Protective effect of MOTS-c on acute lung injury induced by lipopolysaccharide in mice.

MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA-c), a mitochondrial-derived 16-amino acid peptide, targets the methionine-folate cycle, increases 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels, and eventually activates AMP-activated protein kinase (AMPK). AMPK activation can attenuate neutrophil pro-inflammatory activity and attenuates lipoteichoic acid (LTA) and lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. However, to our knowledge, the role of MOTS-c in LPS-induced ALI remains unclear. Hence, we investigated the potential effectiveness and underlying mechanism of MOTS-c against LPS-induced ALI in mice. The intraperitoneal administration of MOTS-c (5 mg/kg, i.p., bid, 6 days) before intratracheal LPS instillation attenuated body weight loss and pulmonary edema, inhibited neutrophilic tissue infiltration in lung tissue, downregulated the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and intercellular cell adhesion molecule-1 (ICAM-1) in lung tissues, decreased the levels of TNF-α, IL-1ß, and IL-6, and increased the expression of IL-10 and SOD in serum, lung tissue, and bronchoalvelolar lavage fluid (BALF). Moreover, MOTS-c treatment significantly promoted p-AMPKα and SIRT1 expression and suppressed LPS-induced ERK, JNK, p38, p65, and STAT3 activation in the mouse lung tissues. Collectively, these findings suggest that MOTS-c plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of MOTS-c are probably orchestrated by activating AMPK and SIRT1, inhibiting ERK, JNK, p65, and STAT3 signaling pathways. Thus, MOTS-c appears to be a novel and promising candidate for the treatment of ALI.

PEGylated HM-3 presents anti-rheumatic bioactivity by inhibiting angiogenesis and inflammation.

PEGylation improves the pharmacokinetic and pharmacodynamic properties of polypeptide drugs. After PEGylation, the modified HM-3 (PEG-HM-3) exhibited a prolonged half-life in blood. In this paper, we evaluated the anti-rheumatic effect of PEG-HM-3, and investigated the target for angiogenesis and inflammation. The anti-rheumatic activity of PEG-HM-3 was documented in an adjuvant-induced arthritis (AIA) model. PEG-HM-3 significantly decreased the paw increase percentage and clinical scores, inhibited characteristic signs such as synovial hyperplasia, pannus formation, inflammatory infiltration and bone erosion in histological analysis, and reduced bone erosion with the X-ray analysis of the hint paws of rats. The target for angiogenesis and inflammation was assessed with in vivo and in vitro techniques. The in vivo experiments confirmed that PEG-HM-3 decreased the number of blood vessels in rheumatic synovium, reduced the level of serum anti-CII autoantibodies, and decreased the levels of synovial TNF-alpha and VEGF in a collagen-induced arthritis (CIA) model. The in vitro results confirmed that the anti-angiogenic effect of PEG-HM-3 was mainly achieved through the inhibition of HUVEC migration. PEG-HM-3 inhibited the mitotic effects in the T-cell population. PEG-HM-3 could significantly inhibit the TNF-alpha and VEGF levels in the LPS-stimulated macrophage and the latter effect was stronger than that seen with HM-3. Furthermore, the simulated molecule docking result showed that the RGD motif of PEG-HM-3 inserted into the pocket site of integrin αvß3, and PEG-HM-3 had a higher predicted affinity with integrin αvß3 compared to the predicted affinity of HM-3 and integrin αvß3. This study has uncovered that PEGylate HM-3 could present an anti-rheumatic bioactivity with a less frequent schedule, and PEG-HM-3 exhibited its anti-rheumatic effects by inhibiting angiogenesis and inflammation. Furthermore, the main targeting site has been confirmed, which explained the changes in the bioactivity of PEG-HM-3.