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    Topic review

    Conifers Phytochemicals

    Subjects: Plant Sciences
    View times: 12
    Submitted by: Natália Cruz-Martins

    Definition

    The phytochemical constituents present in conifer extracts are nontoxic at therapeutic levels, with polyphenolic compounds having significant biological activities. Stilbenes, terpenes, alkaloids, lignins and flavanoids, such as quercetin, rutin, resveratrol, and the compounds PYC and enzogenol, are the phytochemical components of conifer extracts reported to have sedative, antidiabetic, anticancer and anesthetic effects. In addition, phytochemicals present in conifer extracts assist in the regulation of glucose and lipid metabolism, insulin secretion, stimulating β cells, the NF-kB signaling pathway, the inhibition of gluconeogenic enzymes, ROS protective action as well as targeting and modulating cytokines which affect neuron cells and reduce oxidative stress.

    1. Background

    Medicinal plants have long been used as a source for traditional remedies in nearly all cultures [1]. Nature provides an endless supply of novel phytochemicals, which are referred to as natural products (NPs), and natural product drug development is a difficult task for developing new leads [2]. Traditional medicines (TMs) are valuable because they use natural products; for example, Ayurveda, Kampo, traditional Chinese medicine (TCM), traditional Korean medicine (TKM) and Unani use natural products and have been practiced for thousands of years, blossoming into well-regulated medical systems [3]. As time passed and medication progressed, synthetic drugs, such as enoxaparin, aspirin, warfarin, ibuprofen, naproxen, clopidogrel and diclofenac, became available over the counter and were linked to mild (headaches, back pain) to severe side effects (difficulty breathing, excessive bleeding, and hemorrhage) [4]. There are no doubts that the use of natural products has markedly improved certain forms of cancer, diabetes, hypertension, pain, memory deficit, Alzheimer’s disease (AD), and migraine [5], and their further use should be continued in order to meet the urgent need for effective drugs to treat human diseases [6].

    Coniferous plants, such as plants belonging to the Taxus, Cupressus, Picea, Pinus, Cedrus, Araucaria genera, are found worldwide and have shown several beneficial activities against diseases, highlighting the importance of conifers in drug development [7]. Conifers are woody, have needle-shaped single-veined leaves, and consist of male and female unisexual cones with bract scales [8]. They comprise eight families (Pinaceae, Araucariaceae, Cupressaceae, Podocarpaceae, Cephalotaxaceae, Taxaceae, Phyllocladaceae, Sciadopityaceae), 70 genera, and 630 species [9]. A number of genera include a vast number of species, such as Pinus (110), Podocarpus (105), Juniperus (55), Abies (50), Picea (35), Dacrydium (21), Taxodium (29) Pseudotsuga (22), Agathis (22), Araucaria (19), and Taxus (19), whereas there are some genera which contain a lower number of species, including Larix (10), Cedrus (4), Torreya (6) and Cryptomeria (1) [10]. They can be found in abundance in tropical lowland and submontane forests (Figure 1).

    Figure 1. Global distribution of all conifers [11].

    They contain secondary metabolites that combat pathogens and activate the plant’s defense mechanism [12]. The three major phytochemical groups, viz. terpenoids (resin acids and terpenes), alkaloids (piperidines) and polyphenols (phenolic acids, flavonoids, proanthocyanidins, lignans, acetophenones, and stilbenes) [13], present in the species of conifer trees are shown in Table 1, and their phytochemical compounds’ structures are shown in Figure 2. It is very important to understand the evolutionary pathway of Gymnosperms, in accordance with Sporne’s proposal, wherein the conifers represent the core, and the teachings that we can receive from it, comparing the morphological characters and their correlation with the chemical ones [14].

    Table 1. Phytochemical constituents present in conifers.

    Nitrogen Compounds      
    Alkaloids Vellosimine, 1,6-dehydropinidine, cis-pinidine, 1,6-dehydropinidinone, epipinidinone, cis-pinidinol, trans-pinidine, euphococcinine, α-pipecoline 1, (−)-pinidine P. mariana, P. abies, P. sabiniana, P. torreyana, [13][15][16]
    Lignans Lariciıesinol, taxiresinol, 3’-demethylisolariciresino1-9’-hydroxyisopropylethe, isolariciresinol, deoxypodophyllotoxin, (−)-secoisolariciresinol, 3, 3-demethylisolariciresinol, isotaxiresinol 2, α-conidendrin, (+)-pinoresinol, (−)-matairesinol, arctiin, dibenzylbutyrolactol, (−)-wikstromol, (−)-traxillagenin, (−)-arctigenin, traxillaside, 4′-deme-thyltraxillagenin, [(2R,3R)-2-(4′’-hydroxy-3′’-methoxybenzyl)-3-(4′-hydroxy-3′,5′dimethoxybenzyl)-butyrolactone] T. baccata, J. taxifolia, J. sabina, J. virginiana, J. virginiana, P. roxburghii, Cedrus deodara, T. nucifera [17][18][19][20][21][22][23]
    Polyphenols: Flavonoids      
    Flavanonols Taxifolin, cedeodarin C. deodara, L. simbraca, P. roxburghii, P. mariana, P. abies, A. pindrow, A. excelsa; P. pinea, P. halepensis, P. pinaster, P. gerardiana [21][24][25][26][27][28]
    Flavones Pilosanol B, luteolin, apigenin, apigenin 6-C-b-glucopyranoside P. mariana, A. excelsa, P. abies, P. sylvestris, P. menziesii, P. menziesii, J. communis, A. angustifolia, L. deciduas [15][26][27][29][30][31]
    Biflavones Bilobetin, cupressuflavone II-7-O-methyl-robustaflavone T. wallichiana, C. macrocarpa, A. angustifolia [31][32][33][34]
    Flavonols Quercetin, dihydroquercetin, rutin, kaempferol, dihydrokaempferol J. communis, J. oxycedrus, P. gerardiana, P. roxburghii, P. wallichiana, A. angustifolia, P. abies, L. deciduas, P. sylvestris, P. menziesii, M. glyptostroboides, J. excelsa, P. mariana, J. foetidissima [15][21][29][30][31][35][36][37][38]
    Flavan-3-ols Monomers: (−)-epicatechin, (−)-epicatechin-3-gallate, (+)-catechin, sennidin A, (−)-epigallocatechin, P. pinaster, P. pinea, P. halepensis, P. roxburghii, P. wallichiana, P. gerardiana, J. foetidissima, A. angustifolia, P. abies, L. deciduas, P. sylvestris, J. communis, P. menziesii, J. oxycedrus, M. glyptostroboides, J. excelsa [15][21][27][28][29][31][35][36][37][38]
    Polymers: Procyanidin B1, B2, procyanidin A2, P. halepensis, P. pinea, P. pinaster [28]
    Phenolic acids      
    Benzoic acids p-hydroxybenzoic acid, 2,5-dihydroxobenzoic acid, gallic acid, 4-hydroxybenzoic acid, protocatechuic acid, ellagic acid P. abies, L. deciduas, P. sylvestris, P. menziesii, P. kesiya, J. communis, A. excelsa, P. roxburghii, P. wallichiana, P. gerardiana, L. deciduas, J. communis [21][26][29]
    Hydroxycinnamic acid Caffeic acid, t-cinnamic Acid, p-coumaric acid, vanillic acid, ferulic acid, salicylic acid, sinapic acid, syringic acid, chlorogenic acid, 5-caffeoylquinic acid, caffeic acid 4-O-glucoside P. abies, L. deciduas, P. sylvestris, T. baccata, P. mariana, P. pinaster, P. kesiya, L. deciduas, J. communis, P. menziesii, M. glyptostroboides [15][39][27][29][30][37]
    Stilbenes trans-resveratrol, resveratrol, trans-pinosylvin, cis-stilbenes, pinosylvin, dihydro-monomethyl, trans-stilbenes, trans-piceatannol, trans-piceid, trans-isorhapontin, trans-isorhapontigenin, phenanthrenes, astringin, trans-astringin P. mariana, P. abies, J. communis, P. pinaster, P. sylvestris, P. strobes, P. roxburghii, P. wallichiana, P. gerardiana, P. merkusii [8][15][27][40][41][42][43][44][45][46]

