Nutraceuticals:

 Mechanisms of Action for Nutraceuticals

This summary explains key compounds and pathways driving inflammation and oxidative stress in pain conditions (e.g., osteoarthritis, neuropathy), their origins, producing cells/tissues, and how nutraceuticals such as resveratrol, curcumin, omega-3s,  vitamin D, melatonin, and others modulate them. 

 

See:

Nutraceuticals

 

 

 

“Prevention is better than cure.”

 

Key to Links:

  • Grey text – handout
  • Red text – another page on this website
  • Blue text – Journal publication

Definitions and Terms Related to Pain

Mechanisms of Action for Nutraceuticals

Throughout the nutraceuticals sections on this website, references are made to the mechanisms of action for various nutraceuticals. They reference many acronyms without a lot of context to explain them to those not familiar with what these compounds are. In the interest of brevity, it isn’t practical to offer repetitive explanations or reviews of these compounds in that context of the nutraceutical reviews. This section summarizes key compounds and pathways driving inflammation and oxidative stress in pain conditions (e.g., osteoarthritis, neuropathy), their origins, cells/tissues that produce them, and how nutraceuticals modulate them.

 

Overview of Nrf2 and SIRT1

Nrf2 (Nuclear factor erythroid 2-related factor 2) and sirtuins (focusing on SIRT1), separately and together play important roles in inflammation and oxidative stress. Various nutraceuticals reviewed below modulate their interplay to impact pain conditions like osteoarthritis and neuropathy.

Nrf2 and SIRT1 work together to protect against inflammation and oxidative stress, key drivers of chronic pain including osteoarthritis (joint damage) and neuropathy (nerve pain). Nrf2 boosts antioxidants to neutralize harmful free radicals, while SIRT1 calms inflammation and promotes cell survival. Their synergy enhances these effects, making them key targets for nutraceuticals like resveratrol and curcumin.

1. SIRT1 (Sirtuin 1)

  • What It Is: A protein that acts like a longevity switch, controlling cell stress and inflammation.
  • Origin: Found in cell nuclei, regulating gene activity.
  • Cells/Tissues: Produced in cartilage cells (chondrocytes), nerve cells (neurons), immune cells (macrophages).
  • Role: Reduces inflammation by calming harmful genes and protects cells from oxidative damage, preserving joints and nerves.
  • Pain Context: In osteoarthritis, low SIRT1 worsens cartilage damage. In neuropathy, it may protect nerves (preclinical) [Ref 6, 13, web:0].
  • Nutraceutical Impact:
    • Resveratrol: Strongly activates SIRT1, reducing osteoarthritis pain (~20–25%, 500 mg/day) [Ref 16, 24]. Preclinical neuropathy benefits [Ref 12].
    • Curcumin, CoQ10, Melatonin: Mild SIRT1 activation [web:5].
  • Potency: High (Resveratrol); Moderate (Curcumin, CoQ10, Melatonin); Low (others).

2. Nrf2 (Nuclear factor erythroid 2-related factor 2)

  • What It Is: A protein that turns on antioxidant defenses, like a master switch against free radicals.
  • Origin: In cell cytoplasm, moves to nucleus when activated by stress.
  • Cells/Tissues: Active in immune cells (macrophages), cartilage cells, nerve cells, liver.
  • Role: Boosts antioxidants (SOD, glutathione), reducing damage and inflammation in joints/nerves.
  • Pain Context: Protects cartilage in osteoarthritis; may reduce nerve damage in neuropathy (preclinical) [Ref 6, 8, web:0].
  • Nutraceutical Impact:
    • Curcumin, NAC, Selenium: Strong Nrf2 activators, boosting antioxidants [Ref: Anand et al., 2007; web:5].
    • Resveratrol, Matcha: Significant activation [Ref 12; Matcha v1].
    • Omega-3s, Melatonin: Modest effects [web:5].
  • Potency: High (Curcumin, NAC, Selenium); Moderate (Resveratrol, Matcha); Low (others).

