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Flavonoids: an overview


Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.

Flavonoids are an important class of natural products; particularly, they belong to a class of plant secondary metabolites having a polyphenolic structure, widely found in fruits, vegetables and certain beverages. They have miscellaneous favourable biochemical and antioxidant effects associated with various diseases such as cancer, Alzheimer’s disease (AD), atherosclerosis, etc. * Flavonoids are associated with a broad spectrum of health-promoting effects and are an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is because of their antioxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme functions. They are also known to be potent inhibitors for several enzymes, such as xanthine oxidase (XO), cyclo-oxygenase (COX), lipoxygenase and phosphoinositide 3-kinase. *

In nature, flavonoid compounds are products extracted from plants and they are found in several parts of the plant. Flavonoids are used by vegetables for their growth and defence against plaques. * They belong to a class of low-molecular-weight phenolic compounds that are widely distributed in the plant kingdom. They constitute one of the most characteristic classes of compounds in higher plants. Many flavonoids are easily recognised as flower pigments in most angiosperm families. However, their occurrence is not restricted to flowers but are found in all parts of plants. *. Flavonoids are also abundantly found in foods and beverages of plant origin, such as fruits, vegetables, tea, cocoa and wine; hence they are termed as dietary flavonoids. Flavonoids have several subgroups, which include chalcones, flavones, flavonols and isoflavones. These subgroups have unique major sources. For example, onions and tea are major dietary sources of flavonols and flavones.

Flavonoids play a variety of biological activities in plants, animals and bacteria. In plants, flavonoids have long been known to be synthesised in particular sites and are responsible for the colour and aroma of flowers, and in fruits to attract pollinators and consequently fruit dispersion to help in seed and spore germination, and the growth and development of seedlings. * Flavonoids protect plants from different biotic and abiotic stresses and act as unique UV filters *, function as signal molecules, allopathic compounds, phytoalexins, detoxifying agents and antimicrobial defensive compounds. Flavonoids have roles against frost hardiness, drought resistance and may play a functional role in plant heat acclimatisation and freezing tolerance. * Jorgensen * has mentioned that the early advances in floral genetics were primarily due to mutation techniques making an impact on flavonoid-derived flower colours, and demonstrated that functional gene silencing in plants was associated with flavonoid biosynthesis. Flavonoids have been ascribed positive effects on human and animal health and the current interest is for disease therapy and chemoprevention. Currently there are about 6000 flavonoids that contribute to the colourful pigments of fruits, herbs, vegetables and medicinal plants. Dixon & Pasinetti * reviewed plant flavonoids and isoflavonoids in detail and discussed their applications to agriculture and neurosciences in human beings. Kumar & Pandey * reviewed the protective roles of flavonoids against human diseases as well as their functions in plants. Recently Panche et al.*, while reviewing AD and current therapeutic methods, discussed in detail uses of flavonoids as plant secondary metabolites for the treatment of AD and the mechanisms involved. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, their applications as dietary and health benefits along with broad classification and future research directions.

Source: MGM’s Institute of Biosciences and Technology, Mahatma Gandhi Mission, N-6, CIDCO, Aurangabad-431003, India. Department of Bio-Engineering, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India. Journal of Nutritional Sciences (2016): 5: e47.

Antibacterial activity of elder (Sambucus nigra L.) flower or berry against hospital pathogens


An evidence-based scientific scrutiny of Irish traditional medicines for their antimicrobial potency is urgently required for combating antibiotic resistant common nosocomial pathogens. We now report our seminal findings on the major constituents including terpenes identified in native, historically significant herbal medicinal plant Elder (Sambucus nigra L.) flower and elder berry in particular and their concomitant strong antimicrobial effects exhibited on various nosocomial pathogens notably upon methicillin-resistant Staphylococcus aureus MRSA, recognised globally as a clinically significant pathogen, associated with skin and soft tissue infections.

Source: Caroline Hearst, Graham A. McCollum, David H. Nelson, Linda M. Ballard, Beverley Cherie Millar, Colin E. Goldmith, Paul J Rooney, Anne C Loughry, John Ezra Moore, Juluri R. Rao. “Antibacterial activity of elder (Sambucus nigra L.) flower or berry against hospital pathogens” Journal of Medicinal Plants Research Vol. 4(17), Semantic Scholar (2010): 1805-1809.

Antiviral activity of Sambucus Formosana Nakai ethanol extract and related phenolic acid constituents against human coronavirus NL63


Human coronavirus NL63 (HCoV-NL63), one of the main circulating HCoVs worldwide, causes respiratory tract illnesses like runny nose, cough, bronchiolitis and pneumonia. Recently, a severe respiratory illness outbreak of HCoV-NL63 has been reported in a long-term care facility. Sambucus FormosanaNakai, a species of elderberry, is a traditional medicinal herb with anti-inflammatory and antiviral potential. The study investigated the antiviral activity of Sambucus FormosanaNakai stem ethanol extract and some phenolic acid constituents against HCoV-NL63. The extract was less cytotoxic and concentration-dependently increased anti-HCoV-NL63 activities, including cytopathicity, sub-G1 fraction, virus yield (IC50 = 1.17 μg/ml), plaque formation (IC50 = 4.67 μg/ml) and virus attachment (IC50 = 15.75 μg/ml). Among the phenolic acid constituents in Sambucus FormosanaNakai extract, caffeic acid, chlorogenic acid and gallic acid sustained the anti-HCoV-NL63 activity that was ranked in the following order of virus yield reduction: caffeic acid (IC50 = 3.54 μM) > chlorogenic acid (IC50 = 43.45 μM) > coumaric acid (IC50 = 71.48 μM). Caffeic acid significantly inhibited the replication of HCoV-NL63 in a cell-type independent manner, and specifically blocked virus attachment (IC50 = 8.1 μM). Therefore, the results revealed that Sambucus Formosana Nakai stem ethanol extract displayed the strong anti-HCoV-NL63 potential; caffeic acid could be the vital component with anti-HCoV-NL63 activity. The finding could be helpful for developing antivirals against HCoV-NL63.

Source: Jing-Ru Weng, Chen-Sheng Lin, Hsueh-Chou Lai, Yu-Ping Lin, Ching-Ying Wang, Yu-Chi Tsai, Kun-Chang Wu, Su-Hua Huang, Cheng-Wen Lin “Antiviral activity of Sambucus Formosana Nakai ethanol extract and related phenolic acid constituents against human coronavirus NL63” Virus Research Epub (2019): Volume 273.

Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses


Black elderberries (Sambucus nigra L.) are well known as supportive agents against common cold and influenza. It is further known that bacterial super-infection during an influenza virus (IV) infection can lead to severe pneumonia. We have analyzed a standardized elderberry extract (Rubini, BerryPharma AG) for its antimicrobial and antiviral activity using the microtitre broth micro-dilution assay against three Gram-positive bacteria and one Gram-negative bacteria responsible for infections of the upper respiratory tract, as well as cell culture experiments for two different strains of influenza virus.