    Figure 2. Structures of phytochemical compounds present in different conifer spp.

    2. Conifers Phytochemicals Components

    2.1. Terpenes

    Terpenes are isoprenoids not containing nitrogen and sulfur and seem to be the main and largest group of natural phytochemicals group in conifers [12]. The terpenoids can be classified as C5 (hemiterpenes), C15 (sesquiterpenes), C20 (diterpenes), C10 (monoterpenes), C25 (sesterpenes), C40 (tetraterpenes), C40 (polyterpenes), and C30 (triterpenes) on the basis of C5 units [47]Table 1 represents the most common mono-, sesqui- and diterpenes present in conifers. In particular, monoterpenes have been extensively studied, especially for their antiviral properties. Further, Porres-Martínez et al. (2016) reported their biological activities, including the anti-inflammatory, anticancer, antioxidant, and neuroprotective effects [48]. However, taxol diterpene derived from Taxus spp. have potential against malaria and cancer [47]. Sesquiterpenes have antiseptic, antimicrobial and disinfectant properties [49]. Kopaczyk et al. (2020) showed that the antioxidant activity of terpenes can prevail over oxidative stress aggravated by internal and external stimuli [12].

    2.2. Alkaloids

    There are several classes of alkaloids which are classified on the basis of the heterocyclic ring system and biosynthetic precursor which are of great interest. The alkaloids comprise quinolizidines, indoles, tropanes, pyrrolidines, pyrrolizidines, imidazoles, piperidines and isoquinoline purines [50]. There are numerous studies on the biological activity and medicinal uses of alkaloids [51]. In addition, alkaloids have been shown to have antitumor, anti-hyperglycemic and antibacterial activities [13]. Virjamo et al. (2020) reported that among the piperidine compounds of P. abies, only 1,6-dehydropinidine exhibited antibacterial effects by using a larger number of strains, whereas cis-pinidine was revealed to be toxic for vertebrates, which may only act in defense against herbivores [13].

    2.3. Polyphenols

    Polyphenols are of major relevance and perform a range of functions from skeletal constituents in various tissues to pigmentation in many plant organs [52]. They act as natural antioxidants, being able to inhibit lipid peroxidation, carcinogenesis, antimicrobial activity, direct capillary constrictive action, phytohormones, and have also the ability to stabilize ascorbic acid [53]. Flavonoids (isoflavones, flavonols, flavanonols, flavones, tannins, flavanones, anthocyanidins), stilbenes (resveratrol), phenolic acids (hydroxybenzoic and hydroxycinnamic acids), lignans, can all be found in plants [54]. Polyphenols, especially flavonoids, such as rutin, quercetin, apigenin, and epicatechin, are widely found in conifers. The genera Araucaria, Pinus, Cedrus, etc. are reported for their antimicrobial, anticancer, antidiabetic, neuroprotective [31] and anti-inflammatory properties and can be used in the treatment of neurodegenerative diseases, as well as being helpful in reducing αβ toxicity and neuronal dysfunction [55].

    2.3.1. Flavonoids

    Flavonoids are the most abundant phenol group in nature, present in a wide range of conifers [56]. Flavonoids have a central three-ring structure, but the different subclasses vary due to the centrally located heterocyclic ring structure (C-ring), which connects the two benzene rings [57]. To date, more than 6000 flavonoids have been recorded in several studies from plants. Flavonoids are aglycones in their basic structure, but most of them are glycosides in plants [58]. The subclasses of flavonoids found in the leaves, barks and seeds of conifers are represented in Table 1.

    2.3.2. Lignans

    Lignans are phenylpropanoids dimers made up of two coniferyl or sinapyl alcohol units bound together at the tails [59]. Isolariciresinol, taxiresinol, lariciresinol, pinoresinol, and their glycosides are examples of such compounds. There is a growing interest in lignans, especially because of their chemotherapeutic ability [60]. The most commonly present lignin compounds in conifer spp. are shown in Table 1.

    2.3.3. Stilbenes

    Stilbenes are produced by a number of conifer species, including Pinus sylvestris and Picea abies. Briefly, stilbenes are phenolic compounds with a heterologous bridge connecting two aromatic rings [61]. Many other compounds, such as trans-pinosylvin, cis-stilbene, resveratrol and piceatannol, have been isolated from the barks of conifer species (Table 1). For stilbenes, excellent antimicrobial effects have been reported [56].

    2.3.4. Tannins

    Tannins are polyphenolic compounds that can be in a wide range of plants. Tannins are colored pigments, astringent and are characterized by a bitter taste [62]. Tannin-rich conifer bark extracts have antimicrobial properties and high potential in preventing lipids from oxidation in the liposome model [63]. As a result, the tannins can be divided into four main classes based on their structural characteristics: gallotannins, complex tannins, ellagitannins and condensed tannins [64]. Condensed tannins (CTs), also well-known as proanthocyanidins, are prevalent in P. abies and P. sylvestris tree bark [62]. Condensed tannins are considered as polymers or oligomers of flavan3-ol units connected by C-C bonds that are hydrolysis resistant [65]. Procyanidins (PCs) and prodelphinidins (PDs) are the most popular PAs. Catechin and other epicatechin units make up PCs. Epigallocatechin units make up PDs [66].

    Tannins exhibit antioxidant activity through various pathways, including free radical scavenging, transition metal chelation, and inhibition of pro-oxidative enzymes [67], besides having the capability to bind and form complexes with proteins and other compounds, and being responsible for their biological activity [68]. Tannins also act as antimicrobial agents, inhibiting extracellular microbial enzymes, depriving microbial growth substrates, and exerting a direct action on microbial metabolism, such as the denaturation of cell membrane proteins [69]. In the food industry, they could be used as functional coatings, adhesives, preservatives and as flavor compounds [56]. In a study, pine and spruce bark-derived PA-rich extracts revealed good potential for use in the food industry to develop preservative agents and to prevent lipid peroxidation in food items containing fatty-acids [63].

