Low-Molecular Weight Metabolites from Polyphenols as Effectors for

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Low molecular weight metabolites from polyphenols as effectors for attenuating neuroinflammation Diogo Carregosa, Rafael Monteiro Carecho, Inês Figueira, and Claudia Nunes Santos J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b02155 • Publication Date (Web): 26 Jun 2019 Downloaded from pubs.acs.org on July 19, 2019

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Journal of Agricultural and Food Chemistry

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Low molecular weight metabolites from polyphenols as effectors for

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attenuating neuroinflammation

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Diogo Carregosa1,2, Rafael Carecho1,3, Inês Figueira2,3, Cláudia Nunes dos Santos1,2,3*

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1

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Lisboa, Lisboa, Portugal.

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2

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901 Oeiras, Portugal

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3

CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de

iBET, Instituto de Biologia Experimental e Tecnológica, Av. da República, Apartado 12, 2781-

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av.

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da República, 2780-157 Oeiras, Portugal

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*Corresponding author:

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Cláudia Nunes dos Santos

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Molecular Nutrition and Health Laboratory

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CEDOC - Centro de Estudos de Doenças Crónicas

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NOVA Medical School / Faculdade de Ciências Médicas

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Universidade Nova de Lisboa

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Edifício CEDOC II, Rua Câmara Pestana 6

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1150-082 | Lisboa

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email: [email protected] ;

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phone +351 218 803 101

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fax: +351 218 851 920

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Abstract:

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Age-associated pathophysiological changes such as neurodegenerative diseases are

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multifactorial conditions with increasing incidence and no existing cure. The possibility of altering

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the progression and development of these multifactorial diseases through diet is an attractive

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approach with increasing supporting data. Epidemiological and clinical studies have highlighted

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the health potential of diets rich in fruits and vegetables. Such food sources are rich in

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(poly)phenols, natural compounds increasingly associated with health benefits, having potential

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to prevent or retard the development of various diseases. However, absorption and blood

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concentration of (poly)phenols is very low when compared with their corresponding (poly)phenolic

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metabolites. Therefore, these serum-bioavailable metabolites are much more promising

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candidates to overcome cellular barriers and reach target tissues, such as the brain. Bearing this

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in mind, it will be reviewed the molecular mechanisms underlying (poly)phenolic metabolites

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effects ranging from 0.1 – 300 µM and their role on neuroinflammation, a central hallmark in

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neurodegenerative diseases.

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Keywords: Neurodegenerative Diseases, microglia, flavonoid, microbiota, brain

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1. Neurodegenerative disorders and dietary (poly)phenols

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Neurodegenerative diseases (NDs) are chronic and progressive neurological syndromes,

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consequence from nervous system dysfunction that ultimately leads to neuronal cell failure. These

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disorders are incapacitating and are characterized by impaired mental and movement function 1.

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These diseases present a deeply complex pathophysiology prompting atrophy of structures of the

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central or peripheral nervous system and can be caused by hereditary or sporadic conditions 2.

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However, we still do not have available disease-modifying therapies to delay or reverse disease

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progression and their pharmacotherapy strategies are only dealing on symptomatic relief. Overall,

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NDs represent a current burden in the developed world which is projected to accelerate over time.

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These factors make the discovery of novel therapies to delay and prevent the development of

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these diseases an urgent but yet an unmet need.

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A huge number of diseases are known to affect the nervous system, being most of them

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considered heterogeneous and multifactorial disorders, including Alzheimer's disease (AD),

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Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS),

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multiple sclerosis (MS), brain cancer, degenerative nerve diseases, encephalitis, epilepsy, among

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others. They develop alterations in different brain regions and have different aetiologies. The

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aggregation of misfolded proteins is one of the most common pathological processes, shared in

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AD, PD, HD and others, commonly denominated as protein conformational disorders 2. Besides

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the determinant role of protein aggregation, several other factors are common across major NDs.

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A new paradigm has begun to emerge to develop interventions targeting common mechanisms

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associated with ageing to delay the onset of more than one age-related disease at the same time3.

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Increased oxidative stress, protein carbonylation, lipid peroxidation, DNA damage, mitochondrial

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dysfunction, vascular dysfunction, endoplasmic reticulum (ER) stress, unfolded protein response

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(UPR) dysregulation and imbalanced proteostasis and neuroinflammation are common ND

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hallmarks which may require multitargeted interventions to tackle disease progression.

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Neuroinflammation appears as one of the key processes involved in the major NDs and it

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is as a double-edged sword, being not only essential for recovery from several conditions, but

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also playing detrimental roles contributing to disease progression. This process is controlled by



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microglia cells, the innate immune cells of the central nervous system (CNS), which can be

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stimulated to protect or act as a self-propelling mechanism of progressive neurodegeneration (Fig

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1)

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continuous surveillance of their surrounding microenvironment by extending and retracting their

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highly motile processes, maintaining homeostasis and neuronal integrity. Under detrimental

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stimuli, microglia cells are activated, losing their surveillance phenotype and their ramiﬁed

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morphology which is converted to amoeboid-like structure that responds accordingly to the nature

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of the stimuli (Fig 1). Under moderate or transient damage, microglia cells behave as protective

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cells, i.e. play immune resolving, anti-inflammatory functions and support cell renewal by

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secreting trophic factors (Fig 1). In contrast, under intensive acute or chronic activation, usually

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associated with NDs, microglia cells become neurotoxic and secrete an array of pro-inflammatory

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cytokines and reactive oxygen and nitrogen species (ROS, NOS) that may potentially impair

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neuronal activity (Fig 1) 5. The neurotoxic phenotype of microglia cells blocks their ability to

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circumvent inflammatory damage, feeding instead a vicious cycle of toxicity. Activation of

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microglia cells by low concentrations of cytokines such as interferon-γ (IFN-γ), interleukin (IL)-4

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or IL-10 supports differentiation and provides neuroprotection by regulating the levels of both

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insulin-like growth factor 1 (IGF-1) and tumour necrosis factor-α (TNF-α). However, stimulation

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with either toxic protein aggregates e.g. amyloid β 42 (Aβ 42) and α-synuclein (syn), hallmarks

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of AD and PD respectively), glutamate or lipopolysaccharide (LPS, only used in vitro) exacerbates

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the inflammatory response. Whenever facing strong “toxic” stimuli, short-lived microglia cells can

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potentially manage the neurotoxic factors, supporting regeneration and secreting neurotrophic

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factors. Nevertheless, when upon a chronic stimulus, microglia cells develop this neurotoxic

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phenotype. Different markers have been associated with the neurotoxic phenotype [e.g. TNF-α,

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IL-1β , IL-6, prostaglandins (COX-2), ROS and NO], and with the neuroprotective phenotype [e.g.

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IL-10, transforming growth factor-β (TGFβ ), enzymes able to inhibit ROS production (e.g.

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arginase-1), proteins that maintain the extracellular matrix (Ym-1) or perform phagocytic removal

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of toxic protein aggregates and of cellular debris] (Fig 1) 5,6. The main signalling cascade behind

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the activation of microglia cells involves the Nuclear Factor kappa B (NF-κB) through a mitogen-

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activated protein kinase (MAPK) signal transduction pathway

4,5.

The primary role of microglia cells is to maintain the normal functions of the CNS by

7


. MAPK is a common signalling

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hub to transduce extracellular signals to the nucleus in microglia cells. Major MAPK cascades

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involved in gene expression alterations are ERK1/2, Jun N-terminal Kinase (JNK) and p38 7,8.

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Several epidemiological studies from the last decades illustrate that diets rich in fruits and

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vegetables can have beneficial effects in human health

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and cognitive decline

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synaptic plasticity, e.g. memory and/or learning improvement in both animals and humans 10,13,14,

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albeit their mechanism of action on CNS remain poorly understood

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supplementation in animal models suggests they can activate neuronal receptors, interact with

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signaling pathways (e.g. MAPK) and control the expression of specific genes 16.

11,12.

9,10,

preventing degenerative disorders

Dietary phenolics are described to modulate different aspects of

15.

Their long-term

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In fact, emerging evidence, indicate that adherence to Mediterranean diet, rich in

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polyphenols, is associated with a reduction of markers of inflammation. Therefore, the impact of

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(poly)phenol metabolites present in the Mediterranean diet on the innate immune system cannot

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be overlooked. Recently, a number of studies have described the contribution of this diet to the

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decrease of several markers of systemic inflammation which can have knock-on effects on the

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neuroinflammation status of the brain 17. Another example is the effects of increased consumption

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of berries on a large prospective cohort of older women, establishing a relation with a reduced

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gradual progression of cognitive decline

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levels of anthocyanin is associated with reduced risk of PD development 19. Various studies also

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show significant cognitive benefits of phenolics consumption in humans

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supplementation with wild blueberry was proven to improve cognitive function in older adults

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A recent study have shown that chronic blueberry supplementation improved brain perfusion,

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task-related activation, and cognitive function in healthy older adults, suggesting that

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supplementation with an anthocyanin-rich concentrate can improve brain activation in areas

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associated to cognitive function

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addition of easily achievable quantities of blueberry to the diets of older adults improved some

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aspects of cognition 25. The results shown in these studies are supporting the idea that diets rich

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in (poly)phenols may have a positive impact on neurodegenerative diseases.

24.

18.

Moreover, it was shown that consumption of high

20–22.

In fact, diet 23.

Moreover, in a double-blind, placebo controlled trial, the

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2. (Poly)phenol metabolites and their brain permeability

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Research accumulating recently has suggested the huge potential of (poly)phenols towards

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health benefits 26. Still for a profound understanding of (poly)phenols effects in human health and

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their underlying mechanisms of action, their absorption, distribution, metabolism and excretion in

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the human digestive tract must be considered and the ensuing circulating metabolites evaluated

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for their potential.

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The term (poly)phenols represent a class of compounds possessing multiple aromatic rings

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and at least one hydroxyl group

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multitude of authors referred to the metabolic monomeric units as polyphenolic. To avoid

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confusion, the term polyphenols was recently updated to (poly)phenols in order to engulf a wider

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range of structurally and metabolic related phenolics 28,29. Inside the (poly)phenol family, several

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branches are present, namely, flavonoids, lignans, tannins, stilbenes, ellagic acid, phenolic acids

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and many others. Amongst these, flavonoids and phenolic acids represent the most biologically-

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relevant class of compounds, due to their significant presence in dietary products and their ability

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to reach circulation.

27.

Nevertheless, this definition was not consensual since a

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Flavonoids are composed by three rings, A, B and C (Fig 2). Depending upon the chemical

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groups present on the C ring or the position of the B ring, flavonoids can be classified into different

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classes: flavones, flavonols, flavan-3-ols, isoflavones, flavanones and anthocyanins. Chalcones

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and dihydrochalcones although not having a C ring are also classified by many as flavonoids, due

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to their similar backbone. All the above-mentioned classes represent the high percentage of

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flavonoids in dietary products including tea, citrus fruit, berries, red wine, apples, and legumes 30.

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These flavonoids mainly occur naturally in fruit and vegetables as glycosides, with the exception

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for flavan-3-ols that can be found conjugated with gallic acid such is the case of (epi)catechin

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gallate31. Other flavonoids like dihydroflavonols, flavan-3,4-diols, coumarins, aurones and

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neoflavonols also represent compounds with interesting properties and biological activities. Yet

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their lower presence in dietary products makes less important from a nutritional perspective.

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Results from intervention studies have shown that flavonoids are subjected to a series of

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metabolic events, resulting in a huge variety of low molecular weight phenolic metabolites that

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reach circulation at considerable higher concentrations than their parent compounds 32.


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Even though the full mechanism behind the metabolism of (poly)phenols into low molecular

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weight phenolic metabolites has not been fully unveiled, some consensus has been established.

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Phenolic metabolites resulting from digestive and hepatic activity, usually differ from their parent

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compounds, which are found in fruits and vegetables

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by multiple metabolic reactions, which occur in the small and large intestine, in the liver and in

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cells, resulting in a wide variety of derivatives (e.g. sulfated, methylated and glucuronidated).

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Upon ingestion, flavonoid aglycones can be absorbed in the small intestine due to the action of

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glycosidases such as lactase phloridzin hydrolase (LPH) in the brush border of the small intestine

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epithelial cells, or cytosolic β-glucosidase (CBG) within epithelial cells 34. (Poly)phenol conjugates

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with sugar moieties that are resistant to the action of LPH/CBG, and that are not absorbed in the

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small intestine to any degree, reach the colon

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cleaved and the resulting aglycones undergo ring fission by the action of host microbiota

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producing several low molecular weight phenolic metabolites 35. Ring fission sites are dependent

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on the structure of phenolic parent compound (Fig 3). For example, ring fission of flavan-3-ols like

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catechin, epicatechin and epigallocatechin produce 5-(hydroxyphenyl)valeric acid and 5-

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(hydroxyphenyl)-γ-valerolactones which are not produced by any other flavonoid classes.

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Furthermore,

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(hydroxyphenyl)hydracrylic acid) while isoflavones produce 2-(hydroxyphenyl)propanoic acid.

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Another exclusive class of metabolites are urolithins, that are the result of the ellagic acid

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metabolism. The production of urolithin A, B or no urolithin production is dependent on the host

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microbiota composition, which can divide dividing the host into metabotypes A, B and 0 36. Also,

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urolithins, unlike other low molecular weight phenolic metabolites, are not further metabolized into

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smaller compounds but rather excreted intact in urine as phase II conjugates 37.

only

ring

fission

of

34.

flavanones

10,33.

