CELL
·
2025
·
IF 42.5
Yaozhen Chen,Shouwen Chen,Zhixin Liu,Yafen Wang,Ning An,Yutong Chen,Yihao Peng,Zheng Liu,Qin Liu,Xingbin Hu
The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.
研究领域:
免疫学
·
血液学
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细胞生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Zhonghao Liao,Jiang Yu,Fangming Liang,Yubo Liu,Zhenyang Zhao,Yue Wang,Xianbao Shi,Yongjun Wang,Hongzhuo Liu
Adeno-associated virus (AAV) has been extensively employed in gene therapy owing to its outstanding safety profile and low immunogenicity. AAV vector-mediated gene therapy necessitates repeated administrations to achieve prolonged therapeutic efficacy. However, clinical trials have demonstrated that subsequent to the initial administration of AAV, the host mounts an immune response against the vectors, thereby hindering the clinical feasibility of repeated AAV administration. Moreover, when the AAV dosage exceeds 1.0 × 10 13 vg/kg, there is a significant risk of excessive activation of the complement system, which can result in severe adverse reactions. Notably, research indicates that merely depleting IgG antibodies does not enable high-dose re-administration of AAV or alleviate excessive complement activation; IgM antibodies also play a pivotal role in both the immune response against AAV and complement system activation. In this study, we synthesized a series of rapamycin lipid prodrugs utilizing succinic anhydride as a chemical linker and co-assembled them with dexamethasone palmitate to produce co-assembled nanoparticles ranging from 100 to 180 nm in size. These co-assembled nanoparticles are capable of inducing regulatory T cell (Treg) generation while inhibiting T follicular helper (Tfh) cell formation, thus reducing germinal center B (GC B) cell production and consequently suppressing anti-AAV IgG and IgM antibody responses along with complement system activation. The findings suggest that these rapamycin lipid prodrug co-assembled nanoparticles facilitate high-dose re-administration of AAV while enhancing gene expression delivered by the vector.
研究领域:
生物医学工程
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免疫学
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基因治疗
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DOI
高影响因子
JOURNAL OF BIOACTIVE AND COMPATIBLE POLYMERS
·
2015
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IF 2.352
Yeyun Fu,Xiaoyan Wang,Yu Zhang,Zonghua Liu,Wei Xue
Cyclodextrins have been extensively used in various biomedical and pharmaceutical applications. In these applications, cyclodextrins administered in vivo would inevitably enter blood stream. However, there is not enough information on the hemocompatibility of cyclodextrins until now. In this study, we investigated the influences of cyclodextrins (α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) on human blood components and functions in vitro, that is, morphology and lysis of red blood cells, structure and conformation of fibrinogen, complement activation, and blood coagulation. It was found that 10 mg/mL of α- or β-cyclodextrins caused abnormal red blood cell morphology and serious hemolysis, while γ-cyclodextrin at 10 mg/mL did not impair red blood cell membrane morphology and integrity. The three cyclodextrins at up to 10 mg/mL affected the local microstructure but did not change the conformation of fibrinogen. The three cyclodextrins from 0.01 to 1 mg/mL all significantly activated the complement system in a concentration-dependent way. The three cyclodextrins at up to 5 mg/mL in blood plasma did not cause significantly different coagulation times compared with the negative control. In addition, the three cyclodextrins at up to 5 mg/mL in whole blood did not cause abnormal coagulation parameters. These results provide significant information on blood safety of the three cyclodextrins for their biomedical and pharmaceutical applications.
