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Bioactivity of Carotenoids – Chasms of Knowledge

January 2016
International Journal for Vitamin and Nutrition Research 87(1)

January 2016
87(1)

Authors:

LIH Luxembourg Institute of Health

Carotenoid dietary intake, especially within fruits/vegetables and their plasma levels have been associated in many epidemiological studies with a reduced risk of several chronic diseases, including type-2 diabetes, cardiovascular diseases, several types of cancer, and age-related macular degeneration. However, intervention trials with isolated carotenoids (as supplements) have fallen short of fulfilling the hopes that were placed in these lipophilic pigments, often producing no positive or even adverse effects, such as increased lung cancer rate or total mortality. More recent studies have suggested that certain metabolites, and not necessarily the native compounds may be (the most) biologically active ones, such as certain apocarotenals (originating following enzymatic cleavage) and other more polar compounds, acting as more suitable electrophiles to react with transcription factors such as nuclear factor kappa-B (NF-kB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, it appears that questions of dosing are likewise crucial, as may be interactions of non-provitamin A carotenoids and their derivatives with retinoic acid receptors (RAR) or retinoid X receptors (RXR). Furthermore, our picture on carotenoid metabolism may be incomplete, as our knowledge on e.g. the interaction with the microbiota is virtually nil. In this position article, it is aimed to highlight some of the discrepancies that appear to trouble carotenoid-related research, and point out some of the existing gaps in our knowledge.

Potential interrelation between carotenoid exposure, oxidative stress, infl ammation, and toxicological relevant pathways (pattern fi ll). Higher carotenoid concentrations (depending on carotenoid type, organism, bioavailability etc.) may increase the risk, at least intermittently, of reactive oxygen species (ROS) production, activating nuclear factor (erythroid derived 2)-like 2 (Nrf2) translocation and expression of anti-oxidant enzymes . Likewise, nuclear factor-kappa B (NF-κB) translocation may be inhibited, limiting pro-infl ammatory responses. Lower concentrations, possibly covering the lower/physiological range, may even reduce Nrf2 translocation, effects for NF-κB are less clear. Certain derivatives of β-carotene, but also of lycopene, can alter retinoic acid receptor (RAR) and retinoid x receptor (RXR) activity, effecting apoptosis, with lower concentrations of retinoic acid/other derivatives possibly favouring cell proliferation [22]. Higher concentrations of native carotenoids may reduce the proportion of carotenoid derivatives (non-fi lled arrows, possibly involving β-carotene oxygenases 1/2 (BCO1/2). High concentrations of native compounds have further been suggested to trigger cytochrome P450 enzyme (CYP) activation, producing pro-carcinogenic compounds [38]. *effects for higher/lower doses (on NFκB and Nrf2) shown in vitro and in vivo especially for astaxanthin, β-carotene, lutein, lycopene [16]. +: Data for β-carotene and derivatives. $: Data for β-carotene derivatives and indications for apo-15-lycopenoids. CAT: catalase; GPx: glutathione peroxidase; HO-1: heme-oxygenase 1; IL-1β: interleu- kin-1-beta; IL-6: interleukin-6; NO: nitric oxide; SOD: superoxide-dismutase; TNF-α: tumor necrosis factor alpha.

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https://doi.org/10.1024/0300-9831/a000400

News and Views

Bioactivity of Carotenoids –

Chasms of Knowledge

Torsten Bohn1

1 Luxembourg Institute of Health, Population Health Department, 1 A–B rue Thomas Edison, L-1445 Strassen, Luxembourg

Received: April 28, 2016; Accepted: June 22, 2016

Abstract: Carotenoid dietary intake, especially within fruits/vegetables and their plasma levels have been associated in many epidemiological

studies with a reduced risk of several chronic diseases, including type-2 diabetes, cardiovascular diseases, several types of cancer, and age-

related macular degeneration. However, intervention trials with isolated carotenoids (as supplements) have fallen short of fulﬁ lling the hopes

that were placed in these lipophilic pigments, often producing no positive or even adverse effects, such as increased lung cancer rate or total

mortality. More recent studies have suggested that certain metabolites, and not necessarily the native compounds may be (the most) biologi-

cally active ones, such as certain apocarotenals (originating following enzymatic cleavage) and other more polar compounds, acting as more

suitable electrophiles to react with transcription factors such as nuclear factor kappa-B (NF-KB) and nuclear factor (erythroid-derived 2)-like 2

(Nrf2). In addition, it appears that questions of dosing are likewise crucial, as may be interactions of non-provitamin A carotenoids and their

derivatives with retinoic acid receptors (RAR) or retinoid X receptors (RXR). Furthermore, our picture on carotenoid metabolism may be incom-

plete, as our knowledge on e. g. the interaction with the microbiota is virtually nil. In this position article, it is aimed to highlight some of the

discrepancies that appear to trouble carotenoid-related research, and point out some of the existing gaps in our knowledge.

Keywords: Xanthophylls, carotenes, metabolites, NF-κB, Nrf-2, RAR/RXR, colon.

