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关键词： Protein aggregates   Immunogenicity   Vessel wall   Vascular toxicity   Protein corona   Fc gamma R   Membrane microparticles   Biologics   Contaminants  

摘要： In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200-2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1-20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNF alpha-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on Fc gamma RII receptor expression on HUVEC, which increased after TNF alpha-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNF alpha-stimulated HUVEC via Fc gamma RII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.

关键词： 3 '-UTR haplotype   HLA-G   Northwest Iran   polymorphisms   recurrent spontaneous abortion  

摘要： Background and Objective(s)Human leukocyte antigen-G (HLA-G) is a critical protein in immune regulation and tolerance. Recurrent spontaneous abortion (RSA) is a complex disease influenced by genetic, immune dysfunction, and environmental factors. This study investigates the role of HLA-G polymorphisms in the development of *** samples were collected from 80 women with RSA and 200 women without a history of RSA. After DNA extraction, PCR was used to sequence the 3 '-UTR region. Allelic and genotypic frequencies were analyzed, and Haploview software was used for haplotype *** polymorphisms did not significantly differ between the two groups. However, haplotype analysis revealed significant differences. The UTR-2 haplotype was more frequent in the RSA group compared to the healthy control group (p = 0.020), suggesting a potential association. Conversely, the UTR-4 haplotype had a significantly lower frequency in the RSA group (p = 0.041), indicating a protective role against *** individual polymorphisms did not differ significantly, haplotype analysis identified significant associations with RSA. These findings provide valuable insights into the genetic basis of the disease and may contribute to the development of new treatments and diagnostic tools.

关键词： Breast cancer   Multidrug resistance   Nanoparticles   Emodin   Epithelial mesenchymal transition  

摘要： Multidrug resistance (MDR) is one of the main reasons affecting the efficacy of chemotherapy in breast cancer (BC). Our previous studies constructed polymer lipid hybrid nanoparticles encapsulated with Emodin (EMO) (E-PLNs) and proved that they can inhibit epithelial mesenchymal transition (EMT) and reverse MDR in BC. This study aims to explore the mechanisms by which the EMT involved in MDR and the E-PLNs exerted effects. The prepared E-PLNs were characterized by Dynamic light scattering, infrared spectroscopy, X-ray, and differential scanning calorimetry. The effects of drugs or treatments were evaluated by detecting cell viability, apoptosis, invasion, EMT markers, and MDR related proteins in vitro. The results showed that IL-6 could promote proliferation, EMT, invasion and MDR of MCF-7/ADR cells (induced from MCF-7 cells) by activating the JAK2/STAT3 signaling pathway, and these effects could be reversed by AG490 (JAK2 inhibitor) or E-PLNs combined with Doxorubicin (DOX). E-PLNs might be an effective MDR reversal agent for BC. Polymer lipid hybrid nanoparticles encapsulated with Emodin had good physical and chemical properties, improving the bioavailability and efficacy of Emodin. Compared with parental MCF-7 cells, MCF-7/ADR cells overexpressed markers of epithelial mesenchymal transition (EMT), and Galunisertib (EMT inhibitor) inhibited EMT and reversed MDR. Compared with parental MCF-7 cells, MCF-7/ADR cells secreted high level of IL-6. Exogenous IL-6 promoted proliferation, invasion, EMT, and MDR of MCF-7/ADR cells by activating the JAK2/STAT3 pathway. AG490 (JAK2 inhibitor) and/or E-PLNs combined with DOX downregulated the IL-6/JAK2/STAT3 pathway and inhibited its mediated proliferation, invasion, EMT, and MDR in MCF-7/ADR cells.

关键词： CAR-NK   CXCL10   CXCR3   Immunotherapy   Ovarian cancer  

摘要： Introduction: Ovarian cancer is the most malignant gynecological tumor. Previous studies have demonstrated that chimeric antigen receptor (CAR)-engineered NK-92 cells targeting folate receptor alpha (alpha FR) (NK-92-alpha FR-CAR) can specifically kill alpha FR-positive ovarian cancer cells. However, the migration barrier restricts antitumor effects of CAR-engineered cells. Objectives: To elucidate the mechanism by which NK-92-alpha FR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92-alpha FR-CAR-CXCR3A can target alpha FR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer. Methods: Study the mechanism of CXCL10 expression strongly induced by TNF-alpha and IFN-gamma combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92-alpha FR-CAR-CXCR3A cells, which were coexpressed CXCR3A and alpha FR-CAR. Evaluate the killing and migration effects of NK-92-alpha FR-CAR-CXCR3A in vitro and in vivo. Results: RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92-alpha FR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN-gamma and TNF-alpha secreted by NK-92-alpha FR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN-gamma and TNF-alpha enhanced the activation level of the IFN-gamma-IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92-alpha FR-CAR-CXCR3A cells could not only efficiently kill alpha FR-positive ovarian cancer cells in vitro but also secrete IFN-gamma and TNF-alpha. Higher migration than that of NK-92-alpha FR-CAR was detected in NK-92 alpha FR-CAR-CXCR3A using transwell assay. NK-92-alpha FR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and i

关键词： HLA-DPB1*03:01:27   HLA   next-generation sequencing (NGS)  

摘要： The novel HLA-DPB1*03:01:27 allele differs from HLA-DPB1*03:01:01 by one nucleotide substitution in codon 199 exon 4.

