Brusatol Derivative-34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway.

Brusatol derivative-34 (Bru-34), a derivative of brusatol, has been shown significantly anti-inflammatory activity in mice in our previously work. However, to our knowledge, there were very limited studies on how Bru-34 affected airway inflammation. Thus, in this present study, the effects and potential mechanisms of Bru-34 on allergic airway inflammation were examined both in vivo and in vitro. The results showed that Bru-34 attenuated the allergic airway inflammation in mice, with significant decreasing of the inflammatory cells and mediators in bronchoalveolar lavage fluids and attenuation of the histopathological alterations in the lung tissues. In addition, Bru-34 significantly inhibited the release of inflammatory cytokines in antigen induced rat basophilic leukemia -2H3 (RBL-2H3) cells. What's more, Bru-34 significantly decreased the expression of spleen tyrosine kinase (Syk), p-Syk, cytoplasmic phospholipase A2 (cPLA2), p-cPLA2, nuclear factor-κB (NF-κB) and p-NF-κB both in allergic mice lung tissue and antigen induced RBL-2H3 cells. Furthermore, the collaborative effects of Bru-34 with inhibitors against Syk, cPLA2, and NF-κB, showed that Syk was an important target of Bru-34, and cPLA2 and NF-κB played important roles in the coordinated inflammatory response. In conclusion, Bru-34 could significantly modulate the allergic airway inflammation, and its potential mechanism was revealed at least partially via down-regulating of Syk-cPLA2 -NF-κB signaling.

Comparison of Incidence and Outcomes of Neuroblastoma in Children, Adolescents, and Adults in the United States: A Surveillance, Epidemiology, and End Results (SEER) Program Population Study.

BACKGROUND This United States (U.S.) population study aimed to compare the incidence of neuroblastoma and outcomes in children, adolescents, and adults using the Surveillance, Epidemiology, and End Results (SEER) program database. MATERIAL AND METHODS Patients with neuroblastoma were identified in the SEER database from 1975 to 2013. According to the age at diagnosis, patients were divided into "Children" (≤14 years old) and "Adolescents/Adults" group (>14 years old). Then, comparisons in basic characteristics, incidence rates (IRs) and long-term survival outcomes between patients in 2 groups were made. RESULTS A total of 4280 patients were identified, including 3998 children and 282 adolescent/adult patients. Adolescent/adult patients were more likely to have localized diseases than children and to be diagnosed with ganglioneuroblastoma (all P<0.05). The IR of neuroblastoma presented with upward and downward trends in children and adolescent/adult populations, respectively. Adolescents/adults had worse overall survival (OS) than children despite the earlier tumor stage. Lastly, multivariate Cox proportional hazards analyses showed that tumor stage, histology, sequence of primary malignancy, primary site, the administration of surgery, and treatment era were prognostic factors for children, and sequence of primary malignancy, primary site, undergoing surgery, and treatment era were tightly related to OS in adolescent/adult patients. CONCLUSIONS Analysis of the SEER program database between 1975 to 2013 showed that in the U.S., the incidence of neuroblastoma in children increased, but the incidence decreased in adolescents and adults. There was a trend for improved overall survival in all age groups despite the increased stage at presentation in children.

Novel nitric oxide-releasing derivatives of brusatol as anti-inflammatory agents: design, synthesis, biological evaluation, and nitric oxide release studies.

Brusatol, a biologically active natural product, was modified in four distinct positions through the covalent attachment of a furoxan moiety, which acts as a nitric oxide (NO) donor. Forty derivatives were synthesized and evaluated for their inhibitory effects on excess NO biosynthesis in activated macrophages. Among them, compound 75 demonstrated inhibition (IC50 = 0.067 µM) comparable to that of brusatol but were less cytotoxic. More importantly, even at very low doses (2 µmol/kg/day), compound 75 also showed substantial inhibitory efficacy against chronic obstructive pulmonary disease (COPD)-like inflammation in the mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Particularly, this compound was over 100-fold less toxic (LD50 > 3852 µmol/kg) than brusatol and could be a promising lead for further studies. Notably, the improved properties of this derivative are associated with its NO-releasing capability.

Five new fawcettimine-related alkaloids from Lycopodium japonicum Thunb.

Five new trace alkaloids with fawcettimine-related structures (1-5), i.e., 6-hydroxyl-6,7-dehydrolycoflexine (1), 6-hydroxyl-6,7-dehydro-8-deoxy-13-dehydroserratinine (2), together with three known ones (6-8), were isolated from the club moss Lycopodium japonicum Thunb. Their structures were elucidated by extensive NMR spectroscopic analysis, HRESIMS, CD and comparison with known ones. Compounds 1 and 2 are characterized by the enol moiety that is rarely reported in Lycopodium alkaloids, and Compound 5 is the second example of Lycopodium alkaloids with a C-16-C-4 linkage. A plausible biogenetic pathway for the isolates was proposed.

Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo.

Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18-20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED50 values ranging from 337 to 141 µM, which are values comparable to that of the leading GL compound (1) (ED50 = 70 µM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data.

Bioactive quassinoids from the seeds of Brucea javanica.

Six new quassinoids (1-6) and eight known compounds of this type (7-14) were isolated from the seeds of Brucea javanica. Their structures were elucidated by analysis of their spectroscopic data and from chemical evidence. Compounds 1-5 were found to be unusual quassinoids with a 2,3-seco A ring. The configurations at C-4 in 4 and 5 were determined by a difference circular dichroism method. In in vitro bioassays, 8 and 10 showed inhibitory activities for nitric oxide production in LPS-activated macrophages, with IC(50) values of 1.9 and 5.0 µM, respectively, while compounds 6, 8-11, 13, and 14 exhibited cytotoxicity against five human tumor cell lines (HCT-8, HepG2, BGC-823, A549, and SKVO3), having IC(50) values in the range 0.12-9.3 µM.