Min-Yu Chung

Molecular mechanisms of chemopreventive phytochemicals against gastroenterological cancer development

Cancer is one of the leading causes of death worldwide. Commonly used cancer treatments, including chemotherapy and radiation therapy, often have side effects and a complete cure is sometimes impossible. Therefore, prevention, suppression, and/or delaying the onset of the disease are important. The onset of gastroenterological cancers is closely associated with an individuals lifestyle. Thus, changing lifestyle, specifically the consumption of fruits and vegetables, can help to protect against the development of gastroenterological cancers. In particular, naturally occurring bioactive compounds, including curcumin, resveratrol, isothiocyanates, (-)-epigallocatechin gallate and sulforaphane, are regarded as promising chemopreventive agents. Hence, regular consumption of these natural bioactive compounds found in foods can contribute to prevention, suppression, and/or delay of gastroenterological cancer development. In this review, we will summarize natural phytochemicals possessing potential antioxidant and/or anti-inflammatory and anti-carcinogenic activities, which are exerted by regulating or targeting specific molecules against gastroenterological cancers, including esophageal, gastric and colon cancers.

Hypoglycemic Health Benefits of d-Psicose

Diabetes is an emerging health problem worldwide. The incidence of type 2 diabetes has dramatically increased and is expected to increase more rapidly in the future. Most patients with type 2 diabetes suffer from obesity and diabetes-related complications, including cardiovascular disease and hepatic steatosis. It has been proposed that simple sugar consumption is one of the major risk factors in the development of diabetes. Hence, the replacement of sugars with a low glycemic response would be an effective strategy to prevent type 2 diabetes. Accumulating evidence demonstrates that D-psicose, which has 70% the sweetness of sucrose and no calories, is a functional sugar exerting several health benefits preventing the development of diabetes. Although D-psicose presents in small amounts in natural products, a recent new technique using biocatalyst sources enables large-scale D-psicose production. More importantly, several clinical and animal studies demonstrated that D-psicose has hypoglycemic, hypolipidemic, and antioxidant activities, which make it an ideal candidate for preventing diabetes and related health concerns. This review will summarize the protective effects of D-psicose against type 2 diabetes and its complications, suggesting its potential benefits as a sucrose substitute.

Quercetin suppresses invasion and migration of H-Ras-transformed MCF10A human epithelial cells by inhibiting phosphatidylinositol 3-kinase.

Quercetin is a major flavonoid compound found in red wine at a much higher concentration than the phytoalexin resveratrol. In this study, we examined potential anti-metastatic effects and found that compared to resveratrol, quercetin more potently inhibits H-Ras-induced invasion and migration in MCF10A human epithelial cells, an effect likely mediated by the mitigation of matrix metalloproteinase (MMP)-2 activation. We then measured Akt phosphorylation to investigate whether the decreased MMP-2 activation was attributable to the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signalling. Quercetin, but not resveratrol at equivalent concentrations, suppressed the phosphorylation of Akt and was a more potent inhibitor of PI3K activity than resveratrol. An ex vivo binding assay further revealed that quercetin directly binds to PI3K. Collectively, these results suggest that PI3K is a molecular target of quercetin for the inhibition of H-Ras-induced invasion and migration of MCF10A cells.

Quercetin suppresses intracellular ROS formation, MMP activation, and cell motility in human fibrosarcoma cells.

