191 results
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2. Opinion paper: Stimulation of complement amplification or activation of the alternative pathway of complement?
- Author
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Lutz HU, Fumia S, Schurtenberger C, and Alaia V
- Subjects
- Animals, Humans, Complement Pathway, Alternative immunology, Complement System Proteins immunology
- Abstract
In this opinion paper, we suggest that the scheme of the complement system should be redrawn in order to better illustrate its potencies. This can be achieved by putting the amplification loop of the alternative complement pathway at the center of the complement system. This arrangement emphasizes that C3b molecules, generated by any pathway, can stimulate complement amplification. Furthermore, it allows one to differentiate between this type of stimulation of amplification and that driven by those immune complexes that capture dimeric C3b molecules, which are more potent C3 convertase precursors than C3b. Schemes similar to the one drawn may help to better illustrate the interplay of the pathways and convey a clearer comprehension of the mechanics of the complement system.
- Published
- 2007
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3. Structural differences among serum IgA proteins of chimpanzee, rhesus monkey and rat origin.
- Author
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Endo T, Radl J, and Mestecky J
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- Animals, Carbohydrate Sequence, Chromatography, Gel, Electrophoresis, Paper, Macaca mulatta, Molecular Sequence Data, Oligosaccharides chemistry, Pan troglodytes, Protein Conformation, Rats, Sialic Acids chemistry, Species Specificity, Carbohydrate Conformation, Immunoglobulin A chemistry
- Abstract
Asparagine-linked sugar chains were quantitatively released from chimpanzee, Rhesus monkey and rat IgA proteins as oligosaccharides by hydrazinolysis, converted to radioactive oligosaccharides by reduction with NaB3H4, and separated into neutral and two acidic fractions by paper electrophoresis. The acidic oligosaccharides were converted to neutral ones by sialidase digestion, indicating that they are sialyl derivatives. However, the content of N-acetyl and N-glycolyl neuraminic acids was different among three species. The neutral and sialidase-treated acidic oligosaccharides were fractionated by Bio-Gel P-4 column chromatography in combination with linkage-specific sequential exoglycosidase digestion. Although IgA molecules from these species have mainly biantennary complex-type sugar chains, the contents of fucose and bisecting N-acetylglucosamine residues displayed marked species differences. In addition to these sugar chains, a small amount of the high mannose-type sugar chains was detected in chimpanzee and rat, but not in Rhesus monkey IgA. These results indicated that the processing of asparagine-linked sugar chains of IgA is different in each species.
- Published
- 1997
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4. An amino acid substitution in the gamma 1 chain of human immunoglobulin G associated with the Gm (2) allotype.
- Author
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Cook CE and Steinberg AG
- Subjects
- Amino Acid Sequence, Chromatography, Paper, Chromatography, Thin Layer, Epitopes, Humans, Immunoglobulin Fc Fragments, Myeloma Proteins immunology, Peptide Fragments analysis, Immunoglobulin Allotypes, Immunoglobulin G
- Published
- 1979
- Full Text
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5. An analysis of B-cell epitope discontinuity
- Author
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Adrian J. Shepherd and Ganesh N. Sivalingam
- Subjects
Functional epitope ,ASA, accessible surface area ,Immunology ,Structural epitope ,Peptide ,Computational biology ,Antigen-Antibody Complex ,Biology ,Crystallography, X-Ray ,Epitope ,Article ,Antigen ,PDB, Protein Data Bank ,Databases, Protein ,Molecular Biology ,Antibody ,Sequence (medicine) ,chemistry.chemical_classification ,Linear epitope ,computer.file_format ,Protein Data Bank ,Discontinuity (linguistics) ,chemistry ,biology.protein ,Epitopes, B-Lymphocyte ,Peptides ,computer - Abstract
Highlights ► All the structural B-cell epitopes we examined are discontinuous. ► Only 18% of structural epitopes are spanned by a peptide fragment of 40 residues. ► Centralized and random distributions were considered for key functional residues. ► Fragments with only 7 residues will successfully span most key functional residues., Although it is widely acknowledged that most B-cell epitopes are discontinuous, the degree of discontinuity is poorly understood. For example, given that an antigen having a single epitope that has been chopped into peptides of a specific length, what is the likelihood that one of the peptides will span all the residues belonging to that epitope? Or, alternatively, what is the largest proportion of the epitope's residues that any peptide is likely to contain? These and similar questions are of direct relevance both to computational methods that aim to predict the location of epitopes from sequence (linear B-cell epitope prediction methods) and window-based experimental methods that aim to locate epitopes by assessing the strength of antibody binding to synthetic peptides on a chip. In this paper we present an analysis of the degree of B-cell epitope discontinuity, both in terms of the structural epitopes defined by a set of antigen–antibody complexes in the Protein Data Bank, and with respect to the distribution of key residues that form functional epitopes. We show that, taking a strict definition of discontinuity, all the epitopes in our data set are discontinuous. More significantly, we provide explicit guidance about the choice of peptide length when using window-based B-cell epitope prediction and mapping techniques based on a detailed analysis of the likely effectiveness of different lengths.
- Published
- 2012
6. Inhibiting caspase-3/GSDME-mediated pyroptosis ameliorates septic lung injury in mice model.
- Author
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Qin H, Lu N, Chen K, Huang Y, Rui Y, Huang L, Gao Q, and Hu J
- Subjects
- Animals, Mice, Male, Mice, Inbred C57BL, Interleukin-6 metabolism, Caspase Inhibitors pharmacology, Lung pathology, Lung metabolism, Oligopeptides pharmacology, Gasdermins, Pyroptosis drug effects, Sepsis complications, Disease Models, Animal, Caspase 3 metabolism, Acute Lung Injury pathology
- Abstract
Acute lung injury is one of the most serious complications of sepsis, which is a common critical illness in clinic. This study aims to investigate the role of caspase-3/ gasdermin-E (GSDME)-mediated pyroptosis in sepsis-induced lung injury in mice model. Cecal ligation (CLP) operation was used to establish mice sepsis-induced lung injury model. Lung coefficient, hematoxylin and eosin staining and transmission electron microscopy were used to observe the lung injury degree. In addition, caspase-3-specific inhibitor Z-DEVD-FMK and GSDME-derived inhibitor AC-DMLD-CMK were used in CLP model, caspase-3 activity, GSDME immunofluorescence, serum lactate dehydrogenase (LDH) and interleukin-6 (IL-6) levels, TUNEL staining, and the expression levels of GSDME related proteins were detected. The mice in CLP group showed the increased expressions of cleaved-caspase-3 and GSDME-N terminal, destruction of lung structure, and the increases of LDH, IL-6, IL-18 and IL-1β levels, which were improved in mice treated with Z-DEVD-FMK or AC-DMLD-CMK. In conclusion, caspase-3/GSDME mediated pyroptosis is involved in the occurrence of sepsis-induced lung injury in mice model, inhibiting caspase-3 or GSDME can both alleviate lung injury., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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7. Anti-ulcerative colitis effect of rotating magnetic field on DSS-induced mice by modulating colonic inflammatory deterioration.
- Author
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Yang H, Zhou C, Nie S, Xu S, Li M, Yu Q, Wei Y, and Wang X
- Subjects
- Animals, Mice, Magnetic Field Therapy methods, Male, Inflammation pathology, Disease Models, Animal, Magnetic Fields, Mice, Inbred C57BL, Colitis, Ulcerative chemically induced, Colitis, Ulcerative pathology, Dextran Sulfate toxicity, Colon pathology, Cytokines metabolism
- Abstract
Ulcerative colitis (UC) is a prevalent inflammatory disorder that emerges in the colon and rectum, exhibiting a rising global prevalence and seriously impacting the physical and mental health of patients. Significant challenges remain in UC treatment, highlighting the need for safe and effective long-term therapeutic approaches. Heralded as a promising physical treatment, the rotating magnetic field (RMF) demonstrates safety, stability, manageability, and efficiency. This study delves into RMF's potential in mitigating DSS-induced UC in mice, assessing disease activity indices (DAI) and pathological alterations such as daily body weight, fecal occult blood, colon length, and morphological changes. Besides, several indexes have been detected, including serum concentrations of pro-inflammatory cytokines (IL6, IL-17A, TNF-α, IFN-γ) and anti-inflammatory cytokines (TGF-β, IL-4, IL-10), the ratio of splenic CD3+, CD4+, and CD8+ T cells, the rate of apoptotic colonic cells, the expression of colonic inflammatory and tight junction-associated proteins. The results showed that RMF had beneficial effects on the decrease of intestinal permeability, the restoration of tight junctions, and the mitigation of mitochondrial respiratory complexes (MRCs) by attenuating inflammatory dysfunction in colons of DSS-induced UC model of mice. In conclusion, this study demonstrates that RMF attenuates colonic inflammation, enhances colonic tight junction, and alleviates MRCs impairment by regulating the equilibrium of pro-inflammatory and anti-inflammatory cytokines in UC mice, suggesting the potential application of RMF in the clinical treatment of UC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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8. The roles of B cells in cardiovascular diseases.
- Author
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Ma J, Wang X, Jia Y, Tan F, Yuan X, and Du J
- Subjects
- Humans, Animals, Fibrosis immunology, Cardiovascular Diseases immunology, B-Lymphocytes immunology
- Abstract
Damage to the heart can start the repair process and cause cardiac remodeling. B cells play an important role in this process. B cells are recruited to the injured place and activate cardiac remodeling through secreting antibodies and cytokines. Different types of B cells showed specific functions in the heart. Among all types of B cells, heart-associated B cells play a vital role in the heart by secreting TGFβ1. B cells participate in the activation of fibroblasts and promote cardiac fibrosis. Four subtypes of B cells in the heart revealed the relationship between the B cells' heterogeneity and cardiac remodeling. Many cardiovascular diseases like atherosclerosis, heart failure (HF), hypertension, myocardial infarction (MI), and dilated cardiomyopathy (DCM) are related to B cells. The primary mechanisms of these B cell-related activities will be discussed in this review, which may also suggest potential novel therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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9. Rosmarinic acid activates the Ras/Raf/MEK/ERK signaling pathway to regulate CD8+ T cells and autophagy to clear Chlamydia trachomatis in reproductive tract-infected mice.
