Chrysin (Often extracted from Passion Flower)

*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.

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Setting The Record Straight On Chrysin

A few weeks ago, a client sent me a recorded webinar from a Long Haul clinic that hosted some of their MD’s discussing treatment options they are exploring for Long Haul and ME CFS. One of the MD’s started talking about Chrysin, and he did get a couple of things right, and some of it was just plain wrong. This article is intended to provide some factual basis (via published research) on the mechanisms of action from Chrysin.

“Chrysin is a strong inhibitor of iNOS (NOS2), and IL-10. It also modulates the HIF1a / AhR axis. Mutations on IL-10 are the most statistically from a genetic database of 4,000 clinically diagnosed folks with ME CFS versus controls. One mutation, has a p value of .07 by itself. Incredible”

A little background on Chrysin[1]

• Chrysin belongs to the group of natural polyphenols. It can be found, among others, in honey, propolis and fruits and has a wide range of biological activities, including the prevention of oxidative stress, inflammation, neurodegeneration and carcinogenesis.

• Being a part of the human diet, chrysin is considered to be a promising compound to be used in the prevention of many diseases, including cancers, diabetes and neurodegenerative diseases such as Alzheimer’s or Parkinson’s. Nevertheless, due to the low solubility of chrysin in water and under physiological conditions, its bioavailability is low. For this reason, attempts at its functionalization have been undertaken, aiming to increase its absorption and thus augment its in vivo therapeutic efficacy.

• The aim of this review is to summarize the most recent research on chrysin, including its sources, metabolism, pro-health effects and the effects of its functionalization on biological activity and pharmacological efficacy, evaluated both in vitro and in vivo.

Product Content of Chrysin

Really the only way to get significant quantities is to extract it from the below compounds into a concentrated extract. This is typically how we see it appear in supplements, from 100-500mg.

1. Ref. Manuka honey 0.131 mg/100 g [20]

2. Propolis extract

   • Acetone: 14.62 mg g 1 70%

   • EtOH: 18.64 mg g 1 96%

   • EtOH: 11.41 mg g 1

3. Diaphragma juglandis fructus Up to 40 mcg/g 1

4. Hyphaene thebaica 0.083 mg/g 1

5. Chaetomium globosum 13%

6. Cytisus villosus 4 mg/kg

Some of the major mechanisms of action of Chrysin:

Chrysin promotes resolution of iNOS activation from infection, immune responses (histamine/mast cell) and such. The resolution of iNOS upregulation coincides with the resolution of hypoxic metabolism, and promotes more normalized endothelial function, away from using Xanthine Oxidase as an endothelial nitric oxide producer.

• Nitric Oxide:

  • iNOS (NOS2) inhibition

  • Supports NOS3 through SIRT1 and SIRT3

  • no known effects on NOS1

  • IL-10, IL-6, TNFA inhibitor [5]

    Modulation of HIF1a and AhR axis, promotes the resolution of hypoxic metabolism, the resolution of inhibition of the krebs cycle, and various other oxygen sensitive pathways such as : the heme pathway, nitric oxide synthase, krebs cycle, mitochondrial ETC, etc.

• Effect on HIf1a / AhR Axis [55-57]

  • Enhanced Hif1a degradation: Chrysin increases the ubiquination and degradation of Hif1a by promoting its prolyl hydroxylation (PHD) leading to reduced stability of the protein.

  • Interference with Chaperone Interaction: It disrupts the interaction between HIF1a, and HSP90 which is essential for HIF1a stability

  • Inhibition of Signaling Pathways: Chrysin inhibits the AKT signaling pathway, which is involved in the expression of HIF1a.

  • AhR activation - selective activation of AhR, through binding to Chrysin.

Chrysin exerts a number of inflammation related pathway from the classic TNFA/PLA2/ALOX5 yielding prostaglandin synthesis, to NADPH Oxidase, to Inflammasome production across NLRP3/NFKB/IL-1B/Casp1-3 yielding dysregulation of the all important ion channels and receptors (NMDA, TRP, VGCC, VGPC, VGSC, MUSC).

• Inflammatory Pathways

  • IL-10, IL-6, TNFA inhibitor [5]

    • Caution most be offered against long term use, due to its potent IL-10 inhibition properties.

