Anthocyanidins

Anthocyanidins

1. Identity: Chemical Nature, Botanical Sources, and Preparations

1.1 Chemical Identity

Anthocyanins in nature are usually found in the form of glycosides. Their aglycone forms—the sugar-free molecules—are called anthocyanidins. They belong to the polyphenol family and are included in the large class of secondary metabolites known as flavonoids, with a core structure in the form of 2-phenylbenzopyrylium or flavylium cation. The two benzene rings are connected by three carbon atoms to form a C6–C3–C6 skeleton, which is the anthocyanin/anthocyanidin motif. Anthocyanins mainly occur in plants in the form of polyhydroxy and polymethoxy glycosides derived from the flavylium cation. Structural differences between anthocyanins are related to the number of hydroxyl or methoxy groups in the anthocyanidin backbone, the position and number of saccharide residues, and the aliphatic or aromatic acids bound to them.

Anthocyanins have a distinctive ability to form flavylium cations and acquire different colors, from red to blue or violet, depending on the pH of the medium. Anthocyanins are more stable in acidic solutions (pH 1–3), where they exist as flavylium cations.

1.2 The Six Principal Anthocyanidins

To date, over 1,000 structurally distinct anthocyanin molecules and approximately 27 structurally distinct anthocyanidins have been identified. However, only six of them account for 90% of anthocyanins found in nature. The six most common anthocyanidins are cyanidin (Cd), malvidin (Mv), pelargonidin (Pg), delphinidin (Dp), petunidin (Pt), and peonidin (Pn). Cyanidin, delphinidin, pelargonidin, peonidin, malvidin, and petunidin account for approximately 50%, 12%, 12%, 12%, 7%, and 7% of the anthocyanidin content in nature, respectively. The differences between their chemical structures result from the different number and position of the methoxy and hydroxyl groups in the structure of the flavylium ion.

The number and position of the hydroxyl and methoxy groups in the anthocyanidin structure strongly influence not only the color of anthocyanidins but most of all their antioxidant and biological activities.

1.3 Botanical Sources

Anthocyanins are a class of water-soluble flavonoids widely present in fruits and vegetables. Dietary sources of anthocyanins include red and purple berries, grapes, apples, plums, cabbage, and foods containing high levels of natural colorants. These colored constituents occur in various berries and fruits of the genera representing Prunus, Vaccinium, Vitis, Ribes, Morus, Fragaria, Aronia, and Rubus. Anthocyanins are mainly present in flowers, cereals, and root vegetables, being greatest in quantity in fruits, especially grapes and berries.

These water-soluble compounds are synthesized in various plant tissues, including leaves, stems, fruits, and flowers, predominantly in response to environmental cues such as light exposure, temperature fluctuations, and nutrient availability. The accumulation of anthocyanins in plant tissues serves multiple purposes, including attracting pollinators, deterring herbivores, and protecting against environmental stresses such as UV radiation and pathogen attacks.

Anthocyanin consumption is approximately nine times higher than other nutritional flavonoids in certain food products. The daily intake of anthocyanins in residents of the United States is estimated to be about 200 mg, or about 9-fold higher than that of other dietary flavonoids.

1.4 Supplement Forms and Preparations

Anthocyanidins and anthocyanin-rich extracts are available in a range of commercial preparations. Berries, currants, grapes, and some tropical fruits have high anthocyanin content. Red to purplish blue-colored leafy vegetables, grains, roots, and tubers are edible vegetables that also contain high levels of anthocyanins. Common supplemental forms derived from these sources include standardized bilberry (Vaccinium myrtillus) extract, blackcurrant (Ribes nigrum) extract, elderberry (Sambucus nigra) extract, chokeberry (Aronia melanocarpa) extract, and grape-skin extract. Formulation and encapsulation of anthocyanins are recognized as valuable strategies for improving the control of anthocyanin release and overcoming their bioavailability limitations.

