Upregulation of glycolytic enzyme PFKFB3 by deubiquitinase OTUD4 promotes cardiac fibrosis post myocardial infarction.

Metabolic dysregulations have emerged as a major mediator of cardiovascular disorders and fibrotic diseases. Metabolic reprogramming contributes a lot to cardiac fibroblast activation and cardiac fibrosis post-myocardial infarction (MI), yet the mechanism remains incompletely understood. Our work aimed to determine whether or not glycolytic reprogramming, regulated by phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), is a therapeutic target for alleviating post-MI cardiac fibrosis. Here, we showed that cardiac fibroblasts displayed cell energy phenotype toward augmented glycolysis in response to transforming growth factor-beta 1 (TGF-ß1), evidenced by significant extracellular acidification rate (ECAR) increase and lactate accumulation. The expression of glycolytic enzyme PFKFB3, a master activator of glycolysis, was up-regulated in TGF-ß1-treated cardiac fibroblasts and in cardiac fibroblasts of post-MI mice. Pharmacological inhibition of PFKFB3 by 3PO diminished TGF-ß1-mediated profibrotic phenotypes, attenuated cardiac fibrosis, and preserved cardiac functions in post-MI mice. Meanwhile, the genetic inhibition of PFKFB3 decreased the cardiac fibroblast activation and reversed the differentiated phenotypes in vitro and in vivo. Mechanistically, we identified deubiquitinase OTUD4 as a new binding protein of PFKFB3, and their interaction blocked PFKFB3 degradation via OTUD4-mediated deubiquitylation. Taken together, this work characterized a key role for PFKFB3 in cardiac fibroblast activation and suggested that inhibiting PFKFB3-involved glycolysis is an alternative way to alleviate post-MI cardiac fibrosis. KEY MESSAGES: PFKFB3, a master activator of glycolysis, was highly expressed in ischemic cardiac fibroblasts to enhance cardiac fibrosis The deubiquitinase OTUD4 was identified as a new binding protein of PFKFB3 TGF-ß1 blunted the ubiquitination-mediated degradation of PFKFB3 via OTUD4-mediated deubiquitylation Blockade of PFKFB3 contributed to ameliorating ischemia-induced cardiac fibrosis.

Bioactive Compounds from the Zingiberaceae Family with Known Antioxidant Activities for Possible Therapeutic Uses.

The Zingiberaceae family is a rich source of diverse bioactive phytochemicals. It comprises about 52 genera and 1300 species of aromatic flowering perennial herbs with characteristic creeping horizontal or tuberous rhizomes. Notable members of this family include ginger (Zingiber officinale Roscoe), turmeric (Curcuma longa L.), Javanese ginger (Curcuma zanthorrhiza Roxb.), and Thai ginger (Alpinia galanga L.). This review focuses on two main classes of bioactive compounds: the gingerols (and their derivatives) and the curcuminoids. These compounds are known for their antioxidant activity against several maladies. We highlight the centrality of their antioxidant activities with notable biological activities, including anti-inflammatory, antidiabetic, hepatoprotective, neuroprotective, antimicrobial, and anticancer effects. We also outline various strategies that have been applied to enhance these activities and make suggestions for research areas that require attention.

Omics and Transgenic Analyses Reveal that Salvianolic Acid B Exhibits its Anti-Inflammatory Effects through Inhibiting the Mincle-Syk-Related Pathway in Macrophages.

Salvianolic acid B (Sal B), the main water-soluble compound in Salvia miltiorrhiza, is known to exhibit anti-inflammatory activity, however, the underlying mechanism(s) is not completely uncovered. In this study, Sal B inhibited lipopolysaccharide (LPS)-induced M1 activation and promoted the transformation of macrophages from M1- to M2-type polarization. The altered lipid profiles of LPS-induced RAW 264.7 macrophages were partly restored by Sal B treatment. At the proteomic level, a total of 5612 proteins were identified and 432 were significantly changed in macrophages under LPS treatment. The differential proteins were classified into four clusters according to their expression level in blank, LPS, and Sal B groups. LPS-induced proteins in Cluster IV including Kif14, Mincle, and Sec62 were significantly recovered to almost normal levels by Sal B treatment. Use of knockdown Mincle or picetannol (inhibitor of Syk) led to significant reductions in the gene expressions of IL-1ß, iNOS, and IL-12 and the release of NO. The converse was, however, observed for overexpressed Mincle. In addition, LPS- or trehalose-6,6-dibehenate-induced phosphorylation of Syk and PKCδ was decreased by Sal B treatment. These results suggest that Sal B inhibition of LPS-induced inflammation might be through inhibition of the Mincle-Syk-PKCδ signaling pathway.