Source: Christian Krawitz, Mobarak Abu Mraheil, Michael Stein, Can Imirzalioglu, Eugen Domann, Stephan Pleschka, Torsten Hain,  “Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses” BMC Complementary and Alternative Medicine (2011): Article 16.

The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines


Sambucus nigra L. products – Sambucol – are based on a standardized black elderberry extract. They are natural remedies with antiviral properties, especially against different strains of influenza virus. Sambucol was shown to be effective in vitro against 10 strains of influenza virus. In a double-blind, placebo-controlled, randomized study, Sambucol reduced the duration of flu symptoms to 3-4 days. Convalescent phase serum showed a higher antibody level to influenza virus in the Sambucol group, than in the control group. The present study aimed to assess the effect of Sambucol products on the healthy immune system – namely, its effect on cytokine production. The production of inflammatory cytokines was tested using blood – derived monocytes from 12 healthy human donors. Adherent monocytes were separated from PBL and incubated with different Sambucol preparations i.e., Sambucol Elderberry Extract, Sambucol Black Elderberry Syrup, Sambucol Immune System and Sambucol for Kids. Production of inflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8) was significantly increased, mostly by the Sambucol Black Elderberry Extract (2-45 fold), as compared to LPS, a known monocyte activator (3.6-10.7 fold). The most striking increase was noted in TNF-alpha production (44.9 fold). We conclude from this study that, in addition to its antiviral properties, Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production. Sambucol might therefore be beneficial to the immune system activation and in the inflammatory process in healthy individuals or in patients with various diseases. Sambucol could also have an immunoprotective or immunostimulatory effect when administered to cancer or AIDS patients, in conjunction with chemotherapeutic or other treatments. In view of the increasing popularity of botanical supplements, such studies and investigations in vitro, in vivo and in clinical trials need to be developed.

Source: V. Barak, T. Halperin, I Kalickman. “The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines”. European Cytokine Network (2001): 12(2): 290-6.

Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections


Elderberry has been used in folk medicine for centuries to treat influenza, colds and sinusitis, and has been reported to have antiviral activity against influenza and herpes simplex. We investigated the efficacy and safety of oral elderberry syrup for treating influenza A and B infections. Sixty patients (aged 18-54 years) suffering from influenza-like symptoms for 48 h or less were enrolled in this randomized, double-blind, placebo-controlled study during the influenza season of 1999-2000 in Norway. Patients received 15 ml of elderberry or placebo syrup four times a day for 5 days, and recorded their symptoms using a visual analogue scale. Symptoms were relieved on average 4 days earlier and use of rescue medication was significantly less in those receiving elderberry extract compared with placebo. Elderberry extract seems to offer an efficient, safe and cost-effective treatment for influenza. These findings need to be confirmed in a larger study.

Source: Z. Zakay-Rones, E. Thom, T Wollan, J. Wadstein. “Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections” The Journal of International Medical Research (2004): 32(2):132-40.


Antioxidant activity of cichoric acid and alkamides from Echinacea purpurea, alone and in combination


The antioxidant activity of extracts of the stems, leaves, and roots of Echinacea purpurea was compared with the antioxidant activity of purified cichoric acid and alkamides, both constituents of Echinacea purpurea. The antioxidant activity was determined using different methods: effect on oxygen consumption rate of a peroxidating lipid emulsion, and scavenging of radicals, i.e. 2,2-diphenyl-1-picrylhydrazyl (DPPH), measured by two different techniques. The efficacy of the extracts in the reaction with DPPH correlated well with the amount of cichoric acid present in the various extracts. The alkamides alone showed no antioxidant activity in any of the tests. Alkamides present in the extract increased, however, the antioxidative effect of cichoric acid in the peroxidating lipid emulsion. The activity was further compared with that of rosmarinic acid, a well-characterised antioxidant, and the extracts as well as cichoric acid were found to be efficient scavengers of radicals with an activity comparable to that of rosmarinic acid. Cichoric acid was found to have a stoichiometric factor of 4.0 in scavenging DPPH and to react in a second-order reaction with DPPH with a rate constant of 40 l/mol/s at 25 °C in methanol.

Source: Line Thygensen, Johanna Thulin, Alan Mortensen, Leif H. Skibsted, Per Molgaard. “Antioxidant activity of cichoric acid and alkamides from Echinacea purpurea, alone and in combination” Food Chemistry (2007): Volume 101, Issue-1, 74-81.

Enhancement of innate and adaptive immune functions by multiple Echinacea species


Echinacea preparations are commonly used as nonspecific immunomodulatory agents. Alcohol extracts from three widely used Echinacea species, Echinacea angustifolia, Echinacea pallida, and Echinacea purpurea, were investigated for immunomodulating properties. The three Echinacea species demonstrated a broad difference in concentrations of individual lipophilic amides and hydrophilic caffeic acid derivatives. Mice were gavaged once a day (for 7 days) with one of the Echinacea extracts (130 mg/kg) or vehicle and immunized with sheep red blood cells (sRBC) 4 days prior to collection of immune cells for multiple immunological assays. The three herb extracts induced similar, but differential, changes in the percentage of immune cell populations and their biological functions, including increased percentages of CD49+ and CD19+ lymphocytes in spleen and natural killer cell cytotoxicity. Antibody response to sRBC was significantly increased equally by extracts of all three Echinacea species. Concanavalin A-stimulated splenocytes from E. angustifolia- and E. pallida-treated mice demonstrated significantly higher T cell proliferation. In addition, the Echinacea treatment significantly altered the cytokine production by mitogen-stimulated splenic cells. The three herbal extracts significantly increased interferon-alpha production, but inhibited the release of tumor necrosis factor-gamma and interleukin (IL)-1beta. Only E. angustifolia- and E. pallida-treated mice demonstrated significantly higher production of IL-4 and increased IL-10 production. Taken together, these findings demonstrated that Echinacea is a wide-spectrum immunomodulator that modulates both innate and adaptive immune responses. In particular, E. angustifolia or E. pallida may have more anti-inflammatory potential.

Source: Zili Zhai, Yi Liu, Lankun Wu, David S. Senchina, Eve S. Wurtele, Patricia A. Murphy, Marian L. Kohut, Joan E. Cunnick. “Enhancement of innate and adaptive immune functions by multiple Echinacea species” Journal of Medicinal Food (2007):10(3):423-34.

Echinacea purpurea: A Proprietary Extract of Echinacea purpurea Is Shown to be Safe and Effective in the Prevention of the Common Cold


The research study in this review represents the largest clinical trial to date that evaluated the safety and efficacy of Echinacea purpurea for prophylactic treatment of the common cold, in addition to investigating its risk-benefit in a long-term treatment period. The clinical application of the proprietary standardized Echinacea purpurea extract(Echinaforce) demonstrated efficacy as a preventive cold treatment option over a 4-month duration. This study showed that Echinacea’s long-term prevention was associated with a reduction in the total number of cold episodes, a reduction in the number of days with colds, and a reduction in cold episodes requiring additional medication. Furthermore, the Echinacea test agent inhibited virally confirmed colds, exhibited maximal effects on recurrent infections, and demonstrated that its preventive effects increased relative to therapy compliance and adherence to the protocol. In summary, Echinacea purpurea when taken as recommended for the prevention of the common cold appears to provide a positive risk to benefit ratio.