研究领域:
医学
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药理学
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DOI
高影响因子
Frontiers in Pharmacology
·
2025
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IF 4.8
Sha Li,Si-Ming Yan,Li-Wei Zhang,Xiao-Yan Yang,Zhong Guo
Introduction: Polydopamine nanoparticles (PDA NPs) exhibit numerous outstanding characteristics, including simple preparation, broad light absorption, drug binding ability, excellent biocompatibility and adhesive properties, making them suitable for biomedical application. However, the limited information on their hemocompatibility may hinder their progression from laboratory research to clinical application.Methods: In this study, we investigated comprehensively the hemocompatibility of PDA NPs, assessed the effects of PDA NPs on red blood cells (RBCs) morphology and lysis, fibrinogen structure and conformation, blood coagulation, platelet activation, complement system activation, and organ toxicity.Results: The results indicated that PDA NPs can induce morphological changes and hemolysis in RBCs in a concentration-dependent manner. Interactions with fibrinogen suggested a disturbance in the protein’s microenvironment without significantly altering its secondary structure. This study also revealed that PDA NPs have a concentration-dependent effect on blood coagulation, platelet activation, and complement system activation. Additionally, PDA NPs showed no significant acute toxicity after intravenous injection.Conclusion: The findings offer important insights into the hemocompatibility of PDA NPs, which is essential for their safe and effective clinical use. Understanding their interactions with blood components is key to ensuring their compatibility in biomedical applications. These results are vital for guiding the development of PDA NPs for medical use, particularly in blood-contacting applications.
研究领域:
生物医学工程
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材料科学
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血液学
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产品关联
DOI
PubMed
高影响因子
BMC Pulmonary Medicine
·
2020
·Vol. 20
·期 1
·1-12
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IF 2.813
Guo Jing,Li Min,Yang Yi,Zhang Lin,Zhang Li-wei,Sun Qian-yun
Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study.Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting.Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung.Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.
研究领域:
药理学
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免疫学
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病理学
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呼吸医学
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2017
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IF 1.74
Yunfei Ji,Ruijun Wang,Ying Peng,Chongsheng Peng,Xiaobo Li
Sijunzi Decoction (SJZD) is a conventional prescription for curing spleen deficiency in Traditional Chinese Medicine and polysaccharide is its main ingredient. In order to explore the effective ingredients contributing to the immunological activity of SJZD, we isolated and purified seven homogeneous polysaccharides from Radix Ginseng (RS-3-1 and RS-3-2), Rhizoma Atractylodis Macrocephalae (BZ-3-1, BZ-3-2, and BZ-3-3), Poria (FL-3-1), and Radix Glycyrrhizae (GC-3-1) decoctions, respectively. The molecular weight of seven homogeneous polysaccharides ranged from 5.42 × 104 to 5.65 × 104 Da. Monosaccharide composition determined by GC-MS analysis showed that these polysaccharides were primarily composed of Rha, Ara, Xyl, Man, Glc, and Gal with various ratios. Immunological activity assay revealed that polysaccharides from four crude drug components of SJZD displayed inhibitory effects on the complement system. RS-3-1, BZ-3-1, FL-3-1, and GC-3-1 could significantly enhance the phagocytosis and increase the NO production and tumor necrosis factor (TNF-α) level in RAW 264.7 cells (). These results demonstrated the immunological activities of these polysaccharides from the four crude drugs. This study supports the therapeutic effect of SJZD in clinical use and is essential for further identification the immunopolysaccharide from SJZD decoction.
研究领域:
中医药
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·335
·
IF 4.3
Pan Gaowei,Liu Xiaoling,Zhang Xiaoyue,Gao Hao,Xu Ting,Li Kemin,Wang Lei,Ji Shangrong,Li Ting,Zhang Shengxiang
Monomeric C-reactive protein (mCRP) is a key acute phase reactant involved in inflammatory responses. Cerebral ischemia triggers persistent neuroinflammation. However, the effects of mCRP on global cerebral ischemia are poorly understood. In present study, mCRP was intracerebroventricularly injected to brain, and a bilateral common carotid artery ligation (BCAL) model was established in CX3CR1 GFP/+ mice. Behavioral tests were employed to evaluate spontaneous activity, rotarod performance (latency to fall), and forelimb grasping strength in mice. Nissl and Fluoro-Jade C (FJ-C) staining were used to assess neuronal injury. Skeletonization analysis and CD16/32, CD206 staining were used to assess microglial activation. RT-qPCR was applied to evaluate the changes of inflammatory factors and complement system. Primary cultured microglia and oxygen–glucose deprivation (OGD) model were used to verify the effects of mCRP on microglia in vitro . Results showed that mCRP treatment exacerbated behavioral performance post-ischemia. Nissl staining showed that mCRP caused a significant decrease in neuronal density. Additionally, FJ-C staining indicated an increase in degenerative cells after mCRP treatment. Immunofluorescence analysis revealed an increase in CD16/32 and CD206-positive microglia, and skeletonization analysis showed increased de-ramification of microglia following mCRP administration. RT-qPCR results further demonstrated that mCRP treatment upregulated the expression of pro-inflammatory and anti-inflammatory factors, as well as complement system components, in both brain tissue and primary cultured microglia following ischemia or OGD. These findings suggest that mCRP significantly enhances microglial activation, increases the level of inflammatory response, exacerbates neuronal loss and degenerative damage, and impairs behavioral performance after ischemia.