Absorption events are accompanied

In the colon, the remaining conjugates are

produce

3-hydroxypropionic

acid

(3-

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Ring fission of most flavonoids happens on the C ring leading to the formation of 3-

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(hydroxyphenyl)cinnammic acids, such as ferulic acid and caffeic acid, from the B ring and

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hydroxybenzenes or benzaldehydes, such as phloroglucinol or phloroglucinaldehyde, from the A

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ring 38. The 2,3 double bonds of the B ring derived phenolic compounds can be reduced leading

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to the formation of the saturated 3-(hydroxyphenyl)propionic acids, such as dihydroferulic and

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dihydrocaffeic acid

38.

Noteworthy, the mechanism of formation of 3-(hydroxyphenyl)propionic



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acid from flavanones is not still fully elucidated and could be produced by 3-

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(hydroxyphenyl)cinnamic acid reduction or dihydroxylation of 3-(hydroxyphenyl)hydracrylic acid.

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Further oxidation of 3-(hydroxyphenyl)propionic acids can produce 2-(hydroxyphenyl)acetic

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acid. Several authors suggest that 3-(hydroxyphenyl)hydracrylic acid can be dehydroxylated to 2-

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(hydroxyphenyl)mandelic acid that can also generate 2-(hydroxyphenyl)acetic acid, although this

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route is not so well characterized. The same is valid for the conversion of 2-

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(hydroxyphenyl)propanoic acid originating from isoflavones into 2-(hydroxyphenyl)acetic acid.

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Moreover 2-(hydroxyphenyl)acetic acid can be oxidized into hydroxybenzoic acids, such as

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protocatechuic acid, gallic acid and syringic acid. These components can be further converted

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into two different sets of metabolites; hippuric acids through glycination and hydroxybenzenes,

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such as catechol and pyrogallol, through decarboxylation.

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Therefore, these low molecular weight phenolic metabolites are the culmination of multiple

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steps, involving both microbiota and human metabolism. The convergence of multiple flavonoid

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classes happens during several hours after ingestion. Flavonoid conjugates and their first

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metabolites like 3-(hydroxyphenyl)cinnamic acid appear in circulation in minutes to an hour after

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ingestion

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present up to 24 hours after ingestion of edible fruits.

39.

Meanwhile end-point metabolites like hippuric acid and hydroxybenzoics can be

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In any step of their catabolism, circulating phenolic metabolites can undergo phase II

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metabolism in the liver, leading to the formation of sulfate, glucuronide and methylated conjugates

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through the action of sulfotransferases (SULTs), uridine-5′-diphosphate glucuronosyltransferases

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(UGTs), and catechol-O-methyltransferases (COMTs), respectively

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understood if phase II conjugates can still be catabolized into smaller metabolites or if are directly

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excreted in the urine without further modifications. Moreover, since both endogenous human and

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microbiota metabolism play important roles in producing low molecular weight phenolic

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compounds in blood circulation, it is difficult to unravel the origin of one compound. For example,

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ferulic acid in blood could arise from direct ingestion of dietary conjugated ferulic acid, from ring

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fission of flavonoids or from the action of COMT on caffeic acid 41.

40.

It is however still not fully

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Overall, the correlation between parent compounds and the derived gut-phenolic metabolites

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is puzzling; many low molecular weight phenolic metabolites can arise through the metabolism of


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a wide group of structurally diverse parent compounds (e.g. flavonols, flavan-3-ols, anthocyanins,

230

chalcones, isoflavones, flavanones and flavones) (Fig 3 and Table 1) whereas few are associated

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with an unique gut-phenolic metabolites (e.g. urolithins from ellagitannins)42. For other

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(poly)phenolic components, data is still lacking (e.g. pyranoanthocyanins, coumarins and other

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minor dietary components)

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(poly)phenols and the generation of low molecular weight metabolites is rapidly consolidating and

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is of great importance 43.

42.

In general, the role of gut microbiota in the metabolism of

236

A very important aspect when considering the bioactivity of (poly)phenol metabolites, is their

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circulating concentrations. Parent (poly)phenols or their phase II conjugates only reach the

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circulation in concentrations in the nanomolar range. On the other hand, low molecular weight

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phenolic metabolites which can originate from different flavonoid classes (Fig 3), tend to be

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present in concentrations vastly superior when compared to the parent compounds. Czank et al.

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(2013) found that ingestion of 500 mg of

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abundance of

243

maximum serum concentration

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concentration of 141 nM at 1.8 hours. Meanwhile, 14 different metabolites where also detected,

245

with the most abundant, hippuric acid, reaching a concentration of 1962 nM at 15.7 hours

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Pimpão et al. (2014), in a human intervention study using 500mL of a puree of berries, have found

247

that hydroxybenzoic phase II metabolites reached concentrations of over 20 µM in some

248

volunteers 45. Moreover, hippuric acid has been found in circulation up to 24 hours and reaching

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concentrations well above 25 µM 46.

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13C-labeled

13C

metabolites relative to 44.

cyanidin-3-glucoside provided 42-fold higher 13C

cyanidin-3-glucoside at their respective

The flavonoid conjugate was present in serum at a maximum

44.

The ability of any dietary phenolic to directly influence the nervous system will be dictated

251

by the ability of its ensuing phenolic metabolites to cross the blood-brain barrier (BBB)

252

BBB is a very dynamic and complex interface, carrying the responsibility of protecting the CNS

253

from toxic agents. It controls the molecular exchanges between the blood and the neuronal tissue,

254

hence playing a key role in the control of the accessibility of nutrients and other compounds to

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the brain

256

literature, alongside studies consistent with potential activity of phenolic metabolites in the brain

257

49,50

258

directly or their derived phenolic metabolites, have reported their capacity to reach the brain, e.g.

48.

35,47.

The

Evidence of BBB capacity to uptake some phenolic metabolites is growing in

. The majority of these studies that focussed on oral administration of dietary phenolics,



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(-)epicatechin

260

despite the fact that gut-phenolic metabolites are in general accepted to comprise a considerable

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percentage of the total diversity of phenolic metabolites 44,45, only a very limited number of studies

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have specifically focussed on bioaccessibility of gut-phenolic metabolites to the brain (e.g.

263

valerolactones and phenolic acids) 55. In a recent pharmacokinetic study in rats, upon intravenous

264

administration, some gut-phenolic metabolites were observed to reach the brain

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methods now being implemented, such as microdialysis sampling, give the ability to recover

266

(poly)phenols in vivo. Using this system coupled with HPLC with chemiluminescence detection,

267

Liang Wu et al. (2012) demonstrated the ability of (+)catechin and (-)epicatechin to reach the

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brain 56. Using a similar system, Zhang et al. (2012) shown that nearly 30% of orally administered

269

protocatechuic acid can be recovered in the rat brain 57.

51,

hesperetin and naringenin

52,

quercetin

53

and anthocyanins

49,54.

50

To date,

. Recent

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BBB permeation has also been ascertained by using in vitro assays with immortalized human

271

microvascular endothelial cells such as hBMEC or hCMEC/D3 in monolayers in transwell inserts

272

to test for apical and basal presence of the compounds. Faria et al. have shown that (+)catechin

273

and (-)epicatechin are able to cross hCMEC/D3

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have also been shown to cross these BBB models

275

hydroxybenzenes and benzoic acid derivatives 15. Transport through the BBB varies between 5-

276

10% for the tested low molecular weight polyphenol metabolites. Additionally, two of the gut-

277

phenolic metabolites, namely catechol-sulfate and pyrogallol-sulfate, lead to new end-point

278

metabolites in human brain endothelial cells 15.

58.

Hydroxycinammic acids such as ferulic acid 59,

and the same was demonstrated for

279

Whether the effects induced by dietary phenolics on brain functions are mediated directly in

280

the brain or involve other mechanisms triggered from cells in the periphery remains unclear. Some

281

reports indicated that the effects of flavonoids and metabolites on the brain do not seem to be

282

exclusively dependent on their blood-brain barrier permeation 16. (Poly)phenols have been shown

283

to impact cardiovascular functions modulating blood pressure, vasodilation and the presence of

284

inflammatory markers in circulation that can directly affect the brain

285

metabolites do have a direct effect on the brain, then the low molecular weight phenolic

286

metabolites may have the capacity to have a major contribution, due to their higher circulating

287

concentrations.


60,61.

But if phenolic

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This review will be focused on the data available only for the direct effects of low molecular

289

weight phenolic metabolites (Table 1) in the context of the molecular mechanism associated with

290

neuroinflammation.

291 292 293

3. Low molecular weight (poly)phenol metabolites as effectors for attenuating neuroinflammation

294 295

For a full comprehension of dietary (poly)phenols effects on NDs, an unified view of in vitro,

296

cellular and animal model studies is required to reveal the complete panorama of their molecular

297

targets and mechanisms. Associations between higher intakes of flavonoid-rich diets with lower

298

levels of inflammatory biomarkers have been established 62. However, inconsistent results on the

299

preventive anti-inflammatory effects of flavonoid supplementation reinforce the necessity for more

300

prospective randomised trials with larger sample sizes and under rigorous clinical conditions

301

Moreover, while human trials are more reliable and the closest to the real scenario, they are time-

302

consuming, costly and it is difficult to assess the direct effect of the (poly)phenols in trials related

303

to neurodegenerative diseases. Animal and cellular models have provided unparalleled tools for

304

compound screening assays to reveal their mechanisms of action. Despite of the importance of

305

animal studies with isolated compounds, it does not reflect a nutritional scenario but, in most

306

cases, a pharmacological perspective. Besides that, nutritional studies reveal overall effects and

307

pathways affected but most of them do not identify the relevant metabolites that can comprise the

308

true effectors against neurodegeneration acting in the brain, especially since their presence on

309

the brain has been overlooked. In vitro assays are of most importance to reveal crucial

310

interactions of (poly)phenols with other small molecules, proteins or even metals. They can prove

311

an indispensable tool to get a comprehensive picture and tune our understanding in vivo. We will

312

highlight and discuss our recent knowledge on cellular studies focused on the low molecular

313

weight (poly)phenol metabolites (Table 1) to delineate their main molecular mechanisms of

314

attenuation of neuroinflammation and identify their putative targets. Cellular models are starting

315

points to reveal the molecular mechanisms of (poly)phenol metabolites and the role on cellular

62.



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homeostasis when considered under experimental conditions close to physiological conditions.

317

We will not address nutritional studies in animals for the reasons described above.

318

Accumulating evidence highlights the molecular and cellular pathways modulated by parent

319

(poly)phenols, which, though not always nutritionally relevant, can give us clues about the putative

320

mode of action of their (poly)phenol metabolites in a nutritional context. Flavonoids have been

321

shown to inhibit the production of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1 in

322

microglial cells, suggesting close involvement in pathways such as NF-κB or MAPK 63. In addition,

323

there is strong evidence that blueberry (poly)phenols inhibit the production of NO, IL-1β and TNF-

324

α in activated microglia cells

325

activity, however with poor bioavailability, is caffeic acid phenethyl ester (CAPE). Some studies

326

highlight its potential to modulate NF-κB activation in microglia cell models stimulated with TNF-

327

α and significantly attenuate TNF-α-induced Toll-like receptor (TLR) 2 expression

328

CAPE has low solubility and poor bioavailability that limits in vivo efficacy. Consequently some

329

nanotechnologies strategies are emerging to enhance bioavailability and improve the clinical use

330

of CAPE

331

defined (poly)phenol metabolites in specific cells/tissues, instead of those of their parent dietary

332

phenolics, under near physiological concentrations and residence time. The potential to reduce

333

LPS‐induced TNFα secretion in THP‐1 monocytes was evaluated, demonstrating that some

334

metabolites of flavonoids, individually and in combination, appear to present more anti ‐

335

inflammatory effects than their parent compounds 67. Importantly, the study of isolated polyphenol

336

metabolites is often limited to their molecular mechanisms in neurodegeneration cell models and

337

their specific biological effects in animal models, and such studies miss the synergetic effects of

338

the diversity of (poly)phenol metabolites that co-exist in serum. The overall diet complexity, the

339

potential synergy that may occur in compounds derived from the metabolism cannot be fully

340

depicted in studies using isolated pure compounds

341

fractions or with the bulk of digested/metabolized compounds may be useful to approach these

342

interactions and depict the molecular effects of the overall metabolites in cells 15,69,70. For instance,

343

simulated gastro-intestinal digestion blackberry extracts revealed neuronal protection to oxidative

344

insult that was not unrelated to the levels of ROS and glutathione (GSH) , suggesting a pre-

345

conditioning effect by the induction of caspase activity

66.

64.

Another example of a parent compound with anti-inflammatory

65.

However,

Nevertheless, in a nutritional scenario, the current trend is to analyse the effect of

68.

Studies with (poly)phenol-enriched

69,71.

Moreover, bioaccessible raspberry


Page 13 of 60


346

metabolites resulting from the in vitro digestion of raspberry extract significantly inhibited

347

microglial pro-inflammatory activation by LPS through the inhibition of Iba1 expression, TNF-α

348

release and NO production72.