Epidemiological studies

and carotenoids

Apart from representing essential precursors for vitamin A

[1; 2; 3], several large and prospective epidemiological stu-

dies have shown a positive correlation between the dietary

intake of carotenoids and reduced risk of developing seve-

ral chronic diseases. For example, in a meta-analysis with

over 135,000 participants, Hamer and Chida [4] have

shown that the consumption of total carotenoids was asso-

ciated with a reduced risk (almost 30 %) of type 2 diabetes

(T2D). Similarly, in a study with over 70,000 female parti-

cipants, dietary intake of α- and β-carotene was signi -

cantly associated with a reduced risk (25 % and 20 %, res-

pectively) of coronary artery disease, when comparing

quintiles of highest vs. lowest intake [5]. A comparable re-

sult was found by Buijsse et al. [6] in a meta-analysis of

prospective cohort studies (with ca. 4500 participants),

showing that plasma β-carotene in elderly men was associ-

ated with an overall reduced total mortality (of almost

30 %). Though the mechanisms of action remained unc-

lear at the time, it was speculated that carotenoid antioxi-

dant capacity (involving quenching of free radicals such as

of lipid peroxides) was likely to be associated with the ob-

served e ects [7].

Intervention trials with carotenoid

supplements – hard endpoints

These positive  ndings and related antioxidant activity

seen in many in vitro trials [8] sparked a number of large-

scale supplementation trials, especially with β-carotene.

Most recognized for their adverse e ects on smokers, both

the ATBC [9] and the CARET trial [10], in which

β-carotene was (co-) administered at high daily doses of

20mg with 50mg α-tocopherol and 30mgwith 25,000

IU vitamin A, respectively, for several years, had to be dis-

continued due to increased lung-cancer mortality. Similar

 ndings were encountered in a meta-analysis by Bjelako-

vic et al. (also including healthy subjects), suggesting that

β-carotene supplements resulted in enhanced mortality

when given alone or together with other antioxidants [11].

Supplementation trials  nding a positive (or at least, no

negative) e ect do also exist, such as the Linxian trial [12],

though it may be speculated that e ects can be, at least in

part, explained by a reduced status of certain micronutri-

ents in these populations, and that supplementation rather

ameliorated these de ciencies.

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2 T. Bohn, Carotenoids – Quo Vadis?

Short-term dietary intervention

trials – surrogate markers

Several intervention trials with whole foods, notably with

tomato products rich in carotenoids (lycopene, β-carotene)

have been conducted, which generally suggested some po-

sitive health e ects, as measured by surrogate markers,

such as those related to in ammation, e. g. interleukin-6

(IL–6), interleukin-8 (IL–8), interleukin 1-beta (IL–1β), tu-

mor necrosis factor alpha (TNF-α), C-reactive protein

(CRP), or oxidative stress, e. g. improving superoxide dis-

mutase (SOD), glutathione peroxidase (GPx), catalase

(CAT), or heme-oxygenase 1 (HO–1) [13; 14]). The same

appears to be true to some extent for non-healthy subjects,

in which the intervention with supplements, such as with

lycopene or lutein, has shown some bene ts, as measured

e. g. by improved serum amyloid A (a marker of in amma-

tion), and IL–6 [14; 15].

These endpoints were chosen, as mechanistic, i. e. in

vitro/cellular trials, had suggested that not the direct anti-

oxidant e ects (e. g. free radical quenching) may be res-

ponsible for the proposed health e ects, but also (and

perhaps especially) e ects on gene expressions, such as

via altering cellular transcription factors linked to in am-

mation and oxidative stress, as reviewed by Kaulmann

and Bohn [16]. It appears that certain carotenoids and

their derivatives can bind to cysteine residues of nuclear

factor kappa-B (NF-KB) or nuclear factor (erythroid-deri-

ved 2)-like 2 (Nrf2). This can prevent the degradation of

the inhibitor of NF-KB and thus the liberation of free NF-

kB (and subsequent translocation to the nucleus which

up-regulates pro-in ammatory gene-expression,  gure

1); and for Nrf2 fostering dissociation from the kelch-like

ECH-associated protein 1 (keap-1) repressor, with Nrf2

then translocating to the nucleus, up-regulating expressi-

on of anti-oxidant enzymes [17; 18].

Are we looking at

the right compounds?

How to explain the conundrum of discrepancies between

epidemiological  ndings and intervention trials? Are we

targeting the wrong molecules? Are other compounds,

such as dietary  bre, anti-oxidant vitamins (C/E), or other

bioactive secondary plant compounds (e. g. phytosterols,

glucosinates etc.), and not carotenoids, responsible for the

observed health e ects?

This extreme position may also fall short of the reality.

There are several aspects to consider prior to “ripping o ”

Figure 1. Potential interrelation between carotenoid exposure, oxidative stress, inﬂ ammation, and toxicological relevant pathways (pattern ﬁ ll).

Higher carotenoid concentrations (depending on carotenoid type, organism, bioavailability etc.) may increase the risk, at least intermittently, of reac-

tive oxygen species (ROS) production, activating nuclear factor (erythroid derived 2)-like 2 (Nrf2) translocation and expression of anti-oxidant enzy-

mes. Likewise, nuclear factor-kappa B (NF-κB) translocation may be inhibited, limiting pro-inﬂ ammatory responses. Lower concentrations, possibly

covering the lower/physiological range, may even reduce Nrf2 translocation, effects for NF-κB are less clear. Certain derivatives of β-carotene, but

also of lycopene, can alter retinoic acid receptor (RAR) and retinoid x receptor (RXR) activity, effecting apoptosis, with lower concentrations of retinoic

acid/other derivatives possibly favouring cell proliferation [22]. Higher concentrations of native carotenoids may reduce the proportion of carotenoid

derivatives (non-ﬁ lled arrows, possibly involving β-carotene oxygenases 1/2 (BCO1/2). High concentrations of native compounds have further been

suggested to trigger cytochrome P450 enzyme (CYP) activation, producing pro-carcinogenic compounds [38]. *effects for higher/lower doses (on NF-

κB and Nrf2) shown in vitro and in vivo especially for astaxanthin, β-carotene, lutein, lycopene [16]. +: Data for β-carotene and derivatives. $: Data for

β-carotene derivatives and indications for apo-15-lycopenoids. CAT: catalase; GPx: glutathione peroxidase; HO-1: heme-oxygenase 1; IL-1β: interleu-

kin-1-beta; IL-6: interleukin-6; NO: nitric oxide; SOD: superoxide-dismutase; TNF-α: tumor necrosis factor alpha.

