Cyanidin

Cyanidin is one of the six Anthocyanin subsets, and its glucoside Cyanidin-3-Glucoside (C3G) has been garnering attention for its ability to decrease blood glucose levels, and its ability to not hinder muscle protein synthesis at the same time (downstream of AMPK activation).

This page features 59 unique references to scientific papers.

Summary

All Essential Benefits/Effects/Facts & Information

In Progress


This page on Cyanidin is currently marked as in-progress. We are still compiling research.



Cyanidins are a sub-category of the dark pigments found in blue-black fruits and berries as well as some purple vegetables known as Anthocyanins. Cyanidins can be seen as the most pharmaceutically effective anthocyanin subcomponent as they seem to have the greatest uptake rate, the least decay, and the most clinical significance out of all anthocyanins.

It has various effects in cells, most of which can be described as being anti-diabetic and possibly slightly benefit other parameters associated with 'metabolic syndrome' (anti-inflammatory, anti-oxidant, etc.)

It does have some problems with absorption though, so the results you see in in vitro (in laboratory) studies may not apply to when it is consumed. Its bioavailability (percent absorbed) is a concern, and human intervention studies important for this reason.

Things to Know

Also Known As

Cyanidin-3-Glucoside, C3G, Cyanidin-3-Rutinoside

Do Not Confuse With

Anthocyanins, Delphinidin

Things to Note

  • Cyanidins are non-stimulatory

  • If using supplemental Cyanidins in powder or capsules, they may stain clothes. Anthocyanins in general are the reason grape juice stains.

  • Cyanidins have relatively poor bioavailability in vivo

Is a Form Of

Goes Well With

Does Not Go Well With

Caution Notice

Examine.com Medical Disclaimer

How to Take

Recommended dosage, active amounts, other details

Benefits have been seen with blood sugar reductions in the range of 150mg/kg bodyweight, a dose well above what is achieved through foods.

It is possible long-term benefits may be seen with a lower dose of cyanidin compounds through foods, due to the many correlations of plant intake and health; however, causation has not been given to cyanidins as of yet.

Additionally, it may be possible to increase bioavailability and thus lower the needed dose by inhibiting P450 enzymes (similar to curcumin being potentiated by piperine). However, this is for the most part currently an untested hypothesis.

Editors' Thoughts on Cyanidin

Eat some red-blue veggies or fruits now, that should cover some preventative health effects although it may not be enough to physique changes.

The mechanisms of action of cyanidins (anthocyanins in general) are astounding, and seem titrated for looking good naked while not getting cancer. However, supplemental dosages for aesthetics seem to be expensive.

That being said, the most intriguing aspect of them is their digestion. Its normally bad, but lots of factors affect it. If this can be made better, then Cyanidins are a promising agent for body composition.


Kurtis Frank

Scientific Research

Table of Contents:

  1. 1 Sources and Structure
    1. 1.1 Sources
    2. 1.2 Structure
  2. 2 Digestion and Uptake of Cyanidins
    1. 2.1 Stomach
    2. 2.2 Small intestines
    3. 2.3 Bioavailability and P450
    4. 2.4 Post-hepatic and Post-intestinal bioavailability
    5. 2.5 Summation
  3. 3 Effects on Fat Metabolism
    1. 3.1 In vitro
    2. 3.2 In vivo
    3. 3.3 Overall
  4. 4 Effects on muscle
  5. 5 Effects on Glucose Metabolism and Diabetes
    1. 5.1 In vitro
    2. 5.2 In vivo
  6. 6 Effects on carcinogenesis and other health benefits
    1. 6.1 In vitro and mechanisms of action
    2. 6.2 In vivo results
  7. 7 Synergism and Antagonism


1Sources and Structure

1.1. Sources

The main fruit sources of Cyanidins are Blackberries and Bilberries; approximately 80% of the Cyanidin content is in the form of Cyanidin-3-Glucoside (Cyanidin bound to glucose) and about 20% in the form of Cyanidin-3-Rutinoside (Cyanidin bound to the disaccharide rutinose).[1] Trace amounts come from less abundant Cyanidin moieties (3,5-diglucose, 3-galactose).[2]

