Introduction

Grape pomace (GP) is essentially a solid organic waste containing grape skin, stem, pulp, and seed, which are deliberately discarded in various grape processing industries, such as wine or juice manufacturing (Peixoto et al., 2018; Spanghero et al., 2009). Generally, GP accounts for 25–35% of the total weight of grape processed (Oliveira and Duarte, 2016; Teixeira et al., 2014). GP contains significant amounts of dietary fiber and diverse phytochemicals that possess potent antioxidant activities, as determined in various studies (Fig. 1) (Rockenbach et al., 2011; Silva et al., 2018; Souquet et al., 2000; Yu and Ahmedna, 2013). In general, grape polyphenolics vary in chemical structure and activity and may be fundamentally categorized into two major classes: flavonoids and non-flavonoids (Garrido-Bañuelos et al., 2019). Flavonoids, the most abundant polyphenolics in grape, are distributed throughout the peel, seed, and stem, and include anthocyanins, proanthocyanidins (procyanidins and prodelphinidins), and flavan-3-ols (Cotoras et al., 2014; Garrido-Bañuelos et al., 2019). In contrast, hydroxycinnamic acids, the most abundant non-flavonoids in wine, include caftaric acid and coutaric acid (Lu and Foo, 1999). Most of these polyphenolic compounds occur as glycosylated derivatives in plants and foods and undergo enzymatic transformations in the gut before intestinal absorption (Bang et al., 2015; Marín et al., 2015).

Fig. 1
figure 1

Major phytochemicals present in grape processing by-products

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In vinification, bioactive polyphenolic compounds are partially extracted while the majority remain as glycosides embedded in the grape peel, pulp, or seed (Chafer et al., 2005). Additionally, the amount of polyphenols released into the final wine product greatly depends on the fermentation process, suggesting that an insufficient extraction technique prevents the liberation of phytochemicals that are essentially confined in grape cell walls and pulp cell vacuoles (Adams, 2006; Canals et al., 2005; Yacco et al., 2016). Despite the notable abundance of antioxidant phytochemicals in GP and intensive research efforts involving extraction strategies to optimize the recovery of antioxidants from GP for food or drug development (Otero-Pareja et al., 2015; Romero-Perez et al., 2001), enormous quantities of GP are still being disposed worldwide annually (Rondeau et al., 2013). In the context of the current environmental concerns, the conversion of GP to a safe and usable form introduces a practical approach to sustainable environmental waste management (Boussetta et al., 2009).

The abundance of bioactive polyphenols and minor quantities of other essential phytochemicals, such as carotenoids (lutein and β-carotene), especially the volatile ones, in GP, is influenced predominantly by converging factors, like the type of cultivar, climate, topography, and soil quality (Parker et al., 2011; Yuan and Qian, 2016). The techniques for extracting polyphenols from GP, considering environmental and economic implications, as mentioned above, have been reflected in various methodologies with a common objective, that is, to explore suitable conditions for maximum recovery of bioactive compounds from different grape varieties (Chafer et al., 2005; Cho et al., 2006; Meini et al., 2019; Otero-Pareja et al., 2015; Pintać et al., 2018; Romero-Perez et al., 2001). Conventional and emerging strategies for the extraction of bioactive components from GP operate via different mechanisms, and extraction techniques considering crucial parameters, such as temperature, pressure, length of extraction time, type of solvent, physicochemical characteristics of the source, operational cost, and environmental effects, have been explored (Castro-López et al., 2016).

GP extract has been extensively studied for its wide range of activities, including cardioprotective, anti-cancer, anti-inflammatory, anti-aging, anti-microbial, and other health-promoting properties (Peixoto et al., 2018; Yu and Ahmedna, 2013). Given that the bioactive components of GP extract are strongly correlated with a broad spectrum of beneficial effects, exploring the underlying mechanisms could lead to promising functional applications. Collectively, this review discusses the compelling potential of GP-derived bioactive polyphenols in disease prevention and/or therapy, considering critical factors, such as origin, variety, and polyphenolic composition.