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T. Bohn, Carotenoids – Quo Vadis? 3

Are we overlooking something?

Other pathways, which so far have been mostly overlooked,

may also play a role, which likewise may involve carotenoid

metabolites. Caris-Veyrat et al. [27] have suggested that ly-

copene metabolites such as apo-15-lycopenoids show vita-

min A – like behaviour, as they may activate retinoid X re-

ceptor (RXR) and retinoic acid receptor (RAR) [28; 29; 30].

Also e ects together with other bioactive compounds, such

as with docosahexaenoic acid (DHA) and ATRA, on RAR/

RXR mediated apoptosis have been reported [31], highligh-

ting potential additive/synergistic interactions with other

micronutrients. Also in this respect, more is known for

other phytochemicals such as for polyphenols [32], but litt-

le on carotenoids.

When highlighting potential dose e ects, it is also im-

portant to stress out inter-individual di erences in dose-

responses, possibly related to genetic di erences such as

single nucleotide polymorphisms (SNPs), altering carote-

noid metabolism and bioavailability [33; 34]. Possibly also

epigenetic di erences do play a role, however, no informa-

tion on this is available.

Finally, several aspects of potential carotenoid meta-

bolism have never been investigated. A good example

is the human colon and its microbiota. As only 10–40 %

of carotenoids are absorbed (presumably, in the small in-

testine), the majority of carotenoids can reach the large

intestine. In vitro studies have further suggested that ca-

rotenoids are not completely recovered, only 10 % [35] –

50 % [36]. Obviously, they are fermented – but into what?

From polyphenols, we know that these may be converted

into numerous metabolites, following ring  ssion, degly-

cosylation, hydrolysis, deglucuronidation, and deme-

thylation [37]. However, nothing is known regarding ca-

rotenoids. It is not impossible that bioactive, more polar

degradation products are formed. Though admittedly

this is speculation, it is remarkable that nothing on colo-

nic metabolism is known.

Conclusions and Perspectives

Our current view on potential bioactive properties on caro-

tenoids appears to be incomplete. Missing aspects include

the following:

1. Which metabolites and breakdown products are formed

in the human body?

2. Does the colon and especially microbiota play any role

in carotenoid metabolism?

3. Are the (more polar) metabolites the (more) bioactive

molecules – rather than the native compounds? If so,

which exactly?

carotenoids the status of any health bene ts. It rather ap-

pears that our understanding of carotenoid bioavailability

and bioactivity, especially regarding the active com-

pounds and possibly dose-related aspects, is incomplete:

It can be hypothesized that carotenoids, administered at

high doses (supplements), may override the body’s meta-

bolism capacity, increasing the ratio of native compounds

to metabolites, resulting in more pro-oxidant and pro-in-

 ammatory conditions.

Indeed, several studies have suggested that β-carotene

oxygenase 1/2 (BCO1/2) cleavage metabolites, due to

their enhanced electrophilic properties (with improved

binding ability to cysteine residues of NF-KB and Nrf2),

and higher solubility in the cytosol, are better alterators

of these pathways, resulting in anti-in ammatory e ects,

and stimulating the body’s own antioxidant system [17].

Highest bioactivity regarding these pathways was associ-

ated with apocarotenals with 12 C-atoms, and having a

methyl-group 3 C-atoms distant from the terminal alde-

hyde function [17]. In addition, several studies in vitro

[18] and even in vivo in rats [19] have shown that polar

carotenoid breakdown products of lycopene and lutein

(following UV-Vis irradiation), respectively, are more

bioactive with respect to anti-in ammatory/antioxidant

targets (related to transcription factors), supporting this

hypothesis.

Higher, i. e. supra-physiological doses on the other

hand (1–10 μM in cellular trials, or doses exceeding the

daily intake of ca. 10–20mg [20]), have in part been rela-

ted to pro-oxidative e ects in some, though not all stu-

dies, as reviewed earlier [16]. For example, in several cel-

lular trials, concentrations of > 1 μM of all-trans retinoic

acid (ATRA), a potential metabolite of β-carotene, have

been associated with pro-oxidative e ects [21], as oppo-

sed to lower, nutritionally plausible concentrations (< 1

μM) [16]. Earlier results in smoke-exposed ferrets [22]

have likewise suggested arbitrary e ects at low vs. high

concentrations of β-carotene (0.4 vs. 2.4 mg/kg bw.,

equal to 6 and 30mg/kg bw. for humans), in line with the

ATBC/CARET trial, resulting in lower retinoic acid con-

centrations and reduced retinoic acid receptor (RAR)-β

expression, hampering apoptosis but increasing cyto-

chrome P450 activation, possibly resulting in the forma-

tion of harmful metabolites.

Such concentrations (> 30mg/kg bw.), taken for several

weeks, are likely to considerably increase the typical

β-carotene plasma concentration from 0.3–1.0 μM to 3–5

μM or higher [23; 24; 25], which thus may not be desirable.