2. Traditional and Historical Use

The use of plant-based products is from antiquity, and plants have entered the traditional system of medicine as well as the folklores of various civilizations and cultures around the world. Anthocyanins from Hibiscus sp. have historically been used in remedies for liver dysfunction and hypertension, and bilberry (Vaccinium) anthocyanins have an anecdotal history of use for vision disorders, microbial infections, diarrhea, and diverse other health disorders.

The anthocyanins' utility as a traditional medicament for liver protection and cure, and their importance as strong plant-based antioxidants, have conferred these plant products different biological activities. These activities include anti-inflammation, liver protective, analgesic, and anti-cancer properties, which have provided anthocyanins with immense commercial value.

Anthocyanin treatment is known to improve night vision. In World War II, British Air Force pilots consumed blueberry jam in night flights to obtain clear night vision. While the use of anthocyanins for therapeutic purposes has long been supported by both anecdotal and epidemiological evidence, it is only in recent years that some of the specific, measurable pharmacological properties of isolated anthocyanin pigments have been conclusively verified by rigorously controlled in vitro, in vivo, or clinical research trials.

The colored anthocyanin pigments have been traditionally used as a natural food colorant. Epidemiologic studies suggest that the consumption of anthocyanins lowers the risk of cardiovascular disease, diabetes, arthritis, and cancer due, at least in part, to their anti-oxidant and anti-inflammatory activities.

3. Key Constituents and Mechanisms of Action

3.1 Overview of Bioactive Forms

After digestion, not only intact anthocyanins but also their highly bioactive metabolites such as aglycones, phenolic acids, and phenolic aldehydes contribute to the pharmaceutical effects. Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. The extensive degradation and metabolism of anthocyanins was confirmed in a stable isotope-labelled cyanidin-3-glucoside (C3G) feeding study, in which the relative bioavailability of C3G was established as 12.4 ± 1.4%, suggesting that the extent of anthocyanin absorption and metabolism had been previously underestimated. Furthermore, the observed cardiovascular benefits of anthocyanin consumption are probably the consequence of the metabolites, which are present within the circulation for significantly longer and at higher concentrations than the parent anthocyanins.

3.2 Antioxidant Mechanisms

Biological effects include direct neutralization of reactive oxygen and nitrogen species (RONS), activation of nuclear factor erythroid 2–related factor 2 (Nrf2), inhibition of nuclear factor kappa B (NF-κB), and modulation of the mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and p38 signaling pathways.

Consumption of anthocyanins has been documented to involve interference with signaling pathways, including Nrf2, leading to activation of biosynthesis of antioxidant proteins and NF-κB, and inhibition of inflammation. Anthocyanins can also activate the antioxidant response by promoting the nuclear translocation of Nrf2 or by stimulating the activity of antioxidant enzymes, such as SOD, CAT, and GPx.

3.3 Anti-Inflammatory Mechanisms

Nuclear factor kappa B (NF-κB) is a major regulator for anti-inflammatory and antioxidant effects of anthocyanins. Malvidin-3-glucoside, a major anthocyanin of blueberries and grapes, suppressed TNFα- and IL4-stimulated inflammatory markers in human umbilical vein endothelial cells and peripheral blood mononuclear cells by inhibiting nuclear translocation of p65 of NF-κB. Anthocyanins inhibit the nuclear translocation of NF-κB, thereby preventing the activation of proinflammatory molecules, such as COX-2, iNOS, IL-1β, and TNF-α.

Anthocyanin extracts suppress LPS-induced expression of genes such as tumor necrosis factor (TNF)α, interleukin (IL)1β, inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein (MCP)1, and cyclooxygenase (COX)2.

3.4 Anticancer Mechanisms (Preclinical)

The potential antitumour effects of anthocyanins are reported to be based on a wide variety of biological activities including antioxidant, anti-inflammation, anti-mutagenesis, induction of differentiation, inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest, and stimulating apoptosis or autophagy of cancer cells, as well as anti-invasion, anti-metastasis, reversing drug resistance of cancer cells, and increasing their sensitivity to chemotherapy.

