The Wonders of Proanthocyanidins: Marine Pine Bark, Pycnogenol, Grape Seed Extact, and Red Rice Germ

*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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Proanthocyanidins (Marine Pine Bark; Pycnogenol)

This is one of my favorite herbs, but like anything, only in certain circumstances and within the right context. Pycnogenol is a great free radical scavenger, stimulates genes in the NAD pathway, enhances NOS3 expression, and is a COX-2 inhibitor to boot, to name just a few of its mechanism’s of action.

Pycnogenol has broad range of mechanistic actions promoting circulation (nitric oxide), reducing inflammation, and modulating neurological over stimulation.

Major Mechanisms Of Action of Pycnogenol

• Stimulates two genes in the NAD+ pathway, specifically, QPRT (which will lower elevations in quinolinic acid) and NADSYN, which is later in the pathway allowing for more conversion to NAD+.[1] This pathway is sensitive to oxidative stress, in particular, from Nitrosylation.

• Stimulates anti oxidant pathways: Nrf2, NQO1, HMOX1, SOD1, CAT, GPX1

• Stimulates SIRT1 to PGC1a and NOS3 (endothelial nitric oxide synthase). Activates SIRT3.

• Inhibits Inflammasome Production: NLRP3, NFKB, IL-1B, IL-6 (inflammation), CASP-1, IL-18, CASP-3, GSDMD[5]

• Inhibits Neural Inflammation: TGFB1 (inflammation)

• Inhibits Adhesion Molecules in Vascular: VCAM1, ICAM1 (adhesion factors)

• Inhibits Inflammatory pathways: MMP9, MMP2

• Stimulates AMPK - metabolic effects on lipids, glucose[6]

• Inhibits Inflammatory pathways leading to prostaglandin production: TNFA, PLA2, ALOX5, COX-1, COX-2, and prostaglandin synthesis[5]

• Supports Nitric Oxide Production: inhibits iNOS(NOS2), stimulates NOS3 (eNOS), and modestly increases NOS1 (nNOS)

• Strong free radical scavenging capability for: Super Oxide, Hydroxyl Radicals, Peroxyl Radicals, Peroxynitrite, Hypochlorous Acid (from MPO), and Lipid Radicals. Modest scavenging capacity for:Hydrogen Peroxide, Nitric Oxide, Singlet Oxygen radicals

• Stimulates anti oxidant genes: PPAR Gamma, and Pon1

• Inhibits NAPDH Oxidase (NOX1, NOX2, NOX4)

• Lowers TRP Receptor Activity (TRPV1, TRPM1, TRPC6)

• Reduces Ca2+ influx via VGCC’s

• Stabilizes Na+ Sodium Ion Channels

• Inhibits CYP450 Phase Detox Pathways

  • CYP1A1, CYP1B1, CYP2E1

  • Modest inhibition of CYP3A4

• Stimulates Some Phase 2 Detoxification Pathways:

  • GST’s increased (Glutathione Conjugation)

  • UGT’s increased (Glucuronidation)

  • Minor increase in SULT’s (sulfation)

  • NQO1 strongly increased (Ubiquination)

  • GCLC, GCLM, GSR are increased (Glutathione pools and recycling)

  • SOD2, GPX4, PRDX3 (mitochondrial redox/anti oxidant genes)

• Modulate gut microbiome, by increasing Lactobacillus and Bifidobacteria[4]

• Supports expression and function of mitochondrial enzymes like:

  • Complex II: SDHA, SDHB

  • Complex IV: COX4I1

  • Complex V: DUFS1, NDUFV1, ATP5A1, ATP5b, ATP Synthase

  • Krebs Cycle: ACO2, IDH2, OGDH, MDH2

Pycnogenol is generally well tolerated, and it has received numerous sponsored research articles, citing the above benefits. It can lower blood pressure slightly, and it can also mildly stimulate the immune system while also lowering platelet clotting. Consider these factors. Life Extension and other brands offer the standardized patent extract (Pycnogenol - 100mg/cap), Life Extension also offers Arterial Protect that adds Gotu Kola to Pycnogenol. Among Gotu Kola’s effects, is stimulating NOS3, and inhibting PLA2. Other lower cost brands like Zazzee offer “French MariTime Pine Bark Extract”, and their Extra Strength (20:1 extract) version has 350mg , standardized to 95% proanthocyanidins. Compounding companies, and distributors like Bulk Supplements offer Pine Bark. All are good sources of proanthocyanidins.