Cardiovascular and metabolic health

In the past years, moderate regular intake of red wine has often been depicted in the prevention or amelioration of risk of coronary ailments (Avellone et al., 2006; Leikert et al., 2002; Ribeiro et al., 2016). However, GP (Vitis vinifera L. Syrah, Brazil) extract has been reported to contain significantly greater total anthocyanin, flavonol, stilbene, and flavanol contents than the red wine from which it is produced and, thus, most likely also possesses the biological activities of wine (de Oliveira et al., 2017). Accordingly, the levels of very-low-density lipoprotein cholesterol and triacylglycerols in Wistar rats were suppressed more effectively by GP extract compared to its wine counterpart, suggesting that GP could be used in food and nutraceutical industries as an inexpensive source of bioactive phenolics against coronary and other age-associated ailments (de Oliveira et al., 2017). Likewise, the symptoms of cardiovascular pathologies were significantly mitigated by the dietary administration of powdered GP (V. vinifera L. Malbec variety, Argentina) through concomitant induction of endothelial-derived nitric oxide in high-fat-fructose-fed Wistar rats (Perdicaro et al., 2017). The cardioprotective effect of GP observed could be attributed to the abundance of significant quantities of flavonoids (flavanols, tannins, and flavonols), non-flavonoids (hydroxybenzoic acids, hydroxycinnamic acids, stilbenes, and phenylethanol analogs), flavanols [(+)-catechin, (−)-epicatechin and (−)-epicatechin gallate], and anthocyanins (malvidin 3-O-glucoside, malvidin 3-O-p-coumaroylglucoside, and petunidin 3-O-glucoside) (Perdicaro et al., 2017).

The long-term cardioprotective effect of a polyphenol-rich mixture of Cabernet Sauvignon, Marselan, and Syrah varieties was also confirmed using middle-aged Wistar rats (Chacar et al., 2019). Among the polyphenols identified in the extract were malvidin, delphinidin, rutin, quercetin, catechin, coumaric acid, kaempferol, and trans-cinnamic acid, which could explain the prevention of hypertrophy, inflammation, fibrosis, and cardiomyocyte apoptosis observed upon administration of the extract (Chacar et al., 2018; 2019). In addition, the potential in vivo cardioprotective effect of fresh (high condensed tannins and anthocyanin contents) and fermented (high polyphenolic content) GP extracts from V. vinifera L. Pinot noir cultivar from Romania was demonstrated (Balea et al., 2018). In accordance with other studies, GP polyphenols could promote cardioprotection via different mechanisms. For instance, GP treatment effectively attenuated myocardial infarction in rats by reducing serum oxidative biomarkers, such as malondialdehyde, and increasing the serum total oxidative status and antioxidant reserves (Annapurna et al., 2009; Balea et al., 2018).

Furthermore, the effect of supplementing GP (V. vinifera L. Pinot noir variety, Poland) in a baking product formulation was demonstrated by measuring the levels of Nε-(carboxymethyl)lysine (CML), a stable marker of advanced glycation end-products (Mildner-Szkudlarz et al., 2015). CML is generated by excessive thermal treatment in food preparations and is correlated with numerous variable pathologies, such as diabetes, atherosclerosis, Alzheimer’s disease, and normal aging (Holik et al., 2018; Nerlich and Schleicher, 1999). Although further studies are required to identify the specific phenolic compounds responsible for preventing CML formation in the baking product formulation, the study demonstrated the propitious preliminary value of GP for food valorization and as an anti-aging agent (Mildner-Szkudlarz et al., 2015).

