Resveratrol

Environ Mol Mutagen. 2015 Apr;56(3):333-46.

Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression.[Pubmed: 25339131]

Arsenic trioxide (As2 O3 ) is commonly used to treat acute promyelocytic leukemia and solid tumors. However, the clinical application of the agent is limited by its cyto- and genotoxic effects on normal cells. Thus, relief of As2 O3 toxicity in normal cells is essentially necessary for improvement of As2 O3 -mediated chemotherapy.
METHODS AND RESULTS:
In this study, we have identified a series of protective effects of Resveratrol against As2 O3 -induced oxidative damage in normal human bronchial epithelial (HBE) cells. We showed that treatment of HBE cells with Resveratrol significantly reduced cellular levels of DNA damage, chromosomal breakage, and apoptosis induced by As2 O3 . The effect of Resveratrol against DNA damage was associated with a decreased level of reactive oxygen species and lipid peroxidation in cells treated by As2 O3 , suggesting that Resveratrol protects against As2 O3 toxicity via a cellular anti-oxidative stress pathway. Further analysis of the roles of Resveratrol demonstrated that it modulated biosynthesis, recycling, and consumption of glutathione (GSH), thereby promoting GSH homeostasis in HBE cells treated by As2 O3 . This was further supported by results showing that Resveratrol prevented an increase in the activities and levels of caspases, Fas, Fas-L, and cytochrome c proteins induced by As2 O3 .
CONCLUSIONS:
Our study indicates that Resveratrol relieves As2 O3 -induced oxidative damage in normal human lung cells via maintenance of GSH homeostasis and suppression of apoptosis.

Anticancer Res. 2015 Jan;35(1):273-81.

Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs.[Pubmed: 25550561 ]

Resveratrol increases nitric oxide (NO) production via increased expression and activation of endothelial-form-NO-synthase (eNOS) in endothelial cells. However, the role of downstream cGMP/protein kinase G (PKG) signaling, a pathway activated by NO/eNOS, in pro- and anti-angiogenic effects of Resveratrol is still unclear.
METHODS AND RESULTS:
Endogenous NO/cGMP/PKG pathway and downstream cell-survival proteins (Inhibitor of Apoptosis Proteins, IAPs) were studied in relation to pro- and anti-angiogenic effects of Resveratrol in human umbilical vein endothelial cells (HUVECs). Resveratrol at higher/anti-angiogenic concentrations inhibits HUVEC tube formation and cell migration/invasion (indices of angiogenesis). Resveratrol at lower concentrations stimulates proliferation and protects HUVECs against spontaneous apoptosis. 8-Br-cGMP, a direct activator of PKG, protects against pro-apoptotic effects of high-concentration Resveratrol. Western blot analyses showed that anti-angiogenic concentrations of Resveratrol suppress endogenous PKG kinase activity and decrease the expression of four cell-survival proteins, c-IAP1, c-IAP2, livin and XIAP.
CONCLUSIONS:
Resveratrol-induced anti-angiogenesis/pro-apoptosis induced suppression of PKG signaling and decreased expression of the cell-survival proteins c-IAP1, c-IAP2, livin and XIAP.

Biochem Pharmacol . 2016 May 15;108:75-89.

Baicalein exhibits anti-inflammatory effects via inhibition of NF-κB transactivation[Pubmed: 27019135]

NF-κB is a crucial mediator of inflammatory and immune responses and a number of phytochemicals that can suppress this immune-regulatory transcription factor are known to have promising anti-inflammatory potential. However, we report that inducer of pro-inflammatory transcription factor NF-κB functions as an anti-inflammatory agent. Our findings reveal that a plant derived flavonoid baicalein could suppress mitogen induced T cell activation, proliferation and cytokine secretion. Treatment of CD4+ T cells with baicalein prior to transfer in to lymphopenic allogenic host significantly suppressed graft versus host disease. Interestingly, addition of baicalein to murine splenic lymphocytes induced DNA binding of NF-κB but did not suppress Concanavalin A induced NF-κB. Since baicalein did not inhibit NF-κB binding to DNA, we hypothesized that baicalein may be suppressing NF-κB trans-activation. Thioredoxin system is implicated in the regulation of NF-κB trans-activation potential and therefore inhibition of thioredoxin system may be responsible for suppression of NF-κB dependent genes. Baicalein not only inhibited TrxR activity in cell free system but also suppressed mitogen induced thioredoxin activity in the nuclear compartment of lymphocytes. Similar to baicalein, pharmacological inhibitors of thioredoxin system also could suppress mitogen induced T cell proliferation without inhibiting DNA binding of NF-κB. Further, activation of cellular thioredoxin system by the use of pharmacological activator or over-expression of thioredoxin could abrogate the anti-inflammatory action of baicalein. We propose a novel strategy using baicalein to limit NF-κB dependent inflammatory responses via inhibition of thioredoxin system.

Drug Des Devel Ther . 2016 Apr 18;10:1419-41.

Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway[Pubmed: 27143851]

Abstract Background: The flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms. Methods: MTT assay was used to examine the inhibition of baicalein on proliferation of MDA-MB-231 cells. Wound healing assay and the in vitro invasion assay was carried out to investigate the effects of baicalein on migration and invasion of MDA-MB-231 cells, respectively. In order to explore the effects of baicalein on tumor metastasis in vivo, xenograft nude mouse model of MDA-MB-231 cells was established. Animals were randomly divided into four groups (control, therapy group, and low-dose and high-dose prevention group, n=6), and treated with baicalein as designed. Following sacrifice, their lungs and livers were collected to examine the presence of metastases. qRT-PCR and Western blot were performed to study the effects of baicalein on expression of SATB1, EMT-related molecules, and Wnt/β-catenin signaling components of MDA-MB-231 cells as well as the metastatic tissue. Effects of baicalein on the expression of target proteins in vivo were also analyzed by immunohistochemistry. Results: Our results indicated that baicalein suppressed proliferation, migration, and invasion of MDA-MB-231 cells in a time- and dose-dependent manner. Based on assays carried out in xenograft nude mouse model, we found that baicalein inhibited tumor metastasis in vivo. Furthermore, baicalein significantly decreased the expression of SATB1 in MDA-MB-231 cells. It suppressed the expression of vimentin and SNAIL while enhancing the expression of E-cadherin. Baicalein also downregulated the expression of Wnt1 and β-catenin proteins and transcription level of Wnt/β-catenin-targeted genes. Conclusion: Our results demonstrate that baicalein has the potential to suppress breast cancer metastasis, possibly by inhibition of EMT, which may be attributed to downregulation of both SATB1 and the Wnt/β-catenin pathway. Taken together, baicalein may serve as a promising drug for metastasis treatment of breast cancer. Keywords: EMT; SATB1; Wnt/β-catenin pathway; baicalein; breast cancer; metastasis.

Biochem Biophys Res Commun. 2015 Feb 27;458(1):86-91.

Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice.[Pubmed: 25640840]

Circadian rhythmic disorders induced by high-fat diet are associated with metabolic diseases. Resveratrol could improve metabolic disorder, but few reports focused on its effects on circadian rhythm disorders in a variety of studies.
METHODS AND RESULTS:
The aim of the present study was to analyze the potential effects of Resveratrol on high-fat diet-induced disorders about the rhythmic expression of clock genes and clock-controlled lipid metabolism. Male C57BL/6 mice were divided into three groups: a standard diet control group (CON), a high-fat diet (HFD) group and HFD supplemented with 0.1% (w/w) Resveratrol (RES). The body weight, fasting blood glucose and insulin, plasma lipids and leptin, whole body metabolic status and the expression of clock genes and clock-controlled lipogenic genes were analyzed at four different time points throughout a 24-h cycle (8:00, 14:00, 20:00, 2:00). Resveratrol, being associated with rhythmic restoration of fasting blood glucose and plasma insulin, significantly decreased the body weight in HFD mice after 11 weeks of feeding, as well as ameliorated the rhythmities of plasma leptin, lipid profiles and whole body metabolic status (respiratory exchange ratio, locomotor activity, and heat production). Meanwhile, Resveratrol modified the rhythmic expression of clock genes (Clock, Bmal1 and Per2) and clock-controlled lipid metabolism related genes (Sirt1, Pparα, Srebp-1c, Acc1 and Fas). The response pattern of mRNA expression for Acc1 was similar to the plasma triglyceride.
CONCLUSIONS:
All these results indicated that Resveratrol reduced lipogenesis and ultimately normalized rhythmic expression of plasma lipids, possibly via its action on clock machinery.

Exp Cell Res. 2015 Mar 1;332(1):116-27.

Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors.[Pubmed: 25645941]

Many intracellular functions have been attributed to Resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that Resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells.
METHODS AND RESULTS:
Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in Resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the Resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting Resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by Resveratrol with transcription of the Egr-1 gene.
CONCLUSIONS:
These data were corroborated by the observation that stimulation of the cells with Resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as Resveratrol-responsive elements. Thus, Resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1.

Cell. 2012 Feb 3;148(3):421-33.

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.[Pubmed: 22304913]

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery.
METHODS AND RESULTS:
Here, we report that the metabolic effects of Resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, Resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of Resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice.
CONCLUSIONS:
Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Biochem Biophys Res Commun. 2015 Feb 20;457(4):608-13.

Resveratrol induces cell apoptosis in adipocytes via AMPK activation.[Pubmed: 25603053]

Resveratrol is identified as polyphenolic compound with anti-inflammatory, antioxidant, anti-insulin resistance characteristics. Moreover, Resveratrol exerts pro-apoptotic effects in varieties of cancer cell lines. However, effects and mechanisms of Resveratrol on the regulation of adipocytes apoptosis remain largely unknown.
METHODS AND RESULTS:
In this study, we found that Resveratrol treatment could induce cell apoptosis in murine 3T3-L1 adipocytes. Furthermore, Resveratrol activated the mitochondrial apoptotic signaling pathway with the decrease in the mitochondrial membrane potential (MMP), and the activation of caspase 3. Mechanistically, we found that phosphorylation level of AMP-activated protein kinase α (AMPKα) was elevated, accompany with reduced level of phosphorylation of protein kinase B (AKT) when cells were exposed to Resveratrol. By using small interfering RNAs of AMPKα and specific inhibitor for p-AKT, it was shown that activation of AMPKα could inhibit downstream of p-AKT, consequently activating mitochondrion-mediated apoptotic pathway. Additionally, we observed similar pro-apoptotic effects of Res on mouse primary adipocytes.
CONCLUSIONS:
Our findings clarified the apoptotic effects and underlying mechanisms of Resveratrol in adipocytes, suggesting its potential therapeutic application in the treatment or prevention of obesity and related metabolic symptoms.