    3. Traditional Medicinal Uses

    Since prehistoric times, coniferous plants have been used as a medicinal source. Plant-based research has received more attention in recent years, and the literature supports the possible use of medicinal plants in conventional processes [70]T. orientalis leaves and stems are utilized in traditional medicine to cure nervous system disorders, insomnia, heart palpitations, hemorrhage and fever. Fresh cedar leaves steeped for seven days in a 60% alcohol solution are often used by traditional Chinese physicians to encourage hair growth [71]Cupressus spp. leaves, cones, stem bark have also been revealed to be useful in the treatment of hemorrhoids, bleeding varicose veins, asthma cough, spasms, diarrhea, rheumatism, common colds, piles, urinary tract ailments and vaginal discharge [7]. Different parts of the Pinus spp. bark, leaf, cone, and resin are also prescribed to treat cold-influenza, cough, tuberculosis, and bronchitis as a diaphoretic, rubefacient, antiseptic, diuretic, stimulant and febrifuge, while resin is also used in wound healing and injury [72]. The extract from Juniperus spp. leaves, berries and bark has also been used for the treatment of chronic eczema, hyperglycemia, obesity, tuberculosis, bronchitis, and pneumonia. The female cones, wood and leaves of J. foetidissima, J. communis and J. excelsa are used as a tonic for gout and rheumatism, a carminative, a diuretic, a treatment for urinary tract infection and stomach ache, an expectorant, a stimulant, an emmenagogue, and a treatment for the common cold [7].

    Different parts of Taxus spp. have precise ethnomedicinal uses; for example, the leaves’ juice is used to cure cancer and bronchitis; bark juice and other parts, such as the leaf, are used for asthma and bronchitis, while trunk oil and cones are used to treat sheep diseases, bad breath, halitosis, inflammatory diseases of the lower urinary tract, renal stones, urinary infection, rheumatism dyspeptic complaints, hemorrhoids and cancer [7][73], and powdered dried leaves are considered to be effective in epilepsy, asthma, headache, diarrhea, bronchitis and hiccoughs [74]. A decoction developed from the bark is used to relieve pain from the muscles, knees, and rheumatoid arthritis, whereas a decoction made from the leaves is used to treat liver issues [75].

    4. Conifers Extracts Rich in Phytochemical with Putative Health Effects

    4.1. Oxidative Stress

    The role of oxidative stress in the progression of degenerative ageing is well understood. Diabetes mellitus, coronary heart disease, cancer, inflammation, stroke, neurological conditions (e.g., AD), and ageing have all been linked to reactive oxygen species (ROS) generation [37]. Both enzymatic and non-enzymatic reactions are involved in the synthesis of ROS. ROS are known to be generated by enzymatic reactions present in many cell processes, including the respiratory chain system, prostaglandin synthesis and phagocytosis [76]. All ROS are produced through enzymatic action, including NADPH oxidase, xanthine oxidase and peroxidase in many cell processes, in whom the superoxide radical (O2●−) is generated [77]. Different ROS, formed during enzymatic reactions and with the action of enzymes (amino acid oxidase and xanthine oxidase), include hypochlorous acid (HOCl), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hydroxyl radicals (OH) [78]. The “Fenton reaction” between O2− and H2O2 takes place in the presence of Fe2+ or Cu+, which work as catalysts, producing OH, the most reactive free radical species [79]. The production of ROS has been related to non-enzymatic interactions between oxygen and organic compounds, as well as when cells are in contact with ionizing radiation during mitochondrial respiration [79][80]. Extensive research is currently needed to discover phytochemical compounds with the ability to boost the immune system and reduce oxidative stress [81]. The quest for new antioxidant molecules is a crucial part of promoting healthy ageing and combating oxidative stress [78]. Flavonoids, phenolic acids, vitamins and carotenoids are examples of natural compounds with antioxidant potential that have antagonistic effects on degenerative and inflammatory processes throughout the body, have beneficial effects on the immune and digestive systems, prevent ROS-related chronic problems and improve the overall quality of life, as shown in Figure 3 [73].

    Figure 3. Action mechanism of conifers’ phytochemical compounds in oxidative stress, apoptosis, and neurodegenerative diseases. The phytochemicals’ multi-target effects in the brain include mitochondrial protection, anti-aggregation, anti-oxidant, anti-apoptotic and anti-inflammatory activity.

    4.2. Synergism between ROS and other Diseases

    The overproduction of ROS has been linked to a variety of chronic diseases, including cardiovascular, inflammatory and neurodegenerative diseases, and even cancer. The following sections explain on the relationship between ROS and chronic diseases.

    4.2.1. Antioxidant Activity

    In chronic obstructive pulmonary diseases (COPD), ROS play an important role [82]. The bark, wood, needle, and cone extracts of the Pinaceae family are high in polyphenolic compounds (Pycnogenol), primarily procyanidins, stilbenes, tannins and phenolic acids, and have significant antioxidant activity against ROS [83]. The antioxidant activity of conifer extracts has been confirmed by DPPH, FRAP and reducing power assays [40].

    Flavonoids’ ability to scavenge free radicals can protect the human body from oxidative damage, which accelerates the ageing process [84]. Pycnogenol®, a polyphenol-rich compound extracted from the bark of P. pinaster, P. glauca, and P. mariana, has shown the ability to boost plasma antioxidant capacity and ameliorate pulmonary function and asthma traits [40][85]. In a study by Senthilmohan et al. (2003), 6–12 weeks of supplementation of Enzogenol®, and proanthocyanidin-rich flavonoid extracted from Pinus radiata bark in combination with vitamin C reduced DNA and protein oxidative damage in 55–75-year-old people [86]. In vivo studies have reported that the intake of quercetin alone did not protect DNA, but the combination of flavonoids (quercetin and myricetin) and isoflavonoids provides protection against DNA damage [87]. It has been found that the stilbenoid component resveratrol and piceatannol obtained from conifer spp. have more potent biological activities, namely as antioxidants [88]. Terpenoids and phenolic compounds, such as pinene, lycopene, camphene, gallocatechin, lutein, limonene and catechin found in the extract of conifer bark and needles have also been reported for their antioxidant potential by DPPH, FRAP, H2O2, ABTS assays, as shown in Table 2 [89].