 

3. SOD, Glutathione, Catalase

  • What They Are: Antioxidants that neutralize free radicals, like shields protecting cells.
    • SOD: Converts superoxide to less harmful molecules.
    • Glutathione: Detoxifies free radicals.
    • Catalase: Breaks down hydrogen peroxide.
  • Origin: Produced inside cells, especially in mitochondria and liver.
  • Cells/Tissues: SOD/catalase in most cells; glutathione in liver, red blood cells, all tissues.
  • Role: Prevent oxidative damage to cartilage and nerves, reducing inflammation.
  • Pain Context: Low levels worsen osteoarthritis cartilage damage; may protect nerves in neuropathy [Ref 8, 12, web:0].
  • Nutraceutical Impact:
    • NAC, Selenium: Boost glutathione/SOD (Selenium v2) [web:5].
    • Resveratrol, Curcumin: Upregulate via Nrf2 in osteoarthritis [Ref 16, 24; Anand et al., 2007].
    • CoQ10, Matcha, Melatonin, Omega-3s: Modest upregulation [web:5; Matcha v1].
  • Potency: High (NAC, Selenium); Moderate (Resveratrol, Curcumin); Low (others).

4. COX-2 (Cyclooxygenase-2)

  • What It Is: An enzyme producing prostaglandins, chemicals causing pain and swelling.
  • Origin: Made by cells during injury or inflammation.
  • Cells/Tissues: Immune cells (macrophages), cartilage cells, joint synovial cells, nerve cells.
  • Role: Fuels inflammation and pain by sensitizing nerves and increasing swelling.
  • Pain Context: Drives joint pain in osteoarthritis; amplifies nerve pain in neuropathy [Ref 6, 15].
  • Nutraceutical Impact:
    • Curcumin: Strong COX-2 inhibition in osteoarthritis [Ref: Anand et al., 2007].
    • Resveratrol, Omega-3s, PEA: Moderate inhibition [Ref 16, 20; web:5].
  • Potency: High (Curcumin); Moderate (Resveratrol, Omega-3s, PEA); Low (others).

5. NF-κB (Nuclear Factor-kappa B)

  • What It Is: A protein complex controlling inflammation, like a switch for inflammatory genes.
  • Origin: In cell cytoplasm, moves to nucleus when activated by stress.
  • Cells/Tissues: Immune cells (macrophages, T-cells), cartilage cells, nerve cells, synovial cells.
  • Role: Triggers inflammatory cytokines (IL-1β, IL-6, TNF-α) and enzymes (COX-2), causing tissue damage.
  • Pain Context: Worsens cartilage breakdown in osteoarthritis; promotes nerve pain in neuropathy [Ref 6, 13].
  • Nutraceutical Impact:
    • Curcumin, PEA: Strong inhibition in osteoarthritis, sciatica [Ref: Anand et al., 2007; web:5].
    • Resveratrol, Omega-3s, Matcha: Significant inhibition [Ref 16; Matcha v1].
  • Potency: High (Curcumin, PEA); Moderate (Resveratrol, Omega-3s, Matcha); Low (others).

6. IL-1β, IL-6, TNF-α, Nitric Oxide (NO)

  • What They Are: Inflammatory signals worsening pain.
    • IL-1β, IL-6, TNF-α: Cytokines recruiting immune cells.
    • NO: A gas causing tissue damage in excess.
  • Origin: Cytokines secreted by immune cells; NO produced via enzymes (iNOS).
  • Cells/Tissues: Macrophages, T-cells, synovial cells, glial cells; NO in blood vessels, nerves.
  • Role: Cause swelling, pain, and tissue damage in joints/nerves.
  • Pain Context: Drive joint destruction in osteoarthritis; inflame nerves in neuropathy [Ref 6, 15, web:0].
  • Nutraceutical Impact:
    • Curcumin, PEA: Potent reduction in osteoarthritis, sciatica [Ref: Anand et al., 2007; web:5].
    • Resveratrol, Omega-3s, Matcha: Significant reduction [Ref 16, 24; Matcha v1].
    • NAC, Selenium, Melatonin: Indirect reduction [web:5].
  • Potency: High (Curcumin, PEA); Moderate (Resveratrol, Omega-3s, Matcha); Low (others).

