Glucosinolates and their hydrolysis products as potential nutraceuticals to combat cytokine storm in SARS-COV-2.

INTRODUCTION: The high mortality rate in severe cases of COVID-19 is mainly due to the strong upregulation of cytokines, called a cytokine storm. Hyperinflammation and multiple organ failure comprise the main clinical features of a cytokine storm. Nrf2 is a transcription factor which regulates the expression of genes involved in immune and inflammatory processes. Furthermore, Nrf2, as a master regulator, controls the activity of NF-κB which binds to the promoter of many pro-inflammatory genes inducible of various inflammatory factors. Inhibition of Nrf2 response was recently demonstrated in biopsies from patients with COVID-19, and Nrf2 agonists inhibited SARS-CoV-2 replication across cell lines in vitro. Glucosinolates and their hydrolysis products have excellent anti-inflammatory and antioxidant effects via the Nrf2 activation pathway, reduction in the NF-κB activation, and subsequent reduced cytokines levels. CONCLUSION: Accordingly, these compounds can be helpful in combating the cytokine storm associated with COVID-19.

Health Benefits of Plant-Derived Sulfur Compounds, Glucosinolates, and Organosulfur Compounds.

The broad spectrum of the mechanism of action of immune-boosting natural compounds as well as the complex nature of the food matrices make researching the health benefits of various food products a complicated task. Moreover, many routes are involved in the action of most natural compounds that lead to the inhibition of chronic inflammation, which results in a decrease in the ability to remove a pathogen asymptomatically and is connected to various pathological events, such as cancer. A number of cancers have been associated with inflammatory processes. The current review strives to answer the question of whether plant-derived sulfur compounds could be beneficial in cancer prevention and therapy. This review focuses on the two main sources of natural sulfur compounds: alliaceous and cruciferous vegetables. Through the presentation of scientific data which deal with the study of the chosen compounds in cancer (cell lines, animal models, and human studies), the discussion of food processing's influence on immune-boosting food content is presented. Additionally, it is demonstrated that there is still a need to precisely demonstrate the bioavailability of sulfur-containing compounds from various types of functional food, since the inappropriate preparation of vegetables can significantly reduce the content of beneficial sulfur compounds. Additionally, there is an urgent need to carry out more epidemiological studies to reveal the benefits of several natural compounds in cancer prevention and therapy.

Broccoli sprout supplementation in patients with advanced pancreatic cancer is difficult despite positive effects-results from the POUDER pilot study.

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with short survival and limited therapeutic options. Broccoli sulforaphane is a promising new treatment due to the results of recent epidemiological, experimental and patient studies. Upon approval from the ethics committee and registration at ClinicalTrials.gov, 40 patients with palliative chemotherapy were placed into a placebo and treatment group in an unblinded fashion. Fifteen capsules with pulverized broccoli sprouts containing 90 mg/508 µmol sulforaphane and 180 mg/411 µmol glucoraphanin or methylcellulose were administered daily for up to 1 year. Twenty-nine patients were included in the treatment group and 11 patients were in the placebo group; these patients were followed for up to 1 year. The patient characteristics, overall survival and feasibility were assessed. Compared to those of the placebo group, the mean death rate was lower in the treatment group during the first 6 months after intake (day 30: 0%/18%, day 90: 0%/25%, and day 180: 25%/43%), and Kaplan-Meier analysis revealed a higher survival rate. There was a high drop-out rate (72% in the treatment group and 55% in the placebo group) after 1 year. We concluded from the Karnofsky index that the broccoli sprouts did not impact patient's self-care and overall abilities severely. The intake of 15 capsules daily was difficult for some patients, and the broccoli sprouts sometimes increased digestive problems, nausea and emesis. We did not obtain statistically significant results (p = 0.291 for the endpoint at day 180), but the knowledge about the feasibility is the basis for the development of new sulforaphane drugs.

Dietary intake of glucoraphanin prevents the reduction of dopamine transporter in the mouse striatum after repeated administration of MPTP.

AIMS: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although diet may influence the development of PD, the precise mechanisms underlying relationship between diet and PD pathology are unknown. Here, we examined whether dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane in cruciferous vegetables, can affect the reduction of dopamine transporter (DAT) in the mouse striatum after repeated administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). METHODS: Normal food pellet or 0.1% GF food pellet was given into male mice for 28 days from 8-week-old. Subsequently, saline (5 mL/kg × 3, 2-hour interval) or MPTP (10 mg/kg × 3, 2-hour interval) was injected into mice. Immunohistochemistry of DAT in the striatum was performed 7 days after MPTP injection. RESULTS: Repeated injections of MPTP significantly decreased the density of DAT-immunoreactivity in the mouse striatum. In contrast, dietary intake of 0.1% GF food pellet significantly protected against MPTP-induced reduction of DAT-immunoreactivity in the striatum. CONCLUSION: This study suggests that dietary intake of GF food pellet could prevent MPTP-induced dopaminergic neurotoxicity in the striatum of adult mice. Therefore, dietary intake of GF-rich cruciferous vegetables may have beneficial effects on prevention for development of PD.

