
==== Front
Food Chem X
Food Chem X
Food Chemistry: X
2590-1575
Elsevier

S2590-1575(24)00664-3
10.1016/j.fochx.2024.101776
101776
Review Article
Effects of derivatization and probiotic transformation on the antioxidative activity of fruit polyphenols
Wang Yixuan a1
Wang Chenxi a1
Shi Junling sjlshi2004@nwpu.edu.cn
b⁎
Zhang Yan yanzhangzqgh@shzu.edu.cn
a⁎
a School of food science and technology, Shihezi University, Road Beisi, Shihezi, Xinjiang Province 832003, China.
b Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Shaanxi, Xi'an Province 710072, People's Republic of China.
⁎ Corresponding authors. sjlshi2004@nwpu.edu.cnyanzhangzqgh@shzu.edu.cn
1 co-first author.

26 8 2024
30 10 2024
26 8 2024
23 10177626 6 2024
15 8 2024
24 8 2024
© 2024 The Authors. Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Fruits contain numerous polyphenols in the form of conjugates, which exhibit low antioxidant activity. Probiotic fermentation is a strategy to improve the antioxidant activity of these conjugated polyphenols by modifying their structure. However, the mechanisms underlying the effects of functional groups and derivatizations on the antioxidative activities of polyphenols and the antioxidation enhancement by probiotic biotransformation haven't been comprehensively explored. This review aimed to explore the structure–antioxidant activity relationships of four functional groups and three derivatizations in flavonoids and phenolic acids. Further, the review elucidated the antioxidant mechanisms underlying the biotransformation of flavonoids and phenolic acids as glycoside, methylated, and ester conjugates by probiotic biotransformation. Deglycosylation, demethylation, and hydrolysis catalyzed by enzymes produced by Bifidobacterium and Lactobacillus facilitated the conversion of conjugated polyphenols into flavonoids and phenolic acids with hydrolyzed forms and highly active functional groups, thereby increasing hydrogen supply and electron transfer capacity to enhance the antioxidant activity.

Highlights

• The structure-antioxidant relationships and action mechanisms were unveiled.

• 5 key functional groups effects antioxidant of flavonoids and phenolic acids.

• Probiotics modify structure of flavonoids and phenolic acids by 4 classes of enzymes.

• Probiotics transformations endowed functional groups to enhance antioxidant activity.

• Application of probiotic transformation in functional validation and fermented foods.

Keywords

Polyphenol derivatization
Structure-activity relationship
Antioxidant mechanism
Probiotic fermentation
==== Body
pmc1 Introduction

Polyphenols are secondary metabolites with diverse chemical structure and function and are widespread in fruits, which are more than 8000 phenolic structures currently known(Durazzo et al., 2019). They comprise a wide variety of molecules that contain a classic phenol ring structure (i.e. several hydroxyl groups in aromatic rings), which structure can vary from simple molecules to complex polymers with highly polymerized compounds (Câmara et al., 2020). These can be classified by origin, biological activities, and chemical structure, which is the most commonly used classification(Wojtunik-Kulesza et al., 2020).There are two key structural groups of polyphenols: flavonoids and phenolic acids (Fig. 1A). Both flavonoids (e.g. flavonols, flavones, chalcones, anthocyanins, flavanones and flavanols) and phenolic acids (e.g. hydroxybenzoic acids, hydroxycinnamic acids) generally accumulate in the vacuoles of fruits as glycoside, methoxy and ester conjugates or as hydrolyzed glycoside, methoxy and ester conjugates (Fig. 1B). Flavonoids are classified into different subclasses due to the oxidation state of the C-ring and the hydroxyl groups attached to different positions in the B-ring. Among which there are many substances represented by flavonols, such as kaempferol (e.g., kaempferol-3-O-rutinoside and kaempferol-3-O-glucoside), quercetin (e.g., quercetin-3-O-rutinoside and quercetin-3-O-glucoside), myricetin (e.g. myricetin-3-rutinoside and myricetin-3-glucoside) and isorhamnetin (e.g., isorhamnetin-3-rutinoside and isorhamnetin-3-glucoside), and some represented by flavones, such as apigenin (e.g., vitexin), luteolin (e.g., luteolin-7-O- glucoside), as well as others represented by isoflavones, such as daidzein, genistein, glycitein, and phlorizim which represented by chalcones are found in different fruits (e.g., tomato, sea buckthorn, lycium chinense, grapes, and jujube.)(Aparecida Plastina Cardoso et al., 2021; Fia, Bucalossi, Proserpio, & Vincenzi, 2021; Kumar et al., 2021; Neelam, Dey, Sim, Lee, & Au Eong, 2021).Fig. 1 The structural characteristics and form of phytogenic polyphenols (A): Structural characteristics and representative substances of flavonoids and phenolic acids. The blue bond polyphenols was the types of polyphenols; The positions of the A, B and C rings are marked in blue in the structure of flavonoids; Oxygen represents red; methyl group represents green; (B): Glycoside, methylated, and ester conjugates and hydrolyzed conjugates in different classes of polyphenols in fruits. The polyphenols in the red circle was the form of glycoside, methylated, and ester conjugates (Bond form) in the different fruits; The polyphenols in the blue circle was the hydrolyzed glycoside, methoxy and ester conjugates form (free form) in the different fruits. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 1

Fruits also contain various flavonoid aglycones and polyhydroxy compounds, such as kaempferol, quercetin, gallocatechin, epicatechin, catechin, myricetin, apigenin, luteolin, naringenin, hesperetin, cyanidin and phloretin. Phenolic acids are the majority of the non-flavonoid class of polyphenols, and are characterized by a carboxyl group linked to the benzene ring. These compounds can be further subdivided into hydroxybenzoic acids (C1-C6 backbone) and hydroxycinnamic acids (C3-C6 backbone)(Durazzo et al., 2019). Phenolic acids also contain glycoside, methoxy and ester conjugates, as well as methylated (e.g., vallic acid and syringic acid), esterified (e.g., rosmarinic acid) and glycoside forms (e.g., gallic acid 4-O-glucoside, protocatechuic acid 4-O-glucoside, and p-Coumaric acid 4-O-glucoside)(Domínguez et al., 2020; Gómez-García, Campos, Aguilar, Madureira, & Pintado, 2020; Tkacz et al., 2020). Gallic acid, protocatechuic acid and p-hydroxybenzoic acid are the main hydroxybenzoic acids in fruits, and caffeic, p-coumaric, and ferulic acids are examples of hydroxycinnamic derivatives present in fruits as glycoside, methoxy, and ester conjugates (Kuşçu & Bulantekin, 2020).

Multiple biological functions of polyphenols have been reported. Polyphenols can affect multiple diseases (e.g., cardiovascular disease, atherosclerosis, hypertension, diabetes, insulin resistance and obesity) and impact several bioactivities (e.g., anti-oxidative, anti-inflammatory, anti-aging, anti-mutagenic and anti-carcinogenic activities). Aglycones and hydrolyzed conjugates are bioavailable molecules with human health benefits. Septembre-Malaterre et al. summarized the effects of quercetin to decrease serum enzyme markers, resist virus cells (e.g., HCV, HBV, and MNoV) and inhibit the production of inflammatory factors (e.g., TNF-α, iNOS, and NO)(Septembre-Malaterre et al., 2022). Robert Kubina et al. reported that kaempferol can decrease inflammation, change disease activity, and alleviate resistance to antibiotics and chemotherapeutics(Kubina, Iriti, & Kabała-Dzik, 2021). Naringenin downregulates inflammation-mediated nitric oxide overproduction and potentiates endogenous antioxidant status during hyperglycemia(Rehman, Khan, Akash, Jabeen, & Haider, 2020). Yang, A.Y et al. reported that hesperetin has antioxidant, antiapoptotic, and anti-inflammatory effects in in a mouse model of lipopolysaccharide-induced cute kidney injury(A. Y. Yang, Choi, Kim, & Leem, 2023). Phloretin can suppress the NLRP3/Caspase-1/IL-1beta pathway to reverse structural and electrical remodeling after myocardial infarction to prevent the occurrence of ventricular arrhythmias and heart failure, and inhibited doxorubicin-induced oxidative stress and reduced nitric oxide levels in cardiac tissues of rats(B. Li, Xu, Liu, Zhou, & Jiang, 2023). Furthermore, apigenin, myricetin, epicatechin, cyanidin, gallic acid, and caffeic acid have antioxidant, cardio protective, anti-inflammatory, antibacterial, antiviral, and anticancer activities (Septembre-Malaterre et al., 2022).

Different compounds can vary in activity. Among flavonoids, gallocatechin, epicatechin and catechin, as typical representatives of flavanols, also have different activities due to their structural differences. Gallocatechin is the flavanol with has three hydroxyl groups in Ring B. Gallocatechin has high antioxidant activity and showed positive correlation with ABTS and DPPH free radical scavenging(Gris et al., 2011). Epicatechin has two hydroxyl groups in positions 3′ and 4′ and exhibits stable time-dependent antioxidant activity (IC50 value of 1.5 mug mL(−1)) and anticardioprotection activity(Jug, Naumoska, & Vovk, 2021). Catechin has a 4′-hydroxyl group, and has both antioxidant and anticholinesterase activities(Franca et al., 2023). Phloretin is a kind of chalcone and phlorizin is the glycoside form of phloretin, however, phlorizin has lower anti-inflammatory and antioxidant activities than phloretin(Chang, Huang, & Liou, 2012; Ongay, Granato, & Barreto, 2023). For phenolic acids, p-hydroxybenzoic and p-coumaric acid have a mono hydroxylation structure and lower antioxidant activity than protocatechuic acid and caffeic acid that have a di-hydroxylation structure. Caffeic acid has a higher antioxidant activity than that of protocatechuic acid, likely due to the different substituents and the position of substituents on the benzene ring(Gao, Li, Li, Zhang, & Liang, 2022). However, phenolic compounds substituted with a higher number of hydroxylic groups are reported to exhibit better antioxidant and anti-cancer properties compared with ones with no hydroxylic group substitution or –OCH3 derivatization. Vanillic acid and syringic acid are hydroxybenzoic acids with methoxy groups. These two phenolic acids both have anti-inflammatory properties(Grigalius & Petrikaite, 2017), but only vanillic acid showed positive correlation with DPPH free radical scavenging activity(Ashengroph, Nahvi, Zarkesh-Esfahani, & Momenbeik, 2011). And some flavonoids and phenolic acids with glycosides, methoxy and ester conjugates typically have lower activity, and few of these substances have been reported to have antioxidant and anti-inflammatory properties (Laoué, Fernandez, & Ormeño, 2022).

In general, flavonoids and phenolic acids almost all exist as glycosides, methoxy and ester conjugates in fruits, including as products of derivatization (e.g., glycosylation, methylation and esterification). These polyphenolic conjugates typically have lower activities than their hydrolyzed products, and different functional groups can affect the antioxidant activity of polyphenols that are not derivatised. This suggests that polyphenol structure is an important determinant of bioactivity.

Many studies have investigated the relationships between different structures and functional activities of polyphenols, especially for the antioxidant activity of flavonoids and phenolic acids(Gulcin, 2020; J. Yang, Chen, Hao, & Liu, 2021). For phenolic acids, the antioxidant activity is dependent on: (1) The number and position of the hydroxyl groups; (2) Glycosylation or methylation; (3) The distance between the -COOH and the aromatic ring; (4) The presence of a -CH=CH-COOH group. For flavonoids, the antioxidant activity is dependent on: (1) A-ring and B-ring with an ortho-dihydroxy (catechol) group; (2) the number and position of the hydroxyl groups in the A-ring and B-ring; (3) A-ring and C-ring with a 4-oxo group and a double bond between C-2 and C-3; (4) A-ring and C-ring with a 3- hydroxyl group and a double bond between C-2 and C-3; (5) A-ring and C-ring with 4-oxo groups and -OH groups near C-3 and C-5; and (6) Glycosylation or a methoxyl group at the C-3 position; both can reduce the high free radical scavenging ability.

