Novel NETosis inhibitor TcpC and application thereof
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A technology of inhibitors and proteins, applied in the fields of molecular biotechnology and medicine, can solve problems such as the incomplete elucidation of the pathophysiological role of NETosis
Inactive Publication Date: 2020-07-24
ZHEJIANG UNIV CITY COLLEGE
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[0005] So far, the pathophysiological role of NETosis has not been fully elucidated. In recent years, studies have found that in addition to playing an anti-infective role, NETs are not degraded after formation or the process of NETosis is out of control, which is involved in various diseases such as cancer, autoimmune disease, diabetes, and cardiovascular disease. development
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Embodiment 1
[0028] Example 1: Nucleotide (SEQ ID No. 1) and amino acid sequence (SEQ ID No. 2) of GenBank (GQ903014.1) TcpC.
Embodiment 2
[0029] Example 2: Construction of mouse pyelonephritis model
[0030] (1) 24 female C57BL / 6 mice aged 6-8 weeks were divided into 3 groups, which were blank control group and CFT073 wt group with CFT073 Δtcpc groups, with 8 mice in each group.
[0031] (2) Shake the strain with LB medium until the absorbance is 0.6-0.8, centrifuge at 5500rpm / min at 4°C for 30 minutes, discard the supernatant and save the precipitate, wash the bacteria with normal saline for 3 times, and then resuspend the bacteria with normal saline to 10 10 CFU / ml.
[0032] (3) Insert a 0.61mm soft polyethylene catheter into the bladder through the mouse urethra, and instill 0.1ml of bacterial solution (10 9 CFU); the blank control group was instilled with 0.1ml of normal saline per mouse.
[0033] (4) After 3 days, the mice were killed by neck dislocation, and the kidneys were taken for pathological examination.
[0034] Found CFT073 wt The kidneys of mice infected with the strain had obvious abscesses...
Embodiment 3
[0035] Example 3: Detection of in situ NETosis in model mouse kidney by confocal laser microscopy
[0036] (1) A mouse pyelonephritis model was established according to the above method. After 72 hours, the model mouse was perfused with 4% paraformaldehyde under anesthesia, and the kidney tissue was embedded in paraffin and routinely sectioned.
[0037] (2) Dewaxing to water: place the kidney tissue slices at room temperature for 10 minutes, put the slices in xylene for 30 minutes—absolute ethanol for 5 minutes—replace 95% ethanol for 5 minutes—85% alcohol for 5 minutes—75% alcohol for 5 minutes—50% alcohol 5min—wash with ddH2O for 5min.
[0038] (3) Antigen retrieval: place dewaxed sections in citric acid antigen retrieval solution (diluted to 1X for use), and carry out antigen retrieval in a microwave oven, medium heat for 8 minutes—stop fire for 8 minutes—medium and low fire for 7 minutes. During this process, buffer solution should be prevented. Excessive evaporation, nev...
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Abstract
The invention discloses a novel NETosis inhibitor TcpC and an application of thereof. The invention finds that the TcpC has an inhibiting effect on formation of neutrophil extracellular traps (NETosis), and not only can inhibit NETOsis in vitro, but also can inhibit NETOsis in vivo. Research shows that a Toll / interleukin 1 receptor structural domain containing protein TcpC, which is secreted by aurinary tract pathogenic escherichia coli (UPEC) CFT073 strain, can enhance ubiquitination degradation of an NETosis key protein, namely peptide arginine deaminase 4 (PAD4), of neutrophile granulocyte, and inhibit formation of NETosis. The uropathogenic E.coli (UPEC) is killed by escaping neutrophile granulocyte, and survival and pathopoiesis of bacteria in organisms are facilitated. NETosis participates in occurrence and development of various diseases such as malignant tumors, autoimmune diseases and cardiovascular diseases, and the invention discovers that the TcpC is used as an inhibitor of NETosis and can be used for developing medicines for treating diseases such as malignant tumors, diabetes mellitus, autoimmune diseases and cardiovascular diseases.
Description
technical field [0001] The invention belongs to the fields of molecular biotechnology and medicine, and specifically relates to a new NETosis inhibitor TcpC and its application. Background technique [0002] Urinary tract infection (UTI) is the most common infectious disease, which is inflammation of the urinary tract caused by various pathogens that invade the urinary system. About 150 million people around the world have UTI caused by E. coli infection every year, and the medical expenses exceed 6 billion US dollars. About 80% of UTIs are caused by Escherichia coli, and Uropathogenic E. coli (UPEC) can specifically adhere to and implant in the epithelial cells of the urinary tract mucosa, causing urinary tract infections. UPEC can secrete a protein containing TIR domain (TIR-containing protein encoded by E.coli), namely TcpC. Our previous research found that TcpC is an E3 ubiquitin ligase targeted by MyD88, which can escape the body's innate immune response by enhancing ...
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