Also higher doses of lycopene (3.3mg/kg bw. in rats) have

shown arbitrary e ects, interestingly especially when

ethanol reduced BCO2 activity [26], also pointing out to

the importance of the balance between metabolites and

native carotenoids.

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4 T. Bohn, Carotenoids – Quo Vadis?

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de induced inﬂ ammation in rats. Food Funct 6, 450–460.

20. Biehler, E., Alkerwi, A., Hoffmann, L., Krause, E. et al. (2012)

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21, 2245–2253.

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of β-carotene supplementation on the concentrations and dis-

tribution of carotenoids, vitamin E, vitamin A, and cholesterol in

plasma lipoprotein and non-lipoprotein fractions in healthy ol-

der women. J Am Coll Nutr 14, 614–620.

4. To what extent do various (epi-) genetic di erences

(SNPs, copy number variations etc.) alter inter-individu-

al di erences regarding bioavailability and bioactivity?

5. Which are the predominant mechanisms of action –

which nuclear receptors are important?

6. How much of a dose- (i. e. concentration related) e ect is

there for the various carotenoids and derivatives or what

is the “therapeutic” (and nutrition/physiological rele-

vant) window, if any?

These merely constitute some of the most pressing questi-

ons that should be addressed in order to lift the veil of the

unresolved bioactivity that carotenoids may exert, and

should be addressed prior to future large-scale supple-

mental experiments. It can be hoped for that improved in

vitro (e. g. 3-D cell culture) and in vivo (e. g. knock-out) mo-

dels, higher availability of (metabolite) standards, and im-

proved analytical capabilities will contribute to solve some

of these persistent puzzles.

Acknowledgements

The insights obtained during participation in the EU-COST

Actions Positive (FA-1403) and Eurocaroten (CA-15136)

are much appreciated.

Conﬂ ict of interest

The author is also Editor-in-Chief of this journal.

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Torsten Bohn

Luxembourg Institute of Health, Population Health Department

1 A–B rue Thomas Edison

L-1145 Strassen

Luxembourg

Phone: +352-621-216-637

Fax: +352-265-32-872

torsten.bohn@gmx.ch

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induces retinoic acid receptor transcriptional activation in

mice. Mol Nutr Food Res 56, 702–712.

31. Abdolahi, M., Shokri, F., Hosseini, M., Shadanian, M., Saboor-Ya-

raghi, A. A. (2016) The combined effects of all-trans-retinoic acid

and docosahexaenoic acid on the induction of apoptosis in hu-

man breast cancer MCF-7 cells. J Cancer Res Ther 12, 204–208.

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nation of single-nucleotide polymorphisms is associated with

http://econtent.hogrefe.com/doi/pdf/10.1024/0300-9831/a000400 - Torsten Bohn <torsten.bohn@gmx.ch> - Saturday, March 04, 2017 8:19:47 AM - IP Address:78.141.142.36

Carotenoids-Quo Vadis-finalfinal

Data

July 2016

Torsten Bohn

Evaluation of a Standardized Extract Obtained from Cashew Apple (Anacardium occidentale L.) Bagasse in DSS-Induced Mouse Colitis

Article

Full-text available

Sep 2023

Inflammatory bowel diseases (IBD) include Crohn’s disease and ulcerative colitis. Several studies relate eating habits to different aspects of IBD, such as progression and worsening of the clinical condition. Therefore, many natural products (NPs) such as polyphenols and carotenoids have been identified as promising agents in supporting IBD. An interesting source for obtaining bioactive NPs is the by-products of the food industry. The present study evaluated the potential beneficial effect of a standardized extract (CAE) obtained from cashew apple bagasse in the dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. This was the first time that CAE had been evaluated in this experimental model. Chemical evaluation of CAE identified carotenoids (96.28 ± 0.15 mg/100 g), phenolic compounds (37.49 ± 0.64 mg/100 g), and a mixture of anacardic acids (C15:3 = 94.2 ± 0.6 mg/100 g; C15:2 = 108.4 ± 0.1 mg/100 g; C15:1 = 214.8 ± 0.2 mg/100 g). Administration of CAE (500 mg/kg, 4 days, p.o.) after DSS challenge was more effective in delaying disease progression compared with prior treatment (500 mg/kg, 30 days, p.o.), according to the disease activity index. However, no treatment strategy with CAE was able to prevent or inhibit disease progression, since all parameters evaluated (macroscopic, biochemical, and histopathological) in CAE-treated animals were similar to those observed in DSS-challenged animals. Despite the high dose (500 mg/kg), the standardized extract (CAE) did not result in an effective concentration of carotenoids. Furthermore, as some anacardic acids have been reported as histone acetyltransferases inhibitors, there could be a possible antagonistic relationship between carotenoids and anacardic acids. Complementary research will be necessary to test the hypothesis of antagonism. Thus, an optimized extract, with an even higher concentration of carotenoids, obtained from cashew apple bagasse, can be developed as a possible adjuvant food supplement for inflammatory bowel diseases.