349

A plethora of mammalian cell models have been used to study the protective action of

350

(poly)phenol metabolites towards NDs. Although there is some evidence mainly highlighting the

351

ability of several circulating metabolites to reduce oxidative stress, lipid peroxidation and

352

cytotoxicity in neuronal models, few studies have explored their anti-neuroinflammatory properties

353

73,74.

354

particular pathological processes associated to each disease as well as toxicity of specific disease

355

proteins

356

neurodegeneration are in general based on using microglia cells and explore the therapeutic

357

potential of metabolites to mitigate inflammation induced by LPS or TNF-α. Since microglia are

358

the resident innate immune cells of the CNS, microglial cell lines such as N9 and BV2 have been

359

preferred. Although the evidence for modulatory effects of (poly)phenol metabolites in microglial

360

cells is still very scarce, the ability of the low molecular weight phenolic metabolites to reduce

361

neuroinflammatory markers has been reported (Table 2) and in some cases the underlying

362

involved pathways have been proposed.

On the other hand, more complex models have addressed effects of (poly)phenols in

75,76.

Cellular models to access the anti-inflammatory potential of (poly)phenols for

363

Benzene diols and triols and their conjugates (Table 1) are abundant low molecular weight

364

flavonoid metabolites since they can appear in circulation either by ring fission from the A and B

365

rings (Fig 3). Moreover, some are present in specific foods, e.g. catechol, guaiacol, pyrogallol and

366

4-methylcatechol occur in coffee, beer and cocoa

367

effects of catechol and its conjugates (Fig 4, Table 2) that consistently decreased LPS-induced

368

NO and TNF-α production in the BV-2 microglia cell line. Moreover, these compounds also

369

inhibited the expression of inducible nitric oxide synthase (iNOS), as well as nuclear translocation

370

of p65 subunit of NF-κB, IκB degradation and phosphorylation of p38 MAPK

371

inflammatory processes. Other substituted catechols (3-methylcatechol and 4-tert-butylcatechol)

372

are equally effective, which opens the window to inspire further modifications for pharmacological

373

applications. A more recent study, using a different microglia cell line (N9), showed that catechol

374

and pyrogallol conjugates (both methyl and sulfates, Fig 4, Table 2) improved cellular responses

30.

A study from 2008 reported the beneficial

77,

key players in



Page 14 of 60

375

to oxidative and inflammatory injuries via modulation of NF-κB pathway

376

catechol-sulfate was ineffective to interfere with the key players of NF-κB pathway, suggesting

377

that the slight modification of sulfation of one hydroxyl, leaving only a single free hydroxyl, could

378

alter its activity 15. It will be interesting to have more data for further physiological conjugates.

15.

In the same study,

379

A different view of the effect of benzene diols and triols on neuronal cells came from the 60s.

380

Although pyrogallol is a bioavailable polyphenol metabolite which results from the consumption

381

of polyphenol-rich meals, it also has toxic and pro-oxidant effects at higher concentrations.

382

Pyrogallol was seen as potent modulator of neurotransmitter levels in the brain

383

understanding of its brain penetration

384

methyltransferase

385

metabolite, appearing to be a versatile molecule with an evident modulatory potential in brain

386

activity. Such potential led to the understanding of how pyrogallol can influence several fine-tuned

387

mechanisms such as blood pressure

388

consequently, cellular oxidative stress

389

non-physiological concentrations both in vitro and in vivo 84,85, reviewed in 86. This duality of roles

390

for pyrogallol may rely on the fact that at low concentrations, as it is detected circulating after

391

consumption of polyphenol-rich meals, may be pre-conditioning the cells to a later insult.

392

Pyrogallol is priming the cells to better respond to more hostile alterations in cell environment that

393

may arise. It might be plausible similar mechanisms for other low molecular weight phenolic

394

metabolites.

80

78.

The

and effects on monoamine oxidase and catechol-O-

79

highlighted the fact that pyrogallol is undoubtfully a brain bioavailable

81,

83.

dopamine levels

82

and iron homeostasis and,

As such, pyrogallol was used as neurotoxic agent at

395

Benzoic acids conjugates were also studied as attenuators of neuroinflammation (Table 2).

396

This is a very important class not only because majority of flavonoids metabolism converge to

397

benzoic acid derivatives (Fig 3) but also because they are very well represented in diverse foods

398

and therefore could be ingested directly (e.g. gallic acid and protocatechuic acid in beer, wine,

399

berries, cereals, grape, apple, kiwi, olive oil, vinegar, chicory)

400

colleagues have demonstrated the neuroprotective effects of gallic acid (Fig 5, Table 2), using

401

the BV-2 cell line and primary microglia cells prior to Aβ stimulation. Conditioned media was

402

transferred to Neuro-2A cells and in both situations, gallic acid prevented Aβ neurotoxicity by

403

inhibiting the expression levels of iNOS, COX-2, IL-1β, TNF-α


89.

30,87,88.

Mi-Jeong Kim and

Gallic acid conjugates (methyl

Page 15 of 60


404

and sulfate) (Fig 5, Table 2) also proved efficacy in reducing LPS-induced NO as well the levels

405

of intracellular superoxide 88, which suggests that these further metabolic alterations do not affect

406

its ability to modulate the inflammatory markers.. In addition, protocatechuic acid, that differs from

407

gallic acid in only one hydroxyl (Fig5, Table 2) has also presented potent anti-inflammatory effects

408

in BV-2 LPS-stimulated microglia. Mechanistic assays have revealed its ability to inhibit the

409

production of TNF-α, IL-6, IL-1β and PGE2. Protocatechuic acid also suppressed the activation of

410

NF-κB and MAPKs and it was also able to inhibit the TLR4 expression 87.

411

Although there are many food sources of free and conjugated ferulic acid, its bioavailability

412

depends on the form in which it is ingested as free ferulic acid has limited solubility in water, and

413

hence poor bioavailability. However, ferulic acid appears in circulation as result of the metabolism

414

of caffeic acid, chlorogenic acid, and anthocyanins 30,90. Some studies have evaluated the ability

415

of ferulic acid to attenuate inflammatory markers in microglia cells (Fig 6 Table 2) 91,92. While the

416

trend observed for this compound was to reduce more than one pro-inflammatory mediators in

417

microglia cells (Table 2), only the study of Byung-Wook Kim and colleagues had nutritional

418

relevance, since they tested physiologically-relevant levels of ferulic acid likely to reach the

419

circulation 91. In another microglia cell line, ferulic acid was ineffective in reducing LPS stimulated

420

production of NO, TNF-α and IL-6 and was only effective in other mediators at non-physiological

421

concentrations over 50 µM (Table 2)

422

attenuated the JNK/NF-κB inflammatory signaling pathway and apoptosis in LPS-induced BV2

423

microglia cells at both 10 µM and 100 µM but then focused on assessing effects on the TLR4-

424

mediated signaling pathway but only for the most effective concentration (100 µM)

425

acid (Fig 6, Table 2) is another example of an effective metabolite tested for reducing several pro-

426

inflammatory markers although at levels (> 100 µM) only suitable for pharmacological approaches

427

94.

428

microglia. Although relevant metabolites, ferulic and isoferulic acid are not the major metabolites

429

derived from coffee consumption 95 as sulfates are the dominant conjugates over the glucuronides

430

95

431

bioavailable conjugates as attenuators of neuroinflammation.

93.

Similarly, another study observed that ferulic acid

92.

Cinnamic

The data gathered reveals ferulic acid potential for attenuating pro-inflammatory mediators in

Therefore, it will be very important to fill the gap in evaluating the activity of these circulating



432

Page 16 of 60

Phenylacetic acids and phenylpropionic acids metabolites found in blood after wine

433

consumption

434

(4-hydroxyphenyl)propionic acid and 3-(3-hydroxyphenyl)propionic acid (Fig 7, Table 2) have

435

shown to be neuroprotective by significantly decreasing ERK 1/2 activation. Moreover 2-(3-

436

hydroxyphenyl)acetic acid and 3-(4-hydroxyphenyl)propionic acid also reduce mitogen-activated

437

protein kinase (MAPK) p38 and in SH-SY5Y cells, modulating neuroinflammatory pathways

438

normally triggered by nitrosative stress.97.

96,

such as 2-(3,4-dihydroxyphenyl)acetic acid, 2-(3-hydroxyphenyl)acetic acid, 3-

439

Other studies evaluated the anti-inflammatory potential in microglia cells for other

440

compounds similar to low molecular (poly)phenol metabolites. For example, phloroglucinol

441

derivatives have potent anti-inflammatory effects and can effectively cross the blood-brain barrier

442

98.

443

Src/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt signaling

444

Notably, these results were supported using two more complex cellular approaches as primary

445

mixed mesencephalic neuronal/glial cultures and primary rat microglia cultures, both stimulated

446

with LPS 98.

Mechanistic studies have revealed neuroinflammation inhibition potentially by targeting 98.

447

In general, we may infer that the main molecular targets of the low molecular weight

448

(poly)phenol metabolites in stimulated microglia cells includes (Fig 8): (1) inhibiting the microglial

449

activation of inflammatory cytokines, including TNF-α, IL-1β, IL-6; (2) inhibiting iNOS induction

450

and subsequent nitric oxide (NO) production in response to glial activation; (3) inhibiting

451

expression of COX-2 and resulting reduction of prostaglandins; and (4) downregulating activity of

452

pro-inflammatory transcription factors such as NF-κB through modulation of glial and neuronal

453

signalling pathways.

454

Overall, cellular studies taking into consideration (poly)phenol metabolism and biological

455

activity against neurodegeneration, using physiologically-relevant concentrations and relevant

456

resident times, mark a mentality shift and the beginning of a new era in (poly)phenol health

457

benefits research.

458 459

4. Final considerations

460 16 ACS Paragon Plus Environment

Page 17 of 60


461

Many studies corroborate the theory that (poly)phenol-rich supplements or foods have a

462

positive impact preventing or attenuating neuroinflammation and therefore ameliorating NDs

463

development and progression. A large amount of evidence has come from in vitro research using

464

single flavonoids, typically aglycones, at supra-physiological concentrations which have given

465

valuable clues for further studies with relevant circulating metabolites. In fact, increasing evidence

466

suggest that metabolism of (poly)phenols may actually increase their biological activity. The anti-

467

inflammatory effects of physiologically attainable (poly)phenol metabolites in healthy subjects is

468

starting to be unveiled.

469

The sustained release of pro-inflammatory mediators that characterizes neuroinflammation

470

is harmful to microglia cells. Therefore, having compounds that can promote a shift in cells from

471

inflammatory and neurotoxic phenotype to an anti-inflammatory and neuroprotective phenotype

472

are crucial to efficiently repair the damage and restore the homeostasis, downregulating

473

inflammation. The data gathered has identified the main molecular targets of the low molecular

474

weight (poly)phenol metabolites in stimulated microglia cells and highlighted their potential to

475

attenuate neuroinflammation. These low molecular weight (poly)phenol metabolites produced by

476

gut microbiota are well absorbed in the intestine and persist in the plasma for a substantial time.

477

Therefore, they could play a relevant role and alter our perspective of an effective prevention and

478

co-treatment for NDs.

479

Still, the uncovering of the neuroprotective potential of (poly)phenol metabolites to attenuate

480

neuroinflammation and their mode of action in neuronal cells is in its infancy. More studies are

481

examine the diversity of the metabolites and evaluate how and when various types of conjugates

482

(sulfates, glucuronides and methylated) may alter their efficacy of the metabolites. Moreover,

483

metabolites have different pharmacokinetics and some of them may circulate simultaneously in

484

specific time windows, which increases the complexity of possible interactions and synergistic

485

actions. Another layer of complexity needed to embrace the physiological environment where the

486

metabolites act in vivo inside the brain is to use more biological relevant cellular models. Current

487

cell culture methodologies (2D) used to assess (poly)phenols metabolites biological activity are

488

limited in their ability to reconstruct and mimic the cellular environment that is present in vivo. In

489

vitro models for preclinical research using stem cells, patient-specific induced pluripotent stem

490

cells and reprogrammed somatic cells from patients are already applied in disease modelling and



491

drug discovery and may be applicable to test the brain benefits of (poly)phenol metabolites.

492

Three-dimensional (3D) culture systems represent a more physiologically accurate model

493

allowing more relevant cell-cell and cell-matrix interactions. The development of increasingly

494

robust advanced model systems is a fast-growing field fed by the demands of the pharmaceutical

495

industry. Some attempts have already evaluated cytoprotection by (poly)phenol metabolites in a

496

3D model containing neurons and astrocytes.

497

(poly)phenol metabolites and neuroglia signalling and communication is crucial for tuning

498

translation of how diet can modify age-related neurological diseases, like PD and AD 15,99.

15,99.

Approaching the missing link between

499

In the future, (poly)phenol research may accelerate the discovery of bioactive molecules with

500

potential application in the prevention and therapeutics of neurodegenerative conditions. Still to

501

design nutritional or pharmaceutical approaches using (poly)phenols it is imperative to explore

502

their benefits in animal models to examine their effects at the whole organism level. This is a

503

promising area and will definitely provide knowledge of particular added value to postpone the

504

development of NDs. Translation of these concepts could contribute to designing new dietary

505

recommendations, and the established knowledge on bioactivity of phenolic metabolites can

506

leverage future development of cost-effective nutraceutical/pharmaceutical therapies towards

507

NDs. Both approaches may contribute to increase healthy life expectancy by delaying the onset

508

of neurodegenerative diseases.

