Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability
Abstract
:1. Introduction
2. Chemistry and Natural Sources of ACNs
3. Immunomodulatory Potential of ACNs
- Inflammation disrupts immune homeostasis, leading to diverse diseases or disease conditions. However, ACNs have been proven to play a crucial role in regulating inflammatory pathways by inhibiting the production of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and proinflammatory mediators (COX, LOX, MPO, and PGE2), thereby offering protection against the development of various inflammatory conditions [29,32,50];
- ACNs influence immune cell activation and proliferation by modulating various pathways. Moreover, they have a significant impact on gene expression within immune cells, leading to the heightened expression of genes responsible for antioxidant defense, anti-inflammatory pathways, and immune cell activation [29,51,52];
- Recent research indicates that ACNs can influence gut microbiota composition and functionality. Given the pivotal role of the gut microbiota in regulating the immune system, this interaction has the potential to contribute significantly to the immunomodulatory effects exhibited by ACNs [53,54,55,56,57].
4. Gut Microbiota in the Immunity and Metabolism of ACNs
5. Nutraceutical Potential of ACNs
6. Factors Influencing Pharmacokinetics of ACNs
7. Strategies for Enhanced ACN Bioavailability
8. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Anthocyanin and Its Aglycons | Dose | Methodology | Major Findings | Reference |
---|---|---|---|---|
Cyanidin-3-glucoside | 100 μM | In Vitro Osteoclasts from C57BL/6J mice cultured with M-CSF (30 ng/mL) and the receptor activator of a nuclear factor kappa B ligand (RANKL) (100 ng/mL) and supplemented with the test sample. | Inhibited osteoclast differentiation and formation induced by RANKL. | [60] |
Protocatechuic acid (anthocyanin metabolite) | 0–25 μM | In Vitro Osteoclasts from ICR mice were cultured in the presence of M-CSF (30 ng/mL) and RANKL (50 ng/mL) and treated with the test sample. | Inhibited RANKL-induced osteoclast differentiation and suppressed the bone-resorbing activity of mature osteoclasts. | [61] |
25 mg/kg/d | In Vivo Nine days of administration in LPS (5 mg/kg)-induced bone destruction in male ICR mice. | Recovered the bone volume per tissue volume, trabecular separation, and trabecular number. | ||
Delphinidin | 50 μM | In Vitro Jurkat E6-1 cells were preincubated with gadolinium and N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide for 15 min. | Induced Ca2+ and Sr2+ influx through the CRAC channel and induced NFAT pathway activation; thereby, the production of IL-2 occurs. | [62] |
Anthocyanidins | 5–20 μM | In Vitro TPA (20 ng/mL)-induced cell transformation was investigated in the parental JB6 Cl41 cells or AP-1-luciferase stable transfectant JB6 cells. | Ortho-dihydroxyphenyl structure (delphinidin) on the B-ring of aglycon inhibited cell transformation and activator protein-1 transactivation. | [63] |
Delphinidin | 25–100 μM | In Vitro RAW264 cells were treated with LPS (40 ng/mL) for 6 h. | Inhibited MAPK-mediated COX-2 expression. | [64] |
Cyanidin-3-O-galactoside and cyaniding-3-sambubioside rich extract of Sambucus ebulus | 200 mL infusion | Interventional study Fifty-three volunteers enrolled in a 4-week intervention involving the consumption of infusion. | Decreased pro-inflammatory status and complemented activity markers in healthy volunteers. | [65] |
Cyanidin-3-O-glucoside and peonidin-3-O-glucoside rich fraction of black rice germ and bran. | 0–200 μg/mL | In Vitro A549 cells and THP-1 macrophages exposed to SARS-CoV-2 spike glycoprotein S1 (100 ng/mL). | Inhibited NF-κB activity and the NLRP3 inflammasome pathway, leading to the inhibition of inflammatory genes and cytokine secretions. | [66] |