Cell metastasis is a major cause of death from cancer and can arise from excessive levels of oxidative stress. The objective of this study was to investigate whether the natural flavonoid quercetin can inhibit matrix metalloproteinase (MMP)-2 and -9 activities through the attenuation of reactive oxygen species (ROS) formation, an event expected to lead to the inhibition of cell motility. To induce sustained ROS formation, cells were treated with phenazine methosulfate (PMS; 1 μM). Noncytotoxic concentrations of quercetin inhibited PMS-induced increases in cell motility in HT1080 human fibrosarcoma (HT1080) cells. While nearly 100% of cells were observed to migrate after 24 h of PMS treatment, quercetin significantly (P < 0.01) suppressed this effect. We also found that quercetin, up to 10 μg/mL, attenuated PMS-induced MMP-2 activation. We then investigated whether the decreased levels of MMP-2 activation could be attributable to lower levels of ROS formation by quercetin. We found that quercetin treatments significantly attenuated PMS-induced ROS formation (P < 0.01) and resulted in decreased cell motility associated with a reduction in MMP-2 and -9 activitiy in HT1080 cells, even in the absence of PMS treatment. Collectively, these results suggest that quercetin inhibits cell motility via the inhibition of MMP activation in HT1080 cells in the presence and absence of PMS. This is likely to be a result of the suppression of intracellular ROS formation by quercetin.

Caffeic Acid Phenethyl Ester, a Major Component of Propolis, Suppresses High Fat Diet-Induced Obesity through Inhibiting Adipogenesis at the Mitotic Clonal Expansion Stage

In the present study, we aimed to investigate the antiobesity effect of CAPE in vivo, and the mechanism by which CAPE regulates body weight in vitro. To confirm the antiobesity effect of CAPE in vivo, mice were fed with a high fat diet (HFD) with different concentrations of CAPE for 5 weeks. CAPE significantly reduced body weight gain and epididymal fat mass in obese mice fed a HFD. In accordance with in vivo results, Oil red O staining results showed that CAPE significantly suppressed MDI-induced adipogenesis of 3T3-L1 preadipocytes. FACS analysis results showed that CAPE delayed MDI-stimulated cell cycle progression, thereby contributing to inhibit mitotic clonal expansion (MCE), which is a prerequisite step for adipogenesis. Also, CAPE regulated the expression of cyclin D1 and the phosphorylation of ERK and Akt, which are upstream of cyclin D1. These results suggest that CAPE exerts an antiobesity effect in vivo, presumably through inhibiting adipogenesis at an early stage of adipogenesis.

Benzo[a]pyrene-7,8-diol-9,10-epoxide inhibits gap junction intercellular communication via phosphorylation of tumor progression locus 2 in WB-F344 rat liver epithelial cells.

Benzo[a]pyrene‐7,8‐diol‐9,10‐epoxide (B[a]PDE), a major metabolite of benzo[a]pyrene, has been reported to function as a human carcinogen. However, the molecular mechanism of how B[a]PDE regulates signaling pathways during tumor promotion remains unclear. In this study, we investigated the effects of B[a]PDE on the regulation of gap junction intercellular communication (GJIC), one of the major carcinogenic processes, and its main regulatory signaling pathways using WB‐F344 rat liver epithelial (WB‐F344 RLE) cells. Treatment of benzo[a]pyrene or B[a]PDE resulted in GJIC inhibition, and B[a]PDE was more active at lower concentrations than benzo[a]pyrene in the suppression of GJIC. This suggests that B[a]PDE is a stronger GJIC inhibitor. B[a]PDE at 1 µM reversibly inhibited GJIC in WB‐F344 RLE cells, which was attributable to hyperphosphorylation of connexin43 (Cx43) via phosphorylation of mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MEK) and extracellular signal‐regulated kinase (ERK). We found that B[a]PDE induced phosphorylation of tumor progression locus 2 (Tpl2), a direct upstream regulator of MEK. Tpl2 inhibitor recovered B[a]PDE‐induced GJIC inhibition and attenuated B[a]PDE‐induced MEK/ERK phosphorylation in WB‐F344 RLE cells. Collectively, our results suggest that B[a]PDE suppresses GJIC by activating Tpl2 and subsequently the MEK/ERK pathway and Cx43 phosphorylation in WB‐F344 RLE cells. These results outline the potential importance of Tpl2 as a novel therapeutic target for B[a]PDE‐induced GJIC inhibition during cancer promotion.