The antioxidant activity of flavonoids and phenolic acids is also dependent upon the presence of hydroxyl groups at specific positions on the skeleton of flavonoids and phenolic acids. Various action mechanisms are involved in the quenching of free radicals by flavonoids and phenolic acids, with three considered primary antioxidant actions(Z. Xiao, Wang, Wang, Li, & Ma, 2019). First, hydrogen atom transfer (HAT), a one-step reaction governed by the O—H bond dissociation enthalpy. Second, single electron transfer followed by proton transfer (SET-PT), a first step that is governed by the ionization potential. Thirdly, sequential proton-loss electron transfer (SPLET), a first step governed by proton affinity.

However, there has been no systematical summarized of the antioxidant mechanisms of the different functional groups and flavonoids and phenolic acids with the structures of glycoside, methoxy and ester conjugates and non-derivatised. Overall, a better understanding of the differences in structure–antioxidant activity relationships and antioxidant mechanisms of flavonoids and phenolic acids in the form of glycoside, methoxy and ester conjugates and glycoside, methoxy and ester conjugates hydrolyzed would greatly help the determination of strategies to enhance antioxidant potential. Additionally, there is an ongoing demand to explore processing techniques to transform the polyphenolic compounds in the form of glycoside, methoxy and ester conjugates with lower antioxidant activities to the polyphenolic compounds in the form of glycoside, methoxy and ester hydrolyzed conjugates with higher antioxidant activities.

In recent years, biotransformation has been explored as a strategy with immense potential to produce novel bioactive polyphenols. However, the bioavailability of bioactive polyphenols in the gastrointestinal (GI) tract is crucial to their health benefits. The polyphenolic compounds in the form of glycoside, methoxy, and ester conjugates improve the stability of bioactive polyphenols. However, these polyphenols have poor bioavailability due to factors such as solubility and complex chemical structure, which limit their metabolism (Câmara et al., 2020). Flavonoids in the form of rhamnoglucosides and polymeric tannins, such as rutin, hesperidin, naringin, and procyanidins, have low bioavailability in the GI tract (Amaretti, Raimondi, Leonardi, Quartieri, & Rossi, 2015; Mueller et al., 2017). Probiotics fermentation, especially with Lactobacillus and Bifidobacterium species, can modify the structure of plant-based polyphenols to improve their bioavailability and antioxidant potential (Cao, Chen, Jassbi, & Xiao, 2015). The transformation of the polyphenolic compounds from glycoside, methoxy, and ester conjugates with lower bioavailability into hydrolyzed conjugates with higher bioavailability through probiotics fermentation enhances the antioxidant potential of bioactive polyphenols in the human body. There have been several qualitative reviews on probiotics biotransformation of polyphenols have been published, with reports of changes in deglycosylation, demethylation, hydrolysis, decarboxylation, hydroxylation, dehydrogenation and oxidation(Braune & Blaut, 2016; Gaur & Gänzle, 2023). However, there has been no comprehensive review of the mechanisms of probiotics biotransformation, which transforms low antioxidant active polyphenols into high antioxidant active polyphenols. Therefore, in this review, we summarize recent research progress on fruit polyphenols including structural characteristics, form, and function. We also discuss the structure–antioxidant activity relationship and antioxidant mechanisms of flavonoids and phenolic acids in the form of glycoside, methoxy and ester conjugates and which in the form of glycoside, methoxy and ester hydrolyzed conjugates, and explore the mechanistic basis of enhanced antioxidant activity of the phenolics in the form of glycoside, methoxy and ester conjugates and partially phenolics in the form of glycoside, methoxy and ester hydrolyzed conjugates by probiotic biotransformation with reference to the structure–antioxidant activity relationships and antioxidant action mechanisms.

2 Effects of functional groups on the antioxidative activity of polyphenols

It has been widely found that the antioxidative activity of polyphenols varies greatly with their structure. The mechanisms for polyphenols to perform their antioxidative activity include: direct scavenging of radicals, inhibition of reactive oxygen species (ROS), activation of antioxidant enzymes, activation of metal-chelating activity, inhibition of oxidases (e.g., xanthine oxidase [XO], cyclooxygenase [COX], lipoxygenase, and phosphoinositide 3-kinase [PI3K]), and reduction of α-tocopheryl radicals. Of these mechanisms, study of the antioxidant mechanism has revealed that free radical scavenging is related to the overall polyphenol structure(Gulcin, 2020). Free radicals are highly active molecules produced during cellular respiration and normal metabolism, and reactive oxygen species (ROS) are closely related to physiological and pathological processes in animals. The species mainly include superoxide anion free radicals (O2-), hydroxyl free radicals (OH-), hydrogen peroxide (H2O2), and others. Numerous action mechanisms are involved in the quenching of free radicals by flavonoids and phenolic acids, with three considered primary antioxidant actions (Z. Xiao et al., 2019), which including hydrogen atom transfer (HAT), single electron transfer followed by proton transfer (SET-PT) and sequential proton-loss electron transfer (SPLET). The structure of flavonoids and phenolic acids affects the mechanism by which the moiety interacts with surrounding free radicals and therefore the antioxidant activity. There are two main findings of recent work in this area: 1) the key functional groups affect the antioxidant activity of polyphenols; 2) addition of glycoside, methoxy and ester conjugates after derivatization, can reduce antioxidant activity (as shown in Table S1).

2.1 Key functional groups for the antioxidative activities of flavonoids and phenolic acids

2.1.1 Hydroxyl groups

Hydroxylation is the process of introducing hydroxyl groups (OH) via substitution of functional groups or hydrogen atoms. This contributes to the formation of different classes of phenolic acids and flavonoids and increases the number of hydroxyl groups(Staniek et al., 2013). Panche et al. suggested that hydroxylation of flavonoids can improve their biological properties, including antioxidant and chelation activities(Panche, Diwan, & Chandra, 2016). Flavonoids with more than hydroxyl groups on the A-ring(Mierziak, Kostyn, & Kulma, 2014) and B-ring(L. Chen & Kang, 2013) exhibit higher antioxidant activity. For example, dihydroxy B-ring flavonoids, such as quercetin and lignans, are better scavengers of free radicals generated by UV irradiation than monohydroxy B-ketones, such as apigenin and kaempferol(Agati, Azzarello, Pollastri, & Tattini, 2012; Fini, Brunetti, Di Ferdinando, Ferrini, & Tattini, 2014). However, polyhydroxy phenolic acids including caffeic acid and gallic acid have higher antioxidant activities than mono-hydroxycinnamic acid (p-coumaric acid) and mono-hydroxybenzoic acid (protocatechuic acid)(Masek, Chrzescijanska, & Latos, 2016; Rzepecka-Stojko et al., 2015). Mono-hydroxy derivatives of phenolic acid have good antioxidant properties due to meta-hydroxylation, and dihydroxy derivatives of phenolic acids have high antioxidative activity by ortho- and meta-hydroxylation(J. Chen et al., 2020). The presence of polyhydroxyl groups provides more OH hydrogen bonding sites in ArOH, forming more unstable electrons for hydrogen supply and electron transfer, and ultimately scavenging free radicals (Gulcin, 2020)(Fig. 2A).Fig. 2 Constitutive mechanism for key functional groups for the antioxidative activities of flavonoids and phenolic acids. (A): Mechanisms of a high number of hydroxyl groups increases the antioxidant activity. (B): Mechanisms of -CH=CH and -COOH groups increases the antioxidant activity of phenolic acid. (C): Mechanism of A-ring or B-ring with an ortho-dihydroxy(catechol) group increases antioxidant activity of flavonoids. (D): Mechanism of A-ring and C-ring with a 4-oxo group and a double bond between C-2 and C-3 increases the antioxidant activity of flavonoids. (E): Mechanism of A-ring and C-ring with 4-oxo groups and -OH groups near C-3 and C-5 increase the antioxidant activity of flavonoids.ROO represents peroxyl Radical; ArOH represents benzene ring structure with hydroxyl groups in the side chain.

Fig. 2

2.1.2 -CH=CH-COOH groups

Both hydroxycinnamic and hydroxybenzoic acids have antioxidant activity, with higher antioxidant activity for hydroxycinnamic acid compared to that of hydroxybenzoic acid. Caffeic acid, p-hydroxybenzoic acid, p-coumaric acid, gallic acid and protocatechuic acid have strong antioxidant activity(Castelluccio et al., 1995; RiceEvans, Miller, & Paganga, 1996; Singh, Kim, & Lee, 2022), with higher antioxidant activities of hydroxycinnamic acids (caffeic acid) than those of hydroxybenzoic acids (protocatechuic acid)(Masek et al., 2016). This is because hydroxybenzoic and hydroxycinnamic acid have -COOH groups, and -COOH can affect the ionic domains around ArOH to promote the formation of unstable electrons to facilitate the scavenging of free radicals. Similarly, -CH=CH also can affect the ionic domains around ArOH to increase the scavenging of free radicals (Gulcin, 2020). Hydroxycinnamic acid analogues with -CH=CH-COOH groups generate more ROOH through the efficacy superposition of the two groups, and the composite group can also generate ROO− to stabilize free radicals. Therefore, hydroxycinnamic acids with -CH=CH-COOH exhibit higher antioxidant activities than the corresponding hydroxybenzoic acids(Balasundram, Sundram, & Samman, 2006; RiceEvans et al., 1996) (Fig. 2B).

2.1.3 A or B-ring with an ortho-dihydroxy(catechol) group

Ortho-dihydroxy(catechol) groups are widely present in phenolic acids and flavonoids. The importance of an A or B-ring with an ortho-dihydroxy(catechol) group in flavonoids and antioxidant activity has been studied. Gomes(Gomes et al., 2012) compared the antioxidant activity of trihydroxyflavones containing hydroxyl groups in different positions and found that the ortho-dihydroxy group is required for free radical scavenging activity. Similarly, Ignas Grigalius reported that trihydroxyflavones have high DPPH free radical scavenging and anti-lung (A549), breast (MCF-7), and brain epithelial (U87) cancers due to the presence of the ortho-dihydroxy (catechol) group in B-ring, with higher antioxidant activity than apigenin which lacks this structure(Grigalius & Petrikaite, 2017). Other groups reported that hydroxybenzoic acid containing the ortho-dihydroxy(catechol) group had enhanced antioxidant activity. ŽIVANOVIĆ et al. investigated the effect of UV irradiation on polyphenol contents in tomatoes and found that hydroxycinnamic acids with ortho-dihydroxyl substitution on the B-ring (e.g. caffeic acid) are more efficient antioxidants than those with a single hydroxyl group(ŽivanoviĆ et al., 2017). Thus, the presence of an A-ring or B-ring with an ortho-dihydroxy(catechol) group increases the antioxidant activity of flavonoids. This is because one hydroxyl group in catechol can supply hydrogen to bind with ROO• to form ROOH. Catechol− is formed when catechol loses one H+, and this can supply hydrogen to bind to ROO• to form ROOH. Catechol− can also bind to ROO• to form ROO−. The formation of ROOH decreases free radicals, and the formation of ROO− stabilizes free radicals. Thus, these two mechanisms explain why flavonoids containing the ortho-dihydroxy(catechol) group have higher antioxidant activities (Fig. 2C).

2.1.4 A-ring and C-ring with a 4-oxo group and a double bond between C-2 and C-3

Flavones and flavonols have an A-ring and C-ring with a 4-oxo group and a double bond between C-2 and C-3. Compared to flavones and flavonols, flavanones and flavanols lack these structures(Trigo, Alexandre, Saraiva, & Pintado, 2019). In studies of the antioxidant activities of these four groups of compounds, the flavones and flavonols exhibit stronger activities than those of flavanones and flavanols. Quercetin in flavonols and epicatechin in flavanols have the same number of hydroxyl groups, but the antioxidant activity of catechin is lower than that of quercetin(Chimi, Cillard, & Rahmani, 1991). Dome Barna et al. reported a stronger positive correlation between flavones such as apigenin and antioxidant activity than flavanones such as naringenin(Barna et al., 2022). Similarly, Cristina Arteaga et al. reported that apigenin could protect zebrafish embryos against oxidative stress while naringenin did not(Arteaga et al., 2021). Epicatechin does not have a double bond at the C2 and C3 and does not have a 4-oxo group, and naringenin also lacks the double bond at the C2 and C3. There are two main effects of these two groups. First, these two groups affect the ionic domains around ArOH in flavonoids, which further increases the formation of unpaired ArO• and ArO− and promotes the scavenging of free radicals by hydrogen supply and electron transfer(Burda & Oleszek, 2001). Second, these two groups can affect the electrons around the radicals and promote the formation of ROO− (Bors, Heller, Michel, & Saran, 1990; Gulcin, 2020)(Fig. 2D).