Cyanidin-3-O-glucoside | 0–20 μg/mL | |||
Peonidin-3-O-glucoside | 0–20 μg/mL | |||
Cyanidin-3-O-glucoside delivered by enteric sodium alginate | 25 mg/kg/d | In Vivo Male BALB/c mice received two sensitization doses of 100 µg ovalbumin and 2.0 mg alum, administered in 200 µL of phosphate-buffered saline via intraperitoneal injection on day 0 and day 14. | Enhanced the intestinal epithelial barrier by up-regulating the tight junction protein expression and promoting secretory IgA and β-defensin secretion and regulated Th1/Th2 immune balance in the intestinal mucosa. | [67] |
Anthocyanin-rich roselle extract | 0–400 mg/kg | In Vivo 1-day-old Ross 308 broiler chicks were fed on basal diets supplemented with extract for 35 days. | Improved metabolic functions, blood biochemistry, intestinal morphology, antioxidant activity, immune status, and higher ω-3 content in the breast muscle. | [68] |
Cyanidin-3-glucoside-enriched diet. | 26 mg/kg/d | Ex Vivo Myocardial ischemia/reperfusion (I/R) injury in mice. Pretreated with the sample for a month. | Diet changed the microbiome and the transplantation of the fecal microbiota transferred the cardioprotection. | [69] |
Total anthocyanin from boysenberry and apple juice concentrate | 2.5 mg/kg | In Vivo Ovalbumin-induced airway inflammation in male C57BL/6J mice. | Reduced immune cell infiltration and tissue damage. | [71] |
Cyanidin 3-O-glucoside | 10 mg/kg | In Vivo Five-week-old male spontaneously hypertensive and Wistar-Kyoto rats were treated daily for a period of 15 weeks. | Treatment normalized the splenic production of TNFα and IFNγ and the proportion of CD62Llo and CD62L− helper T-cells. | [74] |
Cyanidin-3-O-glucoside | 25 mg/kg | In Vivo Treated twice per week for six consecutive administrations in Sprague Dawley with bovine type II collagen-induced arthritis. | The study suggests that CD38+ NK cells inhibiting Treg cell differentiation may contribute to the immune imbalance seen in both rheumatoid arthritis and collagen-induced arthritis. | [75] |
25–100 μM | In Vitro RA synovial fibroblasts collected from arthritic patients. | |||
50 μM | In Vitro Mononuclear cells were collected from arthritic patients. | |||
50 μM | In Vitro Mononuclear cells were cocultured with CD38+ NK cells. | |||
Delphinidin-3-O-glucoside and cyanidin-3-O-glucoside | 50–600 µg/mL | In Vitro Both the compounds alone or in combinations were added and incubated with HCT-116 and HT-29 human colorectal cancer cells for 24 h. | Both showed potential for binding with and inhibiting immune checkpoints, PD-1 and PD-L1, which can activate the immune response in the tumor microenvironment and induce cancer cell death. | [76] |
Anthocyanin-rich mix | 40 mg/kg BW | In Vivo High-fat-diet-induced obesity, dyslipidemia, insulin resistance, and steatosis in C57BL/6J mice. | Increased glucagon-like peptide-2 levels, the intestinal hormone that upregulates tight junction protein expression. | [77] |
Anthocyanin-rich mix (AC mix) | 5 μg/mL | In Vitro Caco-2 cell monolayers were pre-incubated for 24 h with IFNγ (10 ng/mL) to upregulate the TNFα receptor. | PCA, C3G, and the AC mix, fully prevented p65, ERK1/2, and MLC phosphorylation. D3G inhibited TNFα-triggered p65 phosphorylation; Peo3G had no effect. | |
Protocatechuic acid (PCA) | 0.5 μM | |||
Delphinidin-3-O-glucoside (D3G) | 0.5 μM | |||
Cyanidin-3-O-glucoside (C3G) | 1 μM | |||
Peonidin-3-O-glucoside (Peo3G) | 0.1 μM | |||
Cyanidin-3-glucoside-rich anthocyanin extract of Lonicera caerulea fruit | 0–0.8 mg/mL | In Vitro Human hepatoma cell line SMMC-7721. | Inhibits proliferation of the tumor cells. | [78] |
50, 100 and 200 mg/kg BW | In Vivo Tumor-bearing male Kunming strain mice model was established using the murine H22 hepatoma cells line. Treated with sample for 15 days. | Extract effectively combats tumours by dynamically adjusting the redox balance and enhancing immunoregulatory activity. | ||
