Green and sustainable valorization of bioactive phenolic compounds from pinus by-products

molecules Review Green and Sustainable Valorization of Bioactive Phenolic Compounds from Pinus By-Products Pedro Ferreira-Santos , Elisa Zanuso , Zlatina Genisheva, Cristina M. R. Rocha and JoséA. Teixeira * CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] (P.F.-S.); [email protected] (E.Z.); [email protected] (Z.G.); [email protected] (C.M.R.R.) *Correspondence: [email protected]; Tel.: +253-604-406 Academic Editor: Vassiliki Oreopoulou Received: 2 June 2020; Accepted: 23 June 2020; Published: 25 June 2020   Abstract: In Europe, pine forests are one of the most extended forests formations, making pine residues and by-products an important source of compounds with high industrial interest as well as for bioenergy production. Moreover, the valorization of lumber industry residues is desirable from a circular economy perspective. Different extraction methods and solvents have been used, resulting in extracts with different constituents and consequently with different bioactivities. Recently, emerging and green technologies as ultrasounds, microwaves, supercritical fluids, pressurized liquids, and electric fields have appeared as promising tools for bioactive compounds extraction in alignment with the Green Chemistry principles. Pine extracts have attracted the researchers’ attention because of the positive bioproperties, such as anti-inflammatory, antimicrobial, anti-neurodegenerative, antitumoral, cardioprotective, etc., and potential industrial applications as functional foods, food additives as preservatives, nutraceuticals, pharmaceuticals, and cosmetics. Phenolic compounds are responsible for many of these bioactivities. However, there is not much information in the literature about the individual phenolic compounds of extracts from the pine species. The present review is about the reutilization of residues and by-products from the pine species, using ecofriendly technologies to obtain added-value bioactive compounds for industrial applications. Keywords: pine; by-products; biorefinery; green process; polyphenols; biological activity; traditional applications; high value-added products 1. Introduction Agroforestry industries are an important part of the manufacturing industry, and their growth can help to achieve the objectives of European Union (EU) industrial policy, acting in different strategic areas, such as increasing energy efficiency, deploying renewable sources, circular economy, bioeconomy, and natural carbon sinks [ 1 , 2 ]. Moreover, the development of these industries should also be in line with the 17 sustainable development goals by 2030 dictated by the United Nations; in particular, the agroindustry can directly impact on at least 4 of these goals related to the use of clean energy, industry innovation, responsible consumption, and climate action [3]. Nowadays, 5 billion tons of biomass residues from agroforestry and food industries are estimated worldwide and represent an emission for 3.3 billion tonnes of carbon dioxide each year [ 4 , 5 ]. In the EU, the total annual biowaste is estimated at around 100 million tonnes, generating a negative ecological impact [6]. One of the strategies for the reduction of generated environmental impact is the reuse of industrial biowastes to obtain new natural ingredients. Concomitantly, the growing interest in the development Molecules 2020,25, 2931; doi:10.3390/molecules25122931 www.mdpi.com/journal/molecules Molecules 2020,25, 2931 2 of 29 of effective/intensified processes and application of green technologies to obtain sustainable, ecological, safe and high-quality products has become a reality [ 7 , 8 ]. This idea is in close association with the principles governing the concept of green chemistry, which are mainly aimed at reducing wastes and promoting a more efficient use of energy and resources [9]. The decrease in the use of “non-recyclable” fossil derivatives and the increase in the use of biowastes and by-products is in the sights of the EU and the world, contributing to the reduction of the negative impact of processes in the environment and the fight against climate changes [2]. In this sense, the use of different plant by-products as sources of materials, biofuels, energy, and bioactive compounds has come to be explored following the concept of biorefinery, contributing to a circular economy [6]. The present review focuses on the appreciation of different green extraction strategies related to the recovery of high added-value compounds (such as polyphenols) from pine by-products, their potential bioactivities, and possible industrial applications. 2. Biorefinery and Lignocellulosic By-Products Resources depletion, waste accumulation, and climate change are a combination of forces driving the need for the sustainable practices we are facing nowadays. Additionally, urbanization and population growth are causing the global energy demand to be in continuous rise. With the energy demand increasing, the necessity of detachment from fossil fuels and the transition to renewable resources is mandatory to reduce the environmental problems. Energy resources such as biomass, wind, and solar energy can meet the energy requirements if large-scale technologies are well developed [ 10 ]. In this sense, biorefinery is analogous to fossil fuel refinery. The biorefinery term dates back to 1980. Since then, several definitions have been considered. These definitions are based on the type of feedstock used, type of processes, and type of products obtained [ 11 ]. In general, the biorefinery concept is the synergy of technologies that convert biomass into their building blocks to produce a variety of biofuels, chemicals, and high added-value compounds. Hereof, the development of a sustainable process involves not only the use of biomass but also implies reducing the use of harmful chemicals, transition to greener processes, efficient use of energy, and elimination of wastes (Figure 1) [9]. Figure 1. Pine valorization under biorefinery concept. Molecules 2020,25, 2931 3 of 29 Ethanol is a well-known biofuel product of the second generation biorefinery. Second generation or lignocellulosic biorefinery usually begins with the pretreatment of the biomass in order to increase the digestibility of cellulose, to solubilize the hemicellulose, and to relocate the lignin [ 12 ]. Pretreatments can be mechanical, chemical, physicochemical, or biological [ 13 ]. Afterward, to liberate the fermentable sugars (i.e., monosaccharide units) from the pretreated biomass, acid or enzymatic hydrolysis processes are applied [ 14 ]. Then, the fermentation of the obtained sugars to obtain ethanol can be carried out using microorganisms as yeast or bacteria [ 15 , 16 ], where, in an integrated biorefinery, ethanol can also be considered as a precursor for chemicals, hydrocarbon fuels, and aromatic compounds [ 17 ]. Hence, the research and development of sustainable processes are growing not only for biofuels but also for the high added-value compounds than can allow an economically viable process (Figure 1). Currently, lignocellulosic biomass has been largely studied as a potential substrate in fermentation processes, and mainly for biofuel production. Nevertheless, innovative and new emerging technologies are being studied to increase the obtainment of high-value compounds of interest, particularly bioactive ones. The recovery of these of high-value compounds is linked to the biorefinery concept and the green chemistry principles. Lignocellulosic biomass (in which pine by-products may be included) is mostly considered as a residue from crops as straw, sugarcane bagasse, corn stover, and wood waste. Cellulose is the major component of the lignocellulosic materials, followed by hemicellulose and lignin. Cellulose is the world’s most abundant biopolymer made up of glucose units. Applications of cellulose extracted from lignocellulosics include the manufacture of cellulosic fiber and nanocrystalline cellulose in a wide range of industries such as automotive, textile, and medicine due to the strength on its structure, availability, modifiable surface, renewability, and low cost [ 18 , 19 ]. Hemicellulose is the second most abundant polysaccharide in lignocellulosic biomass mainly composed by monomeric units as xylose, mannose, arabinose, glucose, galactose, and acids such as uranic acid [ 20 ]. Hemicellulose and specific target products from hemicellulose are used in a variety of areas as food, medicine, and chemicals due to the biocompatibility and bioactivity properties they show [ 20 ]. Pine sawdust has been used to produce levulinic, formic, and acetic acid and furfural form hemicellulose extracted by steam explosion [ 21 ]. In addition, pinewood (Pinus eldarica) pretreated with dilute sodium hydroxide was used to produce ethanol from the pretreated solid where the solubilized hemicellulose fraction was used to produce biogas [ 22 ]. The third main component of lignocellulosic materials is lignin, which is an amorphous phenolic polymer that provides mechanical strength and rigidity to plants [ 23 ]. In the biorefinery process, lignin cannot be used as a substrate for fermentation as it contains no sugars. Therefore, a wide area of research is on lignin valorization. Lignin is mainly used to generate heat and electricity due to the high heating value although other applications are possible, including the use as a precursor for carbon fiber