2.1.5 A- and C-rings with 4-oxo groups and -OH groups near C-3 and C-5

Among flavonoids, flavonols have been reported to have strong antioxidant activity and defend against oxidative stress-related diseases due to their A- and C-rings with 4-oxo groups and -OH groups near C-3 and C-5(Samsonowicz & Regulska, 2017). The most studied flavonols are kaempferol, quercetin, and myricetin with demonstrated antioxidative properties and a potential role in UV-defense, suggesting these compounds are critical for plant adaptation to climate change(Laoué et al., 2022). These three flavonols all have high antioxidant, anticancer, antiviral and anti-inflammatory activities(Septembre-Malaterre et al., 2022). Compared with flavonols, flavones lacking a 3-OH have lower antioxidant activity. As an example, in vegetable amaranth, there are higher levels of flavonols such as myricetin, leading to an increase in the ability to scavenge free radicals, while flavones such as apigenin do not have this ability(Sarker & Oba, 2020). This suggests that flavonoids with 4-oxo groups in both A- and C-rings and -OH groups near C-3 and C-5 have higher antioxidant activity. Studies of this correlation have determined that the structure can influence the ionic domains around ArOH to contribute to the formation of unstable free radicals. This increases hydrogen supply and electron transfer, to promote the scavenging of free radicals(Apak, Özyürek, Güçlü, & Çapanoğlu, 2016). Additionally, this structure can chelate with metal ions such as O on C-4, C-3 and C-5, which can combine with Fe for unstable forms. Electron transfer during metal chelation affects the ionic domains around the free radicals, which contributes to the formation of more ROO− with stabilized forms(Ghosh et al., 2015; Gulcin, 2020) (Fig. 2E).

As described above, the presence of key functional groups increases the antioxidant activity of polyphenols, whereas during plant growth, polyphenols undergo derivatization to form more stable glycoside, methoxy and ester conjugates, and these structures lead to reduce antioxidant activity.

2.2 Decrease of antioxidative activity by derivatization

2.2.1 Glycosylation

Polyphenol structure can be modified by glycosylation(Subramanyam, Takahashi, Nagatoishi, Kuroda, & Tsumoto, 2018), such as replacing hydroxyl groups with O-glycosides or linking with C to form C-glycosides. Glycosylation affects the water solubility, transportability, and stability of plant polyphenols(Alseekh, Perez de Souza, Benina, & Fernie, 2020). João P. Trigo et al. reviewed studies of the effect of glycosylation on the functional activity of polyphenols and reported that substitution of hydroxyl groups by glycosylation generally decreases antioxidant activity(Trigo et al., 2019). Among isoflavonoids, soy isoflavone glycosides (e.g. daidzin, genistein, and glycitin) have significantly lower antioxidant activities than their aglycone counterparts (e.g. daidzein, genistein, and glycitein)(Cai, Mei, Jie, Luo, & Corke, 2006). Jianbo Xiao reported that flavonols and flavonol aglycones (quercetin, kaempferol, apigenin, baicalein, and luteolin) extracted from traditional Chinese medicines showed higher free radical scavenging rates than their corresponding glycosides, including quercetin 3-O-glucoside, quercetin 3-O-rutinoside, quercetin 3-O-rhamnoside, quercetin 3-O-glucoside-7-O-rhamnoside, kaempferol 3-O-glucoside, apigenin-7-O-glucoside, baicalin, and luetrolin-7-O-glycoside(J. Xiao, 2015). Overall, phenolic acids and flavonoids with glycosides have lower antioxidant activities than their aglycones. There are two main conclusions of recent investigations into the constitutive mechanism through which glycosides reduce antioxidant activity. First, glycosides reduce the formation of unpaired ArO• and ArO− by affecting hydrogen bonding in ArOH in flavonoids and phenolic acids, which further reduces the binding of the H-atoms and ROO• and the transfer of single electrons to ultimately reduce the scavenging of free radicals by ArOH(Xu et al., 2020). Second, glycosides will directly reduce the ability of ArOH to bind directly to ROO• and then reduce the formation of the stable form of free radicals (ROO•)(Choi et al., 2002) to thus reduce the antioxidant activity (Fig. 3A).Fig. 3 Constitutive mechanism of decrease of antioxidative activity by derivatization. (A): Mechanisms of glycosylation decreases the antioxidant activity of phenolic acid and flavonoids. (B): Mechanisms of methylation decreases the antioxidant activities of phenolic acid and flavonoids. (C): Mechanisms of an ester bond decreases the antioxidant activity of some phenolic acids and flavonoids. ROO represents peroxyl Radical; ArOH represents benzene ring structure with hydroxyl groups in the side chain.

Fig. 3

2.2.2 Methylation

In addition to glycosylation, methylation also affects the physicochemical properties of plant polyphenols including changes such as decreasing solubility, improving stability and transportability, and affecting color stability(Yang et al., 2011). However, Chen et al. investigated the effects of polyphenol methylation on polyphenol bioactivity in plants and found that methylation tends to reduce the antioxidant potential of some flavonoids and phenolics. For example, O-methoxy substances formononetin and biochanin A have low antioxidant activities(Curiel & Landete, 2022). In addition, 3′,4′-dimethoxyflavone and homoeriodictyol extracted from G. robertianummay may decrease antioxidant activity due to the presence of one or two methylated OH groups, respectively, on the orthocatechol group. Wang and others measured the IC50 of DPPH scavenging activity for quercetin and its methylated forms from Halimodendron halodendron and found that the activities were in the following order: quercetin (0. 024 mM) > 3,3′-di-O-methylquercetin (0.436 mM) > 3,3′ -di-O-methylquercetin 7-O-b-D-glucopyranoside (0.440 mM) > 3-O-b-D-rutinoside (0.842 mM)(J. Wang et al., 2012). Therefore, some phenolic acids and flavonoids with methyl groups have lower antioxidant activities than those of the unmethylated forms. Mechanistic studies have found that the hydrogen bonding of ArOH is affected by the methyl group, reducing the formation of unpaired electrons (ArO• and ArO−), which further reduces hydrogen donation and electron transfer to ultimately decrease the free radical scavenging power(Chen et al., 2017) (Fig. 3B).

2.2.3 Esterization

In nature, esterification can alter the physicochemical properties of polyphenols and phytosomes(Olszowy, 2019). For example, phenolic acids in the form of glycoside, methoxy and ester conjugates to arabinoxylans and other cell wall polysaccharides via ester bonds have enhanced stability(Vitaglione, Napolitano, & Fogliano, 2008), and phenolic acids and flavonoids linked to homogeneous or heterogeneous substances via ester bonds form macromolecular tannins to impart bitter and astringent flavors to phytosomes. Although intriguing, these findings does not directly reveal the effect of ester bonds on antioxidant activity, but a few studies suggested decreasing antioxidant activity of polyphenols in the ester conjugates form with the substitution of ester bonds for functional groups and functionalities. For instance, in Brazilian wines, ellagic acid and epicatechin gallate have diester bonds and corresponded to decreased DPPH and ABTS free radical scavenging ability, while their counterparts gallic acid and epicatechin were positively correlated with the above two indicators(Gris et al., 2011). Chlorogenic acid is a polyphenol and the ester of caffeic acid and quinic acid, and Sato, Y et al. found that caffeic acid had stronger antioxidant activity than that of chlorogenic acid(Sato et al., 2011). Substitution of functional groups by ester bonds reduces antioxidant activity mainly due to the substitution of functional hydroxyl groups by ester bonds. This substitution reduces the number of hydroxyl groups, and thus reduces the scavenging ability of functional hydroxyl groups for free radicals by limiting hydrogen supply and electron transfer(Gülçin, 2011). The substitution of functional groups by ester bonds mainly reduces the antioxidant activity because the -CH=CH-COOH functional groups in phenolic acids can influence the ionic domain of ArOH, which generates unstable electrons to scavenge free radicals by reacting with free radicals. When the two functional groups are present at the same time, they can further influence the nearby ionic domains to stabilize the free radicals(Chimi et al., 1991; Gulcin, 2020). Therefore, when -COOH is esterified, the effect of the functional groups disappears resulting in reduced free radical scavenging and stabilizing abilities, especially for hydroxycinnamic acids (Fig. 3C).

As described above, the structure of phenolic acids and flavonoids affects the antioxidant activity. Removal of derivatised glycosides, methyl and ester conjugates to form functional groups and functionally active sites with high antioxidant activity can enhance the antioxidant activity of polyphenols, suggesting strategies to transform low oxidative activity polyphenols into high antioxidant activity polyphenols.

3 Enhancement of the antioxidative activity of fruit polyphenols and flavonoids by probiotic fermentation

The modification of polyphenol structures can be performed using physical, chemical, enzymatic, and biological methods(Cao et al., 2015). Biological methods include the structural modification of polyphenols by conversion using microbial fermentation. This method has advantages of high efficiency and convenience, and it can increase the quality and functionality of plant polyphenol-derived foods (e.g., antioxidant, antibacterial, and anti-inflammatory activities)(Fouad, Sharaf, Abdelghany, & El Sayed, 2018) There is growing interest in the use of microbial fermentation and the production of probiotic-fermented foods(Lillo-Pérez, Guerra-Valle, Orellana-Palma, & Petzold, 2021). Most of the lactic acid bacteria (LAB) are autochthonous microbiota of raw vegetables and fruits. To get desirable properties on fermented plant-derived food products, LAB has to be adapted to the characteristics of the plant raw materials where phenolic compounds are abundant. In summary, as shown in Fig. 4 and Table S2, Bifidobacterium and Lactobacillus are commonly used in food fermentation and these bacteria can increase the antioxidant activities of the fermented foods. To dissect the mechanism by which antioxidant activity is enhanced by probiotic fermentation, many studies have explored the biotransformation of phytogenic functional active polyphenols by Bifidobacterium and Lactobacillus(Kowalski, Gustafson, Carroll, & Gonzalez de Mejia, 2020; Maisto et al., 2021). Conversion reactions that improve antioxidant activity can be classified into two types: 1) The process of removing derivatization that convert derivatization products into polyphenols with key functional groups, including processes of glycosylation, demethylation and hydrolysis that remove glycosides, methyl groups and hydrolyze ester bonds. These processes have been extensively studied in Bifidobacterium and Lactobacillus (Gaur & Gänzle, 2023); 2) Conversion of polyphenols with low activity to high activity through processes of hydroxylation, dehydrogenation and oxidation to generate highly antioxidant-active substances with multiple hydroxyl groups, double bond, and 4-oxo structure. However, little is known about the hydroxylation, dehydrogenation and oxidation of polyphenols by Bifidobacterium and Lactobacillus. The following section focuses on what is known about the process of removing derivatization that convert derivatization products into polyphenols with key functional groups, including processes of glycosylation, demethylation and hydrolysis that remove glycosides, methyl groups and hydrolyze ester bonds.Fig. 4 Enhancement of antioxidant activity by the fermentation of plant-based food by Bifidobacterium and Lactobacillus. L. rhamnosus: Lacticaseibacillus rhamnosus; L. paracasei: Lacticaseibacillus paracasei; B. animalis:Bifidobacterium animalis; B. animalis sp. lactis: Bifidobacterium animalis subsp. lactis; L. acidophilus:Lactobacillus acidophilus; L. plantarum:Lactiplantibacillus plantarum; L. helveticus: Lactobacillus helveticus.