Anthocyanins hinder cell migration, invasion, and proliferation by inducing apoptosis, suppressing cell cycle at G0/G1, S, or G2/M stages, and modulating signaling pathways such as apoptotic cascades, PI3K/Akt, MAPK, and NF-κB. Moreover, anthocyanins downregulate oncogenes (Bcl-2, MYC, and HER2) and improve the activity of tumor suppressor genes (TP53, BRCA1, and RB1).

3.5 Gut Microbiome Interaction

Following consumption, anthocyanin absorption occurs along the gastrointestinal tract, the distal lower bowel being the place where most of the absorption and metabolism occurs. In the intestine, anthocyanins first undergo extensive microbial catabolism followed by absorption and human phase II metabolism. This produces hybrid microbial-human metabolites which are absorbed and subsequently increase the bioavailability of anthocyanins. Another important factor which may mediate the effect of anthocyanins on oxidative stress is the effect on the intestinal microbiome. It should be taken into account that anthocyanins are subject to metabolic transformations and degradation, including by the intestinal microbiome.

4. Scientific Evidence by Health Area

4.1 Cardiovascular Health

Evidence level: Moderate (multiple RCTs and meta-analyses, some inconsistency in effects on blood pressure)

Pooled analysis of RCTs showed that purified anthocyanin supplementation could significantly reduce blood LDL cholesterol (weighted mean difference [WMD]: −5.43 mg/dL, 95% CI: −8.96, −1.90 mg/dL; p = 0.003) and triglyceride (WMD: −6.18 mg/dL, 95% CI: −11.67, −0.69 mg/dL; p = 0.027) while increase HDL cholesterol (WMD: 11.49 mg/dL, 95% CI: 7.43, 15.55 mg/dL; p < 0.001) concentrations. This meta-analysis by Tian et al. (2021) incorporated 44 eligible RCTs and 15 prospective cohort studies.

Purified anthocyanins also markedly decreased circulating tumor necrosis factor alpha (WMD: −1.62 pg/mL, 95% CI: −2.76, −0.48 pg/mL; p = 0.005) and C-reactive protein (WMD: −0.028 mg/dL, 95% CI: −0.050, −0.005 mg/dL; p = 0.014). Administration of anthocyanin-rich berries could significantly lower blood total cholesterol (WMD: −4.48 mg/dL, 95% CI: −8.94, −0.02 mg/dL; p = 0.049) and C-reactive protein (WMD: −0.046 mg/dL, 95% CI: −0.070, −0.022 mg/dL; p < 0.001).

Neither purified anthocyanins nor anthocyanin-rich berries could cause any substantial improvements in BMI, blood pressure, or flow-mediated dilation. The effects of anthocyanins on adiposity, blood pressure, and chronic low-grade inflammation were still conflicting.

An earlier systematic review of 12 RCTs (representing 10 studies) through 2014 corroborated these findings: supplementation with anthocyanins significantly improved LDL cholesterol among diseased individuals or those with elevated biomarkers. Data on study compliance and evaluation of baseline status of flavonoid and/or polyphenol intakes may improve the consistency between small clinical interventions. More carefully controlled longer-duration trials assessing dose response across various populations are needed to adequately determine whether an effect of supplementation exists.

One crossover, randomized, double-blind clinical trial examined the acute effects of fruit-based anthocyanins on vascular and inflammatory responses to a high-fat high-energy meal challenge in overweight older adults. C-reactive protein was lower 4 h postprandially in the anthocyanins arm (1.80 mg/L, IQR 0.90) versus the control arm (2.30 mg/L, IQR 1.95) (P = 0.026), with a trend for lower interleukin-6 (P = 0.075). No significant postprandial differences were observed between treatments for blood pressure, triacylglycerol, total cholesterol, serum derivatives of reactive oxidative metabolites, TNF-alpha, interleukin-1 beta, or maximum microvascular perfusion following iontophoresis of acetylcholine.