    4.2.2. Anti-Inflammatory Activity

    When contagious microorganisms such as fungi, bacteria and viruses come into contact with the body, they remain in specific tissues and flow into the bloodstream, causing inflammation [90]. This also occurs as an end result of tissue damage, cancer, cell death, degeneration and ischemia [91][92][93]. In most cases, both the innate and adaptive immune responses are responsible for inflammation development [94]. The primary protection against invading foreign microbodies and cancer cells is the innate immune system, which involves macrophages, dendritic cells, and mast cells [90]. In the adaptive immune system, specialized cells (B and T cells) remove foreign pathogens and cancer cells by generating specific receptors and antibodies [95]. Cytokines such as interleukins, interferons, tumor necrosis factor, eicosanoids (leukotrienes and prostaglandins), modulatory inflammation-transcription nuclear factor (NF-ĸB) and chemokines (monocyte chemoattractant protein 1), are the inflammatory mediators and cellular pathways that have been extensively studied in relation to human pathological conditions [96]. Tumor necrosis factor-α (TNF) is a pro-inflammatory cytokine that is secreted by a variety of cells and has a variety of cellular effects [97]. It has also been linked to a variety of human illnesses, including cancer, mental and skin disorders, immune and inflammatory diseases. IL-1 is another cytokine that primarily has a pro-inflammatory effect [98]. It raises the levels of pro-inflammatory cytokines, including IL-1, TNF and IL-6 [99]. On the other hand, IL-1 has been linked to anti-inflammatory properties. Likewise, IL-1α and IL-6 originating from activated mast cells in the innate immune response also boost acute phase protein synthesis and thus show some anti-inflammatory effects [100]. The cytokine family members, including IL-12, IL-27, IL-23 and IL-35, function as a pro- and anti-inflammatory response [96][101][102]. On the other hand, IL-10 has been recognized as an effective anti-inflammatory cytokine, and helps in preventing several pro-inflammatory mediators from further action [103]. It protects tissue from homeostasis, defends against injury and damage caused by an overactive inflammatory response [103][104][105]. TNF-α accelerates PGE2 synthesis changes caused by edema and the flow of blood [34]. The extraction of plant materials is the first step in deciding the plant biological activities. The is a high probability of synergism between bioactive components when a whole extract is used, which could be lost if each and every component is isolated [106]. This form of synergism has been documented in numerous medical studies, generally for anti-inflammatory function [90]. There are different types of extraction and separation processes, such as:

    1. Soxhlet extraction: The Soxhlet extraction method is a more efficient extraction method with high extraction yield and requires less solvent and time. This method requires electricity and solvents such as methanol, petroleum ether, and acetonitrile for the extraction process. However, sometimes high temperature and long extraction time enhance the possibility of thermal degradation and the loss of bioactive compound fraction activity [107].

    2. Percolation: Extraction yield is better in percolation than maceration; in this process, pre-soaked plant material is added to a container, which allows the constantly controlled removal of the extract via a valve at the bottom and adding fresh solvent from the top.

    3. Maceration: Maceration is carried out at room temperature by soaking the material with the solvent with eventual stirring. It has the advantage of moderate extraction conditions but suffers from high solvent consumption, long extraction times and low extraction yields. It could be used for the extraction of thermo labile components.

    4. Ultrasound-assisted extraction: In UAE, the plant material, usually in a glass container, is covered by the extraction solvent and put into an ultrasonic bath. It decreases extraction time and improves extraction yields due to mechanical stress, which induces cavitation and cellular breakdown, and has gained increasing popularity [108]. For the isolation of extract from the solvent, the distillation process and many evaporators are used. After isolation to concentrate the extract, many researchers used a rotary evaporator, a normal air-drying process and distillation methods. Generally, to separate different solvent extracts, a separatory funnel is required [109].

    Anti-inflammation is one of the main recorded effects of conifer phytochemicals among the numerous biological activities that have been studied so far. Table 3 reported the anti-inflammatory effect of conifer phytochemicals in in vivo and in vitro models.

    Cupressuflavone (CUF) isolated from C. macrocarpa has the ability to reduce the levels of several cytokines, including IL-1b, IL-6, TNF-α and PGE2, in plasma dose-dependently, and thus acts as an anti-inflammatory agent [34]. Triterpenoids and abietane type’s compounds extracted from Abies chensiensis show anti-inflammatory effects against NO production in RAW 264.7 macrophage cells [110]. It has been found that tasumatrol, deacetylbaccatin, paclitaxel and many other terpenoids extracted from Taxus spp. are effective in the anti-inflammatory process initiated through the carrageenan and cotton pellets induced edema model [39][111]. Kyung-Jae Cha. (2016) reported that in atopic dermatitis, the Picea wilsonii mast extract is useful and potent only in the inhibition of the production of the inflammatory cytokines IL-6, MCP-1 and IL-13, without significant change in IL-8 production induced in human adult low-calcium high-temperature (HaCaT) cell lines [100]T. occidentalis mother tincture-containing terpenoids (thujone), polyphenols and flavanoids have potential in reducing ulcerative colitis inflammation in the mouse intestine and rectum by decreasing the stimulation of the pro-inflammatory cytokines IL6 and TNF-α induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) [112]. THP-1 cell adhesion to TNF was suppressed by enzogenol at a concentration of 5–25 g/mL onto TNF-α-activated human umbilical vein endothelial cells (HUVEC) by reducing integrin β2 induction and inhibiting monocyte trans-endothelial migration [113]. The anti-inflammatory and platelet-inhibitory effects of pycnozenol, extracted from Pinus maritime bark extract, inhibited the activity of cyclooxygenase (COX)-1 and COX-2 present in human plasma [114]. Inflammation has been attributed to cancer and neurodegenerative diseases [34].

    4.2.3. Anticancer Activity

    According to the report by the World Health Organization, cancer was a major cause of death in 2018, with a death rate of 9.6 million people [115]. Hippocrates, before 370 B.C., coined the word “cancer” to describe carcinoma tumors [116]. On the basis of evidence, bone cancer was identified in Ancient Egyptian mummies in around 1600 B.C., and cancer of the breast was identified in 1500 B.C., although there is no record of a cure for cancer [117]. Giovanni’s research laid the foundation for scientific cancer techniques in 1761, when he performed the first autopsies on dead human bodies to determine the connection between a patient’s disease and their death, as well as pathologic studies [118]. Cancer has been identified as the chief matter of public health concern around the world [119]. Surgery, radiotherapy, and chemotherapy are some of the conventional cancer treatments [120][121]. On the other hand, despite the use of a variety of synthetic drugs for cancer treatment and the successful completion of different management schedules, current therapies are not able to achieve the desired results, as tumor relapse and metastasis are common [122]. Nature contains various chemicals and pharmacologically active substances which act as anticancer drugs [123]. Recently, many of the phytochemicals and synthetic analogs, such as HS-1793 (resveratrol), have been identified as inhibiting the growth of cells and inducing apoptotic cell death, helping to cure cancer [124]. While only a few phytochemical compounds obtained from natural products have been developed into clinically active drugs, their bioactive components may be used as a basis for the development of more successful analogues and prodrugs using chemical techniques such as metabolomics, complete or combinatorial fabrication, and biosynthetic pathway modification [125]. Many phytochemical compounds are highly efficient in inducing apoptosis and cytotoxicity by modulating different MAPK andAKT/PI3K pathways, and suppress cancer cells line invasion and migration potential along with the stimulation of senescence phenotype, regulation of Bax or p53 genes, cell cycle arrest and modulation of IL-8, IFN-γ, TNF, IL-6 [126]. Many of the compounds derived from conifers’ bark and leaves act as antitumor drugs, such as paclitaxel (PTX) (trade name Pycnogenol® and Taxol®), a diterpene found in the crude extract of P. pinaster and Taxus brevifolia bark [127]. Paclitaxel, as well as its analogues docetaxel (taxoteres) and jevtanas (cabazitaxel), are examples of chemotherapeutic synthetic analogues derivative from plants that have been formulated and validated clinically [125]. By binding microtubules, PTX and other microtubule-targeting agents (MTAs) induce cellular death [128]. Microtubules are tubulin heterodimers that play a role in disease and perform numerous cellular functions including transport, force production in cell division, and structural support [129]. During the G2 phase of the cell cycle, tubulin is produced, and microtubules are assembled. Microtubule stabilizing agents, such as PTX, bind to α/β tubulin in order to disassemble microtubules. As a result, they cause cell death and are used as an anti-cancer agent [130]. In general, cells exposed to PTX are stuck in the G2/M phase, resulting in death due to failure to move through the cell cycle [131][132]. Recently, a study published in 2017 found that pycnogenol and PTX at doses of 20 g/mL and 0.5 μM cause DNA and mitochondrial damage in cancer breast cell line (MDA-MB) in 24 h, and concluded that it is possibly a target drug for cancer treatment through DNA and mitochondrial damage mechanisms [127]. From different conifer species crude extracts, the anticancer activities on different cancer cell lines are summarized in Table 4.

