An updated review on molecular mechanisms underlying the anticancer effects of capsaicin.

The quest for developing anticancer principles from natural sources has a long historical track record and remarkable success stories. The pungent principle of hot chili pepper, capsaicin, has been a subject of research for anticancer drug discovery for more than three decades. However, the majority of research has revealed that capsaicin interferes with various hallmarks of cancer, such as increased cell proliferation, evasion from apoptosis, inflammation, tumor angiogenesis and metastasis, and tumor immune escape. Moreover, the compound has been reported to inhibit carcinogen activation and chemically induced experimental tumor growth. Capsaicin has also been reported to inhibit the activation of various kinases and transcription that are involved in tumor promotion and progression. The compound activated mitochondria-dependent and death receptor-mediated tumor cell apoptosis. Considering the growing interest in capsaicin, this review provides an update on the molecular targets of capsaicin in modulating oncogenic signaling.

Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1.

Somatic heterozygous mutations of isocitrate dehydrogenase-1 (IDH1) are abundantly found in several types of cancer and strongly implicate altered metabolism in carcinogenesis. In the present study, we have identified α-mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have observed that α-mangostin competitively inhibits the binding of α-ketoglutarate (α-KG) to IDH1-R132H. The structure-relationship study reveals that α-mangostin exhibits the strongest core inhibitor structure. Finally, we have observed that α-mangostin selectively promotes demethylation of 5-methylcytosine (5mC) and histone H3 trimethylated lysine residues in IDH1 (+/R132H) MCF10A cells, presumably via restoring the activity of cellular α-KG-dependent DNA hydroxylases and histone H3 lysine demethylases. Collectively, we provide evidence that α-mangostin selectively inhibits IDH1-R132H.

Acetylshikonin Inhibits Human Pancreatic PANC-1 Cancer Cell Proliferation by Suppressing the NF-κB Activity.

Acetylshikonin, a natural naphthoquinone derivative compound, has been used for treatment of inflammation and cancer. In the present study, we have investigated whether acetylshikonin could regulate the NF-κB signaling pathway, thereby leading to suppression of tumorigenesis. We observed that acetylshikonin significantly reduced proliferation of several cancer cell lines, including human pancreatic PANC-1 cancer cells. In addition, acetylshikonin inhibited phorbol 12-myristate 13-acetate (PMA) or tumor necrosis-α (TNF-α)-induced NF-κB reporter activity. Proteome cytokine array and real-time RT-PCR results illustrated that acetylshikonin inhibition of PMA-induced production of cytokines was mediated at the transcriptional level and it was associated with suppression of NF-κB activity and matrix metalloprotenases. Finally, we observed that an exposure of acetylshikonin significantly inhibited the anchorage-independent growth of PANC-1 cells. Together, our results indicate that acetylshikonin could serve as a promising therapeutic agent for future treatment of pancreatic cancer.

Interleukin-5 enhances the migration and invasion of bladder cancer cells via ERK1/2-mediated MMP-9/NF-κB/AP-1 pathway: involvement of the p21WAF1 expression.

Inflammatory cytokines may be a critical component of epithelial cancer progression. We examined the role of interleukin (IL)-5 in the migration of bladder cancer cells. The expression of IL-5 and its receptor IL-5Rα was enhanced in patients with muscle invasive bladder cancers (MIBC), and then it was detected in bladder cancer cell lines 5637 and T-24. IL-5 increased migration and MMP-9 expression via activation of transcription factors NF-κB and AP-1, and induced activation of ERK1/2 and Jak-Stat signaling in both cells. Treatment with ERK1/2 inhibitor U0126 significantly inhibited induction of migration, MMP-9 expression, and activation of NF-κB and AP-1 in IL-5-treated cells. However, none of the Jak inhibitors affected the IL-5-induced migration of bladder cancer cells. Moreover, gene knockdown for IL-5Rα, using siRNA transfection, suppressed migration, ERK1/2 activation, MMP-9 expression, as well as the binding activation of NF-κB and AP-1 in IL-5-treated bladder cancer cells. Similar results were observed in ßc siRNA (si-ßc) transfected cells. Unexpectedly, IL-5 treatment resulted in significant induction of p21WAF1 in both cell lines. The p21WAF1-specific small interfering RNA inhibited IL-5-induced cell migration, ERK activity, MMP-9 expression, and activation of NF-κB and AP-1 in bladder cancer cells. The effects of IL-5-induced cell responses were confirmed by transfection of IL-5 gene, which demonstrated that p21WAF1 participates in the induction of cell migration, leading to an increase in ERK1/2-mediated MMP-9 expression through activation of NF-κB and AP-1 in IL-5-treated bladder cancer cells. These unexpected results provide a theoretical basis for the therapeutic targeting of IL-5 in bladder cancer.