Fig. 4

3.1 Deglycosylation

Depending on the site of conversion of glycoside polyphenols by the enzymes produced by probiotics and the substrates for conversion, the deglycosylation reactions of probiotics can be categorized into i) 7-O- glycoside flavonoids ii) 3-O- glycoside flavonoids iii) chalcone glycosides and iv) hydroxycinnamic acid glycoside deglycosylation, as shown in Fig. 5. Overall, deglycosylation improves the antioxidant activity of polyphenols by the removal of glycosides, increasing the number of functional hydroxyl groups, and promoting the formation of other functional groups.Fig. 5 Principles of polyphenol deglycosylation and mechanisms of enhancing antioxidant activity by probiotics. (A): The schematic and reactions and mechanisms of 7-O- glycoside increases the antioxidant activity of flavonoids. (B): The schematic and reactions and mechanisms of 3-O- glycoside increases the antioxidant activity of flavonoids. (C): The schematic and reactions and mechanisms of chalcone glycosides increases the antioxidant activity of flavonoids. (D): The schematic and reactions and mechanisms of hydroxycinnamic acid glycosides increases the antioxidant activity of phenolic acid. L. rhamnosus: Lacticaseibacillus rhamnosus; L. paracasei: Lacticaseibacillus paracasei; L. plantarum:Lactiplantibacillus plantarum; B. animalis sp. lactis: Bifidobacterium animalis subsp. lactis; B. longum: Bifidobacterium longum; L. acidophilus:Lactobacillus acidophilus; B. longum subsp. Infantis:Bifidobacterium longum subsp. infantis; B. breve: Bifidobacterium breve; L. bulgaricus:Lactobacillus bulgaricus; B. lactis: Bifidobacterium animalis subsp. lactis; B. adolescentis: Bifidobacterium adolescentis; B. bifidum:Bifidobacterium. bifidum; L. buchneri: Lactobacillusbuchner; L. leichmanii: Lactobacillus leichmanii.

Fig. 5

3.1.1 Deglycosylation of 7-O- glycoside flavonoids

Bifidobacterium and Lactobacillus remove glycosides by generating glycosidase, which breaks the C—O bond at site 7. Polyphenols improve antioxidant activity by removing 7-O-glycosides from the A-ring of isoflavones and flavanones (Fig. 5A). Isoflavone glycosides (daidzin and genistin) can remove 7-O- monoglycosides to isoflavone aglycones (daidzein and genistein) in the form of glycoside hydrolyzed conjugates using the β-glucosidase produced by Lacticaseibacillus rhamnosus, Lacticaseibacillus paracasei, and Lactiplantibacillus plantarum(Tsangalis, Ashton, McGill, & Shah, 2002; Zhu, Wang, & Zhang, 2019).

Bifidobacterium animalis sp. lactis BB12 or Bifidobacterium breve C0422 produce α-L-rhamnosidase that can remove the 7-O-diglycoside from hesperidin, flavanone with disaccharide glycosides, into hesperetin(Amaretti et al., 2015; Mueller et al., 2017). Another flavanone with disaccharide glycosides, eriocitrin, can similarly be converted into eriodictyol by Bifidobacterium adolescentis JCM 1275, Bifidobacterium bifidum IFO 14252, L. plantarum IAM 12477, Lactobacillus acidophilus, Lactobacillus buchneri, Lacticaseibacillus casei, or Lactobacillus leichmanii. However, the details of transformation and the enzymes released by the reactive strains have not been reported(Miyake, Yamamoto, & Osawa, 1997).

The improved antioxidant activity of the aglycones after the deglycosylation of the site 7 in the form of glycoside, methylated, and ester conjugates isoflavones and flavanones is sequential proton loss electron transfer (SPLET). The reaction enthalpy of the first step of this reaction corresponds to the proton affinity of the phenoxide anion (ArO−)(Vianello & Maksić, 2006). In the second step, electron transfer from the phenoxide anion to ROO· occurs, and the phenoxy radical is formed. The reaction enthalpy of this step is denoted as electron transfer enthalpy. The 7-O-glycosides affect the hydrogen bonding of the ArOH of isoflavones and flavanones, which promotes the formation of unstable ArO− that can combine with ROO− to scavenge free radicals(Gocer et al., 2015). Additionally, 7-O-glycosides promote electron transfer from the ArOH of isoflavones and flavanones to ROO· to produce the stabilized form of ROO−.

3.1.2 Deglycosylation of 3-O- glycoside flavonoids

Bifidobacterium and Lactobacillus produce glycosidase that acts on the C—O bond at site 3 to remove glycosides. The antioxidant activity of flavonols and anthocyanin glycosides can be enhanced by the removal of 3-O-glycosides from the middle C-ring by Bifidobacterium and Lactobacillus (Fig. 5B). The deglycosylation of 3-O-glycosides occurs with flavonols such as quercetin-3-O-glucoside, 3-O-rutinoside, and kaempferol-3-O-glucoside. The α-glucosidase produced by L. rhamnosus can remove the 3-O-glucoside from quercetin-3-O-glucoside to yield quercetin(Lin et al., 2014). Kaempferol-3-O-glucoside can be deglycosylated to kaempferol by the β-glucosidase produced by Bifidobacterium. longum subsp. infantis B7875 or Bifidobacterium breve B7824(Marotti, Bonetti, Biavati, Catizone, & Dinelli, 2007). Isorhamnetin-3-glucoside can be deglycosylated to isorhamnetin by the β-glucosidase produced by Bifidobacterium animalis subsp. lactis AD011(Ahn et al., 2020). Rutin with rhamnoside (disaccharide glycoside) can be deglycosylated to quercetin by the α-rhamnosidase produced by L. rhamnosus or L. acidophilus(Francesca et al., 2016).

There are two main explanations of the higher antioxidant activity of the aglyconees after removal of 3-O-glucosides. First, the removal of 3-O glucosides can increase the number of hydroxyl groups on the benzene ring. When polyphenols encounter free radicals, there are more ArOH to generate unstable electrons, which further promotes hyrdogen donation and electron transfer to scavenge free radicals(Gulcin, 2020; Lespade & Bercion, 2012). Second, for flavonols, the structure with 4-oxo groups and -OH groups near C-3 and C-5 will be formed after the removal of the glycoside at 3 site to supplement H. This structure can promote ArOH to generate unstable electrons to scavenge free radicals by affecting the ionic domains around flavonols(Bors et al., 1990; Ghosh et al., 2015). Additionally, it can chelate with metal ions, which affects the electron domains around the free radicals promoting a more stable form.

3.1.3 Deglycosylation of chalcones glycosides

In addition to 7-O-glycosides and 3-O -glycosides, there are 5-O-glycosides. The 5-O-glycosides of chalcones can be removed by Bifidobacterium and Lactobacillus for improved antioxidant activity (Fig. 5C). Phlorizin is a chalcone glycoside and phloretin is the corresponding chalcone algycone. Liu et al. found that β-glucosidase produced by L. rhamnosus L08(Liu et al., 2021) can remove glycosides from the glycoside precursor phlorizin to get phloretin with higher antioxidant activity than phlorizin.

The enhanced antioxidant activity that results from the deglycosylation of phlorizin is due to the formation of phloretin after the removal of glycosides, with addition of a hydroxyl group at the 5 site. Compared to phlorizin, phloretin has more ArOH to generate unstable electrons, which further promotes hyrdogen donation and electron transfer to scavenge free radicals for higher antioxidant activity(Gulcin, 2020; Shahidi & Ambigaipalan, 2015; Wright, Johnson, & DiLabio, 2001).

3.1.4 Deglycosylation of hydroxycinnamic acid glycosides

The glycoside form hydroxycinnamic acid can be deglycosylated by enzymes produced by Lactobacillus and Bifidobacterium to increase antioxidant activity, with compounds such as caffeic Acid 3-β-D-Glucoside and (E)-Ferulic acid 4-O-β-D- glucoside (Fig. 5D). Caffeic Acid 3-β-D-Glucoside can be deglycosylated to form caffeic acid by the β-glucosidases produced by L. acidophilus, Lactobacillus bulgaricus, Bifidobacterium animalis or L. plantarum(do Carmo, Pressete, Marques, Granato, & Azevedo, 2018). (E)-Ferulic acid 4-O-β-D-glucoside can be deglycosylated to form ferulic acid by enzymes produced by Bifidobacterium animalis subsp. lactis(Nyambe-Silavwe et al., 2015).

After transforming, the antioxidant activity of caffeic acids and ferulic acids was higher than the glycoside forms of caffeic acid 3-β-D-glucoside and (E)-Ferulic acid 4-O-β-D-glucoside. The removal of the glycoside can increase the number of hydroxyl groups on the benzene ring, and these hydroxyl groups can scavenge free radicals through hydrogen donation and electron transfer. At the same time, the formed catechol can either directly supply hydrogen to scavenge free radicals or lose an H+ to form catechol,− which combines with ROO• to form ROO− to stabilize free radicals(Gomes et al., 2012; Gulcin, 2020; ŽivanoviĆ et al., 2017).

3.2 Demethylation

Polyphenols in the methoxy form are mainly phenolic acids and some flavonoids, as shown in Fig. 6. There have been few studies of the demethylation of polyphenols by probiotics, with only the demethylation reaction of Bifidobacterium to methoxylated isoflavonoids reported. Pilar Gaya et al. found that formononetin and biohcanin A can be converted in daidzein and genistein through an O- Demethylation reaction of L. paracasei INIA P461, B. animalis INIA P900, and B. breve INIA P734(Gaya, Peirotén, & Landete, 2017). Jos'e Antonio Curiel et al. first reported the O-demethylase gene from B. breve INIA P734, and verified that this strain can produce O-demethylase to transform formononetin and biohcanin A(Curiel & Landete, 2022). The demethylated products (daidzein and genistein) showed higher antioxidant activity than the methylated precursors (formononetin and biohcanin A).Fig. 6 Principles of polyphenol demethylation and mechanisms of enhancing antioxidant activity by probiotics.L. paracasei: Lacticaseibacillus paracasei; B. animalis:Bifidobacterium animalis.

Fig. 6

Demethylation can enhance the antioxidant activity of polyphenols by the removal of methyl groups, which increases the number of functional hydroxyl groups. The methyl group occupies the site of the functional hydroxyl group, and when the methyl group is removed in formononetin and biohcanin A, a new hydroxyl group is formed on the benzene ring, and the hydroxyl group at this site can further produce new unpaired electron (O• and O−) and scavenge free radicals by hydrogen donation and electron transfer. However, the conformational change due to the demethylation reaction of flavonoids by probiotics and the corresponding antioxidant activity needs to be further explored.

3.3 Hydrolysis

Lactobacillus and Bifidobacterium act on ester bonds using hydrolysis and esterase enzymes to form functional -COOH and -OH. Ester polyphenols, such as ester phenolic acids and tannins(Gaur & Gänzle, 2023) have improved antioxidant activity through hydrolysis by Lactobacillus and Bifidobacterium. As shown in Fig. 7, the penta-O-galloyl-β-d-glucose, a gallotannin, was hydrolyzed to gallic acid by tannin acyl hydrolase produced by L. plantarum and L. rhamnosus(Rodríguez, Landete, Rivas, & Muñoz, 2008; Serrano, Puupponen-Pimiä, Dauer, Aura, & Saura-Calixto, 2009). Chlorogenic acid, an ester phenolic acid, can be hydrolyzed to caffeic acid by feruloyl esterase produced by L. rhamnosus(Gaur & Gänzle, 2023). Another ester phenolic acid, ethyl ferulate, can be hydrolyzed to ferulic acid by hydroxycinnamate esters produced by Bifidobacterium. animalis sp. Lactis, L. plantarum, L. acidophilus, or Lactobacillus helveticus(Rodríguez-Daza et al., 2021; Wu et al., 2020). There are similarities in the conformational changes of the above three hydrolysis reactions to improve antioxidant activity. After the breaking of the ester bond in the penta-O-galloyl-β-d-glucose, chlorogenic acid, and ethyl ferulate, the hydrolysis products have -COOH and -CH=CH-COOH groups. These groups can influence the ionic domains around phenolic acids and free radicals to facilitate the scavenging of unstable electrons to free radicals by hydrogen donation and electron transfer. Additionally, the formation of ROO− can stabilize the free radicals(Gulcin, 2020; J. Yang et al., 2021).Fig. 7 Principles of hydrolysis of ester polyphenols and mechanisms of enhancing antioxidant activity by probiotics. L. plantarum:Lactiplantibacillus plantarum; L. rhamnosus:Lacticaseibacillus rhamnosus; B. animalis sp. lactis: Bifidobacterium animalis subsp. lactis; L. acidophilus:Lactobacillus acidophilus; L. helveticus: Lactobacillus helveticus.