Evidence for the in vivo anti-inflammatory, antioxidant, and anti-hypertensive properties of GP (da Costa et al., 2017; Lanzi et al., 2016; Rasines-Perea et al., 2018) emphasize that high-fat diets associated with obesity and other metabolic disorders can be reversed through diets enriched with phytochemicals found in GP. To further elucidate the potential efficacy of GP in the prevention and therapy of obesity-related metabolic syndrome, GP (V. vinifera L.) of Brazilian origin was extracted and co-administered with a high-fat diet to male mice (da Costa et al., 2017). In agreement with other studies, antioxidant-rich GP extract mediated insulin sensitivity and glucose homeostasis, attenuated oxidative stress by lowering the malondialdehyde and carbonyl levels in the muscle and adipose tissues, and mitigated inflammatory markers (tumor necrosis factor-α and interleukin-6) (da Costa et al., 2017; Li et al., 2016). The beneficial impacts of GP extract could be attributed to its anthocyanidin-rich composition, including peonidin-3-O-glucoside, petunidin-3-O-glucoside, malvidin-3-O-glucoside, and malvidin-3-(6-O-trans-p-coumaryl)-5-O-diglucoside (da Costa et al., 2017). Collectively, the antioxidant-rich GP extract exhibits promising applications in coronary care and overall protection from serious risks of metabolic syndromes.

Cancer prevention

Along with studies relating dietary polyphenols to cardiac health and metabolic health, research efforts are increasingly focusing on the anti-cancer properties of polyphenols (Khurana et al., 2013; Petrovski et al., 2011). The major chemopreventive mechanisms of grape-derived polyphenols may include the alteration of phase I and II drug-metabolizing enzymes; antioxidant properties; inhibition of protein kinases; blocking of receptor-mediated functions; attenuation of protease activities; alteration of cell-cycle checkpoint controls, transcription factor expression and apoptosis; and inhibition of angiogenesis, invasion, and metastasis (Dashwood, 2007; Kundu and Surh, 2008). Resveratrol is a polyphenolic compound of great abundance in grape peel. This compound has been shown to inhibit chemical carcinogenesis, a process consisting of initiation, promotion, and progression, through induction of phase II detoxifying enzymes via activation of the Nrf2/Keap1 signaling pathway, one of the most important cell defense and survival pathways (Jang et al., 1997). In addition, resveratrol induces apoptosis in prostate cancer cell lines, by upregulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4, and TRAIL-R2/DR5 while downregulating the expression of Bcl-2, Bcl-XL, and survivin (Shankar et al., 2007). Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents, and gamma-radiation (Radhakrishnan et al., 2011; Yu and Ahmedna, 2013).

There is consistent evidence to support the multi-targeted putative cancer preventive property of phytochemicals in GP (Del Pino-García et al., 2017; Luo et al., 2017; Mokni et al., 2016). In cancer chemoprevention, chronic administration of phytochemicals may impede the occurrence of cell malignancy through attenuation of reactive oxygen (ROS)/nitrogen species, which could result in irreversible DNA damage and/or inhibition of cancer cell proliferation (Landis-Piwowar and Iyer, 2014; Manson et al., 2000; Steward and Brown, 2013). Such anti-proliferative and anti-genotoxic effects of red wine pomace (V. vinifera cv. Tempranillo variety, Spain) seasonings against colon cancer cells have emphasized the relevant contribution of hydroxybenzoic acids and hydroxycinnamic acids (Del Pino-García et al., 2017).

Current strategies in skin cancer prevention and therapy also take advantage of the potential of GP-derived polyphenol-rich extracts against cancer invasiveness and metastasis (Chojnacka and Lewandowska, 2018; Mohansrinivasan et al., 2015). In a skin cancer cell-line model, grape (V. vinifera L. Burgund Mare variety, Romania) seed extract rich in proanthocyanidins, anthocyanidins, and catechins significantly alleviated apoptosis, lipid peroxide levels, lesion scores, and DNA damage (Perde-Schrepler et al., 2013). Furthermore, the novel integration of GP extract (V. vinifera) as a stabilizing agent in the synthesis of gold nanoparticles (AuNPs) significantly inhibited cancer cell proliferation and induced cell death by inducing the generation of ROS and disrupting the mitochondrial membrane potential (Nirmala et al., 2017). The remarkable protective function against skin cancer and the synergistic action of GP-derived polyphenols with AuNPs displayed the potential applications of GP extract in skin care and drug delivery, respectively (Nirmala et al., 2017; Perde-Schrepler et al., 2013).