关键词： Microglia   Displacement   Synapse   Homeostasis   Motor learning  

摘要： Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1 beta negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1 beta on synaptic displacement. This study demonstrates that IL-1 beta is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.

关键词： Idiopathic pulmonary fibrosis   Barrier integrity   Lung microbiota   IFN gamma   Gut-Lung axis   Xuanfei Baidu Decoction  

摘要： Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia, the available treatment option is limited because the etiology and pathological process are not well understood. Although gut-lung axis reported with an emerging area of host-associated microbiota exist in many chronic lung diseases, the connection between gut-lung microbiota composition with in-site inflammation in IPF development is not yet established. Purpose: We aimed to address the microbiota and immunity connection, and make it clear how a listed drug, Xuanfei Baidu Decoction (XFBD) affect the lung-gut crosstalk for IPF amelioration, which was previously reported for restoring disrupted lung in IPF and protecting intestinal injury. Methods: Firstly, Micro-CT (mu CT) and histopathology were used to check for pathological changes in the lungs and intestines of bleomycin (BLM)-induced IPF mice. Then, Reverse Transcription and Quantitative Real-time PCR (RT-qPCR) and Western blot (WB) assays were employed to detect the integrity of the barrier of lungs and intestines in IPF mice. Subsequently, flow cytometry and 16S rRNA sequencing were used to evaluate the immune and microbial microenvironment of the lungs and intestines. We analyzed the lung-gut microbiota crosstalk for further mechanism exploration. Results: Firstly, we revealed that XFBD protected the integrity of the lung and intestinal barriers in the IPF mice, as evidenced by the up-regulation of ZO-1, Claudin-1, Occludin, and VE Cadherin protein expression. Then, we analyzed the changing microbiota and T cell in the gut-lung axis in IPF, and with XFBD, six highly relevant microenvironments were demonstrated that crossing damaged lung-gut barriers and XFBD could reverse these chaotic bacterial and immunity micro-environment, among them Akkermansia was an essential bacteria affecting the expression of systemic IFN-gamma downstream STAT1/STAT3 axis was also studied. XFBD prominently up-regulated the production of

关键词： Influenza A virus   GRP78   Antiviral   Interferon   Innate immunity  

摘要： Influenza is an acute viral respiratory infection that causes mild to severe illness in humans and animals. Current studies show that glucose-regulated protein 78 (GRP78) can exert crucial functions during viral infection;however, the mechanism by which GRP78 regulates influenza A virus (IAV) infection remains unclear. In the present study, we found that IAV infection increased GRP78 expression. Overexpression of GRP78 significantly inhibited IAV replication, as indicated by reduced viral mRNA levels, protein levels, and viral titers. Mechanistically, Type I interferon (IFN) response signaling is upregulated during IAV infection by GRP78. Further study showed that GRP78 interacts with tyrosine kinase 2 (TYK2) and enhances its phosphorylation, thereby activating downstream STAT1/2 and antiviral IFN-stimulated gene (ISG) expression. Collectively, these results demonstrate an important mechanism by which GRP78 exerts in innate antiviral effect in IAV infection. This mechanism could be used as a therapeutic target for anti-influenza treatment.

关键词： Hepatitis E infection   IL1RN   NKG2A   Polymorphism   Western Indian population  

摘要： Interleukin 1 receptor antagonist (IL1RN) is a competitive inhibitor of interleukin 1 (IL-1). Natural killer cells (NK cells) contribute to the elimination of viruses by their antiviral effector function, which depends on a balance between inhibitory and activating receptor genes such as NKG2D and NKG2A. Using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays, the association of intronic single-nucleotide polymorphisms (SNPs) in these genes with viral infection were assessed in 111 patients with hepatitis E virus (HEV) infection and 222 HEV-naive healthy controls. An SNP in the IL1RN (VNTR) gene revealed allele 2 to be associated with protection against HEV infection (IL1RN *1/*1 vs. IL1RN *2/*2, OR = 0.26, 95% CI = 0.14-0.47, p < 0.001). Similarly, a polymorphism in the intronic region of NKG2A revealed an association with protection in a co-dominant model (A/A vs. A/G: OR = 0.40;95% CI = 0.24-0.67;A/A vs. G/G: OR = 0.25;95% CI = 0.10-0.57;p < 0.05) and an association with susceptibility in a dominant model (A/A + A/G vs. G/G: OR = 2.28;95% CI = 1.06-4.93;p < 0.05) and a recessive model (AA vs. AG + GG: OR = 2.71;95% CI = 1.66-4.48;p < 0.001). Our data suggest that genetic polymorphisms in host NKG2A and IL1RN have both protective and detrimental roles in HEV infection, although their impact on disease outcome remains unknown.