- Author
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Yun ZS, Zhihua S, Xuelian T, Min X, Rongjing H, and Mei L
- Subjects
- Animals, Female, Mice, ras Proteins metabolism, raf Kinases metabolism, Disease Models, Animal, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects, Autophagy drug effects, Chlamydia Infections immunology, Chlamydia Infections drug therapy, Chlamydia trachomatis drug effects, Chlamydia trachomatis immunology, Depsides pharmacology, MAP Kinase Signaling System drug effects, Rosmarinic Acid, Cinnamates pharmacology
- Abstract
Chlamydia trachomatis (CT) is the leading cause of bacterial sexually transmitted diseases worldwide, which can cause diseases such as pelvic inflammatory disease, and cervical and fallopian tube inflammation, and poses a threat to human health. Rosmarinic acid (RosA) is an active ingredient of natural products with anti-inflammatory and immunomodulatory effects. This study aimed to investigate the role of RosA in inhibiting autophagy-regulated immune cells-CD8+ T cells via the Ras/Raf/MEK/ERK signaling pathway in a CT-infected mouse model. Mice were inoculated with CT infection solution vaginally, and the mechanistic basis of RosA treatment was established using H&E staining, flow cytometry, immunofluorescence, transmission electron microscopy, and western blot. The key factors involved in RosA treatment were further validated using the MEK inhibitor cobimetinib. Experimental results showed that both RosA and the reference drug azithromycin could attenuate the pathological damage to the endometrium caused by CT infection; flow cytometry showed that peripheral blood CD8+ T cells increased after CT infection and decreased after treatment with RosA and the positive drug azithromycin (positive control); immunofluorescence showed that endometrial CD8 and LC3 increased after CT infection and decreased after RosA and positive drug treatment; the results of transmission electron microscopy showed that RosA and the positive drug azithromycin inhibited the accumulation of autophagosomes; western bolt experiments confirmed the activation of autophagy proteins LC3Ⅱ/Ⅰ, ATG5, Beclin-1, and p62 after CT infection, as well as the inhibition of Ras/Raf/MEK/ERK signaling. RosA and azithromycin inhibition of autophagy proteins activates Ras/Raf/MEK/ERK signaling. In addition, the MEK inhibitor cobimetinib attenuated RosA's protective effect on endometrium by further activating CD8+ T cells on a CT-induced basis, while transmission electron microscopy, immunofluorescence, and western blots showed that cobimetinib blocked ERK signals activation and further induced phagocytosis on a CT-induced basis. These data indicated that RosA can activate the Ras/Raf/MEK/ERK signaling pathway to inhibit autophagy, and RosA could also regulate the activation of immune cells-CD8+T cells to protect the reproductive tract of CT-infected mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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10. Recruitment or activation of mast cells in the liver aggravates the accumulation of fibrosis in carbon tetrachloride-induced liver injury.
- Author
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Zhang M, Yang J, Yuan Y, Zhou Y, Wang Y, Cui R, Maliu Y, Xu F, and Wu X
- Subjects
- Animals, Rats, Male, Transforming Growth Factor beta1 metabolism, Rats, Sprague-Dawley, Ketotifen pharmacology, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Chemical and Drug Induced Liver Injury immunology, Oxidative Stress drug effects, NF-E2-Related Factor 2 metabolism, Signal Transduction drug effects, Smad2 Protein metabolism, Smad3 Protein metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Vascular Endothelial Growth Factor A metabolism, Mast Cells metabolism, Mast Cells immunology, Mast Cells drug effects, Carbon Tetrachloride toxicity, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Liver Cirrhosis immunology, Liver Cirrhosis chemically induced, Cromolyn Sodium pharmacology, Liver pathology, Liver metabolism, Liver drug effects
- Abstract
Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-β1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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11. Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation.
- Author
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Wu B, Li D, Bai H, Mo R, Li H, Xie J, Zhang X, Yang Y, Li H, Idris A, Li X, and Feng R
- Subjects
- Animals, Humans, Active Transport, Cell Nucleus, Cell Nucleus metabolism, HEK293 Cells, Immunity, Innate immunology, Interferon-beta metabolism, Interferon-beta immunology, Phosphorylation, Protein Serine-Threonine Kinases, Reoviridae Infections immunology, Viral Proteins metabolism, DEAD Box Protein 58 metabolism, Interferon Regulatory Factor-3 metabolism, Interferon-Induced Helicase, IFIH1 metabolism, Interferon-Induced Helicase, IFIH1 genetics, Orthoreovirus, Mammalian immunology, Orthoreovirus, Mammalian physiology, Receptors, Immunologic, Signal Transduction immunology, Capsid Proteins metabolism
- Abstract
Mammalian reovirus (MRV) is a non-enveloped, gene segmented double-stranded RNA (dsRNA) virus. It is an important zoonotic pathogen that infects many mammals and vertebrates that act as natural hosts and causes respiratory and digestive tract diseases. Studies have reported that RIG-I and MDA5 in the innate immune cytoplasmic RNA-sensing RIG-like receptor (RLR) signaling pathway can recognize dsRNA from MRV and promote antiviral type I interferon (IFN) responses. However, the mechanism by which many MRV-encoded proteins evade the host innate immune response remains unclear. Here, we show that exogenous μ1 protein promoted the proliferation of MRV in vitro, while knockdown of MRV μ1 protein expression by shRNA could impair MRV proliferation. Specifically, μ1 protein inhibited MRV or poly(I:C)-induced IFN-β expression, and attenuated RIG-I/MDA5-mediated signaling axis transduction during MRV infection. Importantly, we found that μ1 protein significantly decreased IFN-β mRNA expression induced by MDA5, RIG-I, MAVS, TBK1, IRF3(5D), and degraded the protein expression of exogenous MDA5, RIG-I, MAVS, TBK1 and IRF3 via the proteasomal and lysosomal pathways. Additionally, we show that μ1 protein can physically interact with MDA5, RIG-I, MAVS, TBK1, and IRF3 and attenuate the RIG-I/MDA5-mediated signaling cascades by blocking the phosphorylation and nuclear translocation of IRF3. In conclusion, our findings reveal that MRV outer capsid protein μ1 is a key factor in antagonizing RLRs signaling cascades and provide new strategies for effective prevention and treatment of MRV infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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12. Prednisone combined with Dihydroartemisinin attenuates systemic lupus erythematosus by regulating M1/M2 balance through the MAPK signaling pathway.
- Author
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Chen Y, Tao T, Liang Z, Chen X, Xu Y, Zhang T, and Zhou D
- Subjects
- Animals, Humans, Mice, Cytokines metabolism, Disease Models, Animal, Drug Therapy, Combination, Macrophages drug effects, Macrophages metabolism, Artemisinins pharmacology, Artemisinins therapeutic use, Lupus Erythematosus, Systemic drug therapy, MAP Kinase Signaling System drug effects, Prednisone pharmacology, Prednisone therapeutic use
- Abstract
Objective: Dihydroartemisinin (DHA) plays a very important role in various diseases. However, the precise involvement of DHA in systemic lupus erythematosus (SLE), relation to the equilibrium between M1 and M2 cells, remains uncertain. Therefore, we aimed to investigate the role of DHA in SLE and its effect on the M1/M2 cells balance., Methods: SLE mice model was established by pristane induction. Flow cytometry was employed to measure the abundance of M1 and M2 cells within the peripheral blood of individuals diagnosed with SLE. The concentrations of various cytokines, namely TNF-α, IL-1β, IL-4, IL-6, and IL-10, within the serum of SLE patients or SLE mice were assessed via ELISA. Immunofluorescence staining was utilized to detect the deposition of IgG and complement C3 in renal tissues of the mice. We conducted immunohistochemistry analysis to assess the expression levels of Collagen-I, a collagen protein, and α-SMA, a fibrosis marker protein, in the renal tissues of mice. Hematoxylin-eosin staining, Masson's trichrome staining, and Periodic acid Schiff staining were used to examine histological alterations. In this study, we employed qPCR and western blot techniques to assess the expression levels of key molecular markers, namely CD80 and CD86 for M1 cells, as well as CD206 and Arg-1 for M2 cells, within kidney tissue. Additionally, we investigated the involvement of the MAPK signaling pathway. The Venny 2.1 online software tool was employed to identify shared drug-disease targets, and subsequently, the Cytoscape 3.9.2 software was utilized to construct the "disease-target-ingredient" network diagram. Protein-protein interactions of the target proteins were analyzed using the String database, and the network proteins underwent enrichment analysis for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways., Results: The results showed that an increase in M1 cells and a decrease in M2 cells within the peripheral blood of individuals diagnosed with SLE. Further analysis revealed that prednisone (PDN) combined with DHA can alleviate kidney damage and regulate the balance of M1 and M2 cells in both glomerular mesangial cells (GMC) and kidney. The MAPK signaling pathway was found to be involved in SLE kidney damage and M1/M2 balance in the kidney. Furthermore, PDN and/or DHA were found to inhibit the MAPK signaling pathway in GMC and kidney., Conclusion: We demonstrated that PDN combined with DHA attenuates SLE by regulating M1/M2 balance through MAPK signaling pathway. These findings propose that the combination of PDN and DHA could serve as a promising therapeutic strategy for SLE, as it has the potential to mitigate kidney damage and reinstate the equilibrium of M1 and M2 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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13. Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis.
- Author
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Zhang S, Shan J, Jie Y, Zhang X, Zhu M, Shen J, Mao K, Chen W, Wang Y, and Wen Y
- Subjects
- Animals, Mice, Macrophages immunology, Macrophages drug effects, Macrophages metabolism, Macrophages, Peritoneal immunology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Phosphoinositide-3 Kinase Inhibitors pharmacology, Signal Transduction drug effects, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases metabolism, Mice, Inbred C57BL, Pyroptosis drug effects, Sepsis immunology, Sepsis drug therapy, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory drug effects, Th17 Cells immunology, Th17 Cells drug effects
- Abstract
Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis., Competing Interests: Conflict of Interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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14. Melanoma extracellular vesicles inhibit tumor growth and metastasis by stimulating CD8 T cells.
