Fig

Background: The food industry constantly searches for natural derived bioactive molecules with preventive and therapeutic effects using innovative and sustainable strategies. Fig production and processing generate a considerable amount of by-products (leaves, pulp, peels, seeds, and latex) with limited commercial exploitation and negative impact on the environment. These by-products are important sources of high value-added ingredients, including anthocyanins and pectins that can be of particular interest to the food industry as functional colourants, emulsifiers, and additives. Scope and approach: This review curates recent advances in the valorisation of fig by-products as valuable sources of bioactive molecules for functional food development. Special attention was given to widely used extraction processes, main bioactive compounds, relevant biological properties, and the application of recovered bioactives for functional food development. Key findings and conclusions: Fig by-products are essential sources of structurally diverse bioactive molecules with unique antidiabetic, anti-inflammatory, anti-tumour, immunomodulatory and cardioprotective properties. Owing to these health-promoting potentials, an integral valorisation approach involving sustainable technologies to recover these high value-added ingredients and its utilisation in novel food formulation development should be further stimulated.


Introduction: current state of Fig and Fig by-products
Ficus is one of the largest genera of angiosperm with more than 800 species worldwide. This genus belongs to the Moraceae family, rich in edible species with milky latex and aggregated drupes or achenes as fruit. Ficus carica is the most important commercial species within the genus due to its fruits, which are enclosed inflorescence with a hollow succulent receptacle (Mawa et al., 2013). This species may generate two crops per year: the main fruit, figs, which are produced during the concurrent growing year and are picked up at the end of the harvest and the breba crops, that are formed in the previous growing year and remain dormant during the winter producing an early harvest crop (Aradhya et al., 2010). F. carica is native to the Middle East, domesticated from a group of fig trees in the Mediterranean region, associated with grape and olive fruit trees in the beginning of this region's horticulture. Its domestication history and expansion worldwide have strongly influenced its current distribution, fruit morphology, and genetic diversity. The above-mentioned together with poor documentation of germplasm passport data, synonymous with local and regional names for the same clonal cultivars, and the modifications within cultivars, make proper identification of F. carica cultivars difficult (Ferrara et al., 2016). However, based on their reproduction biology and pollination, is parthenocarpic and not needs caprification; the San Pedro type, which produces parthenocarpy brebas and figs by caprification; and the Smyrna type, which is non-parthenocarpic (Ikegami et al., 2013).
F. carica is an important crop that appears on the market more often in its fresh or dry form, being consumed directly or as part of culinary dishes. In the last ten years (data available from 2010 to 2019), Turkey, Egypt, and Algeria have been the largest fig producers in the world. According to FAOSTAT, only Spain appeared in the top 10 fig producers in Europe. The consumption of this fruit has grown worldwide, and it is estimated to grow significantly in the coming years. This growth is attributed to the increased utilisation of these fruits in developing functional foods and beverages, contributing to a healthier diet. They are rich sources of vitamins (mainly thiamin and riboflavin), sugars, carbohydrates, minerals, and organic acids. In addition, the fresh and dry figs are a good source of fibre and phenolic compounds, mainly proanthocyanidins, furanocoumarins, and phenolic acids (Badgujar et al., 2014). The demand for fresh figs has attracted lots of attention due to the growing awareness of consumers of the potential health-promoting benefits of figs. The leaves and fruits also have been processed as ingredients of juices, jams, jellies, infusions, and alcoholic beverages (Badgujar et al., 2014;Barolo et al., 2014;Mawa et al., 2013). F. carica also presents many biological activities related to their phytochemicals, and is used in folk medicine for its endocrine, cardiovascular, respiratory, antispasmodic, and anti-inflammatory benefits (Mawa et al., 2013;Wang, Wu, et al., 2017).
The fig processing industry produces many by-products from fresh fig discarded because of spoilage, size, texture, low quality as table fruit, inadequate ripening, and over-ripening. These bio-residues constitute a real economic loss due to their richness in bioactive compounds, which can be extracted and used as value-added ingredients (Barolo et al., 2014). Hence, integral approaches for the sustainable valorisation of fig by-products to further improve the economic performance of the Mediterranean region and promote a circular economy in line with current consumer preferences towards sustainability still need to be adopted.

