PMID: 

Arch Pharm Res. 2020 Mar 10. Epub 2020 Mar 10. PMID: 32152852

Abstract Title: 

Sulforaphane as an anticancer molecule: mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems.

Abstract: 

Sulforaphane is an isothiocyanate compound that has been derived from cruciferous vegetables. It was shown in numerous studies to be active against multiple cancer types including pancreatic, prostate, breast, lung, cervical, and colorectal cancers. Sulforaphane exerts its therapeutics action by a variety of mechanisms, such as by detoxifying carcinogens and oxidants through blockage of phase I metabolic enzymes, and by arresting cell cycle in the G2/M and G1 phase to inhibit cell proliferation. The most striking observation was the ability of sulforaphane to potentiate the activity of several classes of anticancer agents including paclitaxel, docetaxel, and gemcitabine through additive and synergistic effects. Although a good number of reviews have reported on the mechanisms by which sulforaphane exerts its anticancer activity, a comprehensive review on the synergistic effect of sulforaphane and its delivery strategies is lacking. Therefore, the aim of the current review was to provide a summary of the studies that have been reported on the activity enhancement effect of sulforaphane in combination with other anticancer therapies. Also provided is a summary of the strategies that have been developed for the delivery of sulforaphane.

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PMID: 

Cancer Prev Res (Phila). 2020 Mar 11. Epub 2020 Mar 11. PMID: 32161072

Abstract Title: 

Epigenome, transcriptome and protection by sulforaphane at different stages of UVB-induced skin carcinogenesis.

Abstract: 

Sulforaphane (SFN), a potent antioxidant and anti-inflammatory agent, has been shown to protect against cancers especially at early stages. However, how SFN affects UVB-mediated epigenome/DNA methylome and transcriptome changes in skin photodamage has not been fully assessed. Herein, we investigated the transcriptomic and DNA methylomic changes during tumor initiation, promotion, and progression and its impact and reversal by SFN using next-generation sequencing (NGS) technology. The results show that SFN reduced tumor incidence and tumor number. SFN's protective effects were more dramatic in the early stages than with later stages. Bioinformatic analysis of RNA-seq data shows differential expressed genes (DEGs) and identifies the top canonical pathways related to SFN treatment of UVB-induced different stages of epidermal carcinogenesis. These pathways include p53 signaling, cell cycle: G2/M DNA damage checkpoint regulation, Th1, and Th2 activation pathway, and PTEN signaling pathways. The top upstream regulators related to UVB and SFN treatment as time progressed include dextran sulfate, TP53, NFE2L2 (Nrf2), IFNB1 and IL10RA. Bioinformatic analysis of Methyl-seq data shows several differential methylation regions (DMRs) induced by UVB were attenuated by SFN. These include Notch1, Smad6, Gnai3, and Apc2. Integrative analysis of RNA-Seq and DNA-seq/CpG methylome yields a subgroup of genes associated with UVB and SFN treatment. The changes in gene expression were inversely correlated with promoter CpG methylation status. These genes include Pik3cd, Matk, and Adm2. In conclusion, our study provides novel insights on the impact of SFN on the transcriptomic and DNA methylomic of UVB-induced different stages of skin cancer in mice.

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PMID: 

Toxicol Appl Pharmacol. 2020 Feb 29 ;393:114941. Epub 2020 Feb 29. PMID: 32126212

Abstract Title: 

Benzyl isothiocyanate ameliorates high-fat/cholesterol/cholic acid diet-induced nonalcoholic steatohepatitis through inhibiting cholesterol crystal-activated NLRP3 inflammasome in Kupffer cells.