synthesis, resins, and low molecular weight aromatic and phenolic compounds [ 24 , 25 ]. Nowadays, the modern polymer industry from natural sources of aromatic compounds is limited due to the high prices of the final product. Here, lignin plays an important role, since phenolic compounds can be obtained from lignin deconstruction [26]. Historically, wood has been a major energy source for human beings. Forest biomass is the most abundant feedstock on earth, representing 89.3% of the total biomass [ 27 ]. In Europe, forest area is one of the most important renewable resources, representing near 5% of the world’s forest and covering 43% of its land, comprising close to 182 million hectares of forest. Forest is also considered as a resource for improving life quality and job generation [ 28 ]. Wood biomass can be densified into solid fuels, as pellets, or converted into heat, electricity, biofuels, and other bioproducts through a variety of chemical, thermochemical, and biochemical processes [ 29 ]. On the other hand, the lumber industry generates a considerable amount of waste that includes leaves, barks, sawdust, chips, cones, resins, and branches. These residues are not usually well valued and are thrown out, burned, or used for animal bedding, although they can be a profitable source of high added-value compounds [ 30 ]. Therein, wood biomass residues increase their overall value due to the metabolites that are present in lower abundance compared with cellulose, hemicellulose, and lignin. These extractive compounds combine alkaloids, waxes, phenolics, pectins, resins, and essential oils [ 31 ], and they are of great importance Molecules 2020,25, 2931 4 of 29 considering the wide industry applications, more precisely, in food and pharmaceutical industries due to the antioxidant, antimicrobial, anti-inflammatory, and antitumoral effects they show [32]. 3. Pine as Feedstocks This work is mainly focused on the valorization of the Pinus species (and its by-products), which are evergreen trees of resinous conifers group from the Pinaceae family. In the EU, there are more than 14 different species, representing one of the largest forest occupations. Table 1describes the main Pinus species distributed in the European countries according to the “European forest genetic resources program (EUFORGEN)” [33]. In Portugal, pine forests are the third forest formation after eucalyptus and cork oaks, with an area of approximately 1 million hectares, representing an important part of the total forest, about 23% [34]. Table 1. Pinus trees species implemented in European countries, as well as its geographical distribution. Latin Name Common Name Geographical Distribution Pinus sylvestris Scots pine All countries of Europa and Asia Pinus nigra European black pine Mountain areas of Europe, United States, and Asia Minor Pinus brutia Brutia pine Eastern Coast of the Mediterranean (Turkey, Greece, Italy) Pinus pinaster Maritime pine Western Mediterranean Sea, Central and Southern Europe, and North Africa Pinus halepensis Aleppo pine Coastal areas of the Western Mediterranean region, Southern France and Italy, and North Africa Pinus cembra Swiss stone pine Continental Alps and regions of the Carpathian Mountains Pinus uncinata Mountain pine Mountains of Western Europe, Northern Europe, and Mediterranean Pinus pinea Stone pine Mediterranean Basin, extending from Portugal to Syria Pinus strobus White pine Eastern North America and Carpathian Mountains in Czech Republic and Southern Poland Pinus mugo Mountain pine Mountains of Central and Eastern Europe Pinus heldreichii Bosnian pine Southern and Western part of the Balkans, near the Mediterranean basin Pinuscontorta Lodgepole pine Western North America, Europe, and New Zealand Pinus peuce Macedonian pine Mountain areas of the Balkan Peninsula Pinus radiata Monterey pine Central Coast of California, Australia, New Zealand, Mexico, Argentina, Chile, Uruguay, Kenya, Spain, and South Africa The chemical composition of pine and its constituents (wood, bark, leaves, cones, seeds, and resin) varies depending on the Pinus tree and also on many other factors, such as genotypic, ecological, and seasonal, among others [ 35 ]. The methodology used for the determination of chemical composition of plant resources is also a factor to consider, since different methods lead to different results [36]. The general chemical/nutritional composition of pine by-products has been described by several authors (wood [ 37 – 42 ], bark [ 43 – 47 ], needles [ 48 , 49 ], cones [ 41 , 50 ], seeds (nuts) [ 51 – 53 ], and resin or oleoresin [54,55]) and is summarized in Figure 2. Molecules 2020,25, 2931 5 of 29 Figure 2. General chemical/nutritional composition of pine by-products. Pine Applications At present, agroforestry residues and by-products are mainly used as combustion feedstock for biofuels production [ 56 ]. The most important biomasses are obtained from lumber industry (bark and sawdust) or forest activities, the residues from farms and agro-business, the organic fraction of municipal solid wastes, and the plants deliberately grown for energetic purposes. In this sense, it is important to reduce and give a “second life” to these residues, moving to “zero waste”. The Pinus plant is very important economically, as it is considered good feedstock for the bioeconomy (Figure 1) [ 57 ]. In its natural environment, it has an important protective function, such as improving water infiltration, preventing soil erosion on dry slopes, and serving as a windbreak [ 33 ]. Trees are also used as ornamental plants in urban and industrial contexts. Other uses include Christmas trees and fuelwood. Interestingly, in a study by Ehn and co-workers [ 58 ], it has been found that pine forest aroma (for its content in volatile compounds, terpenes) can limit climate change, preventing the global warming. The main industrial activities are related to the usage of pine wood and wooden products, including sawmills, wood panels, cellulose pulp and paper production, wood fuels, carpentry, packing, and wood furniture [ 33 ]. These feedstock, their components, and their by-products are considered a good source for wood biorefineries, transforming the lignocellulosic fractions into biofuels, chemical products, and composite materials, as previously mentioned [57]. Pine bark, the by-product obtained in larger quantities that is produced when wood is transformed, is almost exclusively used as fuel, being also subjected to composting to filling substrate in nurseries, utilized for cover in public gardens, or simply thrown away on landscapes [ 44 , 59 ]. Nowadays, this by-product has been used as low-cost and green alternatives waste-based biosorbents for the removal of a wide range of water pollutants [60]. The pine leaves (needles) are normally used in agriculture to enrich the soil, and the seeds are used for human consumption because they are highly nutritious and much appreciated by consumers in cooked/prepared dishes (food industry) or simply as edible pine nuts. The resins, a product resulting from the exploitation of these species, are more regularly used as a sealant, glue, varnish, and also as a solvent and paint thinner (turpentine oil) [55,57,61]. Molecules 2020,25, 2931 6 of 29 In addition to the “traditional” uses of these by-products, it is important to take advantage of these bio-resources to create high value-added products. Currently, the agroforestry by-products have been increasingly exploited to isolate biocompounds with high industrial interest. Studies using natural matrices as a potential source of bioactive compounds have been published in recent decades [ 7 , 62 – 67 ]. For instance, in a new review paper [ 68 ], the authors report that in addition to fruits and vegetables, tree barks are rich in phenolic compounds with excellent biological properties (such as antioxidant, immunostimulatory, anticancer, antibacterial, anti-inflammatory, antimutagenic, etc.) and may used to obtain functional ingredients. Pine bark is one of the most sought after sources of antioxidant biocompounds of natural origin. The extracts obtained from this by-product are mostly composed of phenolic compounds with high biological activity [ 46 , 59 , 62 , 69 – 72 ]. Nowadays, there are numerous studies reporting the applicability of pine bioactive extracts in various areas, such as health care, food, agrochemical, and others [ 73 – 75 ]. One of the most promising applications for these extracts is in the preservation and enrichment of foods, thus replacing synthetic antioxidants, as well as a nutraceutical, cosmeceutical, or pharmaceutical. The pine wood/sawdust extractives, rich in phenolic antioxidant compounds, have a potential for food and pharmaceutical applications, such as preservatives or nutraceuticals [40,76]. Pine tars, a by-product of pine wood and bark, are known to contain tricyclic diterpenoid resin acids, tricyclic diterpene hydrocarbons, alkylphenanthrenes, and fatty acids. This water-resistant by-product has a wide range of applications, for example, as a multipurpose adhesive, sealant, and in medicine [77,78]. Knowing the chemical composition and physicochemical properties, pine seeds or nuts appear to have a positive effect on human health [ 52 , 53 ]. The seed lipids, rich in linoleic acid, have a beneficial effect on blood pressure and cholesterol. The fatty acid composition and the relatively high polyphenol content present high protection against oxidative stress. In this sense, pine seeds can potentially be used in the food industry and other non-food industries, such as pharmaceutical and cosmetics [ 79 – 81 ]. Oleoresins are widely used in the synthesis of perfumed compounds for cosmetics, essences as additives for food and beverages, food protection (antimicrobial), bioinsecticides (high repellent activity), tapping green chemicals, biofuels, and carbon sequestration from multipurpose trees [54,55,57,61]. Interestingly, this search for functional extracts, new natural molecules, and the creation of new high value-added products has increased the use/study of agroforestry by-products and residues, including pine bark, sawdust, leaves, seeds, and resin. This makes it possible to potentially bring these “wastes” back to the market. 