    Table 2. Antioxidant capacity of extracts obtained from different conifer spp.

    Conifer spp. Part Used Compounds Nature of Extract Radical Scavenging Assay Dose/Concentration Main Effects References
    Aurocaria cookii Leaves Phenolic compounds Methanol, chloroform, petroleum ether DPPH 1000 μg/mL Methanol extract shows the best antioxidant activity with 63% inhibition, higher than the other two compounds [133]
    A. excelsa Needle Flavanoids Methanol DPPH 50–72.5 μg/mL Methanol/water extract shows antioxidant activity [26]
    C. deodara Heart wood Tannins, flavonoids, and phenolic compounds Water/alcohol DPPH, superoxide radical-scavenging activity, ABTS DPPH-IC50 (μg/mL): 61.89 (water extract),
    75.79 (alcohol extract)
    superoxide radical-scavenging activity—
    IC50 (μg/mL): 87.76 (water extract), 121.55 (alcohol extract).
    ABTS-IC50 (μg/mL): 115.29 (water extract), 122.42 (alcohol extract).
    DPPH radical-scavenging activity and the reducing power of C. deodara were potent in water and alcohol extract [134]
    C. japonica All parts Phenolic compounds Methanol ORAC,
    SOD
    4.09–7.64 TE/mg
    3.63–4.06μg/mL
    The methanol extracts from each part of C. japonica except for pollen showed strong activities in the bioactivity assays. [135]
    J. communis Berry Flavanoids (quercetin rutin,
    apigenin) chlorogenic acid
    Alcohol/Water DPPH EC50 1.42 mg/mL against standard Ascorbic acidEC50 value of 0.365 mg/mL The antioxidant activity was confirmed as 81.63 ± 0.38% by the DPPH assay. [30]
    L. laricina Bark Phenolic compounds Ethanol/Water ORAC IC50 0.878 μg/mL. Bark extract of LL shows significant antioxidant activity [40]
    Metasequoia glyptostroboides Cone Terpenoid Ethyl acetate DPPH, NO, superoxide, and H2O2 5–250 μg /mL Sugiol derived from cone extract show good antioxidant activity—78.38, 72.42, 74.45 and 85.04%, respectively. [136]
    Picea abies Bark Atilbenoids Ethanol/Water DPPH 49.74 μg/mL UVA-induced modification of the stilbene-rich inner bark extracts increased the antioxidant activity as UVA irradiation decreased the capacity of the extracts to prevent lipid oxidation in the liposome system method [42]
    P. smithiana Leaves Phenolic compounds Methanol DPPH IC50 (μg/mL)- Results of the DPPH radical scavenging activity and FRAP study determine that methanol extracts of leaf displayed the highest antiradical efficiency [137]
    228
    FRAP 494
    Reducing Power assay 978
    Pinus gerardiana Bark Phenolic compounds Ethanol DPPH IC50 value μg/mL P. gerardiana shows promising H2O2 radical scavenging activity [89]
    102.8
    H2O2 81.83
    NO2 109.2
    P. halepensis Bark Phenolic compounds Ethanol/Water   IC50 (μg/mL). Ethanol and the water Ethanol and water extract of bark exhibited significant free radical neutralization capacities, at conc. 0.5–8 μg/mL [138]
    DPPH 3.28, 3.26
    ABTS 3.1, 3.59
    P. pinaster Bark Phenolic compounds Ethanol/Water   PB (50%) and (90%) IC50 value μg/mL PP bark extracts formed from PB 50% (50% ethanol) have maximum (DPPH, ABTS) radical scavenging activity while FRAP shows activity with (PB 90%) [27]
    DPPH 49.74
    ABTS 59.41
    FRAP 101.3
    P. roxburghii Bark Phenolic compounds Ethanol   IC50 value μg/mL Pine extract shows significant antioxidant activity [89]
    DPPH 97.54
    H2O2 86.90
    NO2 111.38
    P. wallichiana Bark Phenolic compounds Ethanol   IC50 (μg/mL) Pine extract shows significant radical scavenging activity [89]
    DPPH 111.40
    H2O2 84.18
    NO2 98.5
    Thuja occidentalis Leaves Flavonoids, phenols Methanol DPPH, FRAP 20–100 μg/mL Crude extract shows significant antioxidant activity [139]
    T. occidentalis Non-woody
    branches with leaves
    Polyphenol, flavonoids Mother tincture (MT) DPPH, ORAC, NO 25 or 50 mg/kg T. occidentalis mother tincture displayed 88.3% antioxidant activity by DPPH and about 78% by NO assay [112]
    Taxus baccata Leaves and
    cones
    Flavonoids, phenols Methanol DPPH IC50 (μg/mL) 105.41, 518.51 leaves and cones resp. Acetone and ethyl acetate extract of leaves show good scavenging activity [140]
    Water DPPH 533.66, >1000 leaves and cones resp.
    Acetone DPPH 25.24, 81.43 leaves and cones resp.
    Ethyl acetate DPPH 29.84, 180.26 leaves and cones resp.
    Petroleum ether DPPH 438.92, > 1000 leaves and cones resp.
    T. wallichiana Leaves Terpenoids, flavonoids     IC50 values (μg/mL) The maximum DPPH activity was observed in methanol extract (91.25%), followed by water (87.64%), ethanol (85.23%), and ethyl acetate (83.27%) at the highest concentration (700μg/ml) [141]
    Methanol Superoxide radical 170.30
    DPPH 212.00
    LPO 126.09
    Hydroxyl radical 82.34
    Ethyl acetate Superoxide radical 297.55
    DPPH 301.80
    LPO 151.96
    Hydroxyl radical 199.05
    Water Superoxide radical 257.00
    DPPH 258.29
    Hydroxyl radical 175.33
    T. wallichiana Leaf, stem Polyphenols, flavanoids, terpenoids Methanol DPPH
    FRAP
    IC50 value (μg/mL.)
    Leaves (23.18)
    Stem (56.75)
    DPPH and FRAP activity of TW leaves and stem extract have high antioxidant activities. [142]

    PB-Pine bark; TW-Taxus wallichiana.