Main by-products from Fig processing
In recent years, there has been great concern in the food industry about a large amount of waste generated and new solutions have been proposed. Food waste is essential to global food security because it can cause serious environmental, economic, and social concerns. According to Directive 2006/12/EC 'waste' shall mean any substance or object which the holder discards or intends or is required to discard. However, according to FUSIONS, food removed from the food supply chain to be valorised for animal feed, non-food products, and fuel are considered food wastes that are not designated as fit for human consumption. Moreover, raw materials recovered from the processing, distribution, and consumption of food, represent food surplus that could be recycled for value addition. Hence, several integral strategies are needed to obtain value addition from food by-products using emerging technologies to obtain novel foods with additional functionalities with minimal contamination risks (Lavelli, 2021).
According to FAOSTAT, fig world production is increasing in the last years (1,142,611 tons in 2009; 1,148,211 tons in 2014; and 1,315,588 tons in 2019). Due to the high perishability of figs, the whole fruit is mainly consumed in dried form. In addition, the food industry also applies this methodology to produce paste, concentrate and powder (Bey et al., 2013). According to the International Nut and Dried Fruit Council Foundation, the consumption of dried figs in 2020/2021 reached 148, 400 tons, and the largest consumers were Iran, the United States of America, Germany, France, India, and Italy.
The different parts of F. carica, leaves, pulp, peels, seeds, and latex, can be used for distinct applications (Palmeira et al., 2019). In general, potential functional food ingredients can be generated during the primary production, processing, manufacturing, distribution, retail, and final consumption of figs (Comunian et al., 2021). In the example of fig at primary production, the main by-products are the leaves but also the "imperfect" foods that do not meet the quality criteria to be commercialized. On the other hand, the main by-product from the processing and manufacturing of fresh figs, including juices, syrups, and jams, are fig peels.
Therefore, the leaves and peels represent the main by-products resulting from fig production that can be valorised due to their richness in bioactive molecules and potential nutritional value. Considering that peels represent approximately 27% of the total weight of the fig fruit, 366,928 tons of fig peels can be produced from this raw product, generally discarded as industrial waste (Mahmoudi et al., 2018). Fig peels and leaves characterization presents structurally diverse metabolites, including organic acids, phenolic acids, triterpenoids, flavonoids, tocopherols, and fatty acids. In Table 1, a summary of the most common bioactive compounds identified in fig by-products is shown.
To our best knowledge, the phytochemical composition and biological properties of F. carica by-products have been well documented. Still, there is a lack in their unique application as sources of functional ingredients in novel foods (Barolo et al., 2014;Mawa et al., 2013). Furthermore, they revealed that fig by-products exhibit higher phytochemical properties than the pulp of the fruit, fully justifying its valorisation and application (Ammar et al., 2015;Mahmoudi et al., 2018;Palmeira et al., 2019).

Extraction, separation, and refinement of Fig biomolecules
The use of Fig and Fig by-products as a source of food or pharmacological agents to improve human health dates back thousands of years. Figs are an excellent source of different biologically active biomolecules and are responsible for a wide range of bioactive effects: antioxidant, anti-inflammatory, anticancer, antimicrobial, anti-ageing, and wound healing effects (Abdel-Rahman et al., 2021;Boyacıoglu et al., 2021). The main bioactive molecules present in various fig and fig by-products are terpenoids, carotenoids, phytosterols, volatile organic compounds, phenolic acids, and flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones (Pereira et al., 2017). The presence of these high value-added metabolites with attractive applications in food, cosmeceutical, and nutraceutical fields has reinforced the potential valorisation of these by-products. The use of fig as a low-cost source of bioactive compounds as ingredients for new products and/or nutraceuticals, or as raw materials for secondary processes, greatly depends on the availability of adequate extraction technology of these bioactive compounds (Alexandre et al., 2017;Bey et al., 2013). These vital extraction procedures, achieved through several conventional extraction methodologies, including soxhlet, maceration (M), and hydrodistillation, usually require organic solvents, a large volume of solvents, long extraction time, and high energy consumption (Taofiq et al., 2019). Some of these conventional methodologies have been traditionally applied to recover different high-value compounds from fig by-products using solvents, such as ethanol, methanol, acetone, or ethyl acetate either alone or in combination with water, as shown in Table 2.
There is a renewed effort to efficiently extract different bioactive compounds from plant biomass using sustainable and environmentally friendly technologies. These methodologies offer several advantages, including high extraction efficiency in the shortest period and minimal energy consumption (Taofiq et al., 2019). Some common green and sustainable extraction methods utilised to obtain phenolic acids, anthocyanins, and furanocoumarins from Fig by-products, include ultrasound-assisted (UAE), microwave-assisted (MAE), pressurized liquid, supercritical fluid, and subcritical water extraction (Backes et al., 2018;Wang, Wu, et al., 2017;Yu et al., 2020). More emphasis has been made on these green extraction processes that are environmentally friendly and sustainable for sample preparation in recent years. In this regard, many researchers have explored green solvents such as ionic liquids (ILs), deep eutectic solvents (DESs), and natural deep eutectic solvents (NADESs) as substitutes to traditional toxic and volatile organic solvents that present serious environmental and human concerns to extract bioactive molecules from Fig by-products (Wang, Wu, et al., 2017). These solvents also offer many excellent advantages: cheapness, sustainability, biocompatibility, environmental friendliness, favourable thermal and chemical stabilities, high solubilizing capacity, and non-flammability (Wang, Wu, et al., 2017). However, the use of these green solvents at the industrial scale is still faced with some challenges. Hence, more work is needed in life cycle assessment to select the most environmentally favourable alternative solvent mixtures that effectively recover target biomolecules from different fig by-products.

