Health Effects of European Elderberry and American Elderberry: History
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Contributor:
Ahmed G. Osman
,
Bharathi Avula
,
Kumar Katragunta
,
Zulfiqar Ali
,
Amar G. Chittiboyina
,
Ikhlas A. Khan

Elderberry is highly reputed for its health-improving effects. Multiple pieces of evidence indicate that the consumption of berries is linked to enhancing human health and preventing or delaying the onset of chronic medical conditions. Compared with other fruit, elderberry is a very rich source of anthocyanins (approximately 80% of the polyphenol content). These polyphenols are the principals that essentially contribute to the high antioxidant and anti-inflammatory capacities and the health benefits of elderberry fruit extract. These health effects include attenuation of cardiovascular, neurodegenerative, and inflammatory disorders, as well as anti-diabetic, anticancer, antiviral, and immuno-stimulatory effects.

  • Sambucus nigra
  • Sambucus canadensis
  • extracts
  • elderberry fruit

1. Link between Antioxidative Activity and Boosting the Immune System

People who are immunocompromised or have a weakened immune system are more vulnerable to infections and other diseases. Low immunity may be ascribed to certain diseases or conditions, such as acquired immunodeficiency syndrome (AIDS), cancer, diabetes, malnutrition, certain genetic disorders, and certain medicines/treatments, such as anticancer drugs, radiation therapy, and stem cell or organ transplants.
An imbalance between reactive oxygen species (ROS)––a result of the immune system response––and the antioxidant defense may lead to the development of oxidative stress-induced systemic inflammation. This condition subsequently impairs immune reactivity, in turn, increasing susceptibility to disease. Polyphenols including anthocyanins possess a powerful antioxidant capacity, and the high intake of dietary anthocyanins or sources rich in anthocyanins, such as elderberry, can mediate the restoration of the balance between oxidants and antioxidants [1][2]. Polyphenols including anthocyanins act by scavenging for the ROS liberated from the immune cells, preventing the self-destruction of immune cells, while also inducing antioxidant enzymes. Antioxidant polyphenols help to restore the reactivity of the immune response, impaired by the excessive generation of ROS [3][4][5].

