Protection against Lipopolysaccharide-Induced Endotoxemia by Terrein Is Mediated by Blocking Interleukin-1ß and Interleukin-6 Production.

Terrein is a fungal metabolite and has been known to exert anti-melanogenesis, anti-cancer, and anti-bacterial activities. However, its role in endotoxemia has never been investigated until now. In the present study, we examined the effect of terrein on lipopolysaccharide (LPS)-induced endotoxemia in mice and characterized the potential mechanisms of action. Treatment with terrein increased the survival of mice and decreased the production of inflammatory cytokines, including interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in an LPS-induced endotoxemia model. In addition, terrein suppressed the LPS-induced production of IL-1ß and IL-6 in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expression of IL-1ß and IL-6 was also inhibited by terrein in LPS-stimulated RAW 264.7 cells. Further study demonstrated that terrein blocked LPS-induced phosphorylation of p65 subunit of nuclear factor (NF)/κB and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) was also suppressed by terrein treatment. Collectively, these results suggest that terrein exerts a protective effect again LPS-induced endotoxemia in mice by blocking the production of inflammatory cytokines. Our results also suggest that the anti-inflammatory effect of terrein might be mediated, at least in part, by blocking the activation of NF-κB, JNK, and p38 MAPK signaling pathways.

Targeted Induction of Endogenous VDUP1 by Small Activating RNA Inhibits the Growth of Lung Cancer Cells.

Recent studies have reported that small double-strand RNAs (dsRNAs) can activate endogenous genes via an RNA-based promoter targeting mechanism termed RNA activation (RNAa). In the present study, we showed that dsVDUP1-834, a novel small activating RNA (saRNA) targeting promoter of vitamin D3 up-regulated protein 1 (VDUP1) gene, up-regulated expression of VDUP1 at both mRNA and protein levels in A549 lung cancer cells. We also demonstrated that dsVDUP1-834 inhibited cell proliferation in A549 lung cancer cells. Further studies showed that dsVDUP1-834 induced cell-cycle arrest by increasing p27 and p53 and decreasing cyclin A and cyclin B1. In addition, knockdown of VDUP1 abrogated dsVDUP1-834-induced up-regulation of VDUP1 gene expression and related effects. The activation of VDUP1 by dsVDUP1-834 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 3 (H3ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) at the target site of VDUP1 promoter. Moreover, the enrichment of Ago2 was detected at the dsVDUP1-834 target site, and Ago2 knockdown significantly suppressed dsVDUP1-834-mediated inhibition of cell proliferation and modulation of cell-cycle regulators. Taken together, the results presented in this report demonstrate that dsVDUP1-834 induces VDUP1 gene expression by epigenetic changes, resulting in cell growth inhibition and cell-cycle arrest. Our results suggest that targeted induction of VDUP1 by dsVDUP1-834 might be a promising therapeutic strategy for the treatment of lung cancer.

Bifidobacterium longum subsp. infantis YB0411 Inhibits Adipogenesis in 3T3-L1 Pre-adipocytes and Reduces High-Fat-Diet-Induced Obesity in Mice.

Although the health benefits of probiotics have been widely known for decades, there has still been limited use of probiotic bacteria in anti-obesity therapy. Herein, we demonstrated the role of Bifidobacterium longum subsp. infantis YB0411 (YB, which was selected by an in vitro adipogenesis assay) in adipogenic differentiation in 3T3-L1 pre-adipocytes. We observed that YB-treatment effectively reduced triglyceride accumulation and the expression of CCAAT/enhancer-binding protein α, ß, and δ (C/EBPα, C/EBPß, and C/EBPδ), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 4 (aP2), and acetyl-CoA carboxylase (ACC). YB-treatment also reduced the levels of core autophagic markers (p62 and LC3B) in 3T3-L1 pre-adipocytes. Small-interfering-RNA-mediated knockdown and competitive-chemical-inhibition assays showed that AMP-activated protein kinase (AMPK) commenced the anti-adipogenic effect of YB. In addition, YB supplement markedly reduced body weight and fat accretion in mice with high-fat-diet-induced obesity. Our findings suggest that YB may be used as a potential probiotic candidate to ameliorate obesity.

Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton's Tyrosine Kinase.

As a member of the tyrosine protein kinase Tec (TEC) family, Bruton's tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure-activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.

Inhibition of Skin Inflammation by Scytonemin, an Ultraviolet Sunscreen Pigment.

Scytonemin is a yellow-green ultraviolet sunscreen pigment present in different genera of aquatic and terrestrial blue-green algae, including marine cyanobacteria. In the present study, the anti-inflammatory activities of scytonemin were evaluated in vitro and in vivo. Topical application of scytonemin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear swelling in BALB/c mice. The expression of tumor necrosis factor-a (TNF-a) and inducible nitric oxide synthase (iNOS) was also suppressed by scytonemin treatment in the TPA-treated ear of BALB/c mice. In addition, scytonemin inhibited lipopolysaccharide (LPS)-induced production of TNF-a and nitric oxide (NO) in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expressions of TNF-a and iNOS were also suppressed by scytonemin in LPS-stimulated RAW 264.7 cells. Further study demonstrated that LPS-induced NF-kB activity was significantly suppressed by scytonemin treatment in RAW 264.7 cells. Our results also showed that the degradation of IkBa and nuclear translocation of the p65 subunit were blocked by scytonemin in LPS-stimulated RAW 264.7 cells. Collectively, these results suggest that scytonemin inhibits skin inflammation by blocking the expression of inflammatory mediators, and the anti-inflammatory effect of scytonemin is mediated, at least in part, by down-regulation of NF-kB activity. Our results also suggest that scytonemin might be used as a multi-function skin care ingredient for UV protection and anti-inflammation.

Two-port cholecystectomy maintains safety and feasibility in benign gallbladder diseases: a comparative study.

PURPOSE: In an effort to overcome the limitations of single-port laparoscopic cholecystectomy (LC) while preserving the cosmetic benefits of reduced ports cholecystectomy, we have developed a 2-port LC that allows for the full, unrestricted use of 4 laparoscopic instruments. METHODS: We retrospectively analyzed data of patients who had undergone either 4-port LC or 2-port LC for benign gallbladder diseases between March 2007 and March 2013. Two incisions of 2-port LC were composed of an umbilical incision as the manner of single-port laparoscopic surgery and a 5-mm epigastric incision. These two incisions were utilized for comfortable bimanual manipulation under the liver-elevated vision provided by a liver retractor. RESULTS: During the study period, 766 patients underwent LC; 263 (34.3%) started with 4-port LC, and 503 (65.7%) started with 2-port LC. Of patients started with 2-port LC, 486 patients (96.6%) was ended up with 2-port without open conversion or addition of port(s). The two groups had similar operative time, open conversion rate, incidence of complications, analgesic requirement, and length of postoperative hospital stay. Multivariate analyses revealed that the independent factors related to prolonged operative time (≥ 90 th percentile) in 2-port LC were the presence of cholecystitis (odds ratio [OR] 2.412, 95% CI 1.246-4.668, p = 0.009) and admission through the emergency department (OR 2.132, 95% CI 1.135-4.004, p = 0.019). CONCLUSION: This study suggests that 2-port LC for benign gallbladder diseases is as safe and feasible as 4-port LC when it is performed by surgeons trained in conventional laparoscopic techniques.