Other dietary sources include chokeberries, boysenberries, elderberries, purple vegetables (such as carrots and yams), black raspberries, and Hibiscus sabdariffa extract.[3] Basically, dark blue to purple colored plants. Interestingly, the darker than normal color in blood oranges relative to normal oranges is due to cyanidin compounds.[4] Red cabbage (reddish-purple in nature) is also a source of novel cyanidin glycosides.[5]

Although the cyanidin molecule does not change, it is found in a wide variety of differing glucosides; or bound to different sugars. Such as:

  • Cyanidin-3-Glucosides (Bound to Glucose)

  • Cyanidin-3-Sambubiosides (Sambubiose)

  • Cyanidin-3-Rutinosides (Rutinose)

  • Cyanidin-3-Sophorosides (Sophorose)

  • Cyanidin-3-Galactosides (Galactose)

Both the isolated cyanidin molecule as well as the glucoside (above bulleted compounds) may exert different effects.

1.2. Structure

Cyanidins share the typical anthocyanin backbone, but with a hydroxylation (addition of -OH) on one of its two possible sidechains (the R1 sidechain). The other is merely hydrogenated.[6] If both side chains were hydroxylated, the compound would be a Delphinidin.

The form that is most well researched is Cyanidin-3-O-b-Glucoside, a form found occurring in foods and is sometimes found in the blood even with the glucose moiety still attached.


2Digestion and Uptake of Cyanidins

2.1. Stomach

The stomach is a novel site for uptake of dietary cyanidins and cyanidins from food components. It allows for rapid delivery into the blood and avoids hepatic metabolism. The acidic environment of the stomach is also conducive to anthocyanin stability.[7][8][5]

Uptake of Cyanidins bound to monosaccharides (like glucoside) are taken up fairly well, whereas those with larger sugar sidechains (such as Rutinoside) are hindered somewhat.[9][10] Lower doses seem to have higher uptake percentages than higher dosages, implicating gastric digestion as a site for cost-efficacy supplementation[9] and may be a reason that after ingestion of anthocyanins their intact glycosides can be found in the blood almost immediately.[11][12][13]

2.2. Small intestines

Cyanidins are absorbed in the small intestine, like many anthocyanins, moderately well to poorly. Cyanidins had an uptake rate of 19.1% in one rat study and had an intestinal decay rate of 2.32 ± 0.67% to 22.4 ± 2.0% over 45 minutes.[14] The most intestinally stable form of Cyanidins appears to be the 3-glucoside, although all cyanidins appear to be sensitive to the alkaline environment.[5]

In the intestines, Cyanidins can be taken up into the blood in their unchanged glycone forms or can be sulphated or glucuronidated by P450 enzymes after stripped from their sugar moieties.[14][1]

These rates may be much higher when paired with a Labrasol emulsifier, as one study to look at in vivo effects noted significance in a Labrasol + C3G group rather than a group without Labrasol.[15] However, no studies have confirmed this increased rate of absorption beyond this.

2.3. Bioavailability and P450

One review[3] looked at cyanidin bioavailability from various foods, and summarized the percentage of an oral dose (from various foods) of various cyanidin compounds that was absorbed and excreted in the urine was between 0.018-0.37%, with an average of less than a thousandth absorbed. Highest (measured) Cmax was 95-96nmol of cyanidin compounds, measured at an oral intake of 720mg.[16][17][18][19][20][21][22][23][24][25][26][27][28] All mentioned studies collected urine for between 7 and 24 hours, and used varying glycosides of cyanidin, and would thus exclude longer pharmacokinetics.

2.4. Post-hepatic and Post-intestinal bioavailability

When measured in the blood, cyanidins appear to exist primarily as metabolites of the liver. One study found that after ingestion of 721mg Cyanidin-3-Glucoside, that 32.5% of what was taken up was the parent compound, whereas 67.5% existed as metabolites, as a mixture of methylated conjugates (primarily) and sulphates and glucuronides.[29] Oxidized metabolites of cyanidin have also been noted in serum.[30]

It appears that the main pathway of metabolism for cyanidin compounds, after being cleaved from their glycosides, is either glucuronidation or methylation by P450 enzymes.[19][31][32][33][34][19][30] One study[4] noted that only two studies have found significant levels of sulphation end products[35][19], so this may not be a major metabolite in vivo. It appears that methyl end products are most prominent followed by glucuronides[19][36] with sulphation end products coming in last.

