PMID: 

Food Funct. 2018 Sep 19 ;9(9):4695-4701. PMID: 30091431

Abstract Title: 

Sulforaphane ameliorates glucose intolerance in obese mice via the upregulation of the insulin signaling pathway.

Abstract: 

Sulforaphane (SFN) is a dietary component with multiple bioactivities; however, its role in obesity-related metabolic derangement remains unclear. Here, the effect of SFN on the glucose intolerance of obese mice and the underlying mechanism were determined. C57B/6J male mice were randomly divided into two groups, having free access to water and a normal-fat diet (ND, n = 6) or a high-fat diet (HFD, n = 33) for 8 weeks; thereafter twelve mice having the greatest weight gain among the HFD-fed mice were considered as obese mice. These obese mice were randomly divided into two groups and treated orally for 6 weeks with or without SFN (100μmol per kg bw, 3 times per week). During this period the animals were continuously maintained on a ND or a HFD. Blood glucose and serum insulin were examined; then glucose tolerance and insulin resistance were evaluated. In addition, the expression of insulin signaling pathway-related genes in themuscle was determined. Our data showed that the obese mice presented a marked insulin resistance and glucose intolerance as compared to the control group, while SFN treatment exerted a prominently protective effect. In addition, the SFN-treated obese mice had a significantly increased insulin receptor substrate 1 (IRS-1) protein level (P

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PMID: 

Drug Des Devel Ther. 2018 ;12:2905-2913. Epub 2018 Sep 11. PMID: 30254420

Abstract Title: 

Chemopreventive activity of sulforaphane.

Abstract: 

Cancer is one of the major causes of morbidity and mortality in the world. Carcinogenesis is a multistep process induced by genetic and epigenetic changes that disrupt pathways controlling cell proliferation, apoptosis, differentiation, and senescence. In this context, many bioactive dietary compounds from vegetables and fruits have been demonstrated to be effective in cancer prevention and intervention. Over the years, sulforaphane (SFN), found in cruciferous vegetables, has been shown to have chemopreventive activity in vitro and in vivo. SFN protects cells from environmental carcinogens and also induces growth arrest and/or apoptosis in various cancer cells. In this review, we will discuss several potential mechanisms of the chemopreventive activity of SFN, including regulation of Phase I and Phase II drug-metabolizing enzymes, cell cycle arrest, and induction of apoptosis, especially via regulation of signaling pathways such as Nrf2-Keap1 and NF-κB. Recent studies suggest that SFN can also affect the epigenetic control of key genes and greatly influence the initiation and progression of cancer. This research may provide a basis for the clinical use of SFN for cancer chemoprevention and enable us to design preventive strategies for cancer management, reduce cancer development and recurrence, and thus improve patient survival.

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PMID: 

Exp Dermatol. 2019 Jan ;28(1):28-34. Epub 2018 Dec 11. PMID: 30315662

Abstract Title: 

Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase-2.

Abstract: 

Although there are many treatment options for skin cancer, the chemotherapeutic agents for skin cancer are linked with many adverse effects as well as the development of multidrug resistance. Sulforaphane is an isothiocyanate, which is found in cruciferous vegetables. Consumption of sulforaphane-rich diet has been linked to inhibition of UV-exposed skin carcinogenesis. Therefore, the goal of this study was to determine the ability of sulforaphane to reduce skin cancer in mice through inhibition of sulfatase-2 enzyme. Epicutaneous application of 7,12-dimethylbenz (a) anthracene was performed on the shaved dorsal skin of mice followed by croton oil. Sulforaphane (9 μmol/mouse/day) was administered to mice orally. Skin was removed from the dorsal area for assessment of sulfatase-2, glypican-3, heparan sulphate proteoglycans (HSPGs), nuclear factor (NF)κB, nuclear factor E2-related factor 2 (Nrf2), tumor necrosis factor (TNF)-α, IL-1β and caspase-3. In addition, skin sections were stained with haematoxylin/eosin, Mallory and cytokeratin immunostaining. We found that, sulforaphane blocked sulfatase-2 activity, leading to significant elevation in HSPGs as well as significant reduction in glypican-3. In addition, sulforaphane significantly activated Nrf2 and reduced both the gene and protein expression of NFκB, TNF-α, IL-1β and caspase-3. In parallel, stained sections obtained from skin cancer mice treated with sulforaphane showed significant reduction in hyperkeratosis, acanthosis and epithelial dysplasia. The collective results indicate thatsulforaphane suppresses skin cancer via blocking sulfatase-2 with subsequent elevation in HSPGs and reduction in glypican-3. Moreover, sulforaphane attenuated skin cancer-induced activation of inflammatory and apoptotic pathways.

