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International Journal of Molecular... Nov 2020Sulforaphane (SFN) is a phytocompound belonging to the isothiocyanate family. Although it was also found in seeds and mature plants, SFN is mainly present in sprouts of... (Review)
Review
Sulforaphane (SFN) is a phytocompound belonging to the isothiocyanate family. Although it was also found in seeds and mature plants, SFN is mainly present in sprouts of many cruciferous vegetables, including cabbage, broccoli, cauliflower, and Brussels sprouts. SFN is produced by the conversion of glucoraphanin through the enzyme myrosinase, which leads to the formation of this isothiocyanate. SFN is especially characterized by antioxidant, anti-inflammatory, and anti-apoptotic properties, and for this reason, it aroused the interest of researchers. The aim of this review is to summarize the experimental studies present on Pubmed that report the efficacy of SFN in the treatment of neurodegenerative disease, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Therefore, thanks to its beneficial effects, SFN could be useful as a supplement to counteracting neurodegenerative diseases.
Topics: Anti-Inflammatory Agents; Antioxidants; Apoptosis; Humans; Isothiocyanates; Neurodegenerative Diseases; Sulfoxides
PubMed: 33207780
DOI: 10.3390/ijms21228637 -
Molecules (Basel, Switzerland) Oct 2019There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane.... (Review)
Review
There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Brassica; Clinical Trials as Topic; Humans; Isothiocyanates; Molecular Structure; Plant Extracts; Sulfoxides
PubMed: 31590459
DOI: 10.3390/molecules24193593 -
BMC Pharmacology & Toxicology Apr 2018Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-β1-induced model and an in vivo bleomycin (BLM)-induced model.
METHODS
In vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-β1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-β1, E-cadherin (E-cad), and α-smooth muscle actin (SMA) in lung tissues.
RESULTS
SFN reversed mesenchymal-like changes induced by TGF-β1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and α-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-β1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-β1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and α-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-β1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-β1 expression, and the levels of collagen I in the lungs of mice.
CONCLUSIONS
SFN showed a significant anti-fibrotic effect in TGF-β-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.
Topics: Animals; Bleomycin; Cell Line; Collagen Type I; Collagen Type IV; Epithelial-Mesenchymal Transition; Humans; Isothiocyanates; Lung; Male; Mice, Inbred C57BL; Pulmonary Fibrosis; Smad2 Protein; Smad3 Protein; Sulfoxides; Transforming Growth Factor beta
PubMed: 29609658
DOI: 10.1186/s40360-018-0204-7 -
Aging Jan 2021The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the...
The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the nematode model and fed the wildtype and 9 mutant strains ±sulforaphane. The lifespan, phenotype, pharyngeal pumping, mobility, lipofuscin accumulation, and RNA and protein expression of the nematodes were assessed by using Kaplan-Meier survival analysis, live imaging, fluorescence microscopy, and qRT-PCR. Sulforaphane increased the lifespan and promoted a health-related phenotype by increasing mobility, appetite and food intake and reducing lipofuscin accumulation. Mechanistically, sulforaphane inhibited DAF-2-mediated insulin/insulin-like growth factor signaling and its downstream targets AGE-1, AKT-1/AKT-2. This was associated with increased nuclear translocation of the FOXO transcription factor homolog DAF16. In turn, the target genes , and , known to enhance stress resistance and lifespan, were upregulated. These results indicate that sulforaphane prolongs the lifespan and healthspan of through insulin/IGF-1 signaling. Our results provide the basis for a nutritional sulforaphane-enriched strategy for the promotion of healthy aging and disease prevention.
Topics: Animals; Anticarcinogenic Agents; Appetite; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Eating; Forkhead Transcription Factors; Insulin-Like Growth Factor I; Isothiocyanates; Longevity; Receptor, Insulin; Signal Transduction; Sulfoxides
PubMed: 33471780
DOI: 10.18632/aging.202512 -
Biomedicine & Pharmacotherapy =... Aug 2022Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study...
Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies, the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Antioxidants; Diabetes Mellitus, Type 2; Diet, High-Fat; Insulin Resistance; Isothiocyanates; NF-E2-Related Factor 2; Oxidative Stress; Sulfoxides
PubMed: 35709656
DOI: 10.1016/j.biopha.2022.113273 -
Proceedings of the National Academy of... Oct 2014Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly... (Randomized Controlled Trial)
Randomized Controlled Trial
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.