509 510 511 512 513 514 515 516 517 18 ACS Paragon Plus Environment

Page 18 of 60

Page 19 of 60


518

Abbreviatures

519

AD

Alzheimer’s disease

520

ALS

Amyotrophic lateral sclerosis

521

Aβ

Amyloid beta

522

CAPE

Caffeic acid phenethyl ester

523

COX-2

Cyclooxygenase 2

524

ER

Endoplasmic reticulum

525

HD

Huntington disease

526

IFN-γ

Interferon gamma

527

IGF1

Insulin-like growth factor 1

528

IL

Interleukin

529

iNOS

Inducible nitric oxide synthase

530

JNK

c-Jun N-terminal kinases

531

LPS

Lipopolysaccharides

532

MAPK

Mitogen-activated protein kinase

533

ND

Neurological disease

534

NF-ĸB

Nuclear factor kappa-light-chain-enhancer of activated B cells

535

PD

Parkinson’s disease

536

ROS

Reactive oxygen species

537

TGF-β

Transforming growth factor beta

538

TLR

Toll like receptor

539

TNF-α

Tumor necrosis factor alpha



540

UPR

Unfolded protein response

541

αsyn

Alpha synuclein

542 543

Acknowledgments

544

This work has received funding from the European Research Council (ERC) under the

545

European Union’s Horizon 2020 research and innovation programme under grant agreement No

546

804229. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by

547

Fundação para a Ciência e Tecnologia (FCT) / Ministério da Ciência e do Ensino Superior,

548

through national funds, and by FEDER under the PT2020 Partnership Agreement, is

549

acknowledged. Authors would like to acknowledge FCT for financial support of RC

550

(PD/BD/135492/2018). We acknowledge language revision by Gordon McDougall (James Hutton

551

Institute).

552

References

553

(1)

Brettschneider, J.; Tredici, K. Del; Lee, V. M.-Y.; Trojanowski, J. Q. Spreading of

554

Pathology in Neurodegenerative Diseases: A Focus on Human Studies. Nat. Rev.

555

Neurosci. 2015, 16 (2), 109–120. https://doi.org/10.1038/nrn3887.

556

(2)

557 558

Soto, C. Unfolding the Role of Protein Misfolding in Neurodegenerative Diseases. Nat. Rev. Neurosci. 2003, 4 (1), 49–60. https://doi.org/10.1038/nrn1007.

(3)

Figueira, I.; Fernandes, A.; Mladenovic Djordjevic, A.; Lopez-Contreras, A.; Henriques,

559

C. M.; Selman, C.; Ferreiro, E.; Gonos, E. S.; Trejo, J. L.; Misra, J.; et al. Interventions

560

for Age-Related Diseases: Shifting the Paradigm. Mech. Ageing Dev. 2016, 160, 69–92.

561

https://doi.org/10.1016/j.mad.2016.09.009.

562

(4)

Qin, L.; Wu, X.; Block, M. L.; Liu, Y.; Breese, G. R.; Hong, J.-S.; Knapp, D. J.; Crews, F.

563

T. Systemic LPS Causes Chronic Neuroinflammation and Progressive

564

Neurodegeneration. Glia 2007, 55 (5), 453–462. https://doi.org/10.1002/glia.20467.

565

(5)

566

London, A.; Cohen, M.; Schwartz, M. Microglia and Monocyte-Derived Macrophages: Functionally Distinct Populations That Act in Concert in CNS Plasticity and Repair. Front.


Page 20 of 60

Page 21 of 60


567 568

Cell. Neurosci. 2013, 7. https://doi.org/10.3389/fncel.2013.00034. (6)

Rangarajan, P.; Karthikeyan, A.; Dheen, S. T. Role of Dietary Phenols in Mitigating

569

Microglia-Mediated Neuroinflammation. NeuroMolecular Med. 2016, 18 (3), 453–464.

570

https://doi.org/10.1007/s12017-016-8430-x.

571

(7)

Kaminska, B.; Mota, M.; Pizzi, M. Signal Transduction and Epigenetic Mechanisms in the

572

Control of Microglia Activation during Neuroinflammation. Biochim. Biophys. Acta - Mol.

573

Basis Dis. 2016, 1862 (3), 339–351. https://doi.org/10.1016/j.bbadis.2015.10.026.

574

(8)

575 576

ElAli, A.; Rivest, S. Microglia Ontology and Signaling. Front. Cell Dev. Biol. 2016, 4. https://doi.org/10.3389/fcell.2016.00072.

(9)

Medina-Remón, A.; Tresserra-Rimbau, A.; Pons, A.; Tur, J. A.; Martorell, M.; Ros, E.;

577

Buil-Cosiales, P.; Sacanella, E.; Covas, M. I.; Corella, D.; et al. Effects of Total Dietary

578

Polyphenols on Plasma Nitric Oxide and Blood Pressure in a High Cardiovascular Risk

579

Cohort. The PREDIMED Randomized Trial. Nutr. Metab. Cardiovasc. Dis. 2015, 25 (1),

580

60–67. https://doi.org/10.1016/j.numecd.2014.09.001.

581

(10)

Rodriguez-Mateos, A.; Vauzour, D.; Krueger, C. G.; Shanmuganayagam, D.; Reed, J.;

582

Calani, L.; Mena, P.; Del Rio, D.; Crozier, A. Bioavailability, Bioactivity and Impact on

583

Health of Dietary Flavonoids and Related Compounds: An Update. Arch. Toxicol. 2014,

584

88 (10), 1803–1853. https://doi.org/10.1007/s00204-014-1330-7.

585

(11)

Nooyens, A. C. J.; Bueno-de-Mesquita, H. B.; van Boxtel, M. P. J.; van Gelder, B. M.;

586

Verhagen, H.; Verschuren, W. M. M. Fruit and Vegetable Intake and Cognitive Decline in

587

Middle-Aged Men and Women: The Doetinchem Cohort Study. Br. J. Nutr. 2011, 106

588

(5), 752–761. https://doi.org/10.1017/S0007114511001024.

589

(12)

Psaltopoulou, T.; Sergentanis, T. N.; Panagiotakos, D. B.; Sergentanis, I. N.; Kosti, R.;

590

Scarmeas, N. Mediterranean Diet, Stroke, Cognitive Impairment, and Depression: A

591

Meta-Analysis. Ann. Neurol. 2013, 74 (4), 580–591. https://doi.org/10.1002/ana.23944.

592

(13)

Spencer, J. P. E. Food for Thought: The Role of Dietary Flavonoids in Enhancing Human

593

Memory, Learning and Neuro-Cognitive Performance. Proc. Nutr. Soc. 2008, 67 (2),

594

238–252. https://doi.org/10.1017/S0029665108007088.



595

(14)

Williams, R. J.; Spencer, J. P. E. Flavonoids, Cognition, and Dementia: Actions,

596

Mechanisms, and Potential Therapeutic Utility for Alzheimer Disease. Free Radic. Biol.

597

Med. 2012, 52 (1), 35–45. https://doi.org/10.1016/j.freeradbiomed.2011.09.010.

598

(15)

Figueira, I.; Garcia, G.; Pimpão, R. C.; Terrasso, A. P.; Costa, I.; Almeida, A. F.;

599

Tavares, L.; Pais, T. F.; Pinto, P.; Ventura, M. R.; et al. Polyphenols Journey through

600

Blood-Brain Barrier towards Neuronal Protection. Sci. Rep. 2017, 7 (1), 11456.

601

https://doi.org/10.1038/s41598-017-11512-6.

602

(16)

Rendeiro, C.; Rhodes, J. S.; Spencer, J. P. E. The Mechanisms of Action of Flavonoids

603

in the Brain: Direct versus Indirect Effects. Neurochem. Int. 2015, 89, 126–139.

604

https://doi.org/10.1016/j.neuint.2015.08.002.

605

(17)

Mayr, H. L.; Thomas, C. J.; Tierney, A. C.; Kucianski, T.; George, E. S.; Ruiz-Canela, M.;

606

Hebert, J. R.; Shivappa, N.; Itsiopoulos, C. Randomization to 6-Month Mediterranean

607

Diet Compared with a Low-Fat Diet Leads to Improvement in Dietary Inflammatory Index

608

Scores in Patients with Coronary Heart Disease: The AUSMED Heart Trial. Nutr. Res.

609

2018, 55, 94–107. https://doi.org/10.1016/j.nutres.2018.04.006.

610

(18)

Devore, E. E.; Kang, J. H.; Breteler, M. M. B.; Grodstein, F. Dietary Intakes of Berries

611

and Flavonoids in Relation to Cognitive Decline. Ann. Neurol. 2012, 72 (1), 135–143.

612

https://doi.org/10.1002/ana.23594.

613

(19)

Gao, X.; Cassidy, A.; Schwarzschild, M. A.; Rimm, E. B.; Ascherio, A. Habitual Intake of

614

Dietary Flavonoids and Risk of Parkinson Disease. Neurology 2012, 78 (15), 1138–

615

1145. https://doi.org/10.1212/WNL.0b013e31824f7fc4.

616

(20)

Kennedy, D. O. Polyphenols and the Human Brain: Plant “Secondary Metabolite”

617

Ecologic Roles and Endogenous Signaling Functions Drive Benefits. Adv. Nutr. 2014, 5

618

(5), 515–533. https://doi.org/10.3945/an.114.006320.

619

(21)

Macready, A. L.; Kennedy, O. B.; Ellis, J. A.; Williams, C. M.; Spencer, J. P. E.; Butler, L.

620

T. Flavonoids and Cognitive Function: A Review of Human Randomized Controlled Trial

621

Studies and Recommendations for Future Studies. Genes Nutr. 2009, 4 (4), 227–242.

622

https://doi.org/10.1007/s12263-009-0135-4.


Page 22 of 60

Page 23 of 60

623


(22)

Nehlig, A. The Neuroprotective Effects of Cocoa Flavanol and Its Influence on Cognitive

624

Performance. Br. J. Clin. Pharmacol. 2013, 75 (3), 716–727.

625

https://doi.org/10.1111/j.1365-2125.2012.04378.x.

626

(23)

Krikorian, R.; Shidler, M. D.; Nash, T. A.; Kalt, W.; Vinqvist-Tymchuk, M. R.; Shukitt-

627

Hale, B.; Joseph, J. A. Blueberry Supplementation Improves Memory in Older Adults. J.

628

Agric. Food Chem. 2010, 58 (7), 3996–4000. https://doi.org/10.1021/jf9029332.

629

(24)

Bowtell, J. L.; Aboo-Bakkar, Z.; Conway, M. E.; Adlam, A.-L. R.; Fulford, J. Enhanced

630

Task-Related Brain Activation and Resting Perfusion in Healthy Older Adults after

631

Chronic Blueberry Supplementation. Appl. Physiol. Nutr. Metab. 2017, 42 (7), 773–779.

632

https://doi.org/10.1139/apnm-2016-0550.

633

(25)

Miller, M. G.; Hamilton, D. A.; Joseph, J. A.; Shukitt-Hale, B. Dietary Blueberry Improves

634

Cognition among Older Adults in a Randomized, Double-Blind, Placebo-Controlled Trial.

635

Eur. J. Nutr. 2018, 57 (3), 1169–1180. https://doi.org/10.1007/s00394-017-1400-8.

636

(26)

637 638

J. Clin. Nutr. 2005, 81 (1), 317–325. https://doi.org/10.1093/ajcn/81.1.317S. (27)

639 640

Arts, I. C.; Hollman, P. C. Polyphenols and Disease Risk in Epidemiologic Studies. Am.

Tsao, R. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2010, 2 (12), 1231–1246. https://doi.org/10.3390/nu2121231.

(28)

Feliciano, R. P.; Boeres, A.; Massacessi, L.; Istas, G.; Ventura, M. R.; Nunes dos

641

Santos, C.; Heiss, C.; Rodriguez-Mateos, A. Identification and Quantification of Novel

642

Cranberry-Derived Plasma and Urinary (Poly)Phenols. Arch. Biochem. Biophys. 2016,

643

599, 31–41. https://doi.org/10.1016/j.abb.2016.01.014.

644

(29)

Rodriguez-Mateos, A.; Heiss, C.; Borges, G.; Crozier, A. Berry (Poly)Phenols and

645

Cardiovascular Health. J. Agric. Food Chem. 2014, 62 (18), 3842–3851.

646

https://doi.org/10.1021/jf403757g.

647

(30)

Rothwell, J. A.; Perez-Jimenez, J.; Neveu, V.; Medina-Remon, A.; M’Hiri, N.; Garcia-

648

Lobato, P.; Manach, C.; Knox, C.; Eisner, R.; Wishart, D. S.; et al. Phenol-Explorer 3.0:

649

A Major Update of the Phenol-Explorer Database to Incorporate Data on the Effects of

650

Food Processing on Polyphenol Content. Database 2013, 2013.



651 652

https://doi.org/10.1093/database/bat070. (31)

Mena, P.; Bresciani, L.; Brindani, N.; Ludwig, I. A.; Pereira-Caro, G.; Angelino, D.;

653

Llorach, R.; Calani, L.; Brighenti, F.; Clifford, M. N.; et al. Phenyl-γ-Valerolactones and

654

Phenylvaleric Acids, the Main Colonic Metabolites of Flavan-3-Ols: Synthesis, Analysis,

655

Bioavailability, and Bioactivity. Nat. Prod. Rep. 2019.