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PMID: 

Oncotarget. 2018 Sep 21 ;9(74):33982-33994. Epub 2018 Sep 21. PMID: 30338040

Abstract Title: 

Sulforaphane inhibits growth and blocks Wnt/β-catenin signaling of colorectal cancer cells.

Abstract: 

The naturally occurring isothiocyanate sulforaphane (SFN) from cruciferous vegetables is associated with growth inhibition of various cancer types, including colorectal cancer. Colorectal cancer is most frequently driven by hyperactive Wnt/β-catenin signaling. Here, we show that SFN treatment reduced growth of three unrelated colorectal cancer cell lines (SW480, DLD1 and HCT116) via induction of cell death and inhibition of proliferation. Importantly, SFN inhibits Wnt/β-catenin signaling in colorectal cancer cells as shown by inhibition of β-catenin-dependent luciferase reporters and repression of β-catenin target genes (,). SFN inhibits Wnt signaling downstream ofβ-catenin degradation and induces the formation of nuclear β-catenin structures associated with closed chromatin. Co-expression of the transcription factors LEF1 or TCF4 prevented formation of these structures and rescued inhibition of Wnt/β-catenin signaling by SFN. Our findings provide a molecular basis explaining SFN effects in colorectal cancer cells and underline its potential for prevention and therapy of colorectal cancer.

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PMID: 

Cell Physiol Biochem. 2018 ;50(3):1201-1215. Epub 2018 Oct 24. PMID: 30355942

Abstract Title: 

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling.

Abstract: 

BACKGROUND/AIMS: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism.METHODS: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer.RESULTS: SFN can inhibit pancreatic cancer cell growth， promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group.CONCLUSION: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.

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PMID: 

FEBS Open Bio. 2018 Dec ;8(12):2022-2034. Epub 2018 Nov 14. PMID: 30524952

Abstract Title: 

Sulforaphane-induced metabolomic responses with epigenetic changes in estrogen receptor positive breast cancer cells.

Abstract: 

Estrogen is a risk factor for breast cancer. The isothiocyanate sulforaphane (SFN), found in cruciferous vegetables, has been identified as an effective chemopreventive agent, and may prevent or treat breast cancer by reversing estrogen-induced metabolic changes. Here, we investigated metabolic changes in estrogen receptor-positive breast cancer (MCF-7) cells treated with estradiol (E) and/or SFN to identify key metabolite panels that might provide new insights into the underlying mechanisms of the antitumor effects of SFN. Gas chromatography-mass spectrometry and ultra performance liquid chromatography-mass spectrometry (UPLC-OrbitrapMS) were used to obtain the metabolic profiles of MCF-7 cells. The data were analyzed using Student's-test and multivariate statistics, including principal component analysis and partial least squares discriminant analysis. Hydroxymethylation was detected by UPLC-OrbitrapMS and verified by immunofluorescence assay. We report that significant changes in metabolites induced by Eand SFN were associated with differences in glycolysis and energy metabolism, and also amino acid, purine, and folic acid metabolism. Emay alter methylation and hydroxymethylation status via the folic acid pathway. We also identified biomarkers that may be of use in interpretation of the metabolic pathways evoked by the effects of Eand SFN on breast cancer cells. The identified biomarkers associated with metabolic pathways provide new insight into the chemopreventive mechanisms of SFN.

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PMID: 

Mol Nutr Food Res. 2019 02 ;63(4):e1800795. Epub 2019 Jan 11. PMID: 30578708

Abstract Title: 

Sulforaphane Improves Lipid Metabolism by Enhancing Mitochondrial Function and Biogenesis In Vivo and In Vitro.

