The Benefits of Sulforaphane /Glucoraphanin Myrosinase and on Immune Regulation

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• At the end of 2019,  the world has been shocked by the Infectious disease epidemic situation. Experts remind the public to improve their immunity and minimize the possibility of illness. The human immune system is composed of immune organs, immune cells and immune active substances. They all play an important role in human immunity. Immune cells mainly include phagocytes, natural killer (NK) cells, NKT cells, lymphocytes (B cells, T cells), etc. Immune active substances mainly include antibodies, immunoglobulins, cytokines such as interferons, and interleukins.
  Sulforaphane (SFN) is a product of glucoraphanin hydrolyzed by myrosinase. SFN exerts its effect on immune system through different biochemical and cellular mechanisms. SFN improves immune system, thus helping in prevention and reducing severity of viral pulmonary diseases. Cuadrado et al. suggested that due to its ability to activate Nrf2, induce antioxidant enzymes, reduce pro-inflammatory cytokines, and its efficacy and safety, SFN is a promising candidate to counteract inflammatory reaction and protect lungs from severe damage during SARS-COV 2 infection[1]. And Horowitz and Freeman suggested that clinical trials including administration of Nrf2-activating molecules, such as SFN, are imperative to support a possible three-party strategy to fight the COVID-19 pandemic, which includes prevention, diagnostic, and treatment[2].

  1.Academic Research

  Data indicate that phaseⅡantioxidant enzyme pathways could play a role in virus-associated inflammation and immune clearance. SFN has shown to enhance immunological response against influenza. 2011, researchers utilized differentiated human nasal epithelial cells (NEC) and an enzymatic virus-like particle entry assay, to examine the role Nrf2-dependent gene expression has on viral entry and replication. Supplementation with the potent Nrt2 activators SFN significantly decreased viral entry and replication[3]. 
  2016, Furuya et al. investigated the effect of SFN on human macrophages and T-cells after infection with HIV. In immune cells isolated from donor blood, SFN halts HIV infection in primary macrophages with the activation of Nrf2[4].
  2018, Liang et al. studied the effect of SFN on the redox regulation in human T-cells, in order to uncover the mechanism that underlays the immunosuppressive effect of SFN in chronic Th17-related diseases. They reported that SFN exerts a redox-related immunosuppressive effect on untransformed human T-cells, downregulation of the pro-inflammatory Th17 cytokines associated with autoimmune/inflammatory diseases, and inhibition of cartilage-disruptive proteins. These processes produce a significant reduction in the clinical symptoms[5]. 
  2019, Yoo et al. administered SFN (orally, 50 mg/kg/day over 14 days) to an autoimmune encephalomyelitis model (mouse). The clinical symptoms of SFN-treated animals were diminished significantly in comparison with those observed in control animals. This was attributed to the anti-inflammatory and anti-oxidative effects of SFN, resulting in neuroprotection[6].

  2.Animal models

  Progressive tumor growth in human and animal models is accompanied by down-regulation of cytotoxic cells, such as T lymphocytes and NK cells, which are an integral part of the cell-mediated immune system. In 2006, P. Thejass, et al. studied the effect of SFN on cell-mediated immune (CMI) response in normal as well as Ehrlich ascites tumor-bearing BALB/c mice. Administration of SFN significantly enhanced natural killer (NK) cell activity in both normal as well as tumor-bearing animals. The results showed that administration of SFN significantly enhanced the production of Interleukin-2 and Interferon-γ in normal as well as tumor-bearing animals[7].
  The decline in cellular immunity with ageing is of considerable public health importance. Studies suggest that the redox equilibrium of dendritic cells (DC) is a key actor in maintaining protective cellular immunity and that a disturbance of this homeostatid mechanism could contribute to immune senescence. In 2008, Kim et al. assessed the effect of boosting of glutathione levels by SFN on the contact Hypersensitivity (CHS) response to contact antigens in old mice. Treatment of DC from old animals with SFN ex vivo restored the in vivo challenge response. It indicated that SFN up-regulate Th1 immunity in ageing through a restoration of redox equilibrium[8].
  2009, Singh et al. studied the effect of administering a SFN analogue on prostate carcinogenesis and pulmonary metastasis in an animal model. The results showed that SFN stimulates NK cells cytotoxicity, thus enhancing immunological function and inhibits prostate cancer progression. Also, SFN increased the infiltration of lymphocyte T-cells in prostate tumors resulting in a reduction of metastasis[9].
  Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD. In 2011, Harvey et al. test whether SFN restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa ( PA) by alveolar macrophages from patients with COPD. The results show that SFN treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients[10]. 
  2017, Deng et al. demonstrated that SFN delivered as broccoli nanoparticles to mice is involved in prevention of colitis, an autoimmune disease that can lead to ulcers. The mechanism consists in the induction of tolerogenic dendritic cells by adenosine monophosphate activated protein kinase (AMPK), thus regulating the intestinal immune homeostasis[11].