656

https://doi.org/10.1039/C8NP00062J.

657

(32)

Williamson, G.; Manach, C. Bioavailability and Bioefficacy of Polyphenols in Humans. II.

658

Review of 93 Intervention Studies. Am. J. Clin. Nutr. 2005, 81 (1), 243S–255S.

659

https://doi.org/10.1093/ajcn/81.1.243S.

660

(33)

Stalmach, A.; Edwards, C. A.; Wightman, J. D.; Crozier, A. Gastrointestinal Stability and

661

Bioavailability of (Poly)Phenolic Compounds Following Ingestion of Concord Grape Juice

662

by Humans. Mol. Nutr. Food Res. 2012, 56 (3), 497–509.

663

https://doi.org/10.1002/mnfr.201100566.

664

(34)

Day, A. J.; Cañada, F. J.; Dı́az, J. C.; Kroon, P. A.; Mclauchlan, R.; Faulds, C. B.; Plumb,

665

G. W.; Morgan, M. R. .; Williamson, G. Dietary Flavonoid and Isoflavone Glycosides Are

666

Hydrolysed by the Lactase Site of Lactase Phlorizin Hydrolase. FEBS Lett. 2000, 468

667

(2–3), 166–170. https://doi.org/10.1016/S0014-5793(00)01211-4.

668

(35)

Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J. P. E.; Tognolini, M.; Borges, G.; Crozier,

669

A. Dietary (Poly)Phenolics in Human Health: Structures, Bioavailability, and Evidence of

670

Protective Effects Against Chronic Diseases. Antioxid. Redox Signal. 2013, 18 (14),

671

1818–1892. https://doi.org/10.1089/ars.2012.4581.

672

(36)

González-Sarrías, A.; García-Villalba, R.; Romo-Vaquero, M.; Alasalvar, C.; Örem, A.;

673

Zafrilla, P.; Tomás-Barberán, F. A.; Selma, M. V; Espín, J. C. Clustering According to

674

Urolithin Metabotype Explains the Interindividual Variability in the Improvement of

675

Cardiovascular Risk Biomarkers in Overweight-Obese Individuals Consuming

676

Pomegranate: A Randomized Clinical Trial. Mol. Nutr. Food Res. 2017, 61 (5), 1600830.

677


678

(37)

Espín, J. C.; Larrosa, M.; García-Conesa, M. T.; Tomás-Barberán, F. Biological


Page 24 of 60

Page 25 of 60


679

Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The

680

Evidence So Far. Evidence-Based Complement. Altern. Med. 2013, 2013, 1–15.

681

https://doi.org/10.1155/2013/270418.

682

(38)

683 684

Plant Phenolics and Human Health; Fraga, C. G., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2009. https://doi.org/10.1002/9780470531792.

(39)

Bialonska, D.; Kasimsetty, S. G.; Khan, S. I.; Ferreira, D. Urolithins, Intestinal Microbial

685

Metabolites of Pomegranate Ellagitannins, Exhibit Potent Antioxidant Activity in a Cell-

686

Based Assay. J. Agric. Food Chem. 2009, 57 (21), 10181–10186.

687

https://doi.org/10.1021/jf9025794.

688

(40)

Brinquin, L.; Philip, Y.; Le Gulluche, Y.; Bonsignour, J. P.; Buffat, J. J. Anesthésie Pour

689

Chirurgie d’un Phéochromocytome Malin. Accès Hypertensif Après Administration de

690

Dropéridol. Ann. Fr. Anesth. Reanim. 1987, 6 (3), 204–206.

691

https://doi.org/10.1016/S0750-7658(87)80080-1.

692

(41)

Perez-Ternero, C.; Macià, A.; de Sotomayor, M. A.; Parrado, J.; Motilva, M.-J.; Herrera,

693

M.-D. Bioavailability of the Ferulic Acid-Derived Phenolic Compounds of a Rice Bran

694

Enzymatic Extract and Their Activity against Superoxide Production. Food Funct. 2017,

695

8 (6), 2165–2174. https://doi.org/10.1039/C7FO00243B.

696

(42)

Williamson, G.; Clifford, M. N. Role of the Small Intestine, Colon and Microbiota in

697

Determining the Metabolic Fate of Polyphenols. Biochem. Pharmacol. 2017, 139, 24–39.

698

https://doi.org/10.1016/j.bcp.2017.03.012.

699

(43)

Pasinetti, G. M.; Singh, R.; Westfall, S.; Herman, F.; Faith, J.; Ho, L. The Role of the Gut

700

Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. J.

701

Alzheimer’s Dis. 2018, 63 (2), 409–421. https://doi.org/10.3233/JAD-171151.

702

(44)

Czank, C.; Cassidy, A.; Zhang, Q.; Morrison, D. J.; Preston, T.; Kroon, P. A.; Botting, N.

703

P.; Kay, C. D. Human Metabolism and Elimination of the Anthocyanin, Cyanidin-3-

704

Glucoside: A 13C-Tracer Study. Am. J. Clin. Nutr. 2013, 97 (5), 995–1003.

705

https://doi.org/10.3945/ajcn.112.049247.

706

(45)

Pimpão, R. C.; Ventura, M. R.; Ferreira, R. B.; Williamson, G.; Santos, C. N. Phenolic



707

Sulfates as New and Highly Abundant Metabolites in Human Plasma after Ingestion of a

708

Mixed Berry Fruit Purée. Br. J. Nutr. 2015, 113 (3), 454–463.

709

https://doi.org/10.1017/S0007114514003511.

710

(46)

Penczynski, K. J.; Krupp, D.; Bring, A.; Bolzenius, K.; Remer, T.; Buyken, A. E. Relative

711

Validation of 24-h Urinary Hippuric Acid Excretion as a Biomarker for Dietary Flavonoid

712

Intake from Fruit and Vegetables in Healthy Adolescents. Eur. J. Nutr. 2017, 56 (2), 757–

713

766. https://doi.org/10.1007/s00394-015-1121-9.

714

(47)

Schaffer, S.; Halliwell, B. Do Polyphenols Enter the Brain and Does It Matter? Some

715

Theoretical and Practical Considerations. Genes Nutr. 2012, 7 (2), 99–109.

716

https://doi.org/10.1007/s12263-011-0255-5.

717

(48)

Cardoso Jr, C. G.; Gomides, R. S.; Queiroz, A. C. C.; Pinto, L. G.; Lobo, F. da S.;

718

Tinucci, T.; Mion Jr, D.; Forjaz, C. L. de M. Acute and Chronic Effects of Aerobic and

719

Resistance Exercise on Ambulatory Blood Pressure. Clinics 2010, 65 (3), 317–325.

720

https://doi.org/10.1590/S1807-59322010000300013.

721

(49)

Milbury, P. E.; Kalt, W. Xenobiotic Metabolism and Berry Flavonoid Transport across the

722

Blood−Brain Barrier. J. Agric. Food Chem. 2010, 58 (7), 3950–3956.

723

https://doi.org/10.1021/jf903529m.

724

(50)

Gasperotti, M.; Passamonti, S.; Tramer, F.; Masuero, D.; Guella, G.; Mattivi, F.;

725

Vrhovsek, U. Fate of Microbial Metabolites of Dietary Polyphenols in Rats: Is the Brain

726

Their Target Destination? ACS Chem. Neurosci. 2015, 6 (8), 1341–1352.

727

https://doi.org/10.1021/acschemneuro.5b00051.

728

(51)

van Praag, H.; Lucero, M. J.; Yeo, G. W.; Stecker, K.; Heivand, N.; Zhao, C.; Yip, E.;

729

Afanador, M.; Schroeter, H.; Hammerstone, J.; et al. Plant-Derived Flavanol (-

730

)Epicatechin Enhances Angiogenesis and Retention of Spatial Memory in Mice. J.

731

Neurosci. 2007, 27 (22), 5869–5878. https://doi.org/10.1523/JNEUROSCI.0914-07.2007.

732

(52)

El Mohsen, M. A.; Marks, J.; Kuhnle, G.; Rice-Evans, C.; Moore, K.; Gibson, G.;

733

Debnam, E.; Srai, S. K. The Differential Tissue Distribution of the Citrus Flavanone

734

Naringenin Following Gastric Instillation. Free Radic. Res. 2004, 38 (12), 1329–1340.


Page 26 of 60

Page 27 of 60


735 736

https://doi.org/10.1080/10715760400017293. (53)

Ishisaka, A.; Ichikawa, S.; Sakakibara, H.; Piskula, M. K.; Nakamura, T.; Kato, Y.; Ito, M.;

737

Miyamoto, K.; Tsuji, A.; Kawai, Y.; et al. Accumulation of Orally Administered Quercetin

738

in Brain Tissue and Its Antioxidative Effects in Rats. Free Radic. Biol. Med. 2011, 51 (7),

739

1329–1336. https://doi.org/10.1016/j.freeradbiomed.2011.06.017.

740

(54)

Talavéra, S.; Felgines, C.; Texier, O.; Besson, C.; Gil-Izquierdo, A.; Lamaison, J.-L.;

741

Rémésy, C. Anthocyanin Metabolism in Rats and Their Distribution to Digestive Area,

742

Kidney, and Brain. J. Agric. Food Chem. 2005, 53 (10), 3902–3908.

743

https://doi.org/10.1021/jf050145v.

744

(55)

Bò, C. Del; Ciappellano, S.; Klimis-Zacas, D.; Martini, D.; Gardana, C.; Riso, P.; Porrini,

745

M. Anthocyanin Absorption, Metabolism, and Distribution from a Wild Blueberry-Enriched

746

Diet ( Vaccinium Angustifolium ) Is Affected by Diet Duration in the Sprague−Dawley

747

Rat. J. Agric. Food Chem. 2010, 58 (4), 2491–2497. https://doi.org/10.1021/jf903472x.

748

(56)

Wu, L.; Zhang, Q.-L.; Zhang, X.-Y.; Lv, C.; Li, J.; Yuan, Y.; Yin, F.-X. Pharmacokinetics

749

and Blood–Brain Barrier Penetration of (+)-Catechin and (−)-Epicatechin in Rats by

750

Microdialysis Sampling Coupled to High-Performance Liquid Chromatography with

751

Chemiluminescence Detection. J. Agric. Food Chem. 2012, 60 (37), 9377–9383.

752

https://doi.org/10.1021/jf301787f.

753

(57)

Zhao, W.; Wang, J.; Bi, W.; Ferruzzi, M.; Yemul, S.; Freire, D.; Mazzola, P.; Ho, L.;

754

Dubner, L.; Pasinetti, G. M. Novel Application of Brain-Targeting Polyphenol Compounds

755

in Sleep Deprivation-Induced Cognitive Dysfunction. Neurochem. Int. 2015, 89, 191–

756

197. https://doi.org/10.1016/j.neuint.2015.07.023.

757

(58)

Faria, A.; Pestana, D.; Teixeira, D.; Couraud, P.-O.; Romero, I.; Weksler, B.; de Freitas,

758

V.; Mateus, N.; Calhau, C. Insights into the Putative Catechin and Epicatechin Transport

759

across Blood-Brain Barrier. Food Funct. 2011, 2 (1), 39–44.

760

https://doi.org/10.1039/C0FO00100G.

761 762

(59)

Wu, K.; Wang, Z.-Z.; Liu, D.; Qi, X.-R. Pharmacokinetics, Brain Distribution, Release and Blood–brain Barrier Transport of Shunaoxin Pills. J. Ethnopharmacol. 2014, 151 (3),



763 764

1133–1140. https://doi.org/10.1016/j.jep.2013.12.027. (60)

Bauer, S. R.; Ding, E. L.; Smit, L. A. Cocoa Consumption, Cocoa Flavonoids, and Effects

765

on Cardiovascular Risk Factors: An Evidence-Based Review. Curr. Cardiovasc. Risk

766

Rep. 2011, 5 (2), 120–127. https://doi.org/10.1007/s12170-011-0157-5.

767

(61)

Monagas, M.; Khan, N.; Andres-Lacueva, C.; Casas, R.; Urpí-Sardà, M.; Llorach, R.;

768

Lamuela-Raventós, R. M.; Estruch, R. Effect of Cocoa Powder on the Modulation of

769

Inflammatory Biomarkers in Patients at High Risk of Cardiovascular Disease. Am. J.

770

Clin. Nutr. 2009, 90 (5), 1144–1150. https://doi.org/10.3945/ajcn.2009.27716.

771

(62)

Flanagan, E.; Müller, M.; Hornberger, M.; Vauzour, D. Impact of Flavonoids on Cellular

772

and Molecular Mechanisms Underlying Age-Related Cognitive Decline and

773

Neurodegeneration. Curr. Nutr. Rep. 2018, 7 (2), 49–57. https://doi.org/10.1007/s13668-

774

018-0226-1.

775

(63)

Poulose, S. M.; Fisher, D. R.; Larson, J.; Bielinski, D. F.; Rimando, A. M.; Carey, A. N.;

776

Schauss, A. G.; Shukitt-Hale, B. Anthocyanin-Rich Açai (Euterpe Oleracea Mart.) Fruit

777

Pulp Fractions Attenuate Inflammatory Stress Signaling in Mouse Brain BV-2 Microglial

778

Cells. J. Agric. Food Chem. 2012, 60 (4), 1084–1093. https://doi.org/10.1021/jf203989k.