Abstract: 

Incidence of nonalcoholic fatty liver disease is increasing worldwide. Activation of the NLRP3 inflammasome is central to the development of diet-induced nonalcoholic steatohepatitis (NASH). We investigated whether benzyl isothiocyanate (BITC) ameliorates diet-induced NASH and the mechanisms involved. C57BL/6 J mice fed a high-fat diet containing cholesterol and cholic acid (HFCCD) and Kupffer cells stimulated with LPS and cholesterol crystals (CC) were studied. LPS/CC increased the expression of the active form of caspase 1 (p20) and the secretion of IL-1β by Kupffer cells, and these changes were reversed by MCC950, an NLRP3 inflammasome inhibitor. LPS/CC-induced NLRP3 inflammasome activation and IL-1β production were dose-dependently attenuated by BITC. BITC decreased cathepsin B release from lysosomes and binding to NLRP3 induced by LPS/CC. Compared with a normal diet, the HFCCD increased serum levels of ALT, AST, total cholesterol, and IL-1β and hepatic contents of triglycerides and total cholesterol. BITC administration (0.1% in diet) reversed the increase in AST and hepatic triglycerides in the HFCCD group. Moreover, BITC suppressed lipid accumulation, macrophage infiltration, fibrosis, crown-like structure formation, and p20 caspase 1 and p17 IL-1β expression in liver in the HFCCD group. These results suggest that BITC ameliorates HFCCD-induced steatohepatitis by inhibiting the activation of NLRP3 inflammasome in Kupffer cells and may protect against diet-induced NASH.

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PMID: 

Acta Pharmacol Sin. 2020 Mar 4. Epub 2020 Mar 4. PMID: 32132657

Abstract Title: 

PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells.

Abstract: 

Phenethyl isothiocyanate (PEITC) is an isothiocyanate that largely exists in cruciferous vegetables and exhibits chemopreventive and chemotherapeutic potential against various cancers. However, it is little known about the molecular mechanisms of its antitumor action against osteosarcoma, which is the second highest cause of cancer-related death in children and adolescents. In this study, we investigated the effects of PEITC on K7M2 murine osteosarcoma both in vitro and in vivo. We found that treatment with PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an ICvalue of 33.49 μM at 24 h. PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G/M cell cycle arrest, depleted glutathione (GSH), generated reactive oxygen species (ROS), altered iron metabolism, and triggered multiple forms of cell death, namely ferroptosis, apoptosis, and autophagy in K7M2 cells. We further revealed that PEITC treatment activated MAPK signaling pathway, and ROS generation was a major cause of PEITC-induced cell death. In a syngeneic orthotopic osteosarcoma mouse model, administration of PEITC (30, 60 mg/kg every day, ig, for 24 days) significantly inhibited the tumor growth, but higher dose of PEITC (90 mg/kg every day) compromised its anti-osteosarcoma effect. Histological examination showed that multiple cell death processes were initiated, iron metabolism was altered and MAPK signalingpathway was activated in the tumor tissues. In conclusion, we demonstrate that PEITC induces ferroptosis, autophagy, and apoptosis in K7M2 osteosarcoma cells by activating the ROS-related MAPK signaling pathway. PEITC has promising anti-osteosarcoma activity. This study sheds light on the redox signaling-based chemotherapeutics for cancers.

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PMID: 

Mol Carcinog. 2020 Mar 18. Epub 2020 Mar 18. PMID: 32189414

Abstract Title: 

Phenethyl isothiocyanate synergistically induces apoptosis with Gefitinib in non-small cell lung cancer cells via endoplasmic reticulum stress-mediated degradation of Mcl-1.

Abstract: 

Isothiocyanates (ITCs) are natural compounds abundant in cruciferous vegetables. Numerous studies have shown that ITCs exhibit anticancer activity by affecting multiple pathways including apoptosis and oxidative stress, and are expected to be developed into novel anticancer drugs. In our previous studies, we demonstrated that ITCs effectively inhibit the proliferation of non-small cell lung cancer (NSCLC) cells, also induce apoptosis and autophagy. In the present study, we found that phenethyl isothiocyanate (PEITC) had significant synergistic effects with epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in NSCLC cell lines NCI-H1299 and SK-MES-1; and the degradation of antiapoptotic factor myeloid cell leukemia 1 (Mcl-1) caused by PEITC treatment played key roles in the sensitivity of NSCLC cells to Gefitinib. We further illustrated that PEITC regulated the expression of Mcl-1 through protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α-CHOP-Noxa pathway by a posttranscriptional modulation. Pretreatment with endoplasmic reticulum stress (ER stress) inhibitor tauroursodeoxycholic acid and knockdown of PERK expression attenuated the degradation of Mcl-1 caused by PEITC. In in vivo study, nude mice bearing NCI-H1299 xenograft wereadministrated with PEITC (50 mg/kg, ip) and Gefitinib (50 mg/kg, ig) for 15 days, the PEITC-Gefitinib combination treatment resulted in a significant synergistic reduction in tumor growth, and significantly induced both ER stress and Mcl-1 degradation in tumor tissues. In conclusion, we exploredthe prospect of PEITC in improving the efficacy of targeted drug therapy and demonstrated the synergistic effects and underlined mechanisms of PEITC combined with Gefitinib in NSCLC cells treatment. This study provided useful information for developing novel therapy strategies by combination treatment of PEITC with targeted drugs.