Skin health

With the growing consumer concern about premature skin aging, the incorporation of anti-aging products into the diet and lifestyle has become widespread in recent years. Consequently, strategies to preserve the external appearance of the skin, such as the development of skin anti-aging formulations, are constantly emerging (Ganceviciene et al., 2012).

Skin aging is a complex natural process involving the breakdown of collagen and elastin fibers, which maintain the integrity of the extracellular matrix (ECM) (Fisher et al., 1996). Excessive degradation of the ECM, due to multiple factors stimulating the action of proteases (collagenases and elastases), leads to skin wrinkling and accelerated skin aging. Considering the adverse role of proteases in skin health, collective efforts to explore the inhibitory capacity of GP-derived polyphenols that target collagenase and elastase have been conducted (Maidin et al., 2018; Wittenauer et al., 2015). A comparison of the GP (V. vinifera L. Barbera variety, Italy) extracts obtained using water and ethanol as separate solvents exhibited different polyphenolic compositions, with stronger inhibitory activity of the skin-related enzymes exhibited by the aqueous extract (Maidin et al., 2018). Additionally, fractionation enhanced the active polyphenols present in both crude extracts and intensified the inhibitory activity against collagenase, suggesting the suitability of the extracts for topical cosmetic formulations, which commonly contain between 25 and 100 µmol polyphenols/L (Maidin et al., 2018; Zillich et al., 2015). The potential of GP-derived polyphenols as an antioxidant material in cosmetic formulations was confirmed in another study in which GP extract diminished the cytotoxicity of hydrogen peroxide (H2O2) in mouse fibroblasts (Maluf et al., 2018).

In skin aging and other forms of skin damage, the generation of ROS exceeds the capacity of the endogenous antioxidant defense system of the skin, thereby resulting in oxidative stress (Kruk and Duchnik, 2014). In recent work, supplementation of GP-derived polyphenols modulated the cellular antioxidant system of the skin, maintaining its internal redox balance (Averilla et al., 2019; Manca et al., 2016). In particular, GP (Cannonau variety, Italy) extract incorporated in innovative phospholipid vesicles significantly mitigated skin damage by regulating H2O2-induced oxidative stress in keratinocytes and fibroblasts (Manca et al., 2016). Consistent with this study, grape (Vitis labrusca Campbell variety, South Korea) peel extract enriched with resveratrol and other antioxidants exhibited cytoprotective activity against H2O2-induced oxidative stress in human keratinocytes by enhancing reduced glutathione levels and, consequently, attenuating the accumulation of intracellular ROS (Averilla et al., 2019). Although understanding the exact mechanism was proposed for further studies, these results initially confirmed GP extract could be an ideal candidate in formulating cosmetic and pharmaceutical products (Averilla et al., 2019; Manca et al., 2016).

Gut health

Despite the extensive reporting of the potency of polyphenolics present in GP, limited information surrounds the gut health, immunity, and metabolic health associated with the consumption of these compounds (Pasinetti et al., 2015; Peixoto et al., 2018; Reinisalo et al., 2015). In this context, the gut microbial health implication of consistent long-term administration (2.5–20.0 mg polyphenolics/kg body weight/day) of GP (a mixture of Cabernet Sauvignon, Marselan, and Syrah varieties) extract was investigated in rats (Chacar et al., 2018). Interestingly, the polyphenol-rich GP extract stimulated microbial gut homeostasis, which resulted in notable beneficial effects against aging (Chacar et al., 2018).

In other work, proanthocyanidins present in grape seed extract (French origin) mediated parameters involved in metabolic disorders in female Wistar rats (Casanova-Marti et al., 2018). Previous assertions that grape seed proanthocyanidins upregulate plasma glucagon-like peptide-1 (GLP-1) levels and prompt satiety agents consequently stimulated investigations into whether these phytochemicals also potentially influence gut microbial modifications and enterohormone secretions (González-Abuin et al., 2014; Serrano et al., 2016). Oral administration of the extract had a positive short-term consequence on the variations in the microbiota that was accompanied by a reduction in the ratio of Firmicutes-to-Bacteroidetes in the gut and augmentation of the plasma GLP-1 level that was allegedly attributed to the harmonious execution of metabolic processes (Casanova-Marti et al., 2018).