An Update on Potential Perspectives of Glucosinolates on Protection against Microbial Pathogens and Endocrine Dysfunctions in Humans.

Glucosinolates are the major bioactive secondary metabolites found in the Brassicaceae family and studied extensively in biosynthetic and application perspectives. Because of their potential applications in the welfare of plants (protection against plant pathogens) and human life (prevention of cancer and other diseases), these compounds attracted much interest in the scientific community. In this review, we presented updates on glucosinolate derivatives in protection against microbial pathogens and endocrine related diseases in human. Further, the mechanism of action of glucosinolate derivatives and the strategies to improve their efficiency through modern approaches were discussed. Finally, the genetic enrichment of their contents in plant systems has also been discussed.

Enhancement of broccoli indole glucosinolates by methyl jasmonate treatment and effects on prostate carcinogenesis.

Broccoli is rich in bioactive components, such as sulforaphane and indole-3-carbinol, which may impact cancer risk. The glucosinolate profile of broccoli can be manipulated through treatment with the plant stress hormone methyl jasmonate (MeJA). Our objective was to produce broccoli with enhanced levels of indole glucosinolates and determine its impact on prostate carcinogenesis. Brassica oleracea var. Green Magic was treated with a 250 µM MeJA solution 4 days prior to harvest. MeJA-treated broccoli had significantly increased levels of glucobrassicin, neoglucobrassicin, and gluconasturtiin (P < .05). Male transgenic adenocarcinoma of mouse prostate (TRAMP) mice (n = 99) were randomized into three diet groups at 5-7 weeks of age: AIN-93G control, 10% standard broccoli powder, or 10% MeJA broccoli powder. Diets were fed throughout the study until termination at 20 weeks of age. Hepatic CYP1A was induced with MeJA broccoli powder feeding, indicating biological activity of the indole glucosinolates. Following ∼ 15 weeks on diets, neither of the broccoli treatments significantly altered genitourinary tract weight, pathologic score, or metastasis incidence, indicating that broccoli powder at 10% of the diet was ineffective at reducing prostate carcinogenesis in the TRAMP model. Whereas broccoli powder feeding had no effect in this model of prostate cancer, our work demonstrates the feasibility of employing plant stress hormones exogenously to stimulate changes in phytochemical profiles, an approach that may be useful for optimizing bioactive component patterns in foods for chronic-disease-prevention studies.

Antiinflammatory activity of glucomoringin isothiocyanate in a mouse model of experimental autoimmune encephalomyelitis.

Glucomoringin (4(α-L-rhamnosyloxy)-benzyl glucosinolate) (GMG) is an uncommon member of glucosinolate group belonging to the Moringaceae family, of which Moringa oleifera Lam. is the most widely distributed. Bioactivation of GMG with the enzyme myrosinase forms the corresponding isothiocyanate (4(α-L-rhamnosyloxy)-benzyl isothiocyanate) (GMG-ITC), which can play a key role in antitumoral activity and counteract the inflammatory response. The aim of this study was to assess the effect of GMG-ITC treatment in an experimental mouse model of multiple sclerosis (MS), an inflammatory demyelinating disease with neurodegeneration characterized by demyelinating plaques, neuronal, and axonal loss. For this reason, C57Bl/6 male mice were injected with myelin oligodendrocyte glycoprotein35-55 which is able to evoke an autoimmune response against myelin fibers miming human multiple sclerosis physiopatogenesis. Results clearly showed that the treatment was able to counteract the inflammatory cascade that underlies the processes leading to severe MS. In particular, GMG-ITC was effective against proinflammatory cytokine TNF-α. Oxidative species generation including the influence of iNOS, nitrotyrosine tissue expression and cell apoptotic death pathway was also evaluated resulting in a lower Bax/Bcl-2 unbalance. Taken together, this work adds new interesting properties and applicability of GMG-ITC and this compound can be suggested as a useful drug for the treatment or prevention of MS, at least in association with current conventional therapy.

Protective role of (RS )-glucoraphanin bioactivated with myrosinase in an experimental model of multiple sclerosis.