779

(64)

Lau, F. C.; Bielinski, D. F.; Joseph, J. A. Inhibitory Effects of Blueberry Extract on the

780

Production of Inflammatory Mediators in Lipopolysaccharide-Activated BV2 Microglia. J.

781

Neurosci. Res. 2007, 85 (5), 1010–1017. https://doi.org/10.1002/jnr.21205.

782

(65)

Syed, M. M.; Phulwani, N. K.; Kielian, T. Tumor Necrosis Factor-Alpha (TNF-α)

783

Regulates Toll-like Receptor 2 (TLR2) Expression in Microglia. J. Neurochem. 2007, 103

784

(4), 1461–1471. https://doi.org/10.1111/j.1471-4159.2007.04838.x.

785

(66)

Tambuwala, M. M.; Khan, M. N.; Thompson, P.; McCarron, P. A. Albumin Nano-

786

Encapsulation of Caffeic Acid Phenethyl Ester and Piceatannol Potentiated Its Ability to

787

Modulate HIF and NF-KB Pathways and Improves Therapeutic Outcome in Experimental

788

Colitis. Drug Deliv. Transl. Res. 2019, 9 (1), 14–24. https://doi.org/10.1007/s13346-018-

789

00597-9.

790

(67)

di Gesso, J. L.; Kerr, J. S.; Zhang, Q.; Raheem, S.; Yalamanchili, S. K.; O’Hagan, D.;


Page 28 of 60

Page 29 of 60


791

Kay, C. D.; O’Connell, M. A. Flavonoid Metabolites Reduce Tumor Necrosis Factor-α

792

Secretion to a Greater Extent than Their Precursor Compounds in Human THP-1

793

Monocytes. Mol. Nutr. Food Res. 2015, 59 (6), 1143–1154.

794


795

(68)

Verpoorte, R.; Choi, Y. H.; Kim, H. K. Ethnopharmacology and Systems Biology: A

796

Perfect Holistic Match. J. Ethnopharmacol. 2005, 100 (1–2), 53–56.

797

https://doi.org/10.1016/j.jep.2005.05.033.

798

(69)

Tavares, L.; Figueira, I.; McDougall, G. J.; Vieira, H. L. A.; Stewart, D.; Alves, P. M.;

799

Ferreira, R. B.; Santos, C. N. Neuroprotective Effects of Digested Polyphenols from Wild

800

Blackberry Species. Eur. J. Nutr. 2013, 52 (1), 225–236. https://doi.org/10.1007/s00394-

801

012-0307-7.

802

(70)

Giampieri, F.; Afrin, S.; Stewart, D.; McDougall, G.; Brennan, R.; Blyth, L.; Gasparrini,

803

M.; Mazzoni, L.; Capocasa, F.; Alvarez-Suarez, J.; et al. Phytochemical Composition and

804

Cytotoxic Effects on Liver Hepatocellular Carcinoma Cells of Different Berries Following

805

a Simulated In Vitro Gastrointestinal Digestion. Molecules 2018, 23 (8), 1918.

806

https://doi.org/10.3390/molecules23081918.

807

(71)

Tavares, L.; Figueira, I.; Macedo, D.; McDougall, G. J.; Leitão, M. C.; Vieira, H. L. A.;

808

Stewart, D.; Alves, P. M.; Ferreira, R. B.; Santos, C. N. Neuroprotective Effect of

809

Blackberry (Rubus Sp.) Polyphenols Is Potentiated after Simulated Gastrointestinal

810

Digestion. Food Chem. 2012, 131 (4), 1443–1452.

811

https://doi.org/10.1016/j.foodchem.2011.10.025.

812

(72)

Garcia, G.; Nanni, S.; Figueira, I.; Ivanov, I.; McDougall, G. J.; Stewart, D.; Ferreira, R.

813

B.; Pinto, P.; Silva, R. F. M.; Brites, D.; et al. Bioaccessible (Poly)Phenol Metabolites

814

from Raspberry Protect Neural Cells from Oxidative Stress and Attenuate Microglia

815

Activation. Food Chem. 2017, 215, 274–283.

816

https://doi.org/10.1016/j.foodchem.2016.07.128.

817 818

(73)

Kuo, P.-C.; Liao, Y.-R.; Hung, H.-Y.; Chuang, C.-W.; Hwang, T.-L.; Huang, S.-C.; Shiao, Y.-J.; Kuo, D.-H.; Wu, T.-S. Anti-Inflammatory and Neuroprotective Constituents from the



819

Peels of Citrus Grandis. Molecules 2017, 22 (6), 967.

820

https://doi.org/10.3390/molecules22060967.

821

(74)

Kim, H. J.; Hwang, I. K.; Won, M. H. Vanillin, 4-Hydroxybenzyl Aldehyde and 4-

822

Hydroxybenzyl Alcohol Prevent Hippocampal CA1 Cell Death Following Global

823

Ischemia. Brain Res. 2007, 1181, 130–141.

824

https://doi.org/10.1016/j.brainres.2007.08.066.

825

(75)

826 827

Cuadrado, A. NRF2 in Neurodegenerative Diseases. Curr. Opin. Toxicol. 2016, 1, 46– 53. https://doi.org/10.1016/j.cotox.2016.09.004.

(76)

Doig, A. J.; Derreumaux, P. Inhibition of Protein Aggregation and Amyloid Formation by

828

Small Molecules. Curr. Opin. Struct. Biol. 2015, 30, 50–56.

829

https://doi.org/10.1016/j.sbi.2014.12.004.

830

(77)

Zheng, L. T.; Ryu, G.-M.; Kwon, B.-M.; Lee, W.-H.; Suk, K. Anti-Inflammatory Effects of

831

Catechols in Lipopolysaccharide-Stimulated Microglia Cells: Inhibition of Microglial

832

Neurotoxicity. Eur. J. Pharmacol. 2008, 588 (1), 106–113.

833

https://doi.org/10.1016/j.ejphar.2008.04.035.

834

(78)

Weil-Malherbe, H.; Posner, H. S.; Bowles, G. R. Changes in the Concentration and

835

Intracellular Distribution of Brain Catecholamines: The Effects of Reserpine. Beta-

836

Phenyliso-Propylhydrazine, Pyrogallol and 3,4-Dihydroxyphenyl Alanine, Alone and in

837

Combination. J. Pharmacol. Exp. Ther. 1961, 132, 278–286.

838

(79)

Rogers, K. J.; Angel, A.; Butterfield, L. The Penetration of Catechol and Pyrogallol into

839

Mouse Brain and the Effect on Cerebral Monoamine Levels. J. Pharm. Pharmacol. 1968,

840

20 (9), 727–729. https://doi.org/10.1111/j.2042-7158.1968.tb09845.x.

841

(80)

Baldessarini, R. J.; Greiner, E. Inhibition of Catechol-o-Methyl Transferase by Catechols

842

and Polyphenols. Biochem. Pharmacol. 1973, 22 (2), 247–256.

843

https://doi.org/10.1016/0006-2952(73)90277-3.

844

(81)

Lai, F. M.; Spector, S. The Potentiating Effect of Clorgyline and Pyrogallol on the Blood

845

Pressure Responses to Norepinephrine. Arch. Int. Pharmacodyn. Ther. 1978, 234 (2),

846

279–286.


Page 30 of 60

Page 31 of 60

847


(82)

Kita, T.; Wagner, G. C.; Philbert, M. A.; King, L. A.; Lowndes, H. E. Effects of Pargyline

848

and Pyrogallol on the Methamphetamine-Induced Dopamine Depletion. Mol. Chem.

849

Neuropathol. 1995, 24 (1), 31–41.

850

(83)

Agrawal, R.; Sharma, P. K.; Rao, G. S. Release of Iron from Ferritin by Metabolites of

851

Benzene and Superoxide Radical Generating Agents. Toxicology 2001, 168 (3), 223–

852

230. https://doi.org/10.1016/S0300-483X(01)00412-7.

853

(84)

Yamada, J.; Yoshimura, S.; Yamakawa, H.; Sawada, M.; Nakagawa, M.; Hara, S.; Kaku,

854

Y.; Iwama, T.; Naganawa, T.; Banno, Y.; et al. Cell Permeable ROS Scavengers, Tiron

855

and Tempol, Rescue PC12 Cell Death Caused by Pyrogallol or Hypoxia/Reoxygenation.

856

Neurosci. Res. 2003, 45 (1), 1–8. https://doi.org/10.1016/S0168-0102(02)00196-7.

857

(85)

Liao, P.-C.; Kuo, Y.-M.; Chang, Y.-C.; Lin, C.; Cherng, C.-F. G.; Yu, L. Striatal Formation

858

of 6-Hydroxydopamine in Mice Treated with Pargyline, Pyrogallol and

859

Methamphetamine. J. Neural Transm. 2003, 110 (5), 487–494.

860

https://doi.org/10.1007/s00702-002-0829-x.

861

(86)

Upadhyay, G.; Gupta, S. P.; Prakash, O.; Singh, M. P. Pyrogallol-Mediated Toxicity and

862

Natural Antioxidants: Triumphs and Pitfalls of Preclinical Findings and Their

863

Translational Limitations. Chem. Biol. Interact. 2010, 183 (3), 333–340.

864

https://doi.org/10.1016/j.cbi.2009.11.028.

865

(87)

Wang, H.; Wang, H.; Wang, J.; Wang, Q.; Ma, Q.-F.; Chen, Y.-Y. Protocatechuic Acid

866

Inhibits Inflammatory Responses in LPS-Stimulated BV2 Microglia via NF-ΚB and

867

MAPKs Signaling Pathways. Neurochem. Res. 2015, 40 (8), 1655–1660.

868

https://doi.org/10.1007/s11064-015-1646-6.

869

(88)

Ren, Z.; Zhang, R.; Li, Y.; Li, Y.; Yang, Z.; Yang, H. Ferulic Acid Exerts Neuroprotective

870

Effects against Cerebral Ischemia/Reperfusion-Induced Injury via Antioxidant and Anti-

871

Apoptotic Mechanisms in Vitro and in Vivo. Int. J. Mol. Med. 2017, 40 (5), 1444–1456.

872

https://doi.org/10.3892/ijmm.2017.3127.

873 874

(89)

Kim, M.-J.; Seong, A.-R.; Yoo, J.-Y.; Jin, C.-H.; Lee, Y.-H.; Kim, Y. J.; Lee, J.; Jun, W. J.; Yoon, H.-G. Gallic Acid, a Histone Acetyltransferase Inhibitor, Suppresses β-Amyloid



875

Neurotoxicity by Inhibiting Microglial-Mediated Neuroinflammation. Mol. Nutr. Food Res.

876

2011, 55 (12), 1798–1808. https://doi.org/10.1002/mnfr.201100262.

877

(90)

da Silva, A.; Giacomoni, F.; Pavot, B.; Fillâtre, Y.; Rothwell, J. A.; Sualdea, B. B.; Veyrat,

878

C.; Garcia-Villalba, R.; Gladine, C.; Kopec, R.; et al. PhytoHub V1. 4: A New Release for

879

the Online Database Dedicated to Food Phytochemicals and Their Human Metabolites.

880

In Proceedings of the 1st International Conference on Food Bioactivities & Health,

881

Norwich, UK; 2016; pp 13–15.

882

(91)

Kim, B.-W.; Koppula, S.; Park, S.-Y.; Kim, Y.-S.; Park, P.-J.; Lim, J.-H.; Kim, I.-S.; Choi,

883

D.-K. Attenuation of Neuroinflammatory Responses and Behavioral Deficits by

884

Ligusticum Officinale (Makino) Kitag in Stimulated Microglia and MPTP-Induced Mouse

885

Model of Parkinson‫׳‬s Disease. J. Ethnopharmacol. 2015, 164, 388–397.

886

https://doi.org/10.1016/j.jep.2014.11.004.

887

(92)

Rehman, S. U.; Ali, T.; Alam, S. I.; Ullah, R.; Zeb, A.; Lee, K. W.; Rutten, B. P. F.; Kim,

888

M. O. Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4

889

Receptor in the Mouse Hippocampus. Mol. Neurobiol. 2019, 56 (4), 2774–2790.

890

https://doi.org/10.1007/s12035-018-1280-9.

891

(93)

Koshiguchi, M.; Komazaki, H.; Hirai, S.; Egashira, Y. Ferulic Acid Suppresses

892

Expression of Tryptophan Metabolic Key Enzyme Indoleamine 2, 3-Dioxygenase via

893

NFκB and P38 MAPK in Lipopolysaccharide-Stimulated Microglial Cells. Biosci.

894

Biotechnol. Biochem. 2017, 81 (5), 966–971.

895

https://doi.org/10.1080/09168451.2016.1274636.

896

(94)

Chakrabarti, S.; Jana, M.; Roy, A.; Pahan, K. Upregulation of Suppressor of Cytokine

897

Signaling 3 in Microglia by Cinnamic Acid. Curr. Alzheimer Res. 2018, 15 (10), 894–904.

898

https://doi.org/10.2174/1567205015666180507104755.

899

(95)

Stalmach, A.; Mullen, W.; Barron, D.; Uchida, K.; Yokota, T.; Cavin, C.; Steiling, H.;

900

Williamson, G.; Crozier, A. Metabolite Profiling of Hydroxycinnamate Derivatives in

901

Plasma and Urine after the Ingestion of Coffee by Humans: Identification of Biomarkers

902

of Coffee Consumption. Drug Metab. Dispos. 2009, 37 (8), 1749–1758.


