Unravelling Potential Health-Beneficial Properties of Corema album Phenolic Compounds: A Systematic Review

Corema (C.) album belongs to the family Ericaceae and can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic coast. C. album berries have been used for centuries in traditional medicine. Recent studies have revealed that not only the berries but also the leaves have relevant antioxidant, antiproliferative, and anti-inflammatory properties, bringing this plant to the forefront of discussion. A systematic review of the literature was carried out to summarize the phenolic compounds and bioactive properties identified in C. album berries and leaves and to search for research gaps on this topic. The search was conducted in three electronic databases (PubMed, SCOPUS, and Web of Science) using PRISMA methodology. The inclusion criteria were the chemical compositions of the berries, leaves, or their extracts and their bioactive properties. The exclusion criteria were agronomic and archaeological research. The number of studies concerning phenolic compounds’ composition and the bioactive properties of C. album berries and leaves is still limited (11 articles). However, the variety of polyphenolic compounds identified make it possible to infer new insights into their putative mechanism of action towards the suppression of NF-kB transcription factor activation, the modulation of inflammatory mediators/enzymes, the induction of apoptosis, the modulation of mitogen activated protein kinase, cell cycle arrest, and the reduction of oxidative stress. These factors can be of major relevance concerning the future use of C. album as nutraceuticals, food supplements, or medicines. Nevertheless, more scientific evidence concerning C. album’s bioactivity is required.


Introduction
Plants as natural medicinal agents have been used since ancient civilizations to treat diseases such as cancer, inflammation, fever, etc. Their value as sources of molecules with therapeutic potential has been recognized and, recently, they have gained much attention in the drug discovery field, since many drugs from natural sources have been emerging, currently constituting up to 50% of all drugs in the pharmaceutical industry [1].
Corema belongs to the family Ericaceae and includes two species: Corema conradii and Corema album. The first is native to the Northwest coast of the USA and the latter can be found in the Iberian Peninsula, especially on the coastal areas facing the Atlantic [2]. In addition, Corema conradii differs from Corema album mainly by its very small fruit that lacks fleshiness and is covered with oily appendages [3]. Both species are coastal shrubs with sexual dimorphism. Concerning Corema album, this plant is a densely branched and longliving shrub with evergreen leaves [4]. While male flowers are bigger and have reddish petals and stamens with red-purple anthers, female flowers are smaller with pink-reddish

Literature Search Process
From the 74 records identified, only 34 remained for the title and abstract screening. The remaining reports were duplicated articles, reviews, or opinion articles ( Figure 1). Then, 21 articles were excluded based on the title and abstract reviews because these studies involved agronomic or archaeological studies and did not include the chemical composition of the berries, leaves, or of the respective extracts. The remaining 13 papers proceeded to the full text review. From those, only 11 were about phenolic compounds' identification in C. album; thus, they were considered eligible for the data extraction [7,[10][11][12][13][14][15][16][17][18][19].

Phenolic Compounds in Berries and Leaves from C. album
Both berries and leaves from C. album revealed a rich content in several phenolic compounds, which are summarized in Tables 1 and 2, respectively. The phenolic compounds were divided into three main groups, namely, phenolic acids, flavonoids, and stilbenes, according to their structural similarities. Phenolic acids are commonly divided into two groups: the benzoic acids (C6-C1) with seven carbon atoms and cinnamic acids (C6-C3) with nine carbon atoms. Usually, these compounds occur predominantly in their