Protection from microbial infection

Besides the bioactivities of its phytochemicals in promoting the growth of beneficial gut microbiota and healthy somatic cells, GP is also known to actively inhibit the growth of infectious microorganisms (Gouvinhas et al., 2018). With the widespread antibiotic resistance, researchers continuously survey natural products containing compounds that show synergistic interactions with antibiotics. Remarkably, the polyphenols in GP extract obtained from Cabernet Sauvignon grape (Chile) potentiated the effects of various classes of antibiotics against Staphylococcus aureus and Escherichia coli, especially the multi-drug resistant clinical isolates (Sanhueza et al., 2017). Moreover, the same GP extract was found to contain polyphenolic components, such as quercetin, gallic acid, protocatechuic acid, luteolin, (+)-catechin, (−)-epicatechin, vanillic acid, kaempferol, syringic acid, p-coumaric acid, and ellagic acid (de la Cerda-Carrasco et al., 2015; Sanhueza et al., 2017). Despite the unclear mechanism of synergism between polyphenols and antibiotics, the correlation between the polyphenolic components and beneficial effects introduced the potential uses of polyphenols in improving the potency of currently existing antibiotics (Sanhueza et al., 2017).

A recent comparative study of the antioxidant and antibacterial activities of two red grape varieties (Touriga Nacional and Preto Martinho) from Portugal confirmed the effective inhibition of the Gram-negative (Klebsiella pneumoniae) and Gram-positive bacteria (S. epidermis, Listeria monocytogenes, and S. aureus) by the anthocyanins and tannins present in GP (Silva et al., 2018). Both grape varieties exhibited substantial antimicrobial activity, especially the seed extracts, indicating that GP-derived polyphenols may function as an adjunctive substance to intensify the effects of available antibiotics (Silva et al., 2018).

Concluding remarks and future prospects

The varying compositions of different varieties of GP originating from diverse locations displayed remarkable biological activities, as summarized in Table 1. Therefore, the crude or highly purified form of GP extract could be recommended for further studies to resolve some of the potential limitations of GP utilization, such as toxicity (e.g., products of polyphenol metabolism or compatibility with other food/drug constituents), storage stability, and the cost and method of recovery (Fig. 2). Despite these potential challenges, the promising health benefits, sustainability, and environmental impact of GP utilization encourage discoveries of new applications in pharmacological, agricultural, food processing, and other related industries (Del Pino-García et al., 2017).

Table 1 Summary of health benefits, biological activities, and compositions of GP extracts from various sources
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Fig. 2
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Potential benefits and challenges of GP utilization

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Given the potent synergistic or antagonistic effects of combinations of polyphenols and other food, drug, or cosmetic constituents, feasible formulations that simultaneously prevent and treat diseases require further investigation. Understanding the association of the polyphenol-mediated modulation of the gut microbial metabolism with pathological diseases may introduce new perspectives in developing techniques for suitable modes of delivery to the systemic circulation, processing, handling, and packaging. Moreover, investigating the formation and characteristics of polyphenolic metabolites, their stability in the gut, and the digestive-resistance of some phytochemicals, such as anthocyanins, may provide possible solutions to the limited bioaccessibility of several phytochemicals (Lingua et al., 2018). Lastly, identifying possible sources of hazardous contaminants during handling, such as pesticides, heavy metals, or the presence of pathogenic microorganisms, may be useful to ensure the safety of GP as a food additive, food preservative, drug stabilizer/carrier, cosmetic component, and in many other industrial uses (Mildner-Szkudlarz et al., 2015; Yu, et al., 2018).

As evidenced in prior research, GP-derived polyphenolic constituents have multiple targets and multiple mechanisms of action that vary, depending largely on several factors, such as the grape composition, variety, and origin. Accordingly, GP could be considered as a natural source of functional polyphenolic components for oral or topical use and is recommended for further investigation. In conclusion, the integration of the polyphenol-rich GP in various applications for human consumption may potentially promote health and ameliorate many types of detrimental diseases.