Suppressive effects of an ethanol extract of Gleditsia sinensis thorns on human SNU-5 gastric cancer cells.

The thorns of Gleditsia sinensis are a traditional Oriental medicine used for the treatment of swelling, suppuration, carbuncle and skin diseases. In the present study, we identified a novel molecular mechanism by which an ethanol extract of Gleditsia sinensis thorns (EEGS) inhibits the growth of the SNU-5 human gastric cancer cell line. EEGS treatment inhibited cell growth and was associated with G1 phase cell cycle arrest at a concentration of 400 µg/ml (IC50) in SNU-5 cells. Treatment with EEGS also stimulated p21WAF1 expression, which significantly decreased the expression of cyclins and cyclin-dependent kinases (CDKs). Further study suggested that p38 MAP kinase pathways may be involved in the inhibition of cell proliferation through p21WAF1­dependent G1 phase cell cycle arrest in EEGS-treated cells. In addition, NF-κB and AP-1 transcription factor binding sites were identified as the cis-elements for tumor necrosis factor-α (TNF-α)-induced matrix metalloproteinase-9 (MMP-9) expression in SNU-5 cells, as determined by gel-shift assay. Treatment of cells with EEGS suppressed MMP-9 expression induced by TNF-α via a decrease in the binding activity of both NF-κB and AP-1 motifs. These data demonstrate that EEGS-mediated inhibition of cell growth appears to involve the activation of p38 MAP kinase, subsequently leading to the induction of p21WAF1 and the downregulation of cyclin D1/CDK4 and cyclin E/CDK2 complexes. Moreover, EEGS strongly inhibited TNF-α-induced MMP-9 expression by impeding the DNA binding activity of NF-κB and AP-1. Overall, these results provide a potential mechanism for EEGS in the treatment of gastric cancer.

Interleukin-20 promotes migration of bladder cancer cells through extracellular signal-regulated kinase (ERK)-mediated MMP-9 protein expression leading to nuclear factor (NF-κB) activation by inducing the up-regulation of p21(WAF1) protein expression.

The role of inflammatory cytokine interleukin-20 (IL-20) has not yet been studied in cancer biology. Here, we demonstrated up-regulation of both IL-20 and IL-20R1 in muscle-invasive bladder cancer patients. The expressions of IL-20 and IL-20R1 were observed in bladder cancer 5637 and T-24 cells. We found that IL-20 significantly increased the expression of matrix metalloproteinase (MMP)-9 via binding activity of NF-κB and AP-1 in bladder cancer cells and stimulated the activation of ERK1/2, JNK, p38 MAPK, and JAK-STAT signaling. Among the pathways examined, only ERK1/2 inhibitor U0126 significantly inhibited IL-20-induced migration and invasion. Moreover, siRNA knockdown of IL-20R1 suppressed migration, invasion, ERK1/2 activation, and NF-κB-mediated MMP-9 expression induced by IL-20. Unexpectedly, the cell cycle inhibitor p21(WAF1) was induced by IL-20 treatment without altering cell cycle progression. Blockade of p21(WAF1) function by siRNA reversed migration, invasion, activation of ERK signaling, MMP-9 expression, and activation of NF-κB in IL-20-treated cells. In addition, IL-20 induced the activation of IκB kinase, the degradation and phosphorylation of IκBα, and NF-κB p65 nuclear translocation, which was regulated by ERK1/2. IL-20 stimulated the recruitment of p65 to the MMP-9 promoter region. Finally, the IL-20-induced migration and invasion of cells was confirmed by IL-20 gene transfection and by addition of anti-IL-20 antibody. This is the first report that p21(WAF1) is involved in ERK1/2-mediated MMP-9 expression via increased binding activity of NF-κB, which resulted in the induction of migration in IL-20/IL-20R1 dyad-induced bladder cancer cells. These unexpected results might provide a critical new target for the treatment of bladder cancer.