4. Extraction Processes for Phenolic Compounds Recovery The recovery of bioactive and functional purified biomolecules or extracts from plant materials is an important step to enable the reuse of natural resources for subsequent application in pharmaceutical and cosmetic products, food enrichment and preservatives, dietary supplements, and nutraceuticals. The extraction process of natural extracts depends on several factors, including the applied extraction technique, the parameters associated with the technique (such as temperature, time, and the extraction solvent), and the raw materials composition [ 63 ]. It is known that the phenolic compounds are metabolites present in the cell vacuoles [ 82 ]. Therefore, it is also important to promote the opening of pores or even the rupture of the cell wall to facilitate the release of the compounds into the extraction medium. In this sense, it is important to study all variables of the process in order to maximize the potential of the extraction method, developing a highly efficient process [ 8 ]. On the other hand, all variables in the process have to make it possible to obtain a safe and high quality final product (eco-extract), in addition to maximizing the extraction of the compounds of interest. Figure 3illustrates the main principles of an efficient extraction process, following the concept of green extraction. Molecules 2020,25, 2931 7 of 29 Figure 3. Principles of efficient process for obtaining natural extracts. Adapted from Chemat et al. [ 8 ]. 4.1. Extraction Solvents The reduction use of hazardous solvents is also considered one of the priorities of the EU policy for the 2010 to 2050 period [ 7 ]. Nowadays, extraction using conventional organic solvents is the most commonly used procedure to prepare extracts from plant materials due to their ease of use, efficiency, and wide applicability. The efficiency of the extraction methods depends on the choice of the solvent, since solvents with different polarities are needed for the isolation of compounds with different chemical constitution. In addition, it is difficult to define a single method for the efficient extraction of all compounds, since the polarities of the molecules to be extracted vary [63]. A suitable solvent has to be able to obtain safe and high-quality extracts and to preserve the biological effects of the extracted compounds without exhibiting toxicity when consumed. Furthermore, it should be recyclable and reusable, preventing negative environmental effects. Other parameters, such as flammability, explosiveness, volatility, mass transfer, and (in)ability to dissociate the complex extract should be considered [ 65 ]. The extraction yield depends not only on the solvent used but also on several other factors such as sample/solvent ratio, temperature, extraction time, stirring, and raw material composition [83]. Conventional solvents from “non-natural”/petroleum resources, such as methanol, ethanol, acetone, ethyl acetate, dichloromethane, hexane, etc. and their aqueous solutions have been used for the extraction of bioactive compounds from plant materials. Several studies have been done demonstrating the importance of these solvents in the recovery of natural molecules and active extracts from different plants and by-products [ 65 , 84 – 86 ], including the lignocellulosic by-products [ 87 ]. Researchers also studied the influence of these different solvents in obtaining antioxidant phenolic compounds from pine by-products, and depending on the solvent used, the extracted fraction (extract composition) is different [ 59 , 85 , 88 ]. For example, in a work by Venkatesan and collaborators [ 85 ], the impact of different extraction solvents (such as ethanol, methanol, isopropanol, acetonitrile, and acetone) was analyzed to obtain phenolic extracts with antioxidant activity from Pinus densiflora bark. Their results showed that low concentrations of ethanol and acetonitrile are favorable for the extraction of phenolics with high antioxidant activity. In another study, using Pinus niruri, methanol was more efficient than other solvents such as ethanol, hexane, and ethyl acetate, showing an enhanced extraction rate of phenolic and flavonoid compounds with higher biological activities [88]. It is known that water is an efficient solvent for the extraction of various compounds, due to its properties and thanks to the fact that water is easily available, safe, non-toxic, non-flammable, and environmentally friendly [ 8 ]. In this sense, it is considered the cleanest/greenest solvent (apart from Molecules 2020,25, 2931 8 of 29 the use of no solvent, which is the greenest), according to the principles of green chemistry [ 64 , 89 ]. However, it is not suitable for the extraction of less polar substances. Other possible environmental friendly solvents’ option is to replace petroleum-based solvents by “bio-solvents”. For instance, “bioethanol” can be produced from bioresources, by fermentation. This second-generation solvent could be made cost-competitive by the development of biorefinery-based processes for the integral use of lignocellulosic biomass, substituting ethanol obtained from petroleum derivatives [90]. As alternatives to conventional solvents, the use of green solvents such as ionic liquids (ILs) and natural deep eutectic solvents (NADES) is emerging, in order to make the extraction process eco-friendly and more effective [ 91 ]. In general, ILs and NADES are derived from cheap, abundant, low toxic, and biodegradable natural components [ 6 , 7 ]. NADES can be defined as “mixtures of pure naturally occurring compounds that present an eutectic point temperature below an ideal liquid mixture” [ 6 , 92 ]. ILs are liquid molten salts at temperatures below 100 ◦ C composed by cations and organic or inorganic anions with exclusive and adjusted physicochemical properties [93]. However, a lack of information on the biological activity and toxicity of the obtained extracts limits the use and industrial applications of ILs and NADES [ 7 ], leading to these solvents not being regulated by the Federal Drug Administration (FDA) [ 94 ]. Furthermore, although they can be tuned for enhanced affinity toward the compound of interest, their separation from the final mixture may be hindered by the high boiling point characteristic of these solvents. Murador and collaborators [ 95 ] summarize the main chemical constituents of these ILs and NADES and mention some works where they are applied in the extraction of antioxidant compounds, such as phenolic compounds and carotenoids, among others. Specifically, ILs and NADES have been applied to the phenolic compounds and other antioxidant compounds extraction from lignocellulosic biomass and agri-food wastes [4,6,93,96–98]. In the case of pine plants as feedstock, the process of extracting bioactive compounds with added value (such as phenolics) using these green solvents is not widely explored. In a recent study, ILs were combined with enzymes and microwave technology to promote cell wall disruption for the extraction of essential oil and procyanidins from pine cones of Pinus koraiensis [ 99 ]. However, there are no reports using ILs and NADES as alternative solvents for extraction of bioactive molecules of other parts of pine plant, despite the advantage they showed for obtaining functional compounds in other lignocellulosic residues. 