3'-Hydroxypterostilbene Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Mouse Skin Carcinogenesis.

BACKGROUND: A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear. PURPOSE: The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism. STUDY DESIGN AND METHODS: This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated. RESULTS: The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes. CONCLUSION: This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.

Adzuki Bean Water Extract Attenuates Obesity by Modulating M2/M1 Macrophage Polarization and Gut Microbiota Composition.

SCOPE: Obesity is a chronic condition resulting in excessive fat accumulation in adipose tissues. Adipose tissue is now considered as an immune organ, at the crossroads between metabolism and immunity. Thus, this study investigates the effects of adzuki beans on obesity and gut microbiota in high fat diet-induced mice. METHODS AND RESULTS: In this study, adzuki bean hot water extract (AWE) is determined to have the most significant anti-adipogenic effect; it is able to inhibit lipid accumulation in 3T3-L1 adipocytes and reduces body weight and adipose tissue weight in a dose-dependent manner. AWE treatment also decreases M1-polarized adipose tissue macrophages (ATMs) while inducing M2-polarized ATMs. The number and size of fat vacuoles in liver lesions are significantly reduced, indicating that AWE could ameliorate steatosis in high fat diet-induced mice. The results also demonstrate that AWE-treated groups inhibit adipogenesis via activating the Wnt/ß-catenin pathway and reduce peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding proteins α expression. Moreover, the studies confirm that AWE decreases obesity through modulating gut microbiota. CONCLUSION: The results demonstrate that AWE supplementation ameliorates high fat diet-induced obesity and gut microbiota composition and suggests that AWE may have the potential to be developed into a functional food to improve metabolic disorders.

CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-ß, Wnt and STAT3 signaling pathways.

CCM111 is an aqueous extract of Antrodia cinnamomea (AC) that has exhibited anti-liver fibrosis functions. However, the detailed mechanisms of AC action against liver fibrosis have not been elucidated yet. The present research showed that CCM111 significantly lowered the levels of the hepatic enzyme markers glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT), prevented liver damage and collagen deposition, and downregulated TGF-ß/Smad signaling in a dose-dependent manner compared with CCl4 treatment alone. CCM111 markedly inhibited TGF-ß, Wnt and STAT3 signaling pathway-regulated downstream genes in the liver by next-generation sequencing. The antifibrotic mechanisms of CCM111 were further demonstrated in HSC-T6 cells. Our data demonstrated for the first time that CCM111 can protect against CCl4-induced liver fibrosis by the cooperative inhibition of TGF-ß-, Wnt- and STAT3-dependent proinflammatory and profibrotic mediators, suggesting that CCM111 might be a candidate for preventing and treating chronic fibrotic liver diseases.

Optimized Extraction of Phenolics from Jujube Peel and Their Anti-inflammatory Effects in LPS-Stimulated Murine Macrophages.

The extraction of phenolics from jujube peel (PJP) was optimized using response surface methodology (RSM). A Box-Behnken design was utilized to analyze the effects of NaOH concentration, temperature, and extraction time on the total phenolic content (TPC). The results showed that RSM could be an adequate approach for modeling the extraction of PJP. The optimal extraction condition for the highest TPC was obtained with 3.4 M NaOH concentration for 67 min at 50 °C. Not only PJP but also phenolics from the jujube seed (PJS) contain considerable amounts of phenolics, particularly flavonoids. Quercetin and galangin were found to be the predominant phenolics. PJP markedly down-regulated the levels iNOS and COX-2 proteins in macrophages by inhibiting the activation of NF-κB through interfering with the MAPK signaling pathways. Compared to PJS, PJP presented higher anti-inflammatory activities, reflecting increased amounts of TPC and total flavonoid content (TFC). These findings suggest that PJP could be a potential source of anti-inflammatory agents.

Protective effects of theasinensin A against carbon tetrachloride-induced liver injury in mice.

Theasinensins have been identified as a major group of unique catechin dimers mainly found in oolong tea and black tea. Among several types of theasinensins, theasinensin A (TSA), an epigallocatechin gallate (EGCG) dimer with an R-biphenyl bond, is the most abundant theasinensin prevalent in oolong tea. Previous studies have reported that TSA exhibits antioxidative, anti-inflammatory and anti-cancer activities in vitro and in vivo. However, little is known about the hepatoprotective effect of TSA. Thus, the aim of this study was to investigate the inhibitory effect of TSA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. After intraperitoneal injection of CCl4 for eight weeks, histological lesions in the liver tissue and elevated serum levels of alanine aminotransferase and alkaline phosphatase were found in mice. Conversely, oral administration of TSA relieved CCl4-induced liver injury as well as ameliorated liver functions. Our immunohistochemical staining results revealed that collagen deposition was profoundly reduced due to supplementation with TSA. In addition, we also found that hepatic α-smooth muscle actin (α-SMA) and matrix metallopeptidase 9 (MMP-9) expression was suppressed through the inhibition of transforming growth factor ß (TGF-ß). Taken together, our current findings suggest that TSA may serve as a potent bioactive constituent from oolong tea that acts against liver fibrosis through the inhibition of hepatic stellate cell (HSC) activation.