Furanocoumarin
Furanocoumarins are tricyclic aromatic compounds containing the α-benzopyrone fused furan ring system. Psoralen, isopsoralen, and bergapten are the main furanocoumarin compounds found predominantly in the leaves and unripe fruit of F. carica. Furanocoumarins have also been recovered in whole fig fruit and fig latex, and have been reported to display anti-inflammatory, antipyretic, anticancer, and antibacterial properties (Belguith-Hadriche et al., 2017;Irudayaraj et al., 2016). They have also been used with UV radiation to treat autoimmune skin diseases such as psoriasis, vitiligo, and eczema via multiple pathways (Son et al., 2017). However, DNA damage and hepatoxicity have been associated with these low-polar compounds (Gaaliche et al., 2017). This phototoxic property is associated with their ability to react with nucleobases in DNA under the influence of UVA radiation, leading to a higher incidence of skin cancer (Son et al., 2017). Several research findings report a high incidence of furanocoumarins in Ficus leaves compared to other plant parts (Belguith-Hadriche et al., 2017;Wang, Wu, et al., 2017). Oxypeucedanin hydrate, psoralen, methoxypsoralen, and prenyl methoxypsoralen are the main furanocoumarins detected in the hydroethanolic leaves extract of two different cultivars from Tunisia prepared by dynamic maceration using HPLC-DAD-QTOF-MS (Belguith-Hadriche et al., 2017). A tailor-made DES made up of glycerol, xylitol, and D-Fructose was utilised to recover phenolic compounds and furanocoumarins from fig leaves. The UAE-DES system at the optimized condition (Temp: 64.46 • C, liquid-solid ratio:17.53%, and ultrasonic time: 24.43 min) yielded three major furanocoumarins, namely, psoralic acid-glucoside (16.34 mg/g), psoralen (15.22 mg/g) and bergapten (2.475 mg/g), accounting for more than 74% of the extract. The use of ionic liquids as extraction solvents in the recovery of phenolic compounds has also gained increasing attention in recent years, mainly due to their excellent solubilizing properties. Eight different pH-dependent ionic liquids were employed in a UAE system to recover psoralen (Wang et al., 2018) from the leaves of F. carica. Among all the tested solvents, [1-butyl-3-methylimidazolium bromide ([Bmim]Br)-citric acid mixture yielded 31.22 mg/g of psoralen (96.32%), being 1.45, 2.45 and 3.68 times more efficient than [Bmim]Br-water, ethanol-critic acid, and ethanol, respectively. This finding showed that the recovery of furanocoumarins is highly dependent on the solvent used.

Other phenolic compounds
Other phenolic compounds found in F. carica by-products include phenolic acids, flavonols, flavones, flavanones, flavanols, and flavanonols. These compounds have been the most important contributors to several health benefits associated with fig by-product extracts due to their multifunctional biological properties (Ammar et al., 2015;Raafat & Wurglics, 2019;Sedaghat & Rahemi, 2018). F. carica by-products have shown to be interesting sources of phenolic acids belonging to both subclasses (hydroxycinnamic acids and hydroxybenzoic acids derivatives). These derivatives (caffeic acid hexoside, caffeoylmalic, 5-O-caffeoylquinic, vanillic acid di-deoxyhexoside, 5-p-coumaroylquinic, vanillic acid malonyl di-deoxyhexoside, ferulic, sinapic, and p-coumaric acids) have been identified in the peel, and pulp extract obtained by maceration (Ammar et al., 2015;Palmeira et al., 2019), in the leaves extract using a surfactant-based microwave-assisted extraction (Yu et al., 2020) and deep eutectic solvents based-MAE (Wang, Wu, et al., 2017) (Pereira et al., 2017). These by-products, as shown in Table 2, are interesting sources of structurally diverse phenolic compounds (Fig. 1). However, more in-depth studies still need to be conducted to exhaustively describe all the compounds in these by-products and their related biological properties to foster their application in the food, pharmaceutical, and cosmetic industries, promoting a circular economy.