Page 32 of 60

Page 33 of 60


903 904

https://doi.org/10.1124/dmd.109.028019. (96)

van Dorsten, F. A.; Grün, C. H.; van Velzen, E. J. J.; Jacobs, D. M.; Draijer, R.; van

905

Duynhoven, J. P. M. The Metabolic Fate of Red Wine and Grape Juice Polyphenols in

906

Humans Assessed by Metabolomics. Mol. Nutr. Food Res. 2009, 54 (7), 897–908.

907


908

(97)

Esteban-Fernández, A.; Rendeiro, C.; Spencer, J. P. E.; del Coso, D. G.; de Llano, M. D.

909

G.; Bartolomé, B.; Moreno-Arribas, M. V. Neuroprotective Effects of Selected Microbial-

910

Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y

911

Neuroblastoma Cells and Their Putative Mechanisms of Action. Front. Nutr. 2017, 4, 3.

912

https://doi.org/10.3389/fnut.2017.00003.

913

(98)

Wang, Y.-D.; Bao, X.-Q.; Xu, S.; Yu, W.-W.; Cao, S.-N.; Hu, J.-P.; Li, Y.; Wang, X.-L.;

914

Zhang, D.; Yu, S.-S. A Novel Parkinson’s Disease Drug Candidate with Potent Anti-

915

Neuroinflammatory Effects through the Src Signaling Pathway. J. Med. Chem. 2016, 59

916

(19), 9062–9079. https://doi.org/10.1021/acs.jmedchem.6b00976.

917

(99)

Figueira, I.; Tavares, L.; Jardim, C.; Costa, I.; Terrasso, A. P.; Almeida, A. F.; Govers,

918

C.; Mes, J. J.; Gardner, R.; Becker, J. D.; et al. Blood–brain Barrier Transport and

919

Neuroprotective Potential of Blackberry-Digested Polyphenols: An in Vitro Study. Eur. J.

920

Nutr. 2019, 58 (1), 113–130. https://doi.org/10.1007/s00394-017-1576-y.

921

(100) Loke, W. M.; Jenner, A. M.; Proudfoot, J. M.; McKinley, A. J.; Hodgson, J. M.; Halliwell,

922

B.; Croft, K. D. A Metabolite Profiling Approach to Identify Biomarkers of Flavonoid

923

Intake in Humans. J. Nutr. 2009, 139 (12), 2309–2314.

924

https://doi.org/10.3945/jn.109.113613.

925

(101) Cialdella-Kam, L.; Nieman, D. C.; Sha, W.; Meaney, M. P.; Knab, A. M.; Shanely, R. A.

926

Dose–response to 3 Months of Quercetin-Containing Supplements on Metabolite and

927

Quercetin Conjugate Profile in Adults. Br. J. Nutr. 2013, 109 (11), 1923–1933.

928

https://doi.org/10.1017/S0007114512003972.

929 930

(102) van der Hooft, J. J. J.; de Vos, R. C. H.; Mihaleva, V.; Bino, R. J.; Ridder, L.; de Roo, N.; Jacobs, D. M.; van Duynhoven, J. P. M.; Vervoort, J. Structural Elucidation and



931

Quantification of Phenolic Conjugates Present in Human Urine after Tea Intake. Anal.

932

Chem. 2012, 84 (16), 7263–7271. https://doi.org/10.1021/ac3017339.

933

(103) Welsch, F. Routes and Modes of Administration of Resorcinol and Their Relationship to

934

Potential Manifestations of Thyroid Gland Toxicity in Animals and Man. Int. J. Toxicol.

935

2008, 27 (1), 59–63. https://doi.org/10.1080/10915810701876687.

936

(104) Curzon, G.; Pratt, R. T. C. Origin of Urinary Resorcinol Sulphate. Nature 1964, 204

937

(4956), 383–384. https://doi.org/10.1038/204383a0.

938

(105) Guo, K.; Li, L. Differential 12 C-/ 13 C-Isotope Dansylation Labeling and Fast Liquid

939

Chromatography/Mass Spectrometry for Absolute and Relative Quantification of the

940

Metabolome. Anal. Chem. 2009, 81 (10), 3919–3932.

941

https://doi.org/10.1021/ac900166a.

942

(106) Toshimitsu, N.; Kenji, M.; Toyokazu, O.; Akira, S.; Kaizo, K. A Gas Chromatographic-

943

Mass Spectrometric Analysis for Phenols in Uremic Serum. Clin. Chim. Acta 1981, 110

944

(1), 51–57. https://doi.org/10.1016/0009-8981(81)90299-0.

945

(107) Baldrick, F. R.; McFadden, K.; Ibars, M.; Sung, C.; Moffatt, T.; Megarry, K.; Thomas, K.;

946

Mitchell, P.; Wallace, J. M. W.; Pourshahidi, L. K.; et al. Impact of a (Poly)Phenol-Rich

947

Extract from the Brown Algae Ascophyllum Nodosum on DNA Damage and Antioxidant

948

Activity in an Overweight or Obese Population: A Randomized Controlled Trial. Am. J.

949

Clin. Nutr. 2018, 108 (4), 688–700. https://doi.org/10.1093/ajcn/nqy147.

950

(108) Mateo Anson, N.; Aura, A.-M.; Selinheimo, E.; Mattila, I.; Poutanen, K.; van den Berg,

951

R.; Havenaar, R.; Bast, A.; Haenen, G. R. M. M. Bioprocessing of Wheat Bran in Whole

952

Wheat Bread Increases the Bioavailability of Phenolic Acids in Men and Exerts

953

Antiinflammatory Effects Ex Vivo. J. Nutr. 2011, 141 (1), 137–143.

954

https://doi.org/10.3945/jn.110.127720.

955

(109) Clark, A.; Mach, N. Exercise-Induced Stress Behavior, Gut-Microbiota-Brain Axis and

956

Diet: A Systematic Review for Athletes. J. Int. Soc. Sports Nutr. 2016, 13 (1), 43.

957

https://doi.org/10.1186/s12970-016-0155-6.

958

(110) de Ferrars, R. M.; Czank, C.; Zhang, Q.; Botting, N. P.; Kroon, P. A.; Cassidy, A.; Kay,


Page 34 of 60

Page 35 of 60


959

C. D. The Pharmacokinetics of Anthocyanins and Their Metabolites in Humans. Br. J.

960

Pharmacol. 2014, 171 (13), 3268–3282. https://doi.org/10.1111/bph.12676.

961

(111) Blacklock, C. J. Salicylic Acid in the Serum of Subjects Not Taking Aspirin. Comparison

962

of Salicylic Acid Concentrations in the Serum of Vegetarians, Non-Vegetarians, and

963

Patients Taking Low Dose Aspirin. J. Clin. Pathol. 2001, 54 (7), 553–555.

964

https://doi.org/10.1136/jcp.54.7.553.

965

(112) Boto-Ordóñez, M.; Urpi-Sarda, M.; Queipo-Ortuño, M. I.; Corella, D.; Tinahones, F. J.;

966

Estruch, R.; Andres-Lacueva, C. Microbial Metabolomic Fingerprinting in Urine after

967

Regular Dealcoholized Red Wine Consumption in Humans. J. Agric. Food Chem. 2013,

968

61 (38), 9166–9175. https://doi.org/10.1021/jf402394c.

969

(113) Olthof, M. R.; Hollman, P. C. H.; Buijsman, M. N. C. P.; van Amelsvoort, J. M. M.; Katan,

970

M. B. Chlorogenic Acid, Quercetin-3-Rutinoside and Black Tea Phenols Are Extensively

971

Metabolized in Humans. J. Nutr. 2003, 133 (6), 1806–1814.

972

https://doi.org/10.1093/jn/133.6.1806.

973

(114) Clifford, M. N.; Copeland, E. L.; Bloxsidge, J. P.; Mitchell, L. A. Hippuric Acid as a Major

974

Excretion Product Associated with Black Tea Consumption. Xenobiotica 2000, 30 (3),

975

317–326. https://doi.org/10.1080/004982500237703.

976

(115) Guertin, K. A.; Loftfield, E.; Boca, S. M.; Sampson, J. N.; Moore, S. C.; Xiao, Q.; Huang,

977

W.-Y.; Xiong, X.; Freedman, N. D.; Cross, A. J.; et al. Serum Biomarkers of Habitual

978

Coffee Consumption May Provide Insight into the Mechanism Underlying the Association

979

between Coffee Consumption and Colorectal Cancer. Am. J. Clin. Nutr. 2015, 101 (5),

980

1000–1011. https://doi.org/10.3945/ajcn.114.096099.

981

(116) Guy, P. A.; Renouf, M.; Barron, D.; Cavin, C.; Dionisi, F.; Kochhar, S.; Rezzi, S.;

982

Williamson, G.; Steiling, H. Quantitative Analysis of Plasma Caffeic and Ferulic Acid

983

Equivalents by Liquid Chromatography Tandem Mass Spectrometry. J. Chromatogr. B

984

2009, 877 (31), 3965–3974. https://doi.org/10.1016/j.jchromb.2009.10.006.

985

(117) Zamora-Ros, R.; Achaintre, D.; Rothwell, J. A.; Rinaldi, S.; Assi, N.; Ferrari, P.;

986

Leitzmann, M.; Boutron-Ruault, M.-C.; Fagherazzi, G.; Auffret, A.; et al. Urinary



987

Excretions of 34 Dietary Polyphenols and Their Associations with Lifestyle Factors in the

988

EPIC Cohort Study. Sci. Rep. 2016, 6 (1), 26905. https://doi.org/10.1038/srep26905.

989

(118) Kern, S. M.; Bennett, R. N.; Mellon, F. A.; Kroon, P. A.; Garcia-Conesa, M.-T. Absorption

990

of Hydroxycinnamates in Humans after High-Bran Cereal Consumption. J. Agric. Food

991

Chem. 2003, 51 (20), 6050–6055. https://doi.org/10.1021/jf0302299.

992

(119) Roowi, S.; Mullen, W.; Edwards, C. A.; Crozier, A. Yoghurt Impacts on the Excretion of

993

Phenolic Acids Derived from Colonic Breakdown of Orange Juice Flavanones in

994

Humans. Mol. Nutr. Food Res. 2009, 53 (S1), S68–S75.

995


996

(120) Del Rio, D.; Stalmach, A.; Calani, L.; Crozier, A. Bioavailability of Coffee Chlorogenic

997

Acids and Green Tea Flavan-3-Ols. Nutrients 2010, 2 (8), 820–833.

998

https://doi.org/10.3390/nu2080820.

999 1000

Figure 1 - Microglia cells phenotypes under resting surveillance state (grey ramified) and upon

1001

activations by signals to Neuroprotective (green amoeboid) and Neurotoxic (red amoeboid)

1002

phenotypes. IL - interleukin, IFN-γ – interferon gamma, LPS - lipopolysaccharides, TGF-β -

1003

transforming growth factor beta, TNF-α – tumour necrosis factor alpha, COX - cyclooxygenase,

1004

ROS – reactive oxygen species.

1005

Figure 2 - Different flavonoid classes with nutritional relevance. Flavonoid classes are represented

1006

as their 5,7-dihydroxyflavonoid derivatives. Red labeled bounds and chemical groups represent

1007

the major chemical characteristics of the flavonoid class.

1008

Figure 3 - Conversion pathway demonstrating the metabolism of the most representative

1009

flavonoids in dietary products (black boxes) into low molecular weight phenolic metabolites. Red

1010

arrows inside the black boxes indicate the possible microbiota mediated ring fission sites for each

1011

flavonoid. Red arrows emerging from the black boxes indicate ring fission metabolites.

1012

Compounds inside doted black boxes represent the general structure of the low molecular weight

1013

phenolic metabolites subjected to further metabolism. Further metabolic reactions are

1014

represented by the black arrows reinforce the convergence into more low molecular weight


Page 36 of 60

Page 37 of 60


1015

phenolic metabolites with the potential to accumulate in higher concentrations than the remaining

1016

upstream compounds, like hydroxybenenes and (hydroxy)hippuric acids. Part of these metabolic

1017

reactions seem to be shared between both microbial and hepatic enzymes. Note that these

1018

metabolites can undergo phase I and II metabolism into sulfate and glucuronide conjugates. α-

1019

Ox: alfa oxidation, β-Ox: beta oxidation, dOH: dehydroxylation, dCOOH: decarboxylation, red:

1020

reduction, Glyc: glycination.

1021

Figure 4 - Benzene diols and triols evaluated as attenuators of neuroinflammation in microglia

1022

cells. 1 Other structural isomer exist for this molecule as shown in table 1.

1023

Figure 5 - Benzoic acids evaluated as attenuators of neuroinflammation in microglia cells.

1024

Figure 6 - Cinnamic acids evaluated as attenuators of neuroinflammation in microglia cells.

1025

Figure 7 - Phenylacetic acids and phenylpropionic acids evaluated as attenuators of

1026

neuroinflammation in microglia cells.

1027

Figure 8 - Main molecular targets of the low molecular weight (poly)phenols metabolites in

1028

stimulated microglia cells. The pathways are the main highlighted in table 2 as affected by the

1029

indicated physiological concentrations (also indicated in table 2, ranging from 0.1 – 300 µM) of

1030

the metabolites in microglia cell systems.