Catalytic effects of ZnO nanorods grown by sonochemical decomposition of zinc acetate dihydrate.

In this study, we prepared ZnO nanorods by a sonochemical method using a zinc acetate dihydrate as a new precursor. Well-aligned high-quality ZnO nanorods were synthesized on FTO glass by the sonochemical decomposition of zinc acetate dihydrate using a ZnO thin-film as the catalytic layer. The ZnO thin-films were deposited on the FTO glass by a sputtering method. To investigate their catalytic effects on the ZnO nanorods, catalytic ZnO thin-films of 20 nm, 40 nm, and 60 nm thickness were prepared by adjusting the sputtering time. The ZnO nanorods grown on catalytic layers with different thicknesses were characterized by SEM, XRD, and PL. The ZnO nanorods grown on the catalytic layer of 40 nm thickness show the best crystal and spatial orientation and as a result display the best optical properties. It was found that a catalytic ZnO thin-film of 40 nm in thickness yields well-aligned high-quality ZnO nanorods, due to its small surface roughness and structural strain.

Enhancement of lipid extraction from marine microalga, Scenedesmus associated with high-pressure homogenization process.

Marine microalga, Scenedesmus sp., which is known to be suitable for biodiesel production because of its high lipid content, was subjected to the conventional Folch method of lipid extraction combined with high-pressure homogenization pretreatment process at 1200 psi and 35°C. Algal lipid yield was about 24.9% through this process, whereas only 19.8% lipid can be obtained by following a conventional lipid extraction procedure using the solvent, chloroform:methanol (2:1, v/v). Present approach requires 30 min process time and a moderate working temperature of 35°C as compared to the conventional extraction method which usually requires >5 hrs and 65°C temperature. It was found that this combined extraction process followed second-order reaction kinetics, which means most of the cellular lipids were extracted during initial periods of extraction, mostly within 30 min. In contrast, during the conventional extraction process, the cellular lipids were slowly and continuously extracted for >5 hrs by following first-order kinetics. Confocal and scanning electron microscopy revealed altered texture of algal biomass pretreated with high-pressure homogenization. These results clearly demonstrate that the Folch method coupled with high-pressure homogenization pretreatment can easily destruct the rigid cell walls of microalgae and release the intact lipids, with minimized extraction time and temperature, both of which are essential for maintaining good quality of the lipids for biodiesel production.

Enhanced production of gamma-aminobutyric acid using rice bran extracts by Lactobacillus sakei B2-16.

An efficient and simple fermentation process was developed for the production of gamma-amminobutyric acid (GABA) by Lactobacillus sakei B2-16. When the L. sakei B2-16 was cultivated in the rice bran extracts medium containing 4% sucrose, 1% yeast extract and 12% monosodium glutamate, the maximum GABA concentration reached 660.0 mM with 100% conversion yield, showing the 2.4-fold higher GABA concentration compared to the modified MRS medium without the rice bran extracts. The GABA production was scaled-up from a laboratory scale (5 L) to a pilot (300 L) and a plant scales (5,000 L) to investigate the application possibility of GABA production to industrial fields. The GABA production at the pilot and plant scales was similar to the laboratory scale using rice bran extracts medium which could be effective for the low-cost production of GABA.