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-18
·
IF 9.3
Su Xi,Wang Guanyu,Liu Senqi,Li Jinming,Shao Minglong,Yang Yongfeng,Song Meng,Han Yong,Li Wenqiang,Lv Luxian
Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.
研究领域:
神经科学
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分子生物学
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行为科学
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遗传学
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DOI
PubMed
高影响因子
Journal of Chemistry
·
2018
·
IF 1.726
Ruijun Wang,Yunfei Ji,Ying Peng,Xiaobo Li
Sijunzi decoction (SJZD) is a classical herbal prescription in traditional Chinese medicine (TCM) used for enhancing the function of immune system. In previous studies, a polysaccharide fraction S-3 was screened from SJZD by assessment of immune system regulation, intestinal microbiota, and SCFA in order to explore the immune active ingredients in SJZD. In the present study, S-3 was further purified, and a homogeneous polysaccharide S-3-1 with a molecular mass of 13.5 × 104 Da was obtained after further fractionation by Sephadex G-150 size-exclusion chromatography. The immunological activities of S-3-1 were assayed in vitro for the first time. The determination of the anticomplement activity showed that S-3-1 displayed inhibitory effects on classical pathway of the complement system, with CH50 values of 530 μg/mL. The FT-IR analysis showed that S-3-1 had absorptive peaks characteristic of polysaccharides. The methylation and GC-MS analysis showed that it is comprised of Rha, Ara, Xyl, Man, Gal, and Glc in a relative molar ratio of 0.35 : 0.37 : 1.4 : 0.31 : 3 : 0.8 and that it mainly contained 1,4-linked-Glc and 1,6-linked-Gal glycosidic bonds. The morphology of S-3-1 was observed by atomic force microscope (AFM). These results provided evidences for tracking the material basis of SJZD immune activity.
研究领域:
中药学
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药理学
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免疫学
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生物化学
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产品关联
DOI
高影响因子
EXPERIMENTAL EYE RESEARCH
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2016
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IF 2.998
Xinyi Ren,Jia Li,Xianxing Xu,Chunming Wang,Yuanguo Cheng
Uncontrolled activation of complement and upregulation of vascular endothelial growth factor (VEGF) play fundamental roles in age-related macular degeneration (AMD). However, most drugs used to treat AMD focus on a single target, and the percentage of effectively treated patients in clinical practice needs to be improved. Therefore, novel AMD treatment approaches are needed. IBI302 is a novel bispecific decoy receptor fusion protein designed with both a VEGF inhibition domain and a complement cascade inhibition domain, which are connected by the Fc region of human immunoglobulin . In this study, we systematically evaluated the binding affinity between IBI302 and VEGF isoforms and complement proteins by using surface plasmon resonance (SPR) technology. Anti-VEGF blockers (aflibercept and bevacizumab) and complement receptor 1 were used as references. The SPR assay results indicated that IBI302 could bind different VEGF isoforms and complement proteins with high affinity. The biological activity of IBI302 was also studied. IBI302 showed an inhibitory effect on human primary umbilical vein endothelial cell proliferation and the activation of complement pathways in vitro. Finally, the pharmacokinetic (PK) properties of IBI302 were evaluated in rhesus monkeys . The PK results showed that after a 0.5 mg/eye intravitreal dosage, IBI302 became rapidly distributed from the vitreous humor into targeted tissues and remained active over 504 h. Overall, the favorable anti-angiogenic and anti-complement effects of IBI302 along with the good PK profiles in rhesus monkeys support the selection and development of IBI302 as a promising candidate for AMD treatment.