Abstract: 

SCOPE: Sulforaphane (SFN) is reported to reduce the accumulation of lipids. However, the underling mechanism remains unclear. In this study, the potential of SFN to improve lipid metabolism is investigated through altering mitochondrial function and biogenesis-related mechanisms.METHODS AND RESULTS: The abnormal lipid metabolism model was established both in HHL-5 cells and in rats by feeding a high-fat diet (HFD) for 10 weeks. The current findings suggest that SFN alleviates the swelling of mitochondria and stimulates mitochondrial biogenesis. The reduced expression of NRF1 and TFAM, were reversed by SFN. SFN increases the levels of antioxidant compounds via nuclear factor erythroid-2-related factor (Nrf2) activation. Furthermore, SFN improves multiple mitochondrial bioactivities, such as mitochondrial membrane potential, ATP, and the electron transfer chain based on PGC-1α pathway. SFN also activates lipolysis by transcriptionally upregulating adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL).CONCLUSIONS: SFN enhances utilization of lipids via both the PGC- 1α-dependent promotion of mitochondrial biogenesis and Nrf2 dependent improvement of mitochondrial function.

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PMID: 

Oxid Med Cell Longev. 2018 ;2018:4125297. Epub 2018 Nov 18. PMID: 30581529

Abstract Title: 

Sulforaphane Modulates AQP8-Linked Redox Signalling in Leukemia Cells.

Abstract: 

Sulforaphane, a biologically active isothiocyanate compound extracted from cruciferous vegetables, has been shown to exert cytotoxic effects on many human cancer cells, including leukemia. However, the exact molecular mechanisms behind the action of sulforaphane in hematological malignancies are still unclear. Like other cancer cells, leukemia cells produce high level of reactive oxygen species; in particular, hydrogen peroxide derived from Nox family is involved in various redox signal transduction pathways, promoting cell proliferation and survival. Recent evidence show that many tumour cell types express elevated level of aquaporin isoforms, and we previously demonstrated that aquaporin-8 acts as HOtransport facilitator across the plasma membrane of B1647 cells, a model of acute myeloid human leukemia. Thus, the control of AQP8-mediated HOtransport could be a novel strategy to regulate cell signalling and survival. To this purpose, we evaluated whether sulforaphane could somehow affect aquaporin-8-mediated HOtransport and/or Nox-mediated HOproduction in B1647 cell line. Results indicated that sulforaphane inhibited both aquaporin-8 and Nox2 expression, thus decreasing B1647 cells viability. Moreover, the data obtained by coimmunoprecipitation technique demonstrated that these two proteins are linked to each other; thus, sulforaphane has an important role in modulating the downstream events triggered by the axis Nox2-aquaporin-8. Cell treatment with sulforaphane also reduced the expression of peroxiredoxin-1, which is increased in almost all acute myeloid leukemia subtypes. Interestingly, sulforaphane concentrations able to trigger these effects are achievable by dietary intake of cruciferous vegetables, confirming the importance of the beneficial effect of a diet rich in bioactive compounds.

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PMID: 

Environ Toxicol Pharmacol. 2019 Feb ;66:43-54. Epub 2018 Dec 13. PMID: 30597379

Abstract Title: 

Comparison of the effects of sulforaphane and pioglitazone on insulin resistance and associated dyslipidemia, hepatosteatosis, and endothelial dysfunction in fructose-fed rats.

Abstract: 

The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showedsignificant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-β indices demonstrated impaired insulin sensitivity and glucose utilizationin HFrD-fed rats. SFN and PIO treatments significantly reduced OGTT(Glass's Delta values = 1.12 and 0.84, respectively), decreased ITT(Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-β value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactiveprotein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.

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PMID: 

Int J Food Sci Nutr. 2019 Aug ;70(5):570-578. Epub 2019 Jan 9. PMID: 30624124

Abstract Title: 

Sulforaphane inhibits gastric cancer stem cells via suppressing sonic hedgehog pathway.

Abstract: 

Sulforaphane (SFN) is the major component extracted from broccoli/broccoli sprouts. It has been shown to possess anti-cancer activity. Gastric cancer is common cancer worldwide. The objective of this work was to evaluate the inhibitory effect of SFN on gastric cancer by Sonic hedgehog (Hh) Pathway. The results found that tumorsphere formation and the expression levels of gastric cancer stem cells (CSCs) markers were significantly decreased after SFN treatment. SFN also exerted inhibitory effects by suppressing proliferation and inducing apoptosis in gastric CSCs. Intriguingly, SFN inhibited the activation of Sonic Hh, a key pathway in maintaining the stemness of gastric CSCs. Upregulation of Sonic Hh pathway diminished the inhibitory effects of SFN on gastric CSCs. Collectively, these data revealed that SFN could be a potent natural compound targeting gastric CSCs via suppression of Sonic Hh pathway, which might be an promising agent for gastric cancer intervention.

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