Pectin
Pectin is a complex polysaccharide consisting mainly of galacturonic acid units. It is predominant in the cell wall of fig peels, possessing unique chemical, physical, and biological properties. It is applied as a high value-added functional thickener, colourant, emulsifier, gelling, and stabilizing agent (Gharibzahedi et al., 2019a). Standard extraction methods used to recover pectin include hot acidic extraction, which is energy consuming, requiring chemicals with high corrosivity and negative environmental impacts (Çavdaroglu et al., 2020). More sustainable systems such as UAE have been utilised to recover a high pectin yield from fig. Gharibzahedi et al. (2019b) obtained a pectin-rich extract from fig peels using a hybrid ultrasound-microwave assisted extraction (UMAE) system. They yielded 14.0% pectin with an average molecular mass of 6.89 × 10 3 kDa. The pectin rich extract also presented antioxidant and cytotoxic effects against Human non-small cell lung cancer (A549) and human hepatocellular carcinoma (HepG2) cells. Gharibzahedi et al. (2019a) also compared the best method to recover pectin from fig peels using hot water (HWE), UAE, MAE, and UMAE systems. The UMAE-pectin presented the highest galacturonic acid content (76.85%), the best emulsifying capacity, and emulsion stability at different storage conditions. Enzyme-assisted extraction is also promising in the recovery of bioactive compounds from various plant matrices on a large scale (Wang, Wu, et al., 2017). Chen et al. (2015) used a complex enzyme extraction (CEE) to obtain polysaccharide-rich extracts from dried figs. Response surface methodology (RSM) was employed and at the optimal condition, two heteropolysaccharides (FPs-1-1 and FPs-2-1) were fractionated by DEAE-Sepharose and Sephadex G-200 column chromatography, with a molecular weight of 1.52 × 10 6 and 4.75 × 10 5 Da, respectively. Hence finding industrially scalable methods based on innovative technologies to recover and process pectin from Fig by-products remains the major bottlenecks. Some of these challenges are still responsible for the high, non-competitive market price, and low supply of pectin.

Ficin
F. carica typically exudes a milky juice (latex) from the various plant parts, including its fruits, stems, and seeds, containing diverse secondary metabolites, including terpenoids, organic acids, alkaloids, fatty acids, tannins, sterols, enzymes, and amino acids (Barolo et al., 2014). This juice is secreted in an appreciable amount, and its principal activity is the protection and self-healing of plants from external assaults. These diverse metabolites present in the latex are responsible for the biological properties of latex extracts, namely, antioxidant, cytotoxic and wound healing effects (Abdel-Aty et al., 2019;Boyacıoglu et al., 2021). Ficin (EC:3.4.22.3), a cysteine endopeptidase enzyme, represents an essential component of Ficus latex. These enzymes are involved in triggering, regulating, and executing all sorts of biological and physiological processes such as protein degradation, cell maintenance, signalling, differentiation, growth, development, apoptosis, ripening, germination, senescence, and necrosis (Baeyens-Volant et al., 2015;Baidamshina et al., 2020;Zare et al., 2013). Several isoforms designated as A, B, C, D1, D2, and unnamed isoforms have been obtained from Ficus latex suspension . A novel ficin, termed ficin E, was purified from fig latex using a combination of cation-exchange chromatography on SP-Sepharose Fast Flow, Thiopropyl Sepharose 4B and Fast Protein Liquid-gel filtration chromatography (Baeyens-Volant et al., 2015). Detailed characterization showed a molecular weight of 24,294 ± 10 Da, an optimum activity at pH 6.0 and 50 • C, and at 10 mM, the enzyme activity was not affected by divalent cations (Mg 2+ , Mn 2+ , and Ca 2+ ). One major obstacle regarding ficin recovery is its autolytic effect, using neighbouring native proteolytic proteins as substrate. Some studies showed that the rate of autolysis was significantly increased with increasing storage time, irrespective of the storage temperature (Zare et al., 2013). Nevertheless, the successful utilisation of ficin for several applications is still faced with certain drawbacks, including low stability during storage and thermal degradation. A three-phase partitioning (TPP) purification step was first reported by Gagaoua et al. (2014) as a simple, effective, and inexpensive procedure for the efficient recovery of ficin from Ficus latex. This method involves the salting-out, isoionic precipitation, and co-solvent precipitation process of the protein. The authors reported a 167% recovery of ficin from Ficus latex, with the enzyme presenting a molecular weight of 23.4 kDa and thermal stability between 40 and 70 • C for 1 h. Hence, Ficus latex is an important matrix to obtain a purified fraction of ficin for its widespread usage in biotechnological, food, pharmaceutical, and biomedical applications .