4.2. Extraction Technologies Conventionalmethodsofextraction,suchasthesolid–liquidmethod,hydrodistillation,maceration, and Soxhlet require the use of large amounts of water or organic solvents, agitation, long extraction time, high temperatures, and energy consumption, as well as the generation of a considerable quantity of wastes [8,100,101]. The need for obtaining greener, sustainable, and viable processes has led scientists and industries to develop new processes in full correspondence with the green extraction concept [ 102 , 103 ]. In this context, the search for alternative extraction technologies with environmental and economic advantages, taking into account the characteristics of the final products has emerged [ 104 ]. As a result, techniques such as ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), supercritical fluid extraction (SFE), pressurized liquid extraction (PLE), and ohmic heating (OH) electrotechnology have been developed, optimized, and applied to improve the extraction process of antioxidant phenolic compounds from plant resources, such as pine by-products (Table 2). In the following sub-sections, a brief introduction to these extraction technologies and some examples of their application in obtaining phenolic compounds from pine by-products will be presented. Molecules 2020,25, 2931 9 of 29 4.2.1. Ultrasound-Assisted Extraction Ultrasound produces high-intensity sound waves (typically higher than 20 kHz) [ 104 ]. The operation mechanism of UAE is based in pressure variations that form microbubbles resulting in microturbulence and a high collision of particles. The collapse of microparticles caused by ultrasound waves can promote higher penetration of the solvent into the cellular material causing the cell walls disruption and increasing the release of intracellular compounds into the extraction medium [ 105 , 106 ]. UAE is an alternative technology with advantages compared to conventional techniques, since less processing time, low solvent usage, and lower extraction temperatures are required, preserving heat-sensitive compounds. In addition, it leads to an increase in extraction yield, requiring less energy in the process [ 106 ]. Due to its advantages, ultrasound technology is mentioned as an eco-friendly and cheap process and can be easily implemented to extract phenolic compounds from plants and plant by-products [76,107–110]. In the last decade, UAE has been used to obtain extracts rich in phenolic compounds from pine by-products. In a study of Liazid and co-workers [ 111 ], UAE was used to obtain phenolic extracts from seeds of two pine species (Pinus maritima and Pinus d’Alpes). The results of this work showed that the application of ultrasound waves, using water as a solvent at 75 ◦ C during 20 min, doubled the recovery of phenolic compounds compared to a conventional maceration technique, increasing the antioxidant activity of these extracts. Using the bark of the Pinus radiata as a raw material, Asp é and collaborators [ 112 ] verified that the synergetic effect of ultrasounds (35 kHz/85 W) with acetone 70% (v/v) allows the formation of pores in the matrix cells, promoting the rapid rupture of the cell wall, facilitating the extraction of phenolic compounds, and drastically reducing the extraction time (from 180 min for conventional extraction in a water bath or Soxhlet, for 6 min when using UAE). In another study, authors used ultrasound technology in combination with methanol 70% (v/v) as a solvent to extract phenolic compounds, such as flavonoids from leaves (needles) of four different pine species (Pinus peuce,P. nigra,P. mugo and P. sylvestris) [ 113 ]. UAE proved to be a potential tool for the sustainable recovery of phenolic compounds from pine leaves, without using temperature in the process. Recently, Meullemiestre and co-workers [ 76 ] reported that the UAE, in addition to increasing the extraction of phenolic compounds from maritime pine wood (sawdust waste) by 40% compared to conventional extraction techniques (solid–liquid), also allowed reducing the time of the process. On the other hand, they also reported that UAE is a scalable technique and can be applied industrially to obtain bio-functional extracts. 4.2.2. Microwave Assisted Extraction MAE is a heating process using electromagnetic waves of frequency between 300 MHz and 300 GHz that interact with samples to extract analytes from a matrix to a solvent. The microwave irradiation increases the internal pressure of the plant cells by heating the cells from the inside, leading to cell disruption and releasing the compounds of interest. Some of the advantages of MAE are a lower time of extraction compared with other extraction processes, the possibility of multiple extractions, low solvent volume, an attainment of high temperatures, and more effective, uniform and selective heating [ 107 , 114 ]. To have better extraction yields, it is important to consider the capability of the solvent to absorb microwaves, as it can be a drawback when the solvent lacks the capacity of energy absorption. Furthermore, the thickness of the sample to be heated may also be a drawback, particularly in the scalability of the extraction process, as the ability of microwaves to penetrate a sample is limited. Liazid et al. [ 111 ] studied the extraction of phenolic compounds from Pinus pinaster seeds using water as solvent and demonstrated that MAE produces extracts with great polyphenols content, since it can achieve high temperatures, which is a decisive factor in phenolic compounds extraction, as most of these processes are temperature dependent. In this work, the polyphenolic extracts obtained at 75 ◦ C demonstrated high antioxidant activity. In another work, the extraction time to obtain phenolic compounds from Pinus radiata bark was reduced by 98.3% using MAE compared with the Soxhlet Molecules 2020,25, 2931 16 of 29 depends on the particle size [ 76 ]. The particle size has a direct effect on the amount of the polyphenol extracted. The smaller the particle size is, the more extracts are obtained (best results were registered for size 0.4 mm). However, there is no impact on the nature of the extract and on the types of the compounds extracted [ 115 ]. There is a lower limit of the particle size beyond which the quantity of extracted polyphenols decreased. It was registered that very fine particles stayed in suspension at the surface of the solvent and therefore were not subjected to proper extraction [76]. The extraction of polyphenols would also depend on the solid/liquid ratio. Meullemiestre et al. [ 76 ] found the optimum ratio to be about 6 g of dry material/100 mL; when concentrations were higher than 7.5 g of dry material/100 mL, the maritime pine wood absorbed all available liquid. Eighteen phenolic compounds were identified in the extracts of P. pinaster by Ferreira-Santos and co-workers [ 45 , 59 ]. In one of the studies, the authors tried to understand the action of the type of solvent (water and ethanol) and method of extraction (conventional or ohmic heating) over the chemical profile of the extracts. Extracts made with the different solvents were found to be statistically different in terms of content of phenolic compounds [ 59 ]. The antioxidant activity of the extracts were always higher in the hydroethanolic extracts comparing with the aqueous extracts. Moreover, significant correlations were found between total phenolic content and antioxidant activities of the obtained extracts [ 59 ]. In a second study, from the same author, pine bark extracts made with different concentrations of ethanol (from 0% to 90%) were evaluated for their bioactivities (antioxidant, antimicrobial, and antidiabetic) and in vitro cell viability (in normal and cancer cell lines). The study demonstrated that the pine bark extracts have high potential antioxidant, antidiabetic, and antimicrobial activities, especially when made with 50% and 70% of ethanol [ 45 ]. Moreover, the authors concluded that pine bark extracts act selectively on cancer cells, as these are negatively selected and the non-tumor cells are not. In general, both studies [ 45 , 59 ] showed that the compounds with the highest concentrations in all samples were ellagic acid and taxifolin. The concentrations of ellagic acid accounted for between 9.0% and 50% of the total phenolic compounds, while taxifolin accounted for between 15% and 42% of the total phenolic compounds. Individual concentrations of phenolic compounds such as catechin, taxifolin, quercetin, caffeic acid, o-coumaric acid, ferulic acid, and ellagic acid in the extracts made with 50% ethanol were almost twice as high as in the correspondent extracts obtained with water. There are not many studies showing the identification and even less studies showing the quantification of polyphenols in extracts from Pine species. The extracts are obtained mostly from the pine bark, and fewer are obtained from needles (Table 3). The chemical composition of the extracts depends on the type of pine used (species, location), on the part of the plant, on the method of extraction, and on the solvent. For example, the main group of polyphenols compounds found in the P. sylvestris is the group of stilbenes [ 151 ], while in P. pinaster, the main group of compounds are the flavonoids [59]. Table 3. Individual phenolic compounds found in pine by-products and their reported bioactivities. Name Chemical Formula Concentration Range (mg/g) Bioactivities Reference NEEDLES Epicatechin C15H14O61.5 antioxidant [152,153] p-Coumaric Acid C9H8O32.3 antioxidant, anti-inflammatory, hepatoprotective and renoprotective, anti-neurodegenerative, anti-cholesterolemic, improve insulin resistance, anti-tyrosinase, antimicrobial [152,154–156] Molecules 2020,25, 2931 17 of 29 Table 3. Cont. Name Chemical Formula Concentration Range (mg/g) Bioactivities Reference SEEDS Protocatechuic Acid C7H6O40.5 anti-tyrosinase, antimicrobial, and anti-inflammatory activities [156,157] Catechin C15H14O60.5 hepatoprotective activity [145,157] Epigallocatechin Gallate C22H18O11 0.5 antimicrobial, antioxidant, photoprotective [145,157] Vanillic Acid C8H8O40.9 anti-inflammatory, neuroprotective [157,158] Syringic Acid C9H10O51.0 cardioprotective, antioxidant, antimicrobial, anti-inflammatory, neuro and hepatoprotective activities [157,159] Epicatechin C15H14O61.3 antioxidant [157] Taxifolin C15H14O71.7 antioxidant, anticancer, anti-inflammatory [157] Cinnamic Acid C9H8O20.1 anti-tyrosinase, antimicrobial, and anti-inflammatory [156,157] Eriodictyol C15H12O63.8 anti-inflammatory [157,160] m-Coumaric Acid C9H8O3traces not found [157] BARK Gallic Acid C7H6O5traces–5.5 anti-inflammatory, antihyperlipidemic, antioxidant, antitumor, antihyperglycemic, and anti-neurodegenerative, cardioprotective [59,154,155,159, 161] Gallocatechin C15H14O70.07–0.95 inhibitor of melanin