Source: Stephanie Maxine Ross. “Echinacea purpurea: A Proprietary Extract of Echinacea purpurea Is Shown to be Safe and Effective in the Prevention of the Common Cold” Holistic Nursing Practice (2016): 30(1):54-7.

Echinacea purpurea Protects Against Restraint Stress-Induced Immunosuppression in BALB/c Mice


Echinacea purpurea has been widely used for the prevention and treatment of upper respiratory tract infections and the common cold. The restraint stress has been reported to suppress a broad spectrum of immune functions. The aim of this study was to investigate the protective effects of the pressed juice of E. purpurea (L.) Moench (EFLA®894; Echinacea) against restraint stress-induced immunosuppression in BALB/c mice. Echinacea significantly normalized the restraint stress-induced reduction in splenocyte proliferation and splenic natural killer (NK) cell activity (P < .05). Echinacea treatment significantly increased the percentages of CD4+ and CD8+ T lymphocytes in the blood (P < .05). In addition, Echinacea restored serum cytokine levels, including interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-17 (IL-17), as well as the mRNA expressions of these cytokines in spleen (P < .05). Our findings suggest that Echinacea might have beneficial effects on restraint stress-induced immunosuppression by increasing splenocyte proliferation and NK cell activity, while modulating T lymphocyte subsets and cytokine levels in the blood.

Source: Seonyoung Park, Mak-Soon Lee, Sunyoon Jung, Seohyun Lee, Oran Kwon, Matthias Heinrich Kreuter, Tania Perrinjaquet-Moccetti, Bokkee Min, Seong Ho Yun, Yangha Kim. “Echinacea purpurea Protects Against Restraint Stress-Induced Immunosuppression in BALB/c Mice” Journal of Medicinal Food (2018): 21(3):261-268.

Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial


Background: Echinacea has antiviral activity against influenza viruses in vitro and has traditionally been used for treatment of colds and flu.

Objectives: This randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new echinacea formulation with the neuraminidase inhibitor oseltamivir, the gold standard treatment for influenza.

Methods: Following informed consent, 473 patients with early influenza symptoms (≤48 hours) were recruited in primary care in the Czech Republic and randomized to either 5 days of oseltamivir followed by 5 days of placebo, or 10 days of an Echinacea purpurea-based formulation called Echinaforce Hotdrink (A. Vogel Bioforce AG, Roggwil, Switzerland). The proportion of recovered patients (influenza symptoms rated as absent or mild in the evening) was analyzed for noninferiority between treatment groups using a generalized Wilcoxon test with significance level α = 0.05 (2-sided) and using a CI approach in the per-protocol sample.

Results:Recovery from illness was comparable in the 2 treatment groups at 1.5% versus 4.1% after 1 day, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.8% after 10 days of treatment with Echinaforce Hotdrink and oseltamivir, respectively. Noninferiority was demonstrated for each day and overall (95% CI, 0.487–0.5265 by generalized Wilcoxon test). Very similar results were obtained in the group with virologically confirmed influenza virus infections and in a retrospective analysis during the peak influenza period. The incidence of complications was lower with Echinaforce Hotdrink than with oseltamivir (2.46% vs 6.45%; P = 0.076) and fewer adverse events (particularly nausea and vomiting) were observed with Echinaforce Hotdrink.

Conclusions:Echinaforce Hotdrink is as effective as oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza virus infections with a reduced risk of complications and adverse events. It appears to be an attractive treatment option, particularly suitable for self-care. Clinical trial identifier: Eudra-CT: 2010-021571-88. (Curr Ther Res Clin Exp. 2015; 77:66–72)

Karel Raus, Stephan Pleschka, Peter Klein MSc, Roland Schoop MSc, Peter Fisher. “Effect of an Echinacea-Based Hot Drink Versus Oseltamivir in Influenza Treatment: A Randomized, Double-Blind, Double-Dummy, Multicenter, Noninferiority Clinical Trial” Current Therapeutic Research (2015): Vol 77: 66-72.

Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis


Echinacea is one of the most commonly used herbal products, but controversy exists about its benefit in the prevention and treatment of the common cold. Thus, we did a meta-analysis evaluating the effect of echinacea on the incidence and duration of the common cold. 14 unique studies were included in the meta-analysis. Incidence of the common cold was reported as an odds ratio (OR) with 95% CI, and duration of the common cold was reported as the weighted mean difference (WMD) with 95% CI. Weighted averages and mean differences were calculated by a random-effects model (DerSimonian-Laird methodology). Heterogeneity was assessed by the Q statistic and review of L’Abbé plots, and publication bias was assessed through the Egger weighted regression statistic and visual inspection of funnel plots. Echinacea decreased the odds of developing the common cold by 58% (OR 0·42; 95% CI 0·25–0·71; Q statistic p<0·001) and the duration of a cold by 1·4 days (WMD −1·44, −2·24 to −0·64; p=0·01). Similarly, significant reductions were maintained in subgroup analyses limited to Echinaguard/Echinacin use, concomitant supplement use, method of cold exposure, Jadad scores less than 3, or use of a fixed-effects model. Published evidence supports echinacea’s benefit in decreasing the incidence and duration of the common cold.

According to the National Institute of Allergy and Infectious Diseases, the US population has 1 billion colds annually. Adults have between two and four colds per year, whereas children have between six and ten colds. Although rhinovirus and coronavirus are the most common viruses precipitating cold symptoms, approximately 200 other viruses are also known to cause the common cold. In the USA, about 40% of lost work time and 30% of time lost from school are attributed to symptoms caused by the common cold. The common cold is also associated with a large financial burden on society, with about US$1·5 billion spent annually for physicians’ visits and another $2 billion spent on non-prescription cough and cold treatments. In 2002, approximately 20% of the adult US population used nutraceuticals (herbal products, functional foods, animal based supplements). Echinacea, a collection of nine related plant species indigenous to North America, was the most common nutraceutical used and was consumed by over 40.3% of these people. Echinacea angustifolia, Echinacea pallida, and Echinacea purpurea are the most common species recognised for their medicinal value. The mechanism of action underlying the proposed immunostimulatory effects of echinacea remains unclear. Some evidence suggests that upregulation of tumour necrosis factor-α mRNA, which is stimulated by agonistic activity of the cannabinoid receptor (CB2) by alkamides present in echinacea, has a role.

The German Commission E, WHO, and the Canadian Natural Health Products Directorate have advocated echinacea use for the common cold. However, there is controversy about the efficacy of echinacea for the prevention or treatment of the common cold with some studies showing benefit and others showing a null effect. Meta-analysis can be useful in situations such as this, since it can show what the preponderance of evidence in the published work suggests. A past systematic review by Melchart and colleagues concluded that echinacea preparations from the aerial part of the plant were effective for the treatment of colds but the evidence for the prevention of a cold was lacking. It is important to note, however, that this review excluded studies using an experimental rhinovirus infection and echinacea preparations with supplements, and it did not include a more recent study by Turner and colleagues. We therefore did a meta-analysis evaluating the effect of echinacea on the incidence and duration of the common cold in randomised placebo-controlled studies.