2. Effect of Elderberry Fruit Extracts on Oxidative Stress

Free radicals are highly reactive atoms or molecules. ROS and reactive nitrogen species (RNS) are derivatives of oxygen and nitrogen, respectively. ROS comprise O2•− superoxide, •OH hydroxyl radical, 1O2 singlet oxygen, H2O2 hydrogen peroxide, and ONOO− peroxynitrite [6]. ROS and RNS are generated in all aerobic cells and are implicated in aging as well as in age-related diseases [7]. Despite the damage they cause in cells and tissues, ROS and RNS play an important role in the generation of energy from organic molecules, in immune defense, and in signaling pathways [8]. There are endogenous and exogenous sources of ROS and RNS. The endogenous sources comprise nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), myeloperoxidase (MPO), lipoxygenase, and angiotensin II. Superoxide, or radical superoxide anion (O2•−), is the origin of ROS and RNS, while mitochondria are the major origin of O2•− [6]. The predominant source of the radical superoxide anion (O2•−) is NADPH oxidase. Most of the O2•− is dissociated into hydrogen peroxide (H2O2) by superoxide dismutase (SOD) [8]. H2O2 is dissociated into the highly reactive hydroxyl ion (•OH). Hydroxyl radicals react with phospholipids in cell membranes, lipids, polypeptides, proteins, and nucleic acids.
The exogenous sources of ROS and RNS include oxygen, air, and water pollution, tobacco, alcohol, heavy or transition metals, certain drugs, industrial solvents, and radiation. These substances are metabolized in the body into free radicals [9]. ROS and RNS react with the cellular macromolecules, including carbohydrates, lipids, proteins, and DNA [10]. Antioxidants provide protection against cell and tissue injury by reactive free radicals. This defense system includes endogenous and exogenous antioxidants. Endogenous antioxidants comprise the enzymes, superoxide mutase SOD, catalase (CAT), glutathione peroxidase (GSH-Px), glutathione-S-transferase, and glucose-6-phosphate dehydrogenase [11]. The exogenous non-enzymatic defense system includes ascorbic acid, which is responsible for scavenging for the hydroxyl and superoxide radical anion, α-tocopherol, which protects against lipid peroxidation of cell membranes, vitamin A, glutathione, and polyphenols [6]. Oxidative stress is a natural phenomenon initiated by an imbalance between oxidative agents (ROS and RNS) and antioxidants. This is caused by the excessive production of these oxidative species in the cells and tissues, exceeding the capacity of the antioxidants, or by the diminished ability to scavenge for these radical or to restore the damaged cells or tissues [10]. There is a close relationship between oxidative stress, inflammation, and aging. Chronic oxidative stress and inflammation feed each other and, consequently, increase age-related morbidity and mortality [12][13]. Oxidative stress plays a major role in aging [6][14], and its persistence over a long duration leads to the development of chronic medical conditions, such as diabetes [15], cardiovascular [16][17][18][19] and cardiac disease [20], hypercholesterolemia [21], neurodegenerative disorders [22], inflammation, cancer [23], and autoimmune diseases [24]. Oxidative stress is more likely to happen when the body has low levels of antioxidants. Antioxidants have an enormous effect on preventing, reducing the risk, or attenuating the severity of heart disease, glucose homeostasis, cancer, and other oxidative stress-related disorders [25][26][27][28]. Therefore, the consumption of large quantities of polyphenol-rich vegetables and fruit––rich sources of antioxidant polyphenols––protects against the potential development of oxidative stress-mediated health disorders.
Anthocyanins, which are the major fraction of the constituents of the European elderberry (S. nigra) and the American elderberry (S. canadensis), are polyphenolic compounds. These are a subclass of flavonoids and are the most commonly occurring flavonoids in food. The proportion of anthocyanins is estimated to be approximately nine times higher than other nutritional flavonoids in certain food products. Anthocyanins are water-soluble glycosides; chemically, they are derivatives of the 2-phenylbenzopyrylium or flavylium salts. 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. The term “anthocyanin” is assigned to the glycoside, while “anthocyanidin” is assigned to the aglycone [29]. Anthocyanins are more stable in acidic solutions (pH 1–3), where they occur as flavylium cations. These colored constituents occur in a variety of berries and fruit [30].
The composition of anthocyanin content (the chemical profile of anthocyanin) is dependent on the cultivar, maturity, season of collection, geographic region, and other factors [31][32]. Anthocyanins have shown the ability to attenuate ROS and RNS in human, animal, and in vitro studies [33][34][35][36]. The therapeutic and health-promoting effects of anthocyanins are attributed to their anti-inflammatory and antioxidant activities. Moreover, anthocyanins contribute to the alleviation of the severity of diabetes, obesity, and cancers via inhibition of the NF-κB-mediated inflammatory pathways. Nevertheless, substantial disparities in the effects of anthocyanins have been observed, primarily due to the structural diversity of anthocyanins [37].
Preclinical studies have demonstrated that extracts of the S. nigra berry, which is rich in anthocyanins, exhibit a wide spectrum of bioactivities, including anti-inflammatory, antioxidant, antiviral, antiproliferative, anti-diabetic, and immune-stimulatory activities [38][39], as well as improving blood pressure and dyslipidemia [40]. The neuroprotective effects of elderberry extract were reported in research performed under a neurodegeneration research-driven hypothesis focused on microglial activation or amyloid-β peptide toxicity [39]. In addition, anthocyanins show cytoprotective, antitumor, anti-obesity, and lipidomic effects. Epidemiological evidence indicates the existence of a direct correlation between anthocyanin intake and a lower incidence of chronic and degenerative disorders [41]. The significant antioxidant activity of these polyphenolic constituents, which has been verified at multiple levels of research, constitutes the basis for the underlying mechanism of action in many of their health-enhancing properties. Anthocyanins have been implicated in the regulation of cholesterol metabolism, with the ability to significantly reduce blood levels of cholesterol and triglycerides in the liver [42]. Further, anthocyanins have been reported to exhibit neuroprotective effects, which have been verified based on in vitro and in vivo studies [29][43][44][45].
Moreover, anthocyanins have been reported to play a role in the induction of antioxidant enzymes. In addition to the free-radical scavenging pathway, other mechanisms and pathways are implicated in the pharmacological and health-enhancing effects of anthocyanins, including the cyclooxygenase pathway, the mitogen-activated protein kinase pathway, and inflammatory cytokines signaling [46]. Elderberry fruit extract has reportedly inhibited oxidative stress in a dose-dependent manner, with 1.0 mg/mL of colon-digested elderberry fruit extract exerting an antioxidant activity that was able to protect colon cells against the harmful effects of oxidative stress. This effect was achieved by decreasing the production of excessive intracellular ROS and preventing the oxidative damage of DNA in human mucosal cells of the colon. The major constituents of elderberry fruit extract are the polyphenols, anthocyanins, representing approximately 80% [3]. Oxidative stress is linked to diseases such as diabetes, heart injury, liver injury, and renal dysfunction. ROS produce signaling responses, cause disruption of cellular functions, and lead to tissue damage [47]. Oxidative stress also contributes to the pathogenesis of neurodegenerative diseases [48]. A large body of literature pertaining to in vitro, in vivo, and human trials has demonstrated the health functions of elderberry based on the attenuation of oxidative stress via its antioxidative effect and its anti-inflammatory, anti-diabetic, cardiovascular-protective, and neuroprotective activities. The in vitro and in vivo antioxidant effects of elderberry fruit extract are mediated by regulating antioxidant enzymes (e.g., SOD, GPx, and NOX4), which suppresses intracellular ROS and reduces cell and tissue damage. The pharmacological effects of elderberry fruit extract are ascribed largely to the polyphenolic constituents, anthocyanins, being present as the largest portion of the total constituents of the elderberry fruit [3].