biosynthesis [45,59,162] Epicatechin C15H14O60.06–1.9 antioxidant [71,161] Epicatechin Gallate C22H18O10 0.3–0.9 antioxidant [161] Catechin C15H14O60.095–7.7 antioxidant, anticancer, cardioprotective, antifungal [45,59,71,161,162] Vanillic Acid C8H8O40.02–0.07 neuroprotective, anti-inflammatory [45,59,158] Caffeic Acid C9H8O40.03–0.2 antioxidant, photoprotective [45,59,163] Rosmaniric Acid C18H16O80.4–0.8 antioxidant, antidiabetic, antibacterial, antiviral [59,164,165] Catechin Gallate C22H18O10 0.002–1.5 antioxidant, anticancer [71,166] Taxifolin C15H12O70.01–4.7 antioxidant, anticancer, anti-inflammatory [45,59,148,167] 3,4 Dihydroxy-Benzoic Acid C9H10O40.08–0.8 neuroprotective, antioxidant, nematicidal activity [45,59,168] Ellagic acid C14H6O80.4–4.0 anti-inflammatory, antioxidant [45,59,169] Naringin C27H32O17 0.8–2.0 not found [45,59] Apigenin C15H10O50.3–0.5 anticancer, antioxidant, anti-inflammatory [45,59,170] Resveratrol C14H12O30.03–0.4 antioxidant, anti-cancer, cardioprotective, anti-inflammatory [45,59,159,171] Ferulic acid C10H10O40.06–0.5 antioxidant, photoprotective [45,59,163] p-coumaric acid C9H8O3n.q. antioxidant, anti-inflammatory, hepatoprotective and renoprotective, anti-neurodegenerative, anti-cholesterolemic, improve insulin resistance, anti-tyrosinase, antimicrobial [59,154–156] Molecules 2020,25, 2931 18 of 29 Table 3. Cont. Name Chemical Formula Concentration Range (mg/g) Bioactivities Reference Quercetin C15H10O70.06–1.1 inflammatory, antimicrobial, anticancer [45,59] Procyanidin A2 C30H24O12 n.q. antioxidant [148] Procyanidin B1 C30H26O12 n.q. antioxidant, neuroprotective, anti-proliferative activity [148] Procyanidin B2 C30H26O12 n.q. antioxidant, anti-inflammatory, cardioprotective, neuroprotective, anti-proliferative activity [148] n.q.–not quantified. As one can see from Table 3, the main polyphenol compounds found in extracts from pine needles are p-coumaric acid and epicatechin, in pine seeds eriodictyol and taxifolin, and in pine bark catechin, gallic acid, and taxifolin. In the following text, we summarize the bioactivities of the individual compound found in the extracts of pine species. However, we want to draw the attention of the reader to the idea that, in terms of expressing biological activities, the polyphenols act as group of compounds rather than individual compounds, and synergistic and/or antagonist or simply different effects may be found. The p-coumaric acid together with ferulic and caffeic acids are the most common hydroxycinnamic acids in pine-based extracts. The hydroxylation of p-coumaric acid results in the formation of ferulic acid, while the oxymethylation of p-coumaric acid produces caffeic acid, respectively. These phenolic acids are used as precursors in the synthesis of lignins and other phenolics [ 136 ]. Taofiq et al. [ 156 ] conducted a study on individual compounds as possible ingredients in cosmeceutical formulations. The authors concluded that p-coumaric, protocatechuic, and cinnamic acids displayed anti-tyrosinase, antimicrobial, and anti-inflammatory activities, showing their potential for the cosmeceutical industry. Caffeic acid and, at a higher degree, ferulic acid proved to protect the skin against UVB-induced erythema. Besides as antioxidants, these two hydroxycinnamic acids can be used as photoprotectors in skin cosmetics [163]. The protocatechuic, vanillic, and syringic acids are the three commonly found hydroxybenzoic acids [ 136 ]. This tree hydroxybenzoic acids were also found in pine extracts (Table 3). Vanillic acid demonstrated anti-inflammatory activity with neuroprotective activity and was found to be a promising candidate for preventing and/or delaying the onset and progression of ischemic injury and vascular dementia [ 158 ]. In other cases, the use of a mixture of phenolic compounds rather than the individual compounds exhibits stronger activities. For example, the combined use of syringic acid, resveratrol, and gallic acid, in rats, revealed antioxidant and cardioprotective activities [ 159 ]. Resveratrol also showed an anticancer effect when examined in lung, prostate, breast, skin, and gastrointestinal cancers [ 172 ]. Resveratrol is the most known constituent of wines and grapes, but it was also found in pine bark extracts (Table 3). It was also proven that resveratrol has anti-inflammatory capacity, especially in the skeletal muscle, but it is less active in liver [ 171 ]. Moreover, gallic and p-coumaric acids were considered as promising adjuvant agents against the progression of neurodegeneration in the brain by diabetes [ 155 ]. Rosmarinic acid is known to have a number of potentially beneficial biological effects and is an acid ester of caffeic acid and 3(3,4-dihydroxyphenyl)lactic acid. The use of rosmarinic acid in gelatin edible film showed long-term antibacterial activity. Rosmarinic acid edible films may have promising application in the fields of food and pharmaceutical packaging, as they showed a good antibacterial activity even after 3 months of storage [ 173 ]. Rosmarinic acid was found in extracts of pine bark in concentrations between 0.4 and 0.8 mg/g [ 59 ]. This acid was found to be the predominant compound of Salvia species. Strong correlations between the rosmarinic acid contents and bioactivites of Salvia samples were established [ 165 ]. Moreover, this acid demonstrated potent antiviral properties [ 164 ]. 3,4 dihydroxybenzoic acid is universal in the Angiosperm plants, as it Molecules 2020,25, 2931 19 of 29 is constituent of lignin. It is a strong antioxidant, as well as a neuroprotective against A β -induced neuronal damage [ 168 ]. This acid can be used in formulations for phytonematode control, as it showed nematicidal activity against juveniles of M. incognita [174]. As we can see from the Table 3, in different pine extracts, many catechin compounds with diphenylpropane (C 6 –C 3 –C 6 –) skeletons were found. Epigallocatechin, epigallocatechin gallate, and epicatechin are the main constituents of the leaves of Camellia sinensis (the tea plant), while catechin gallate is a minor polyphenolic constituent in green tea: 1.28% (by weight) of the total catechin content in green tea [ 166 ]. These catechins are responsible for the astringent and bitter taste of the green tea [ 153 ]. Catechin is the main phenolic compound present in P.pinaster bark extract followed by epicatechin and epicatechin gallate [ 161 ]. Gallocatechin was found also in Norway spruce and confirmed to be a strong inhibitor of melanin biosynthesis; however, there is little information on the biological activities of this compound [ 162 ]. All these catechins have strong antioxidants and anticancer activities against different types of cancer [ 166 ]. Catechins have received considerable attention as promising candidates for development of therapeutic agents. Taxifolin, as an individual compound, is extensively studied. It was found in the pine extracts of seeds and bark; in bark, it is present in much higher concentrations than in seeds [ 45 , 59 , 157 ]. For instance, this compound was recovered from P.nigra bark [ 120 ] with a maximum extraction recovery of 34%. Taxifolin was detected as the major compound in other needle leaved trees such as the Japanese larch, Larix kaempferi [ 175 ]. Its main bioactivities are antioxidant, anticancer, and anti-inflammatory [ 148 , 167 ]. Quercetin is a taxifolin-related flavonoid found in onions, and it showed anti-inflammatory, antimicrobial, and anticancer properties ( in vitro and in vivo ) [ 176 ]. Quercetin-rich extracts from onion skin can be used in functional bread production [176]. According to Lantto and co-workers [ 157 ], eriodictyol was one of the main compounds found in extracts of Siberian pine bark. Eriodictyol, as taxifolin, can be find in citrus fruits. It has showed antioxidant and anti-inflammatory activities. Recent findings indicated that eriodictyol might be a new preventative agent for psteoarthritis [ 177 ]. Another promising therapeutic agent for the treatment of osteoarthritis is ellagic acid [ 169 ]. It is found in high concentrations in the ethanolic extracts of P. pinaster [59], which is also a constituent in the fruit peel of berries and nuts [169]. Apigenin is found abundantly in herbs, fruits, and vegetables (peppermint, grape fruit, parsley). It has potent antioxidant, anti-inflammatory, and anticancer properties [ 170 ]. Gascon et al. [ 148 ] found three procyanidin compounds in pine bark extracts: A2, B1, and B2. The activities of procyanidins depend on their structure, especially on their degree of polymerization. Procyanidin B2 is one of the most active molecules within the procyanidins, as well as the most studied. It is also found in cocoa and grape seeds. The three compounds have antioxidant activity; B-type procyanidins have also neuroprotective activity. The richest set of bioactivities agglomerates for the procyanidins B2, but as we mentioned, this is also the most studied one. There are several pine bark commercial extracts: Oligopin ® , Pycnogenol ® , and Flavangenol ® . Pycnogenol ® is the most known and most studied one. Its extraction involves standardized consecutive steps using water and ethanol as solvents. It is a polyphenol-rich extract prepared from P. pinaster (French maritime pine). The main constituents are procyanidins (85%), flavonoids (catechin, taxifolin), as well as some phenolic acids in minor amounts (gallic, caffeic, and ferulic acid) [ 149 ]. This extract proved to have