Fig. 7

Bora, Li, Zhu, and Du reported that (−)-epicatechin-3-O-gallate, an ester polyphenol formed by polymerization of a flavanol and hydroxybenzoic acid, can be hydrolyzed to form the corresponding flavanol monomer (−)-epicatechin and the monomer hydroxybenzoic acid gallic acid by L. plantarum IFPL935(Sánchez-Patán et al., 2012). However, the specific enzyme was not identified. In this reaction, the hydrolysis of (−)-epicatechin-3-O-gallate gives the monomeric flavanol a hydroxyl group at C-3, and the increased number of hydroxyl groups increases the instabilities (ArO• and ArO−) in the flavanol that can provide hydrogen atoms and electron transfer for an increase in the scavenging of free radicals (Gulcin, 2020; Shahidi & Ambigaipalan, 2015). Additionally, the formation of carboxyl groups in hydroxybenzoic acid affects the ionic domains of phenolic acids, which further promote the scavenging of free radicals by unstable electrons through hydrogen donation and electron transfer(J. Yang et al., 2021). Although both Lactobacillus and Bifidobacterium can hydrolyze polyphenols, less is known about the hydrolytic capacity of Bifidobacterium, so further studies on ester hydrolysis in this species are warranted.

Besides the aforementioned forms of biotransformations, other forms include hydroxylation, hydrogenation, dehydrogenation, oxidation, isomerization, and multi-step synthesis of polyphenols through the fermentation of Bifidobacterium and Lactobacillus (Cao et al., 2015; Gaur & Gänzle, 2023). For example, after Bifidobacterium fermentation, dihydroartemisinin is produced through hydrogenation, vanillin is converted into vanillic acid through oxidation, and pelargonidin is the product of a multi-step synthesis from naringenin (Wang et al., 2022). However, the structure–antioxidant relationships for hydroxylation, dehydrogenation, and oxidation of polyphenols by Bifidobacterium and Lactobacillus are less explored. Overall, the antioxidant activities of fruit polyphenols and flavonoids generally increase during fermentation due to the biotransformation of flavonoids and phenolic acids in the form of glycoside, methoxy, and ester conjugates. This process increases the content of free-form polyphenols and flavonoids in the system and produces new chemical compounds. Nevertheless, given the complexity of the fermentation system, three additional sources can enhance the antioxidant activity of the system: (1) the transformation of polyphenol precursors, (2) the transformation of non-polyphenol antioxidant compounds, and (3) the metabolism of antioxidant compounds by Bifidobacterium and Lactobacillus. In the first case, phenylpropanoid synthesis is a precursor pathway for the formation of polyphenols and flavonoids. It is the main pathway in metabolomics-based enrichment of metabolic pathways after probiotic plant-based fermentation, and phenylpropanoids are directly or indirectly transformed with flavonoids and phenolic acids (Shen et al., 2022; Y. Wang et al., 2024). In the second case, the structures of converted non-polyphenol products, such as amino acids with multiple sulfhydryl or hydroxyl groups, carbohydrates with reactive oxygen on benzene rings, and fatty acids with unsaturated bonds, short chains, and glycosides, have higher antioxidant activity in reducing free radicals compared with their precursors after Bifidobacterium fermentation(Y. Wang, Wang, Lan, et al., 2024). Meanwhile, these non-polyphenol products form polyphenols with antioxidant activity through the multi-step biosynthesis of secondary metabolites. In the third case, metabolites such as carboxylic acids, pyrimidines, purines, fatty acids, and amino acids are isolated from Lactobacillus. Wang et al. reported that uridine diphosphate (UDP) was the central metabolite of purines, which exhibited an indirect translational relationship with upregulated orotic acid. Further, orotic acid was detected only in Lacticaseibacillus paracasei YL-29–fermented juice and exhibited anti-inflammatory properties (C. Wang, Wang, Teng, & Zhang, 2024). Similarly, acetyl-CoA served as a key metabolite in lipid metabolism and was indirectly converted into citraconic acid and cortisone. Cortisone with high antioxidant activity was specifically detected in L. paracasei YL-29–fermented juice (C. Wang, Wang, Teng, & Zhang, 2024). Therefore, new free-form polyphenols and flavonoids were generated during probiotics fermentation, the conjugated fruit polyphenols and flavonoids were released through biotransformation, and other new antioxidant profiles were formed. However, further studies are needed to investigate the structure–antioxidant relationship between the aforementioned three additional sources and the polyphenolic compounds in terms of their conversion and the mechanisms underlying the enhancement of antioxidant activity.

4 Key factors for the enhancement of antioxidant activity by probiotic fermentation

Many studies have explored the transformation of plant-derived functional polyphenols by probiotics, providing insights into the enzymes, metabolic pathways, transformation mechanisms, and product functionality of the bacterial strains involved in transformation.

4.1 Microbial enzymes

The bacterial transformation of polyphenols depends on the action of bacterial enzymes produced by the strain on specific sites of the polyphenol structure.

Bifidobacterium and Lactobacillus can release glycosidases, hydrolases, decarboxylases, demethylases, reductases, and esterases that can act on flavonoids and phenolic acids. However, identification of specific bacterial enzymes providing esterase and glycosidase activities in food fermentation remains incomplete. Most studies rely on quantification of a decrease in concentration of specific compounds with a corresponding increase in expected metabolites. Few studies used isogenic mutants to confirm the activity of specific enzymes in fermentation(Gaur & Gänzle, 2023) and there are little data on the expression of genes in complex food substrates. The recent identification of several genes related to the metabolism of phenolic compounds provides the necessary tools to address this limitation. To explore transforming enzymes, Kin Kwan Lai et al. selected esterases from Lactobacillus johnsonii(Lai, Lorca, & Gonzalez, 2009) by using genomic analysis coupled to protein purification and catalytic screening. Gaya et al. cloned β-glucosidase genes from Lactobacillus mucosae INIA P508 and verified that the produced synthetase resulted in the transformation of the glycoside daidzin into the correspondent aglyconee daidzein by HPLC(Gaya, Peirotén, & Landete, 2020).

In addition, datasets from 16S rDNA analysis and transcriptomics measurements have expanded understanding of the genomes of probiotics and suggested enzymes whose metabolic functions contribute to the bioavailability and bioactivity of unabsorbed (poly)phenols. Putative transforming enzymes can be verified by analyzing genes with significant differences in expression before and after fermentation, using database information to annotate the enzyme genes, and performing real-time quantitative analysis of functional enzyme gene expression. To date, the polyphenol metabolism of L. plantarum is one of the best-studied among probiotic bacteria. The genes encoding enzymes of intracellular tannase (tanBLP), gallate decarboxylase (lpdB, lpdC), aryl glycosidase(Landete, Curiel, Rodríguez, de Las Rivas, & Muñoz, 2014), rhamnosidases (rhaB1, rhaB2)(Reverón, de Las Rivas, Matesanz, Muñoz, & López de Felipe, 2015), phenolic acid decarboxylase (hcrB, lp_3665), and vinylphenol reductase (lp_3125) in L. plantarum have been identified, and future work is required to assay the roles of these genes in the transformation of functional polyphenols(Ávila et al., 2009).

4.2 Transformation pathway

The transformation of polyphenols by probiotics can differ for different phenolic species. In previous studies, qualitative and quantitative analysis of polyphenols in the fermentation matrix was performing using total phenolic content measurement, liquid chromatography–mass spectrometry, and HPLC or HPLC-MS(High Performance Liquid Chromatography-tandem Mass Spectrometry). The types of substances transformed by probiotics were tentatively identified based on changes of species and content. Ratchadaporn Kaprasob et al. predicted the transformation of tannins by Lactobacillus plantarum, L. casei and L. acidophilus by determining the total phenolic contents, the condensed tannin contents and the hydrolysable tannin contents(Kaprasob, Kerdchoechuen, Laohakunjit, Sarkar, & Shetty, 2017). Similarly, Tianlin Li et al. predicted that L. acidophilus, L. casei, L. helveticus and L. plantarum have the ability to transform flavonoid polyphenols based on total polyphenol contents, flavonoid contents, and HPLC assay results. However, these results can only suggest the type of polyphenol transformation by probiotics, and cannot locate the specific profiles and transformation types. Thus, this approach has only demonstrated the transformation of a few polyphenols by probiotics.

With the development of localization and omics techniques, single-omic or multi-omics analysis by isotope tracer technology can further localize metabolic pathways in the fermentation process, facilitating the identification of functional transforming enzymes. Gallardo-Fernandez et al. elucidated biosynthesis pathways in Saccharomyces cerevisiae for hydroxytyrosol formation by isotope tracer technology(Gallardo-Fernández et al., 2022). In whole crop corn ensiling systems with homofermentative Lactobacillus plantarum or heterofermentative Lactobacillus buchneri., metabolomic analysis revealed changes in many metabolites with biofunctional activities like bacteriostatic (naringin and 3,4-dihydroxybenzoic acid), antioxidant (ferulic acid and catechol), central nervous system inhibitory (4-aminobutyric acid), and anti-inflammatory (salicin) compounds(Xu et al., 2020). The expression of genes for anthocyanin synthesis were up-regulated in red wine based on metabolomics and transcriptomics analysis.

Interestingly, the anthocyanin glycoside concentrations in red wine were low or even not detected(Yue, Xu, Xiang, Yu, & Yao, 2018). Overall, the mining of metabolic pathways and substance transformations can facilitate biosynthesis and engineering functional production. To improve the medicinal value of the caffeic acid titer, Lian Wang et al. enhanced caffeic acid production in Escherichia coli by engineering the biosynthesis pathway and transporter. The overexpression of ycjP, as a sugar ABC transporter permease, improved the caffeic acid titer to 775.7 mg/L, and was further improved to 7922.0 mg/L in a 5-L fermenter, the highest titer achieved by microbial fermentation(L. Wang, Li, Yu, & Zhou, 2023). Clearly, the specific transformation reactions (corresponding reaction precursors and transformation products) and detailed metabolic pathways in the conversion of polyphenols by probiotics should be the focus of future work. Wang et al. used metabolomics analysis to reveal flavonoid, isoflavonoids, flavone and flavonol biosynthetic pathways involved in the transformation of polyphenols by Bifidobacterium animalis subsp. lactis HN-3, predicted the enzymes in the deglycosylation and hydroxylation reactions of the strain, and verified the deglycosylation of coniferin by Bifidobacterium animalis subsp. Lactis HN-3(Y. Wang et al., 2022).

4.3 Validation evaluation

4.3.1 In vitro assays

There is significant interest in the food industry in identifying new functions of food. In particular, probiotic fermented plant-based products are a developmental focus of functional food development. Fermentation of food by probiotics can significantly improve the content of functional components in fruit juices, especially polyphenols with antioxidant activity. The antioxidant activity of probiotic-fermented foods can be measured using in vitro antioxidant indexes. These analyses are widely used because they are inexpensive and can be performed quickly. As in vitro indicators of antioxidant compound activity, 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) inhibition, Ferric Reducing Antioxidant Power (FRAP), Oxygen Radical Absorbance Capacity (ORAC), 2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and Cupric Reducing Antioxidant Power (CUPRAC) are measured(Mota, Almeida, Freitas, Stockler-Pinto, & Guimarães, 2023). In vitro antioxidant index changes and polyphenol content changes demonstrated that probiotics can be used to improve the functional activity of fermented juice (Kowalski et al., 2020; Wu et al., 2020).