  • NLRP3, Caspase-1 (CASP1), NFKB (RELA), Caspase-3 inhibitor

  • No direct effects on Gsdermin D (GSDMD) or Gasdermin B (GSDMB)

  • Chrysin inhibits leukotriene induced inflammation, reducing CysLT1 mediated esonophil infuiltration, indirect inhibition of CysLT1

  • Reduces CD36 expression in macrophages and hepatocytes, direct downregulation[9]

  • Inhibits PLA2, ALOX-5, COX-2 (strongly) and prostaglandin synthesis

  • Inhibits NADP Oxidase (NOX2, Nox4)

• Ion Channels , Receptors, and Neuro Over Activation

  • Indirect effects on TRPV1 (inhibition)

  • Attenuates Ca2+ influx, and lowers NMDA receptor over activation, but not a direct agonist to NMDA

  • Inhibits L-Type Calcium Channels, reducing Ca2+ overload in neuron and cardiomyocytes.[10]

  • Inhibits voltage gated potassium channels (like ketones), and can contribute to immuno suppressive activity.[11]

  • Inhibits P2X7 mediated NLP3 activation

  • No direct action against PANX1, CaSR, Chloride Channels

  • No direct effects on Muscarinic receptors

Chrysin offers support, albeit indirect protection, primarily to Complex 2 and Complex 5, due to support by its oxidative stress protection properties, a return to normoxia metabolism and away from the activation of the Itaconate Shunt pathway.

• Effects Mitochondrial Complex genes:

  • Complex i: Indirect support - NDUSF1, NDUFV1, NDUFA9

  • Complex 2: SDHA, SDHB (stabilizes function under oxidative stress)

  • Complex 3: No effect - UQCRC1, UQCRFS1

  • Complex 4: COX4I1, COX5A (indirect protection via lowering ox stress / inflammation)

  • Complex 5: ATP5A1, ATP5B (ATP levels preserved)

• Effects On Kreb Cycle Genes

  • CS - Citrate Synthase - No direct evidence

  • ACO2 (Aconitase 2) - indirect protection from oxidative damage

  • IDH2 (Isocitrate Dehydrogenase 2) - no direct effect

  • OGDH (Oxoglutarate Dehydrogenase) - no direct evidence

  • SDH - function preserved via protection from ox-stress

Chrysin offer modest upregulation of the classic NrF2 and associated anti oxidant gene and detoxification systems. It also stimulates Glut4, allowing more glucose uptake as the krebs cycle returns to more full functioning, and inhibits PDK-4 so that PDH can allow pyruvate to be unrestricted in how it is shuttled into the krebs cycle (CS).

• Anti Oxidant Genes

  • Stimulates NrF2 (GPX, GCLC, GSR, SOD2, CAT)

  • No direct stimulation of ADH5, TNRDX, PRDX

• Glucose / fatty Acid Metabolism

  • Inhibits PDK4

    • PDK4 inhibits PDH, thus allowing PDH4 to be more free

  • Inhibits ACAT2 - reducing cholesterol ester formation

  • GLUt4 stimulated

  • AMPK activated

• Effect On Detoxification Genes, via NrF2

  • Stimulates glucuronidation UGT1A1

  • Stimulates Sulfation SULT1E1

Perhaps one of the better known herbs to help those with estrogen challenges, due to various issues including poor detoxification genetics in SULT and UGT families.

• Inhibits estrogenic effects, inhibits aeromatic gene: cyp19a1

  • Inhibits aromatase CYP19A1, lowers conversion from testosterone to estradiol

  • Downregulates Estrogen Receptors (ESR1), but not ESR2

  • Inhibits CYP1B1 - hydroxylates estrogens

  • Modulate CYP1A1 - hydroxylate estrogens

  • Reduces metabolite 4-OH-E2, linked to breast cancer

Chrysin also provides some effect on the dopamine and serotonin systems, and has shown to offer benefits in depression and in some with ADHD.

• Neurotransmitter Effects - Anti Depressant / Anxiety [7,54]

  • Hypothyroidism is often associated with psychiatric disorders such as depression.

  • Noradrenaline content was not altered by Chrysin treatments.

  • Chrysin treatment reverses depressive-like behaviors in hypothyroid conditions and suggests the involvement of 5HT and dopamine in these effects.

  • Anxiolytic and antidepressant-like effects of chrysin occurs through its interaction with specific neurotransmitter systems, principally the GABAergic and the serotonergic, and activation of other neurotrophic factors. However, it is not possible to discard the antioxidant and anti-inflammatory activities of chrysin while producing its anxiolytic- and antidepressant-like effects.

This is a long list of mechanisms of action of Chrysin, and depending on the situation it may be something that could be considered, but its not for everybody. Additionally, its a potent IL-10 inhibitor, which is a key gene in managing immune response via the GI Tract. It should not be suppressed for lengthy terms.