  3.Clinical trials

  2014, a randomized, double-blind, placebo-controlled trial compared broccoli sprout homogenate (BSH) to continuous sampling of nasal lavage fluid (NLF) cytokines, the number of virus sequences, and the expression of Nrf2-dependent enzymes in NLF cells. Researchers found that  short-term ingestion of BSH reduces markers of viral replication in nasal lavage fluid cells after inoculation with the LAIV vaccine in smokers[12].
  2016，in order to investigate the systemic effects of short-term SFN-containing broccoli sprout homogenates (BSH) supplementation in the context of  live attenuated influenza virus (LAIV) inoculation. Loretta, M., et al. examined peripheral blood immune cell populations in non-smoking subjects, with a particular focus on natural killer (NK) cells. NK cells are crucial for innate immune responses against viruses such as influenza, via cytokine release and cytotoxicity towards infected target cells. BSH supplementation further increased LAIV-induced granzyme B production in NK cells and granzyme B production is important for NK cells’ ability to kill target cells. They conclude that nasal influenza infection may induce complex changes in peripheral blood NK cell activation, and that BSH increases virus-induced peripheral blood NK cell granzyme B production, an effect that may be important for enhanced antiviral defense responses[13].
  The clinical trial (NCT02885025) that ended in 2020 studied the effect of administering SFN (as BS extract) to subjects (n = 47) suffering allergic rhinitis to grass. The randomized trial considered a three-week treatment aiming at evaluating the effect of BS extract intake in comparison with administration of corticosteroid (fluticasone) and the combination of both. The results showed that SFN alone or in combination with fluticasone reduced pro-inflammatory cytokines expression[14].

  References

  [1]Cuadrado A , Pajares M , Benito C , et al. Can activation of NRF2 be a strategy against COVID-19?[J]. Trends in Pharmacological Sciences, 2020, 41(9).
  [2]Horowitz R I , Freeman P R . Three Novel Prevention, Diagnostic and Treatment Options for COVID-19 Urgently Necessitating Controlled Randomized Trials[J]. Medical Hypotheses, 2020, 143:109851.
  [3]Kesic M J , Simmons S O , Bauer R , et al. Nrf2 expression modifies influenza A entry and replication in nasal epithelial cells[J]. Free Radical Biology & Medicine, 2011, 51(2):444-453.
  [4]Marias F , Sharifi H J , Jellinger R M , et al. Sulforaphane Inhibits HIV Infection of Macrophages through Nrf2[J]. Plos Pathogens, 2016, 12(4):e1005581.
  [5]Liang J, Jahraus B, Balta E, Ziegler JD, Hübner K, Blank N, Niesler B, Wabnitz GH and Samstag Y (2018) Sulforaphane Inhibits Inflammatory Responses of Primary Human T-Cells by Increasing ROS and Depleting Glutathione. Front. Immunol. 9:2584. doi: 10.3389/fimmu.2018.02584
  [6]Yoo I H , Kim M J , Kim J , et al. The Anti-Inflammatory Effect of Sulforaphane in Mice with Experimental Autoimmune Encephalomyelitis[J]. Journal of Korean Medical Science, 2019, 34(28).
  [7]Thejass P , Kuttan G . Augmentation of natural killer cell and antibody-dependent cellular cytotoxicity in BALB/c mice by sulforaphane, a naturally occurring isothiocyanate from broccoli through enhanced production of cytokines IL-2 and IFN-gamma.[J]. Immunopharmacology & Immunotoxicology, 2008, 28(3):443.
  [8]Kim H J , Barajas B , Wang M , et al. Nrf2 activation by sulforaphane restores the age-related decline of T(H)1 immunity: role of dendritic cells.[J]. J Allergy Clin Immunol, 2008, 121(5):1255-1261.e7.
  [9]Singh S V , Warin R , D Xiao, et al. Sulforaphane Inhibits Prostate Carcinogenesis and Pulmonary Metastasis in TRAMP Mice in Association with Increased Cytotoxicity of Natural Killer Cells[J]. Cancer Research, 2009, 69(5):2117-2125.
  [10]Harvey C J , Thimmulappa R K , Sethi S , et al. Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model[J]. Science Translational Medicine, 2011, 3(78):78ra32.
  [11]Deng Z , Rong Y , Teng Y , et al. Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase[J]. Molecular Therapy, 2017:1641.
  [12]Noah TL, Zhang H, Zhou H, Glista-Baker E, Mu¨ller L, et al. (2014) Effect of Broccoli Sprouts on Nasal Response to Live Attenuated Influenza Virus in Smokers: A Randomized, Double-Blind Study. PLoS ONE 9(6): e98671. doi:10.1371/journal.pone.0098671
  [13]Loretta M , Megan M , Bauer R N , et al. Effect of Broccoli Sprouts and Live Attenuated Influenza Virus on Peripheral Blood Natural Killer Cells: A Randomized, Double-Blind Study[J]. Plos One, 2016, 11(1):e0147742.
  [12] Mahn, A.; Castillo, A. Potential of Sulforaphane as a Natural Immune System Enhancer: A Review. Molecules 2021, 26, 752. https://doi.org/10.3390/molecules26030752