excellent antioxidant properties that can promote various health properties such as cardioprotective, anticancer, antihypertensive, and anti-inflammatory [ 118 , 150 ]. In another study, the clinical efficiency of Pycnogenol ® in the management, treatment, and control of chronic venous insufficiency and venous microangiopathy was proven [ 178 ]. This extract showed also anti-diabetic property, as the supplementation of Pycnogenol ® to conventional diabetes treatment lowered glucose levels and improved endothelial function [ 179 ]. Oligopin ® is another extract obtained from the pine tree P. pinaster from a specific location in France (Landes of Gascony). Its production includes two extraction steps and one purification step. This methodology ensure that the obtained extract has Molecules 2020,25, 2931 20 of 29 a specific and constant composition. The main compounds found in Oligopin ® are flavonoids (catechin and taxifolin) and acids (ferulic, gallic, caffeic, p-coumaric, and protocatechic) [180]. As a final remark, the individual polyphenol compounds found in the extracts of pine bark have diverse bioactivities that align with the mentioned previously bioactivities of the hole extracts such as antioxidant, anticancer, cardioprotective, antidiabetic, anti-inflammatory, etc. Pine extracts have active ingredients that are useful for the food industry as supplements or natural pigments, for food preservation and as active food packaging. In the cosmetic formulations, they can be used for protecting the skin against oxygen reactive species, formed by pollution, stress, or ultraviolet reaction. 6. Conclusions and Future Perspectives Pine residues and by-products are an important source of biocompounds with high industrial interest. They can be recovered using the biorefinery concept, thus contributing to the circular economy. More environmentally friendly techniques have been explored to avoid the large amounts of (organic) solvents, energy consumption, and waste generation typical of conventional solvent extraction processes. Although replacing conventional technologies by non-conventional ones has emerged, improvements are necessary in terms of deep knowledge of the extraction processes and scaling up. UAE, MAE, SFE, PLE, and OH are some of these emerging promising technologies for bioactive compounds extraction in alignment with the Green Chemistry principles. Regarding the extraction step, the selection of the most appropriate techniques differs according to the type of compounds targeted for recovery and final aimed functionality/application. However, there is not a universal extraction method suitable for the extraction of all pine phenolics. The different pine species have different individual phenolic composition. For example, the main phenolic compound found in extracts of Portuguese pine is the taxifolin, whereas it was not found in Macedonian pine species. Depending on the final purpose for the extraction, an individual study must be carried on to tune the best extraction procedure. Interestingly, all extracts from pine, regardless the solvent, the method, pine species, and the plant part used, have high amounts of polyphenols. However, there are differences in the concentrations and type of the individual compounds as well as in the strength of the bioactivities. There are not many studies showing identification and even less studies showing quantification of the individual polyphenols in extracts from pine species. Pine extracts have a number of described bioactivities that may be beneficial for the human health. As a consequence, pine extracts have high potential as constituents in formulation for the food, cosmeceutical, and pharmaceutical industries. The possible reutilization of the pine residues is yet limited, compared to its potential. In this context, more studies are needed to find and develop new products and uses resulting from pine residues and by-products. Funding: ThisworkwasfundedbythePortugueseFoundationforScienceandTechnology(FCT)under thescopeof the strategic funding of UIDB/04469/2020 unit and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte and by program INTERREG V-B Sudoe (REDVALUE, SOE1/P1/E0123). Zlatina Genisheva is supported by the project OH2O (POCI-01-0145-FEDER-029145) funded by FCT and Fundo Europeu de Desenvolvimento Regional (FEDER) under the scope of Programa Operacional de Competividade e Internacionalizaçao (POCI)-COMPETE 2020 and Portugal 2020. Elisa Zanuso is recipient of a PhD fellowship supported by the Mexican Science and Technology Council (CONACYT ID 639021/495314). Pedro Santos is recipient of a PhD fellowship supported by a doctoral advanced training (call NORTE-69-2015-15), funded by the European Social Fund under the scope of Norte2020 - Programa Operacional Regional do Norte (NORTE-08-5369-FSE-000036). Conflicts of Interest: The authors declare no conflict of interest. Molecules 2020,25, 2931 21 of 29 References 1. European Commission. Going Climate-Neutral by 2050: A Strategic Long-Term Vision for a Prosperous, Modern, Competitive and Climate-Neutral EU Economy. Available online: https://ec.europa.eu/clima/sites/ clima/files/long_term_strategy_brochure_en.pdf (accessed on 21 January 2020). 2. 2050 Long-Term Strategy |Energy. Available online: https://ec.europa.eu/energy/en/topics/energy-strategyand-energy-union/2050-long-term-strategy (accessed on 21 January 2020). 3. United Nations. Transforming our world: The 2030 Agenda for Sustainable Development. Available online: https://sustainabledevelopment.un.org/post2015/transformingourworld (accessed on 21 May 2020). 4. Torres-Valenzuela, L.S.; Ballesteros-G ó mez, A.; Rubio, S. Green solvents for the extraction of high added-value compounds from agri-food waste. Food Eng. Rev. 2019,12, 83–100. [CrossRef] 5. Naidu, D.S.; Hlangothi, S.P.; John, M.J. Bio-based products from xylan: A review. Carbohydr. Polym. 2018 , 179, 28–41. [CrossRef] [PubMed] 6. Jablonsk ý , M.; Škulcov á , A.; Malvis, A.; Šima, J. Extraction of value-added components from food industry based and agro-forest biowastes by deep eutectic solvents. J. Biotechnol. 2018 ,282, 46–66. [CrossRef] [PubMed] 7. Cvjetko Bubalo, M.; Vidovi´c, S.; Radojˇci´c Redovnikovi´c, I.; Joki´c, S. New perspective in extraction of plant biologically active compounds by green solvents. Food Bioprod. Process. 2018,109, 52–73. [CrossRef] 8. Chemat, F.; Abert-Vian, M.; Fabiano-Tixier, A.S.; Strube, J.; Uhlenbrock, L.; Gunjevic, V.; Cravotto, G. Green extraction of natural products. Origins, current status, and future challenges. Trac Trends Anal. Chem. 2019 , 118, 248–263. [CrossRef] 9. Herrero, M.; Ibañez, E. Green extraction processes, biorefineries and sustainability: Recovery of high added-value products from natural sources. J. Supercrit. Fluids 2018,134, 252–259. [CrossRef] 10. Gielen, D.; Boshell, F.; Saygin, D. Climate and energy challenges for materials science. Nat. Publ. Gr. 2016 , 15, 117–120. [CrossRef] 11. Wenger, J.; Stern, T. Reflection on the research on and implementation of biorefinery systems—A systematic literature review with a focus on feedstock. Biofuels Bioprod. Bior. 2019,13, 1347–1364. [CrossRef] 12. Ruiz, H.A.; Conrad, M.; Sun, S.-N.; Sanchez, A.; Rocha, G.J.M.; Roman í , A.; Castro, E.; Torres, A.; Rodr í guez-Jasso, R.M.; Andrade, L.P.; et al. Engineering aspects of hydrothermal pretreatment: From batch to continuous operation, scale-up and pilot reactor under biorefinery concept. Bioresour. Technol. 2020 ,299, 122685. [CrossRef] 13. Pachapur, V.L.; Kaur Brar, S.; Le Bihan, Y. Integrated wood biorefinery: Improvements and tailor-made two-step strategies on hydrolysis techniques. Bioresour. Technol. 2020,299, 122632. [CrossRef] 14. Pino, M.S.; Rodr í guez-Jasso, R.M.; Michelin, M.; Flores-Gallegos, A.C.; Morales-Rodriguez, R.; Teixeira, J.A.; Ruiz, H.A. Bioreactor design for enzymatic hydrolysis of biomass under the biorefinery concept. Chem. Eng. J. 2018,347, 119–136. [CrossRef] 15. Avelino Gonçaves, F.; Ruiz, H.A.; Silvino dos Santos, E.; Teixeira, J.A.; Ribeiro de Macedo, G. Bioethanol production by Saccharomyces cerevisiae, Pichia stipitis and Zymomonas mobilis from delignified coconut fibre mature and lignin extraction according to biorefinery concept. Renew. Energy 2016 ,94, 353–365. [CrossRef] 16. Akhtar, N.; Gupta, K.; Goyal, D.; Goyal, A. Recent advances in pretreatment technologies for efficient hydrolysis of lignocellulosic biomass. Env.. Prog. Sustain. Energy 2016,35, 498–511. [CrossRef] 17. Sorokina, K.N.; Taran, O.P.; Medvedeva, T.B.; Samoylova, Y.V.; Piligaev, A.V.; Parmon, V.N. Cellulose biorefinery based on a combined catalytic and biotechnological approach for rroduction of 5-HMF and ethanol. ChemSusChem 2017,10, 562–574. [CrossRef] [PubMed] 18. Brinchi, L.; Cotana, F.; Fortunati, E.; Kenny, J.M. Production of nanocrystalline cellulose from lignocellulosic biomass: Technology and applications. Carbohydr. Polym. 2013,94, 154–169. [CrossRef] [PubMed] 19. Nuruddin, M.; Hosur, M.; Uddin, M.J.; Baah, D.; Jeelani, S. A novel approach for extracting cellulose nanofibers from lignocellulosic biomass by ball milling combined with chemical treatment. J. Appl. Polym. Sci. 2016,133. [CrossRef] 20. Luo, Y.; Li, Z.; Li, X.; Liu, X.; Fan, J.; Clark, J.H. The production of furfural directly from hemicellulose in lignocellulosic biomass: A review. Catal. Today 2019,319, 14–24. [CrossRef] Molecules 2020,25, 2931 22 of 29 21. Clauser, N.M.; Guti é rrez, S.; Area, M.C.; Felissia, F.E.; Vallejos, M.E. Techno-economic assessment pellet production in a pine sawdust. BiofuelsBioprod. Biorefining 2018,12, 997–1012. [CrossRef] 22. Safari, A.; Karimi, K.; Shafiei, M. Dilute alkali pretreatment of softwood pine: A biorefinery approach. Bioresour. Technol. 