3. Effect of Elderberry on Huntington’s Disease

Huntington’s disease (HD) is a genetically inherited, progressive brain disorder. It is one of the neurodegenerative diseases. This disease damages the striatum, cerebral cortex, and basal ganglia; however, the striatum is the first area to be affected. HD is manifested by uncontrolled movements, emotional problems, and cognitive decline, later followed by loss of cognitive function. It causes the gradual breakdown and death of nerve cells (neurons) in parts of the brain. Oxidative stress has been demonstrated to play a critical role in the onset of HD, though the exact mechanism of the pathological events has not been elucidated. Elderberry, rich in anthocyanins, which are reported to suppress oxidative stress, was examined in vivo on a rat model as a potential therapeutic candidate for the treatment of HD or the attenuation of the severity of the disease. Thus, in a recently published study on the role of elderberry extract in the treatment of HD, a ground material of lyophilized elderberry fruit was added to the diet of rats injected with 3-nitropropionic acid in an experimental model of HD (the 3-NP-induced rat model of Huntington’s disease) for two months. This was compared with a control group of HD model rats, which had been fed on an ordinary standard diet. Rats fed on the diet containing elderberry showed significant recovery of their motor and muscle coordination in the 3-nitropropionic acid injected rats compared with the control group. In addition, feeding the HD model rats with the elderberry diet resulted in a significant drop in the 3-nitropropionic acid-induced elevated caspase-3 and TNF-α levels. The incorporation of elderberry extract into the diet of the HD model rats significantly enhanced the antioxidative ability of the striatum to suppress ROS generation. There was also a noticeable elevation in the level of glutathione, possibly associated with motor recovery. The underlying mechanism was presumably based on augmenting the antioxidative action and attenuating neuro-inflammation in the HD model rats, properties that anthocyanins are well known to exhibit [49].