7. MMPs (Matrix Metalloproteinases) and Chondrocyte Apoptosis

  • What They Are:
    • MMPs: Enzymes breaking down cartilage.
    • Chondrocyte Apoptosis: Death of cartilage cells.
  • Origin: MMPs produced by cartilage/synovial cells; apoptosis from stress/inflammation.
  • Cells/Tissues: Cartilage cells, synovial lining in joints.
  • Role: Degrade cartilage, weaken joints.
  • Pain Context: Cause stiffness/pain in osteoarthritis; less relevant in neuropathy [Ref 16, 24].
  • Nutraceutical Impact:
    • Resveratrol, Curcumin: Strong inhibition, protecting cartilage [Ref 16, 24; Anand et al., 2007].
    • Omega-3s: Modest MMP reduction [web:5].
  • Potency: High (Resveratrol, Curcumin); Moderate (Omega-3s); Low (others).

8. Amyloid-β and BDNF (Brain-Derived Neurotrophic Factor)

  • What They Are:
    • Amyloid-β: Sticky protein causing nerve inflammation.
    • BDNF: Protein promoting nerve growth.
  • Origin: Amyloid-β from neurons; BDNF from neurons/glial cells.
  • Cells/Tissues: Brain/peripheral nerve neurons, glial cells.
  • Role: Amyloid-β harms nerves; BDNF supports repair.
  • Pain Context: Amyloid-β worsens neuropathy pain; low BDNF impairs nerve repair [web:5].
  • Nutraceutical Impact:
    • Resveratrol, Curcumin, Matcha, Melatonin: Reduce amyloid-β, boost BDNF (preclinical) [Ref 20; Matcha v1; web:5].
  • Potency: Moderate (Resveratrol, Curcumin, Matcha, Melatonin); Low (others).

9. AMPK (AMP-activated Protein Kinase)

  • What It Is: An enzyme regulating cell energy, like a fuel gauge.
  • Origin: In cell cytoplasm, activated by low energy/stress.
  • Cells/Tissues: Muscle, liver, heart, cartilage, nerve cells.
  • Role: Reduces inflammation, improves metabolism, protects nerves.
  • Pain Context: Supports cartilage in osteoarthritis; may calm nerves in neuropathy [Ref 18, web:0].
  • Nutraceutical Impact:
    • Resveratrol: Strong AMPK activation in osteoarthritis [Ref 18].
    • Curcumin, Omega-3s, CoQ10: Modest activation [web:5].
  • Potency: High (Resveratrol); Moderate (Curcumin, Omega-3s, CoQ10); Low (others).

10. LDL (Low-Density Lipoprotein)

  • What It Is: “Bad” cholesterol causing artery plaque buildup.
  • Origin: Produced by liver, influenced by diet.
  • Cells/Tissues: Circulates in blood, affects blood vessels, heart.
  • Role: Triggers inflammation, worsening pain indirectly.
  • Pain Context: High LDL amplifies inflammation in osteoarthritis/neuropathy [Ref 19].
  • Nutraceutical Impact:
    • Omega-3s, Resveratrol: Strong LDL reduction [Ref 19, web:2].
    • Curcumin, CoQ10: Modest reduction [web:5].
  • Potency: High (Omega-3s, Resveratrol); Moderate (Curcumin, CoQ10); Low (others).

11. ROS (Reactive Oxygen Species)

  • What It Is: Unstable molecules, like sparks from metabolism, damaging cells.
  • Origin: Generated in mitochondria or by immune cells during inflammation.
  • Cells/Tissues: All cells, especially immune cells (macrophages), cartilage cells, neurons.
  • Role: Excess ROS harm cartilage/nerves, increasing inflammation/pain.
  • Pain Context: Degrade cartilage in osteoarthritis; harm nerves in neuropathy [Ref 6, 8, web:0].
  • Nutraceutical Impact:
    • NAC, Selenium, Curcumin: Potent ROS scavengers [Ref: Anand et al., 2007; web:5].
    • Resveratrol, CoQ10, Matcha, Omega-3s: Significant reduction [Ref 16, web:5].
  • Potency: High (NAC, Selenium, Curcumin); Moderate (Resveratrol, CoQ10, Matcha, Omega-3s); Low (others).

12. IL-10

  • What It Is: An anti-inflammatory cytokine, like a peacekeeper calming immune responses.
  • Origin: Secreted by immune cells to reduce inflammation.
  • Cells/Tissues: Macrophages, T-cells, glial cells in joints/nerves.
  • Role: Suppresses inflammatory cytokines, reducing pain/swelling.
  • Pain Context: Limits joint inflammation in osteoarthritis; may reduce neuropathy pain [web:5].
  • Nutraceutical Impact:
    • PEA, Omega-3s: Strong IL-10 upregulation [web:5].
    • Resveratrol, Curcumin: Modest upregulation [web:5].
  • Potency: High (PEA, Omega-3s); Moderate (Resveratrol, Curcumin); Low (others).