2017,234, 67–76. [CrossRef] 23. Charisteidis, I.; Lazaridis, P.; Fotopoulos, A.; Pachatouridou, E.; Matsakas, L.; Rova, U.; Christakopoulos, P.; Triantafyllidis, K. Catalytic fast pyrolysis of lignin isolated by hybrid organosolv — Steam explosion pretreatment of hardwood and softwood biomass for the production of phenolics and aromatics. Catalyst 2019,9, 935. [CrossRef] 24. Ragauskas, A.J.; Ragauskas, A.J.; Beckham, G.T.; Biddy, M.J.; Chandra, R.; Chen, F.; Davis, M.F.; Davison, B.H.; Dixon, R.A.; Gilna, P.; et al. Lignin valorization: Improving lignin processing in the biorefinery. Science. 2014 , 344, 1246843. [CrossRef] [PubMed] 25. Yuan, T.-Q.; Xu, F.; Sun, R.-C. Role of lignin in a biorefinery: Separation characterization and valorization. J. Chem. Technol. Biotechnol. 2013,88, 346–352. [CrossRef] 26. Paone, E.; Tabanelli, T.; Mauriello, F. The rise of lignin biorefinery. Curr. Opin. Green Sustain. Chem. 2019 ,24, 1–6. [CrossRef] 27. Chen, J.; Yuan, Z.; Zanuso, E.; Trajano, H.L. Response of biomass species to hydrothermal pretreatment. In Hydrothermal Processing in Biorefineries: Production of Bioethanol and High Added-Value Compounds of Second and Third Generation Biomass; Springer International Publishing: Cham, Switzerland, 2017. 28. Forests, Forestry and Logging - Statistics Explained. Available online: https://ec.europa.eu/eurostat/statisticsexplained/index.php/Forests,_forestry_and_logging (accessed on 21 January 2020). 29. Cambero, C.; Sowlati, T.; Pavel, M. Economic and life cycle environmental optimization of forest-based biorefinery supply chains for bioenergy and biofuel production. Chem. Eng. Res. Des. 2016 ,107, 218–235. [CrossRef] 30. Vega, L.Y.; L ó pez, L.; Vald é s, C.F.; Chejne, F. Assessment of energy potential of wood industry wastes through thermochemical conversions. Waste Manag. 2019,87, 108–118. [CrossRef] 31. Belt, T.; Keplinger, T.; Hänninen, T.; Rautkari, L. Cellular level distributions of Scots pine heartwood and knot heartwood extractives revealed by Raman spectroscopy imaging. Ind. Crop. Prod. 2017 ,108, 327–335. [CrossRef] 32. Tungmunnithum, D.; Thongboonyou, A.; Pholboon, A.; Yangsabai, A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines 2018,5, 93. [CrossRef] 33. Species - EUFORGEN European Forest Genetic Resources Programme. Available online: http://www. euforgen.org/species/(accessed on 27 March 2020). 34. IFN6 — ICNF. Available online: http://www2.icnf.pt/portal/florestas/ifn/ifn6 (accessed on 27 March 2020). 35. Tümen, ˙ I.; Akkol, E.K.; Ta¸stan, H.; Süntar, I.; Kurtca, M. Research on the antioxidant, wound healing, and anti-inflammatory activities and the phytochemical composition of maritime pine (Pinus pinaster Ait). J. Ethnopharmacol. 2018,211, 235–246. [CrossRef] 36. del R í o, P.G.; Gomes-Dias, J.S.; Rocha, C.M.R.; Roman í , A.; Garrote, G.; Domingues, L. Recent trends on seaweed fractionation for liquid biofuels production. Bioresour. Technol. 2019,299, 122613. [CrossRef] 37. Räisänen, T.; Athanassiadis, D. Basic chemical composition of the biomass components of pine, spruce and birch. Sci. Res. 2013. 38. Shemfe, M.B.; Gu, S.; Ranganathan, P. Techno-economic performance analysis of biofuel production and miniature electric power generation from biomass fast pyrolysis and bio-oil upgrading. Fuel 2015,143, 361–372. [CrossRef] 39. Akgül, M.; Çöpür, Y.; Temiz, S. A comparison of kraft and kraft-sodium borohydrate brutia pine pulps. Build. Env. 2007,42, 2586–2590. [CrossRef] 40. Chaula, Z.; Said, M.; John, G.; Manyele, S.; Mhilu, C. Modelling the Suitability of Pine Sawdust for Energy Production via Biomass Steam Explosion. Smart Grid Renew. Energy 2014,5, 1–7. [CrossRef] 41. Gulsoy, S.K.; Ozturk, F. Kraft pulping properties of european black pine cone. Maderas Cienc. Y Tecnol. 2016 , 17, 875–882. [CrossRef] 42. Cotana, F.; Cavalaglio, G.; Gelosia, M.; Nicolini, A.; Coccia, V.; Petrozzi, A. Production of bioethanol in a second generation prototype from pine wood chips. Energy Procedia. 2014,45, 42–51. [CrossRef] 43. Miranda, I.; Mirra, I.; Gominho, J.; Pereira, H. Fractioning of bark of Pinus pinea by milling and chemical characterization of the different fractions. Maderas. Cienc. Y Tecnol. 2017,19, 185–194. [CrossRef] Molecules 2020,25, 2931 23 of 29 44. Fradinho, D.M.; Neto, C.P.; Evtuguin, D.; Jorge, F.C.; Irle, M.A.; Gil, M.H.; Pedrosa de Jesus, J. Chemical characterisation of bark and of alkaline bark extracts from maritime pine grown in Portugal. Ind. Crop. Prod. 2002,16, 23–32. [CrossRef] 45. Ferreira-Santos, P.; Genisheva, Z.; Botelho, C.; Santos, J.; Ramos, C.; Teixeira, J.A.; Rocha, C.M.R. Unravelling the biological potential of pinus pinaster bark extracts. Antioxidants 2020,9, 334. [CrossRef] 46. Miranda, I.; Gominho, J.; Mirra, I.; Pereira, H. Chemical characterization of barks from Picea abies and Pinus sylvestris after fractioning into different particle sizes. Ind. Crop. Prod. 2012,36, 395–400. [CrossRef] 47. Vieito, C.; Pires, P.; Fernandes, É .; Velho, M. Chemical characterization of pine bark (Pinus pinaster Aiton subsp. atlantica), antioxidant properties and phenolic profile of its extracts. Millenium J. Educ. Technol. Heal. 2019,8, 79–87. [CrossRef] 48. Khan, I.U.; Shah, A.A.; Sahibzada, F.A.; Hayyat, A.; Nazar, M.; Mobashar, M.; Tariq, A.; Sultana, N. Carcass characteristics and serum biochemical profile of Japanese quail by the supplementation of pine needles and vitamin E powder. Biologia (Bratisl). 2019,74, 993–1000. [CrossRef] 49. Ramay, M.S.; Yalçın, S. Effects of supplemental pine needles powder (Pinus brutia) on growth performance, breast meat composition, and antioxidant status in broilers fed linseed oil-based diets. Poult. Sci. 2019 , 2019.99, 479–486. [CrossRef] [PubMed] 50. Dönmez, I.E.; Hafizo ˇ glu, H.; Kilic, A.; Tümen, I.; Sivrikaya, H. Chemical composition of fourteen different coniferous species cones growing naturally in Turkey. Wood Res. 2012,57, 339–344. 51. López-Mata, L. Proteins, amino acids and fatty acids composition of nuts from the mexican endemic rarity, Pinus maximartinezii, and its conservation implications. Interciencia 2001,26, 606–610. 52. Cheikh-Rouhou, S.; Hentati, B.; Besbes, S.; Blecker, C.; Deroanne, C.; Attia, H. Chemical composition and lipid fraction characteristics of Aleppo pine (pinus halepensis Mill.) seeds cultivated in Tunisia. Food Sci. Technol. Int. 2006,12, 407–416. [CrossRef] 53. Tukan, S.K.; Al-Ismail, K.; Ajo, R.Y.; Al-Dabbas, M.M. Seeds and seed oil compositions of Aleppo pine (Pinus halepensis Mill.) grown in Jordan. Riv. Ital. Delle Sostanze Grasse 2013,90, 87–93. 54. Rodrigues-Corr ê a, K.C.d.S.; de Lima, J.C.; Fett-Neto, A.G. Pine oleoresin: Tapping green chemicals, biofuels, food protection, and carbon sequestration from multipurpose trees. Food Energy Secur. 2012,1, 81–93. 55. Wiyono, B.; Tachibana, S.; Tinambunan, D. Chemical compositions of pine resin, rosin and turpentine oil from west java. Indones. J. Res. 2006,3, 7–17. [CrossRef] 56. Wang, Z.; Lei, T.; Yan, X.; Chen, G.; Xin, X.; Yang, M.; Guan, Q.; He, X.; Gupta, A.K. Common characteristics of feedstock stage in life cycle assessments of agricultural residue-based biofuels. Fuel 2019 ,253, 1256–1263. [CrossRef] 57. Mitchell, G.R.; Biscaia, S.; Mahendra, V.S.; Mateus, A. High value materials from the forests. Adv. Mater. Phys. Chem. 2016,6, 54–60. [CrossRef] 58. Ehn, M.; Thornton, J.A.; Kleist, E.; Sipilä, M.; Junninen, H.; Pullinen, I.; Springer, M.; Rubach, F.; Tillmann, R.; Lee, B.; et al. A large source of low-volatility secondary organic aerosol. Nature 2014 ,506, 476–479. [CrossRef] [PubMed] 59. Ferreira-Santos, P.; Genisheva, Z.; Pereira, R.N.; Teixeira, J.A.; Rocha, C.M.R. Moderate electric fields as a potential tool for sustainable recovery of phenolic compounds from pinus pinaster bark. Acs Sustain. Chem. Eng. 2019,7, 8816–8826. [CrossRef] 60. Silva, B.; Martins, M.; Rosca, M.; Rocha, V.; Lago, A.; Neves, I.C.; Tavares, T. Waste-based biosorbents as cost-effective alternatives to commercial adsorbents for the retention of fluoxetine from water. Sep. Purif. Technol. 