin 10 (IL10)   Zebrafish   Blood vessel organoid   Hindlimb ischemia   Vasculogenesis and angiogenesis  

摘要： Mesoderm induction is a crucial step for vascular cell specification, vascular development and vasculogenesis. However, the cellular and molecular mechanisms underlying mesoderm induction remain elusive. In the present study, a chemically-defined differentiation protocol was used to induce mesoderm formation and generate functional vascular cells including smooth muscle cells (SMCs) and endothelial cells (ECs) from human induced pluripotent stem cells (hiPSCs). Zebrafish larvae were used to detect an in vivo function of interleukin 10 (IL10) in mesoderm formation and vascular development. A three dimensional approach was used to create hiPSCderived blood vessel organoid (BVO) and explore a potential impact of IL10 on BVO formation. A murine model hind limb ischemia was applied to investigate a therapeutic potential of hiPSC-derived cells treated with or without IL10 during differentiation. We found that IL10 was significantly and specifically up-regulated during mesoderm stage of vascular differentiation. IL10 addition in mesoderm induction media dramatically increased mesoderm induction and vascular cell generation from hiPSCs, whereas an opposite effect was observed with IL10 inhibition. Mechanistic studies revealed that IL10 promotes mesoderm formation and vascular cell differentiation by activating signal transducer and activator of transcription 3 signal pathway. Functional studies with an in vivo model system confirmed that knockdown of IL10 using morpholino antisense oligonucleotides in zebrafish larvae caused defective mesoderm formation, angiogenic sprouting and vascular development. Additionally, our data also show IL10 promotes blood vessel organoid development and enhances vasculogenesis and angiogenesis. Importantly, we demonstrate that IL10 treatment during mesoderm induction stage enhances blood flow perfusion recovery and increases vasculogenesis and therapeutic angiogenesis after hind limb ischemia. Our data, therefore, demonstrate a regulatory role

关键词： IL-8   CXCL8   Transgenic mouse   Neointima  

摘要： IL-8 (aka interleukin 8, CXCL8) is a prototypic cytokine that is highly expressed in the diseased vessel wall and its plasma concentration is strongly associated with cardiovascular events. However, whether IL-8 plays a causative role in cardiovascular diseases remains largely unknown. In this study we used a human IL-8 transgenic (Tg) mouse strain with a bacterial artificial chromosome (BAC) integrated into its genome. This BAC encompasses 166 kb of sequence encompassing the human IL-8 gene locus as well as upstream and downstream DNA sequences containing regulatory elements. This BAC ensured a pathophysiologically regulated, rather than forced constitutive, expression of human IL-8 in the mouse. Tg mice were subjected to complete carotid ligation injury. IL-8 was highly expressed in the ligation-injured carotid artery from 3 days until 2 weeks after injury. As a result, exacerbated neointimal hyperplasia and increased Mac2 and PCNA positive cells were observed in Tg mice. To further confirm its role in promoting neointimal formation, IL-8 was neutralized by anti-IL8 treatment at the ligation site. Consequently, the size of neointima was significantly reduced. Our results provided new insights into the regulation and function of IL-8 in response to vascular insult and during neointima formation.

关键词： Discrimination   Negative cognitive triad   TNF-alpha   Depression   Adolescents  

摘要： Our study is guided by Beck's cognitive stress-vulnerability model of depression. We examined the associations between perceived everyday discrimination (PED) and TNF-alpha, an inflammatory biomarker associated with risk for severe illness, through the negative cognitive triad (NCT;negative thoughts about the self, world, and future) and depressive symptoms in adolescents. We utilized a sample of 99 adolescents (36.4% female;ages 13-16, M = 14.10, SD = 0.52) in our cross-sectional study. We used PROCESS and AMOS to compute regressions and direct, indirect, and total effects of PED, NCT aspects and depressive symptoms on TNF-alpha. Negative views of the self and world mediated between PED and depressive symptoms and that negative views of the self and future mediated between PED and TNF-alpha. In conclusion, Beck's theory can be expanded to physical health providing directions for addressing mental and physical health simultaneously by restructuring adolescents' negative view of the self.

