Anti-Acne Effects of Cembrene Diterpenoids from the Cultured Soft Coral Sinularia flexibilis.

Acne is a skin disease common in adolescents and increasingly common in the adult population. The major pathologic events of acne vulgaris include increased sebum production, retention hyperkeratosis, carrying commensal skin microbiota, and inflammation. In recent years, more than 10,000 compounds have been isolated and identified from marine organisms. The aim of this study was to discover the potential anti-acne activity of fraction 9 + 10 (SF-E) of Sinularia flexibilis extract and six cembrene diterpenoids. We found that the SF-E significantly reduced Cutibacterium acnes-induced edema in Wistar rat ears. The cembrene diterpenoids including 11-dehydrosinulariolide (SC-2), 3,4:8,11-bisepoxy-7-acetoxycembra-15(17)-en-1,12-olide (SC-7), and sinularin (SC-9) reduced nitric oxide (NO) production with 50% inhibitory concentration of 5.66 ± 0.19, 15.25 ± 0.25, and 3.85 ± 0.25 µM, respectively, and inducible NO synthase expression in RAW 264.7 cells. Moreover, treatment with SC-2, SC-7, and SC-9 significantly suppressed lipopolysaccharide- and heat-killed C. acnes-induced expression of proteins involved in mitogen-activated protein kinase pathway in both RAW 264.7 and HaCaT cells. After treatment with SC-2, SC-7, and SC-9, over-proliferation of HaCaT cells was significantly terminated. In summary, SC-2, SC-7, and SC-9 showed anti-inflammatory effects in RAW 264.7 cells, suggesting that these cembrene diterpenoids obtained from S. flexibilis are natural marine products with potential anti-acne activities.

MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1ß in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis.

In renal cell carcinoma (RCC), interleukin (IL)-1ß may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1ß and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1ß in RCC. We found that IL-1ß stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1ß-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target.

LDOC1 Suppresses Microbe-Induced Production of IL-1ß in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3ß Axis.

Poor oral hygiene (POH) is associated with oral squamous cell carcinoma (OSCC). Oral microbes often proliferate due to POH. Array data show that LDOC1 plays a role in immunity against pathogens. We investigated whether LDOC1 regulates the production of oral microbe-induced IL-1ß, an oncogenic proinflammatory cytokine in OSCC. We demonstrated the presence of Candida albicans (CA) in 11.3% of OSCC tissues (n = 80). CA and the oral bacterium Fusobacterium nucleatum stimulate higher levels of IL-1ß secretion by LDOC1-deficient OSCC cells than by LDOC1-expressing oral cells. CA SC5314 increased OSCC incidence in 4-NQO (a synthetic tobacco carcinogen) and arecoline-cotreated mice. Loss and gain of LDOC1 function significantly increased and decreased, respectively, CA SC5314-induced IL-1ß production in oral and OSCC cell lines. Mechanistic studies showed that LDOC1 deficiency increased active phosphorylated Akt upon CA SC5314 stimulation and subsequent inhibitory phosphorylation of GSK-3ßS9 by activated Akt. PI3K and Akt inhibitors and expression of the constitutively active mutant GSK-3ßS9A significantly reduced the CA SC5314-stimulated IL-1ß production in LDOC1-deficient cells. These results indicate that the PI3K/Akt/pGSK-3ß signaling pathway contributes to LDOC1-mediated inhibition of oral microbe-induced IL-1ß production, suggesting that LDOC1 may determine the pathogenic role of oral microbes in POH-associated OSCC.