Source: Sachin A Shah, PharmD, Stephen Sander, PharmD, C. Michael White, Pharm D, Mike Rinaldi, Pharm D, Dr. Craig I Coleman, PharmD. “Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis” Infectious Diseases (2007): Vol 7, Issue 7:473-480.

Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial


Objective: To investigate the safety (risk) and efficacy (benefit) of Echinacea purpurea extract in the prevention of common cold episodes in a large population over a 4-month period. Methods. 755 healthy subjects were allocated to receive either an alcohol extract from freshly harvested E. purpurea (95% herba and 5% root) or placebo. Participants were required to record adverse events and to rate cold-related issues in a diary throughout the investigation period. Nasal secretions were sampled at acute colds and screened for viruses. Results. A total of 293 adverse events occurred with Echinacea and 306 with placebo treatment. Nine and 10% of participants experienced adverse events, which were at least possibly related to the study drug (adverse drug reactions). Thus, the safety of Echinacea was noninferior to placebo. Echinacea reduced the total number of cold episodes, cumulated episode days within the group, and pain-killer medicated episodes. Echinacea inhibited virally confirmed colds and especially prevented enveloped virus infections (𝑃 < 0.05). Echinacea showed maximal effects on recurrent infections, and preventive effects increased with therapy compliance and adherence to the protocol. Conclusions. Compliant prophylactic intake of E. purpurea over a 4-month period appeared to provide a positive risk to benefit ratio.

The common cold is recognized as the most frequent disease in Western civilization and the number one cause of primary health care consultations. * The costs of illness associated with noninfluenza infections are estimated at 40 billion USD, including direct and indirect costs. With the additional costs of illness caused by influenza, upper respiratory tract infections present a serious burden to humanity and to the economy. *

Colds comprise a syndrome of symptoms, typically with nasal complaints, cough, sore throat, and sometimes constitutional complaints, like headache, malaise, and fever. * The symptoms are typically self-limiting, and they represent a reaction to infection by Rhino-, Corona-, Adeno-, Respiratory Syncytial and (Para-) influenza virus. *

The development of effective cold preventives is hampered by the multiplicity of viruses and the complex interplay between host and virus. * For decades, intense research has focused on applications of broad-spectrum antivirals like interferons (αβ, or γ), capsid binding proteins, or soluble receptors directed against rhinoviral infection and/or replication. Some therapies showed efficacy in clinically induced infections but failed to significantly prevent colds in larger field studies that included multiple types of respiratory viruses. Nasal applications of interferons showed good preventative efficacy but were typically accompanied by adverse reactions like nasal bleeding. *

Vaccination presents an effective method for managing seasonal influenza and respiratory, syncytial virus (RSV) in children. However, the efficacy of vaccination depends on the immunological fitness of the recipient and primarily in older individuals or those with chronic heart disease only insufficient immunity can be built up, resulting in a reduced immunity in this vulnerable population. *

Another method for preventing cold infections is to modulate the immune system. * In this context, Echinacea plays an important therapeutic role. * For several decades, Echinacea has been used to prevent colds and the flu. * Despite its worldwide acceptance, only limited data are available on its prophylactic efficacy. Long-term clinical trials that studied spontaneous colds, conducted by Schoeneberger, Schmidt and Schenk, Cohen et al., and Melchart et al., reported mixed results. * Three studies on artificially induced rhinovirus infections showed a trend toward preventing symptomatic cold episodes by Echinacea* Generally, the prophylactic benefits reached significance when data were pooled in a meta-analysis, because single studies tended to have small sample sizes and undefined or low statistical power. *

On the other hand, a good safety profile is mandatory for therapies that are designed to be taken over several months. * Considering the mild-to-moderate nature of the common cold, a potential preventive therapy by itself must induce only a minimal safety risk to produce a positive risk benefit ratio. In the predominant absence of side effects a sufficiently important difference of 20–32% is expected from cold treatments like vitamins and herbal extracts. *

The present study aimed to examine safety parameters of E. purpurea during long-term treatment. The study was designed to also investigate the efficacy profile with predefined, primary variables of efficacy and with an appropriate sample size based on power calculations. Overall, this study represented the largest clinical trial ever performed to test the safety and efficacy of Echinacea extract, and it was the first study to employ virus screening techniques.

Source:  M. Jawad, R. Schoop, A. Suter, P. Klein, and R. Eccles. “Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial” Evidence-Based Complementary and Alternative Medicine (2012) Article 841315.

Antioxidant, Antidiabetic, and Antihypertensive Properties of Echinacea purpurea Flower Extract and Caffeic Acid Derivatives Using In Vitro Models


The extraction yield, total phenols, caffeic acid derivatives (CAD), and antioxidant properties of 50% ethanolic Echinacea purpurea flower extract were determined. The in vitro inhibitory effects of 50% ethanolic extract and CAD on α-amylase, α-glucosidase, and angiotensin-converting enzyme (ACE) linked with type 2 diabetes were also investigated. The extraction yield, total phenols, and total CAD of the extract were 27.04%, 195.69 mg CAE/g and 78.42 mg/g, respectively. Cichoric acid (56.03 mg/g) was the predominant CAD compound in the extract. The extract exhibited good antioxidant properties. The extract and CAD inhibited α-amylase, α-glucosidase, and ACE activities in a concentration-dependent manner. Among the tested samples, chlorogenic acid, and caffeic acid (IC50 of 1.71-1.81 mg/mL) had the highest α-amylase inhibitory activity, cichoric acid (IC50 of 0.28 mg/mL) showed higher α-glucosidase inhibitory activity. Both chlorogenic acid and caffeic acid (IC50 of 0.11-0.14 mg/mL) demonstrated higher ACE-inhibitory activity. The in vitro results suggest that E. purpurea extract and CAD have good potential for managing hyperglycemia and hypertension. Overall, the data suggest it is a choice for developing antihyperglycemia and antihypertension compounds from field-grown E. purpurea.

Source: Shiow-Ying Chiou, Jih-Min Sung, Po-Wei Huang, Sheng-Dun Lin. “Antioxidant, Antidiabetic, and Antihypertensive Properties of Echinacea purpurea Flower Extract and Caffeic Acid Derivatives Using In Vitro Models” Journal of Medicinal Food (2017): 20(2):171-179.

Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt.,Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties


This paper reviews the chemistry, pharmacology and clinical properties of Echinacea species used medicinally. The Echinacea species Echinacea angustifolia, Echinacea pallida and Echinacea purpurea have a long history of medicinal use for a variety of conditions, particularly infections, and today echinacea products are among the best-selling herbal preparations in several developed countries. Modern interest in echinacea is focused on its immunomodulatory effects, particularly in the prevention and treatment of upper respiratory tract infections. The chemistry of Echinacea species is well documented, and several groups of constituents, including alkamides and caffeic acid derivatives, are considered important for activity. There are, however, differences in the constituent profile of the three species. Commercial echinacea samples and marketed echinacea products may contain one or more of the three species, and analysis of samples of raw material and products has shown that some do not meet recognized standards for pharmaceutical quality. Evidence from preclinical studies supports some of the traditional and modern uses for echinacea, particularly the reputed immunostimulant (or immunomodulatory) properties. Several, but not all, clinical trials of echinacea preparations have reported effects superior to those of placebo in the prevention and treatment of upper respiratory tract infections. However, evidence of efficacy is not definitive as studies have included different patient groups and tested various different preparations and dosage regimens of echinacea. On the basis of the available limited safety data, echinacea appears to be well tolerated. However, further investigation and surveillance are required to establish the safety profiles of different echinacea preparations. Safety issues include the possibility of allergic reactions, the use of echinacea by patients with autoimmune diseases and the potential for echinacea preparations to interact with conventional medicines.

Source: Joanne Barnes, Linda A. Anderson, Simon Gibbons, J David Phillipson. “Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt.,Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties” The Journal of Pharmacy and Pharmacology (2005):57(8):929-54.

Activation of PPARgamma by metabolites from the flowers of purple coneflower (Echinacea purpurea)


Thiazolidinediones are insulin sensitizing drugs that target the peroxisome proliferator-activated receptor (PPAR) gamma. An n-hexane extract of the flowers of Echinacea purpurea was found to activate PPARgamma without stimulating adipocyte differentiation. Bioassay-guided fractionations yielded five alkamides, of which one was new, and three fatty acids that all activated PPARgamma. The new alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide (5) was identified by analysis of spectroscopic data and found to activate PPARgamma with no concurrent stimulation of adipocyte differentiation. Compound 5 was further shown to increase insulin-stimulated glucose uptake. The data suggest that flowers of E. purpurea contain compounds with potential to manage insulin resistance and type 2 diabetes.

Source: Kathrine B. Christensen, Rasmus K. Petersen, Sidsel Petersen, Karsten Kistiansen, Lars P Christensen. “Activation of PPARgamma by metabolites from the flowers of purple coneflower (Echinacea purpurea)” Journal of Natural Products (2009): 11;72(5):933-7.

Vitamin C


Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component. *

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism. * Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant * and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E). * Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function * and improves the absorption of nonheme iron, * the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility. *

The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter. * Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.

Oral vitamin C produces tissue and plasma concentrations that the body tightly controls. Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1 g/day, absorption falls to less than 50% and absorbed, unmetabolized ascorbic acid is excreted in the urine. * Results from pharmacokinetic studies indicate that oral doses of 1.25 g/day ascorbic acid produce mean peak plasma vitamin C concentrations of 135 micromol/L, which are about two times higher than those produced by consuming 200–300 mg/day ascorbic acid from vitamin C-rich foods. * Pharmacokinetic modeling predicts that even doses as high as 3 g ascorbic acid taken every 4 hours would produce peak plasma concentrations of only 220 micromol/L. *

The total body content of vitamin C ranges from 300 mg (at near scurvy) to about 2 g. * High levels of vitamin C (millimolar concentrations) are maintained in cells and tissues, and are highest in leukocytes (white blood cells), eyes, adrenal glands, pituitary gland, and brain. Relatively low levels of vitamin C (micromolar concentrations) are found in extracellular fluids, such as plasma, red blood cells, and saliva. *

Source: National Institutes of Health-Office of Dietary Health. “Vitamin C-Fact Sheet for Professionals” (2019).


Zinc and immune function: the biological basis of altered resistance to infection


Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.

Source: A.H. Shankar, A.S. Prasad. “Zinc and immune function: the biological basis of altered resistance to infection” The American Journal of Clinical Nutrition (1998):68(2 Suppl): 447S-463S.


Lysine is one of nine essential amino acids in humans required for growth and tissue repair, Lysine is supplied by many foods, especially red meats, fish, and dairy products. Lysine seems to be active against herpes simplex viruses and present in many forms of diet supplements. The mechanism underlying this effect is based on the viral need for amino acid arginine; lysine competes with arginine for absorption and entry into cells. Lysine inhibits HSV growth by knocking out arginine. (NCI04)

NCI Thesaurus (NCIt)

L-Lysine is a nutritional supplement containing the biologically active L-isomer of the essential amino acid lysine, with potential anti-mucositis activity. Upon oral intake, L-lysine promotes healthy tissue function, growth and healing and improves the immune system. L-Lysine promotes calcium uptake, is essential for carnitine production and collagen formation. As collagen is essential for connective tissue maintenance, this agent may also help heal mucosal wounds. This may help decrease and prevent mucositis induced by radiation or chemotherapy.

NCI Thesaurus (NCIt)

L-lysine is an essential amino acid. Normal requirements for lysine have been found to be about 8 g per day or 12 mg/kg in adults. Children and infants need more, 44 mg/kg per day for an eleven to-twelve-year old, and 97 mg/kg per day for three-to six-month old. Lysine is highly concentrated in muscle compared to most other amino acids. Lysine is high in foods such as wheat germ, cottage cheese and chicken. Of meat products, wild game and pork have the highest concentration of lysine. Fruits and vegetables contain little lysine, except avocados. Normal lysine metabolism is dependent upon many nutrients including niacinvitamin B6riboflavinvitamin Cglutamic acid and iron. Excess arginine antagonizes lysine. Several inborn errors of lysine metabolism are known, such as cystinuria, hyperdibasic aminoaciduria I, lysinuric protein intolerance, propionic acidemia, and tyrosinemia I. Most are marked by mental retardation with occasional diverse symptoms such as absence of secondary sex characteristics, undescended testes, abnormal facial structure, anemia, obesity, enlarged liver and spleen, and eye muscle imbalance. Lysine also may be a useful adjunct in the treatment of osteoporosis. Although high protein diets result in loss of large amounts of calcium in urine, so does lysine deficiency. Lysine may be an adjunct therapy because it reduces calcium losses in urine. Lysine deficiency also may result in immunodeficiency. Requirements for this amino acid are probably increased by stress. Lysine toxicity has not occurred with oral doses in humans. Lysine dosages are presently too small and may fail to reach the concentrations necessary to prove potential therapeutic applications. Lysine metabolites, amino caproic acid and carnitine have already shown their therapeutic potential. Thirty grams daily of amino caproic acid has been used as an initial daily dose in treating blood clotting disorders, indicating that the proper doses of lysine, its precursor, have yet to be used in medicine. Low lysine levels have been found in patients with Parkinson’s, hypothyroidism, kidney disease, asthma and depression. The exact significance of these levels is unclear, yet lysine therapy can normalize the level and has been associated with improvement of some patients with these conditions. Abnormally elevated hydroxylysines have been found in virtually all chronic degenerative diseases and coumadin therapy. The levels of this stress marker may be improved by high doses of vitamin C. Lysine is particularly useful in therapy for marasmus (wasting) and herpes simplex. It stops the growth of herpes simplex in culture, and has helped to reduce the number and occurrence of cold sores in clinical studies. Dosing has not been adequately studied, but beneficial clinical effects occur in doses ranging from 100 mg to 4 g a day. Higher doses may also be useful, and toxicity has not been reported in doses as high as 8 g per day. Diets high in lysine and low in arginine can be useful in the prevention and treatment of herpes. Some researchers think herpes simplex virus is involved in many other diseases related to cranial nerves such as migraines, Bell’s palsy and Meniere’s disease. Herpes blister fluid will produce fatal encephalitis in the rabbit (http://www. dcnutrition. com).