4. Anti-Inflammatory Effects of Elderberry Extract

In an investigation of characterized extracts prepared from the three main Portuguese elderberry cultivars (“Sabugueiro,” “Sabugueira,” “Bastardeira”), the extracts were evaluated in lipopolysaccharide-stimulated RAW 264.7 cells for their potential anti-inflammatory and cellular antioxidant bioactivities. The lipopolysaccharide-stimulated RAW 264.7 cells (monocyte/macrophage-like cells) that were treated with elderberry extract showed dose-dependent inhibition of nitric oxide release, indicating an anti-inflammatory effect of elderberry extract. In another experiment, hepG2 and Caco-2 cells treated with elderberry extract were not affected by the tert-butyl hydroperoxide (t-BOOH) induced toxicity. In a third experiment on Caco-2 cells that were treated with elderberry extract, it was found that the production of ROS was suppressed and abnormal morphological changes and DNA fragmentation were absent. This experiment provided evidence of the protective role of elderberry extract against the toxicity exerted by t-BOOH oxidative stress. The overall results of this research demonstrate the ability of elderberry extract to inhibit and suppress oxidative stress and inflammation [50].

5. Effects of Elderberry Extract on Diabetes

Dried extract of S. nigra fruit was evaluated for its effects on diabetes mellitus using streptozotocin-induced diabetes in rats. The key components of the examined extract were anthocyanins, along with other phenolic constituents. The results of this study showed that the atherogenic index (AI) in diabetic rats was significantly higher than in the healthy groups and higher than the AI for the group of diabetic rats that were administered the elderberry extract. These results demonstrate the ability of elderberry constituents (mainly anthocyanins) to maintain AI values within normal limits. Additionally, the glycosylated hemoglobin in the diabetic rats was reduced due to the administration of the elderberry extract. However, the serum levels of the antioxidants, GSH-Px and GSH, in the diabetic rat group were significantly lower than the levels of the healthy groups and of the group of diabetic rats that were administered elderberry extract. The suppression of endogenous antioxidants is attributed to the oxidative stress developed in response to diabetes. Further, lipid peroxide generation was diminished and LDL oxidation was inhibited by the effects of the elderberry extract. This study demonstrated the antioxidative activity of S. nigra fruit extract and its beneficial effects on diabetic rats [51].

6. Role of Elderberry Anthocyanin in Attenuating Diabetes

An extract of anthocyanins, composed of cyanidin 3-O-glucoside, the main component of elderberry extract, was shown to modulate carbohydrate metabolism and glycaemia by inhibiting certain enzymes, such as α-glucosidase and dipeptidyl peptidase 4 (DPP-4). These effects have been demonstrated in vitro, in vivo, and in clinical trials [29][52]. Epidemiological studies associate the consumption of anthocyanins with a lower risk of type 2 diabetes. The anti-diabetic effects of anthocyanins and proanthocyanins were reported in several clinical trials. In addition, anthocyanins can also protect pancreatic cells from glucose-induced oxidative stress [53]. Anthocyanin and anthocyanidin were reported to improve glucose homeostasis by influencing the mass and function of β-cells, insulin sensitivity, and glucose uptake [54].

7. Elderberry Extract as Adjuvant Therapy for the Treatment of Hypertension

Renin inhibitors are a class of pharmaceutical drugs used to control elevated blood pressure. However, renin inhibitors such as “Aliskiren” cause adverse effects and may cause severe hypotension. A polyphenol extract of S. nigra (PP) was evaluated as adjuvant therapy when combined with Aliskiren to augment its efficacy and possibly attenuate its adverse effects. This was accomplished by carrying out an in vivo study on L-NAME-induced hypertension in rats (drug-induced hypertension). The study extended over 8 weeks and investigated the combination effects on blood pressure, lipid profile, and oxidative stress in rats.
This research demonstrated that administration of the combined therapy (the polyphenol extract of S. nigra and Aliskiren) resulted in elevating the antioxidant capacity in L-NAME-induced hypertension in rats through the suppression of oxidative stress. Moreover, blood pressure was normalized compared with the severe hypotension showed in the animal group that was fed on a diet devoid of S. nigra extract but injected with Aliskiren.
Treatment with the combined therapy showed blood pressure approaching the control group. Additionally, HDL levels in the combined therapy group approached those of the control group and were significantly higher than HDL levels in the induced hypertension group. [40].