Garcinol sensitizes breast cancer cells to Taxol through the suppression of caspase-3/iPLA2 and NF-κB/Twist1 signaling pathways in a mouse 4T1 breast tumor model.

Breast cancer is a significant threat to women's health and has high incidence and mortality. Metastasis in breast cancer patients is a major cause of cancer deaths among women worldwide. Clinical experience suggests that patients with metastatic triple-negative breast cancer (TNBC) relapse quickly and often have chemotherapy resistance. Taxol (paclitaxel) is an effective chemotherapeutic agent for treating metastatic breast cancer, but Taxol at high doses can cause adverse effects and recurrent resistance. Thus, the selection of a synergistic combination therapy is recommended, which is safer and has a more significant response rate than monotherapy. In this study, our strategy is to combine a low dose of Taxol (5 mg kg-1, i.p.) and garcinol (1 mg kg-1, i.g.) to investigate the synergistic antitumor and anti-metastasis effects and to determine the underlying mechanisms of these effects in vivo. For the in vivo study, metastasis-specific mouse mammary carcinoma 4T1 cells were inoculated in Balb/c mice to establish an orthotopic primary tumor and spontaneous metastasis model. Tumor growth and metastases were monitored. The mechanisms of synergistic efficacies were evaluated at different signaling pathways, including proliferation, survival, and epithelial-mesenchymal transition (EMT)-regulated metastatic propensity. We demonstrated that garcinol combined with Taxol significantly increased the therapeutic efficacy when compared with either treatment alone. The synergistic antitumor and anti-metastasis effects were enhanced primarily through the induction of Taxol-stimulated G2/M phase arrest and the inhibition of caspase-3/cytosolic Ca2+-independent phospholipase A2 (iPLA2) and nuclear factor-κB (NF-κB)/Twist-related protein 1 (Twist1) drive downstream events including tumor cell repopulation, survival, inflammation, angiogenesis, invasion, and EMT. Our current findings provide the first experimental evidence that a combination of a low dose of Taxol and garcinol is a promising therapeutic strategy for controlling advanced or metastatic breast cancer. Finally, our results also point to the possible role of NF-κB/Twist1 and caspase-3/iPLA2 signaling pathways as biomarkers to predict the tumor response to treatment.

Peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) potently suppresses dextran sulfate sodium-induced colitis and colon tumorigenesis in mice.

Previous studies reported that peracetylated (-)-epigallocatechin-3-gallate (AcEGCG) has antiproliferative and anti-inflammatory activities. Here, we evaluated the chemopreventive effects and underlying molecular mechanisms of dietary administration of AcEGCG and EGCG in dextran sulfate sodium (DSS)-induced colitis in mice. The mice were fed a diet supplemented with either AcEGCG or EGCG prior to DSS induction. Our results indicated that AcEGCG administration was more effective than EGCG in preventing the shortening of colon length and the formation of aberrant crypt foci (ACF) and lymphoid nodules (LN) in mouse colon stimulated by DSS. Our study observes that AcEGCG treatment inhibited histone 3 lysine 9 (H3K9) acetylation but did not affect histone acetyltransferase (HAT) activity and acetyl- CREB-binding protein (CBP)/p300 levels. In addition, pretreatment with AcEGCG decreased the proinflammatory mediator levels by down-regulating of PI3K/Akt/NFκB phosphorylation and p65 acetylation. We also found that treatment with AcEGCG increased heme oxygenase-1(HO-1) expression via activation of extracellular signal-regulated protein kinase (ERK)1/2 signaling and acetylation of NF-E2-related factor 2 (Nrf2), thereby abating DSS-induced colitis. Moreover, dietary feeding with AcEGCG markedly reduced colitis-driven colon cancer in mice. Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary AcEGCG against inflammatory bowel disease (IBD) and potentially colon cancer associated with colitis. These findings provide insight into the biological actions of AcEGCG and might establish a molecular basis for the development of new cancer chemopreventive agents.

Anti-inflammatory activity of traditional Chinese medicinal herbs.

Accumulating epidemiological and clinical evidence shows that inflammation is an important risk factor for various human diseases. Thus, suppressing chronic inflammation has the potential to delay, prevent, and control various chronic diseases, including cerebrovascular, cardiovascular, joint, skin, pulmonary, blood, lymph, liver, pancreatic, and intestinal diseases. Various natural products from traditional Chinese medicine (TCM) have been shown to safely suppress proinflammatory pathways and control inflammation-associated disease. In vivo and/or in vitro studies have demonstrated that anti-inflammatory effects of TCM occur by inhibition of the expression of master transcription factors (for example, nuclear factor-κB (NF-κB)), pro-inflammatory cytokines (for example, tumor necrosis factor-α (TNF-α), chemokines (for example, chemokine (C-C motif) ligand (CCL)-24), intercellular adhesion molecule expression and pro-inflammatory mediators (for example, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)). However, a handful of review articles have focused on the anti-inflammatory activities of TCM and explore their possible mechanisms of action. In this review, we summarize recent research attempting to identify the anti-inflammatory constituents of TCM and their molecular targets that may create new opportunities for innovation in modern pharmacology.