4.3.2 In vivo validation

However, in vitro antioxidant index assays cannot fully characterize the antioxidant activity of polyphenol products after transforming by probiotics and in vivo experiments are necessary to validate the functional activity of the transformed polyphenol products of probiotics. In previous studies, researchers extracted functional polyphenols from food products and verified animal models. Xiaoyue Gong et al. established an intestinal inflammation model in the model organism zebrafish and extracted polyphenols from Dendrobium candidum to study anti-inflammatory mechanisms. The results showed that fermented D. candidum polyphenols may protect intestinal cells from oxidative damage by up-regulating the activities of SOD and GSH-Px, enhance the antioxidant defense mechanism of intestinal cells, and delay the cell damage caused by intestinal inflammation(Gong, Jiang, Tian, Xiang, & Zhang, 2020). Additionally, the ability of polyphenols like genistein, hesperidin, and phlorizin to modulate glucose metabolism while inhibiting the expression of fatty liver factors was validated by mice models (Li et al., 2022; Zhang et al., 2022).

4.4 Future studies

According to the previous description, it is important to investigate the enzymes, reactions, metabolic pathways and functional activity validation of probiotics conversion to polyphenols for the development of probiotic-fermented functional foods and polyphenol applications. Therefore, future studies should elucidate the types of polyphenols that can be transformed by a given strain, the mode of transformation, the transforming enzymes, and the sites of action.

In the future, strains producing transforming enzymes that act on specific sites can be modified to produce products with better functional activity or applied for the batch production of potential drugs or functional fermented beverages. For the products with better functional substances, the precursors that are abundant in nature and convenient to extract are screened, and the synthesis rate and yield of the functional substances are increased by cloning the expressed enzymes.

And then, it is necessary to explore the corresponding transformation reactions and metabolic pathways of transforming polyphenols by probiotics to provide a theoretical basis for the further production of duplibiotic/symbiotic efficacy products and to improve the production of medicinal polyphenols. In addition, for the functional studies of probiotic transformed polyphenols, it can be proved more comprehensively that probiotics are used as a means of transforming polyphenols to improve the functional activity and be more conducive to the development of functional fermented foods by extracting and purifying the transformed products with high functional activity and combining with the in vitro and in vivo experiments for the verification of the functional activity.

5 Concluding remarks

In recent years, there has been increased attention to the relationship between polyphenol structure and function. Phenolic acids and flavonoids as glycoside, methoxy and ester hydrolyzed onjugates with functional groups (e.g., polyhydroxyl groups, phenolic acids with -CH=CH-COOH, flavonoids with 4-oxo groups and a double bond between C-2 and C-3) or with functional groups in characteristic sites (e.g., flavonoids in A- and C-rings with a 4-oxo group and a double bond between C-2 and C-3 or flavonoids at A- and C-rings with 4-oxo groups and -OH groups near C-3 and C-5) show elevated antioxidant activity. After derivatision, functional groups can decrease the antioxidant activity of flavonoids and phenolic acids because these groups reduce the formation of unstable ions with their own functional hydroxyl groups and also affect the ionic domains of the free radicals. These changes reduce the scavenging ability of unstable ions on the free radicals and the overall stability of the free radicals. Free radical scavenging capacity can be enhanced by increasing electron transfer and the functional capacity of hydroxyl groups with destabilizing functions and by enhancing the stability of free radicals by directly affecting the ionic domain around the radicals after metal chelation. Overall, probiotic fermentation is a powerful approach to modify the structures of bioactive polyphenols for enhanced activity.

In this review, we summarized the types and mechanisms of the reactions of probiotic fermentation that enhance the antioxidant activity of glycoside, methoxy, and ester conjugate polyphenols. In the presence of enzymes produced by probiotics, glycoside, methoxy and ester conjugates can be transformed into hydrolyzed forms through deglycosylation, demethylation, and hydrolysis reactions. With decreased antioxidant active groups, conjugates can increase antioxidant activity by increasing scavenging capacity and stability against free radicals.

Although few studies have been conducted on the probiotic transformation of polyphenols, future work should focus on optimizing the transformation of glycoside, methoxy and ester conjugates into compounds with high antioxidant activity. Strains producing transforming enzymes that act on specific sites can be modified to produce products with better functional activity or applied for the batch production of potential drugs or functional fermented beverages.

CRediT authorship contribution statement

Yixuan Wang: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Methodology, Investigation, Formal analysis, Conceptualization. Chenxi Wang: Writing – review & editing, Writing – original draft, Validation, Supervision, Formal analysis, Conceptualization. Junling Shi: Resources, Project administration. Yan Zhang: Writing – review & editing, Writing – original draft, Resources, Project administration, Investigation, Funding acquisition.

Declaration of competing interest

The author(s) declared no potential conflicts of interest with respect to the research, author- ship, and/or publication of this article.

The authors declared that they have no conflict of interest.

Appendix A Supplementary data

Supplementary material 1: Table S1: The structure-antioxidant activity relationships of flavonoids and phenolic acids.

Image 1

Supplementary material 2: Table S2: Modification of the structure to enhance the antioxidant activity on flavonoids and phenolic acids by probiotic fermentation.

Image 2

Data availability

No data was used for the research described in the article.

Acknowledgments

This work was supported by the 10.13039/501100001809 National Natural Science Foundation of China (grant no. 32260568), National Natural Science Foundation of China (grant no. 32172183), the National Natural Science Foundation of China (grant no. 31760446), and the funding of Shihezi University (CXBJ201901).

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.fochx.2024.101776.
==== Refs
References