Recovery Effect of Onion Peel Extract against H2O2‐Induced Inhibition of Gap‐Junctional Intercellular Communication is Mediated through Quercetin

UNLABELLED Cellular oxidative damage mediated by reactive oxygen species has been reported to inhibit gap-junctional intercellular communication (GJIC). In turn, the inhibition of GJIC can be attenuated by functional food compounds with antioxidant properties. In this study, we compared the protective effects of onion peel extract (OPE) and onion flesh extract (OFE) on oxidative stress-mediated GJIC inhibition, and investigated the mechanisms of action responsible. OPE restored H2 O2 -induced GJIC inhibition to a higher degree than OFE in WB-F344 rat liver epithelial cells. OPE was found to inhibit H2 O2 -induced phosphorylation of ERK1/2 and Cx43. A radical scavenging assay demonstrated superiority of OPE over OFE, suggesting that the observed effects might be mediated via an antioxidant mechanism. Quercetin is the major compound that is likely to be responsible for the protective effect against H2 O2 -mediated GJIC inhibition. This study suggests that OPE, a material often discarded, may be of value for the future development of functional food products. PRACTICAL APPLICATION This study demonstrates that onion peel extract (OPE) exhibits a protective effect against the inhibition of gap-junctional intercellular communication (GJIC) mediated by H2 O2 , which is likely to occur via its antioxidant activity. OPE contains significant concentrations of bioactive phenolic compounds. Reductions in oxidative stress can lead to recovery of GJIC, which has been reported to be implicated in the prevention and treatment of cancers. These findings suggest that onion peel, a common waste product, could be used as potential resources for functional food development. Onion peel could be processed into a quercetin-rich powder or a pill for the prevention of cancer and other oxidative stress-related diseases.

Hirsutenone Directly Targets PI3K and ERK to Inhibit Adipogenesis in 3T3-L1 Preadipocytes

Adipogenesis is a key driver of the expansion of adipose tissue mass that causes obesity. Hirsutenone (HST) is an active botanical diarylheptanoid present in Alnus species. In this study, we evaluated the effects of HST on adipogenesis, its mechanisms of action and the molecular targets involved. Using Oil Red O staining, we observed that HST dose‐dependently suppresses lipid accumulation during adipogenesis in 3T3‐L1 preadipocytes, concomitant with a decrease in peroxisome proliferator‐activated receptor‐γ (PPARγ), CCAAT/enhancer‐binding protein α (C/EBPα) and fatty acid synthase (FAS) protein expression. This inhibitory effect was largely limited to the early stage of adipogenesis, which includes mitotic clonal expansion (MCE), as evidenced by delayed cell cycle entry of preadipocytes from G1 to S phase. Furthermore, the regulation of MCE was accompanied by suppression of phosphatidylinositol 3‐kinase (PI3K) and extracellular‐regulated kinase (ERK) activity. HST was also shown to bind directly to PI3K and ERK1 in a non‐ATP competitive manner. Our results suggest that HST attenuates adipogenesis by directly targeting PI3K and ERK during MCE in 3T3‐L1 preadipocytes, underscoring the potential therapeutic application of HST in preventing obesity. J. Cell. Biochem. 116: 1361–1370, 2015.

Double-Blind Evaluation of the Safety and Efficacy of Tenoxicam (Tilcotil®) Compared with Piroxicam in Patients with Degenerative Arthritis

19 men and 61 women with degenerative arthritis of the knee joint were randomly allocated to receive tenoxicam 20mg (n = 40) or piroxicam 20mg (n = 40) orally before breakfast once daily, for 6 weeks. The study was of a double-blind parallel design and patients underwent a washout period of up to 14 days before beginning the study medications. The 2 groups were of comparable sex ratio, age, weight, disease duration and treatment history, with most patients having a 1to lO-year history of disease and 48 patients having previ-