Cyanidin that is bound to a disaccharide (like rutinose) or larger molecules appear to not be highly conjugated like those bound to monosaccharides.[36] These compounds are taken up and excreted as their intact molecules.

Interestingly, despite the low amount of cyanidins present in the blood after ingestion it may be due to excessive conversion to protocatechuic acid. One study[4] noted that 44% of an oral dose of Cyanidin-3-glucoside could be accounted for as protocatechuic acid, and that it was not able to be measured in the urine (but instead excreted fecally). In this study, 71mg of Cyanidin-3-Glucoside caused a Cmax of 492+/-62nmol/L for protocatechuic acid between 30-120 minutes after consumption, where serum values for Cyanidin-3-Glucoside itself were 1.9+/-0.6nmol/L.[4] This degradation may be spontaneous rather than enzyme mediated.[37]

Another lesser studied metabolite of cyanidins might be phloroglucinaldehyde[37][38] although not much is known about this compound.

2.5. Summation

Among bioflavonoids, cyanidins are fairly well taken up into the intestine's epithelial wall at around 20% of an oral dose. However, only a minimal amount (less than 2%) reaches the blood, with most being conjugated by P450; biological significance of these conjugates is not known. Unless measures are taken to increase bioavailability, or Cyanidins are otherwise superloaded (so 2% is a clinically significant amount), then oral supplementation may not yeild acute results.

Cyanidin supplementation may be a good source of protocatechuic acid though.


3Effects on Fat Metabolism

3.1. In vitro

Like many polyphenols, C3G and related anthocyanins can beneficially affect adipocyte signalling properties[39], causing an increase in secreted adiponectin levels and a decrease in interleukin-6 and plasminogen activator inhibitor-1 activity.[40] Promoting an anti-inflammatory overall effect.

Cyanidins are also able to promote phosphorylation and subsequent nuclear exclusion of FoxO1 (Forkhead Box Protein O1) during feeding[41], a gene which induces skeletogenesis and protein genesis in osteoblasts but hinders protein synthesis in myocytes via mTOR interference.[42][43] Exclusion from the nucleus (interfering with transcripton) makes the effects of FoX01 less potent.

Although the Lipoprotein Lipase (LPL) enzyme is activated in muscle cells, it appears to be suppressed in visceral fat cells with Cyanidin-3-Glucoside administration, with no effect on subcutaneous.[44] These effects were seen through AMPK phosphorylation, suggesting a different mechanism of action.

Uncoupling protein 2 (UCP2) was also induced in cells treated with C3G.[40]

Paradoxically to the above actions, some actions of cyanidins are similar to insulin. Incubating cells with Cyanidins as Cyanidin-3-O-b-Glucoside has been shown to increase the activity of PPARy.[45]

Increased GLUT4 translocation and glucose uptake was also seen in these cells.[45]

3.2. In vivo

The overall effect that the above mechanisms should result in (prevention of obesity from diet, alleviation of diabetic progression) has been noted in animals fed an obesogenic diet, with Cyanidins (as Cyanidin-3-Glucoside) at 2g/kg bodyweight; a large dose not able to be gained through normal human consumption.[46]

3.3. Overall

Cyanidin, typically researched through Cyanidin-3-Glucosides, seem to be able to promote a state of anti-inflammation in fat cells that can potentially alleviate dysregulation in signalling that precedes disease states. Additionally, fat cells can uptake glucose easier via GLUT4 translocation. In vitro studies suggest great potential for Cyanidins as anti-diabetic compounds, and await replication in in vivo models.