Cyanidin-3-O-glucoside | 20 and 40 μM | In Vitro TNF-α-stimulated intestinal cells tested on endothelial cell activation by using cocultures (Caco-2, HUVEC, and mononuclear cells) | Inhibited NF-κB pathway in epithelial cells. | [79] |
Cyanidin chloride and cyanidin 3-O-glucoside | 0–25 μM | In Vitro LPS- (100 ng/mL) or IFNγ- (10 ng/mL) induction in immortalized mouse microglial (bv-2) cells pretreated with samples. | Both compounds reduced ROS production in a dose-dependent manner. Cyanidin chloride showed a maximum decrease in NO production. | [80] |
Cyanidin-3-glucoside chloride | 1.25–5.0 μg/mL | In Vitro EL-4 T cells were pretreated with various concentrations of the sample for 1 h and stimulated with PMA/ionomycin for 16 h. | Suppressed Th2 activation through the downregulation of Th2 cytokines and the GATA3 transcription factor. | [81] |
Black raspberry Ethanol extract | 0–200 μg/mL | In Vitro Normal donor peripheral blood mononuclear cells were induced with IL-6 and GM-CSF (10 ng/mL) and were pretreated with samples for 7 days. | Limited expansion of myeloid-derived suppressor cells (MDSC). Attenuated IL-6-mediated phosphorylation of STAT3 and IL-2-induced STAT5 phosphorylation. Pretreatment of immune cells inhibited MDSC expansion and IL-6-mediated STAT3 signalling. | [82] |
Cyanidin-3-rutinoside | 0–200 μM | |||
Delphinidin-3-glucoside | 0–100 μM | In Vitro BM185 cells were incubated with test samples for 48 h. | Inhibited cell proliferation dose-dependently. | [83] |
Cyanidin-3-rutinoside | 0–100 μM | |||
Anthocyanin-rich berry extract | 10–100 μg/mL | |||
Cyanidin-3-rutinoside | 50 mg/kg/d | In Vivo Eight-week-old female Balb/c mice challenged with BM185 cells treated with samples for 21 days. | Moderate induction of caspases. | [83] |
Anthocyanin-rich berry extract | 500 mg/kg/d | |||
Cyanidin glycosides-rich juice (total polyphenol = 236 mg) | 330 mL/d | Clinical trial Randomized, crossover study divided into five periods each lasting two weeks. | Enhanced antioxidant status, reduced oxidative DNA damage, and stimulated immune cell functions (IL-2 production). | [84] |
Proanthocyanidins | 30 µM | In Vitro LPS (10 ng/mL) or IL-4 (1 ng/mL) activated murine J774 macrophages. LPS (10 ng/mL) or IL-4 (1 ng/mL) activated human U-937 monocytes. | Enhanced the expression of Arg-1 and MRC-1 in a dose-dependent manner. Enhanced the phosphorylation of STAT6. Increased CCL-17 expression. | [85] |
Delphinidin 3-O-β-d-glycoside | 50 µM | In Vitro LPS-induced mesenchymal stem cells. | Modified the immunomodulatory properties and increased the IL-10 production. | [86] |
Black lentil water extract | 600 mg/kg BW | In Vivo Azoxymethane/dextran sodium sulphate-induced C57BL/6 mice model. | Modulated cytokines are involved in mediating communication between immune cells and anti-inflammatory action. Reduced colon mucosa of markers like IL-1β and IL-6 and gene expression, such as CXCR2 and CSF3. | [87] |
Delphinidin 3-O-(2-O-β-D-glucopyranosyl-α-L-arabinopyranoside rich lentil extract | 41 mg/kg BW | |||
Delphinidin chloride | 20 and 40 µM | In Vitro CD4+ T cells were purified from the spleen of C57BL/6 mice and were activated with 1 µg/mL of plate-bound anti-CD3 and plate-bound anti-CD28 antibodies in the presence samples for 3 days. | Promoted the differentiation of Tregs and enhanced immune response control. | [88] |
1.5 and 3 mg/kg | In Vivo allograft model Five-week-old male C57BL/6 mice were subcutaneously injected with a fixed number of P815 cells | Reduced activated T cells by promoting Treg differentiation. | ||