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PMID: 

Eur J Nutr. 2020 Mar 25. Epub 2020 Mar 25. PMID: 32215717

Abstract Title: 

Sulforaphane and iberin are potent epigenetic modulators of histone acetylation and methylation in malignant melanoma.

Abstract: 

OBJECTIVE(S): Growing evidence supports that isothiocyanates exert a wide range of bioactivities amongst of which is their capacity to interact with the epigenetic machinery in various cancers including melanoma. Our aim was to characterise the effect of sulforaphane and iberin on histone acetylation and methylation as a potential anti-melanoma strategy.METHODS: We have utilised an in vitro model of malignant melanoma [consisting of human (A375, Hs294T, VMM1) and murine (B16F-10) melanoma cell lines as well as a non-melanoma (A431) and a non-tumorigenic immortalised keratinocyte (HaCaT) cell line] exposed to sulforaphane or iberin. Cell viability was evaluated by the Alamar blue assay whilst total histone deacetylases and acetyltransferases activities were determined by the Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively. The expression levels of specific histone deacetylases and acetyltransferases together with those of lysine acetylation and methylation marks were obtained by western immunoblotting.RESULTS: Overall, both sulforaphane and iberin were able to (1) reduce cell viability, (2) decrease total histone deacetylase activity and (3) modulate the expression levels of various histone deacetylases as well as acetyl and methyl transferases thus modulating the acetylation and methylation status of specific lysine residues on histones 3 and 4 in malignant melanoma cells.CONCLUSIONS: Our findings highlight novel insights as to how sulforaphane and iberin differentially regulate the epigenetic response in ways compatible with their anticancer action in malignant melanoma.

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PMID: 

Neurochem Int. 2020 Mar 18:104728. Epub 2020 Mar 18. PMID: 32199985

Abstract Title: 

Sulforaphane Attenuates Apoptosis of Hippocampal Neurons Induced by High Glucose via Regulating Endoplasmic Reticulum.

Abstract: 

Diabetic encephalopathy (DE) has been defined as one of the major complications of diabetes, characterized by neurochemical and neurodegenerative changes. However, the molecular mechanism of DE are not fully elucidated at present. Here, the primary hippocampal neurons were cultured in vitro with high glucose (HG) to induce diabetes-like effects, and mice were given streptozotocin (STZ) to induce a model of type 1 diabetes mellitus (T1D) mice. The administration of sulforaphane (SF) were used to observe the protective effects on the hippocampal neurons. We found that the expression of glucose-regulated protein 78 (GRP78), a typical endoplasmic reticulum chaperone, showed a trend of increasing in the early phase but decreasing in the late phase of both HG-induced primary hippocampal neurons and T1D mice. However, SF suppressed the apoptosis induced by HG in vitro and in vivo through TUNEL assay and caspase3 immunofluorescence staining. Meanwhile, the administration of SF suppressed the upregulation of CHOP, Bax and p-JNK protein and the downregulation of Bcl-2 protein induced by HG in hippocampal neurons in vitro and in vivo. The caspase12 gene was upregulated only at 4 weeks in T1D mice compared with control mice, and the upregulation was suppressed by SF. In addition, the combined administration of SF and PX12, which is an inhibitor of thioredoxin (Trx), eliminated the protective effects of SF. We conclude that HG induced the development of endoplasmic reticulum stress (ERS) in hippocampal neurons, eventually leading to the apoptosis of neurons. SF prevented the ERS and attenuates the hippocampal neuron apoptosis induced by HG both in vitro and in vivo. The underlying mechanism may be involved in the suppression of the CHOP-Bax/Bcl-2, JNK and caspase12 signaling pathways by SF through the Trx-1 target protein.