AIM: The discovery of new natural compounds with pharmacological properties is a field of interest widely growing. Recent literature shows that Brassica vegetables (Cruciferae) possess therapeutic effects particularly ascribed due to their content in glucosinolates, which upon myrosinase hydrolysis release the corresponding isothiocyanates. This study examines the potential neuroprotective and immunomodulatory effects of (RS )-glucoraphanin from Tuscan black kale (Brassica oleracea L. var. acephala sabellica) bioactivated with myrosinase (bioactive RS -GRA) (10 mg/kg/day intraperitoneally), in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55 ) in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Clinical score was evaluated using a standardized scoring system. RESULTS: By Western blot analysis of spinal cord tissues, we have demonstrated that treatment with bioactive RS -GRA significantly decreased nuclear factor (NF)-kB translocation, pro-inflammatory cytokine production such as interleukin-1ß (IL-1ß), and apoptosis (Bax and caspase 3 expression). CONCLUSION: Our results clearly demonstrate that bioactive RS -GRA treatment may represent a useful therapeutic perspective in the treatment of this disease.

Sulforaphane and related mustard oils in focus of cancer prevention and therapy.

The plant family Brassicaceae, formerly Cruciferae, contains mustard oil glycosides, from which mustard oils are enzymatically hydrolyzed. Mustard oils offer protection from pests, microorganisms and fungi. More than 120 different mustard oils with various biological functions are known. Since ancient times, these substances are used as natural antibiotics, antiviral drugs and antimycotics. The antioxidative effect of mustard oils contributes to protection from DNA damage. Epidemiological and experimental studies have shown preventive and therapeutic effects of crucifers or isolated substances thereof. Particularly well studied is the mustard oil sulforaphane, which is contained in high concentrations in broccoli and its sprouts. As has been shown in mice recently, sulforaphane also targets the most malignant cancer stem cells, which are not affected by conventional cancer treatments. Based on these promising results, the first prospective clinical studies with cancer patients and sulforaphane-enriched broccoli sprouts have now been initiated in the United States.

Suppressive effect of Yamato-mana (Brassica rapa L. Oleifera Group) constituent 3-butenyl glucosinolate (gluconapin) on postprandial hypertriglyceridemia in mice.

We examined the bioactivity of Yamato-mana (Brassica rapa L. Oleifera Group) constituent glucosinolates and found that 3-butenyl glucosinolate (gluconapin) decreased the plasma triglyceride gain induced by corn oil administration to mice. However, phenethyl glucosinolate (gluconasturtiin) had little effect. 2-Propenyl glucosinolate (sinigrin) also reduced the plasma triglyceride level, which suggests that alkenyl glucosinolates might be promising agents to prevent postprandial hypertriglyceridemia.

Production of the cancer-preventive glucoraphanin in tobacco.

Epidemiological studies have demonstrated reduced risk of developing cancer upon consumption of diets rich in cruciferous vegetables. This chemoprevention has been largely attributed to the presence of the natural products glucosinolates, particularly the methionine-derived glucoraphanin from broccoli. Improved nutrition by functional foods or health-promoting dietary supplements is an attractive means for prevention of lifestyle-based diseases. Towards this goal, we have engineered the glucoraphanin pathway into tobacco. First, we engineered elongation of the side chain of methionine to produce the key intermediate dihomo-methionine. This process is catalyzed through two cycles in a chain-elongation pathway that takes place partly in the cytosol and partly in the chloroplast. Second, by coupling the five enzymes of the chain-elongation pathway to eight enzymes of the glucosinolate pathway, we show production of glucoraphanin together with other glucosinolates derived from chain-elongated isoleucine and/or leucine. The conversion of methionine to glucoraphanin is obtained via 14 intermediates. Demonstrating the production of the high-value glucoraphanin in a heterologous host has great potential in the food and medicinal industry as a means to generate a stable, rich source of glucoraphanin for the benefit of human health.