Source: National Library of Medicine. “Lysine” PubChem (2019).

Zinc and Lysine

The Effect of Zinc and Lysine Supplementation on Infection Rate and CD4 Count In Elderly


Elderly people tend to have higher susceptibility of infections because immune dysfunction, especially cell-mediated immune system which is related to zinc deficiency. Lysine can support zinc role to boost up the cell-mediated immune system which can be determined by CD4 count. The objective of this study is to determine the effect of zinc and lysine supplementation on infection rate and CD4 count in elderly.

A randomized, double-blind, placebo-controlled trial was conducted in a senior center in Surabaya using 24 healthy elderly subjects of both sexes aged 62 to 90 years. They were divided into two experimental groups and one control group. They were given zinc 20 mg per day; or zinc 20 mg and lysine 500 mg per day; or placebo for 2 months. Infection rate during supplementation period was documented. Albumin level, serum zinc level and CD4 count were measured before and after supplementation. The data was analyzed using one way Anova and paired T-test with p < 0.05.

Compared to control group, infection rate was lower in zinc group and zinc + lysine group (p < 0.065). Zinc + lysine supplementation increased serum zinc level significantly (p < 0.012) and had better effect compared to zinc supplementation alone. Zinc + lysine supplementation also increased CD4 count (p < 0,784) and had better effect compared to zinc supplementation alone. Zinc + lysine supplementation did not increase albumin level which was already in the normal level. Zinc + lysine supplementation can reduce infection rate in elderly by increasing zinc level and CD4 count.

Source: M.W. Sugeng, M. Adriani, B. Wirjatmadi “The Effect of Zinc and Lysine Supplementation on Infection Rate and CD4 Count In Elderly” Biochemistry and Physiology (2015) S5:002.

Olive Leaf Extract

Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice


The health-promoting effects of various constituents of the olive tree (Olea europaea) are mainly associated with hypoglycaemic and insulin-sensitising activities and have been widely demonstrated in the metabolic syndrome and type 2 diabetes. However, their biological activity in autoimmune type 1 diabetes (T1D) is poorly characterised. Therefore, the influence of O. europaea-derived components present in dry olive leaf extract (DOLE) was examined in two established preclinical models of human T1D, which differ in some aspects of diabetogenesis: multiple low-dose streptozotocin-induced diabetes in susceptible C57BL/6 and CBA/H mouse strains; cyclophosphamide-accelerated diabetes in non-obese diabetic mice. In both T1D models, in vivo administration of DOLE significantly reduced clinical signs of diabetes (hyperglycaemia and body weight loss) and led to complete suppression of histopathological changes in pancreatic islets. In line with these, insulin expression and release were restored in DOLE-treated mice. Interestingly, inducible NO synthase expression and NO production were significantly elevated in peripheral tissues but were down-regulated within the local environment of the endocrine pancreas. This interference was reflected in NO-mediated suppression of T lymphocyte proliferation and lower production of the proinflammatory cytokines interferon-gamma, IL-17 and TNF-alpha in the spleen, with subsequent blockade of beta-cell destruction. The results suggest that DOLE interferes with development of autoimmune diabetes by down-regulating production of proinflammatory and cytotoxic mediators. Therefore, the potential use of a DOLE-enriched diet for prophylaxis/treatment of human T1D, and possibly other autoimmune diseases, is worthy of further investigation.

Tamara Cvjeticanin, djordje Milikovic, Ivan Stojanovic, Dragana Deanski, Stanislava Stosic-Grujicic. “Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice” British Journal of Nutrition (2010): 103(10):1413-24.

Olive Leaf Extracts Act as Modulators of the Human Immune Response


Background: Olive tree leaves have been used in the Mediterranean area as traditional medicine in virtue of their healthy effects. Olive leaf extracts (OLEs) contain higher amounts of polyphenols than those detected in the extra virgin olive oil and fruit. Several lines of evidence support the cardioprotective, anti-oxidant and anti-inflammatory activities exerted by OLEs.

Methods: Peripheral blood mononuclear cells from twenty-five healthy donors were cultured in the presence of 3 µg of two OLE extracts, extract A (resuspended in water) and extract B (resuspended in 70% ethanol). After harvesting, cell pellets were used for cytofluorimetric phenotyping, while supernatants were assayed for cytokine release by means of ELISA. Furthermore, in the same supernatants nitric oxide (NO) content was determined.

Results: Both extracts, but especially extract A, increased absolute numbers of CD8+ and natural killer (NK) cells. In addition, an increased production of interferon (IFN)-γ by both extracts as an expression of T helper (h)1 activation was observed. Finally, both extracts enhanced NO release.

Conclusion: OLEs, and mostly extract A, are able to in vitro modify healthy human immune response by increasing IFN-γ production which seems to be associated to the higher absolute numbers of CD8+ and NK cells and this may suggest a reinforcement of the anti-tumor activity. Furthermore, increased levels of NO may indicate the potential cardioprotective effects exerted by OLEs in virtue of their vasodilation dependent activity. Finally, OLEs are able to maintain the equilibrium between T regulatory cells and Th17 cells as evidenced by unmodified levels of interleukin (IL)-IL-10 and IL-17, respectively. In the light of these results, OLEs are potential therapeutic compounds for the treatment of chronic inflammatory disease, also preventing cardiovascular event outcome.

Source: Thea Magrone, Anna Spagnoletta, Rosaria Salvatore, Manrico Magrone, Francesco Dentamaro, Matteo A. Russo, Graziana Difonzo, Carmine Summo, Francesco Caponio, Emilio Jirillo. “Olive Leaf Extracts Act as Modulators of the Human Immune Response” Endocrine Metabolic Immune Disorders Drug Targets (2018):18(1):85-93.

Journal of Food Quality Evaluation of Effect of Extraction Solvent on Selected Properties of Olive Leaf Extract


The quest for natural preservatives and functional foods with health benefits has seen an increasing demand for natural products having therapeutic value. Herein, we investigated the influence of ethanol, methanol, acetone (50%, 70%, and 90% v/v), and distilled water on selected properties of olive leaf extract and determined the yield, total phenolic content (TPC), antioxidant activity, and antimicrobial activity. Extracts were analyzed for their oleuropein, hydroxytyrosol, and tyrosol contents by high-performance liquid chromatography (HPLC). The highest extraction yield of 20.41% was obtained when using 90 vol% methanol, while the highest total polyphenol contents of 232 and 231 mggallic-acid-equivalent/100 g were obtained for 90 vol% methanol and 90 vol% ethanol, respectively. Antioxidant activity was determined using the α,α-diphenyl-β-picrylhydrazyl (DPPH) radical scavenging assay, by determining the ferric reducing antioxidant power (FRAP), and using the Fe2+-chelating activity assay, which provided the highest values when 90 vol% methanol was used (33.84%, 0.75, and 12.91%, respectively). HPLC analysis showed that the highest oleuropein contents corresponded to the extracts obtained using 90 and 70 vol% methanol (26.10 ± 0.20 and 24.92 ± 1.22 g/L, respectively), and the highest antimicrobial activity was observed for 90 vol% methanol and distilled water. Olive leaf extracts using 90 vol% methanol had high levels of polyphenols and were highly antioxidant and antimicrobial. The results of this study facilitate the commercial applications of natural extracts with antioxidant and antibacterial activities and are expected to establish a foundation for further optimization studies.