Phytosterols
Phytosterols are triterpenes analogues of cholesterol naturally occurring in plants. They are well known for reducing intestinal cholesterol absorption, contribute to cancer prevention, and lower the risk of cardiovascular and metabolic diseases . GC-MS analysis of the derivatised extract obtained from the leaves of two F. carica cultivars from Tunisia revealed the presence of campesterol, stigmasterol trimethylsilyl ether, β-sitosterol trimethylsilyl ether, α-amyrin, trimethylsilyl ether, lupeol, and β-amyrin (Gaaliche et al., 2017). β-sitosterol trimethylsilyl ether (1158 and 373 μg/g/DW) was the most abundant phytosterol in both the Bidhi and Hemri cultivar, respectively. Few studies have been conducted on the phytosterol composition in the unsaponifiable extract of figs and fig by-products (fruit, bark, stem, pith). Jeong and Lachance (2001)

Antidiabetic activity
Nowadays, diabetes has become the most frequent endocrine illness. It is considered a metabolic disorder characterized by an imbalance of carbohydrate and lipid metabolism, giving rise to high glucose levels (Tripathy et al., 2021). Diabetes incidence is continuously growing, and synthetic antidiabetic drugs are the most widely used therapeutic intervention to treat the disease. There is a preference for natural-derived pharmaceutical formulations compared to their synthetic counter paths due to minimal efficacy and safety concerns associated with the latter. In this context, several plants have been demonstrated to exert antidiabetic activity, among which Ficus sp. is included (Deepa et al., 2018).
Fig extracts show antidiabetic activity through different mechanisms: 1) inhibiting glucose absorption in the intestinal tract through α-glucosidase and α-amylase inhibition, 2) enhancing glucose uptake via Glucose transporter type 4 (GLUT4) -phosphatidylinositol-3 kinase (PI3K)-serine/threonine-protein kinase, and 3) regulating glucose homeostasis via protein kinase (AMPK) activation (Fig. 2) (Deepa et al., 2018). On the other hand, they also show a strong connection with antioxidant activity. A study showed that IC 50 of the leave extract was 5.50 μM (ascorbic acid = 4.8 μM). This activity was attributed to flavonoids (quercetin, kaempferol, and chrysin) and was also correlated with low levels of transaminases and protective effects in the case of diabetic neuropathy (Khan Dureshahwar, Mohammed Mubashir et al., 2019). In the same perspective, oral ingestion of ficusin, a known furanocoumarin, increased the expression of related antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) in rat model (Irudayaraj et al., 2016(Irudayaraj et al., , 2017. In general, most studies about the antidiabetic activity of Ficus carica L. extracts have been conducted in leaves (Deepa et al., 2018) (Table 3).

Anti-inflammatory activity
The term inflammation is somehow an old-fashioned concept. Traditionally, it is characterized by several symptoms (redness, warmth, pain and swelling) produced by the organism in response to external stimulus and the initialization of an elimination process mediated by defence cells and proinflammatory mediators. This process is implicated in the pathophysiology of several diseases, including atherosclerosis, obesity, depression, Alzheimer's, asthma, type 2 diabetes, and several cancer types (Netea et al., 2017). Moreover, even though it is not clear yet, there is evidence that diet and inflammation are connected (Pansarasa et al., 2019).
During this decade, several by-products of F. carica, including fruits, barks, leaves or latex, have been proved to exert anti-inflammatory properties (Lansky et al., 2008). However, these findings have been assessed in vitro mostly by measuring the inhibitory effect of the extracts on nitric oxide (NO) production in RAW 264.7 cells. In a recent study, ficucaricone A was shown as the most effective compound recovered from fig fruits extract, exerting an IC 50 of 0.89 μM, presenting a better inhibitory effect than hydrocortisone (3.68 ± 0.16 μM) used as positive control (Liu et al., 2019) (Table 3). Furthermore, the inhibition of tumour necrosis factor-α (TNF-α) has also been tested on F. carica branches ethanolic extract showing inhibition of 70% at 12.5 μg/mL (Park et al., 2013) (Table 3).
Evaluating percentage reduction of carrageenan-induced paw oedema volume is the most widely utilised model to assess inflammatory effects in vivo. Oral treatment of rats with 100-200 mg/kg of F. carica ethanolic leaves extracts presented 18-76% inhibition of paw oedema volume (Ali et al., 2012;Patil & Patil, 2011) (Table 3). Similar percentages were obtained when treated with indomethacin intraperitoneally (79%) but administrated in a much lower dose (10 mg/kg) (Patil & Patil, 2011). In the same studies, the hydroalcoholic extract of F. carica leaves showed related antioxidant activity with a superoxide radical scavenging activity of IC 50 = 10 mg/mL, hydroxyl radical scavenging activity of IC 50 = 52.5 mg/mL, and lipid peroxide scavenging activity of IC 50 = 136 mg/mL (Ali et al., 2012). Also, the antiangiogenic effect was observed using haemoglobin content reduction up to 56% when ethanolic extract of F. carica leaves was administered in a mouse model, displaying a similar effect to diclofenac sodium (Eteraf-Oskouei et al., 2015).