- Author
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Dan Y, Ma J, Long Y, Jiang Y, Fang L, and Bai J
- Subjects
- Animals, Mice, CD8-Positive T-Lymphocytes, T-Lymphocytes, Cytotoxic, Antigens, Neoplasm, Dendritic Cells, Melanoma, Extracellular Vesicles
- Abstract
Tumor cell-derived extracellular vesicles (EVs) play a crucial role in mediating immune responses by carrying and presenting tumor antigens. Here, we suggested that melanoma EVs triggered cytotoxic CD8 T cell-mediated inhibition of tumor growth and metastasis. Our results indicated that immunization of mice with melanoma EVs inhibited melanoma growth and metastasis while increasing CD8 T cells and serum interferon γ (IFN-γ) in vivo. In vitro experiments showed that melanoma EV stimulates dendritic cells (DCs) maturation, and mature dendritic cells induce T lymphocyte activation. Thus, tumor cell-derived EVs can generate anti-tumor immunity in a prophylactic setting and may be potential candidates for cell-free tumor vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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15. CXCL1-CXCR2 axis mediates inflammatory response after sciatic nerve injury by regulating macrophage infiltration.
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Jiang S, Li W, Song M, Liang J, Liu G, Du Q, Wang L, Meng H, Tang L, Yang Y, and Zhang B
- Subjects
- Animals, Mice, Macrophages metabolism, Phenylurea Compounds pharmacology, Sciatic Nerve, Chemokine CXCL1 metabolism, Peripheral Nerve Injuries, Receptors, Interleukin-8B
- Abstract
Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1β) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves., Competing Interests: Conflicts of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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16. Molecular cloning of the hepcidin gene from crescent sweetlips (Plectorhinchus cinctus) and characterization of its encoded antimicrobial peptide.
- Author
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Wang P, Lin Z, Lin S, Dai Y, Zheng B, Zhang Y, and Hu J
- Subjects
- Animals, Phylogeny, DNA, Complementary genetics, Fishes genetics, Cloning, Molecular, Hepcidins genetics, Antimicrobial Peptides
- Abstract
Hepcidin has been identified as an important antimicrobial peptide exerting important innate immunomodulatory activities in many fish species. In the present study, reverse transcription PCR coupled with the rapid amplification of cDNA ends was used to obtain the full-length cDNA of the crescent sweetlips hepcidin gene, which is 829 bp in length and includes an 273 bp ORF encoding a peptide with 90 amino acid residues. Sequence alignment showed a typical RXKR motif and eight conserved cysteine residues in the deduced amino acid sequences. Four disulfide bonds were predicted to form between these eight cysteines, which may stabilize the hairpin structure in hepcidin molecule. Furthermore, phylogenetic analysis showed that the deduced amino acid sequences of crescent sweetlips hepcidin had high sequence homology to hepcidins from fish species of Eupercaria. In addition, the crescent sweetlips hepcidin peptide demonstrated a strong antimicrobial activity in vitro against several types of pathogenic bacteria in fish. In conclusion, the obtained results suggested that crescent sweetlips hepcidin possessed the typical structure similar to other fish hepcidins and had strong antibacterial activity, which showed great potential in the prevention of fish diseases in aquaculture., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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17. Identification and functional characterization of Caspase-9 in goldfish (Carassius auratus L.) in response to Aeromonas hydrophila infection.
- Author
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Yue X, Liu J, Ban Z, Li X, Jiang J, and Xie J
- Subjects
- Animals, Humans, Goldfish genetics, Aeromonas hydrophila physiology, Immunity, Innate genetics, Caspase 9 metabolism, HEK293 Cells, Fish Proteins genetics, Fish Proteins metabolism, Mammals, Gram-Negative Bacterial Infections veterinary, Fish Diseases
- Abstract
Apoptosis plays a pivotal role in the immune response to combat pathogen infections. In mammals, caspase-9, abbreviated as Casp9, plays an irreplaceable role in the initiation phase of the apoptotic cascade. To investigate the role of Casp9 in teleosts, we conducted a functional characterization of Casp9 in goldfish (Carassius auratus L.). The open reading frame of GfCasp9 spans 1296 base pairs (bp), encoding a protein composed of 431 amino acids. GfCasp9 was ubiquitously expressed in various tissues, with the spleen and brain showing the highest levels of expression. Subcellular localization analysis revealed that GfCasp9 is distributed in both the cytoplasm and nucleus. Overexpressing of GfCasp9 in HEK293 cells elicits a robust apoptotic response. Additionally, infection with Aeromonas hydrophila significantly increases the mRNA and protein expression of GfCasp9. These findings underscore the critical importance of GfCasp9 in immune responses and apoptosis against bacterial infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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18. Progesterone-mediated immunoregulation of cytokine signaling by miRNA-133a and 101-3p in Chlamydia trachomatis-associated recurrent spontaneous abortion.
- Author
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Ray A, Bhati T, Arora R, and Rastogi S
- Subjects
- Pregnancy, Female, Humans, Chlamydia trachomatis, Progesterone, Cytokines metabolism, MicroRNAs genetics, Chlamydia Infections, Abortion, Habitual genetics
- Abstract
miRNAs regulate the expression of various genes involved in cellular and metabolic pathways in pregnancy related complications including recurrent spontaneous abortion (RSA). Modulation of progesterone and associated pro-inflammatory cytokines by miRNAs in Chlamydia trachomatis-associated RSA is still under investigation. Present study aimed to evaluate the expression/correlation of serum-circulating miRNAs-133a, 101-3p, 320b, 146b-5p, 24, 559, progesterone and few cytokines in C. trachomatis-positive spontaneous aborters. Non-heparinized blood and urine was collected from 120 patients with history of RSA (Group I) and 120 patients with ≥ 2 successful deliveries (Group II) attending Department of Obstetrics and Gynecology, Safdarjung hospital, New Delhi, India. C. trachomatis detection was performed by PCR and chlamydial load by real time PCR. Progesterone concentration was estimated by ELISA. miRNAs and cytokine expression was studied by quantitative real-time PCR and correlated with progesterone expression. Twenty six patients were found to be positive for C. trachomatis. miRNAs- 133a, 101-3p showed maximum upregulation in infected versus control patients. miRNA expression showed positive correlation with chlamydial load. Progesterone concentration showed significant decrease while cytokines (IL-6, IFN-γ, TNF-α) were significantly upregulated in C. trachomatis-positive patients. Positive correlation was observed between expression of miRNAs-133a and 101-3p and cytokines while negative correlation was observed with progesterone in infected RSA patients. Correlation between progesterone and cytokines was found to be significantly negative in infected RSA patients. Although further validation is required, the study concludes that miR-133a and 101-3p are of clinical importance and have a role in immunoregulation of progesterone and cytokines in infection associated RSA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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19. Catapol attenuates the aseptic inflammatory response to hepatic I/R injury in vivo and in vitro by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway via the microRNA-410-3p.
- Author
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Feng ZJ, Wang LS, Ma X, Li K, Li XY, Tang Y, and Peng CJ
- Subjects
- Animals, Rats, Apoptosis, Luciferases metabolism, MicroRNAs genetics, MicroRNAs metabolism, Necrosis, NF-kappa B metabolism, Signal Transduction, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Inflammation drug therapy, HMGB1 Protein genetics, HMGB1 Protein metabolism, Liver blood supply, Liver drug effects, Liver pathology, Reperfusion Injury drug therapy, Reperfusion Injury pathology, Quaternary Ammonium Compounds pharmacology, Quaternary Ammonium Compounds therapeutic use
- Abstract
Background: Hepatic ischemia-reperfusion (I/R) injury involves inflammatory necrosis of liver cells as a significant pathological mechanism. Catapol possesses anti-inflammatory activity that is extracted from the traditional Chinese medicine, Rehmannia glutinosa., Methods: The liver function and histopathology, Oxidative stress, and aseptic inflammatory responses were assessed in vivo, and the strongest dose group was selected. For mechanism, the expression of miR-410-3p, HMGB1, and TLR-4/NF-κB signaling pathways was detected. The dual luciferase assay can verify the targeting relationship between miR-410-3p and HMGB1. Knockdown of miR-410-3p in L02 cells is applied in interference experiments., Results: CAT pre-treatment significantly decreased the liver function markers alanine and aspartate aminotransferases and reduced the areas of hemorrhage and necrosis induced by hepatic I/R injury. Additionally, it reduced the aseptic inflammatory response and oxidative stress, with the strongest protective effect observed in the high-dose CAT group. Mechanistically, CAT downregulates HMGB1, inhibits TLR-4/NF-κB signaling pathway activation, and reduces inflammatory cytokines TNF-α, and IL-1β. In addition, the I/R-induced downregulation of microRNA-410-3p was inhibited by CAT pre-treatment in vivo and in vitro. HMGB1 was identified as a potential target of microRNA-410-3p using a dual-luciferase reporter assay. Knockdown of microRNA-410-3p abolished the inhibitory effect of CAT on HMGB1, p-NF-κB, and p-IκB-α protein expression., Conclusions: Our study showed that CAT pre-treatment has a protective effect against hepatic I/R injury in rats. Specifically, CAT attenuates the aseptic inflammatory response to hepatic I/R injury in vivo and in vitro by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway via the microRNA-410-3p., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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20. WHSC1L1-mediated epigenetic downregulation of VMP1 participates in herpes simplex virus 1 infection-induced mitophagy impairment and neuroinflammation.
- Author
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Yao Y, Gu J, Li M, Li G, Ai J, and Zhao L
- Subjects
- Animals, Mice, Down-Regulation, Epigenesis, Genetic, Mice, Inbred C57BL, Microglia metabolism, Mitophagy genetics, Neuroinflammatory Diseases, Herpes Simplex genetics, Herpesvirus 1, Human
- Abstract
Microglia are the first-line defenders against invading pathogens in the brain whose activation mediates virus clearance and leads to neurotoxicity as well. This work studies the role of Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1)/vacuole membrane protein 1 (VMP1) interaction in the activation of microglia and neuroinflammation following herpes simplex virus 1 (HSV-1) infection. Aberrantly expressed genes after HSV-1 infection were screened by analyzing the GSE35943 dataset. C57BL/6J mice and mouse microglia BV2 were infected with HSV-1 for in vivo and in vitro assays. VMP1 was downregulated but WHSC1L1 was upregulated in HSV-1-infected mouse brain tissues as well as in BV2 cells. The VMP1 overexpression enhanced mitophagy activity and suppressed oxidative stress and inflammatory activation of BV2 cells, but these effects were blocked by the autophagy antagonist 3-methyladenine. WHSC1H1 suppressed VMP1 transcription through H3K36me2-recruited DNMT3A. Downregulation of WHSC1H1 similarly enhanced mitophagy in BV2 cells, and it alleviated microglia activation, nerve cell inflammation, and brain tissue damage in HSV-1-infected mice. However, the alleviating roles of WHSC1H1 silencing were negated by further VMP1 silencing. Taken together. this study demonstrates that WHSC1L1 upregulation following HSV-1 infection leads to mitophagy impairment and neuroinflammation through epigenetic suppression of VMP1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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21. Tumor-derived exosomes promote macrophages M2 polarization through miR-1-3p and regulate the progression of liver cancer.