2020,235. [CrossRef] 61. Kim, K.H.; Daugaard, T.J.; Smith, R.; Mba-Wright, M.; Brown, R.C. Recovery of resin acids from fast pyrolysis of pine. J. Anal. Appl. Pyrolysis 2019,138, 132–136. [CrossRef] 62. Shi, J.; Nawaz, H.; Pohorly, J.; Mittal, G.; Kakuda, Y.; Jiang, Y. Extraction of polyphenolics from plant material for functional foods - Engineering and technology. Food Rev. Int. 2005,21, 139–166. [CrossRef] 63. Wen, L.; Zhang, Z.; Sun, D.W.; Sivagnanam, S.P.; Tiwari, B.K. Combination of emerging technologies for the extraction of bioactive compounds. Crit. Rev. Food. Sci. Nutr. 2020,60, 1826–1841. [CrossRef] 64. Chemat, F.; Fabiano-tixier, A.S.; Abert, M.; Allaf, T.; Vorobiev, E. Trends in analytical chemistry solvent-free extraction of food and natural products. Trends Anal. Chem. 2015,71, 157–168. [CrossRef] 65. Lourenço, S.C.; Mold ã o-Martins, M.; Alves, V.D. Antioxidants of natural plant origins: From sources to food industry applications. Molecules 2019,24, 4132. [CrossRef] Molecules 2020,25, 2931 24 of 29 66. Maqsood, S.; Adiamo, O.; Ahmad, M.; Mudgil, P. Bioactive compounds from date fruit and seed as potential nutraceutical and functional food ingredients. Food Chem. 2019,308, 125522. [CrossRef] 67. Fidelis, M.; De Moura, C.; Kabbas, T.; Pap, N.; Mattila, P.; Mäkinen, S.; Putnik, P.; Kovaˇcevi´c, D.B.; Tian, Y.; Yang, B.; et al. Fruit seeds as sources of bioactive compounds: Sustainable production of high value-added ingredients from by-products within circular economy. Molecules 2019,24, 3854. [CrossRef] 68. Tanase, C.; Cosarc ă , S.; Muntean, D.L. A critical review of phenolic compounds extracted from the bark of woody vascular plants and their potential biological activity. Molecules 2019 ,24, 1182. [CrossRef] [PubMed] 69. Sharma, A.; Goyal, R.; Sharma, L. Potential biological efficacy of Pinus plant species against oxidative, inflammatory and microbial disorders. Bmc Complement. Altern. Med. 2016,16, 1–11. [CrossRef] 70. Ku, C.S.; Jang, J.P.; Mun, S.P. Exploitation of polyphenol-rich pine barks for potent antioxidant activity. J. Wood Sci. 2007,53, 524–528. [CrossRef] 71. Yesil-Celiktas, O.; Otto, F.; Parlar, H. A comparative study of flavonoid contents and antioxidant activities of supercritical CO 2 extracted pine barks grown in different regions of Turkey and Germany. Eur. Food Res. Technol. 2009,229, 671–677. [CrossRef] 72. Mellouk, H.; Meullemiestre, A.; Maache-Rezzoug, Z.; Bejjani, B.; Dani, A.; Rezzoug, S.A. Valorization of industrial wastes from French maritime pine bark by solvent free microwave extraction of volatiles. J. Clean. Prod. 2016,112, 4398–4405. [CrossRef] 73. Iravani, S.; Zolfaghari, B. Pharmaceutical and nutraceutical effects of Pinus pinaster bark extract. Res. Pharm. Sci. 2011,6, 1–11. [PubMed] 74. M á rmol, I.; Quero, J.; Jim é nez-Moreno, N.; Rodr í guez-Yoldi, M.J.; Anc í n-Azpilicueta, C. A systematic review of the potential uses of pine bark in food industry and health care. Trends Food Sci. Technol. 2019 ,88, 558–566. [CrossRef] 75. Maimoona, A.; Naeem, I.; Saddiqe, Z.; Jameel, K. A review on biological, nutraceutical and clinical aspects of French maritime pine bark extract. J. Ethnopharmacol. 2011,133, 261–277. [CrossRef] 76. Meullemiestre, A.; Petitcolas, E.; Maache-Rezzoug, Z.; Chemat, F.; Rezzoug, S.A. Impact of ultrasound on solid-liquid extraction of phenolic compounds from maritime pine sawdust waste. Kinetics, optimization and large scale experiments. Ultrason. Sonochem. 2016,28, 230–239. [CrossRef] 77. Egenberg, I.M.; Aasen, J.A.B.; Holtekjølen, A.K.; Lundanes, E. Characterisation of traditionally kiln produced pine tar by gas chromatography-mass spectrometry. J. Anal. Appl. Pyrolysis 2002,62, 143–155. [CrossRef] 78. Stacey, R.J.; Dunne, J.; Brunning, S.; Devi è se, T.; Mortimer, R.; Ladd, S.; Parfitt, K.; Evershed, R.; Bull, I. Birch bark tar in early Medieval England – Continuity of tradition or technological revival? J. Archaeol. Sci. Rep. 2020,29, 102118. [CrossRef] [PubMed] 79. Hoon, Y.L.; Choo, C.; Watawana, M.I.; Jayawardena, N.; Waisundara, V.Y. Short communications Evaluation of the total antioxidant capacity and antioxidant compounds of different solvent extracts of Chilgoza pine nuts ( Pinus gerardiana ). J. Funct. Foods 2015,18, 1014–1021. [CrossRef] 80. Lin, S.; Liang, R.; Xue, P.; Zhang, S.; Liu, Z.; Dong, X. Antioxidant activity improvement of identified pine nut peptides by pulsed electric field (PEF) and the mechanism exploration. LWT Food Sci. Technol. 2017 ,75, 366–372. [CrossRef] 81. Hou, L.; Li, C.; Qiu, J. Comparison of the physicochemical characteristics of Pinus koraiensis L. nut oils from different extraction technologies. Grain Oil Sci. Technol. 2018,1, 113–118. 82. Silva, S.; Costa, E.M.; Calhau, C.; Morais, R.M.; Pintado, M.E. Anthocyanin extraction from plant tissues: A review. Crit. Rev. Food Sci. Nutr. 2017,57, 3072–3083. [CrossRef] 83. da Silva, R.P.F.F.; Rocha-Santos, T.A.P.; Duarte, A.C. Supercritical fluid extraction of bioactive compounds. Trac - Trends Anal. Chem. 2016,76, 40–51. [CrossRef] 84. Marcheafave, G.G.; Tormena, C.D.; Pauli, E.D.; Rakocevic, M.; Bruns, R.E.; Scarminio, I.S. Experimental mixture design solvent effects on pigment extraction and antioxidant activity from Coffea arabica L. leaves. Microchem. J. 2019,146, 713–721. [CrossRef] 85. Venkatesan, T.; Choi, Y.W.; Kim, Y.K. Impact of different extraction solvents on phenolic content and antioxidant potential of pinus densiflora bark extract. Biomed Res. Int. 2019,2019, 1–14. [CrossRef] 86. Mokrani, A.; Madani, K. Effect of solvent, time and temperature on the extraction of phenolic compounds and antioxidant capacity of peach (Prunus persica L.) fruit. Sep. Purif. Technol. 2016 ,162, 68–76. [CrossRef] 87. Fierascu, R.C.; Fierascu, I.; Avramescu, S.M.; Sieniawska, E. Recovery of Natural Antioxidants from Agro-Industrial Side Streams through Advanced Extraction Techniques. Molecules 2019 ,24, 4212. [CrossRef] Molecules 2020,25, 2931 25 of 29 88. Hadzri, H.M.; Yunus, M.A.C.; Zhari, S.; Rithwan, F. The effects of solvents and extraction methods on the antioxidant activity of P. niruri. J. Teknol. Sci. Eng. 2014,68, 47–52. [CrossRef] 89. Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C.R.; Abou-Shehada, S.; Dunn, P.J. CHEM21 selection guide of classicaland less classical-solvents. Green Chem. 2015,18, 288–296. [CrossRef] 90. Dom í nguez, E.; Roman í , A.; Domingues, L.; Garrote, G. Evaluation of strategies for second generation bioethanol production from fast growing biomass Paulownia within a biorefinery scheme. Appl. Energy 2017 , 187, 777–789. [CrossRef] 91. Liu, Y.; Friesen, J.B.; McAlpine, J.B.; Lankin, D.C.; Chen, S.N.; Pauli, G.F. Natural deep eutectic solvents: Properties, applications, and perspectives. J. Nat. Prod. 2018,81, 679–690. [CrossRef] [PubMed] 92. Martins, M.A.R.; Pinho, S.P.; Coutinho, J.A.P. Insights into the nature of eutectic and deep eutectic mixtures. J. Solut. Chem. 2019,48, 962–982. [CrossRef] 93. Ventura, S.P.M.E.; Silva, F.A.; Quental, M.V.; Mondal, D.; Freire, M.G.; Coutinho, J.A.P. Ionic-liquid-mediated extraction and separation processes for bioactive compounds: Past, present, and future trends. Chem. Rev. 2017,117, 6984–7052. [CrossRef] 94. Martins, P.L.G.; Braga, A.R.; de Rosso, V.V. Can ionic liquid solvents be applied in the food industry? Trends Food Sci. Technol. 2017,66, 117–124. [CrossRef] 95. Murador, D.C.; de Souza Mesquita, L.M.; Vannuchi, N.; Braga, A.R.C.; de Rosso, V.V. Bioavailability and biological effects of bioactive compounds extracted with natural deep eutectic solvents and ionic liquids: Advantages over conventional organic solvents. Curr. Opin. Food Sci. 2019,26, 25–34. [CrossRef] 96. Passos, H.; Freire, M.G.; Coutinho, J.A.P. Ionic liquid solutions as extractive solvents for value-added compounds from biomass. Green Chem. 2014,16, 4786–4815. [CrossRef] 97. da Costa Lopes, A.M.; Brenner, M.; Fal é , P.; Roseiro, L.B.; Bogel-Łukasik, R. Extraction and purification of phenolic compounds from lignocellulosic biomass assisted by ionic liquid, polymeric resins, and supercritical CO2.Acs Sustain. Chem. Eng. 2016,4, 3357–3367. [CrossRef] 98. Ivanovi´c, M.; Alañ ó n, M.E.; Arr á ez-Rom á n, D.; Segura-Carretero, A. Enhanced and green extraction of bioactive compounds from Lippia citriodora by tailor-made natural deep eutectic solvents. Food Res. Int. 2018,111, 67–76. [CrossRef] [PubMed] 99. Hou, K.; Bao, M.; Wang, L.; Zhang, H.; Yang, L.; Zhao, H.; Wang, Z. Aqueous enzymatic pretreatment ionic liquid–lithium salt based microwave–assisted extraction of essential oil and procyanidins from pinecones of Pinus koraiensis. J. Clean. Prod. 2019,236, 117581. [CrossRef] 100. Rocha, C.M.R.; Genisheva, Z.; Ferreira-Santos, P.; Rodrigues, R.; Vicente, A.A.; Teixeira, J.A.; Pereira, R.N. Electric field-based technologies for valorization of bioresources. Bioresour. Technol. 2018 ,254, 325–339. [CrossRef] [PubMed] 101. Heleno, S.A.; Diz, P.; Prieto, M.A.; Barros, L.; Rodrigues, A.; Barreiro, M.F.; Ferreira, I.C.F.R. Optimization of ultrasound-assisted extraction to obtain mycosterols from Agaricus bisporus L. by response surface methodology and comparison with conventional Soxhlet extraction. Food Chem. 2016 ,197, 1054–1063. [CrossRef] [PubMed] 102. Alara, O.R.; Abdurahman, N.H.; Ukaegbu, C.I.; Azhari, N.H. Vernonia cinerea leaves as the source of phenolic compounds, antioxidants, and anti-diabetic activity using microwave-assisted extraction technique. Ind. Crop. Prod. 2018,122, 533–544. [CrossRef] 103. Goula,A.M.; Ververi,M.; Adamopoulou,A.; Kaderides,K.Greenultrasound-assistedextractionof carotenoids from pomegranate wastes using vegetable oils. Ultrason. Sonochem. 2017,34, 821–830. [CrossRef] 104. Okolie, C.L.; Akanbi, T.O.; Mason, B.; Udenigwe, C.C.; Aryee, A.N.A. Influence of conventional and recent extraction technologies on physicochemical properties of bioactive macromolecules from natural sources: A review. Food Res. Int. 2019,116, 827–839. [CrossRef] 105. Bouras, M.; Chadni, M.; Barba, F.J.; Grimi, N.; Bals, O.; Vorobiev, E. Optimization of microwave-assisted extraction of polyphenols from Quercus bark. Ind. Crop. Prod. 2015,77, 590–601. [CrossRef] 106. Barba, F.J.; Zhu, Z.; Koubaa, M.; Sant’Ana, A.S.; Orlien, V. Green alternative methods for the extraction of antioxidant bioactive compounds from winery wastes and by-products: A review. Trends Food Sci. Technol. 2016,49, 96–109. [CrossRef] 107. Vinatoru, M.; Mason, T.J.; Calinescu, I. Ultrasonically assisted extraction (UAE) and microwave assisted extraction (MAE) of functional compounds from plant materials. Trac Trends Anal. Chem. 2017 ,97, 159–178. [CrossRef]