Anti-tumor and immunomodulatory properties
Cancer is one of the diseases with the highest mortality in the world. The side effects of chemotherapy and radiotherapy have prompted the search for novel, safe, and effective cancer therapeutic biomolecules from natural sources (Garcia-Oliveira et al., 2021). F. carica has been suggested as a possible candidate since ancient knowledge gathered different preparations of this plant indicated for tumours treatment (Lansky et al., 2008).
Latex has been highlighted as a potential inhibitor of cell proliferation (Abdel-Aty et al., 2019;AlGhalban et al., 2021;Boyacıoglu et al., 2021) (Table 3). The cytotoxic effect of F. carica leaf latex assessed in breast cancer cells (MDA-MB-231) showed a higher cytotoxic effect and involved different molecular mechanisms of action in comparison to F. salicifolia (AlGhalban et al., 2021). On the contrary, F. carica latex extract showed no cytotoxic effect on human normal melanocyte cells (HFB4) in comparison to doxorubicin (86.20 ± 8.88), a known chemotherapeutic agent (Abdel-Aty et al., 2019). In human prostate (PC3) and colon (HT-29) cancer cell lines, good inhibition results were achieved, although it was suggested that ficin peroxidase-like activity was not sufficient to explain all the results (Boyacıoglu et al., 2021). Recently, F. carica extracts have been administered in vivo to suppress the side effects associated with the use of specific drugs in cancer therapies, including 5-fluorouracil and cisplatin, by taking advantage of its synergistic effect with extra virgin olive oil (Elghareeb et al., 2021).
The ethanolic and acetone extract of the leaves from F. carica showed inhibition of the viability of different cell lines (Abdel-Rahman et al., 2021;Mustafa et al., 2021). These results also demonstrated a relation between anti-tumour properties and antioxidant activity, which is in turn caused by the inhibition of certain enzymes, including tyrosinase and α-glucosidase (Meziant et al., 2021). Regarding the mechanism of action, F. carica caused inhibition of mRNA expression of ERK1/2, CREB, GSK-3a/B, and AMPKa1 and confirmed downregulation of ERK, CREB and Akt gene expression. ERK and CREB biomarkers play key roles in cellular proliferation, whereas ERK and Akt indicate acute toxicity and their pathways are related to anoikis programmed cell death (AlGhalban et al., 2021). Furthermore, another study reported downregulation of the expression of Bcl-2, TP53, and cyclin-dependent kinases (CDK1, CDL5, CDK9 and CDK10) when cells were treated with F. carica leaves extract (Mustafa et al., 2021) (Table 3).
In recent years the correlation between bioactive compounds and immunomodulatory activity has been established, which is especially related to anti-tumour and anti-inflammatory properties. Du et al. (2018) isolated a polysaccharide able to modulate the immune response and stimulate the production of TNF-α, interleukin-6 (IL-6) and NO in macrophages by upregulating the expression of p-p38, p-ERK, p-JNK, IκB-α, and p65, through the mitogen-activated protein kinase (MAPK) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathways (Table 3). On this basis, a recent study tested a fermented fig extract in immunosuppressed mice treated with cyclophosphamide and showed an increased production of interferon-γ (IFN-γ), IL-4, IL-6, and TNF-α compared to control animals, consistent with previous results (Zhao et al., 2020).

Cardioprotective and neuroprotective activity
Cardioprotection is a general term used to group all the mechanisms that are related to the prevention of myocardial damage. However, this definition can be extended to all cardiovascular diseases and those factors that can improve the risk, such as hypertension or diabetes and the conjunction of three of them, the metabolic syndrome (Gonzalez-Chávez et al., 2018).
In this sense, different plants from the genus Ficus spp. have shown their potential as anti-hypertensive agents (Alamgeer et al., 2017). F. carica methanolic extract from ripe fruits reduced blood pressure levels in normal and hypertensive rats and a reduction of the contraction force and heart rate on the in vitro experiments. These effects were related to the antioxidant properties of its phenolic compounds (Alamgeer et al., 2017) (Table 3). In addition, thrombosis is one of the pathologies hidden behind cardiovascular diseases, including anticoagulation, fibrinolysis, and platelet activity (Shore-Lesserson, 2002). For this purpose, different properties, including anticoagulant, procoagulant, and antiplatelet activity, have been assessed in F. carica latex and fruits (Gilani et al., 2008;Hamed et al., 2020) (Table 3). A more recent study evaluated the effects of F. carica on the activity of enzymes related to metabolic syndrome such as α-amylase, α-glucosidase, and lipase, associated with diabetes and obesity (Mopuri et al., 2018).
Neurodegenerative disorders are a major concern for public health. F. carica active metabolites from the mesocarp showed a protective effect on the neuroblastoma (SHSY5Y) cell line (Khojah & Edrada-Ebel, 2017). In another study, fig peels extract caused the inhibition of enzymes related to neuroprotection (tyrosinase and α-glucosidase) with IC 50 levels ranging from 0.1 to 3.5 mg/mL (Meziant et al., 2021).