Delphinidin | 10−2 g/L | In Vitro T-lymphocytes from non-metabolic-syndrome and metabolic syndrome patients were stimulated for 24 h with the sample and 5 µg/mL of PHA. | Inhibited Ca2+ signalling via reduced store-operated Ca2+ entry and release and the subsequent decrease of HDAC and NFAT activations. Also inhibited ERK1/2 activation and suppressed differentiation of T cells toward Th1, Th17, and Treg without affecting Th2 subsets. Prevented the PHA-induced proliferation in cells isolated from WT. Inhibited HDAC activity by a mechanism downstream of its effect on Ca2+ signaling. | [89] |
Peripheral blood mononuclear cells isolated either from 57BL/6 females ERα Wild-Type or Knock-Out mice stimulated for 48 h with 5 µg/mL of PHA. | ||||
T-lymphocytes stimulated with thapsigargin (1 µM). | ||||
Delphinidin | 0–20 µM | In Vitro Normal Human epidermal keratinocytes treated with rhIL-22 and TPA. | Suppressed key kinases involved in psoriasis pathogenesis and alleviated IMQ-induced murine psoriasis-like disease, suggesting a novel PI3K/AKT/mTOR pathway modulator for psoriasis. | [90] |
Delphinidin | 0–50 µM | In Vitro Caspase activation in human prostate LNCaP and Du145 cells treated with sample for 12 h. | Sensitized prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, causing caspase-mediated HDAC3 cleavage. | [91] |
Delphinidin | 0–50 µM | In Vitro MH7A and Jurkat cells were treated with the sample and cultured for 2 h with TNFα or LPS. | Inhibited NF-ĸB expression, thereby decreasing cytokine expression. | [92] |
Resveratrol and peonidin 3-O-glucoside rich red grape vine leaf extract | 100 μg/mL | In Vitro THP-1 cells were stimulated with 2 μg/mL Cy3-labeled DNA for 4 h. | Restricted the AIM2 inflammasome activation by preventing DNA entry. | [93] |
140 mg/kg | In Vivo Treated in IMQ-induced BALB/c mice (6–9 weeks old) model for 5 days. | Inhibited proinflammatory caspase-1 activation, IL-1β maturation, and IL-17 production. | ||
Malvidin-3-O-glucoside | 10 µM | In Vitro Murine microglia primary cultures primed and activated with LPS. | Targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase-1 and IL-1β protein levels. Stopped the release of IL-1β in the hippocampus. | [94] |
12.5 mg/kg/d | In Vivo Chronic unpredictable stress was subjected to the mice for 28 days, consisting of different stressors. A 2-week pretreatment was followed. | |||
Malvidin-3-O-glucoside | 0.5 µg/kg/d | In Vivo C57BL/6 male mice were treated with the sample for 2 weeks before and throughout repeated social defeat stress and then performed social avoidance/interaction testing. | Modulated synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. | [95] |
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Ijinu, T.P.; De Lellis, L.F.; Shanmugarama, S.; Pérez-Gregorio, R.; Sasikumar, P.; Ullah, H.; Buccato, D.G.; Di Minno, A.; Baldi, A.; Daglia, M. Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability. Nutrients 2023, 15, 4152. https://doi.org/10.3390/nu15194152
Ijinu TP, De Lellis LF, Shanmugarama S, Pérez-Gregorio R, Sasikumar P, Ullah H, Buccato DG, Di Minno A, Baldi A, Daglia M. Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability. Nutrients. 2023; 15(19):4152. https://doi.org/10.3390/nu15194152
Chicago/Turabian StyleIjinu, Thadiyan Parambil, Lorenza Francesca De Lellis, Santny Shanmugarama, Rosa Pérez-Gregorio, Parameswaran Sasikumar, Hammad Ullah, Daniele Giuseppe Buccato, Alessandro Di Minno, Alessandra Baldi, and Maria Daglia. 2023. "Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability" Nutrients 15, no. 19: 4152. https://doi.org/10.3390/nu15194152
APA StyleIjinu, T. P., De Lellis, L. F., Shanmugarama, S., Pérez-Gregorio, R., Sasikumar, P., Ullah, H., Buccato, D. G., Di Minno, A., Baldi, A., & Daglia, M. (2023). Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability. Nutrients, 15(19), 4152. https://doi.org/10.3390/nu15194152