4.2 Metabolic Syndrome and Glycemic Control / Type 2 Diabetes

Evidence level: Moderate (growing body of RCTs; effects on HbA1c and insulin resistance are promising but require confirmation)

A narrative review summarizing 18 findings from recent clinical research published over the last 5 years investigated the therapeutic effects of dietary anthocyanins on diabetes. Anthocyanin supplementation has been shown to have a regulatory effect on fasting blood glucose levels, glycated hemoglobin, and other diabetes-related indicators. Increased anthocyanin dosages had more favorable implications for diabetes treatment.

The results showed that consuming pure anthocyanins or anthocyanin-rich meals did not have a significant impact on serum insulin levels while significantly reducing the HOMA-IR index in individuals with type 2 diabetes and those who were overweight or obese.

One clinical study examining anthocyanin supplementation at 320 mg/day for four weeks in subjects with metabolic syndrome found that four weeks of anthocyanin consumption significantly decreased fasting blood glucose (15.7% vs 3.2%), TG (18.2% vs −1.39%), cholesterol (33.5% vs 1.56%), and LDL (28.4% vs −15.6%) in the metabolic syndrome compared to the control group (P-value < 0.05, 95% CI).

Clinical trials demonstrate the efficacy and safety of anthocyanins in controlling glucose, reducing oxidative stress, and enhancing insulin sensitivity in diabetic patients. Regarding anthocyanins' effects on glycemic control, future research should focus on the optimal intervention duration. Alleviating the clinical symptoms of diabetes is a gradual process.

4.3 Cognitive Function and Neuroprotection

Evidence level: Preliminary to moderate (systematic reviews with promising results; heterogeneity in populations and preparations limits firm conclusions)

A systematic literature review and meta-analysis evaluated the effect of chronic anthocyanin intake on various cognitive domains across 30 clinical trials in adult populations (18+ years). Overall, evidence from the narrative synthesis shows that anthocyanin consumption improved multiple aspects of cognition and mood, including verbal learning and memory, executive function, working memory, visual spatial function, psychomotor speed, attention, semantic memory, as well as improved symptoms of depression, fatigue, and anxiety.

The neuroprotective effects of anthocyanins are supported by evidence from in vitro studies using fruit extracts, both as isolated anthocyanins or combinations of different anthocyanins, tested in neuronal primary cultures and cell lines. Pre-clinical rodent studies support the in vitro findings by showing promising effects of anthocyanins on various aspects of cognitive function, such as long-term memory, spatial-working memory, and object-recognition memory. Recent systematic reviews of human studies that have assessed the effect of habitual blueberry consumption as a source of anthocyanins reported general improvement in some aspects of cognitive performance, including verbal memory and mood.

Anthocyanin-rich substances have been shown to improve cognitive function by improving the dynamic balance of neurotransmitters, oxidative stress, inflammation, apoptosis, and signal transduction.

In vitro studies have demonstrated that anthocyanins prevent the intracellular calcium overload, thereby reducing excitotoxicity and the progression of neurodegenerative diseases.

4.4 Vision and Eye Health

Evidence level: Preliminary (mechanistic plausibility established; clinical evidence from well-controlled trials is limited and conflicting)

Anthocyanins are widely used as a supplement for eye health in Europe and in East Asia. The bioavailability of anthocyanins is quite low, but they are reported as intact forms and many kinds of metabolites. Anthocyanins pass through the blood-aqueous fluid barrier and blood-retinal barrier. In vitro studies show anthocyanins had a relaxing effect on ciliary muscle, which is important to treat both myopia and glaucoma. Anthocyanins also stimulate the regeneration of rhodopsin in frog rod outer segment.

In a systematic review of 30 clinical studies to examine the bilberry effect on vision in reduced light conditions, Canter and Ernst found that testing of psychophysical outcome parameters was weak evidence due to a lack of strict study designs (e.g., non-randomized or non-placebo-controlled trials). Canter and Ernst reviewed clinical studies that focused on the use of bilberry anthocyanin supplementation to improve night vision, but the results for these studies were negative.