Therapeutic promise of carotenoids as antioxidants and anti-inflammatory agents in neurodegenerative disorders

Article

Full-text available

Feb 2022
BIOMED PHARMACOTHER

Neurodegenerative disorders (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis , Huntington's disease, and multiple sclerosis have various disease-specific causal factors and pathological features. A very common characteristic of NDs is oxidative stress (OS), which takes place due to the elevated generation of reactive oxygen species during the progression of NDs. Furthermore, the pathological condition of NDs including an increased level of protein aggregates can further lead to chronic inflammation because of the mi-.pk (M. Shah), agnieszka.najda@up.lublin.pl (A. Najda), abdeldaim.m@vet.suez.edu.eg (M.M. Abdel-Daim). Anti-inflammatory croglial activation. Carotenoids (CTs) are naturally occurring pigments that play a significant role in averting brain disorders. More than 750 CTs are present in nature, and they are widely available in plants, microorganisms , and animals. CTs are accountable for the red, yellow, and orange pigments in several animals and plants, and these colors usually indicate various types of CTs. CTs exert various bioactive properties because of its characteristic structure, including anti-inflammatory and antioxidant properties. Due to the protective properties of CTs, levels of CTs in the human body have been markedly linked with the prevention and treatment of multiple diseases including NDs. In this review, we have summarized the relationship between OS, neuroinflammation, and NDs. In addition, we have also particularly focused on the antioxidants and anti-neuroinflammatory properties of CTs in the management of NDs.

Circular bioeconomy in the production of fucoxanthin from aquatic biomass: extraction and bioactivities

Article

Full-text available

Oct 2021
J CHEM TECHNOL BIOT

Fucoxanthin is a high‐added‐value carotenoid compound. It has been extracted from marine sources by various extraction methods in different countries. Fucoxanthin finds application in areas such as the pharmaceutical, cosmetic and food industries. However, recent research has shown that fucoxanthin has anticancer, antioxidant, anti‐obesity, antidiabetic, hypoglycemic and neuroprotective activities, which suggest its use as a food supplement. Finally, this review aims to show the latest advances of fucoxanthin from seaweeds in the extraction process, chemical characterization and bioactivities in the development of third‐generation biorefineries and circular bioeconomy. © 2021 Society of Chemical Industry (SCI).

Revisiting carotenoids as dietary antioxidants for human health and disease prevention

Article

Full-text available

Jan 2023

純二寺尾

Humans are unique indiscriminate carotenoid accumulators, so the human body accumulates a wide range of dietary carotenoids of different types and to varying concentrations. Carotenoids were once recognized as physiological...

Effect of carotenoids on gut health and inflammatory status: A systematic review of in vivo animal studies

Article

Jul 2023
CRIT REV FOOD SCI

Carotenoids have anti-inflammatory and antioxidant properties, being a potential bioactive compound for gut health. The objective of this systematic review was to investigate the effects of carotenoids on gut microbiota, gut barrier, and inflammation in healthy animals. The systematic search from PubMed, Scopus, and Lilacs databases were performed up to March 2023. The final screening included thirty studies, with different animal models (mice, rats, pigs, chicks, drosophila, fish, and shrimp), and different carotenoid sources (β-carotene, lycopene, astaxanthin, zeaxanthin, lutein, and fucoxanthin). The results suggested that carotenoids seem to act on gut microbiota by promoting beneficial effects on intestinal bacteria related to both inflammation and SCFA production; increase tight junction proteins expression, important for reducing intestinal permeability; increase the mucins expression, important in protecting against pathogens and toxins; improve morphological parameters important for digestion and absorption of nutrients; and reduce pro-inflammatory and increase anti-inflammatory cytokines. However, different carotenoids had distinct effects on gut health. In addition, there was heterogeneity between studies regarding animal model, duration of intervention, and doses used. This is the first systematic review to address the effects of carotenoids on gut health. Further studies are needed to better understand the effects of carotenoids on gut health.

Carotenoids Diet: Digestion, Gut Microbiota Modulation, and Inflammatory Diseases

Article

Full-text available

May 2023

Several epidemiologic studies have found that consuming fruits and vegetables lowers the risk of getting a variety of chronic illnesses, including several types of cancers, cardiovascular diseases (CVDs), and bowel diseases. Although there is still debate over the bioactive components, various secondary plant metabolites have been linked to these positive health benefits. Many of these features have recently been connected to carotenoids and their metabolites’ effects on intracellular signalling cascades, which influence gene expression and protein translation. Carotenoids are the most prevalent lipid-soluble phytochemicals in the human diet, are found in micromolar amounts in human serum, and are very susceptible to multiple oxidation and isomerisation reactions. The gastrointestinal delivery system, digestion processes, stability, and functionality of carotenoids, as well as their impact on the gut microbiota and how carotenoids may be effective modulators of oxidative stress and inflammatory pathways, are still lacking research advances. Although several pathways involved in carotenoids’ bioactivity have been identified, future studies should focus on the carotenoids’ relationships, related metabolites, and their effects on transcription factors and metabolism.

Influence of Vitamin A supplementation on inflammatory biomarkers in adults: a systematic review and meta-analysis of randomized clinical trials

