Mycobacterial PE12 protein promotes bacterial survival through inhibiting cell apoptosis.

Mycobacterial PE_PGRS family proteins play key roles in pathogen-host interaction. However, the function of most PE_PGRS proteins remains unknown. In this study, we characterized the role of PE12 of Mycobacterium bovis (M. bovis) on bacterial growth, bacterial survival, and host cell apoptosis. Transcriptome sequencing of infected THP-1 cells was also performed. Compared to Ms_Vec, we found that M. bovis PE12 did not alter the colony morphology of M. smegmatis. The survival of Ms_PE12 was obviously higher than that of Ms_Vec. Furthermore, PE12 significantly suppressed the apoptosis of THP-1 induced by M. smegmatis infection. Transcriptome analysis results showed that there were 70 downregulated genes in the Ms_PE12 infection group in comparison with the Ms_Vec infection group, and these differentially expressed genes were enriched in 240 downregulated GO terms and 6 KEGG pathways. The downregulated expression genes are involved in cell adhesion, phagocytosis, apoptosis, inflammatory response, glycolysis and transmembrane transporter activity. Taken together, our study reveals that PE12 can suppress apoptosis and inhibit proinflammatory cytokine response. We propose that PE12 is related to macrophage phagocytosis and apoptosis, providing useful information to the pathogenic mechanisms of M. bovis.

Acute Elevated Resistin Exacerbates Mitochondrial Damage and Aggravates Liver Steatosis Through AMPK/PGC-1α Signaling Pathway in Male NAFLD Mice.

Resistin was identified as a link between obesity and insulin resistance and is associated with many diseases in mice. Deciphering the related development and molecular mechanism is necessary for the treatment of these diseases. Previous studies have revealed that increased resistin levels are correlated with lipid accumulation and play a role in non-alcoholic fatty liver disease (NAFLD) development. However, the exact mechanisms underlying these processes remain unclear. To further clarify whether acute elevated resistin level exacerbated liver steatosis, a high-fat diet-induced NAFLD animal model was used and treated with or without resistin for 6 days. We discovered that resistin altered mitochondrial morphology, decreased mitochondrial content, and increased lipid accumulation in HFD mice. qRT-PCR and western blot analysis showed that acute elevated resistin significantly altered the gene expression of mitochondrial biogenesis and liver lipid metabolism molecules in HFD mice. Consequently, in vitro experiments verified that resistin reduced the mitochondrial content, impaired the mitochondrial function and increased the lipid accumulation of palmitate-treated HepG2 cells. Additionally, we demonstrated that resistin upregulated proinflammatory factors, which confirmed that resistin promoted the development of inflammation in NAFLD mice and palmitate-treated HepG2 cells. Signaling-transduction analysis demonstrated that acute elevated resistin aggravated liver steatosis through AMPK/PGC-1α pathway in male mice. This reveals a novel pathway through which lipogenesis is induced by resistin and suggests that maintaining mitochondrial homeostasis may be key to treatments for preventing resistin-induced NAFLD aggravation.

Enhancing the antibacterial activity of PMAP-37 by increasing its hydrophobicity.

With increasing resistance against conventional antibiotics, there is an urgent need to discover novel substances to replace antibiotics. This need provides an opportunity for the development of antimicrobial peptides (AMPs). To develop new AMPs with effective and safe therapeutic effects, two PMAP-37 analogs called PMAP-37(R13-I) and PMAP-37(K20/27-I) were designed to increase hydrophobicity. Antimicrobial susceptibility testing and animal infection models were used to assess their antibacterial activity. The results showed that the minimal inhibitory concentrations of PMAP-37(R13-I) were lower than those of PMAP-37 for two gram-negative strains. Compared with PMAP-37, PMAP-37(K20/27-I) not only inhibited the growth of most bacterial strains, but also exhibited antibacterial activity against Shigella flexneri CICC21534. In addition, PMAP-37(K20/27-I) exhibited pH and thermal stability. PMAP-37(R13-I) had a therapeutic effect only in mice infected with Salmonella typhimurium SL1344. However, PMAP-37(K20/27-I) exhibited the therapeutic effects, whether in the clinical symptoms, the tissue lesions, or the tissue bacterial loads and the survival rates in mice infected with Staphylococcus aureus ATCC25923 or S. typhimurium SL1344. Therefore, PMAP-37(K20/27-I) can be used as a substitute for antibiotics against infection with bacterial strains.