8. Elderberry Extract as Potential Senolytics

The anthocyanins of S. canadensis were reportedly shown to have potential antiaging effects since they exhibited antioxidant and anti-inflammatory properties [55]. The primary cause of aging and age-related diseases is cell senescence and, consequently, the accumulation of senescent cells in different tissues. Accelerated generation of ROS results in cellular senescence in addition to cellular apoptosis, necrosis, and autophagy [55][56]. Compelling evidence suggests that aging is the main risk factor in initiating many chronic diseases, disabilities, and declining health. The prevalent age-related diseases include Alzheimer’s disease, Parkinson’s disease, cataracts, macular degeneration, glaucoma, atherosclerosis, hypertension, type 2 diabetes, and cancer. Senescent cells are aged cells that permanently stop division (cell cycle arrest) and show resistance to apoptosis, diminishing the regenerative and reparative capability of tissues. Nevertheless, senescent cells are alive, active, and accumulate in various tissues of the body, releasing harmful substances that inflict inflammation and damage on the surrounding healthy cells. Senescent cells may be implicated in the development of cancers and other age-related diseases [57]. Senescence is activated by several cellular stresses. The formation of senescent cells occurs during the course of life and has been shown to have a beneficial role in different physiological and pathological processes, such as wound healing, tumor suppression, and host immunity. However, the steady production of senescent cells with age has adverse consequences. The senescent cells release pro-inflammatory cytokines, responsible for initiating aging-related diseases and morbidity. Thus, the clearance of senescent cells may ameliorate aging-associated health disorders [57][58].
ROS generation has been implicated in the induction of senescence [59]. Conversely, apoptosis and autophagy pathways have been reported to play pivotal roles in the elimination of senescent cells and damaged tissues [58][59]. The use of senolytics has become a promising approach to delay cellular senescence. Senolytics are drugs that have the ability to selectively induce apoptosis of the senescent cells and reduce age-related degeneration of tissues. The human body needs continuous and controlled cell proliferation to replace senescent cells and damaged cells in order to maintain normal functions. The PI3K/AKT/mTOR pathway is an intracellular signaling pathway that is involved in regulating the cell cycle. Hence, this pathway is implicated in cellular quiescence, proliferation, cancer, and longevity. mTOR is a 289-kDa serine/threonine protein kinase in the PI3K-related protein kinases (PIKK) family. The PI3K/AKT/mTOR signaling pathway has also been reported as a vital pathway in regulating cell senescence [60]. The activation of mTOR signaling initiated cell entry into a phase characterized by increases in cell size and increases in cell number. Additionally, the mTOR pathway regulates the accumulation of biomass and metabolism by modulating essential cellular processes, including protein synthesis and autophagy. Consequently, dysregulation of mTOR signaling has reportedly been involved in metabolic disorders, neurodegeneration, cancer, and aging [60]. Furthermore, significant activation of PI3K/Akt/mTOR signaling has been observed in aging cells, but not in young cells [61]. Thus, it has been suggested that cell senescence could be prevented or reduced via the inactivation of the PI3K/AKT/mTOR signaling pathway [57]. In a recent study, the extract of anthocyanins from S. canadensis fruit was assessed for its in vivo and in vitro anti-aging effects using D-galactose-induced senescence in a mouse model. It was found that anthocyanins exhibited the ability to significantly reduce cell senescence and aging of the mouse’s ocular lens. This was achieved by suppressing the activity of PI3K/AKT/mTOR signaling, thereby augmenting the apoptosis of senescent cells, activating autophagic and mitophagic flux, and accelerating the renewal of mitochondria in order to maintain cellular homeostasis. These events attenuated the adverse effects of aging on health. The authors of this investigation suggested the adoption of anthocyanins as new senolytics in age-related health disorders [57].