- Author
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Gu W, Yang Y, Liu J, Xue J, Zhao H, Mao L, and Zhao S
- Subjects
- Humans, Macrophages, Carcinoma, Hepatocellular genetics, Exosomes, Liver Neoplasms, MicroRNAs genetics
- Abstract
Hepatic carcinoma is one of the most life-threatening malignancies in the world. In the clinic, it is urgent to establish a clear mechanism of hepatic carcinoma development as the basis for intervention and treatment. The purpose of this study was to explore the regulatory effect of tumor-derived exosomes on the progression of hepatocellular carcinoma.qPCR was used to detect the expression of miR-1-3p. CCk-8 and EdU staining were used to detect the proliferation and activity of hepatocellular carcinoma cells under different conditions. Transwell assay was used to detect migration and invasion of hepatocellular carcinoma cells. The morphology and size of exosomes were detected by transmission electron microscope and nanoparticle tracking analysis. Western blot was used to detect the expression of markers of exosomes. Immunofluorescence staining was used to explore the location of exosomes in hepatocellular carcinoma cells.The results showed that the expression of miR-1-3p was significantly reduced in hepatocellular carcinoma cells, and the exosomes transfected with miR-1-3p could enter macrophages and express miR-1-3p in large quantities. Macrophages polarized to M2 type under the action of miR-1-3p. Polarized M2 macrophages further down-regulated the proliferation, migration and invasion of Huh-7 cells.In summary, miR-1-3p can enter macrophages through exosomes and affect their polarization, thus affecting the growth of hepatic carcinoma cells. miR-1-3p may be a potentially effective target for regulating liver cancer progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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22. Immunomodulation of cytokine signalling at feto-maternal interface by microRNA-223 and -150-5p in infection-associated spontaneous preterm birth.
- Author
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Bhati T, Ray A, Arora R, Siraj F, Parvez S, and Rastogi S
- Subjects
- Infant, Newborn, Humans, Female, Pregnancy, Matrix Metalloproteinase 14, Interleukin-6, Placenta, Transforming Growth Factor beta, Cytokines, Immunomodulation, Premature Birth genetics, MicroRNAs genetics
- Abstract
Spontaneous preterm birth (sPTB) is a global health concern and it is the most prevalent cause of infant mortality and morbidity with occurrence rate of 5 - 18% worldwide. Studies suggest infection and infection-driven activation of inflammatory responses are the potential risk factors for sPTB. MicroRNAs (miRNAs) are thought to control the expression of several immune genes, making them crucial components of the intricate immune regulatory network and the dysregulation of miRNAs in placenta has been associated to several pregnancy-related complications. However, studies on possible role of miRNAs in immunomodulation of cytokine signalling in infection-associated sPTB are scarce. Present study aimed to investigate expression/ correlation of a few circulating miRNAs (miR-223, -150-5p, -185-5p, -191-5p), miRNA target genes and associated cytokines in sPTB women found infected with Chlamydia trachomatis/ Mycoplasma hominis/ Ureaplasma urealyticum. Non-heparinized blood and placental sample were collected from 140 sPTB and 140 term women visiting Safdarjung hospital, New Delhi (India) for conducting PCR and RT-PCR for pathogen detection and miRNA/ target gene/ cytokine expression, respectively. Common target genes of differentially expressed miRNAs were obtained from databases. The correlation between select target genes/ cytokines and serum miRNAs was determined by Spearman's rank correlation. 43 sPTB were infected with either pathogen and a significant upregulation of serum miRNAs was observed. However, miR-223 and 150-5p showed maximum fold-change (4.78 and 5.58, respectively) in PTB versus control group. IL-6ST, TGF-β R3 and MMP-14 were important target genes among 454 common targets, whereas, IL-6 and TGF-β were associated cytokines. miR-223 and 150-5p showed significant negative correlation with IL-6ST/ IL-6/ MMP-14 and positive correlation with TGF-β R3/ TGF-β. A significant positive correlation was found between IL-6ST and IL-6, TGF-β R3 and TGF-β. However, miR-185-5p and 191-5p were not significantly correlated. Although post-transcriptional validation is required, yet on the basis of mRNA findings, the study concludes that miR-223 and 150-5p are apparently of clinical importance in regulation of inflammatory processes during infection-associated sPTB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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23. Diesel exhaust exposure impairs recovery of lung epithelial and cellular damage in murine model.
- Author
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Singh N, Nagar E, and Arora N
- Subjects
- Mice, Animals, Disease Models, Animal, Lung, Cytokines metabolism, Vehicle Emissions toxicity, Leukocyte Elastase metabolism
- Abstract
Studies have investigated the relationship between diesel exhaust (DE) exposure and lung health, highlighting the potential for DE to induce pulmonary inflammation and oxidative stress. However, the resolution of inflammation upon withdrawal of DE exposure needs further investigation. Therefore, resolution of diesel exhaust-induced lung damage was studied in the murine model. Mice (6 weeks) were divided into three groups. Group 1 (control) mice were exposed to filtered air, Group 2 (DE) mice were exposed to DE (5.1 ± 0.7 mg/m
3 ) & Group 3 (DE-FA) mice were exposed to DE followed by filtered air exposure. Airway hyper-responsiveness was recorded after 24 h of the last exposure. BALF and lung samples were collected for cytokine estimation, immunobiological assays, and western blot analysis. DE exposure showed an increase in lung resistance thereby causing alteration in lung function parameters (p < 0.05) which was restored in the DE-FA group. BALF analysis showed a significant increase in total cell count and protein content in DE with no resolution in DE-FA groups (p < 0.05). Lung histology showed no reduction in the bronchiolar thickness and damage in the DE-FA group suggesting irreversible lung damage (p < 0.05). The significant increase in inflammatory cytokine levels, and collagen deposition showed persistent inflammatory phase and lung damage in the DE-FA group(p < 0.05). ZO-1 was significantly decreased in both test groups indicating disintegrated lung epithelium where in claudin-5 expression showed increased lung permeability. A significant increase in neutrophil elastase activity and decreased expression of, Elafin, resulted in lung epithelial damage in the DE-FA group. Lung injury marker alpha1-antitrypsin was increased in DE-FA groups indicating an immune defense mechanism against neutrophil elastase. The study showed that DE exposure causes persistent lung damage via neutrophil elastase-associated disruption of the epithelial barrier integrity and membrane dysfunction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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24. HSPA5, as a ferroptosis regulator, may serve as a potential therapeutic for head and neck squamous cell carcinoma.
- Author
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Li J, Xiao W, Wei W, Wu M, Xiong K, Lyu J, and Li Y
- Subjects
- Humans, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Squamous Cell Carcinoma of Head and Neck genetics, Ferroptosis, Head and Neck Neoplasms genetics
- Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is a ferroptosis sensitive tumor type with high mortality rate. However, it remains largely unknown whether ferroptosis influences the tumor cell in HNSCC., Materials and Methods: To investigate how ferroptosis regulators were differentially expressed between normal and tumor tissue, data related to HNSCC was downloaded from The Cancer Genome Atlas. The expression levels of key factors in HNSCC and the relationship between key factors and ferroptosis in HNSCC were conducted in vitro, and then analyzed to correlate with the differences in prognosis and survival. This was then combined with TNM staging data, and the migration effects of key factors in HNSCC were verified by scratch test and transwell test., Results: In this study, gene expression analysis and correlation studies between genes showed that HSPA5 was a potentially key associated ferroptosis regulator in HNSCC. Bioinformatics analysis showed that high expression of HSPA5 in HNSCC was positively correlated with poor prognosis and distal metastasis of HNSCC. In vitro immunohistochemistry and western blot tests confirmed that HSPA5 was highly expressed in HNSCC tissues and cell lines. In vitro inhibition of HSPA5 reduced the viability of HNSCC cells and increased ferroptosis. The results of scratch, transwell, and immunofluorescence tests showed that HSPA5 was related to the migration of HNSCC. In addition, a pan-cancer analysis showed that HSPA5 was also overexpressed in many types of cancer with poor prognoses., Conclusion: In total, our study demonstrates the critical role of ferroptosis regulators in HNSCC and that HSPA5, as a ferroptosis regulator, can be regarded as a key molecular target for designing new therapeutic regimens to control HNSCC metastasis and progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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25. GEF-H1/RhoA signaling pathway mediates pro-inflammatory effects of NF-κB on CD40L-induced pulmonary endothelial cells.
- Author
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Chang M, Yi L, Zhou Z, Yi X, Chen H, Liang X, Jin R, and Huang X
- Subjects
- Humans, Animals, Mice, CD40 Ligand metabolism, Endothelial Cells metabolism, Rho Guanine Nucleotide Exchange Factors metabolism, Signal Transduction, Lung metabolism, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, rhoA GTP-Binding Protein pharmacology, NF-kappa B metabolism, Acute Lung Injury metabolism
- Abstract
One of the key targets of the inflammatory response in acute lung injury (ALI) is the human pulmonary micro-vascular endothelial cells (HPMVECs). Owing to its role in the activation of endothelial cells (ECs), CD40L figures prominently in the pathogenesis of ALI. Increasing evidences have showed that CD40L mediates inflammatory effects on ECs, at least in part, by triggering NF-κB-dependent gene expression. However, the mechanisms of such signal transmission remain unknown. In this study, we found that CD40L stimulated the transactivation of NF-κB and expression of its downstream cytokines in a p38 MAPK-dependent mechanism in HPMVECs. In addition, CD40L-mediated inflammatory effects might be correlated with the activation of the IKK/IκB/NF-κB pathway and nuclear translocation of NF-κB, being accompanied by dynamic cytoskeletal changes. GEF-H1/RhoA signaling is best known for its role in regulating cytoskeletal rearrangements. An interesting finding was that CD40L induced the activation of p38 and IKK/IκB, and the subsequent transactivation of NF-κB via GEF-H1/RhoA signaling. The critical role of GEF-H1/RhoA in CD40L-induced inflammatory responses in the lung was further confirmed in GEF-H1 and RhoA knockout mouse models, both of which were established by adeno-associated virus (AAV)-mediated delivery of sgRNAs into mice with EC-specific Cas9 expression. These results taken together suggested that p38 and IKK/IκB-mediated signaling pathways, both of which lied downstream of GEF-H1/RhoA, may coordinately regulate the transactivation of NF-κB in CD40L-activated HPMVECs. These findings may help to determine key pharmacological targets of intervention for CD40L-activated inflammatory effects associated with ALI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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26. Monomeric C-reactive protein evokes TCR Signaling-dependent bystander activation of CD4+ T cells.