Topics: Adolescent; Adult; Child Development Disorders, Pervasive; Humans; Isothiocyanates; Male; Placebos; Social Behavior; Sulfoxides; Treatment Outcome; Young Adult
PubMed: 25313065
DOI: 10.1073/pnas.1416940111 -
Autophagy Apr 2021Oxidative stress underlies a number of pathological conditions, including cancer, neurodegeneration, and aging. Antioxidant-rich foods help maintain cellular redox...
Oxidative stress underlies a number of pathological conditions, including cancer, neurodegeneration, and aging. Antioxidant-rich foods help maintain cellular redox homeostasis and mitigate oxidative stress, but the underlying mechanisms are not clear. For example, sulforaphane (SFN), an electrophilic compound that is enriched in cruciferous vegetables such as broccoli, is a potent inducer of cellular antioxidant responses. NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2), a transcriptional factor that controls the expression of multiple detoxifying enzymes through antioxidant response elements (AREs), is a proposed target of SFN. is a target gene of TFEB (transcription factor EB), a master regulator of autophagic and lysosomal functions, which we show here to be potently activated by SFN. SFN induces TFEB nuclear translocation via a Ca-dependent but MTOR (mechanistic target of rapamycin kinase)-independent mechanism through a moderate increase in reactive oxygen species (ROS). Activated TFEB then boosts the expression of genes required for autophagosome and lysosome biogenesis, which are known to facilitate the clearance of damaged mitochondria. Notably, TFEB activity is required for SFN-induced protection against both acute oxidant bursts and chronic oxidative stress. Hence, by simultaneously activating macroautophagy/autophagy and detoxifying pathways, natural compound SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases. ANOVA: analyzes of variance; AREs: antioxidant response elements; Baf-A1: bafilomycin A; BHA: butylhydroxyanisole; CAT: catechin hydrate; CCCP: carbonyl cyanide m- chlorophenylhydrazone; CLEAR: coordinated lysosomal expression and regulation; DCFH-DA: 2',7'-dichlorofluorescin diacetate; FBS: fetal bovine serum; GFP: green fluorescent protein; HMOX1/HO-1: heme oxygenase 1; KD: knockdown; KEAP1: kelch like ECH associated protein 1; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MCOLN1/TRPML1: mucolipin 1; ML-SA1: mucolipin-specific synthetic agonist 1; ML-SI3: mucolipin-specific synthetic inhibitor 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: nuclear factor: erythroid 2 like 2; NPC: Niemann-Pick type C; PBS: phosphate-buffered saline; PPP2/PP2A: protein phosphatase 2; Q-PCR: real time polymerase chain reaction; ROS: reactive oxygen species; RPS6KB1/S6K1/p70S6K: ribosomal protein S6 kinase B1; SFN: sulforaphane; TFEB: transcription factor EB; WT, wild-type.
Topics: Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Calcineurin; Calcium; Cell Nucleus; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Isothiocyanates; Lysosomes; Mitochondria; NF-E2-Related Factor 2; Oxidative Stress; Phosphorylation; Protein Transport; Reactive Oxygen Species; Sulfoxides; Transcription, Genetic
PubMed: 32138578
DOI: 10.1080/15548627.2020.1739442 -
Cancer May 2019Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in... (Review)
Review
Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in women, requiring effective therapy. Currently, combination therapy has become the hallmark of breast cancer treatment due to the high incidence of tumor recurrence and disease progression after monotherapeutic treatments, including surgery, radiotherapy, endocrine therapy, and chemotherapy. Over the past decades, there has been considerable interest in studying the anticancer effect of bioactive phytochemicals from medicinal plants combined with these conventional therapies. The rationale for this type of therapy is to use combinations of drugs that work by different mechanisms, thereby decreasing the likelihood that cancer cells will develop resistance, and also reduce the therapeutic dose and toxicity of single treatments. Three agents have received great attention with regard to their anticancer properties: 1) piperine, a dietary phytochemical isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.); 2) sulforaphane, an isothiocyanate mainly derived from cruciferous vegetables; and 3) thymoquinone, the active compound from black seed (Nigella sativa L.). This review focused on the combined effect of these 3 compounds on conventional cancer therapy with the objective of observing enhanced efficacy compared with single treatments. This review also highlights the importance of the nanoformulation of such bioactive phytochemicals that could enhance their bioavailability by providing an efficient targeted delivery system with a reduced systemic dose while resulting in a more efficient dosing at the target site.
Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; In Vitro Techniques; Isothiocyanates; Patient Selection; Phytochemicals; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Radiotherapy, Adjuvant; Sensitivity and Specificity; Sulfoxides
PubMed: 30811596
DOI: 10.1002/cncr.32022 -
Acta Pharmacologica Sinica Jun 2022Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2...
Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2 (Nrf2). But the molecular mechanisms underlying the beneficial effect of SFN in the treatment of NAFLD remain controversial. Fibroblast growth factor (FGF) 21 is a member of the FGF family expressed mainly in liver but also in adipose tissue, muscle and pancreas, which functions as an endocrine factor and has been considered as a promising therapeutic candidate for the treatment of NAFLD. In the present study we investigated whether FGF21 was involved in the therapeutic effect of SFN against NAFLD. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to generate NAFLD and continued on the HFD for additional 6 weeks with or without SFN treatment. We showed that administration of SFN (0.56 g/kg) significantly ameliorated hepatic steatosis and inflammation in NAFLD mice, along with the improved glucose tolerance and insulin sensitivity, through suppressing the expression of proteins responsible for hepatic lipogenesis, while enhancing proteins for hepatic lipolysis and fatty acids oxidation. SFN administration significantly increased hepatic expression of FGFR1 and fibroblast growth factor 21 (FGF21) in NAFLD mice, along with decreased phosphorylation of p38 MAPK (the downstream of FGF21). HepG2 cells were treated in vitro with FFAs (palmitic acid and oleic acid) followed by different concentrations of SFN. We showed that the effects of SFN on FGF21 and FGFR1 protein expression were replicated in FFAs-treated HepG2 cells. Moreover, the increased FGFR1 protein occurred earlier than increased FGF21 protein. Interestingly, the rapid effect of SFN on FGFR1 protein was not regulated by the FGFR1 gene transcription. Knockdown of FGFR1 and p38 genes weakened SFN-reduced lipid deposition in FFAs-treated HepG2 cells. SFN administration in combination with rmFGF21 (1.5 mg/kg, i.p., every other day) for 3 weeks further suppressed hepatic steatosis in NAFLD mice. In conclusion, SFN ameliorates lipid metabolism disorders in NAFLD mice by upregulating FGF21/FGFR1 pathway. Our results verify that SFN may become a promising intervention to treat or relieve NAFLD.
Topics: Animals; Diet, High-Fat; Fatty Acids, Nonesterified; Fibroblast Growth Factors; Isothiocyanates; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Sulfoxides
PubMed: 34654875
DOI: 10.1038/s41401-021-00786-2 -
Nutrients Jan 2023Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder with repetitive behaviour which affects interaction and communication. Sulforaphane (SFN), an... (Randomized Controlled Trial)
Randomized Controlled Trial
Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder with repetitive behaviour which affects interaction and communication. Sulforaphane (SFN), an isothiocyanate abundant in the seeds and sprouts of cruciferous vegetables, has been shown to be effective in alleviating autistic behaviour. We performed a prospective double-blind placebo-controlled study to examine the possible effect of SFN in a paediatric cohort aged three to seven years based on measurements of the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Responsiveness Scale-2 (SRS-2), and the Aberrant Behaviour Checklist (ABC). The study consisted of three visits over the duration of 36 weeks (baseline, 18 weeks, and 36 weeks). Twenty-eight of the 40 randomized children completed the study. The mean total raw scores on ABC and SRS-2 improved in both groups, but none of the changes reached statistical significance (ABC: 0 weeks = 0.2742, 18 weeks = 0.4352, and 36 weeks 0.576; SRS-2: 0 weeks = 0.5235, 18 weeks = 0.9176, and 36 weeks 0.7435). Changes in the assessment of the ADOS-2 subscale scores also did not differ between the two study cohorts (ADOS-2: 0 weeks = 0.8782, 18 weeks = 0.4788, and 36 weeks 0.9414). We found no significant clinical improvement in the behavioural outcome measures evaluated in children with ASD aged 3-7 years that were treated with sulforaphane.
Topics: Humans; Child; Autistic Disorder; Autism Spectrum Disorder; Double-Blind Method; Prospective Studies; Isothiocyanates
PubMed: 36771424
DOI: 10.3390/nu15030718