Anti-ageing, wound healing, and antimicrobial properties
Ageing is a natural process that can be intrinsic and associated with specific genes, signalling pathways, and certain antioxidant mechanisms (Cȃtanȃ et al., 2018). In this sense, even though there are no specific studies on this property for F. carica, the wide variety of reports about the antioxidant potential and related properties makes it feasible to extrapolate that its by-products could be a source of potential anti-ageing metabolicompounds (Abdel-Rahman et al., 2021;Ali et al., 2012;Irudayaraj et al., 2016Irudayaraj et al., , 2017Meziant et al., 2021;Mustafa et al., 2021). In the case of wound healing, a recent study showed a reduced dose-dependent migration in cells treated with F. carica latex, showing an anti-metastatic effect (AlGhalban et al., 2021). Also, ficin, extracted from F. carica latex, improved the infected wound healing on rats acting as a biofilm (Baidamshina et al., 2020). μg/mL (Lazreg-Aref et al., 2012). More recently, the peels from F. carica were tested against nine bacteria; the best results were MIC values of 2,5 μg/mL for Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) (Backes et al., 2020). Another study screened 13 species of Ficus spp. and found that three were effective antimicrobials against foodborne pathogens (Elhawary et al., 2018). Therefore, the antimicrobial potential of fig and its by-products needs to be further explored.