1031 1032 1033



1034

Page 38 of 60

Table 1- Low molecular weight phenolic metabolites resulting from dietary sources rich in (poly)phenolic content, mainly flavonoids.

Benzene diols and triols (C6)

Common name

Detected

MW

Reference

1,2-dihydroxybenzene

catechol

urine

110.11

100

2-hydroxyphenyl hydrogen sulfate

catechol-O-sulfate

plasma

190.17

45

2-methoxyphenol

guaiacol

plasma

124.14

101

2-methoxyphenyl hydrogen sulfate

guaiacol-O-sulfate

urine

204.20

102

1,3-dihydroxybenzene

resorcinol

plasma

110.11

103

3-hydroxyphenyl hydrogen sulfate

resorcinol-O-sulfate

plasma

190.17

104

1,2,3-trihydroxybenzene

pyrogallol

plasma

126.11

105

2,3- or 2,6-dihydroxyphenyl hydrogen sulfate 2

pyrogallol-O-sulfate

plasma

206.17

45

(2S,3S,4S,5R,6S)-6-(2,3-or 2,6-dihydroxyphenoxy)-

pyrogallol-1-O-glucuronide

urine

302.24

102

1-methoxy-2,3-dihydroxybenzene

1-methylpyrogallol

urine

140.14

106

2-hydroxy-6- or 3-methoxyphenyl hydrogen sulfate 2

1-methylpyrogallol-O-sulfate

plasma

220.20

45

2-methoxy-1,3-dihydroxybenzene

2-methylpyrogallol

urine

140.14

106

3-hydroxy-2-methoxyphenyl hydrogen sulfate

2-methylpyrogallol-1-O-sulfate

plasma

220.20

45

3,5-dihydroxyphenyl hydrogen sulfate

phloroglucinol-O-sulfate

plasma

206.17

107

3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 2


Page 39 of 60


1,3,5-trimethoxybenzene

trimethoxyphloroglucinol

plasma

168.19

100

4-methyl-1,2-dihydroxybenzene

4-methylcatechol

plasma

124.14

108

2-hydroxy-4- or 5-methylphenyl hydrogen sulfate 2

4-methylcatechol-O-sulfate

plasma

204.20

109

4-hydroxybenzaldehyde

-

plasma

122.12

110

3,4-dihydroxybenzaldehyde

protocatechaldehyde

plasma

138.12

110

2,4,6-trihydroxybenzaldehyde

phloroglucinaldehyde

plasma

154.12

110

4-hydroxy-3-methoxybenzaldehyde

vanillin

plasma

152.15

100

Benzoic acid

-

plasma

122.12

110

2-hydroxybenzoic acid

salicylic acid

plasma

138.12

111


-

plasma

138.12

110


-

plasma

138.12

110

(2S,3S,4S,5R,6S)-6-(4-carboxyphenoxy)-3,4,5-

benzoic acid-4-O-glucuronide

plasma

314.25

110

3,4-dihydroxybenzoic acid

protocatechuic acid

plasma

154.12

110

4-hydroxy-3- or 3-hydroxy-4- (sulfooxy)benzoic acid 2

protocatechuic acid-O-sulfate

plasma

234.18

110

(2S,3S,4S,5R,6S)-6-( 5-or 4-carboxy-2-

protocatechuic acid-O-glucuronide

plasma

330.25

110

Benzaldehydes (C6-C1)

Benzoic acids (C6-C1)

trihydroxytetrahydro-2H-pyran-2-carboxylic acid



Page 40 of 60

hydroxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2carboxylic acid 2 3,4-dimethoxybenzoic acid

veratric acid

plasma

182.18

108

3-hydroxy-4-methoxybenzoic acid

isovanillic acid

plasma

168.15

110

4-methoxy-3-(sulfooxy)benzoic acid

isovanilic acid-3-O-sulfate

plasma

248.21

110

(2S,3S,4S,5R,6S)-6-(5-carboxy-2-methoxyphenoxy)-

isovanilic acid-3-O-glucuronide

plasma

344.27

110

3-methoxy-4-hydroxybenzoic acid

vanillic acid

plasma

168.15

110

3-methoxy-4-(sulfooxy)benzoic acid

vanillic acid-4-O-sulfate

Plasma

248.21

110

(2S,3S,4S,5R,6S)-6-(4-carboxy-2-methoxyphenoxy)-

vanilic acid-4-O-glucuronide

plasma

344.27

110


-

plasma

154.12

112


-

Plasma

154.12

41


-

Plasma

154.12

41


-

plasma

154.12

41

3,4,5-trihydroxybenzoic acid

gallic acid

plasma

170.12

110

3-methoxy-4,5-dihydroxybenzoic acid

3-methylgallic acid

urine

184.15

100

4-methoxy-3,5-dihydroxybenzoic acid

4-methylgallic acid

plasma

184.15

110

3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid


Page 41 of 60


(2S,3S,4S,5R,6S)-6-(5-carboxy-3-hydroxy-2-

4-methylgallic acid-3-O-sulfate

plasma

360.27

45

3,5-dimethoxy-4-hydroxybenzoic acid

syringic acid

plasma

198.17

110

Ethyl 3,4,5-trihydroxybenzoate

ethyl gallate

plasma

198.17

112

phenylacetic acid

-

plasma

136.15

100

2-(2-Methoxyphenyl)acetic acid

-

urine

166.18

100

2-(3-hydroxyphenyl)acetic acid

-

urine

152.15

96


-

plasma

152.15

110

2-(3,4-dihydroxyphenyl)acetic acid

homocaffeic acid

plasma

168.15

110

2-(4-hydroxy-3-methoxyphenyl)acetic acid

homovanillic acid

urine

182.18

96

2-hydroxy-2-phenylacetic acid

mandelic acid

urine

152.15

113

2-hydroxy-2-(4-hydroxyphenyl)acetic acid

4-hydroxy-mandelic acid

urine

168.15

96

2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetic acid

vanilmandelic acid

urine

198.18

96

hippuric acid

plasma

179.18

110,114

methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran2-carboxylic acid

Phenylacetic acids (C6-C2)

Mandelic acids (C6-C2) 2-hydroxyl

Hippuric acids (C6-C2-N) benzoylglycine



Page 42 of 60

3-hydroxybenzoyl glycine

3-hydroxyhippuric acid

plasma

195.17

115

4-hydroxybenzoyl glycine

4-hydroxyhippuric acid

urine

195.17

96

3-(3,4-dihydroxyphenyl)propenoic acid

caffeic acid

plasma

180.16

110

3-(3-hydroxy-4-methoxyphenyl)propenoic acid

isoferulic acid

plasma

194.19

116

3-(3-methoxy-4-hydroxyphenyl)propenoic acid

ferulic acid

plasma

194.19

110

3-(3-hydroxyphenyl)propenoic acid

m-coumaric acid

urine

164.16

117


p-coumaric acid

urine

164.16

100


o-coumaric

urine

164.16

100

3-(4-hydroxy-3,5-dimethoxyphenyl)propenoic acid

sinapic acid

urine

224.21

118

3-(phenyl)prop-2-enoic acid

cinnamic acid

plasma

148.16

100

3-(3-hydroxyphenyl)propionic acid

3-hydroxydihydrocinnamic acid

urine

166.18

115

3-(4-hydroxyphenyl)propionic acid

4-hydroxydihydrocinnamic acid (phloretic

urine

166.18

100

Cinnamic acids (C6-C3) 1 unsaturated

Phenylpropionic acids (C6-C3)

acid) 3-(3,4-dihydroxyphenyl)propionic acid

dihydrocaffeic acid

urine

182.18

96

3-(3-metoxy-4-hydroxyphenyl)propionic acid

dihydroferulic acid

urine

196.20

96

3-(3-hydroxy-4-metoxyphenyl)propionic acid

dihydroisoferulic acid

urine

169.20

119


Page 43 of 60


Phenylhydracrylic acid (C6-C3) 3-(3-Hydroxyphenyl)-3-hydroxypropionic acid

1035

1

1036

2This

3-(3’-Hydroxyphenyl)hydracrylic acid

urine

182.18

120

The compounds mentioned in this class are representing the (E) isomer compound have more than 1 structural isomer

1037 1038 1039 1040 1041 1042 1043 1044 1045 1046

Table 2 - Neuroprotective evidences (in vitro) for some bioavailable (poly)phenol metabolites



Class

(Poly)phenol metabolite

Page 44 of 60

Concentration

Incubation

Anti-inflammatory

(μM)

time

evidences

Cell model

Reference 181

 LPS-induced NO and

Catechol TNF-α production  expression of iNOS  nuclear translocation of Mouse microglia cell line (BV-2) + LPS

30 min pre-

Mouse microglia cell line (BV-2)) + LPS

incubation

NF-κB Benzene diols

4-methylcatechol

+ rat neuroblastoma cells (B35)

77

 IκB degradation (except

161 before insult

4-methylcatechol) and triols  p38 MAP kinase phosphorylation

 LPS-induced TNF-α 6 h prePyrogallol-O-sulfate

Mouse microglia cell line (N9) + LPS

5

incubation before insult

production  nuclear translocation of NF-κB  IκB degradation


88

Page 45 of 60


 LPS-induced TNF-α production  intracellular superoxide

1-O-methylpyrogallol-O-sulfate

production  CD40 production  LPS-induced NO  intracellular superoxide 4-Methylcatechol-O-sulfate

production  CD40 production

Mouse microglia cell line (BV-2)+ β‐amyloid

 iNOS expression levels 12 h pre COX-2 expression levels

Mouse primary glial cells+ β‐amyloid Benzoic acids

Gallic acid

5–50 Conditioned media from BV-2 cells and primary microglial cells were transferred

incubation

89

 IL-1β expression levels before insult  TNFα expression levels

to Neuro-2A cells



Page 46 of 60

 LPS-induced TNF-α production  LPS-induced IL-6 production  LPS-induced IL-1β 1 h preproduction Protocatechuic acid

Mouse microglia cell line (BV-2) + LPS

5-20

incubation before insult

87

 LPS-induced PGE2 production  TLR4 expression  NF-κB activation  MAPKs activation

 LPS-induced NO 6 h pre intracellular superoxide 4-O-methylgallic acid

Mouse microglia cell line (N9) + LPS

5

incubation

15

production before insult  CD40 production


Page 47 of 60


 LPS-induced NO  intracellular superoxide

4-O-methylgallic acid-3-O-sulfate

production  LPS-induced TNF-α Vanillic acid 4-O-sulfate

production

 LPS-induced NO 24 h coCinnamic acids

Ferulic acid

Mouse microglia cell line (BV-2)+ LPS

1, 5 and 25

 LPS-induced iNOS

incubation

 LPS-induced COX-2

with insult

 LPS-induced IL-1β

91

 LPS-induced IL-6



Page 48 of 60

 LPS-induced TLR4 levels  LPS-induced TNF-α levels  LPS-induced iNOS 2 h prelevels 10–100

incubation

92

 LPS-induced p-JNK before insult levels  LPS-induced NF-κB levels  LPS-induced Bax levels


Page 49 of 60


No effect on LPS-induced NO,TNF-α, and IL-6 levels For only 50 and 250 μM of ferulic acid:  LPS-induced 24 h coIndoleamine 2, 3Mouse microglia cell line (MG6) + LPS

10, 50 and 250

incubation

93

dioxygenase mRNA with insult expression  nuclear translocation of NF-κB  MAPK p38 activation



Page 50 of 60

 SOCS3 expression levels  CREB activity  LPS-induced TNF-α production 2 h pre LPS-induced iNOS Cinnamic acid

Mouse microglia cell line (BV-2) + LPS

100-300

incubation

94

production before insult  LPS-induced IL-1β production  LPS-induced IL-6 production

2-(3,4-dihydroxyphenyl)acetic acid Phenylacetic

(3,4-DHPA)

0.1, 1 and 10 acids


18 h pre-

 MAPK p38 activation (3-

incubation

HPA and 4HPP)

Human neuroblastoma cell line (SH-SY5Y) +

SIN-12 before insult

(3HPA)


 ERK1/2 activation

97

Page 51 of 60


3-(4-Hydroxyphenyl)propionic acid Phenylpropionic

(4HPP)

acids

3-(3-Hydroxyphenyl)propionic acid (3HPP)

1047

1Concentration

1048

23-Morpholinosydnonimine

1049

used as a neuronal damage inductor. In the study, SIN-1-induced nitrosative stress in a human neuroblastoma cell line (SH-SY5Y) and was used as a model of

1050

neuroinflammation.

tested was 2 μg/mL and it was converted to molar for comparison purposes (SIN-1) is a peroxynitrite generator described as inducing phosphorylation of protein tyrosine residues in brain cells and has been



1051

1052 1053

Figure 1


Page 52 of 60

Page 53 of 60


1054 1055

Figure 2

1056 1057



1058 1059

Figure 3

1060


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1061 1062

Figure 4

1063 1064 1065 1066 1067 1068 1069 1070 1071



1072 1073

Figure 5

1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085


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1086 1087

Figure 6

1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100



1101 1102

Figure 7

1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 58 ACS Paragon Plus Environment

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1116 1117

Figure 8

1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 59 ACS Paragon Plus Environment


1130

For Table of Contents Only

1131 1132 1133 1134 1135 1136


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Low-Molecular Weight Metabolites from Polyphenols as Effectors for

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