A recent study of the EtOAc extract of the gorgonian Briareum excavatum afforded six new diterpenes of the briarane skeleton, excavatolides U-Z (1-6). The structures and relative stereochemistry of metabolites 1-6 were assigned on the basis of NMR studies and chemical methods. The structure, including the relative configuration of excavatolide U (1), was further confirmed by a single-crystal X-ray analysis. Some of the excavatolides have displayed significant cytotoxicity toward P-388 and HT-29 tumor cells.

Hepatocellular carcinoma is the fifth most common solid cancer worldwide. Sorafenib, a small multikinase inhibitor, is the only approved therapy for advanced HCC. The clinical benefit of sorafenib is offset by the acquisition of sorafenib resistance. Understanding of the molecular mechanism of STAT3 overexpression in sorafenib resistance is critical if the clinical benefits of this drug are to be improved. In this study, we explored our hypothesis that loss of RFX-1/SHP-1 and further increase of p-STAT3 as a result of sorafenib treatment induces sorafenib resistance as a cytoprotective response effect, thereby, limiting sorafenib sensitivity and efficiency. We found that knockdown of RFX-1 protected HCC cells against sorafenib-induced cell apoptosis and SHP-1 activity was required for the process. SC-2001, a molecule with similar structure to obatoclax, synergistically suppressed tumor growth when used in combination with sorafenib in vitro and overcame sorafenib resistance through up-regulating RFX-1 and SHP-1 resulting in tumor suppression and mediation of dephosphorylation of STAT3. In addition, sustained sorafenib treatment in HCC led to increased p-STAT3 which was a key mediator of sorafenib sensitivity. The combination of SC-2001 and sorafenib strongly inhibited tumor growth in both wild-type and sorafenib-resistant HCC cell bearing xenograft models. These results demonstrate that inactivation of RFX/SHP-1 induced by sustained sorafenib treatment confers sorafenib resistance to HCC through p-STAT3 up-regulation. These effects can be overcome by SC-2001 through RFX-1/SHP-1 dependent p-STAT3 suppression. In conclusion, the use of SC-2001 in combination with sorafenib may constitute a new strategy for HCC therapy.

Toll-like receptor 4 (TLR4) plays an important role in innate immunity by eliciting inflammation. Upon receptor engagement, transforming growth factor β-activated kinase 1 (TAK1) is an essential mediator that transmits a signal from the receptor to downstream effectors, IκB kinase (IKK) and the mitogen-activated protein kinases (MAPKs), which control the production of inflammatory cytokines. However, the association between phosphorylation and ubiquitination of TAK1 is not yet clear. Here, we examined the crosstalk between phosphorylation and polyubiquitination of TAK1 and further investigated the mechanism of distinct activation of MAPKs and IKK. Inhibition of TAK1 phosphorylation enhanced Lys63-linked polyubiquitination of TAK1. Conversely, ubiquitin modification was counteracted by phospho-mimic TAK1 mutant, T(184,187)D. Moreover, using LC-MS analysis, Lys562 of TAK1 was identified as a novel Lys63-linked ubiquitination site and as the key residue in the feedback regulation. Mutation of Lys562 of TAK1 leads to a decrease in TAK1 phosphorylation and specific inhibition of the MAPK pathway, but has no effect on formation of the TAK1-containing complex. Our findings demonstrate a feedback loop for phosphorylation and ubiquitination of TAK1, indicating a dynamic regulation between TAK1 polyubiquitiantion and phosphorylated activation, and the molecular mechanism by which IKK and MAPKs are differentially activated in the TLR4 pathway.

BACKGROUND AND SIGNIFICANCEPreterm infants are more vulnerable to fungal infections than full-term infants because of their immature immune systems and poorly developed epithelial skin and mucosal barriers, as well as the high rate of invasive procedures such as central venous catheter insertion and intubation. Candida spp has emerged as a common cause of infections in preterm infants admitted to the neonatal intensive care unit (NICU). In very low birth-weight (VLBW) infants (below 1500 g), Candida albicans is the third most common cause of neonatal late-onset sepsis, which occurs after the first 72 hours of life. 1 Invasive candidal infections are associated with a significant risk of death, neurodevelopmental impairment, and increased healthcare costs. Because Candida spp is a major cause of mortality and morbidity in preterm infants, prophylaxis with antifungal agents in premature infants or those with extremely or very low birth-weight (ELBW or VLBW) has been suggested by some experts and hospital policy. The Infectious Diseases Society of America guidelines recommended the use of intravenous or oral fluconazole prophylaxis 3 to 6 mg/kg twice weekly for 6 weeks in neonates with birth weights less than 1000 g in nurseries with high rates ( > 10%) of invasive candidiasis. 2 The overall incidence of candidiasis in the NICU appears to decrease with the increased use of fluconazole prophylaxis in ELBW infants. 3 , 4 Our institution has used fluconazole prophylaxis for premature infants since 2014.Although fungal infections other than those caused by Candida species are uncommon, the incidence of noncandidal fungal infections, including Malassezia Malassezia furfur Emergence and Candidemia Trends in a Neonatal Intensive Care Unit During 10 Years

The innate immune response is a central process that is activated during pathogenic infection in order to maintain physiological homeostasis. It is well known that dexamethasone (Dex), a synthetic glucocorticoid, is a potent immunosuppressant that inhibits the cytokine production induced by bacterial lipopolysaccharides (LPS). Nevertheless, the extent to which the functional groups of Dex control the excessive activation of inflammatory reactions remains unknown. Furthermore, importantly, the role of Dex in the innate immune response remains unclear. Here we explore the mechanism of LPS-induced TNF-α secretion and reveal p38 MAPK signaling as a target of Dex that is involved in control of tumor necrosis factor-α (TNF-α)-converting enzyme (TACE) activity; that later mediates the shedding of TNF-α that allows its secretion. We further demonstrate that the 11-hydroxyl and 21-hydroxyl groups of Dex are the main groups that are involved in reducing LPS-induced TNF-α secretion by activated macrophages. Blockage of the hydroxyl groups of Dex inhibits immunosuppressant effect of Dex during LPS-induced TNF-α secretion and mouse mortality. Our findings demonstrate Dex signaling is involved in the control of innate immunity.