Source: Won-Young Cho, Da-Hee Kim, Ha-Jung Lee, Su-Jung Yeon, and Chi-Ho Lee. “Journal of Food Quality Evaluation of Effect of Extraction Solvent on Selected Properties of Olive Leaf Extract” Journal of Food Quality (2020): Article 3013649.

Effects of the Olive-Derived Polyphenol Oleuropein on Human Health


The use of the products derived from the olive tree on human health dates back centuries. In several civilizations, the olive tree had and still has a very strong cultural and religious symbolism. Notably, the official seal and emblem of the World Health Organization features the rod of Asclepius over a world map surrounded by olive tree branches, chosen as a symbol of peace and health. Recently, accumulating experimental, clinical and epidemiological data have provided support to the traditional beliefs of the beneficial effect provided by olive derivates. In particular, the polyphenols present in olive leaves, olives, virgin (unrefined) olive oil and olive mill waste are potent antioxidant and radical scavengers with anti-tumor and anti-inflammatory properties. Here, we review the positive impact on human health of oleuropein, the most prevalent polyphenol present in olives. In addition, we provide data collected in our laboratory on the role of oleuropein in counteracting lipid accumulation in a mouse model of non-alcoholic fatty liver disease.

Source: Barbara Barbaro, Gabriele Toietta, Roberta Maggio, Mario Arciello, Mirko Tarocchi, Andrea Galli, Clara Balsano. “Effects of the Olive-Derived Polyphenol Oleuropein on Human Health” International Journal of Molecular Sciences (2014): 15(10): 18508-18524.

Vitamin D

Vitamin D and the Immune System


The immune system defends the body from foreign, invading organisms, promoting protective immunity while maintaining tolerance to self. The implications of vitamin D deficiency on the immune system have become clearer in recent years and in the context of vitamin D deficiency, there appears to be an increased susceptibility to infection and a diathesis, in a genetically susceptible host to autoimmunity.

The classical actions of vitamin D are to promote calcium homeostasis and to promote bone health. Vitamin D enhances absorption of calcium in the small intestine and stimulates osteoclast differentiation and calcium reabsorption of bone. Vitamin D additionally promotes mineralization of the collagen matrix in bone. In humans, vitamin D is obtained from the diet or it is synthesized it in the skin. * As vitamin D is cutaneously produced after exposure to UV B light, its synthesis is influenced by latitude, season, use of sunblock and skin pigmentation. Melanin absorbs UVB radiation inhibiting the synthesis of vitamin D from 7-dihydrocholesterol. This initial vitamin D compound is inactive and it is next hydroxylated in the liver to form 25 OH vitamin D3 (25 D). 25 D is also an inactive compound, but is the most reliable measurement of an individual’s vitamin D status. It is converted in the kidney to the active compound 1,25 dihydroxy vitamin D (1,25 D) or calcidiol by 1-α-hydroxylase (CYP27B1), an enzyme which is stimulated by PTH . 1,25 D may be further metabolized to the inactive 1,24,25 vitamin D by 24-hydroxylase (CYP24). 1,25 D levels are tightly regulated in a negative feedback loop. 1,25 D both inhibits renal 1-α-hydroxylase and stimulates the 24-hydroxylase enzymes, thus maintaining circulating levels within limited boundaries and preventing excessive vitamin D activity/signaling.

1,25 D acts on the intestine where it stimulates calcium reabsorption, and upon bone, where it promotes osteoblast differentiation and matrix calcification. The active hormone exerts its effects on these tissues by binding to the vitamin D receptor (VDR). This complex dimerizes with the retinoid X receptor (RXR) and the 1,25D-VDR-RXR heterodimer translocates to the nucleus where it binds vitamin D responsive elements (VDRE) in the promoter regions of vitamin D responsive genes and induces expression of these vitamin D responsive genes.

Many tissues other than the skeletal and intestine express the VDR including cells in the bone marrow, brain, colon, breast and malignant cells and immune cells suggesting that vitamin D may have functions other than calcium and bone homeostasis. * Additionally, tissues other than the kidney express 1-α-hydroxylase and are capable of converting 25 D to 1,25 D, in non-renal compartments. * Therefore, in addition to its endocrine functions, vitamin D may act in a paracrine or autocrine manner. Some of the more recently recognized non-classical actions of vitamin D include effects upon cell proliferation and differentiation as well immunologic effects resulting in an ability to maintain tolerance and to promote protective immunity. As antigen presenting cells (macrophages and dendritic cells), T cells and B cells have the necessary machinery to synthesize and respond to 1,25 D, vitamin D may act in a paracrine or autocrine manner in an immune environment. Moreover, local levels of 1,25 D may differ from systemic, circulating levels as local regulation of the enzymes synthesizing and inactivating vitamin D are different from the controls originating in the kidney. The extrarenal 1-α-hydroxylase enzyme in macrophages differs from the renal hydroxylase as it is not regulated by PTH. * Instead, it is dependent upon circulating levels of 25 D or it may be induced by cytokines such as IFN-γ, IL-1 or TNF-α. * Furthermore, the macrophage 24 hydroxylase enzyme is a non-functional splice variant, so there is no negative feedback of local 1,25 D production by 1,25 D.

Source: Cynthia Aranow, MD. “Vitamin D and the Immune System” Journal of Investigative Medicine (2011): 59(6): 881-886.

Vitamin D deficiency causes deficits in lung function and alters lung structure


Rationale: The prevalence of vitamin D deficiency is increasing and has been linked to obstructive lung diseases including asthma and chronic obstructive pulmonary disease. Recent studies suggest that vitamin D deficiency is associated with reduced lung function. The relationship between vitamin D deficiency and lung function is confounded by the association between physical activity levels and vitamin D status. Thus, causal data confirming a relationship between vitamin D and lung function are lacking.

Objectives: To determine if vitamin D deficiency alters lung structure and function.

Methods: A physiologically relevant BALB/c mouse model of vitamin D deficiency was developed by dietary manipulation. Offspring from deficient and replete colonies of mice were studied for somatic growth, lung function, and lung structure at 2 weeks of age.

Measurements and main results: Lung volume and function were measured by plethysmography and the forced oscillation technique, respectively. Lung structure was assessed histologically. Vitamin D deficiency did not alter somatic growth but decreased lung volume. There were corresponding deficits in lung function that could not be entirely explained by lung volume. The volume dependence of lung mechanics was altered by deficiency suggesting altered tissue structure. However, the primary histologic difference between groups was lung size rather than an alteration in architecture.