STILBENES
Stilbenes and derivatives [15,16] In C. album leaves, another three predominant compounds were identified: 2′,4′-dihydroxydihydrochalcone, 2′-methoxy-4′-hydroxydihydrochalcone [17], and 2′,4′-dihydroxychalcone [18] (Figure 2). These compounds are chalcones, which are intermediates in the biosynthesis of flavonoids and isoflavonoids [19]. Both the berries and leaves from C. album revealed interesting bioactive properties, which are summarized in Figure 3. Scientific information regarding C. album's bioactive activities is very scarce and is mostly focused on the beneficial healthy properties of its berries. C. album berries were described to have antimicrobial [11] and antioxidant activities [7,11,14,15]. Moreover, this antioxidant activity seems to be increased after simulated digestion [13] and can protect against oxidative stress (yeast: [13]). C. album berries have also been described as having cytotoxic effects in Caco-2 cells when the concentration of the extract exceeds 8% [14]. There is also evidence that these berries are able to inhibit lipid peroxidation and acetylcholinesterase activation [11].
The bioactivity of C. album leaves has been studied regarding its cytotoxicity in yeast [15,20]; colon carcinoma cells (HT-29 cells: [17]), an effect that seems to be mediated through G2/M cell cycle arrest [18,21]; and apoptosis [18]. The cytotoxicity observed was reported to be triggered by the pro-oxidant activity of at least two different hydroxydihydrochalcones found in these leaves [17]. In contrast, a study using an enriched fraction of polyphenols from C. album leaves claimed that this extract has promising cytoprotective effects, modulating key events in Parkinson's disease pathogenesis. Some other reports also describe C. album leaves as having antioxidant effects [15,20]. Both the berries and leaves from C. album revealed interesting bioactive properties, which are summarized in Figure 3. Scientific information regarding C. album's bioactive activities is very scarce and is mostly focused on the beneficial healthy properties of its berries. C. album berries were described to have antimicrobial [11] and antioxidant activities [7,11,14,15]. Moreover, this antioxidant activity seems to be increased after simulated digestion [13] and can protect against oxidative stress (yeast: [13]). C. album berries have also been described as having cytotoxic effects in Caco-2 cells when the concentration of the extract exceeds 8% [14]. There is also evidence that these berries are able to inhibit lipid peroxidation and acetylcholinesterase activation [11].

STI
In C. album leaves, another three predominant compounds were identified: 2′,4′-dihydroxydihydrochalcone, 2′-methoxy-4′-hydroxydihydrochalcone [17], and 2′,4′-dihydroxychalcone [18] (Figure 2). These compounds are chalcones, which are intermediates in the biosynthesis of flavonoids and isoflavonoids [19]. Both the berries and leaves from C. album revealed interesting bioactive properties, which are summarized in Figure 3. Scientific information regarding C. album's bioactive activities is very scarce and is mostly focused on the beneficial healthy properties of its berries. C. album berries were described to have antimicrobial [11] and antioxidant activities [7,11,14,15]. Moreover, this antioxidant activity seems to be increased after simulated digestion [13] and can protect against oxidative stress (yeast: [13]). C. album berries have also been described as having cytotoxic effects in Caco-2 cells when the concentration of the extract exceeds 8% [14]. There is also evidence that these berries are able to inhibit lipid peroxidation and acetylcholinesterase activation [11].
The bioactivity of C. album leaves has been studied regarding its cytotoxicity in yeast [15,20]; colon carcinoma cells (HT-29 cells: [17]), an effect that seems to be mediated through G2/M cell cycle arrest [18,21]; and apoptosis [18]. The cytotoxicity observed was reported to be triggered by the pro-oxidant activity of at least two different hydroxydihydrochalcones found in these leaves [17]. In contrast, a study using an enriched fraction of polyphenols from C. album leaves claimed that this extract has promising cytoprotective effects, modulating key events in Parkinson's disease pathogenesis. Some other reports also describe C. album leaves as having antioxidant effects [15,20]. The bioactivity of C. album leaves has been studied regarding its cytotoxicity in yeast [15,20]; colon carcinoma cells (HT-29 cells: [17]), an effect that seems to be mediated through G2/M cell cycle arrest [18,21]; and apoptosis [18]. The cytotoxicity observed was reported to be triggered by the pro-oxidant activity of at least two different hydroxydihydrochalcones found in these leaves [17]. In contrast, a study using an enriched fraction of polyphenols from C. album leaves claimed that this extract has promising cytoprotective effects, modulating key events in Parkinson's disease pathogenesis. Some other reports also describe C. album leaves as having antioxidant effects [15,20].

Discussion
A wide variety of phenolic compounds were identified in the berries and leaves from C. album, but few studies explore the biological activities and signalling events triggered by their extracts. Nevertheless, their physical-chemical profile and high phenolic content supports a potential market expansion [22]. In particular, their enriched composition in phenolic compounds, both in the berries and leaves, bring valuable insights into their putative mechanism of action. Currently, it is well accepted that phenolic compounds can modulate the activity of several enzymes, kinases, and transcriptional factors involved in the modulation of biological processes such as oxidative stress, inflammation, cell proliferation, apoptosis, and cell death [21,23]. In accordance, the phenolic compounds previously identified in C. album berries and leaves are known to present a modulatory capability in several signalling pathways, signal mediators or enzymes, and/or kinases (Tables 3 and 4). Thus, these mechanisms can be indirectly associated with C. album. Table 3. Protective mechanisms ascribed to phenolic compounds identified in C. album berries.

