{"doi":"10.1016/j.ejphar.2021.174623","title":"Inhibition of PAD4-mediated NET formation by cl-amidine prevents diabetes development in nonobese diabetic mice","abstract":null,"journal":"European Journal of Pharmacology","year":2022,"id":647006,"datarank":0.5676284450877392,"base_score":3.784189633918261,"endowment":3.784189633918261,"self_citation_contribution":0.5676284450877392,"citation_network_contribution":0.0,"self_endowment_contribution":0.5676284450877392,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":734663,"name":"Qi You","orcid":"0000-0002-2706-1394","position":1,"is_corresponding":false},{"id":1654752,"name":"Yiling Wu","orcid":null,"position":2,"is_corresponding":false},{"id":959290,"name":"Jie Wu","orcid":"0000-0003-2445-6750","position":3,"is_corresponding":false},{"id":1338174,"name":"Yiming Shen","orcid":"0000-0001-8404-3136","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Inhibition of PAD4-mediated NET formation by cl-amidine prevents diabetes development in nonobese diabetic mice","abstract":"Many evidences indicated that neutrophil extracellular traps (NETs) play pathogenic roles in type 1 diabetes (T1D). Peptidylarginine deiminases 4 (PAD4) has been proved to be indispensable for generation of NETs. In the current study, we investigated whether oral administration of cl-amidine, an effective inhibitor of PAD4, protects non-obese diabetic (NOD) mice from T1D development. Female NOD mice were orally administrated with cl-amidine (5 μg/g body weight) from the age of 8 weeks up to 16 weeks. It showed that cl-amidine inhibit NET formation in vitro and in vivo. The onset of T1D was delayed nearly 8 weeks and the incidence of disease was significantly decreased in cl-amidine treated mice compared with the control group. Moreover, cl-amidine decreased the serum levels of anti-citrullinated peptide antibody (ACPA) and anti-neutrophil cytoplasmic antibodies (ANCA) in NOD mice. Also, it decreased generation of T1D autoantibodies such as glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase-related islet antigen-2 antibody (IA2A) and zinc transporter 8 antibody (ZnT8A), which were strongly correlated with the reduced serum PAD4 and MPO-DNA levels. Furthermore, cl-amidine administration inhibited pancreatic inflammation and increased frequency of regulatory T cells in pancreatic lymph nodes (PLNs). In addition, cl-amidine improved gut barrier dysfunction and decreased the serum level of lipopolysaccharide (LPS), which was positively correlated with the NETs markers (PAD4 and MPO-DNA) and T1D autoantibody IA2A. In conclusion, our data showed that orally delivery of cl-amidine effectively prevent T1D development and suggested inhibition of PAD4-dependent NET formation as a potential way of clinical treatment in T1D.","is_dataset_classified":null,"base_score":3.784189633918261,"endowment":3.784189633918261,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34767782","pmcid":null,"openalex_id":"https://openalex.org/W3213609084","authors":[],"funders":[{"funder_name":"Double First Class University Plan","grant_id":"CPU2018GF/GY16","title":null},{"funder_name":"Double First Class University Plan","grant_id":"CPU2018GF/GY17","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81973224","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81673340","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81673340,81973224","title":null},{"funder_name":"Double First Class University Plan","grant_id":"","title":null}],"total_grants":6,"fwci":1.3931,"citation_percentile":0.8099691,"influential_citations":1,"citation_trend":[{"year":2021,"count":1},{"year":2022,"count":4},{"year":2023,"count":4},{"year":2024,"count":10},{"year":2025,"count":10},{"year":2026,"count":14}],"oa_status":"closed","license":"https://doi.org/10.15223/policy-004","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0014299921007792?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0014299921007792?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.ejphar.2021.174623","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34767782","host_type":"repository"}],"fields_of_study":["Neutrophil, Myeloperoxidase and Oxidative Mechanisms","Blood disorders and treatments","Immune Response and Inflammation","Medicine"],"mesh_terms":["Protein-Arginine Deiminase Type 4","Administration, Oral","Animals","Autoantibodies","Autoimmune Diseases","Blood Glucose","Diabetes Mellitus, Experimental","Diabetes Mellitus, Type 1","Female","Inflammation","Intestines","Ornithine","Mice, Inbred NOD","Tight Junctions","Protective Agents","T-Lymphocytes, Regulatory","Mice","Extracellular Traps"],"keywords":["NOD mice","Nod","Internal medicine","Endocrinology","Chemistry","Antibody","Diabetes mellitus","Biology","Immunology","Medicine","type 1 diabetes","Neutrophil Extracellular Traps","Cl-amidine","Peptidylarginine Deiminases 4"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T16:13:14.460354Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}