Anthocyanins could inhibit the axial length and ocular length elongation in a negative lens-induced chick myopia model. Clinical studies of anthocyanin intake have also shown improved dark adaptation, transient myopic shift, and improvement in retinal blood circulation in normal tension glaucoma patients.

4.5 Anti-Inflammatory Effects

Evidence level: Moderate from mechanistic and clinical studies; primarily based on biomarker endpoints in RCTs

Clinical studies using anthocyanins have shown a significant decrease in inflammation markers and oxidative stress, a beneficial effect on vascular function and hyperlipidemia by decreasing LDL and increasing HDL. Increasing evidence from randomized controlled trials (RCTs) and mechanistic studies confirms anthocyanins' potential to prevent oxidative stress and inflammation by modulating important signaling pathways, such as Nrf2 and NF-κB.

4.6 Anticancer Activity

Evidence level: Preclinical only — in vitro and animal data are extensive; clinical evidence in humans remains insufficient to draw therapeutic conclusions

Research has comprehensively documented the anticancer potential of anthocyanins against different types of cancer, including breast, prostate, lung, liver, ovarian, and cervical cancers, by highlighting possible signaling pathways (MAPK, NF-κB, and PI3K/Akt) and gene expression (TP53, BRCA1, and BCL-2).

The challenges of translating in vitro findings to in vivo are significant, highlighting the importance of considering dose, bioavailability, and metabolism when assessing the therapeutic potential of anthocyanins. Current research identifies the need for more long-term clinical trials and investigations into potential synergistic effects with other phytochemicals. Although pre-clinical studies have proven anticancer activities, further clinical trials are required to validate its therapeutic impact and standard dose regimens.

5. Body Systems and Health Areas of Association

• Cardiovascular system: Epidemiological studies have suggested an association between anthocyanin intake and improved cardiovascular risk, type 2 diabetes, and myocardial infarction.
• Metabolic/endocrine system: Evidence from pre-clinical studies indicates their role in glucose level regulation, gut microbiota improvement, and inflammation reduction under diabetic conditions.
• Central nervous system: Anthocyanins have been credited with capacity to modulate cognitive and motor function, to enhance memory, and to have a role in preventing age-related declines in neural function.
• Ocular system: Anthocyanin-rich substances also improve vision and eye health by improving oxidative stress status.
• Gastrointestinal system: In vitro studies report that anthocyanins are able to induce the Nrf2/ARE pathway, which plays a key role in maintaining redox homeostasis in the intestinal mucosa by regulating the expression of detoxifying and antioxidant enzymes. This mechanism seems to be critical for the inhibition of proinflammatory pathways such as the NF-κB one.
• Hepatic system: The utility of anthocyanins as a traditional medicament for liver protection and cure has been documented.
• Immune system: Numerous studies, mostly carried out in cell culture models, have shown that anthocyanins exhibit a wide range of health-promoting properties, including anti-inflammatory, antioxidant, antimicrobial, and anticarcinogenic activities.

6. Dosage Forms and Dosages Reported in Studies

Daily anthocyanin doses applied in clinical trials have ranged from 2.1 to 94.47 mg. However, some studies have used substantially higher doses in purified extract form. Specific dosages reported in the literature include:

• Berry-rich anthocyanin supplements at 320 mg/day for four weeks were examined on features of metabolic syndrome components and the expression of PPAR-γ, Nrf2, and NF-κB-dependent genes in metabolic syndrome and healthy subjects.
• A daily intake of 640 mg of purified anthocyanin extract for 4 weeks followed by a washout period of 4 weeks was used in a study examining blood pressure and stress reactivity.
• One elderberry (Sambucus nigra) extract study involved 52 volunteers divided into two groups; a dose of 500 mg/day of the extract for 12 weeks was used.
• In a randomized, double-blind, placebo-controlled study on cognitive function and eye dryness, 69 male and female healthy volunteers were randomized and divided into placebo, D2, and D4 groups. All subjects consumed 120 mL of placebo or functional soup containing "Anthaplex" either at 2 or 4 g per serving per day within 5 minutes in the morning for eight weeks.
• One pharmacokinetics study utilized a 500 mg oral bolus dose of ¹³C-labelled cyanidin-3-glucoside.