Conclusions: Vitamin D deficiency causes deficits in lung function that are primarily explained by differences in lung volume. This study is the first to provide direct mechanistic evidence linking vitamin D deficiency and lung development, which may explain the association between obstructive lung disease and vitamin D status.

Source: Graeme R. Zosky, Luke J. Berry, John G. Elliot, Alan L. James, Shelley Gorman, Prue H. Hart. “Vitamin D deficiency causes deficits in lung function and alters lung structure” American Journal of Respiratory and Critical Care Medicine (2011): 183(10):1336-43.

Vitamin D – Update 2013: From rickets prophylaxis to general preventive healthcare


Since the discovery of its antirachitic effect in the 1920s, the sunshine vitamin was for many years only seen in relation to its function in calcium and bone metabolism. A variety of research results from recent years have shown that vitamin D in its hormonally active form, 1α,25-dihydroxyvitamin D [1α,25(OH)2D; calcitriol] is not only a regulator of calcium and phosphate homeostasis, but has numerous extra-skeletal effects. These include the significant impact of the vitamin D hormone on the cardiovascular system, central nervous system, endocrine system and immune system as well as on cell differentiation and cell growth. *

1α,25(OH)2D manifests its diverse biological effects (endocrine, autocrine, paracrine) by binding to the vitamin D receptor (VDR) found in most body cells (Fig. 1). Vitamin D receptors have been found in over 35 target tissues that are not involved in bone metabolism. These include endothelial cells, islet cells of the pancreas, hematopoietic cells, cardiac and skeletal muscle cells, monocytes, neurons, placental cells and T-lymphocytes. It is estimated that VDR activation may regulate directly and/or indirectly a very large number of genes (0.5–5% of the total human genome i.e., 100–1250 genes).4 The fact that the vitamin D receptor is expressed by many tissues results in the pronounced pleiotropic effect of vitamin D hormone.

Source: Uwe Grober, Jorg Spitz, Jorg Reichrath, Klaus Kisters, Michael F. Holick. “Vitamin D – Update 2013: From rickets prophylaxis to general preventive healthcare” Dermato Endocrinology (2013): 5(3): 331-347.

Vitamin E

The Role of Vitamin E in Immunity


Vitamin E is a fat-soluble antioxidant that can protect the polyunsaturated fatty acids (PUFAs) in the membrane from oxidation, regulate the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and modulate signal transduction. Immunomodulatory effects of vitamin E have been observed in animal and human models under normal and disease conditions. With advances in understating of the development, function, and regulation of dendritic cells (DCs), macrophages, natural killer (NK) cells, T cells, and B cells, recent studies have focused on vitamin E’s effects on specific immune cells. This review will summarize the immunological changes observed with vitamin E intervention in animals and humans, and then describe the cell-specific effects of vitamin E in order to understand the mechanisms of immunomodulation and implications of vitamin E for immunological diseases.

Source: Ga Young Lee, Sung Nim Han. “The Role of Vitamin E in Immunity” Nutrients (2018): 10(11): 1614.

Interaction of Dietary Vitamin C and Vitamin E on Guinea Pig Immune Responses to Mitogens


Guinea pigs were fed semipurified diets with 0.2 g/kg vitamin C and either 0, 30 or 200 mg/kg all-rac-α-tocopheryl acetate or 10 mg/kg vitamin C and either 0, 30 or 200 mg/kg all-rac-α-tocopheryl acetate for 4 weeks. Animals were killed, and blastogenic responses of splenocytes to T- and B-cell mitogens were measured. Both T- and B-cell responses were significantly depressed in vitamin E-deficient guinea pigs when compared to responses from guinea pigs fed diets containing vitamin E. The two dietary levels of vitamin C examined did not affect the magnitude of these responses. The higher dietary vitamin C, however, increased the vitamin E content of the lung at all levels of vitamin E intake.

Source: Adrianne Bendich, Patricia D’Apolito, edda Gabriel, Lawrence J. Machlin. “Interaction of Dietary Vitamin C and Vitamin E on Guinea Pig Immune Responses to Mitogens” The Journal of Nutrition (1984) Vol 114, Issue 9, 1588-1593.

Vitamin D, Vitamin C, Zinc, and Echinacea

Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds


Maintaining a normal healthy immune defense system lowers the incidence and/or the severity of symptoms and/or the duration of common cold (CC). Physical barriers and innate and adaptive immunity have been involved during a CC episode. Vitamins C and D, zinc, and Echinacea have evidence-based efficacy on these immune system barriers. This review includes 82 eligible studies to consider the preventive role of these nutrients in immune clusters and in CC to provide advice on dosage and assumption of these nutrients. Regarding vitamin C, regular supplementation (1 to 2 g/day) has shown that vitamin C reduces the duration (in adults by 8%, in children by 14%) and the severity of CC. Considering zinc, the supplementation may shorten the duration of colds by approximately 33%. CC patients may be instructed to try zinc within 24 hours of onset of symptoms. As for vitamin D, the supplementation protected against CC overall, considering baseline levels and age. Patients with vitamin D deficiency and those not receiving bolus doses experienced the most benefit. Regarding Echinacea, prophylactic treatment with this extract (2400 mg/day) over 4 months appeared to be beneficial for preventing/treating CC. In conclusion, the current evidence of efficacy for zinc, vitamins D and C, and Echinacea is so interesting that CC patients may be encouraged to try them for preventing/treating their colds, although further studies are needed on this topic.

Source: Mariangela Rondanelli, Alessandra Miccono, Silvia Lamburhini, Ilaria Avanzato, Antonella Riva, Pietro Allegrini, Milena Anna Faliva, Gabriella Peroni, Mara Nichetti, Simone Perna.  “Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds” Evidence Based Complementary and Alternative Medicine (2018): 5813095.

Vitamin B6

Vitamin B6 and immune competence


Animal and human studies suggest that vitamin B6 deficiency affects both humoral and cell-mediated immune responses. Lymphocyte differentiation and maturation are altered by deficiency, delayed-type hypersensitivity responses are reduced, and antibody production may be indirectly impaired. Although repletion of the vitamin restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation. Additional human studies indicate that vitamin B6 status may influence tumor growth and disease processes. Deficiency of the vitamin has been associated with immunological changes observed in the elderly, persons infected with human immunodeficiency virus (HIV), and those with uremia or rheumatoid arthritis. Future research efforts should focus on establishing the mechanism underlying the effects of vitamin B6 on immunity and should attempt to establish safe intake levels that optimize immune response.

Source: L.C. Rall, S.N. Meydani. “Vitamin B6 and immune competence” Nutrition Reviews (1993):51(8):217-25.


  1. https://www.researchgate.net/publication/267033120_European_Elderberry_Sambucus_Nigra_L_and_American_Elderberry_Sambucus_Canadensis_L_Botanical_chemical_and_health_properties_of_flowers_berries_and_their_products
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/
  3. https://www.semanticscholar.org/paper/Antibacterial-activity-of-elder-(Sambucus-nigra-L.)-Hearst-McCollum/f33c4a32351a3a1714e06507c89a7e66e295f6e4
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