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Systemic lupus erythematosus (SLE) is an autoimmune disease caused by the disorders of immune regulation but its pathogenesis is poorly understood. Progranulin (PGRN) is an immunomodulatory protein that is upregulated in SLE patients. However, the factors involved in regulating the pathogenesis of SLE by PGRN are largely unknown. We sought to investigate the role and molecular mechanisms of PGRN in SLE to develop a novel therapeutic target. We used an animal model of SLE that was induced in PGRN-deficient and normal wild type (WT) mice using pristane. PGRN concentrations were measured in SLE and the impact of PGRN deficiency was examined by measuring tissue injury and immune responses of T cells (Th1, Th2, Th17, and Treg) and B cells. SLE patients and mice showed elevated PGRN levels. Compared with WT SLE mice, inflammatory cell infiltration, tissue edema, and necrosis were alleviated in PGRN−/− SLE mice and the levels of serum chemistry markers of tissue damage and the presence of anti-double-stranded DNA and anti-ribosomal protein P0 antibodies were all significantly decreased. We further discovered that PGRN deficiency could disturb the immune responses of T cell (Th1, Th2, Th17, and Treg) and B cell responses, leading to the decrease of inflammatory cytokines including interferon-γ and interleukin-17A and increased levels of regulatory B cells. PGRN plays a proinflammatory role in the development of SLE partially through promoting the production of autoantibodies and enhancing Th1 and Th17 cell responses. This may provide new therapeutic options for patients with SLE. [ABSTRACT FROM AUTHOR]

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×103‐fold improved activity against Gram‐positive Streptococcus pneumoniae (S. pneumoniae) and Gram‐negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×103‐fold reduced human cytotoxicity, resulting in 2.08×106‐fold improvements in the therapeutic index. This proof‐of‐principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs. [ABSTRACT FROM AUTHOR]

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00×103‐fold improved activity against Gram‐positive Streptococcus pneumoniae (S. pneumoniae) and Gram‐negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31×103‐fold reduced human cytotoxicity, resulting in 2.08×106‐fold improvements in the therapeutic index. This proof‐of‐principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs. [ABSTRACT FROM AUTHOR]

This study aimed to determine the antibiotic resistance and molecular epidemiology of Haemophilus influenzae isolated from children with acute respiratory infection in Chongqing, China. To this end, 1967 H. influenzae isolates from 2006 to 2009 were analysed regarding β-lactamase production and antibiotic resistance. Ninety-nine β-lactamase-producing H. influenzae isolates from 2010 were analysed for antibiotic resistance and promoter regions of bla TEM-1. β-lactamase production was found in 35.8% (705/1967) of the strains. All ninety-nine β-lactamase-producing strains from 2010 were of the TEM-1 type as determined by PCR but did not produce the predicted 1075 bp product. According to PCR- SSCP and DNA sequencing, the promoter regions of bla TEM-1 were categorized into 6 genotypes as SSCP1 (Pdel), SSCP2 (Pa/Pb), SSCP3 (P4), SSCP4 (Prpt.b), SSCP5 (2Prpt) and SSCP6 (P3.b). The Pdel, Pa/Pb and Prpt.b were common promoters of bla TEM-1 for H. influenzae isolated from children in Chongqing. Strains with Prpt.b were more resistant to ampicillin ( AMP) than strains with Pdel, Pa/Pb and P4 (p < 0.05). Therefore, blaTEM-1 β-lactamase is the main mechanism for resistance of H. influenzae to ampicillin in Chongqing. Furthermore, the Prpt.b promoters may be related to the high resistance of H. influenzae to AMP. [ABSTRACT FROM AUTHOR]