4Effects on muscle

Cyanidins appear to be potent AMPK activators, with downstream effects of increasing glucose and lipid uptake into myocytes[44]

The normally deleterious effects of AMPK activation on muscle growth (in which higher AMPK is inversely related with muscle protein synthesis) are diminished via FOXo1 exclusion, a nuclear protein which AMPK must work through to hinder protein synthesis.[41][47] Thus Cyanidins may prevent the expected inhibition of muscle protein synthesis themselves.

In smooth muscle (organs rather than contractile muscles), Cyanidins can exert pro-inflammatory effects and prevent subsequent damage and oxidation.[48][49]


5Effects on Glucose Metabolism and Diabetes

5.1. In vitro

C3G can exert anti-diabetic effects via stimulation of the GLUT4 transporter activity in fat cells[45], and reducing retinol binding protein 4 (RBP4) expression.[50] The reduction in expression of RBP4 is correlated with decreased levels of TNF-alpha in white adipocytes as well, which is related to an anti-inflammatory state. These anti-inflammatory effects, via inhibiting c-Jun NH2-terminal kinase activation, can possibly protect fat cells from damages associated with a pro-diabetic diet.[51][46] Adding on to these effects, Cyanidin in adipocytes is related to increasing adiponectin secretion from the cultured adipocytes.[45]

Cyanidins also reduces the amount of reactive oxygen species (ROS) produced inside the adipocyte, thus possessing anti-oxidant capabilities.[51]

Cyanidin may also exert anti-diabetic effects via acting on PPARy.[45]

The effects seen in muscle cells downstream of AMPK activation (increasing LPL activity, increased glucose uptake) can also be seen as anti-diabetic.[44]

5.2. In vivo

One study suggest that a dose of 143.5mg/kg bodyweight and a dose of 297.5mg/kg bodyweight 'Cyanidin-3-Glucoside equivalents' anthocyanins resulted in a decrease of blood glucose levels by 33% and 51% respectively when paired with a drug transport system known as Labrasol.[15] These results were reported to rival that of the diabetic drug Metformin. This particular study used the two anthocyanins 'Malvidin-3-O-glucoside' and 'delphinidin-3-O-glucoside' as the C3G active components and found only the former to have active effects on reducing blood sugar, with the latter possibly interfering with the actions of malvidin-3-O-glucoside.


6Effects on carcinogenesis and other health benefits

6.1. In vitro and mechanisms of action

Cyanidins affect carcinogenesis in a number of ways. It can suppress the stimulation of pro-carcinogenic transcription factors which appear to be caused from inhibition of MAPK activity. [52]

C3G can also inhibit proliferation of human cancer cell lines, specifically lung carcinomna[52] leukemia, colonic carcinoma cells.[53]

It also possesses potent anti-oxidant abilities, particularily against OH- and O2 radicals.[52]

6.2. In vivo results

Various animal models have shown anti-tumor effects with Cyanidin anthocyanins, delivered through Pomegranate Juice,[54] Freeze dried berries,[55] Berry extracts added to feed,[56] and Cyanidins have directly been studied twice as components of feed.[57][52]


7Synergism and Antagonism

Inositol Hexaphosphate has been shown to beneficially affect the bioavailability of blackcurrant anthocyanins when coingested, suggesting that the same mechanisms may apply to the Cyanidin subset.[58]

A study noting synergisms in strawberries noted that, when isolated, Cyanidin had its anti-oxidative potential inhibited by Pelargonidin, which was alleviated with Quercetin being added. Quercetin itself was synergistic with Cyanidin, and Cyanidin's synergism with Quercetin is increased further with Ellagic Acid.[59]