Article

Full-text available

Dec 2022

Vitamin A is an anti-oxidant which has been presumed to act as an anti-infective vitamin in many studies. This study aimed to evaluate the association between vitamin A supplementation and c-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) levels in randomized control trials (RCTs) studies on adults. A systematic search was performed on databases including PUBMED, SCOPUS, and the Cochrane library. The studies included were considered for data extraction and subsequently assessed for effect. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were evaluated. Among 13,219 articles 13 studies were included for analysis of CRP and TNF-α, as well as 9 studies included for IL-6 in quality and quantity. The pooled WMD analysis of CRP demonstrated that vitamin A supplementation significantly increased CRP concentration with (WMD: 0.84 mg/L; 95% CI 0.29–1.39, I2 = 0.96.2% and p value < 0.003). However, there was no significant correlation between vitamin A supplementation and lower plasma TNF-α (p < 0.45)). Subgroup analysis by dosage demonstrate significant association between vitamin A supplementation and IL-6 in dosage with 50,000 with (WMD: − 1.53 mg/L; 95% CI − 2.36 to − 0.71, p value < 0.00001) as well as a negative significant association was seen at 44 weeks of supplementation with 50,000 IU/day retinyl palmitate and TNF-a in chronic hepatitis B conditions with (− 0.94 (− 1.19, − 0.69) p < 0.0001). The result of this study demonstrates that supplementation of vitamin A at low and high dosages for short and long durations increases the CRP plasma concentrations on adults and vitamin A supplementation decreases the TNF-α concentrations in chronic hepatitis B on adults. Therefore, there is an inverse association between vitamin A supplementation and plasma and fecal IL-6 concentrations in many infection conditions.

The Impact of Plant Phytochemicals on the Gut Microbiota of Humans for a Balanced Life

Article

Full-text available

Jul 2022
INT J MOL SCI

The gastrointestinal tract of humans is a complex microbial ecosystem known as gut mi-crobiota. The microbiota is involved in several critical physiological processes such as digestion, absorption, and related physiological functions and plays a crucial role in determining the host's health. The habitual consumption of specific dietary components can impact beyond their nutritional benefits, altering gut microbiota diversity and function and could manipulate health. Phyto-chemicals are non-nutrient biologically active plant components that can modify the composition of gut microflora through selective stimulation of proliferation or inhibition of certain microbial communities in the intestine. Plants secrete these components, and they accumulate in the cell wall and cell sap compartments (body) for their development and survival. These compounds have low bioavailability and long time-retention in the intestine due to their poor absorption, resulting in beneficial impacts on gut microbiota population. Feeding diets containing phytochemicals to humans and animals may offer a path to improve the gut microbiome resulting in improved performance and/or health and wellbeing. This review discusses the effects of phytochemicals on the modulation of the gut microbiota environment and the resultant benefits to humans; however, the effect of phytochemicals on the gut microbiota of animals is also covered, in brief.

Carotenoids and Their Health Benefits as Derived via Their Interactions with Gut Microbiota

Article

Full-text available

Dec 2022

Carotenoids have been associated with a number of health benefits. Their dietary intake and circulating levels have been associated with a reduced incidence of obesity, diabetes, certain types of cancer, and even lower total mortality. Their potential interaction with the gut microbiota has been generally overlooked but may be of relevance, as carotenoids largely bypass absorption in the small intestine and are passed on to the colon, where they appear to be in part degraded into unknown metabolites. These may include apo-carotenoids that may have biological effects due to higher aqueous solubility and higher electrophilicity that could better target transcription factors, i.e., NF-κB, PPARγ, RAR/RXRs. If absorbed in the colon, they could have both local and systemic effects. Certain microbes that may be supplemented were also reported to produce carotenoids in the colon. While some bactericidal aspects of carotenoids have been shown in vitro, a few studies have also demonstrated a prebiotic-like effect, resulting in bacterial shifts with health-associated properties. Also, stimulation of IgA could play a role in this respect. Carotenoids may further contribute to mucosal and gut barrier health, such as stabilizing tight junctions. This review highlights potential gut-related health beneficial effects of carotenoids and emphasizes the current research gap regarding carotenoid – gut microbiota interactions.

Fruit Bioactive Compounds: Effect on Lactic Acid Bacteria and on Intestinal Microbiota

Article

Aug 2022
FOOD RES INT

The benefits of bioactive compounds to human health have been highly explored in recent years; they are widely distributed in nature, mainly in fruits. In this review, the effect of the main fruit bioactive compounds (FBC) on lactic acid bacteria (LAB) and on gut microbiota composition was discussed. The fruit dietary fibers, phenolic compounds, fatty acids, carotenoids, and vitamins have important health benefits. Furthermore, they can interact with LAB and modulate the human intestinal microbiota, which favor the diversity of beneficial bacterial groups, thus providing several benefits to human health, such as reducing weight gain, improving the mucosal barrier function of gastrointestinal (GI) tract against pathogens, decreasing chronic inflammation and incidence of diseases, such as cardiovascular ones, diabetes, hypertension and chronic diseases. Additionally, FBC are able to change the Firmicutes/Bacteroidetes ratio and inhibit the putrefactive bacteria in the gut. Due to the complex composition of human gut microbiota and variations among individuals, additional research must be carried out to elucidate the mechanism of interaction between the bioactive compounds and the human microbiota.

Carotenoid and Polyphenol Bioaccessibility and Cellular Uptake from Plum and Cabbage Varieties

Article

Full-text available

Nov 2015
FOOD CHEM

The combined effects of all-trans-retinoic acid and docosahexaenoic acid on the induction of apoptosis in human breast cancer MCF-7 cells