- Author
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Zhou L, Chen SJ, Chang Y, Liu SH, Zhou YF, Huang XP, Hua YX, An H, Zhang SH, Melnikov I, Gabbasov ZA, Wu Y, and Ji SR
- Subjects
- Signal Transduction, Cell Communication, Lymphocyte Activation, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, C-Reactive Protein
- Abstract
Bystander activation of T cells is defined as induction of effector responses by innate cytokines in the absence of cognate antigens and independent of T cell receptor (TCR) signaling. Here we show that C-reactive protein (CRP), a soluble pattern-recognition receptor assembled noncovalently by five identical subunits, can instead trigger bystander activation of CD4 + T cells by evoking allosteric activation and spontaneous signaling of TCR in the absence of cognate antigens. The actions of CRP depend on pattern ligand-binding induced conformational changes that result in the generation of monomeric CRP (mCRP). mCRP binds cholesterol in plasma membranes of CD4 + T cells, thereby shifting the conformational equilibrium of TCR to the cholesterol-unbound, primed state. The spontaneous signaling of primed TCR leads to productive effector responses manifested by upregulation of surface activation markers and release of IFN-γ. Our results thus identify a novel mode of bystander T cell activation triggered by allosteric TCR signaling, and reveal an interesting paradigm wherein innate immune recognition of CRP transforms it to a direct activator that evokes immediate adaptive immune responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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27. An update on the prevalence and diagnosis of cat and dog allergy - Emphasizing the role of molecular allergy diagnostics.
- Author
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van Hage M, Käck U, Asarnoj A, and Konradsen JR
- Subjects
- Animals, Cats, Dogs, Prevalence, Allergens, Immunoglobulin E, Hypersensitivity diagnosis, Hypersensitivity genetics, Hypersensitivity complications, Asthma epidemiology
- Abstract
The clinical presentation of cat and dog allergy vary from discomfort caused by rhinoconjuncitivitis to severe asthma. Exposure to allergens from these animals is ubiquitous and allergic sensitization to cat or dog affect up to 25% of all children and adults, but allergic sensitization does not always cause symptoms. The introduction of molecular-based allergy diagnostics has improved the possibility to characterize the allergic patient in greater detail. However, the full clinical potential of using molecular allergology in the diagnosis, characterization and treatment of patients with allergy to cats and dogs has not yet been established, although significant progress has been made during the last decade, which will be reviewed in detail in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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28. Immune evasion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); molecular approaches.
- Author
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Ahmadi S, Bazargan M, Elahi R, and Esmaeilzadeh A
- Subjects
- Humans, Immune Evasion, Antiviral Agents therapeutic use, Viral Proteins, Antibodies, Viral, SARS-CoV-2, COVID-19
- Abstract
In December 2019, a new betacoronavirus, known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), caused an outbreak at the Wuhan seafood market in China. The disease was further named coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) announced the disease to be a pandemic, as more cases were reported globally. SARS-CoV-2, like many other viruses, employs diverse strategies to elude the host immune response and/or counter immune responses. The infection outcome mainly depends on interactions between the virus and the host immune system. Inhibiting IFN production, blocking IFN signaling, enhancing IFN resistance, and hijacking the host's translation machinery to expedite the production of viral proteins are among the main immune evasion mechanisms of SARS-CoV-2. SARS-CoV-2 also downregulates the expression of MHC-I on infected cells, which is an additional immune-evasion mechanism of this virus. Moreover, antigenic modifications to the spike (S) protein, such as deletions, insertions, and also substitutions are essential for resistance to SARS-CoV-2 neutralizing antibodies. This review assesses the interaction between SARS-CoV-2 and host immune response and cellular and molecular approaches used by SARS-CoV-2 for immune evasion. Understanding the mechanisms of SARS-CoV-2 immune evasion is essential since it can improve the development of novel antiviral treatment options as well as vaccination methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
- Published
- 2023
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29. Galectin-1 mediates interactions between polymorphonuclear leukocytes and vascular endothelial cells, and promotes their extravasation during lipopolysaccharide-induced acute lung injury.
- Author
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Feng C, Cross AS, and Vasta GR
- Subjects
- Humans, Mice, Animals, Lipopolysaccharides pharmacology, Endothelial Cells, Galectin 1, Galectin 3, Cell Adhesion, Lung, Streptococcus pneumoniae, Intercellular Adhesion Molecule-1 metabolism, Neutrophils, Acute Lung Injury chemically induced, Acute Lung Injury metabolism
- Abstract
The lung airway epithelial surface is heavily covered with sialic acids as the terminal carbohydrate on most cell surface glycoconjugates and can be removed by microbial neuraminidases or endogenous sialidases. By desialylating the lung epithelial surface, neuraminidase acts as an important virulence factor in many mucosal pathogens, such as influenza and S. pneumoniae. Desialylation exposes the subterminal galactosyl moieties - the binding glycotopes for galectins, a family of carbohydrate-recognition proteins playing important roles in various aspects of immune responses. Galectin-1 and galectin-3 have been extensively studied in their roles related to host immune responses, but some questions about their role(s) in leukocyte recruitment during lung bacterial infection remain unanswered. In this study, we found that both galectin-1 and galectin-3 bind to polymorphonuclear leukocytes (PMNs) and enhance the interaction of endothelial intercellular adhesion molecule-1 (ICAM-1) with PMNs, which is further increased by PMN desialylation. In addition, we observed that in vitro galectin-1 mediates the binding of PMNs, particularly desialylated PMNs, onto the endothelial cells. Finally, in a murine model for LPS-mediated acute lung injury, we observed that galectin-1 modulates PMN infiltration to the lung without altering the expression of chemoattractant cytokines. We conclude that galectins, particularly galectin-1, may function as adhesion molecules that mediate PMN-endothelial cell interactions, and modulate PMN infiltration during acute lung injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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30. Effects of lactate on metabolism and differentiation of CD4 + T cells.
- Author
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Zhang YT, Xing ML, Fang HH, Li WD, Wu L, and Chen ZP
- Subjects
- T-Lymphocytes, Regulatory, Cell Differentiation, Cytokines metabolism, Transforming Growth Factor beta metabolism, Forkhead Transcription Factors metabolism, NAD metabolism, NAD pharmacology, Lactic Acid metabolism, Lactic Acid pharmacology
- Abstract
Background: Lactate accumulation caused by abnormal tumor metabolism can induce the formation of an inhibitory immune microenvironment through a variety of pathways, which is characterized by regulatory T cells (Treg) infiltration and effector T cells (Teff) depletion. Studies have found that the key reason why Treg cells can survive in harsh environments lies in their flexible metabolic mode, which can use lactate in tumor microenvironment (TME) as an alternative energy substance to maintain their inhibitory activity. In addition, lactate could also promote the differentiation of CD4
+ T cells into Treg, but the mechanism was not completely clear. The purpose of this study was to investigate the possible mechanism by which lactate is utilized by CD4+ T cells to influence Th17/Treg ratio., Methods: Basal cytokines (anti-CD3, anti-CD28, TGF-β) and 10 mM lactate was added into Naïve CD4+ T cells basal medium for 3 days. After TCR stimulation, Naïve CD4+ T converted to CD4+ T. Flow cytometry was used to detect the proportion of Treg cells; ELISA was used to detect the activity of LDHA, LDHB and NADH and the amount of α -Ketoglutaric Acid (α-KG) and 2-Hydroxyglutaric Acid (2HG) after lactate entered the cells; Western Blot and RT-PCR were used to detect the protein and gene expression of Foxp3, RORγt, LDHA and LDHB. In the validation experiment, lactate uptake inhibitor AZD3965, LDHA inhibitor GSK2837808A and NADH conversion inhibitor Rotenone were added respectively to observe the differentiation ratio of Treg cells and confirm the key points of metabolism; the degradation of Treg cell transcription factor Foxp3 was interfered with ubiquitination inhibitors to observe whether it co-ubiquitinated with HIF-1α; the expression and activity of LDHA, LDHB and NADH in mitochondria and cytoplasm were detected to confirm cell localization., Results: When basal cytokines (anti-CD3, anti-CD28, TGF-β) stimulated, lactate was added to the culture medium, and CD4+ T cells absorbed a large amount of lactate not only through MCT1 (monocarboxylic acid transporter), but also increased the expression of lactate dehydrogenase and accelerated the intracellular metabolism of lactate. LDHB in cytoplasm mainly catalyzed the dehydrogenation of lactate to pyruvate, accompanied by the transformation reaction between NAD+ and NADH. The latter further entered the mitochondria and participates in the tricarboxylic acid cycle metabolism. In addition, lactate could significantly increase the level of LDHA in mitochondria and promote the transformation of α-KG to 2HG, accompanied by the transformation of NADH to NAD+ . These metabolic changes eventually led to an increase in the intracellular 2HG/α-KG ratio. Abnormal 2HG increased the proportion of Treg by inhibiting ATP5B-mediated phosphorylation of mTOR and the synthesis of HIF-1α, causing it not be enough to ubiquitinate and degrade with Foxp3., Conclusions: Lactate plays an important role in regulating the differentiation of Treg cells, inducing the expression and function of LDHA and promoting the transformation of α-KG to 2HG may be an important mechanism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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31. Mycobacterium tuberculosis PE_PGRS1 promotes mycobacteria intracellular survival via reducing the concentration of intracellular free Ca 2+ and suppressing endoplasmic reticulum stress.