Compound
Protective Mechanisms (s) Experimental Model Ref.
Mouse macrophages [24] p-coumaric acid   Note that the phenolic compounds may exert their biological effects through signalling pathways separately or in a sequential way. Moreover, a putative crosstalk between these pathways should not be overlooked.
In the inflammatory process, enzymes such as COX-2 and xanthine oxidase (XO) play a key role, and their levels of expression are modulated during the inflammation's progression. The polyphenols identified in the berries of C. album were shown to be capable of suppressing/reducing the activity of XO and/or COX-2: through phenolic acids such as chlorogenic [37] or p-hydroxybenzoic [24] acids or by flavonols such as quercetin-3-Ohexoside [48].

Induction of Apoptosis
Apoptotic regulation involves numerous proteins such as families of p53, bcl-2-like protein 4 (BAX), and caspases [23]. Several flavonols identified in C. album berries seem to be able to induce apoptosis: anthocyanins, such as delphinidin-3-O-hexoside can induce apoptosis by modifying BAX, caspase 3, and Bcl-2 proteins [64]; quercetin-3-O-hexoside seems to be able to promote apoptosis, enhancing the expression of p53 and BAX proteins [46]; and kaempherol-3-O-hexoside was associated with the induction of apoptosis through the upregulation of caspase 3 and the downregulation of Bcl-2 [41,43,44]. Another flavonoid identified in C. album leaves, pinocembrin, was reported to be able to induce apoptosis in many different types of cancer cells [87].

Modulation of Mitogen Activated Protein Kinase
Since mitogen-activated protein kinase (MAPK) pathways are a convergent avenue involved in numerous biological processes, changes in MAPK activity are of utmost importance. p-coumaric acid has been demonstrated to have both antioxidant and antiinflammatory properties since it is capable of preventing oxidative stress-induced apoptosis in human epithelial cells through the modulation of the MAPK signalling pathway [88]. Other phenolic acids identified in C. album berries, such as ferulic acid [28,29], p-hydroxybenzoic acid [24], and neochlorogenic acid [36,40], can also prevent MAPK activation. In the leaves, some polyphenols have also been reported to exert modulatory effects on MAPK pathways, including quercetin rhamnosyl hexoside [79] and procyanidins [73].

Cell Cycle Arrest
The deregulation of the cell cycle is associated with carcinogenesis and phenolic compounds are known to be capable of inhibiting, in a variety of cell types, different cell phases (G1, S, S/G2, and G2) [21,89]. C. album flavonols, identified in the berries, are capable of changing the cell cycle; kaempherol-O-hexoside causes cell cycle arrest at G2 [43,45] while rutin (a quercetin derivative) induces G2/M cell cycle arrest [54].

Zeduction of Oxidative Stress
The antioxidant properties ascribed to C. album seem to be mediated by an upregulation of glutathione and cellularly antioxidant enzymes, as well as by the suppression of reactive oxygen species (ROS) generation [90,91]. Indeed, berries usually exhibit an enriched content of phenolic compounds commonly associated with their high antioxidant properties [15]. Such properties are also exhibited by C. album berries since they have an anthocyanin content that can inhibit the intracellular content of ROS [63][64][65]. In these berries, gallic acid, chlorogenic acid derivatives, and flavonols have also been identified as having antioxidant properties [15,24,51,53].
Some compounds identified in the leaves of C. album also have antioxidant properties: myricetin derivatives [74,75], reported as a modulator of nitric oxide (NO) generation and of iNOS activity; stilbene derivatives [92]; and prenylated chalcone glycoside, which showed radical scavenging activity [93].

Conclusions and Future Perspectives
Although a wide variety of phenolic compounds have been identified in the berries and leaves from C. album, at the time of this review (15th Jun 2022), there are scarce scientific data regarding the potential health benefits exerted by C. album. Only nine studies have evaluated the biological properties of the berries, leaves, or respective extracts of this plant. Nevertheless, the discussion section evidences that their rich composition in phenolic compounds is promising when considering their health benefits and therapeutic potential. The phenolic compounds identified in C. album leaves and berries can modulate several pathophysiological processes, namely, inflammation, oxidative stress, carcinogenesis, etc., and this plant may also be attractive to the pharmaceutical industry with respect to generating new drug(s), nutraceuticals, or supplements, but more scientific evidence concerning C. album's bioactivity is required.