Agati G. Azzarello E. Pollastri S. Tattini M. Flavonoids as antioxidants in plants: Location and functional significance Plant Science 196 2012 67 76 10.1016/j.plantsci.2012.07.014 23017900
Ahn H.J. You H.J. Park M.S. Li Z. Choe D. Johnston T.V. …Ji G.E. Microbial biocatalysis of quercetin-3-glucoside and isorhamnetin-3-glucoside inSalicornia herbaceaand their contribution to improved anti-inflammatory activity RSC Advances 10 9 2020 5339 5350 10.1039/c9ra08059g 35498283
Alseekh S. Perez de Souza L. Benina M. Fernie A.R. The style and substance of plant flavonoid decoration; towards defining both structure and function Phytochemistry 174 2020 10.1016/j.phytochem.2020.112347
Amaretti A. Raimondi S. Leonardi A. Quartieri A. Rossi M. Hydrolysis of the Rutinose-conjugates flavonoids Rutin and hesperidin by the gut microbiota and Bifidobacteria Nutrients 7 4 2015 2788 2800 10.3390/nu7042788 25875120
Apak R. Özyürek M. Güçlü K. Çapanoğlu E. Antioxidant activity/capacity measurement. 1. Classification, physicochemical principles, mechanisms, and Electron transfer (ET)-based assays Journal of Agricultural and Food Chemistry 64 5 2016 997 1027 10.1021/acs.jafc.5b04739 26728425
Aparecida Plastina Cardoso M. Windson Isidoro Haminiuk C. Pedro A.C. De Andrade Arruda Fernandes Fernandes I. Akemi Casagrande Yamato M. Maciel G.M. Do Prado I.N. Biological effects of goji berry and the association with new industrial applications: A review Food Reviews International 39 5 2021 2990 3007 10.1080/87559129.2021.2007261
Arteaga C. Boix N. Teixido E. Marizande F. Cadena S. Bustillos A. The zebrafish embryo as a model to test protective effects of food antioxidant compounds Molecules 26 19 2021 10.3390/molecules26195786
Ashengroph M. Nahvi I. Zarkesh-Esfahani H. Momenbeik F. Pseudomonas resinovorans SPR1, a newly isolated strain with potential of transforming eugenol to vanillin and vanillic acid New Biotechnology 28 6 2011 656 664 10.1016/j.nbt.2011.06.009 21689800
Ávila M. Jaquet M. Moine D. Requena T. Peláez C. Arigoni F. Jankovic I. Physiological and biochemical characterization of the two α-l-rhamnosidases of Lactobacillus plantarum NCC245 Microbiology 155 8 2009 2739 2749 10.1099/mic.0.027789-0 19423635
Balasundram N. Sundram K. Samman S. Phenolic compounds in plants and Agri-industrial by-products: Antioxidant activity, occurrence, and potential uses Food Chemistry 99 1 2006 191 203 10.1016/j.foodchem.2005.07.042
Barna D. Alshaal T.O. Tóth I. Cziáky Z. Fári M.G. Domokos-Szabolcsy É. Bákonyi N. Bioactive metabolite profile and antioxidant properties of brown juice, a processed alfalfa (Medicago sativa) by-product Heliyon 8 11 2022 10.1016/j.heliyon.2022.e11655
Bors W. Heller W. Michel C. Saran M. Flavonoids as antioxidants: Determination of radical-scavenging efficiencies Methods in Enzymology 186 1990 343 355 10.1016/0076-6879(90)86128-i 2172711
Braune A. Blaut M. Bacterial species involved in the conversion of dietary flavonoids in the human gut Gut Microbes 7 3 2016 216 234 10.1080/19490976.2016.1158395 26963713
Burda S. Oleszek W. Antioxidant and antiradical activities of flavonoids Journal of Agricultural and Food Chemistry 49 6 2001 2774 2779 10.1021/jf001413m 11409965
Cai Y.-Z. Mei S. Jie X. Luo Q. Corke H. Structure–radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants Life Sciences 78 25 2006 2872 2888 10.1016/j.lfs.2005.11.004 16325868
Câmara J.S. Albuquerque B.R. Aguiar J. Corrêa R.C.G. Gonçalves J.L. Granato D. …Ferreira I.C.F.R. Food bioactive compounds and emerging techniques for their extraction: Polyphenols as a case study Foods 10 1 2020 10.3390/foods10010037
Cao H. Chen X. Jassbi A.R. Xiao J. Microbial biotransformation of bioactive flavonoids Biotechnology Advances 33 1 2015 214 223 10.1016/j.biotechadv.2014.10.012 25447420
do Carmo M.A.V. Pressete C.G. Marques M.J. Granato D. Azevedo L. Polyphenols as potential antiproliferative agents: Scientific trends Current Opinion in Food Science 24 2018 26 35 10.1016/j.cofs.2018.10.013
Castelluccio C. Paganga G. Melikian N. Bolwell G.P. Pridham J. Sampson J. Riceevans C. Antioxidant potential of intermediates in Phenylpropanoid metabolism in higher-plants FEBS Letters 368 1 1995 188 192 10.1016/0014-5793(95)00639-Q 7615079
Chang W.-T. Huang W.-C. Liou C.-J. Evaluation of the anti-inflammatory effects of phloretin and phlorizin in lipopolysaccharide-stimulated mouse macrophages Food Chemistry 134 2 2012 972 979 10.1016/j.foodchem.2012.03.002 23107715
Chen J. Yang J. Ma L. Li J. Shahzad N. Kim C.K. Structure-antioxidant activity relationship of methoxy, phenolic hydroxyl, and carboxylic acid groups of phenolic acids Scientific Reports 10 1 2020 10.1038/s41598-020-59451-z
Chen L. Kang Y.-H. Anti-inflammatory and antioxidant activities of red pepper (Capsicum annuum L.) stalk extracts: Comparison of pericarp and placenta extracts Journal of Functional Foods 5 4 2013 1724 1731 10.1016/j.jff.2013.07.018
Chen L. Teng H. Xie Z. Cao H. Cheang W.S. Skalicka-Woniak K. …Xiao J. Modifications of dietary flavonoids towards improved bioactivity: An update on structure–activity relationship Critical Reviews in Food Science and Nutrition 58 4 2017 513 527 10.1080/10408398.2016.1196334 27438892
Chimi H. Cillard J. Rahmani P.C.M. Peroxyl and hydroxyl radical scavenging activity of some natural phenolic antioxidants Journal of the American Oil Chemists’ Society 68 1991 307 312 10.1007/BF02657682
Choi J.S. Chung H.Y. Kang S.S. Jung M.J. Kim J.W. No J.K. Jung H.A. The structure-activity relationship of flavonoids as scavengers of peroxynitrite Phytotherapy Research 16 3 2002 232 235 10.1002/ptr.828 12164267
Curiel J.A. Landete J.M. Identification and cloning of the first O-demethylase gene of isoflavones from Bifidobacterium breve INIA P734 Lwt 162 2022 10.1016/j.lwt.2022.113510
Domínguez R. Gullón P. Pateiro M. Munekata P.E.S. Zhang W. Lorenzo J.M. Tomato as potential source of natural additives for meat industry A Review. Antioxidants 9 1 2020 10.3390/antiox9010073
Durazzo A. Lucarini M. Souto E.B. Cicala C. Caiazzo E. Izzo A.A. …Santini A. Polyphenols: A concise overview on the chemistry, occurrence, and human health Phytotherapy Research 33 9 2019 2221 2243 10.1002/ptr.6419 31359516
Fia G. Bucalossi G. Proserpio C. Vincenzi S. Unripe grapes: An overview of the composition, traditional and innovative applications, and extraction methods of a promising waste of viticulture Australian Journal of Grape and Wine Research 28 1 2021 8 26 10.1111/ajgw.12522
Fini A. Brunetti C. Di Ferdinando M. Ferrini F. Tattini M. Stress-induced flavonoid biosynthesis and the antioxidant machinery of plants Plant Signaling & Behavior 6 5 2014 709 711 10.4161/psb.6.5.15069
Fouad I.A. Sharaf N.M. Abdelghany R.M. El Sayed N.S.E.D. Neuromodulatory effect of Thymoquinone in attenuating glutamate-mediated neurotoxicity targeting the Amyloidogenic and apoptotic pathways Frontiers in Neurology 9 2018 10.3389/fneur.2018.00236
Franca M.G.A. Oliveira A.P.S. Lima D.R. Oliveira F.C.E. Paiva C.F. Pessoa C.O. …Silva M.G.V. Flavonoids composition, antioxidant, anticholinesterase, and cytotoxic activities of flowers extract of Senna cearensis Afr Fern. Natural Product Research 37 11 2023 1892 1896 10.1080/14786419.2022.2121922 36083632
Francesca N. Barbera M. Martorana A. Saiano F. Gaglio R. Aponte M. Moschetti G. Settanni L. Optimised method for the analysis of phenolic compounds from caper (Capparis spinosa L.) berries and monitoring of their changes during fermentation Food Chemistry 196 2016 1172 1179 10.1016/j.foodchem.2015.10.045 26593604
Gallardo-Fernández M. Valls-Fonayet J. Valero E. Hornedo-Ortega R. Richard T. Troncoso A.M. Garcia-Parrilla M.C. Isotopic labelling-based analysis elucidates biosynthesis pathways in Saccharomyces cerevisiae for melatonin Serotonin and Hydroxytyrosol formation. Food Chemistry 374 2022 10.1016/j.foodchem.2021.131742
Gao Q. Li Y. Li Y. Zhang Z. Liang Y. Antioxidant and prooxidant activities of phenolic acids commonly existed in vegetables and their relationship with structures Food Science and Technology 42 2022 10.1590/fst.07622
Gaur G. Gänzle M.G. Conversion of (poly)phenolic compounds in food fermentations by lactic acid bacteria: Novel insights into metabolic pathways and functional metabolites Current Research in Food Science 6 2023 10.1016/j.crfs.2023.100448
Gaya P. Peirotén Á. Landete J.M. Transformation of plant isoflavones into bioactive isoflavones by lactic acid bacteria and bifidobacteria Journal of Functional Foods 39 2017 198 205 10.1016/j.jff.2017.10.029
Gaya P. Peirotén Á. Landete J.M. Expression of a β-glucosidase in bacteria with biotechnological interest confers them the ability to deglycosylate lignans and flavonoids in vegetal foods Applied Microbiology and Biotechnology 104 11 2020 4903 4913 10.1007/s00253-020-10588-x 32270251
Ghosh N. Chakraborty T. Mallick S. Mana S. Singha D. Ghosh B. Roy S. Synthesis, characterization and study of antioxidant activity of quercetin–magnesium complex Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 151 2015 807 813 10.1016/j.saa.2015.07.050 26172468
Gocer H. Topal F. Topal M. Küçük M. Teke D. Gülçin İ. …Supuran C.T. Acetylcholinesterase and carbonic anhydrase isoenzymes I and II inhibition profiles of taxifolin Journal of Enzyme Inhibition and Medicinal Chemistry 1-7 2015 10.3109/14756366.2015.1036051
Gomes A. Couto D. Alves A. Dias I. Freitas M. Porto G. …Fernandes E. Trihydroxyflavones with antioxidant and anti-inflammatory efficacy BioFactors 38 5 2012 378 386 10.1002/biof.1033 22806885
Gómez-García R. Campos D.A. Aguilar C.N. Madureira A.R. Pintado M. Valorization of melon fruit (Cucumis melo L.) by-products: Phytochemical and biofunctional properties with emphasis on recent trends and advances Trends in Food Science & Technology 99 2020 507 519 10.1016/j.tifs.2020.03.033
Gong X. Jiang S. Tian H. Xiang D. Zhang J. Polyphenols in the fermentation liquid of Dendrobium candidum relieve intestinal inflammation in zebrafish through the intestinal microbiome-mediated immune response Frontiers in Immunology 11 2020 10.3389/fimmu.2020.01542
Grigalius I. Petrikaite V. Relationship between antioxidant and anticancer activity of Trihydroxyflavones Molecules 22 12 2017 10.3390/molecules22122169
Gris E.F. Mattivi F. Ferreira E.A. Vrhovsek U. Pedrosa R.C. Bordignon-Luiz M.T. Proanthocyanidin profile and antioxidant capacity of Brazilian Vitis vinifera red wines Food Chemistry 126 1 2011 213 220 10.1016/j.foodchem.2010.10.102
Gülçin İ. Antioxidant activity of food constituents: An overview Archives of Toxicology 86 3 2011 345 391 10.1007/s00204-011-0774-2 22102161
Gulcin İ. Antioxidants and antioxidant methods: An updated overview Archives of Toxicology 94 3 2020 651 715 10.1007/s00204-020-02689-3 32180036
Jug U. Naumoska K. Vovk I. (−)-Epicatechin—An important contributor to the antioxidant activity of Japanese knotweed rhizome bark extract as determined by antioxidant activity-guided fractionation Antioxidants 10 1 2021 10.3390/antiox10010133
Kaprasob R. Kerdchoechuen O. Laohakunjit N. Sarkar D. Shetty K. Fermentation-based biotransformation of bioactive phenolics and volatile compounds from cashew apple juice by select lactic acid bacteria Process Biochemistry 59 2017 141 149 10.1016/j.procbio.2017.05.019
Kowalski R. Gustafson E. Carroll M. Gonzalez de Mejia E. Enhancement of biological properties of blackcurrants by lactic acid fermentation and incorporation into yogurt A Review. Antioxidants 9 12 2020 10.3390/antiox9121194
Kubina R. Iriti M. Kabała-Dzik A. Anticancer potential of selected Flavonols: Fisetin, Kaempferol, and quercetin on head and neck cancers Nutrients 13 3 2021 10.3390/nu13030845
Kumar M. Tomar M. Bhuyan D.J. Punia S. Grasso S. Sá A.G.A. …S., Dhumal, S., Senapathy, M., Satankar, V., Anitha, T., Sharma, A., Pandiselvam, R., Amarowicz, R., & Mekhemar, M. Tomato (Solanum lycopersicum L.) seed: A review on bioactives and biomedical activities Biomedicine & Pharmacotherapy 142 2021 10.1016/j.biopha.2021.112018
Kuşçu A. Bulantekin Ö. Determination of phenolics, organic acids, minerals and volatile compounds of jujube (Ziziphus jujuba miller) jam produced by under vacuum evaporation compared with open pan method Journal of Food Measurement and Characterization 15 2 2020 1127 1138 10.1007/s11694-020-00713-9
Lai K.K. Lorca G.L. Gonzalez C.F. Biochemical properties of two Cinnamoyl Esterases purified from a Lactobacillus johnsonii strain isolated from stool samples of diabetes-resistant rats Applied and Environmental Microbiology 75 15 2009 5018 5024 10.1128/aem.02837-08 19502437
Landete J.M. Curiel J.A. Rodríguez H. de Las Rivas B. Muñoz R. Aryl glycosidases from Lactobacillus plantarum increase antioxidant activity of phenolic compounds Journal of Functional Foods 7 2014 322 329 10.1016/j.jff.2014.01.028
Laoué J. Fernandez C. Ormeño E. Plant flavonoids in Mediterranean species: A focus on Flavonols as protective metabolites under climate stress Plants 11 2 2022 10.3390/plants11020172
Lespade L. Bercion S. Theoretical investigation of the effect of sugar substitution on the antioxidant properties of flavonoids Free Radical Research 46 3 2012 346 358 10.3109/10715762.2012.658514 22257113
Li B. Xu L. Liu J. Zhou M. Jiang X. Phloretin ameliorates heart function after myocardial infarction via NLRP3/Caspase-1/IL-1β signaling Biomedicine & Pharmacotherapy 165 2023 10.1016/j.biopha.2023.115083