- Author
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Yu X, Huang Y, Li Y, Li T, Yan S, Ai X, Lv X, Fan L, and Xie J
- Subjects
- Humans, Apoptosis, eIF-2 Kinase metabolism, Endoplasmic Reticulum Stress immunology, Macrophages immunology, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis immunology, Mycobacterium tuberculosis metabolism, Tuberculosis immunology, Tuberculosis microbiology
- Abstract
Mycobacterium tuberculosis (M. tuberculosis) is the causative agent of tuberculosis (TB). And the PE_PGRS family members of M. tuberculosis are closely associated with virulence and antigen presentation but with function largely elusive. PE_PGRS1(Rv0109) contained 7 Ca
2+ binding domains of GGXGXD/NXUX (X is any amino acid), which can reduce intracellular Ca2+ surge. In addition, PE_PGRS1 can mitigate the activation of PERK branch in endoplasmic reticulum (ER) stress by down-regulating the expression of CHOP, Bip, p-PERK, p-eIF2α, and ATF4. Interestingly, we found that two splicing variations of Bax/Bcl-2, Baxβ, and Bcl-2α, were differentially expressed after infection with Ms_PE_PGRS1, and may be involved in the regulation of apoptosis. Hence, this study identified that PE_PGRS1 is a novel calcium-associated protein that can decrease intracellular Ca2+ levels and the PERK axis. And the weakening of the PERK-eIF2α-ATF4 axis reduces THP-1 macrophages apoptosis, promotes the survival of mycobacteria in macrophages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2023
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32. Anti-inflammation of hydrogenated isoflavones in LPS-stimulated RAW264.7 cells via inhibition of NF-κB and MAPK signaling pathways.
- Author
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Li K, Hu W, Yang Y, Wen H, Li W, and Wang B
- Subjects
- Animals, Mice, Humans, Lipopolysaccharides pharmacology, Lipopolysaccharides metabolism, Signal Transduction, Anti-Inflammatory Agents pharmacology, MAP Kinase Signaling System, RAW 264.7 Cells, Nitric Oxide metabolism, NF-kappa B metabolism, Isoflavones pharmacology
- Abstract
Isoflavones are commonly found in diets, such as soybean and clover. Their anti-inflammatory effects are due to the inhibition of the transcriptional regulation of NF-κB. Hydrogenated isoflavones are metabolites of isoflavones with higher bioavailability, however, there have been few studies on their anti-inflammatory effects. In this work, by using the LPS-stimulated RAW264.7 cell model, we investigated the anti-inflammatory effect and the underlying mechanism of hydrogenated isoflavones. Hydrogenated isoflavones reduced the production of LPS-stimulated pro-inflammatory mediators and enzymes, including TNF-α, IL-6, NO, iNOS and COX-2. The level of ROS was also diminished in LPS-stimulated RAW264.7 cells. Further mechanistic studies showcase that hydrogenated isoflavones block NF-κB and MAPK pathways via attenuation of p65 nuclear translocation and JNK, ERK, and p38 phosphorylation, respectively. In addition, we found that hydrogenated isoflavones display anti-proliferation effect in human colon cancer cells with wild-type p53. Together, hydrogenated isoflavones could be used as an adjuvant for the treatment of inflammation and cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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33. The second-generation tyrosine kinase inhibitor afatinib inhibits IL-1β secretion via blocking assembly of NLRP3 inflammasome independent of epidermal growth factor receptor signaling in macrophage.
- Author
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Xie S, Liang J, Zhao Y, Zhang J, Chen X, Jiang H, Zhang Z, Ma S, and Zhang S
- Subjects
- Humans, ErbB Receptors, Inflammasomes metabolism, Macrophages metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Tyrosine Kinase Inhibitors pharmacology, Afatinib pharmacology, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms pathology
- Abstract
Chronic inflammation might lead to many malignancies, and inadequate resolution could play a crucial role in tumor invasion, progression and metastases. Afatinib is a second-generation tyrosine kinase inhibitor targeting epidermal growth factor receptor in non-small cell lung cancer. Few studies showed the correlation of afatinib and the innate immune system especially macrophage. Our study showed that afatinib could block the activation of NLRP3 inflammasome in a dose-dependent manner in macrophage, and that afatinib could prevent the assembly of NLRP3 inflammasome. Besides, afatinib could inhibit NLRP3 inflammasome activation independent of EGFR signaling. Moreover, afatinib was able to alleviate the LPS-induced sepsis in vivo. These investigations provide significant experimental evidence in afatinib as therapeutic drug for non-small cell lung cancer or other tumors and NLRP3-related diseases, and explore new target for afatinib in macrophage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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34. Cancer/testis antigen HEMGN correlated with immune infiltration serves as a prognostic biomarker in lung adenocarcinoma.
- Author
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Jiang Y, Yu L, Hu Q, Kang Y, You J, Huang C, Xu X, and Chen L
- Subjects
- Male, Humans, Prognosis, Testis, Antibodies, Nuclear Proteins, Adenocarcinoma of Lung genetics, Lung Neoplasms genetics
- Abstract
HEMGN belongs to the Cancer/testis antigens (CTAs), which are expressed in various types of human cancers and have received particular attention in cancer immunotherapy. However, the potential function of HEMGN involved in lung cancer and the immune response is not yet elucidated. HEMGN expression in lung adenocarcinoma (LUAD) was estimated via the Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and Human Protein Atlas databases. The prognostic role of HEMGN was investigated by Gene Expression Profiling Interactive Analysis (GEPIA), PrognoScan, and Kaplan-Meier plotter databases. The associations between HEMGN and clinicopathological parameters were analyzed with UALCAN database. Then, immunohistochemical and Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) analysis were performed to further verify the associations in tissue or serum samples. Serum from patients were detected for HEMGN antibody by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect immune cell infiltration in peripheral blood of patients with LUAD. In addition, Gene Set Enrichment Analysis (GSEA) was conducted to investigate the functional role of HEMGN. Furthermore, we obtained the somatic mutation data from the TCGA LUAD dataset and analyzed the mutation profiles with "maftools" package. Finally, we evaluated the associations between HEMGN and immune infiltration level and the characteristic markers of immune cells in TIMER, GEPIA, and CIBERSORT. The mRNA and protein expressions of HEMGN were significantly decreased in LUAD patients. High HEMGN expression was remarkably associated with better prognosis in LUAD patients. The concentration levels of anti-HEMGN antibody in LUAD were significantly higher than that in healthy individuals and were closely correlated with clinical stage. In addition, HEMGN was involved in distinct typical genomic alterations in LUAD. GSEA demonstrated that HEMGN was significantly connected with immunity and substance metabolism. Notably, HEMGN was significantly related to immune infiltrates, including B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, dendritic cells (DCs), and various kinds of functional T cells. Furthermore, HEMGN had a significant association with diverse immune gene markers. HEMGN can be considered as a prognostic biomarker of LUAD and is associated with immune infiltration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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35. Identification and characterization of natural PR-1 protein as major allergen from Humulus japonicus pollen.
- Author
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Wang Y, Tan LX, Xu ZQ, Jiao YX, Zhu DX, Yang YS, Wei JF, Sun JL, and Tian M
- Subjects
- Humans, Allergens chemistry, DNA, Complementary, Pollen, Proteins genetics, Cloning, Molecular, Plant Proteins chemistry, Humulus genetics, Hypersensitivity
- Abstract
Background: The Humulus japonicus pollen is one of the most common allergenic pollens in China. However, little is unveiled regarding the allergenic components in Humulus japonicus pollen. Our study aimed to purify and identify the pathogenesis-related 1 (PR-1) protein from Humulus japonicus pollen, and to characterize the molecular and immunochemical properties of this novel allergen., Methods: The natural PR-1 protein (named as Hum j PR-1) was purified from Humulus japonicus pollen extracts with a combined strategy of chromatography, and identified by mass spectrometry. The coding sequence of Hum j PR-1 was confirmed by cDNA cloning. The recombinant Hum j PR-1 was expressed and purified from Escherichia coli. The allergenicity was assessed by immunoblot, enzyme-linked immunosorbent assay (ELISA), inhibition ELISA, and basophil activation test using Humulus japonicus allergic patients' whole blood. The physicochemical properties and 3-dimensional structure of it were comprehensively characterized by in silico methods., Results: The allergenicity analysis revealed that 76.6 % (23/30) of the Humulus japonicus pollen allergic patients displayed specific IgE recognition of the natural Hum j PR-1. The cDNA sequence of Hum j PR-1 had a 516-bp open reading frame encoding 171 amino acids. Physicochemical analysis indicated that Hum j PR-1 was a stable and relatively thermostable protein. Hum j PR-1 shared a similar 3-dimensional folding pattern with other homologous allergens, which was a unique αβα sandwich structure containing 4 α-helices and 6 antiparallel β-sheets, encompassing 4 conserved CAP domain., Conclusion: The natural PR-1 was firstly purified and characterized as a major allergenic allergen in Humulus japonicus pollen. These findings would contribute to developing diagnostic and therapeutic strategies for Humulus japonicus pollinosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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36. Serum proteomics analysis of biomarkers for evaluating clinical response to MTX/IGU therapy in early rheumatoid arthritis.
- Author
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Zhang T, Shu Q, Zhu H, Wang M, Yang N, Zhang H, and Ge W
- Subjects
- Humans, Proteomics, Drug Therapy, Combination, Blood Proteins, Biomarkers, Treatment Outcome, Methotrexate therapeutic use, Arthritis, Rheumatoid drug therapy
- Abstract
Methotrexate (MTX) and iguratimod (IGU) are conventional synthetic disease modifying antirheumatic drugs widely used in the treatment of Rheumatoid arthritis (RA) in China. Although MTX combined with IGU can significantly inhibit the progression of RA, some patients do not respond to the treatment. The purpose of this study is to explore the difference of serum protein expression between RA patients with good and poor response to the combined therapy by label-free quantitative proteomic approach. From the proteomics data, a total of 782 proteins in the serum of RA patients were detected, and of which 9 were upregulated and 18 were downregulated in the good response group compared to poor response group. Among them, four significantly differentially expressed proteins (RELN, LDHA, MRC1 and TKT) were further validated by multiple reaction monitoring (MRM)-based quantification approach, and three of them (RELN, LDHA and MRC1) were confirmed to be correlated with the response to MTX/IGU therapy. Logistic regression and ROC analysis indicated that the combination of RELN, LDHA and MRC1 had good performance in evaluating the response. This result proved the different serum proteins signature fingerprint between response group and non-response group; and highlighted the potential of the label-free and mass spectrometry-based quantitative proteomic approach in screening biomarkers for evaluating clinical response to MTX/IGU therapy in RA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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37. Margetuximab and trastuzumab deruxtecan: New generation of anti-HER2 immunotherapeutic agents for breast cancer.