9. Role of Elderberry Anthocyanins in Mitigating Mitochondrial Dysfunction

Mitochondria are the source of energy production for the cell in the form of ATP. They play a vital role in the cellular modulation of redox signaling pathways, apoptosis, and autophagic turnover of the constituents of the cell. Mitochondrial dysfunction is one of the causes of cell death. Mitochondrial redox chain dysfunction and oxidative stress are implicated in the onset and progression of several degenerative brain disorders, including Alzheimer‘s and Parkinson’s diseases [62]. In a recent study to evaluate the effect of an elderberry anthocyanin-enriched extract on oxidative stress and mitochondrial dysfunction using rat brain mitochondria and the SH-SY5Y cell line, it was observed that in addition to the powerful antioxidant activity, the anthocyanin-enriched extract displayed an affinity for rat brain mitochondrial membranes. The anthocyanin-enriched extract exhibited the ability to protect the SH-SY5Y cells against the cytotoxicity inflicted by rotenone treatment, demonstrating the neuroprotective potential of anthocyanins. Further, the anthocyanins showed the ability to restore the balance of the cell redox state without affecting the respiratory parameters of brain mitochondria. However, the anthocyanins were able to protect the mitochondrial complex 1 against the rotenone-induced damage, but increased intracellular levels of reactive oxygen species. Additionally, treatment of the SH-SY5Y cells with the anthocyanin-enriched extract elevated the activity of the antioxidant enzymes and mitochondrial respiratory complexes. Consequently, the authors suggested the use of anthocyanin-rich elderberry extract as a potential therapy to mitigate mitochondrial dysfunction, which is an early sign of neurodegeneration. This finding is relevant to the treatment of neurodegenerative diseases, a suggestion that is substantiated by the fact that the antioxidant capacity of elderberry is among the strongest measured in fresh fruits [39].

10. Role of Elderberry Extract and Cyanidin 3-O-Glucoside in Treatment or Prevention of Vascular Endothelial Dysfunction

Endothelial dysfunction may contribute to the initiation and progression of vascular diseases. Several studies have shown that the administration of antioxidants protects endothelial cells against damage caused by oxidative stress. Oxidative stress and inflammation have been reported to be involved in the dysfunction of the vascular endothelium. Several health disorders, including cardiovascular disease, neurodegenerative disease, and cancer, are attributed, at least in part, to defects in the vascular endothelium. Oxidative stress and inflammation inflict an adverse effect on the vascular endothelium by activating transcription factors such as NF-κB, whose function is dependent on cellular redox status. Studies have examined the incorporation of elderberry extract containing four anthocyanins into the plasma membrane and cytosol of endothelial cells (EC) after incubation for 4 h. These studies assessed the potential antioxidative activity of anthocyanins against several of oxidants. Monoglycoside concentrations were found to be higher than those of diglucosides in both the plasma membrane and the cytosol of the endothelial cells, implying that the uptake of the different anthocyanins is structurally dependent. The elderberry-enriched EC (the EC with incorporated elderberry extract) exhibited significant protective activities against various oxidants, including hydrogen peroxide H2O2, 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH), and FeSO4/ascorbic acid. Thus, anthocyanins apparently play a role in maintaining EC function and protecting against EC dysfunction inflicted by oxidative stress that may lead to vascular disease [63][64]. Anthocyanins represent approximately 80% of the polyphenols in elderberry. Among these, cyanidin 3-O-glucoside is a major component [65], occurring in the ripe fruit of black elderberry at the highest level of concentration (794.13 mg/100 g FW) compared with various other fruit, berries, and vegetables with a range of 0.28–41.52 mg/100 g FW). However, unripe fruit contains 138.72 mg/100 g FW; this is much less than the content of ripe fruit, but still the highest level compared with various other edible sources of anthocyanins [65]. The anthocyanins were reported as potent antioxidants and free radical scavengers, implicated in modulating gene expression and signal transduction pathways.
In one study, cyanidin 3-O-glucoside exhibited the ability to protect human endothelial cells against injury induced by TNF-α, a powerful pro-inflammatory agent, and against the adverse effects inflicted by the activation of NF-κB, such as increased gene expression of adhesion molecules, leukocyte adhesion to the endothelium, intracellular accumulation of H2O2, and the harmful effects of lipid peroxidation products. Thus, this work on the role of cyanidin 3-O-glucoside in preventing dysfunction of the vascular endothelium provides additional evidence of the well-documented activity of anthocyanins in counteracting oxidative stress and inflammation. Elderberry extract, with its high content of cyanidin 3-O-glucoside and other anthocyanins, can be considered an adjuvant therapy for the prevention or treatment of diseases associated with inflammation and oxidative stress, such as atherosclerosis.