    Table 3. Anti-inflammatory capacity of different conifers spp.

    Conifer spp. Part Used Nature of Extract Compounds Major Method(s) of Testing Dose. Conc Main Effect References
    Abies chensiensis Twigs and leaves Ethanol Terpenoids Induce lipopolysaccharide to produce inflammation in RAW 264.7 macrophage cells 0.2–50.0 μM 4 compounds—3α-hydroxyl-8,14,22Z,24-tetraenlanosta-26,23-olide; (5R,20R)-8(14→13R)-abeo-17,13-friedo-3-oxolanosta-8,14(30),22Z,24-tetraen-26,23-olide;
    8,14,22Z,24-tetraen-3-oxolanosta-26,23-olide;
    and (23R, 25R)-3,4-seco-9β H-lanosta-4 (28),7-dien-16α-hydroxyl-26,23-olid-3-oate—extracted from extracts showed significant anti-inflammatory activities of inhibition against NO formation with IC50 value of 15.9, 18.7, 20.18, and 10.9 μM
    [110]
    A. georgei Aerial parts Chloroform, ethyl acetate, n-butanol Flavanoids dimethylbenzene-induced ear oedema in mice 200 mg/kg AG ethyl acetate extract shows 18% inhibition against dimethylbenzene-induced ear edema in mice while carrageenin-induced paw edema in rats shows inhibition ratios 28.2% and 35.6%, after 2 and 6h, respectively. [143]
    Carrageenin-induced paw oedema rat 140 mg/kg
    A. webbiana Leaves Methanol/Petroleum ether extract Flavanoids Carrageenan-induced rat hind paw edema model in Albino mice 400 mg/kg Plant leaves extract possesses significant anti-inflammatory properties [144]
    Agathis robusta Leaves Methanol Flavanoids, tannins and saponins Heat induced hemolytic method in human red blood cell (HRBC) membrane 400 μg/kg Leaves extract shows good antiinflammatory activity [145]
    Cedrus deodara Stem bark Methanol Deodarin, quercetin, taxifolin Carrageenin-induced paw edema in Albino rat 100 mg/kg Anti-inflammatory activity with 43.47% inhibition [146]
    Cupressus macrocarpa Leaves Methanol Cupressuflavone (CUF) Carrageenan-induced paw edema model in Mice 40, 80, and
    160 mL/kg
    CUF demonstrated antiinflammatory
    activity by inhibiting paw edema with 55, 60, and 64%, by decreasing the plasma pro-inflammatory mediators PGE2, IL-6, TNF-a and IL-1b
    [34]
    Juniperus communis Berry Alcohol/Water Flavanoids (quercetin rutin, apigenin) chlorogenic acid Acute-dextran and kaolin subacute inflammation induced in Wistar Rat 10 mL/kg The antiinflammatory action of the juniper extract, administered as a microemulsion in acute-dextran model was increased when compared to kaolin subacute inflammation induced model. [30]
    J. oxycedrus Berry Ethanol, n-butanol Flavonoids (amentoflavone, cupressuflavone, hinokiflavone, and rutin) Carrageenan-induced hind paw edema model in mice 100 mg/kg Ethanol extract of Joso berries displayed remarkable inflammatory inhibition ranging between 24.5% and 23.7% at 100 mg/kg in carrageenan-induced edema model [147]
    J. foetidissima Berry Ethanol Flavonoids (amentoflavone, cupressuflavone, hinokiflavone, and rutin) carrageenan-induced hind paw edema model in mice 100 mg/kg JFB extract at a dose of 100 mg/kg. shows high antiinflammatory effect 26.9% [147]
    Pinus gerardiana, P. roxburghii, P. wallichiana Bark Ethanol Flavanoid, tannin against albumin denaturation, HRBC membrane stabilization assay 2500 μg/mL P. roxburghii extract showed highest (%) of inhibition and protection i.e 86.54 and 89.92 against albumin denaturation and HRBC membrane stabilization. However, P. wallichiana have least inhibition and protection percentage, i.e., 76.54 and 81.2% [89]
    Taxus baccata Aerial parts Methanol Terpenoids ear edema induced in mice 3.2 mg/ear T. baccata extract displayed best activity [39]
    T. baccata Bark Ethanol Alkaloids, terpenoids, flavonoids carrageenan-induced paw edema in Wistar Albino rat 200 mg/kg Percentage of inhibition is 44% at a dose of 200 mg/kg [148]
    T. baccata Heart wood Ethanol Taxoids, lignans carrageenan-induced hind paw edema model inS wiss albino mice 30–100 mg/kg TBW shows significant antinociceptive and anti-inflammatory activities [17]
    T. wallichiana Bark Methanol Tasumatrol B, 1,13-diacetyl-10-deacetylbaccatin III (10-DAD) and 4-deacetylbaccatin III (4-DAB) carrageenan-induced paw edema and Cotton-pellet oedema model in Wistar rats and Swiss albino mice 20 and 40 mg/kg; 40 mg/kg In a carrageenan-induced inflammation model, tasumatrol B at a dose of 20 mg/kg showed significant activity, while in a cotton-pellet edema model tasumatrol B was found to be highly significant at the dose of 40 mg/kg. [111]
    Thuja occidentalis Non-woody branches with leaves Mother tincture (MT) Polyphenols, flavonoids Administered 2,4,6-trinitrobenzenesulfonic acid to induce intrarectal colitis in mice 25 or 50 mg/kg MT manage to relieve intestinal inflammation experimentally induce by TNBS in 7 days. [112]

    JFB—Juniper foetidissima berry; AG—Abies georgei; TBW—Taxus baccata heart wood.

    Table 4. In vivo and in vitro anticancer and cytotoxic studies of conifer extracts.