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References:

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2. SPHK/HIF-1 Signaling Pathway Has a Critical Role in Chrysin-Induced Anticancer Activity in Hypoxia-Induced PC-3. Cells .  By Hengmin Han.  Cells 2022, 11, 2787. https://doi.org/10.3390/cells11182787 https://www.mdpi.com/journal/cells

3. Chrysin inhibits expression of hypoxia-inducible factor-1α through reducing hypoxia-inducible factor-1α stability and inhibiting its protein synthesis. By Beibei Fu, et. al. Research Articles: Therapeutics, Targets, and Development| January 19 2007.  Mol Cancer Ther (2007) 6 (1): 220–226.  https://doi.org/10.1158/1535-7163.MCT-06-0526

4. Flavonoids Targeting HIF-1: Implications on Cancer Metabolism, by Marek Samec, et. al. Cancers 2021, 13(1), 130; https://doi.org/10.3390/cancers13010130. Submission received: 2 December 2020 / Revised: 24 December 2020 / Accepted: 29 December 2020 / Published: 3 January 2021

5. Anti-inflammatory activity of extracts from fruits, herbs and spices

   Monika Mueller, et. al. Food Chemistry 122 (2010) 987–996. Contents lists available at ScienceDirect. Food Chemistry.  doi:10.1016/j.foodchem.2010.03.041

6. Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats.  By Taiyang Liao, et. al. Drug Des Devel Ther. . 2020 Jul 28;14:3015–3027. doi: 10.2147/DDDT.S261216.  PMCID: PMC7396814  PMID: 32801641

7. Endocrine pharmacology Chrysin reverses the depressive-like behavior induced by hypothyroidism in female mice by regulating hippocampal serotonin and dopamine Vandreza Cardoso Bortolotto, et. al. European Journal of Pharmacology 822 (2018) 78-84. https://doi.org/10.1016/j.ejphar.2018.01.017.   Contents lists available at ScienceDirect European Journal of Pharmacology.  

8. Review article Comprehensive review on the interaction between natural compounds and brain receptors: Benefits and toxicity Ana R. Silva, et. al. European Journal of Medicinal Chemistry 174 (2019) 87-115 .  https://doi.org/10.1016/j.ejmech.2019.04.028.  Contents lists available at ScienceDirect European Journal of Medicinal Chemistry.  

9. Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ-DEPENDENT MECHANISM. By 
   Miao YuJ, et. al.  Biol Chem. . 2016 Jun 29;291(33):16977–16989. doi: 10.1074/jbc.M116.740092.  PMCID: PMC5016103  PMID: 27358406

10. Exploring the chemical space around chrysin to develop novel vascular CaV1.2 channel blockers, promising vasorelaxant agents. By Federica Falbo, et. al. First published: 06 September 2024

    https://doi.org/10.1002/ardp.202400536

11. Voltage-Gated Potassium Channel Kv1.3 as a Target in Therapy of Cancer, By Andrzej Teisseyre.  REVIEW article.  Front. Oncol., 23 September 2019.  Sec. Cancer Molecular Targets and Therapeutics

    Volume 9 - 2019 | https://doi.org/10.3389/fonc.2019.00933

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26. Mohos V, Fliszar-Nyul E, Schilli G, et al. Interaction of chrysin and its main conjugated metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide with serum albumin. Int J Mol Sci. 2018;19:12. doi: 10.3390/ijms19124073

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29. Zheng W, Tao Z, Cai L, et al. Chrysin attenuates IL-1beta-Induced expression of inflammatory mediators by suppressing NF-kappaB in human osteoarthritis chondrocytes. Inflammation. 2017;40(4):1143–1154. doi: 10.1007/s10753-017-0558-9

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54. Pharmacological, Neurochemical, and Behavioral Mechanisms Underlying the Anxiolytic- and Antidepressant-like Effects of Flavonoid Chrysin, By Juan Francisco Rodríguez-Landa, et. al. Molecules

    . 2022 May 31;27(11):3551. doi: 10.3390/molecules27113551. PMCID: PMC9182416  PMID: 35684488

55. Chrysin inhibits expression of hypoxia-inducible factor-1alpha through reducing hypoxia-inducible factor-1alpha stability and inhibiting its protein synthesis, By Beibei Fu, et. al.  PMID: 17237281 
    DOI: 10.1158/1535-7163.MCT-06-0526. Mol Cancer Ther.  2007 Jan;6(1):220-6.  doi: 10.1158/1535-7163.MCT-06-0526.

56. Chrysin inhibits ferroptosis of cerebral ischemia/reperfusion injury via regulating HIF-1α/CP loop.  Jinfeng Shang Biomed Pharmacother.  2024 May:174:116500.  doi: 10.1016/j.biopha.2024.116500. Epub 2024 Mar 30.  

    PMID: 38555815.  DOI: 10.1016/j.biopha.2024.116500

57. Chrysin Activates the Aryl Hydrocarbon Receptor and Reduces Colon Cancer Cell Viability, By S.M. Ronnekleiv-Kelly, et. al. Journal of Surgical Research. Volume 172, Issue 2p305 February 2012.