Article

Full-text available

Mar 2015
J Canc Res Therapeut

Introduction: Breast cancer is one of the most women's cancers in the worldwide. In vivo and in vitro studies showed that all-trans-retinoic acid (ATRA) and docosahexaenoic acid (DHA) can modulate differentiation and apoptosis in both cancer and immune cells. Nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) activation in the presence of their ligands, plays a critical role in the proliferation, differentiation, and apoptosis of normal cells. Aim of Study: We hypothesized that ATRA and DHA, as ligands of RARs and RXRs respectively, may have synergistic effects on the induction of apoptosis in MCF-7 human mammary carcinoma cell lines. Materials and Methods: MCF-7 cells were seeded in a 24-well plate at 3 ΄ 10 5 cells per well. The cells were treated with 5 mM ATRA, 30 mM DHA, and various combinations of them over a 3-day trial. Apoptosis was measured by Annexin V-FITC kit and flow cytometery. Results: Our results showed that the combination treatment of ATRA and DHA (5 mM and 30 mM and half dose at 2.5 mM and 15 mM, respectively) in a dose-dependent manner induced apoptosis rate in MCF-7 cells significantly more than single treatment of ATRA or DHA, as compared to control group (P < 0.05). Conclusion: We conclude that the combination of ATRA and DHA at the well-balanced proportion may be effective in cancer cell apoptosis. Further studies provide details about the potential synergistically effects of combination treatment of ATRA and DHA in growth inhibition and differentiation of human mammary cancer cells.

Mind the gap-deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites-a position paper focusing on carotenoids and polyphenols

Article

Full-text available

May 2015
MOL NUTR FOOD RES

Various secondary plant metabolites or phytochemicals, including polyphenols and carotenoids, have been associated with a variety of health benefits, such as reduced incidence of type 2 diabetes, cardio-vascular diseases, and several types of cancer, most likely due to their involvement in ameliorating inflammatory and oxidative stress. However, discrepancies exist between their putative effects when comparing observational and intervention studies, especially when using pure compounds. These discrepancies may in part be explained by differences in intake levels and their bioavailability. Prior to exerting their bioactivity, these compounds must be made bioavailable, and considerable differences may arise due to their matrix release, changes during digestion, uptake, metabolism, and biodistribution, even before considering dose and host related factors. Though many insights have been gained on factors affecting secondary plant metabolite bioavailability, many gaps still exist in our knowledge. In this position paper, we highlight several major gaps in our understanding of phytochemical bioavailability, including effects of food processing, changes during digestion, involvement of cellular transporters in influx/efflux through the gastrointestinal epithelium, changes during colonic fermentation, and their phase I and phase II metabolism following absorption. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Vitamin A Value of Plant Food Provitamin A - Evaluated by the Stable Isotope Technologies

Article

Full-text available

Dec 2014

Guangwen Tang

Humans need vitamin A and obtain essential vitamin A by conversion of plant foods rich in provitamin A and/or absorption of preformed vitamin A from foods of animal origin. The determination of the vitamin A value of plant foods rich in provitamin A is important but has challenges. The aim of this paper is to review the progress over last 80 years following the discovery on the conversion of β-carotene to vitamin A and the various techniques including stable isotope technologies that have been developed to determine vitamin A values of plant provitamin A (mainly β-carotene). These include applications from using radioactive β-carotene and vitamin A, depletion-repletion with vitamin A and β-carotene, and measuring postprandial chylomicron fractions after feeding a β-carotene rich diet, to using stable isotopes as tracers to follow the absorption and conversion of plant food provitamin A carotenoids (mainly β-carotene) in humans. These approaches have greatly promoted our understanding of the absorption and conversion of β-carotene to vitamin A. Stable isotope labeled plant foods are useful for determining the overall bioavailability of provitamin A carotenoids from specific foods. Locally obtained plant foods can provide vitamin A and prevent deficiency of vitamin A, a remaining worldwide concern.

Research Recommendations for Applying Vitamin A-Labelled Isotope Dilution Techniques to Improve Human Vitamin A Nutrition

Article

Full-text available

Dec 2014

The current use of serum retinol concentrations as a measurement of subclinical vitamin A deficiency is unsatisfactory for many reasons. The best technique available for vitamin A status assessment in humans is the measurement of total body pool size. Pool size is measured by the administration of retinol labelled with stable isotopes of carbon or hydrogen that are safe for human subjects, with subsequent measurement of the dilution of the labelled retinol within the body pool. However, the isotope techniques are time-consuming, technically challenging, and relatively expensive. There is also a need to assess different types of tracers and doses, and to establish clear guidelines for the use and interpretation of this method in different populations. Field-friendly improvements are desirable to encourage the application of this technique in developing countries where the need is greatest for monitoring the risk of vitamin A deficiency, the effectiveness of public health interventions, and the potential of hypervitaminosis due to combined supplement and fortification programs. These techniques should be applied to validate other less technical methods of assessing vitamin A deficiency. Another area of public health relevance for this technique is to understand the bioconversion of β-carotene to vitamin A, and its relation to existing vitamin A status, for future dietary diversification programs.

Lutein derived fragments exhibit higher antioxidant and anti-inflammatory properties than lutein in lipopolysaccharide induced inflammation in rats

Article

Full-text available

Nov 2014

In the present study, we appraised the anti- inflammatory efficacy of the lutein oxidative degradation derivatives mediated through UV- irradiation over lutein in counteracting the inflammation induced by lipopolysaccharide (LPS) in rats. UV- irradiated lutein fragmented ions were identified as B (m/z 551.5 M++H+-H2O), M1 (m/z 121.19, M+H+- C31H46O), M2 (m/z 285.44, M+H+/2), M3 (m/z 298.46, M+H+- C19H27O) and M4 (m/z 551.5, M+H+-H2O ) and its isomers as 13-Z zeaxanthin, 13-Z lutein, all-trans zeaxanthin, 9-Z lutein. Induction of inflammation by LPS significantly increased the productions of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines like tumor necrosis factor- (TNF-), and interleukins-6 (IL-6). Oxidative derivatives of lutein especially M1, M2 and M3, ameliorated acute inflammation in rats by inhibiting the production of NO, malondialdehyde (MDA), PGE2, TNF-, and IL-6 cytokines more efficiently than lutein in rats. The anti-inflammatory mechanisms of lutein and oxidative derivatives might be related to the decrease of inflammatory cytokine and increase of antioxidant enzymes activities, which would result in the reduction of iNOS, COX-2 and MDA and subsequently inflammatory responses.