11. Neuroprotective and Anti-Diabetic Activity of Cyanidin 3-O-Glucoside

In a study to evaluate the neuroprotective and anti-diabetic activity of cyanidin 3-O-glucoside, a major anthocyanin in elderberry fruit, in vitro enzyme inhibition bioassays were employed as a method of assessment. The enzymes that are implicated in neuroprotection, namely, monoamine oxidase (MAO-A), tyrosinase TYR, and fatty acid amide hydrolase (FAAH), were employed in these experiments. The enzymes considered as the current targets for type 2 diabetes, namely, α-glucosidase (α-GLU) and dipeptidyl peptidase-4 (DPP-4), were also utilized in this investigation. Cyanidin 3-O-glucoside inhibited monoamine oxidase (MAO-A), tyrosinase TYR, and fatty acid amide hydrolase (FAAH) enzymes with IC50 of 7.6 μM, 18.1 μM, and 152.1 μM, respectively, while choline esterase was not inhibited. In addition, cyanidin 3-O-glucoside exhibited inhibitory activity on α-glucosidase and dipeptidyl peptidase-4 with IC50 of 479.8 μM and 125.1 μM, respectively.
The antioxidant activity of cyanidin 3-O-glucoside was assessed using the xanthine/xanthine oxidase method. The results showed that cyanidin 3-O-glucoside was a more powerful antioxidant than gallic acid, which is considered a standard reference in many antioxidant assays. The results of this study, in addition to previous research, suggest that cyanidin 3-O-glucoside should be considered for further investigation in order to assess its therapeutic potential as an antioxidant, neuroprotective, and anti-diabetic [66].

12. Inhibition of UVB-Induced Oxidative Damage and Inflammation by Cyanidin 3-O-Glucoside

Cyanidin 3-O-glucoside, a major anthocyanin in elderberry fruit, has reportedly shown powerful antioxidant and anticarcinogenic properties. The in vivo effects of cyanidin 3-O-glucoside on UVB irradiation-induced chronic inflammatory responses were studied in SKH-1 hairless mice. The research results showed that cyanidin 3-O-glucoside inhibited UVB-induced skin damage and inflammation in the SKH-1 hairless mice model. Cyanidin 3-O-glucoside was able to inhibit the depletion of glutathione and suppress lipid peroxidation and myeloperoxidation in mouse skin caused by chronic exposure to UVB. Further, cyanidin 3-O-glucoside significantly diminished the release of UVB-induced pro-inflammatory cytokines, including IL-6 and TNF-α, which are associated with cutaneous inflammation [67].

13. Anti-Hyperlipidaemic Effect of Elderberry Extract

The level of serum high-density lipoprotein cholesterol (HDL-C) is inversely correlated with the high risk for CVD. High levels of HDL-C protect against the development of atherosclerosis. Atherosclerosis is an inflammatory disease and a responsible factor in the impairment of high-density lipoprotein function, including lowering the levels of HDL-C, HDL antioxidant, and anti-inflammatory activities. The polyphenols, anthocyanins, have been reported to exhibit powerful antioxidant and anti-inflammatory properties. An anthocyanin-rich black elderberry extract was examined for its ability to protect against inflammation-induced HDL dysfunction and against atherosclerosis in apoE−/− mice, a mouse model of hyperlipidemia and HDL dysfunction. The black elderberry extract fed to the mice was rich in cyanidin 3-O-sambubioside and cyanidin 3-O-glucoside. After 6 weeks, the levels of serum lipid of the anthocyanin-fed mice were not significantly different from the control. Levels of aspartate transaminase and fasting glucose were decreased in the black elderberry extract-fed mice. Changes in the hepatic and intestinal mRNA in the black elderberry extract-fed mice indicated improved HDL function. The levels of hepatic cholesterol were also decreased. Additionally, the activity of serum paraoxonase-1 (PON1) aryl esterase was significantly elevated in the elderberry extract-fed mice. PON1 (paraoxonase 1) is a major anti-atherosclerotic component of HDL. PONI 1 occurs in the circulation in association with HDL, and plays a pivotal role in anti-atherosclerosis thanks to its ability to remove harmful oxidized lipids. In this way, it protects against the development of atherosclerosis. Furthermore, the levels of serum chemokine (C–C motif) ligand 2(CCL2), pro-inflammatory cytokines, were significantly decreased in the elderberry extract-fed mice compared with the control-fed mice. Additionally, in the elderberry-fed mice, the total cholesterol content in the aorta of this group was significantly lowered, indicating reduced atherosclerosis progression. Consequently, this in vivo study demonstrated that elderberry extract may have the potential to attenuate chronic inflammation-mediated HDL dysfunction by influencing hepatic gene expression [68].

