Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases.

Neurodegenerative diseases (NDs) are characterized by the aggregation of neurotoxic proteins in the central nervous system. Aberrant protein accumulation in NDs is largely caused by the dysfunction of the two principal protein catabolism pathways, the ubiquitin-proteasome system (UPS), and the autophagy-lysosomal pathway (ALP). The two protein quality control pathways are bridged by ubiquitination, a post-translational modification that can induce protein degradation via both the UPS and the ALP. Perturbed ubiquitination leads to the formation of toxic aggregates and inclusion bodies that are deleterious to neurons. Ubiquitination is promoted by a cascade of ubiquitinating enzymes and counter-regulated by deubiquitinating enzymes (DUBs). As fine-tuning regulators of ubiquitination and protein degradation, DUBs modulate the stability of ND-associated pathogenic proteins including amyloid ß protein, Tau, and α-synuclein. Besides, DUBs also influence ND-associated mitophagy, protein secretion, and neuroinflammation. Given the various and critical functions of DUBs in NDs, DUBs may become potential therapeutic targets for NDs.

Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2.

Acute lung injury (ALI) is a sudden onset systemic inflammatory response. ALI causes severe morbidity and death and currently no effective pharmacological therapies exist. Natural products represent an excellent resource for discovering new drugs. Screening anti-inflammatory compounds from the natural product bank may offer viable candidates for molecular-based therapies for ALI. In this study, 165 natural compounds were screened for anti-inflammatory activity in lipopolysaccharide (LPS)-challenged macrophages. Among the screened compounds, flavokawain B (FKB) significantly reduced LPS-induced pro-inflammatory IL-6 secretion in macrophages. FKB also reduced the formation of LPS/TLR4/MD2 complex by competitively binding to MD2, suppressing downstream MAPK and NF-κB signaling activation. Finally, FKB treatment of mice reduced LPS-induced lung injury, systemic and local inflammatory cytokine production, and macrophage infiltration in lungs. These protective activities manifested as increased survival in the ALI model, and reduced mortality upon bacterial infection. In summary, we demonstrate that the natural product FKB protects against LPS-induced lung injury and sepsis by interacting with MD2 and inhibiting inflammatory responses. FKB may potentially serve as a therapeutic option for the treatment of ALI.