Maca (Lepidium peruvianum Chacón): composición química y propiedades farmacológicas / Maca (Lepidium peruvianum Chacón): chemical constituents and pharmacological effects

La maca (Lepidium peruvianum Chacón) es una planta herbácea anual originaria de los Andes Centrales del Perú. Fue un producto valioso para los Incas no sólo por su alto valor nutricional sino por su uso medicinal, especialmente como revitalizante, afrodisiaco y potenciador de la fertilidad. Entre los constituyentes químicos de la maca que se han relacionado con su actividad, destacan: ácidos grasos (macaeno) y sus correspondientes amidas (macamidas), glucosinolatos, alcaloides (lepidilinas A y B, macaridina), esteroles, ácido (1R, 3S)-1-metil-tetrahidro--carbolin-3-carboxílico y polifenoles. Entre las actividades confirmadas en animales o en humanos, cabe mencionar el aumento de la fertilidad y la mejora de la actividad sexual. Además, actualmente se le han atribuido otras actividades como citostática y antitumoral, antioxidante e antihipoglucemiante. En este artículo se hace una recopilación de los principales estudios que se han desarrollado sobre la raíz de maca para comprobar sus acciones farmacológicas y conocer los compuestos responsables de las mismas (AU)

Maca (Lepidium peruvianum Chacón) is an annual herbnative to the Peru vian Central Andes.It was a staple product for Incas due to its high nutritionalvalue and medicinal uses, mainly as an aphrodisiacand to enhance sexual drive and fertility, and to increase vitality. Among the chemical constituens of maca root that have been related with the biological activity, there are fatty acids (macaene) and their corresponding amides (macamides), glucosinolates,alkaloids(lepidilines A and B, macaridine), sterols, (1R, 3S)-1-methyltetrahydro-*-carboline-3-carboxylic acid and polyphenols.The enhancement of fertility and the improvement of the sexual performace have been confirmed as activities of maca in animal models or in humans. Additionaly, today, antioxidant, citostatic, antitumoral and antihipoglicemiant properties havealso been suggested for macaroot. Thispaper reviews the main studies on maca, aimed to prove their pharmacological effects and the compoundsresponsible of them (AU)

A review of mechanisms underlying anticarcinogenicity by brassica vegetables.

The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in this paper. Brassicas, including all types of cabbages, broccoli, cauliflower and Brussels sprouts, may be protective against cancer due to their relatively high glucosinolate content. Glucosinolates are usually broken down through hydrolysis catalyzed by myrosinase, an enzyme that is released from damaged plant cells. Some of the hydrolysis products, viz. indoles and isothiocyanates, are able to influence phase 1 and phase 2 biotransformation enzyme activities, thereby possibly influencing several processes related to chemical carcinogenesis, e.g. the metabolism, DNA-binding and mutagenic activity of promutagens. A reducing effect on tumor formation has been shown in rats and mice. The anticarcinogenic action of isothiocyanates and indoles depends upon many factors, such as the test system, the target tissue, the type of carcinogen challenge and the anticarcinogenic compound, their dosage, as well as the timing of the treatment. Most evidence concerning anticarcinogenic effects of glucosinolate hydrolysis products and brassica vegetables has come from studies in animals. Animal studies are invaluable in identifying and testing potential anticarcinogens. In addition, studies carried out in humans using high but still realistic human consumption levels of indoles and brassica vegetables have shown putative positive effects on health.

Inhibition of carcinogenesis by some minor dietary constituents.

Previous work has shown that food contains a large number of minor dietary constituents that can inhibit the occurrence of cancer. Additional inhibitors from four different natural sources will be the subject of this presentation. 1. Citrus fruit oils. Orange, tangerine, lemon, and grapefruit oils given p.o. induce increased glutathione (GSH) S-transferase activity in tissues of the mouse. When fed in the diet prior to and during the course of administration of benzo(a)pyrene (BP), the four citrus fruit oils inhibit formation of tumors of both the forestomach and lungs of mice. When fed either before or after the administration of 7,12-dimethylbenz(a)anthracene (DMBA) orange oil inhibits mammary tumor formation. 2. Garlic oil. Allyl methyl trisulfide (AMT), a constituent of garlic oil, has been synthesized recently. When given p.o. 96 and 48 hr prior to BP, AMT inhibits the occurrence of forestomach tumors in mice. 3. Green coffee beans. Two diterpene esters, kahweol palmitate and cafestol palmitate, which are potent inducers of GSH S-transferase activity have been isolated from coffee beans. When administered p.o. prior to DMBA the two diterpene esters inhibit mammary tumor formation. 4. Cruciferous vegetables. Several glucosinolates occur in cruciferous vegetables. Efficient procedures for the isolation of these compounds have been developed recently. The inhibitory effects of three of these i.e. glucobrassicin, glucotropaeolin, and glucosinalbin were studied in several animal models. Glucobrassicin caused substantial inhibition of BP-induced neoplasia of the lung and forestomach of the mouse and DMBA-induced neoplasia of the breast in rats. Glucosinalbin and glucotropaeolin are less active in these systems. In addition to protective effects, indoles derived from the hydrolysis of glucobrassicin have potential harmful properties. The implications of multiple properties and factors which may determine their consequence will be discussed.