ABSTRACT
Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflammation and cartilage damage. Despite great progress in RA therapy, there still lacks the drugs to completely cure RA patients. Herein, we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA (siTNFα) as an alternative anti-inflammatory approach for RA treatment. The loaded siTNFα act as not only the gene therapeutics to inhibit TNFα production by macrophages in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTNFα/neutrophil cytopharmaceuticals (siTNFα/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNFα to macrophages followed by the significant reduction of TNFα expression, and circumvent the pro-inflammatory activity of neutrophils, thus leading to the alleviated synovial inflammation and improved cartilage protection. Our work provides a promising cytopharmaceutical for RA treatment, and puts forward a living neutrophil-based gene delivery platform.
ABSTRACT
An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.
Subject(s)
Humans , Hepatic Stellate Cells/pathology , Receptors, Calcitriol , Liver Cirrhosis/pathology , Macrophages/metabolismABSTRACT
BACKGROUND: It remains disputed whether bone filling bag vertebroplasty and percutaneous kyphoplasty have different treatment efficacy in the treatment of thoracolumbar osteoporotic compression fractures. OBJECTIVE: To systematically analyze the efficacy and safety of bone filling bag vertebroplasty and percutaneous kyphoplasty in the treatment of thoracolumbar osteoporotic compression fractures. METHODS: A computer-based online search of CNKI, Wanfang, VIP, CBM, EMBASE, MEDLINE, and Cochrane libraries was performed to retrieve randomized controlled trial studies regarding bone filling bag vertebroplasty and percutaneous kyphoplasty in the treatment of thoracolumbar osteoporotic compression fractures published before February 2019. Two researchers independently conducted literature screening and data extraction. According to the Cochrane Collaboration Network standard, the quality of the randomized controlled trial studies was evaluated one by one. The studies that met the inclusion criteria were analyzed using the RevMan5. 3 software. RESULTS AND CONCLUSION: Six randomized controlled trial studies were included. A total of 517 patients were included in the final analysis. Among them, 257 patients received bone filling bag vertebroplasty and 260 patients received percutaneous kyphoplasty. Meta-analysis showed that there were no significant differences in postoperative Visual Analogy Score (MD=0. 00, 95%CI: -0. 09-0. 10, P=0. 94), vertebral height recovery (SMD=0. 11, 95%CI: -0. 26-0. 48, P=0. 57), and Oswestry Disability Index (MD=1. 47, 95%CI: -0. 45-3. 39, P=0. 13) between these two surgical procedures. But postoperative Cobb angle (MD=-1. 08, 95%CI: -1. 47 to -0. 70, P < 0. 000 01) and bone cement leakage rate (RR=0. 24, 95%CI: 0. 13-0. 45, P < 0. 000 01) were significantly different between these two surgical procedures. Bone filling bag vertebroplasty exhibits significant advantages in improving postoperative Cobb angle and reducing bone cement over percutaneous kyphoplasty. These two surgical procedures have similar clinical outcomes such as postoperative Visual Analogy Score, vertebral height recovery, and Oswestry Disability Index. Therefore, a large number of high-quality multicenter randomized controlled trials are needed to provide more evidence.
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Objective:To construct NMB0315 eukaryotic expression recombinant vector ,detect specific humoral and cellular immune response induced by the recombint DNA vaccine intramuscularly in female BALB /c mice,evaluate the immunocompetence and immunoprotection of the vaccine , so as to provide experimental basis for the development of a novel nucleic acid vaccine against N.meningitidis serogroup B .Methods: The whole NMB0315 gene was amplified by PCR from the standard strains MC 58 genomic DNA,cloned into a plasmid pcDNA3.1(+),identified by double digestion of the recombinant plasmid with restriction enzymes and se -quencing.The recombinant vector pcDNA 3.1 (+)/NMB0315 was transfected into eukaryotic COS-7 cells and RAW264.7 cells, the NMB0315 protein was detected by immunocytochemical method and Western blot respectively .The levels of specific humoral and cellular immune response were detected after inoculating in female BALB /c mice intramuscularly with the recombinant plasmid .The immune protective effect was investigated with the DNA vaccine and the bactericidal titer of the immune serum was deter mined by serum bactericidal assay ( SBA ) in vitro.Results: The recombinant pcDNA3.1 (+)/NMB0315 was effectively transcripted and expressed in eukaryotic cells and the specific humoral and cellular immune responses were induced in the inoculated mice .In the re-combinant pcDNA3.1(+)/NMB0315 group ,the levels of serum IgG,IgG1,IgG2a,IgG2b and IgG3 and genital tract sIgA were significantly higher than in controls ( P<0.001 ) .The stimulation index in the culture supernatant of the spleen lymphocytes of the vaccine group was higher than that of the control group (P<0.05).The ratios of serum IgG2a/IgG1 in the DNA vaccine group were less than 1.The bactericidal titer of the NMB 0315+CpG group reached 1:128 following three immunizations , the protection rate of the vaccine group was 70%against the N.meningitidis strain MC58.Conclusion:The NMB0315 nucleic acid vaccine could induce higher levels of humoral immunity and cellular immunity and showed effective protection against N .meningitidis serogroup B , the immune serum had strong bactericidal activity in vitro .
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Objective To compare the image quality and adverse effects among different concentrations of nonionic iodinated con-trast media in hysterosalpingography (HSG).Methods 99 female infertile patients were recruited in this study for HSG and were averagely divided into Group A,B and C.The application of contrast media were as follows:iomeprol injection(400 mg I/mL)for Group A,iopamidol injection (370mg I/mL)for Group B,iohexol injection(300 mg I/mL)for Group C.The image quality was in-dependently evaluated by two doctors using a 3-point scale (1 -3 score)and adverse effects were recorded.Results (1 )Scores of image quality:all images met diagnostic desire with (2.55±0.5 1)score in Group A,(2.42±0.50)score in Group B,(2.21±0.42) score in Group C.There were statistically significant differences among goups(H =7.790,P =0.022).Kappa values were 0.693 in Group A,0.687 in Group B,0.672 in Group C.(2)Adverse effects:4 cases in Group A(12.12%),3 cases in Group B(9.09%), 2 cases in Group C(6.06%),which showed no statistically significant differences(χ2 = 0.733,P =0.693).Conclusion The three kinds of concentrations of nonionic iodinated contrast media can all be applied in HSG.The higher of iodinated concentration,the better of image contrast.