13. PPAR-γ (Peroxisome Proliferator-Activated Receptor Gamma)

  • What It Is: A protein regulating fat metabolism and inflammation, like a dimmer switch.
  • Origin: In cell nucleus, activated by fats/stress.
  • Cells/Tissues: Immune cells (macrophages), fat cells, cartilage cells, nerve cells.
  • Role: Inhibits inflammation in joints/nerves, improves insulin sensitivity.
  • Pain Context: Reduces joint inflammation in osteoarthritis; calms nerves in neuropathy [web:5].
  • Nutraceutical Impact:
    • Omega-3s, PEA: Strong PPAR-γ activation [web:5].
    • Curcumin, Resveratrol: Modest activation [web:5].
  • Potency: High (Omega-3s, PEA); Moderate (Curcumin, Resveratrol); Low (others).

 

Recommendations 

Best Nutraceuticals:

Resveratrol and curcumin lower harmful proteins (TNF-α, IL-6) and protect cartilage. Resveratrol and curcumin are safe up to 1,000 mg/day; high doses may cause stomach upset or interact with blood thinners [web:3,6].

For osteoarthritis-related joint pain, use resveratrol and curcumin to calm inflammation and protect cartilage:

  • Resveratrol (500 mg/day, liposomal/micronized, e.g., Kirkman, Thorne)
  • Curcumin (phytosomal, e.g., Thorne Meriva-SF) for targeting (NF-κB, cytokines) and cartilage protection (MMPs) [Ref 16, 24].

For systemic information and oxidative stress, use:

  • PEA, NAC, omega-3s for systemic inflammation;
  • NAC, selenium for oxidative stress [web:5].

For nerve pain, PEA/NAC are promising, but resveratrol lacks human data.

 

 

References

  • Walle T, et al. (2004). Drug Metab. Dispos., 32(12):1377–1382. doi:10.1124/dmd.104.000885.
  • Francioso A, et al. (2014). Drug Deliv., 21(3):182–191. doi:10.3109/03639045.2013.858735.
  • Anand P, et al. (2007). Mol. Pharm., 4(6):807–818. doi:10.1021/mp0700332.
  • Shoba G, et al. (1998). Planta Med., 64(4):353–356. doi:10.1055/s-2006-957450.
  • Manach C, et al. (2004). Am. J. Clin. Nutr., 79(5):727–747. doi:10.1093/ajcn/79.5.727.
  • Salehi B, et al. (2018). Oxid. Med. Cell. Longev., doi:10.1155/2018/8152373.
  • Kumar S, et al. (2013). Neurochem. Res., 38(4):761–769. doi:10.1007/s11064-013-0977-0.
  • Sharma RA, et al. (2007). Fundam. Clin. Pharmacol., 21(1):89–94. doi:10.1111/j.1472-8206.2006.00455.x.
  • Marouf BH, et al. (2018). J. Med. Food, 21(12):1253–1259. doi:10.1089/jmf.2017.4176.
  • Marouf BH, et al. (2021). BioMed Res. Int., 2021:3668568. doi:10.1155/2021/3668568.
  • Nguyen C, et al. (2024). PLoS Med., 21(8):e1004440. doi:10.1371/journal.pmed.1004440.
  • Furman D, et al. (2019). Nat. Med., 25(12):1822–1832. doi:10.1038/s41591-019-0675-0.
  • Liu Z, et al. (2016). Mol. Nutr. Food Res., 60(8):1840–1850. doi:10.1002/mnfr.201500881.
  • Hussain SA, et al. (2020). J. Med. Food, 23(8):837–843. doi:10.1089/jmf.2019.0223.
  • Timmers S, et al. (2011). Cell Metab., 14(5):612–622. doi:10.1016/j.cmet.2011.10.002.
  • Bhatt JK, et al. (2012). Nutr. Metab., 9:99. doi:10.1186/1743-7075-9-99.
  • ConsumerLab.com (2017). Online Supplement Merchant Survey.
  • Web results [web:0,2,3,5,6,10,11,13,14].

 

 

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

Supplements recommended by Dr. Ehlenberger may be purchased commercially online

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

 

 

.