Scientific Support & Reference Citations

References

  1. Hassimotto NM, Genovese MI, Lajolo FM. Absorption and metabolism of cyanidin-3-glucoside and cyanidin-3-rutinoside extracted from wild mulberry (Morus nigra L.) in rats. Nutr Res. (2008)
  2. Anthocyanins Are Efficiently Absorbed from the Stomach in Anesthetized Rats.
  3. Galvano F, et al. Bioavailability, antioxidant and biological properties of the natural free-radical scavengers cyanidin and related glycosides. Ann Ist Super Sanita. (2007)
  4. Vitaglione P, et al. Protocatechuic acid is the major human metabolite of cyanidin-glucosides. J Nutr. (2007)
  5. McDougall GJ, et al. Anthocyanins from red cabbage--stability to simulated gastrointestinal digestion. Phytochemistry. (2007)
  6. Yoshida K, Mori M, Kondo T. Blue flower color development by anthocyanins: from chemical structure to cell physiology. Nat Prod Rep. (2009)
  7. Anthocyanins in Fruits, Vegetables and Grains.
  8. Prior RL, Wu X. Anthocyanins: structural characteristics that result in unique metabolic patterns and biological activities. Free Radic Res. (2006)
  9. Anthocyanins Are Efficiently Absorbed from the Stomach in Anesthetized Rats.
  10. Passamonti S, et al. The stomach as a site for anthocyanins absorption from food. FEBS Lett. (2003)
  11. Matsumoto H, et al. Orally administered delphinidin 3-rutinoside and cyanidin 3-rutinoside are directly absorbed in rats and humans and appear in the blood as the intact forms. J Agric Food Chem. (2001)
  12. Tsuda T, Horio F, Osawa T. Absorption and metabolism of cyanidin 3-O-beta-D-glucoside in rats. FEBS Lett. (1999)
  13. Anthocyanins are absorbed in glycated forms in elderly women: a pharmacokinetic study.
  14. Talavéra S, et al. Anthocyanins are efficiently absorbed from the small intestine in rats. J Nutr. (2004)
  15. Grace MH, et al. Hypoglycemic activity of a novel anthocyanin-rich formulation from lowbush blueberry, Vaccinium angustifolium Aiton. Phytomedicine. (2009)
  16. Absorption and Metabolism of Anthocyanins in Elderly Women after Consumption of Elderberry or Blueberry.
  17. Kurilich AC, et al. Plasma and urine responses are lower for acylated vs nonacylated anthocyanins from raw and cooked purple carrots. J Agric Food Chem. (2005)
  18. Stoner GD, et al. Pharmacokinetics of anthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 days. J Clin Pharmacol. (2005)
  19. Felgines C, et al. Blackberry anthocyanins are mainly recovered from urine as methylated and glucuronidated conjugates in humans. J Agric Food Chem. (2005)
  20. Frank T, et al. Urinary pharmacokinetics of cyanidin glycosides in healthy young men following consumption of elderberry juice. Int J Clin Pharmacol Res. (2005)
  21. The excretion and biological antioxidant activity of elderberry antioxidants in healthy humans.
  22. Anthocyanins Exist in the Circulation Primarily as Metabolites in Adult Men.
  23. Nielsen IL, et al. Absorption and excretion of black currant anthocyanins in humans and watanabe heritable hyperlipidemic rabbits. J Agric Food Chem. (2003)
  24. McGhie TK, et al. Anthocyanin glycosides from berry fruit are absorbed and excreted unmetabolized by both humans and rats. J Agric Food Chem. (2003)
  25. Frank T, et al. Bioavailability of anthocyanidin-3-glucosides following consumption of red wine and red grape juice. Can J Physiol Pharmacol. (2003)
  26. Urinary Excretion of Cyanidin Glucosides and Glucuronides in Healthy Humans After Elderberry Juice Ingestion.
  27. Bitsch I, et al. Bioavailability of anthocyanidin-3-glycosides following consumption of elderberry extract and blackcurrant juice. Int J Clin Pharmacol Ther. (2004)
  28. Harada K, et al. Absorption of acylated anthocyanins in rats and humans after ingesting an extract of Ipomoea batatas purple sweet potato tuber. Biosci Biotechnol Biochem. (2004)
  29. Kay CD, Mazza GJ, Holub BJ. Anthocyanins exist in the circulation primarily as metabolites in adult men. J Nutr. (2005)
  30. Kay CD, et al. Anthocyanin metabolites in human urine and serum. Br J Nutr. (2004)
