Immunity and Immune Evasion Mechanisms of Epstein-Barr Virus.

Epstein-Barr virus (EBV) is the first human oncogenic virus to be identified, which evades the body's immune surveillance through multiple mechanisms that allow long-term latent infection. Under certain pathological conditions, EBVs undergo a transition from the latent phase to the lytic phase and cause targeted dysregulation of the host immune system, leading to the development of EBV-related diseases. Therefore, an in-depth understanding of the mechanism of developing an immune response to EBV and the evasion of immune recognition by EBV is important for the understanding of the pathogenesis of EBV, which is of great significance for finding strategies to prevent EBV infection, and developing a therapy to treat EBV-associated diseases. In this review, we will discuss the molecular mechanisms of host immunological responses to EBV infection and the mechanisms of EBV-mediated immune evasion during chronic active infection.

Gallic Acid Alleviates Gouty Arthritis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis Through Enhancing Nrf2 Signaling.

Gallic acid is an active phenolic acid widely distributed in plants, and there is compelling evidence to prove its anti-inflammatory effects. NLRP3 inflammasome dysregulation is closely linked to many inflammatory diseases. However, how gallic acid affects the NLRP3 inflammasome remains unclear. Therefore, in the present study, we investigated the mechanisms underlying the effects of gallic acid on the NLRP3 inflammasome and pyroptosis, as well as its effect on gouty arthritis in mice. The results showed that gallic acid inhibited lactate dehydrogenase (LDH) release and pyroptosis in lipopolysaccharide (LPS)-primed and ATP-, nigericin-, or monosodium urate (MSU) crystal-stimulated macrophages. Additionally, gallic acid blocked NLRP3 inflammasome activation and inhibited the subsequent activation of caspase-1 and secretion of IL-1ß. Gallic acid exerted its inhibitory effect by blocking NLRP3-NEK7 interaction and ASC oligomerization, thereby limiting inflammasome assembly. Moreover, gallic acid promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and reduced the production of mitochondrial ROS (mtROS). Importantly, the inhibitory effect of gallic acid could be reversed by treatment with the Nrf2 inhibitor ML385. NRF2 siRNA also abolished the inhibitory effect of gallic acid on IL-1ß secretion. The results further showed that gallic acid could mitigate MSU-induced joint swelling and inhibit IL-1ß and caspase 1 (p20) production in mice. Moreover, gallic acid could moderate MSU-induced macrophages and neutrophils migration into joint synovitis. In summary, we found that gallic acid suppresses ROS generation, thereby limiting NLRP3 inflammasome activation and pyroptosis dependent on Nrf2 signaling, suggesting that gallic acid possesses therapeutic potential for the treatment of gouty arthritis.

Update of treatment for mucopolysaccharidosis type III (sanfilippo syndrome).

Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III) is caused by lysosomal enzyme deficiency, which is a rare autosomal recessive hereditary disease. For now, there is no approved treatment for MPS III despite lots of efforts providing new vision of its molecular basis, as well as governments providing regulatory and economic incentives to stimulate the development of specific therapies. Those efforts and incentives attract academic institutions and industry to provide potential therapies for MPS III, including enzyme replacement therapies, substrate reduction therapies, gene and cell therapies, and so on, which were discussed in this paper.

Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis.

OBJECTIVES: Wedelolactone exhibits regulatory effects on some inflammatory diseases. However, the anti-inflammatory mechanism of wedelolactone has not been entirely unravelled. Therefore, the present study focuses on investigating the mechanism of wedelolactone on NLRP3 inflammasome in macrophages and its influence on MSU-induced inflammation. MATERIALS AND METHODS: BMDM, J774A.1 and PMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with ATP or nigericin or MSU crystal in the presence or absence of wedelolactone. The cell lysates and supernatants were collected to detect NLRP3 inflammasome components such as NLRP3, ASC and caspase 1, as well as pyroptosis and IL-1ß production. In addition, the anti-inflammatory effects of wedelolactone on MSU-induced peritonitis and arthritis mice were also evaluated. RESULTS: We found that wedelolactone broadly inhibited NLRP3 inflammasome activation and pyroptosis and IL-1ß secretion. Wedelolactone also block ASC oligomerization and speck formation. The inhibitory effects of wedelolactone were abrogated by PKA inhibitor H89, which also attenuated wedelolactone-enhanced Ser/Thr phosphorylation of NLRP3 at PKA-specific sites. Importantly, wedelolactone could abate MSU-induced IL-1ß production and neutrophils migration into peritoneal cavity, and reduced caspase 1 (p20) and IL-1ß expression in the joint tissue of MSU-induced arthritis. CONCLUSION: Our results indicate that wedelolactone promotes the Ser/Thr phosphorylation of NLRP3 to inhibit inflammasome activation and pyroptosis partly through potentiating PKA signalling, thus identifying its potential use for treating MSU-induced peritonitis and gouty arthritis.