14. Clinical Trials

Numerous clinical trials have been conducted on anthocyanins extracted from berries other than elderberry, and many have shown positive effects on cardiovascular disease, diabetes, and lipid profiles [69][70][71][72][73][74][75]. However, few clinical trials have been carried out on the effects of elderberry, which is rich in anthocyanins, on the abovementioned health disorders. The data from these clinical trials can apparently be extrapolated to elderberry based on the structural similarity of the anthocyanins in all berries, as previously reported [76].
A randomized, double-blind, placebo-controlled trial was conducted to examine the effect of anthocyanin-rich elderberry juice on serum lipid profile. The study was divided into two parts. Part 1 was designed to determine the effect of consumption of anthocyanin-rich elderberry juice on cholesterol and triglyceride blood levels and the resistance of LDL to oxidation. The study was carried out on a cohort of 34 participants. The participants were administered 400 mg capsules containing the powder of spray-dried elderberry juice for two weeks. A subgroup of 14 participants continued taking the capsules of the lyophilized elderberry juice for an additional week to test for resistance of LDL against oxidation. Part 2 was to determine the short-term effect of the anthocyanin-rich elderberry juice on the levels of blood lipids. Each of the six participants was administered a single dose of 50 mL of elderberry juice (equivalent to 10 capsules) together with a high-fat breakfast. The results of this pilot study demonstrated that there was not a significant difference in the blood cholesterol levels between the elderberry group and the placebo group. The resistance of LDL against copper-induced oxidation did not improve with the intake of elderberry juice for three weeks. Additionally, in the single-dose study, the changes in the serum postprandial triglycerides were not significantly different between the elderberry juice plus high-fat breakfast group and the control group. In conclusion, this study indicated that the administration of low doses of lyophilized elderberry juice had a limited effect on lowering serum lipids and did not increase resistance to lipid oxidation [77].
Another randomized, placebo-controlled study was conducted to determine the effect of chronic consumption of anthocyanins (from elderberry) on the biomarkers of CVD risk, liver, and kidney functions. The participants, 52 healthy postmenopausal women (n = 26 in treatment and placebo groups) were administered 500 mg/d anthocyanins as cyanidin glycosides from elderberry or placebo for 12 weeks. The concentrations of anthocyanins and the levels of the biomarkers of CVD (inflammatory biomarkers, platelet reactivity, lipids, and glucose), in addition to the standard parameters of liver and kidney functions, were evaluated in fasted blood at the beginning and at the end of the 12-week study. Anthropometric, blood pressure, and pulse measurements were recorded, and postprandial plasma anthocyanins were measured at different intervals after the administration of a single 500-mg oral dose. The 12-week study demonstrated that chronic intake of 500 mg/d of elderberry extract over 12 weeks is suggested to be safe but did not affect the biomarkers of CVD risk in healthy postmenopausal women [78]. The pharmacological effects and health benefits of elderberry are compiled in Figure 1.
Molecules 28 03148 g002 550
Figure 1. Pharmacological effects and health benefits of elderberry.

This entry is adapted from the peer-reviewed paper 10.3390/molecules28073148

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