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References:

1. Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats, By Gerard Aragonès.  Scientific Reports volume 6, Article number: 24977 (2016)nature. scientific reports.  Published: 22 April 2016

2. Grape-seed proanthocyanidins inhibit the lipopolysaccharide-induced inflammatory mediator expression in RAW264.7 macrophages by suppressing MAPK and NF-κb signal pathways.  By Hongqian Chu, et. al. Environ Toxicol Pharmacol.  . 2016 Jan:41:159-66.  doi: 10.1016/j.etap.2015.11.018. Epub 2015 Dec 7.  PMID: 26708200.  DOI: 10.1016/j.etap.2015.11.018

3. Protective Effects of Proanthocyanidin-Rich Fraction from Red Rice Germ and Bran on Lung Cell Inflammation via Inhibition of NF-κB/NLRP3 Inflammasome Pathway

   by Warathit Semmarath, et. al. .  Nutrients 2023, 15(17), 3793; https://doi.org/10.3390/nu15173793. Submission received: 27 July 2023 / Revised: 24 August 2023 / Accepted: 28 August 2023 / Published: 30 August 2023

4. Dietary proanthocyanidins promote localized antioxidant responses in porcine pulmonary and gastrointestinal tissues during Ascaris suum-induced type 2 inflammation

   Audrey Inge Schytz Andersen-Civil, et. al. First published: 25 March 2022. https://doi.org/10.1096/fj.202101603RR

5. Neuroinflammation: A Critical Factor in Neurodegenerative Disorders.  By Zahieh Suleiman Khoury, et. al. Cureus. . 2024 Jun 13;16(6):e62310. doi: 10.7759/cureus.62310.  PMCID: PMC11246070  PMID: 39006715

6. Proanthocyanidins of Natural Origin: Molecular Mechanisms and Implications for Lipid Disorder and Aging-Associated Diseases.  By panelYu Nie , Stephen R Stürzenbaum Advances in Nutrition.  Volume 10, Issue 3, May 2019, Pages 464-478.  https://doi.org/10.1093/advances/nmy118

7. Analyses on Flavonoids and Transcriptome Reveals Key MYB Gene for Proanthocyanidins Regulation in Onobrychis ViciifoliA.  By Zhongzhiyue Jin, et. al. ORIGINAL RESEARCH article. Frontiers. Plant Sci., 23 June 2022. Sec. Plant Systems and Synthetic Biology. Volume 13 - 2022 | https://doi.org/10.3389/fpls.2022.941918

8. Mitigation Effect of Proanthocyanidin on Secondary Heart Injury in Rats Caused by Mechanical Trauma.  By, Shuo Ma,, et. al. nature.  scientific reports. 

   Published: 15 March 2017. Scientific Reports volume 7, Article number: 44623 (2017)

9. Catechins and Proanthocyanidins Involvement in Metabolic Syndrome. by, Giuseppe Tancredi Patanè, et. al. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy. Int. J. Mol. Sci. 2023, 24(11), 9228; https://doi.org/10.3390/ijms24119228. Submission received: 22 April 2023 / Revised: 19 May 2023 / Accepted: 22 May 2023 / Published: 25 May 2023

10. PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease, et. al. Elahe Taherzadeh-FardMol Neurodegener

    . 2011 May 19;6(1):32.  doi: 10.1186/1750-1326-6-32.  PMID: 21595933,  PMCID: PMC3117738,  DOI: 10.1186/1750-1326-6-32

11. Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy, By Samira Ait-El-Mkadem et. al. PMID: 27989324. 

    PMCID: PMC5223029.  DOI: 10.1016/j.ajhg.2016.11.014Am J Hum Genet.   2017 Jan 5;100(1):151-159.  doi: 10.1016/j.ajhg.2016.11.014. Epub 2016 Dec 15.

12. Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases, By 
    Jin-Ho Koh, et. al. Diabetes Metab Journal . 2021 Nov;45(6):853-865.  doi: 10.4093/dmj.2021.0138. Epub 2021 Nov 22. 

    PMID: 34847642.  PMCID: PMC8640147 .  DOI: 10.4093/dmj.2021.0138