关键词： Wiskott-Aldrich syndrome protein   Regulatory T cell   IL2 receptor   Internalization   Degradation  

摘要： Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency condition caused by ablation of functional WAS protein (WASP) expression, and associated with susceptibility to infections, eczema, and autoimmunity. Regulatory T cell (Treg) defects are an important cause of autoimmunity in WAS. Currently, the mechanisms underlying cytoskeleton involvement in Treg-regulated autoimmunity remain unclear, and WAS is an excellent model for investigation of this question. Here, we examined patients with WAS and WASP knockout (WASp- /- ) mice to uncover a new mechanism involving the actin nucleation promoting factor, WASP, in regulating Treg tolerance by modulating their surface IL-2 receptor (IL-2R) levels. Surface expression levels of IL-2R and its downstream signaling molecules, phosphoinositide 3-kinase/pSTAT5, are decreased in WASp- /- Tregs. Low dosage IL-2 combined with anti-IL-2 monoclonal antibody (IL2 complex) treatment can compensate for Treg deficiency in WAS in vitro and in vivo. Moreover, IL2 complex treatment relieved autoimmune colitis in WASp- / - mice. Reduced surface IL-2R is primarily caused by elevated IL-2R internalization and degradation, and lysosomal and endosomal genes associated with these processes are upregulated in WASp- /- Tregs. Finally, spatiotemporal analysis of dynamin and Neural Wiskott Aldrich Syndrome Protein (N-WASP) recruitment, by generating lipid bilayers and total internal reflection fluorescence microscopy, showed that WASP deficiency promoted IL-2R internalization and degradation by enhancing N-WASP activation. Consistently, N-WASP inhibition in Tregs using wiskostatin reduced IL-2R internalization. Together, our results reveal a novel intrinsic role of WASP in regulation of surface IL-2R dynamics in Tregs, highlighting a potential new therapeutic approach for autoimmune diseases.

关键词： HLA-B   Indian   next generation sequencing   novel allele  

摘要： HLA-B*13:01:01:12 differs from HLA-B*13:01:01:01 by a single nucleotide.

关键词： diabetic kidney disease   EGCG   green tea   inflammation   NLRP3   TXNIP  

摘要： Recent research indicates that the activation of the NLRP3 inflammasome is crucial in the development of diabetic kidney disease (DKD). Epigallocatechin-3-gallate (EGCG), the predominant catechin in green tea, has been noted for its anti-inflammatory properties in DKD. However, the specific mechanisms are not yet fully understood. In this study, our objective was to explore the effects of EGCG on podocytes and in diabetic kidney disease (DKD) mice and investigate how EGCG modulates the TXNIP/NLRP3/IL-1 beta signaling pathway in DKD, both in podocytes and animal models. In vitro, we co-cultured podocytes with EGCG and detected the viability, apoptosis, inflammation and the TXNIP/NLRP3/IL-1 beta signaling pathway. In vivo, DKD mice were given EGCG via oral gavage, followed by evaluations of renal function, inflammation, and the aforementioned signaling pathway. Our findings revealed that oxidative stress, inflammatory cytokines, and the TXNIP/NLRP3/IL-1 beta pathway were upregulated in podocytes exposed to high glucose (HG) and in the kidneys of DKD mice. However, EGCG treatment reduced the expression of the NLRP3 inflammasome and its associated proteins, including TXNIP, ASC, caspase-1, and IL-1 beta, as well as the levels of ROS and inflammatory factors such as TNF-alpha, IL-6, and IL-18. Furthermore, in vivo, EGCG improved kidney function, reduced albuminuria and body weight, and alleviated renal pathological damage. In summary, our study suggests that EGCG mitigates inflammation in podocytes and DKD through the TXNIP/NLRP3/IL-1 beta signaling pathway, indicating potential benefits of EGCG or green tea in managing DKD.

关键词： HLA-B*44:418   NGS HLA typing novel   novel HLA-B allele  

摘要： The new HLA-B*44:418 allele showed one non-synonymous nucleotide difference compared with the HLA-B*44:05:01:01 allele in codon 12.