The joint FAO/WHO committee on food additives has recommended an acceptable daily intake of 2.5 mg/kg/day for grape-skin extract anthocyanins, but this recommended dose is not for general anthocyanins.

7. Bioavailability

Anthocyanins are reported to have low bioavailability, with the majority of studies recording a recovery of less than 1% of the ingested anthocyanin dose. The once general view that anthocyanins have poor bioavailability has been refuted, as recent studies have revealed the significant absorption of microbial-derived metabolites of anthocyanins and higher overall bioavailability.

In general, the bioavailability of anthocyanins in humans is affected by several factors, such as their structural characteristics, dosage, simultaneously ingested other foods and nutrients, food matrix, and food processing.

The extensive degradation and metabolism of anthocyanins was recently confirmed in a stable isotope-labelled C3G feeding study in which the relative bioavailability of C3G was established as 12.4 ± 1.4%, based on the recovery of the ¹³C-label in the urine and breath, suggesting that the extent of anthocyanin absorption and metabolism had been previously underestimated.

8. Safety Considerations and Interactions

8.1 General Safety Profile

The prophylactic and curative therapy roles of anthocyanins, together with no reported toxicity at conventional dietary doses, have offered much-needed impetus and economic benefits to these classes of compounds. The broad spectrum of pharmacological properties supported by preclinical and clinical evidence, associated with a low toxicity, make their pharmacotherapeutic use very attractive.

The joint FAO/WHO committee on food additives has recommended an acceptable daily intake of 2.5 mg/kg/day for grape-skin extract anthocyanins, but this recommended dose is not for general anthocyanins. The European Food Safety Authority decided the recently available toxicologic database could not confirm a numerically suitable daily intake for anthocyanins.

Some animal toxicity data merit note. Shuping et al. (2023) conducted acute and sub-acute toxicity studies on Sprague Dawley rats and mice. For acute oral toxicity, mice were fed on 8,000 mg/kg/day of Lycium ruthenicum anthocyanins extract via intragastric route, and no toxic signs were observed during 14 days. However, Abdelgadir et al. (2024) supplemented Wistar rats with different doses of anthocyanins (10 mg/kg BW, orally) combined with curcumin or sodium nitrite per day for repeated sub-acute toxicity (28 days), finding augmented AST, CK, and LDH enzyme activity, altered hematological parameters, and histopathological abnormalities in the liver and kidneys. They concluded that anthocyanins combined with other substances might induce toxic effects.

8.2 Drug–Nutrient Interactions

The main clinical concern with anthocyanin therapeutics is that certain drugs interact with anthocyanins. Studies have shown that the cytochrome P450 enzyme, which is involved in drug metabolism, is inhibited by flavonoids. An efflux transporter called P-glycoprotein, which decreases the absorption of certain drugs, is also affected.

Interaction of anthocyanins with drug-metabolizing enzymes and transporters may affect the fate of co-administered drugs and thus exert pharmacological consequences.

Anthocyanins can bind to iron, thus decreasing its absorption in the intestine. Some anthocyanins also inhibit cellular absorption of vitamin C.

Regarding anticoagulant interactions, available data from randomized, placebo-controlled clinical trials do not seem to show a clinically relevant interaction between cranberry juice and warfarin. Nevertheless, patients using warfarin with cranberry juice should be closely monitored and warned about potential interaction.

Regarding antiplatelet activity, overall, one clinical study showed that anthocyanins had no significant adverse effect on participants. Due to the bleeding risk of antiplatelet drugs, anthocyanin seems to be a promising alternative for inhibiting platelet hyperactivity and expression of adhesion molecules in individuals with dyslipidemia.

As nutraceuticals contain concentrated bioactive agents, consumed doses exceed those that could be obtained from food. Therefore, apart from anticipated improvement of human health, it is essential to have in mind the possible unexpected effects of anthocyanins.

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