    Conifer spp. Part Used Nature of Extract Compounds In Vitro and in Vivo Model Dose. Conc Main Effects References
    Abies georgei Aerial parts Chloroform, ethyl acetate, n-butanol Flavanoids Human tumor cell lines-A549, QGY-7703, LOVO, 6T-CEM 77.5, 11.1, 7.8, 32.8 μg/mL AGC extract has potent tumour and antiproliferative effects in humor tumor cell lines [143]
    (Mice) S180 tumours cell lines 100, 200 and 400 mg/kg AGC also exhibited activity in tumour growth inhibition in a dose-dependent manner, with ratios of 46.7, 53.1 and 31.0% at doses of 100, 200 and 400 mg/kg, respectively
    Araucaria angustifolia Female strobili Water Fatty acids and polyphenols Laryngeal carcinoma HEp-2 cells 100–500 μg/mL AAE inhibit the activity of mitochondria complex I and induce redox stress and cytochrome c, which leads cleavage of nuclear proteins of larynx HEp-2 cancer cells [149]
    Cedrus deodara Stem wood Chloroform Lignans (Matairesinol, dibenzylbutyrolactol, (−)-Wikstromol) In vitro human cell lines (cervix, breast, colon, liver, CNS, prostrate) In vitro cytotoxicity IC 50 value-Wikstromol (71.31–93.63) and Matairesinol (50.84–95.36) μg/mL CD lignin mixture have potent to show a cytotoxic effect at the maximum in CNS and at the minimum in liver against cancer cell lines in a dose-dependent manner at 100 μg/mL from 49 to 95%. [22]
    Human T lymphoblast, acute lymphoblastic leukemia cell line, Molt-4 and human promyelocytic leukemia cell line (HL-60) IC50 (μg/mL)
    15
    AP9-cd-induced endogenous NO production leads to the generation of peroxide and disruption of mitochondrial membrane potential, leading to apoptotic pathway activation
    Increase in sub-G0 fraction from 35 to 60% in 24 to 48h
    [150]
    In vivo swiss albino mice (K562 cells)   The lignin mixture displays anti-cancer effects by regulating annexin V binding, intracellular caspase activities and DNA fragmentation
    C. deodara Needle Ethanol Kaempferol, myricetin, isorhamnetin and quercetin HepG2 cells IC50 114.12 μg/mL TFPNCD shows potent cytotoxicity by inhibiting the growth of HepG2 cells in a dose-dependent manner
    Regulates cell cycle and apoptosis
    [151]
    Cryptomeria japonica Leaves Methanol Flavonoids Albino mice of Ehrlich Ascites Carcinoma (EAC). 100–400 μg/gm Tumor cell count as well as the amounts of ascetic tumour cells in packed cells were significantly reduced in infected mice treated with MC [152]
    Juniper communis Berry Methanol and water Phenolic compounds CaCo2 and HeLa carcinoma cell lines IC50 1300–2500 μg/mL Methanol and water extracts of JCB show potent antiproliferative activity against cancer cell lines [153]
    J. taxifolia Leaves Chloroform Polyphenols and lignan human leukemia (HL-60) cells 2.5 μg/mL 7α-hydroxysandaracopimaric acid, a diterpenoid compound obtained from J. taxifolia leaves, shows antitumor effects on HL-60 cells [154]
    J. phoenicea Aerial parts Chloroform Polyphenols   IC50 values (μg/mL) It is found that JPCF disrupts cell cycle progression in the G0/G1phase and shows apoptotic, antiproliferative and necrotic effects on cancer cells lines [155]
    Human lung (A549) 34.2
    Breast (MCF-7) 24.5
    Liver (HepG2) cancer cells 57.6
    J. foetidissima Needle Methanol Quercetin, rutin Rat brain tumor (C6) cell lines IC50 values (μg/mL)
    10.65
    J. foetidissima needle extract showed significant antiproliferative activity [38]
    M. glyptostroboides Leaf Water Polyphenols PC12 cells 25 μg/mL M. glyptostroboides leaf extract shows a cytotoxic effect and prevents oxidative damage of neuronal PC12 cells, protecting them from apoptosis; it was also found to significantly inhibit the release of LDH, which may result from apoptosis or necrosis [37]
    Picea wilsonii Whole plant DMSO ND Human keratinocyte HaCaT cell lines 1–3 g/mL PwM extracts inhibit the production of MCP-1 IL-6, IL-13 and but do not inhibit IL-8 production [100]
    Pinus kesiya Woody twig Ethanol Phenolic compounds and flavonoids Human hepatocarcinoma (HepG2) cell lines IC50 (μg/mL) 52.0 PK Extract exhibited a potent cytotoxic effect in the HepG2 cell line [156]
    P. kesiya Branch Ethanol Phenolic compounds and flavonoids Human leukemic U937
    cancer cells
    IC50: 299 μg/mL PK ethanol extract possesses anticancer activity against U937 human leukemic cells via apoptosis [157]
    P. merkusii Leaves Methanol Phenolic compounds MCF-7, A549, HT 1080 and HepG2 Huh-7 cancer cell lines IC50 (μg/mL)
    4.5, 16, 4.1,
    5.6, 9.5
    PM methanol extract possesses anticancer activity against human cancer cell lines [158]
    T. baccata Leaves, cones Methanol Phenolic compounds HCT-116 human colon cancer and MDA-MB-231 human breast cancer cell lines IC50 μg/mL
    Leaves: 14.43 and 4.59 cones: 49.69 and 133.53
    Methanol extracts of leaves had better activity on HCT-116 cells than seed cone extract, with IC50 values of 14.3 for 24 h and 4.59 for 72 h. Meanwhile, extracts did not show any significant cytotoxic effects on the cancer cell lines [140]
    T. wallichiana Heartwood Methanol Lignans 1 (taxiresinol 1) 2, 3 colon, ovarian liver, and breast cancer cell lines IC90 lignan 2 and 3 μg/mL
    Caco 2:0.08 and 0.056 and 0.251
    Taxiresinol 1 shows anticancer activity against ovary, colon, liver and breast cancer cell lines, while lignans 2 and 3 were found to be most active against Caco-2 cell lines [159]
    T. yunnanensis All parts ND α-Conidendrin MCF-7 andMDA-MB-231 cancer cell lines 40 μM α-conidendrin have the potential to inhibit human breast cancer cell lines MDA-MB-231 and MCF-7, showing viability of 73 and 82%, respectively [19]
    P. roxburghii Leaves Water and ethanol Phenolic compounds A549 human lung cancer cell line 111.2 and 112.7 μg/mL PRL extract shows potent anticancer activity against cancer cell lines. [160]
    Taxus cuspidata Branches and leaves Water Polysaccharides MCF7 IC50 μg/mL Purified polysaccharides (Pe4) on HeLa cells had the highest inhibitory effect, and its IC50 value is 89.9, while (Pe1) shows the best cytotoxic capacity against cancer lines HepG2 and MCF7, with IC50 conc. 132.0 and 169.0 μg/mL, respectively [161]
    169.0
    Hela 89.9
    HepG2 132.0
    Thuja occidentalis Leaves and non-woody branches Mother tincture (MT) Polyphenols including flavonoids Caco-2 cells 25 or 50 mg/kg Caco-2 cells exposed to H2O2 and T. occidentalis MT proves its radical scavenging activity by reducing GSH level by 103% and 98% as compared to TNBS group; MT also managed to reduce the lipid peroxidation [112]
    T. occidentalis Leaves Ethanol ND Human NSCLC (A549) cell lines IC50 μg/mL Extract of TO shows both anticancer and antiproliferative activities against NSCLC (A549) cell lines in a dose-dependent manner. [162]
    282
    Human normal embryonic cell lines (L-132) 376
    T. occidentalis ND Mother tincture (MT)
    Thujone-rich fraction (TRF)
    Thujone A375 human malignant melanoma cell line 200 μg/mL TRF as compared with TO MT on exposure to A375 cells exhibited highly cytotoxic, apoptotic and antiproliferative effects, but TRF shows a lower growth inhibitory response towards peripheral blood mononuclear cell (normal cells) [163]

    ND—Not determined; AGC—Abies georgei chloroform extract; AAE—Araucaria angustifolia water extract; TFPNCD—total flavonoids from the pine needles of Cedrus deodara; PRL—P. roxburghii leaves.