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PMID: 

Foods. 2020 Feb 24 ;9(2). Epub 2020 Feb 24. PMID: 32102416

Abstract Title: 

New Evidences of Antibacterial Effects of Cranberry Against Periodontal Pathogens.

Abstract: 

The worrying rise in antibiotic resistances emphasizes the need to seek new approaches for treating and preventing periodontal diseases. The purpose of this study was to evaluate the antibacterial and anti-biofilm activity of cranberry in a validated in vitro biofilm model. After chemical characterization of a selected phenolic-rich cranberry extract, its values for minimum inhibitory concentration and minimum bactericidal concentration were calculated for the six bacteria forming the biofilm (,,,,, and). Antibacterial activity of the cranberry extract in the formed biofilm was evaluated by assessing the reduction in bacteria viability, using quantitative polymerase chain reaction (qPCR) combined with propidium monoazide (PMA), and by confocal laser scanning microscopy (CLSM), and anti-biofilm activity by studying the inhibition of the incorporation of different bacteria species in biofilms formed in the presence of the cranberry extract, using qPCR and CLSM. In planktonic state, bacteria viability was significantly reduced by cranberry (0.05)). Conversely, cranberry significantly (

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PMID: 

BMC Complement Med Ther. 2020 Mar 6 ;20(1):71. Epub 2020 Mar 6. PMID: 32143616

Abstract Title: 

Cranberry extract initiates intrinsic apoptosis in HL-60 cells by increasing BAD activity through inhibition of AKT phosphorylation.

Abstract: 

BACKGROUND: Cranberry has been studied as a potential anticancer agent as it is capable of inducing apoptosis within cancer cells. The aim of this study was to better define the mechanism by which cranberry triggers apoptosis in HL-60 cells.METHODS: The study was carried on cranberry extracts (CB). Anti-apoptotic B-cell lymphoma-2 (BCL-2) and pro-apoptotic BCL-2-associated death promoter death (BAD) proteins in cell lysates were detected through Western blotting techniques. Equivalent protein loading was confirmed through anti-α-tubulin antibody.RESULTS: The results showed that treatment of HL-60 cells with CB causes a significant increase in the levels of caspase-9 and caspases-3/7 and increased mitochondrial outer membrane permeability, leading to the release of cytochrome C and Smac. These apoptotic events were associated with a significant decrease in protein kinase B (AKT) phosphorylation, which caused significant increase in BAD de-phosphorylation and promoted a sequence of events that led to intrinsic apoptosis.CONCLUSION: The study findings have described a molecular framework for CB-initiated apoptosis in HL-60 cells and suggested a direction for future in vivo studies investigating the anticancer effect of cranberry.

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PMID: 

Adv Urol. 2020 ;2020:6325490. Epub 2020 Jan 13. PMID: 32215007

Abstract Title: 

Prospective Multicenter Open-Label One-Arm Trial Investigating a Pumpkin Seed, Isoflavonoids, and Cranberry Mix in Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia: A Pilot Study.

Abstract: 

Phytotherapy for lower urinary tract symptoms (LUTSs) due to benign prostate hyperplasia (BPH) is progressively demanded by patients and trusted by physicians. The aim was to assess the efficacy of a mix of pumpkin seed extract, soy germ isoflavonoids, and cranberry (Novex®) in the management of mild to moderate LUTS in BPH patients. Male patients aged ≥40 years, who had had mild to moderate LUTS for>6 months at screening, with no previous therapy or who are still symptomatic despite current use of alpha-blockers, were recruited. Exclusion criteria were an IPSS>19 and an age>80 years. The mixed compound was administered orally, daily, for 3 months. Patients were evaluated by means of IPSS, urological quality of life (uQoL) index, and International Index of Erectile Function (IIEF-5) at 3 visits: baseline (visit 1), 30 days (visit 2), and 90 days after treatment (visit 3). Among 163 screened patients, 128 patients (61.8 ± 9.9 years) were recruited. IPSS improved from 15 (Q1 : 12-Q3 : 17) in visit 1, to 11 (Q1 : 8-Q3 : 14) in visit 2, and to 9 (Q1 : 6-Q3 : 12) in visit 3 (

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