Development of novel functional foods: recent advancements and challenges
There are newly emerging consumer demands for food formulations with enhanced nutritional values, enriched with health-promoting biomolecules, and improved functional and physical food properties (Gemechu, 2020). However, with the growing population, natural resources are faced with continuous depletion, and as such, there is a renewed interest to sustainably mobilize food by-products as sources of functional ingredients, thereby preventing biodiversity loss and sustainable use of the terrestrial ecosystem.
Food additives and colourants are critical components in the food industry to enhance food quality and safety, appearance during processing, storage, and packaging (Sun et al., 2021). There is a current increasing consumer demand for colourants derived from natural sources to enhance the nutritional and biological efficacies such as antioxidant, anticancer, anti-obesity of the food formulation. F. carica contains anthocyanins and carotenoids with a bright red, purple, and blue colouration. There is a renewed interest to explore these anthocyanin-rich bioresidues as sustainable sources of potential natural food colourants. In this regard, anthocyanin-rich extracts were obtained from the peels of F. carica using a UAE (Backes et al., 2020). The bioactive extract presented antioxidant, antimicrobial, and no cytotoxic effect in a normal cell line model followed by incorporating two dairy confectionery products (doughnut icings and "beijinho" pastry). The anthocyanin-rich extract maintained the colouring effect and improved the texture properties of the final food formulation for at least 24 h without influencing its nutritional properties (moisture content, ashes, proteins, fat, and carbohydrates). The preservative potential of aqueous extract from fig leaves, olive leaves, and their mixture was conducted by Abdel-Aziz et al. (2020). The results showed that 0.6% of these extracts extended the shelf life of pasteurized buffalo milk for 5-16 days, without influencing its sensorial properties. The strong catalytic effect of ficin has enhanced its utilisation in the dairy industry to develop milk protein hydrolysates with improved bioavailability and as a clotting ingredient in cheese production (Aider, 2021).
Hence, extracts obtained from F. carica either solely or in combination with other extracts can contribute further to developing new functional food additives for improved nutrition and health benefits. Despite these promising possibilities, there are some drawbacks associated with the chemical instability of numerous naturally derived food colorants and additives, and as such, more studies still need to be conducted to improve these challenges.
Despite the enormous health effects of natural extracts and their related metabolites, their utilisation either directly as food or their incorporation into food formulations are faced with several challenges during storage and food processing, thereby rendering these bioactive ingredients physically, chemically, and/or enzymatically unstable. This instability leads to the degradation and loss of functionality of the bioactive extracts (Dias et al., 2015). Microencapsulation techniques have been adopted in recent times to improve the retention time of these bioactive in the food, allow for their controlled release, preserve the stability of the bioactive compounds during processing and storage, prevent undesirable interactions with other food matrices, mask unpleasant taste, and increase bioavailability while maintaining the functional properties of the bioactive ingredient and ensuring their efficient absorption in the human digestive system (Ye et al., 2018). A nutritious fruit snack formulation based on dried fig powder and coated with a hydrocolloid solution containing Persian gum and xanthan gum, and chocolate as the outer shell was developed by Yeganehzad et al. (2020). The results showed that the hydrocolloid coatings were effective in lowering the hardness and adhesiveness of the coated samples. Sensory properties of the formulations in terms of appearance, flavour, texture, and total acceptance by 35 panellists considering ethical regulations and international standards showed Total acceptance as the concentration of hydrocolloid coating increase; with the snack formulated with 1.5% Persian gum being the best.
Current food engineering and packaging research has been focused on the development of a new generation of sustainable bio-based packaging materials that maintain and improve the quality of food products. This is due to the growing consumer interest in consuming fresh food products such as fruits, vegetables, fish, shrimp, and meats with short shelf life (Khezrian & Shahbazi, 2018). An active edible coating with antimicrobial activity against Listeria innocua was recently developed using pectin rich extracts obtained from Fig to increase the quality of fresh melon (Çavdaroglu et al., 2020). Properties such as surface wettability, oxygen permeability, and tensile strength of the coating materials were promising. In addition, melons coated with the developed films gave significantly lower Listeria counts in comparison with uncoated controls. Khezrian and Shahbazi (2018) developed novel antimicrobial packaging films based on nanomontmorillonite-chitosan (MMT-Ch) and nanomontmorillonite-carboxymethyl cellulose (MMT-CMC) incorporated with different concentrations of Ziziphora clinopodioides Lam essential oil in combination with F. carica extract. The films were found to be very effective in preserving the shelf life of minced camel's meat. The microbial load (Listeria monocytogenes and Escherichia coli) decreases significantly, and the result confirms the viability of the produced films as promising packaging materials for minced camel's meat. Moreover, sensory parameters such as odour, colour, and overall acceptability were improved significantly in comparison with the untreated control. The authors mentioned that these films formulated with bioactive ingredients constitute a future-oriented direction of food packaging due to their biodegradability, biocompatibility, high-quality film-forming capability, edibility, and non-toxicity. Therefore, they can be explored at the industrial scale to prevent microbial spoilage, lipids peroxidation, and protein oxidation in meats. However, more findings are needed to determine the controlled release of these active ingredients.
The use of fig by-products in food formulation development has shown promising results. However, studies related to factors limiting their use are significantly lacking. In general, allergens are one of the most common limitations in food fortification. Although not very well reported, irritation is an unusual allergic reaction associated with F. carica, mainly due to the presence of ficin (Urbani et al., 2020). A 17 kDa allergen homologous to Bet v I allergen was found in fresh and dried figs. Clinical trials in patients with birch pollen allergy revealed a very high prevalence of cross-sensitization (Hemmer et al., 2010). Hence, more work still needs to be conducted to identify and define the structure-activity relationships of potential allergens from fig by-products. Overall, by-products from F. carica constitute an essential source of bioactive compounds with interesting health-promoting properties that may be applied in the development of innovative food and pharmaceutical formulations. Therefore, their utilisation along the value chain should be stimulated.

Conclusions and future perspectives
Fig by-products, namely leaves, peels, pulp, seeds, and latex, have been explored as a source of bioactive compounds for their application in the food, cosmetic or pharmaceutical industry. However, even though their bioactive and nutritional composition is widely researched, their biological properties are in some cases poorly studied, and few examples of applications have been described. Antidiabetic, anti-inflammatory, anti-tumour, and immunomodulatory properties are the most studied, whereas others such as cardio or neuroprotective properties have been less explored. Despite these promising biological properties, an enormous gap still exists for its exploration using bioassay-guided isolation and fractionation.
Considering the different fig by-products and their specific characteristics, one of the challenges towards valorisation is the correct choice of the extraction technique. Extraction methodologies involving ionic liquids and deep eutectic solvents have been successfully used to recover furanocoumarins and pectin from Fig leaves and peels, enhancing the drive for a green and sustainable paradigm shift. However, a technoeconomic assessment of these novel extraction systems and solvents involving their energy expenses, costs, and carbon dioxide (CO 2 ) emissions are significantly lacking. Hence, these methods should be applied to assess the economic ramifications of utilising these novel technologies on an industrial scale.
On the other hand, new trends should be considered for the screening of biological properties, such as using microencapsulation and nanoencapsulation technologies to enhance bioavailability and control the release of bioactive ingredients. Nanoparticles have been used as carriers for F. carica extracts, demonstrating an antitumoral effect in animal models. Therefore, it is expected that a holistic approach can be adopted that promotes the use of