- Author
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Nur Husna SM and Wong KK
- Subjects
- Humans, Female, Receptor, ErbB-2, Trastuzumab therapeutic use, Antibodies, Monoclonal therapeutic use, Immunotherapy, Breast Neoplasms drug therapy, Immunoconjugates therapeutic use, Immunoconjugates pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology
- Abstract
Advances in the development of anti-HER2 monoclonal antibodies (mAbs) represent one of the most significant milestones in the treatment of HER2
+ breast cancer patients. However, HER2+ metastatic breast cancer (MBC) patients display resistance towards first-generation anti-HER2 mAbs or antibody-drug conjugate (ADC) treatment. In recent years, new generation of anti-HER2 mAb and ADC including margetuximab and trastuzumab deruxtecan (T-DXd), respectively, have been approved for the treatment of previously treated HER2+ MBC patients. The successes of margetuximab and T-DXd have renewed the interest in the research and development of anti-HER2 immunotherapies for both HER2+ and HER2-low breast cancer patients. In this review, we focus on these two immunotherapeutics in terms of their mechanisms of action, preclinical findings and clinical trials leading to their approval, as well as the mechanisms of resistance to conventional anti-HER2 immunotherapies (i.e. trastuzumab, pertuzumab and T-DM1). In the future, combination of either margetuximab or T-DXd with small molecule inhibitors such as tyrosine kinase inhibitors that elicit anticancer immunogenicity may further enhance the efficacy of margetuximab or T-DXd in the treatment of HER2+ MBC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
38. An update on the role of tumor necrosis factor alpha stimulating gene-6 in inflammatory diseases.
- Author
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Li R, Ji C, Dai M, Huang J, Xu W, Ma Y, and Zhang H
- Subjects
- Humans, Cytokines metabolism, Extracellular Matrix metabolism, Inflammation genetics, Inflammation metabolism, Cell Adhesion Molecules metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
At present, the occurrence and development of inflammatory diseases are closely related to the abnormal changes of the content and function of many cytokines. At the same time, targeting related cytokines to prevent and treat diseases has also achieved good results. Therefore, it is very important to explore the role of various cytokines in inflammatory diseases. As an inflammation related protein, Tumor necrosis factor alpha stimulating gene-6 (TSG-6) has attracted more and more attention. In the process of disease, it's like a double-edged sword, showing different responses. It is constitutively expressed in some tissues with high metabolic activity and barrier protection. The diversity of its functions depends on the binding of TSG-6 with a variety of ligands, including matrix molecules, autoimmune regulatory factors and growth factors, participating in extracellular matrix remodeling and regulating protease network. This paper reviews the structure, biological function and research progress of TSG-6 in inflammatory diseases, in order to provide reference for drug development in the future., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
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39. Inflammasome activation and assembly in Huntington's disease.
- Author
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de Oliveira Furlam T, Roque IG, Machado da Silva EW, Vianna PP, Costa Valadão PA, Guatimosim C, Teixeira AL, and de Miranda AS
- Subjects
- Caspases, Humans, Inflammasomes, Interleukin-18, Interleukin-1beta metabolism, Leucine, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nucleotides, Huntington Disease, Neurodegenerative Diseases
- Abstract
Huntington's disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1β and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
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40. Early-Career Complementologists (ECCO) - Past achievements and future directions.
- Author
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Poppelaars F, Gaya da Costa M, Lokki AI, Mallah K, Nord D, Reddaway J, and Schäfer N
- Subjects
- Humans, Research Personnel education, COVID-19, Pandemics
- Abstract
The Early-Career Complementologists (ECCO) is a task force that was established, in close collaboration with the European Complement Network (ECN) and the International Complement Society (ICS), with the specific mission to support and connect early-career researchers (ECRs) in the complement field. ECRs are junior scientists at the early stages of their training which include undergraduate as well as graduate students, Ph.D. graduates, and post-doctoral fellows. This unique population within the scientific community represents the next generation of scientific leaders. However, ECRs are faced with key challenges and the COVID-19 pandemic has disproportionately impacted them. In this paper, we provide further insight into specific needs and challenges of ECRs in the complement field. We surveyed 52 ECRs in the complement field and assessed their perceptions of 1) mentor and peer support, 2) working conditions as well as 3) career interests and prospects. Furthermore, we review the various activities carried out by ECCO over the past years such as our social media presence, social events, and newly-created awards. We also discuss the future activities and events to be carried out by ECCO. Through these initiatives and activities, ECCO strives to boost collaborations between ECRs, provide recognition, and improve the visibility of their work. In addition, continuous joint efforts must also be made by the scientific community, research institutes, and funding organizations to nurture and invest in ECRs., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
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41. The major role of junctional diversity in the horse antibody repertoire.
- Author
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Navas C, Manso T, Martins F, Minto L, Moreira R, Minozzo J, Antunes B, Vale A, McDaniel JR, Ippolito GC, and Felicori LF
- Subjects
- Animals, Antibody Diversity, Horses, Immunoglobulin G genetics, Immunoglobulin M genetics, Nucleotides, Receptors, Antigen, B-Cell genetics, COVID-19
- Abstract
The antibody repertoire (Rep-seq) sequencing revolutionized the diversity of antigen B cell receptor studies, allowing deep and quantitative analysis to decipher the role of adaptive immunity in health and disease. Particularly, horse (Equus caballus) polyclonal antibodies have been produced and used since the century XIX to treat and prophylaxis diphtheria, tuberculosis, tetanus, pneumonia, and, more recently, COVID-19. However, our knowledge about the horse B cell receptors repertories is minimal. We present a deep horse antibody heavy chain repertoire (IGH) characterization of non-infected horses using NGS (Next generation sequencing). This study obtained a mean of 248,169 unique IgM clones and 66,141 unique IgG clones from four domestic adult horses. Rarefaction analysis showed sequence coverage was between 52 % and 82 % in IgM and IgG isotypes. We observed that besides horses antibody can use all functional IGHV genes, around 80 % of their antibodies use only three IGHV gene segments, and around 55 % use only one IGHJ gene segment. This limited VJ diversity seems to be compensated by the junctional diversity of these antibodies. We observed that the junctional diversity in horse antibodies is widespread, present in more than 90 % of horse antibodies. Besides this, the length of this region seems to be higher in horse antibodies than in other species. N1 and N2 nucleotides addition range from 0 to 111 nucleotides. In addition, around 45 % of the antibody clones have more than ten nucleotides in both the N1 and N2 junction regions. This diversity mechanism may be one of the most important in providing variability to the equine antibody repertoire. This study provides new insights regarding horse antibody composition, diversity generation, and particularities compared to other species, such as the frequency and length of N nucleotide addition. This study also points out the urgent need to better characterize TdT in horses and other species to better understand antibody repertoire characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
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42. Lipopolysaccharides and outer membrane proteins as main structures involved in complement evasion strategies of non-typhoidal Salmonella strains.
- Author
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Krzyżewska-Dudek E, Kotimaa J, Kapczyńska K, Rybka J, and Meri S
- Subjects
- Aged, Anti-Bacterial Agents, Bacterial Outer Membrane Proteins, Child, Complement Membrane Attack Complex, Complement System Proteins, Humans, Membrane Proteins, Salmonella, Virulence Factors, Lipopolysaccharides, O Antigens
- Abstract
Non-typhoidal Salmonella (NTS) infections pose a serious public health problem. In addition to the typical course of salmonellosis, an infection with Salmonella bacteria can often lead to parenteral infections and sepsis, which are particularly dangerous for children, the elderly and immunocompromised. Bacterial resistance to serum is a key virulence factor for the development of systemic infections. Salmonella, as an enterobacterial pathogen, has developed several mechanisms to escape and block the antibacterial effects of the complement system. In this review, we discuss the relevance of outer membrane polysaccharides to the complement evasion mechanisms of NTS strains. These include the influence of the overall length and density of the lipopolysaccharide molecules, modifications of the O-antigen lipopolysaccharide composition and the role of capsular polysaccharides in opsonization and protection of the outer membrane from the lytic action of complement. Additionally, we discuss specific outer membrane protein complement evasion mechanisms, such as recruitment of complement regulatory proteins, blocking assembly of late complement components to form the membrane attack complex and the proteolytic cleavage of complement proteins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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43. Enhanced migration and immunoregulatory capacity of BMSCs mediated by overexpression of CXCR4 and IL-35.
- Author
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Tan C, Tan S, Zhang H, Zhang M, Fan H, Nan Z, Liu X, Wang W, Zhang L, Deng S, Zuo D, and Tang Q
- Subjects
- Bone Marrow Cells, Cell Movement genetics, Chemokine CXCL12, Humans, Immunity, Interleukins pharmacology, Receptors, CXCR4 genetics, Stem Cells, Autoimmune Diseases, Mesenchymal Stem Cell Transplantation methods
- Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) have been widely studied for their applications in immunoregulation and tissue repair. However, the therapeutic effects of BMSCs in the body are limited, partly due to the low homing efficiency of BMSCs to affected parts. The stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis is well known to play an essential role in the homing of BMSCs. Interleukin 35 (IL-35) is a newly discovered cytokine confirmed to inhibit overactivated immune function and have a good therapeutic effect on autoimmune diseases. In this study, we innovatively developed dual gene modification of BMSCs by transducing CXCR4 and IL-35 and found that the migration and immunomodulatory activity of genetically engineered BMSCs were significantly enhanced compared to their natural counterparts. These results suggest that BMSCs modified by dual overexpression of CXCR4 and IL-35 may provide a potential treatment strategy for autoimmune diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
44. ECCO - A new initiative to support early-career researchers in the complement field.
- Author
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Poppelaars F, Gaya da Costa M, Inkeri Lokki A, Mallah K, Nord D, Reddaway J, and Schäfer N
- Subjects
- Humans, Research Personnel, Complement System Proteins immunology
- Abstract
Research on the complement system, like most areas of immunology, has seen tremendous progress over the last decades. Further advances in the complement field will rely on the next generation of scientific leaders, which are today's early-career researchers (ECRs). ECRs are emerging scientists who obtained their PhD degree within the past five years. They represent a distinct population within the scientific community, and accordingly have unique needs. Unfortunately, ECRs are faced with significant challenges that require customized solutions. The current paper provides a snapshot of the major obstacles ECRs face, such as an unhealthy work-life balance, lack of mentor and peer support, and uncertain career prospects. Efforts must consequently be taken to ensure stability and success of ECRs, not only to benefit these researchers in the early stages of their career, but the entire field of complement research. The Early-Career Complementologists (ECCO) was, therefore, launched as a new Task Force to support ECRs in the complement field. This new initiative aims to support and connect ECRs in the complement field worldwide. Furthermore, ECCO is supported by both the International Complement Society (ICS) and the European Complement Network (ECN); two professional societies led by scientists investigating the complement system., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
45. Grass carp (Ctenopharyngodon idella) interferon regulatory factor 8 down-regulates interferon1 expression via interaction with interferon regulatory factor 2 in vitro.