研究领域:
眼科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Frontiers
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2024
·
IF 7.4
Ying Yang,Mengfan Luo,Wanyi Zhou,Wenyang Tao,Jingrui Li,Jianrong Xing,Quanqin Tan,Yuxing Guo
In recent years, the development of immunosuppression has become common, and probiotics are a vital immunomodulatory strategy. This study evaluated the alleviating effect of Lactiplantibacillus plantarum ( L. plantarum ) YY-112 on cyclophosphamide-induced immune imbalance and resolved the possible mechanism of action. L. plantarum YY-112 at 10 9 CFU/mL lowered loss of body weight and alleviated splenic injury, intestinal injury, and inflammation, according to the hematoxylin and eosin staining. Biochemical results showed that 10 9 CFU/mL L. plantarum YY-112 increased interleukin-10 and immunoglobulin M levels and decreased interferon-γ levels. Additionally, the immunoregulatory effect at the molecular levels of L. plantarum YY-112 was analyzed by transcriptome sequencing. L. plantarum YY-112 significantly upregulated Cr2 and downregulated C5aR1 to regulate the complement system; downregulated S100a8 , S100a9 , and Mmp9 to inhibit neutrophil aggregation; upregulated Cd19 , Cd72 , Cd3e , Cd28 , Cd80 , Cd8a , and histocompatibility-2-related genes to regulate B- and T-cell activation; and upregulated Xiap , Malt1 , Ikbkb , Mapk11 , Mef2c , Mapk12 , Ras , and Myc to activate immune signaling pathways. Furthermore, L. plantarum YY-112 improved intestinal microbial structure and reduced enrichment of Lachnospiraceae_NK4A136_group , norank_f_Lachnospiraceae , Desulfovibrio , Colidextribacter , and Helicobacter . In conclusion, these findings offer valuable insights into the potential mechanisms through which L. plantarum YY-112 regulates immune imbalance.
研究领域:
免疫学
·
微生物学
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分子生物学
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药理学
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产品关联
DOI
高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2017
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IF 3.148
Liangliang Mu,Xiaoxue Yin,Jing Liu,Liting Wu,Xia Bian,Yuhong Wang,Jianmin Ye
Mannose-binding lectin (MBL) is a pattern recognition protein that plays an important role in innate immunity capable of activating the lectin pathway of the complement system. In this study, a MBL homologue (OnMBL) was identified from Nile tilapia ( Oreochromis niloticus ) and characterized at expression and agglutination functional levels. The open reading frame of OnMBL is 687 bp of nucleotide sequence encoding polypeptides of 228 amino acids. The deduced amino acid sequence is highly homology to teleost and similar to mammalian MBL, containing a canonical collagen-like region, a carbohydrate recognition domain and a neck region. Expression analysis revealed that the OnMBL was highly expressed in the liver, and also exhibited in other tissues including hind kidney , intestines, head kidney and spleen. In addition, the OnMBL expression was significantly up-regulated in spleen and head kidney following challenges with a Gram-positive bacterial pathogen ( Streptococcus agalactiae ) and a Gram-negative bacterial pathogen ( Aeromonas hydrophila ). Recombinant OnMBL ((r)OnMBL) protein was able to agglutinate both S. agalactiae and A. Hydrophila in vitro. Taken together, the results of this study indicated that OnMBL, possessing apparent agglutination ability to bacterial pathogens, might be involved in host defense against bacterial infection in Nile tilapia.
研究领域:
免疫学
·
分子生物学
·
鱼类病理学
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DOI
PubMed
高影响因子
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