Li X. Yao Y. Wang Y. Hua L. Wu M. Chen F. Deng Z.-Y. Luo T. Effect of hesperidin supplementation on liver metabolomics and gut microbiota in a high-fat diet-induced NAFLD mice model Journal of Agricultural and Food Chemistry 70 36 2022 11224 11235 10.1021/acs.jafc.2c02334 36048007
Lillo-Pérez S. Guerra-Valle M. Orellana-Palma P. Petzold G. Probiotics in fruit and vegetable matrices: Opportunities for nondairy consumers Lwt 151 2021 10.1016/j.lwt.2021.112106
Lin S. Zhu Q. Wen L. Yang B. Jiang G. Gao H. Chen F. Jiang Y. Production of quercetin, kaempferol and their glycosidic derivatives from the aqueous-organic extracted residue of litchi pericarp with aspergillus awamori Food Chemistry 145 2014 220 227 10.1016/j.foodchem.2013.08.048 24128471
Liu L. Zhang C. Zhang H. Qu G. Li C. Liu L. Biotransformation of polyphenols in apple pomace fermented by β-glucosidase-producing Lactobacillus rhamnosus L08 Foods 10 6 2021 10.3390/foods10061343
Maisto M. Annunziata G. Schiano E. Piccolo V. Iannuzzo F. Santangelo R. …Grieco P. Potential functional snacks: Date fruit bars supplemented by different species of Lactobacillus spp Foods 10 8 2021 10.3390/foods10081760
Marotti I. Bonetti A. Biavati B. Catizone P. Dinelli G. Biotransformation of common bean (Phaseolus vulgaris L.) flavonoid glycosides by Bifidobacterium species from human intestinal origin Journal of Agricultural and Food Chemistry 55 10 2007 3913 3919 10.1021/jf062997g 17439230
Masek A. Chrzescijanska E. Latos M. Determination of antioxidant activity of Caffeic acid and -Coumaric acid by using electrochemical and spectrophotometric assays International Journal of Electrochemical Science 11 12 2016 10644 10658 10.20964/2016.12.73
Mierziak J. Kostyn K. Kulma A. Flavonoids as important molecules of plant interactions with the environment Molecules 19 10 2014 16240 16265 10.3390/molecules191016240 25310150
Miyake Y. Yamamoto K. Osawa T. Metabolism of antioxidant in lemon fruit (Citrus Limon B-URM. F.) by human intestinal bacteria Journal of Agricultural and Food Chemistry 45 10 1997 3738 3742 10.1021/jf970403r
Mota J.C. Almeida P.P. Freitas M.Q. Stockler-Pinto M.B. Guimarães J.T. Far from being a simple question: The complexity between in vitro and in vivo responses from nutrients and bioactive compounds with antioxidant potential Food Chemistry 402 2023 10.1016/j.foodchem.2022.134351
Mueller M. Zartl B. Schleritzko A. Stenzl M. Viernstein H. Unger F.M. Rhamnosidase activity of selected probiotics and their ability to hydrolyse flavonoid rhamnoglucosides Bioprocess and Biosystems Engineering 41 2 2017 221 228 10.1007/s00449-017-1860-5 29124335
Neelam K. Dey S. Sim R. Lee J. Au Eong K.-G. Fructus lycii: A natural dietary supplement for amelioration of retinal diseases Nutrients 13 1 2021 10.3390/nu13010246
Nyambe-Silavwe H. Villa-Rodriguez J.A. Ifie I. Holmes M. Aydin E. Jensen J.M. Williamson G. Inhibition of human α-amylase by dietary polyphenols Journal of Functional Foods 19 2015 723 732 10.1016/j.jff.2015.10.003
Olszowy M. What is responsible for antioxidant properties of polyphenolic compounds from plants? Plant Physiology and Biochemistry 144 2019 135 143 10.1016/j.plaphy.2019.09.039 31563754
Ongay K.K. Granato D. Barreto G.E. Comparison of antioxidant capacity and network pharmacology of Phloretin and Phlorizin against Neuroinflammation in traumatic brain injury Molecules 28 3 2023 10.3390/molecules28030919
Panche A.N. Diwan A.D. Chandra S.R. Flavonoids: An overview Journal of Nutritional Science 5 2016 10.1017/jns.2016.41
Rehman K. Khan I.I. Akash M.S.H. Jabeen K. Haider K. Naringenin downregulates inflammation-mediated nitric oxide overproduction and potentiates endogenous antioxidant status during hyperglycemia Journal of Food Biochemistry 44 10 2020 10.1111/jfbc.13422
Reverón I. de Las Rivas B. Matesanz R. Muñoz R. López de Felipe F. Molecular adaptation of Lactobacillus plantarum WCFS1 to gallic acid revealed by genome-scale transcriptomic signature and physiological analysis Microbial Cell Factories 14 1 2015 10.1186/s12934-015-0345-y
RiceEvans C.A. Miller N.J. Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids Free Radical Biology and Medicine 20 7 1996 933 956 10.1016/0891-5849(95)02227-9 8743980
Rodríguez H. Landete J.M. Rivas B.D.L. Muñoz R. Metabolism of food phenolic acids by Lactobacillus plantarum CECT 748T Food Chemistry 107 4 2008 1393 1398 10.1016/j.foodchem.2007.09.067
Rodríguez-Daza M.C. Pulido-Mateos E.C. Lupien-Meilleur J. Guyonnet D. Desjardins Y. Roy D. Polyphenol-mediated gut microbiota modulation: Toward prebiotics and further Frontiers in Nutrition 8 2021 10.3389/fnut.2021.689456
Rzepecka-Stojko A. Stojko J. Kurek-Górecka A. Górecki M. Kabała-Dzik A. Kubina R. Moździerz A. Buszman E. Polyphenols from bee pollen: Structure, absorption Metabolism and Biological Activity. Molecules 20 12 2015 21732 21749 10.3390/molecules201219800 26690100
Samsonowicz M. Regulska E. Spectroscopic study of molecular structure, antioxidant activity and biological effects of metal hydroxyflavonol complexes Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 173 2017 757 771 10.1016/j.saa.2016.10.031 27792987
Sánchez-Patán F. Tabasco R. Monagas M. Requena T. Peláez C. Moreno-Arribas M.V. Bartolomé B. Capability of Lactobacillus plantarum IFPL935 to catabolize Flavan-3-ol compounds and complex phenolic extracts Journal of Agricultural and Food Chemistry 60 29 2012 7142 7151 10.1021/jf3006867 22646528
Sarker U. Oba S. Nutraceuticals, phytochemicals, and radical quenching ability of selected drought-tolerant advance lines of vegetable amaranth BMC Plant Biology 20 1 2020 10.1186/s12870-020-02780-y
Sato Y. Itagaki S. Kurokawa T. Ogura J. Kobayashi M. Hirano T. Sugawara M. Iseki K. In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid International Journal of Pharmaceutics 403 1–2 2011 136 138 10.1016/j.ijpharm.2010.09.035 20933071
Septembre-Malaterre A. Boumendjel A. Seteyen A.-L.S. Boina C. Gasque P. Guiraud P. Sélambarom J. Focus on the high therapeutic potentials of quercetin and its derivatives Phytomedicine Plus 2 1 2022 10.1016/j.phyplu.2022.100220
Serrano J. Puupponen-Pimiä R. Dauer A. Aura A.-M. Saura-Calixto F. Tannins: Current knowledge of food sources, intake, bioavailability and biological effects Molecular Nutrition & Food Research 53 S2 2009 S310 S329 10.1002/mnfr.200900039 19437486
Shahidi F. Ambigaipalan P. Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review Journal of Functional Foods 18 2015 820 897 10.1016/j.jff.2015.06.018
Shen N. Wang T. Gan Q. Liu S. Wang L. Jin B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity Food Chemistry 383 2022 10.1016/j.foodchem.2022.132531
Singh A.K. Kim J.Y. Lee Y.S. Phenolic compounds in active packaging and edible films/coatings: Natural bioactive molecules and novel packaging ingredients Molecules 27 21 2022 10.3390/molecules27217513
Staniek A. Bouwmeester H. Fraser P.D. Kayser O. Martens S. Tissier A. …Warzecha H. Natural products - modifying metabolite pathways in plants Biotechnology Journal 8 10 2013 1159 1171 10.1002/biot.201300224 24092673
Subramanyam R. Takahashi T. Nagatoishi S. Kuroda D. Tsumoto K. Thermodynamic and computational analyses reveal the functional roles of the galloyl group of tea catechins in molecular recognition PLoS One 13 10 2018 10.1371/journal.pone.0204856
Tkacz K. Wojdyło A. Michalska-Ciechanowska A. Turkiewicz I.P. Lech K. Nowicka P. Influence carrier agents, drying methods, storage time on Physico-chemical properties and bioactive potential of Encapsulated Sea buckthorn juice powders Molecules 25 17 2020 10.3390/molecules25173801
Trigo J.P. Alexandre E.M.C. Saraiva J.A. Pintado M.E. High value-added compounds from fruit and vegetable by-products – Characterization, bioactivities, and application in the development of novel food products Critical Reviews in Food Science and Nutrition 60 8 2019 1388 1416 10.1080/10408398.2019.1572588 30740995
Tsangalis D. Ashton J.F. McGill A.E.J. Shah N.P. Enzymic transformation of isoflavone phytoestrogens in soymilk by beta-glucosidase-producing bifidobacteria Journal of Food Science 67 8 2002 3104 3113 10.1111/j.1365-2621.2002.tb08866.x
Vianello R. Maksić Z.B. Triadic analysis of substituent effects—Gas-phase acidity of Para-substituted phenols Tetrahedron 62 14 2006 3402 3411 10.1016/j.tet.2006.01.049
Vitaglione P. Napolitano A. Fogliano V. Cereal dietary fibre: A natural functional ingredient to deliver phenolic compounds into the gut Trends in Food Science & Technology 19 9 2008 451 463 10.1016/j.tifs.2008.02.005
Wang C. Wang Y. Teng Y. Zhang Y. Win-win cooperation between plant substrates and probiotics: Revealing biotransformation and bioactive metabolites in Elaeagnus moorcroftii wall. Ex Schlecht fermented by Lacticaseibacillus paracasei YL-29 Lwt 204 2024 116442 10.1016/j.lwt.2024.116442
Wang J. Lou J. Luo C. Zhou L. Wang M. Wang L. Phenolic compounds from Halimodendron halodendron (pall.) Voss and their antimicrobial and antioxidant activities International Journal of Molecular Sciences 13 9 2012 11349 11364 10.3390/ijms130911349 23109858
Wang L. Li N. Yu S.Q. Zhou J.W. Enhancing caffeic acid production in Escherichia coli by engineering the biosynthesis pathway and transporter Bioresource Technology 368 2023 10.1016/j.biortech.2022.128320
Wang Y. Li H. Li X. Wang C. Li Q. Xu M. Guan X. Lan Z. Ni Y. Zhang Y. Widely targeted metabolomics analysis of enriched secondary metabolites and determination of their corresponding antioxidant activities in Elaeagnus angustifolia var. orientalis (L.)Kuntze fruit juice enhanced by Bifidobacterium animalis subsp. Lactis HN-3 fermentation Food Chemistry 374 2022 10.1016/j.foodchem.2021.131568
Wang Y. Wang C. Lan Z. Teng Y. Ni Y. Zhang Y. The biotransformation and influence on the functional activities of metabolites during the fermentation of Elaeagnus moorcroftii Wall.Ex Schlecht Juice by Bifidobacterium animalis subsp. lactis HN-3. Foods 13 6 2024 10.3390/foods13060926
Wojtunik-Kulesza K. Oniszczuk A. Oniszczuk T. Combrzyński M. Nowakowska D. Matwijczuk A. Influence of in vitro digestion on composition, bioaccessibility and antioxidant activity of food polyphenols—A non-systematic review Nutrients 12 5 2020 10.3390/nu12051401
Wright J.S. Johnson E.R. DiLabio G.A. Predicting the activity of phenolic antioxidants: Theoretical method, analysis of substituent effects, and application to major families of antioxidants Journal of the American Chemical Society 123 6 2001 1173 1183 10.1021/ja002455u 11456671
Wu C. Li T. Qi J. Jiang T. Xu H. Lei H. Effects of lactic acid fermentation-based biotransformation on phenolic profiles, antioxidant capacity and flavor volatiles of apple juice Lwt 122 2020 10.1016/j.lwt.2020.109064
Xiao J. Dietary flavonoid Aglycones and their glycosides: Which show better biological significance? Critical Reviews in Food Science and Nutrition 00-00 2015 10.1080/10408398.2015.1032400
Xiao Z. Wang Y. Wang J. Li P. Ma F. Structure-antioxidant capacity relationship of dihydrochalcone compounds in Malus Food Chemistry 275 2019 354 360 10.1016/j.foodchem.2018.09.135 30724207
Xu D. Wang N. Rinne M. Ke W. Weinberg Z.G. Da M. …Guo X. The bacterial community and metabolome dynamics and their interactions modulate fermentation process of whole crop corn silage prepared with or without inoculants Microbial Biotechnology 14 2 2020 561 576 10.1111/1751-7915.13623 32627363
Yang A.Y. Choi H.J. Kim K. Leem J. Antioxidant, Antiapoptotic, and anti-inflammatory effects of Hesperetin in a mouse model of lipopolysaccharide-induced acute kidney injury Molecules 28 6 2023 10.3390/molecules28062759
Yang H.-L. Chen S.-C. Senthil Kumar K.J. Yu K.-N. Lee Chao P.-D. Tsai S.-Y. …Hseu Y.-C. Antioxidant and anti-inflammatory potential of Hesperetin metabolites obtained from Hesperetin-administered rat serum: An ex vivo approach Journal of Agricultural and Food Chemistry 60 1 2011 522 532 10.1021/jf2040675 22098419
Yang J. Chen J. Hao Y. Liu Y. Identification of the DPPH radical scavenging reaction adducts of ferulic acid and sinapic acid and their structure-antioxidant activity relationship Lwt 146 2021 10.1016/j.lwt.2021.111411
Yue Q. Xu L. Xiang G. Yu X. Yao Y. Characterization of gene expression profile, phenolic composition, and antioxidant capacity in red-fleshed grape berries and their wines Journal of Agricultural and Food Chemistry 66 27 2018 7190 7199 10.1021/acs.jafc.8b01323 29920074
Zhang N. Zhang W. Guo X. Liu J. Li S. Zhang H. Fan B. Genistein protects against hyperglycemia and fatty liver disease in diet-induced prediabetes mice via activating hepatic insulin signaling pathway Frontiers in Nutrition 9 2022 10.3389/fnut.2022.1072044
Zhu Y. Wang Z. Zhang L. Optimization of lactic acid fermentation conditions for fermented tofu whey beverage with high-isoflavone aglycones Lwt 111 2019 211 217 10.1016/j.lwt.2019.05.021
ŽivanoviĆ B. VidoviĆ M. MiliĆ KomiĆ S. JovanoviĆ L. KolarŽ P. Morina F. VeljoviĆ JovanoviĆ S. Contents of phenolics and carotenoids in tomato grown underpolytunnels with different UV-transmission rates Turkish Journal of Agriculture and Forestry 41 2017 113 120 10.3906/tar-1612-56
Xue Y. Liu Y. Xie Y. Cong C. Wang G. An L. Teng Y. Chen M. Zhang L. Antioxidant activity and mechanism of dihydrochalcone C-glycosides: Effects of C-glycosylation and hydroxyl groups Phytochemistry 179 2020 10.1016/j.phytochem.2020.112393