  31. Wu X, Pittman HE 3rd, Prior RL. Fate of anthocyanins and antioxidant capacity in contents of the gastrointestinal tract of weanling pigs following black raspberry consumption. J Agric Food Chem. (2006)
  32. Pelargonidin Is Absorbed and Metabolized Differently than Cyanidin after Marionberry Consumption in Pigs.
  33. Aglycones and Sugar Moieties Alter Anthocyanin Absorption and Metabolism after Berry Consumption in Weanling Pigs.
  34. Tian Q, et al. Urinary excretion of black raspberry (Rubus occidentalis) anthocyanins and their metabolites. J Agric Food Chem. (2006)
  35. Strawberry Anthocyanins Are Recovered in Urine as Glucuro- and Sulfoconjugates in Humans.
  36. Wu X, et al. Aglycones and sugar moieties alter anthocyanin absorption and metabolism after berry consumption in weanling pigs. J Nutr. (2005)
  37. Kay CD, Kroon PA, Cassidy A. The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res. (2009)
  38. Sadilova E, Carle R, Stintzing FC. Thermal degradation of anthocyanins and its impact on color and in vitro antioxidant capacity. Mol Nutr Food Res. (2007)
  39. Tsuda T, et al. Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem Biophys Res Commun. (2004)
  40. Microarray profiling of gene expression in human adipocytes in response to anthocyanins.
  41. Guo H, et al. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J Nutr Biochem. (2011)
  42. Kousteni S. FoxO1: a molecule for all seasons. J Bone Miner Res. (2011)
  43. Southgate RJ, et al. FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem. (2007)
  44. Wei X, et al. Cyanidin-3-O-β-glucoside improves obesity and triglyceride metabolism in KK-Ay mice by regulating lipoprotein lipase activity. J Sci Food Agric. (2011)
  45. Scazzocchio B, et al. Cyanidin-3-O-β-glucoside and protocatechuic acid exert insulin-like effects by upregulating PPARγ activity in human omental adipocytes. Diabetes. (2011)
  46. Tsuda T, et al. Dietary cyanidin 3-O-beta-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr. (2003)
  47. Chen BL, et al. Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro. Acta Pharmacol Sin. (2010)
  48. Luo X, et al. Cyanidin-3-glucoside suppresses TNF-α-induced cell proliferation through the repression of Nox activator 1 in mouse vascular smooth muscle cells: involvement of the STAT3 signaling. Mol Cell Biochem. (2012)
  49. Oak MH, et al. Delphinidin and cyanidin inhibit PDGF(AB)-induced VEGF release in vascular smooth muscle cells by preventing activation of p38 MAPK and JNK. Br J Pharmacol. (2006)
  50. Sasaki R, et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol. (2007)
  51. Guo H, et al. Cyanidin 3-glucoside protects 3T3-L1 adipocytes against H2O2- or TNF-alpha-induced insulin resistance by inhibiting c-Jun NH2-terminal kinase activation. Biochem Pharmacol. (2008)
  52. Ding M, et al. Cyanidin-3-glucoside, a natural product derived from blackberry, exhibits chemopreventive and chemotherapeutic activity. J Biol Chem. (2006)
  53. Katsube N, et al. Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the anthocyanins. J Agric Food Chem. (2003)
  54. Afaq F, et al. Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice. Int J Cancer. (2005)
  55. Cancer Prevention with Freeze-dried Berries and Berry Components.
  56. Lala G, et al. Anthocyanin-rich extracts inhibit multiple biomarkers of colon cancer in rats. Nutr Cancer. (2006)
  57. Cooke D, et al. Effect of cyanidin-3-glucoside and an anthocyanin mixture from bilberry on adenoma development in the ApcMin mouse model of intestinal carcinogenesis--relationship with tissue anthocyanin levels. Int J Cancer. (2006)
  58. Matsumoto H, et al. Enhanced absorption of anthocyanins after oral administration of phytic acid in rats and humans. J Agric Food Chem. (2007)
  59. Reber JD, Eggett DL, Parker TL. Antioxidant capacity interactions and a chemical/structural model of phenolic compounds found in strawberries. Int J Food Sci Nutr. (2011)

(Common misspellings for Cyanidin include cyandin, cianidin, ciandin, cyanin, cianin, )