Beta-carotene supplementation decreases leukocyte superoxide dismutase activity and serum glutathione peroxidase concentration in humans

Article

Nov 2003
J NUTR BIOCHEM

The effects of a 30 mg/day beta-carotene supplement for 60 days on blood cell and serum antioxidant enzymes and selenium concentrations were examined in healthy adults. Serum beta-carotene concentrations increased significantly (P < 0.05) in response to supplementation. Forty percent of subjects exhibited hypercarotenemia of the skin after 30 days. There were no changes in the activity of red blood cell or leukocyte catalase activity, red blood cell copper,zinc-dependent superoxide dismutase activity or serum myeloperoxidase concentration in response to beta-carotene supplementation. Leukocyte superoxide dismutase activity decreased significantly (P < 0.05) at 30 and 60 days compared to baseline. Serum glutathione peroxidase concentration decreased significantly (P < 0.05) between baseline and days 45 and 60 of supplementation. Serum selenium and blood hemoglobin concentrations did not change during the study. Supplemental beta-carotene may alter the antioxidant capacity of plasma and/or blood cells in vivo.

The combined effects of all-trans-retinoic acid and docosahexaenoic acid on the induction of apoptosis in human breast cancer MCF-7 cells

Article

Mar 2015

Vitamin Intake from Food Supplements in a German Cohort - Is there a Risk of Excessive Intake?

Article

May 2015

Food supplements, if not properly used, may lead to potentially harmful nutrient intake. The purpose of this survey was to examine vitamin intake from food supplements. Taking into account the intake from food, as obtained from the National Nutrition Survey, it was determined whether the tolerable upper intake levels (ULs) were exceeded via supplements alone, or in combination with food. Data from 1070 supplement users (18 - 93 years) was available. The dietary and supplemental vitamin intakes of three groups were analyzed: average intake (50th percentile food + 50th percentile supplements), middle-high intake (50th + 95th ) and high intake (95th + 95th ). Vitamin C (53 %), vitamin E (45 %) and B vitamins (37 - 45 %) were consumed most frequently. Few subjects (n = 7) reached or exceeded the ULs through supplements alone. The UL for vitamin A and folate was reached by a few men in the middlehigh group, and by a few men and women in the high intake group. Otherwise, even in the high intake group, the recommended vitamin D intake of 20 μg/day (in case of insufficient endogenous synthesis) could not be achieved. The use of food supplements was not associated with excessive vitamin intake in this survey, except in a small number of cases. Vitamin A intake above the UL was the result of high dietary intake which also included the intake of β-carotene, rather than the result of overconsumption of food supplements. Diets mainly included folate from natural sources, which has no associated risk.

Carotenoid derivatives inhibit Nuclear Factor Kappa B activity in bone and cancer cells by targeting key thiol groups.

Article

Jul 2014
FREE RADICAL BIO MED

Aberrant activation of the Nuclear Factor Kappa B (NFkB) transcription system contributes to cancer progression, and has a harmful effect on bone health. Several major components of the NFkB pathway, such as IkB Kinase (IKK) and the NFkB subunits contain cysteine residues that are critical for their activity. The interaction of electrophiles with these cysteine residues results in NFkB inhibition. Carotenoids, hydrophobic plant pigments, are devoid of electrophilic groups, and we have previously demonstrated that carotenoid derivatives, but not the native compounds activate the Nrf2 transcription system. The aim of the current study was to examine whether carotenoid derivatives inhibit NFkB, and, if so, to determine the molecular mechanism underpinning the inhibitory action. We report in the present study that a mixture of oxidized derivatives, prepared by ethanol extraction from partially oxidized lycopene preparation, inhibited NFkB reporter gene activity: In contrast, the intact carotenoid was inactive. A series of synthetic dialdehyde carotenoid derivatives inhibited reporter activity as well as several stages of the NFkB pathway in both cancer and bone cells. The activity of the carotenoid derivatives depended on the reactivity of the electrophilic groups in reactions such as Michael addition to sulphydryl groups of proteins. Specifically, carotenoid derivatives directly interacted with two key proteins of the NFkB pathway: The IKKβ, and the p65 subunit. Direct interaction with IKKβ was found in an in-vitro kinase assay with a recombinant enzyme. The inhibition by carotenoid derivatives of p65 transcriptional activity was observed in a reporter gene assay performed in the presence of excess p65. This inhibition action resulted, at least in part, from direct interaction of the carotenoid derivative with p65 leading to reduced binding of the protein to DNA as evidenced by electrophoretic mobility shift assay (EMSA) experiments. Importantly, we found by using mutation in key cysteine residues of both p65 and IKK that specific thiol groups are essential for NFkB inhibition by carotenoid derivatives. In conclusion, we propose that electrophilic carotenoid derivatives contribute to cancer prevention as well as bone health maintenance via the inhibition of the NFkB transcription system: Pivotal thiol groups of both IKK and p65 play a key role in this process.

Bioactivity of Carotenoids – Chasms of Knowledge

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