- Author
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Chang K, Han K, Qiu W, Hu Z, Chen X, Chen X, Xie X, Wang S, Hu C, and Mao H
- Subjects
- Animals, Cells, Cultured, Gene Expression Regulation genetics, HEK293 Cells, Humans, Immunity, Innate genetics, Poly I-C genetics, Promoter Regions, Genetic genetics, Transcription, Genetic genetics, Up-Regulation genetics, Carps genetics, Down-Regulation genetics, Fish Proteins genetics, Interferon Regulatory Factor-2 genetics, Interferon Regulatory Factors genetics, Interferons genetics
- Abstract
Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a negative regulatory factor of interferon (IFN) and plays an important role in cell differentiation and innate immunity in mammals. In recent years, some irf8 homologous genes have been cloned and confirmed to take part in innate immune response in fish, but the mechanism still remains unclear. In this paper, a grass carp (Ctenopharyngodon idella) irf8 gene (Ciirf8) was cloned and characterized. The deduced protein (CiIRF8) possesses a highly conserved N-terminal DNA binding domain but a less well-conserved C-terminal IRF association domain (IAD). Ciirf8 was widely expressed in all tested tissues of grass carp and up-regulated following poly(I:C) stimulation. Ciirf8 expression was also up-regulated in CIK cells upon treatment with poly(I:C). To explore the molecular mechanism of how fish IRF8 regulates ifn1 expression, the similarities and differences of grass carp IRF8 and IRF2 were compared and contrasted. Subcellular localization analysis showed that CiIRF8 is located both in the cytoplasm and nucleus; however, CiIRF2 is only located in the nucleus. The nuclear-cytoplasmic translocation of CiIRF8 was observed in CIK cells under stimulation with poly(I:C). The interaction of CiIRF8 and CiIRF2 was further confirmed by a co-immunoprecipitation assay in the nucleus. Dual-luciferase reporter assays showed that the promoter activity of Ciifn1 was significantly inhibited by co-transfection with CiIRF2 and CiIRF8. The transcription inhibition of Ciifn1 was alleviated by competitive binding of CiIRF2 and CiIRF8 to CiIRF1. In conclusion, CiIRF8 down-regulates Ciifn1 expression via interaction with CiIRF2 in cells., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2021
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46. RIPK1 regulates cell function and death mediated by UVB radiation and TNF-α.
- Author
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Zhao Y, Chen Y, Li X, Sun Y, Shao Y, Zhang Y, and Liu Z
- Subjects
- CRISPR-Cas Systems genetics, Cell Line, Transformed, Cell Proliferation physiology, Cell Survival physiology, G2 Phase Cell Cycle Checkpoints physiology, Gene Knockout Techniques, HaCaT Cells, Humans, Interleukin-1alpha metabolism, NF-kappa B metabolism, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Signal Transduction physiology, Skin injuries, p38 Mitogen-Activated Protein Kinases metabolism, Apoptosis physiology, Epidermal Cells pathology, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Tumor Necrosis Factor-alpha metabolism, Ultraviolet Rays adverse effects
- Abstract
The RIP family plays a key role in mediating cell inflammation, oxidative stress and death. Among them, RIPK1, as an important regulatory factor in the upstream of the NF-κB pathway, is involved in multiple pathways of cell inflammation and death. Epidermal cells constitute the outermost barrier of the human body. Radiation can induce epidermal cell death, inflammation and oxidative stress to cause damage. Therefore, this paper selected HaCaT cell and used CRISPR/Cas technology to construct a cell model of stable knockout of RIPK1 gene, to analyze the effect and regulation of RIPK1 knockout on the function and death of HaCaT cells induced by UVB or TNF-α. The results showed that knockout of RIPK1 had no significant effect on the morphology of HaCaT cells at rest, but it led to slowing cell proliferation and blocking the G2M phase of cell cycle. Compared with HaCaT
WT , HaCaTRIP1KO was abnormally sensitive to TNF-α-induced cell death and apoptosis, and may be associated with inhibition of NF-κB pathway. Knocking out RIPK1 led to a more significant inhibition of cell growth by UVB, and up-regulation of the expression of the inflammatory factor IL-1α. P38 MAPK and NF-κB pathways may be involved this process. This study further found that RIPK1 in epidermal cell has a regulatory function on pro-survival signals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
47. The role of the tyrosine kinase Lyn in allergy and cancer.
- Author
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Sun Y, Yang Y, Zhao Y, Li X, Zhang Y, and Liu Z
- Subjects
- Animals, Humans, Signal Transduction physiology, Hypersensitivity metabolism, Neoplasms metabolism, Protein-Tyrosine Kinases metabolism, src-Family Kinases metabolism
- Abstract
With worsening air pollution brought by global social development, the prevalence of allergic diseases has increased dramatically in the past few decades. The novel Lck/yes-related protein tyrosine kinase (Lyn) belongs to the Src kinase family (SFK) and plays a pivotal role in the pathogenesis of inflammation, tumor, and allergy. This signaling molecule is vital in the IgE/FcεRI signaling pathway that regulates allergy. The Lyn-FcεRIβ interaction is essential for mast cell activation. The signaling pathway of Lyn has become the focus of immune, inflammatory, tumor, and allergy research. This molecule has positive and negative regulatory effects, which have attracted researchers' attention. This paper reviews the basic characteristics of Lyn and its regulatory mechanism and role in tumor and other diseases, specifically in allergies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
48. Stenotrophomonas-maltophilia inhibits host cellular immunity by activating PD-1/PD-L1 signaling pathway to induce T-cell exhaustion.
- Author
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Wang M, Yin S, Qin Q, Peng Y, Hu Z, Zhu X, Liu L, and Li X
- Subjects
- Adult, Animals, B7-H1 Antigen metabolism, Cell Count, Cell Death genetics, Cell Death immunology, Cells, Cultured, Down-Regulation immunology, Gram-Negative Bacterial Infections pathology, Host-Pathogen Interactions immunology, Humans, Interferon-gamma metabolism, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear microbiology, Mice, Mice, Inbred C57BL, Signal Transduction immunology, T-Lymphocytes pathology, Apoptosis physiology, Gram-Negative Bacterial Infections immunology, Immunity, Cellular, Stenotrophomonas maltophilia physiology, T-Lymphocytes physiology
- Abstract
Background: Smalotrophomonas maltophilia(S. maltophilia) is common in nosocomial infections. However, few studies have revealed the effect of S. maltophilia on cellular immunity in the host's immune system up to now. In clinical work, we accidentally discovered that S. maltophilia directly stimulated T cells to secrete IFN-γ., Materials and Methods: S. maltophilia was co-cultured with PBMCs to detect secretion of cytokines (IFN-γ, TNF-α and IL-2) and expression of cell surface molecules (CD3, CD4, CD8, CD69, CD147 and CD152) of T cells. We used light microscopy and electron microscopy to observe the cell morphology and subcellular structure of S. maltophilia co-cultured with lymphocytes. Flow cytometry and Western Blot were used to detect the expression of PD-1/PD-L1 and annexin V in cells., Results: T cells stimulated by S. maltophilia secreted a large amount of IL-2, IFN-γ, and TNF-α. The expression of CD4 and CD8 on the cell surface were declined, accompanied by the activation of the PD-1/PD-L1 pathway, which eventually led to the massive apoptosis of T cells. Electron microscopy showed that cells showed significant apoptotic morphology. Blocking the PD-1/PD-L1 pathway can inhibit the apoptosis-inducing effect of S. maltophilia on T cells., Conclusions: These indicates that T cells are inhibited after being stimulated by S. maltophilia, and then accelerated to induce death without the initiation of an immunologic cascade. This paper demonstrates for the first time the inhibitory effect of S. maltophilia on cellular immunity, and the immunosuppressive effect induced by infection of S. maltophilia should be considered., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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49. Antigen specificities and functional properties of MR1-restricted T cells.
- Author
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De Libero G, Chancellor A, and Mori L
- Subjects
- Antigens, Bacterial immunology, Antigens, Bacterial metabolism, Histocompatibility Antigens Class I chemistry, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Humans, Ligands, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Minor Histocompatibility Antigens chemistry, Minor Histocompatibility Antigens genetics, Minor Histocompatibility Antigens immunology, Protein Binding, Protein Structure, Tertiary, T-Lymphocytes immunology, Antigen Presentation genetics, Antigen Presentation immunology, Histocompatibility Antigens Class I metabolism, Minor Histocompatibility Antigens metabolism, T-Cell Antigen Receptor Specificity genetics, T-Cell Antigen Receptor Specificity immunology, T-Lymphocytes metabolism
- Abstract
MR1 is an MHC class I-like molecule with unique structural and biological features that make it an important member among the molecules involved in antigen presentation to T cells. Distinctive features include ubiquitous expression of the MR1 gene and its monomorphism. Another relevant property is that the MR1 protein appears at very low levels on the plasma membrane and its surface expression is regulated by antigen binding. Finally, the nature of presented antigens differs from those that bind other presenting molecules and includes small metabolites of microbial and self-origin, small drugs and tumor-associated antigens. This opinion paper describes in detail some of those features and discusses recent literature in the field., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
50. Complement-mediated kidney diseases.
- Author
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Poppelaars F and Thurman JM
- Subjects
- Animals, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Antigen-Antibody Complex immunology, Atypical Hemolytic Uremic Syndrome immunology, Complement Activation immunology, Complement Inactivating Agents immunology, Glomerulonephritis immunology, Humans, Kidney immunology, Complement System Proteins immunology, Kidney Diseases immunology
- Abstract
It has long been known that the complement cascade is activated in various forms of glomerulonephritis. In many of these diseases, immune-complexes deposit in the glomeruli and activate the classical pathway. Researchers have also identified additional mechanisms by which complement is activated in the kidney, including diseases in which the alternative and lectin pathways are activated. The kidney appears to be particularly susceptible to activation of the alternative pathway, and this pathway has been implicated as a primary driver of atypical hemolytic uremic syndrome, C3 glomerulopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as some forms of immune-complex glomerulonephritis. In this paper we review the shared and distinct mechanisms by which complement is activated in these different diseases. We also review the opportunities for using therapeutic complement inhibitors to treat kidney diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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