    4.2.4. Neurodegenerative Diseases

    Neurodegenerative diseases (NDs) are more common among the elderly and may even lead to death, and so are a major threat in the 21st century [164]. AD, Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and the spinocerebellar ataxias are examples of ND [165], whose main features include nitrosative/oxidative stress, mitochondrial dysfunction, aggregated proteins accumulation, synapse loss, neuro-inflammation and decreased neuronal survival [166]. The progression of ND is also affected by genetic and surrounding ecological factors [164]. Indeed, it has been stated that the appropriate mechanism behind the cause of ND is mitochondrial dynamics variation, which elevates the oxidative damage, altering the biological activity of respiratory complexes, which results in brain energy dysfunction [167]. These stimuli trigger cellular stress, which leads to the synthesis and release of brain-derived neurotrophic factor (BDNF), as well as the activation of transcription factor CREB (cAMP response element-binding protein), with consequent expression of Arc (synaptic plasticity), PGC-1 (cellular energy metabolism), and APE1 (DNA repair enzyme), as well as the activation of the tropomyosin-related kinase (Trk B) receptor family and other downstream protein kinases [168].

    Neurotrophins avoid neuron degeneration by binding to and activating the Trk receptor family, which is located in the plasma membrane [166]. Neurotrophins work by binding to and activating the Trk receptor family, which is found in the plasma membrane, to prevent neuron degeneration. Since neurotrosphins bind to Trk receptors, they create a microenvironment that promotes neuron development [169]. Various intracellular signaling pathways, such as ERK and PI3k/AKT, are regulated as a result of this binding, allowing cells to survive and aiding in the recovery of neurons from neurodegeneration. Additionally to signaling pathway activation, neurotrophins support Bcl-2 gene expression, which inhibits intracellular apoptosis [169]. Thus, early diagnosis of neurodegeneration may allow for early treatment, which may help to prevent the disease from progressing further [170]. Inhibition of the N-methyl-D-aspartate (NMDA) receptor can prevent or postpone AD. The drugs memantine and namzaric, which act as antagonists for the NMDA receptor, are used to treat AD patients [171].

    Bioactive molecules have been recognized for their valuable biological effects, including neuroprotective properties, such as the ability to regulate mitochondria in a way that is distinct from TMs [172]. Branco et al. (2018) found that the flavonoid-rich A. angustifolia bracts extract (AAE) has neuroprotective properties by restoring rotenone-induced mitochondrial complex I, inhibiting the formation of lipid peroxidation and neuronal ROS, and through over expression of NDUFS7 protein and NDUFV2 gene levels in human dopaminergic SH-SY5Y cells [31]. Bark extract of P. pinaster shows protective effects against oxidative hemolysis induced by H2O2, the formation of thiobarbituric acid reactive products and lipid peroxidation [173]. In addition, it prevents oxidative damage to many proteins aggregation and may lessen the risk of several NDs, such as AD, PD and HD [174]. The neuro-protective potential of various conifer spp. crude extracts is summarized in Table 5.

    Table 5. Conifers’ phytochemicals demonstrating neuroprotective potential in vitro and in vivo.

    Conifers spp. Compounds with Neuroprotective Potential Model Effective Concentration Relevant Bioactivities Reference
    Abies holophylla Holophyllin-D C6 glioma cells 20 μM Diterpenes compound holophyllin D shows neuroprotective potential in C6 glioma cells by inducing nerve growth factor [175]
    Araucara angustifolia Catechin, epicatechin and rutin Rat 10 mg/mL AAE has antioxidant and neuroprotective properties as it decreases the TBARS levels, CAT activity and NO production in the hippocampus region of the brain in rats. [176]
    A. angustifolia Catechin, epicatechin, rutin, quercetin and apigenin human dopaminergic SH-SY5Y cells 5 μg/mL Decrease in the production of neuron (ROS) and lipid peroxidation. [31]
    A. angustifolia Quercetin cockroach 200–400 μg/g Neurotoxicity modulates the behavior of insects by altering the dopaminergic pathways, as quercetin has the ability to induce selective inhibitory actions on NMDA and GABA receptors and inhibit the enzyme acetylcholinesterase (AChE) [177]
    Cedrus deodara Cedrin PC12 cells 0.1, 1 and 10 μM PC12 cells injured by amyloid β1–42 can be improved by cedrin. Cedrin can reduce (ROS) overproduction, enhance the activity of SOD and decrease MDA content and inhibition of oxidative stress, improvement of mitochondrial dysfunction and suppression of apoptosis in PC12 cells [178]
    Metasequoia glyptostroboides Gallic acid, rutin, myricetin, kaempferol, quercitrin, epigallocatechin, epicatechin gallate epigallocatechin gallate and caffeic acid Neuronal PC12 cells 2 mg/mL The extracts effectively reduced the hydrogen peroxide-induced lipid peroxidation in neuronal PC12 cells by decreasing intracellular ROS accumulation [37]
    Pinus densiflora Catechin, quercetin dehydrate, astragalin and kaempferol Mice 50–100 mg/kg Catechin displayed a potential effect protecting mouse brains from oxidative damage via the improvement of the antioxidant capacities of TAC, the GSH-redox system, SOD and CAT in the hippocampus region as well as the inactivation of cytokines such as NF-kB in pyramidal cells of the hippocampal CA1 region, while PNE shows antiamnesic properties and effects in Alzheimer’s, as it attenuated the increase in serum corticosterone level and up-regulation of GR hippocampal gene expression [179][180]
    P. eldarica Needle extract Mice 50 mg/kg Alkanes, sterols, terpenoids, and quercetin, which is found in P. eldarica, help in inducing sleep and alter the sleep–wake cycle partly via activation of GABA receptors [181]
    P. massoniana Polyprenols Mice 25 mg/kg Polyprenols significantly increased T-AOC, GSHPx, damaging peroxide components from cells in order to stop the lipid peroxidation chain reaction and avoid excessive hydrolysis to form NEP, MDA, SOD activity (remove free radicals) and β-site AβPP cleaving enzyme 1 (BACE1) expression, while NOS activity, MDA concentration, NO, concentration of Aβ1-42 and PS1 were reduced [182]
    P. pinaster Pycnogenol (PYC) Mice 20 mg/kg In the MPTP-induced mouse model, PYC could prevent dopaminergic neurons by reducing oxidative loads, suppressing glial cell activation, and inhibiting inflammatory responses [85][183]
    P. roxburghii Quercetin, rutin, gallic acid Wistar albino 100–300 mg/kg Quercetin and gallic acid, both present in stem bark, have been shown to inhibit neuronal toxicity and apoptosis by reversing mitochondrial dysfunction and free radical development [184]
    Thuja occidentalis Water extract Mice 100 mg/kg CNS depressant activity, anticonvulsant and muscle relaxant activity [185]
    Torreya nucifera, Arctigenin Rat Cortical cells 0.01 µM to 10.0 µM. Arctigenin significantly attenuated glutamate-induced neurotoxicity by inhibiting the binding of [3H]-kainate to its receptors [23]
    T. semen Polyphenols, flavonoids Mice 0–10 mg/mL TS increased the level of total glutathiones [186]

    T-AOC—total antioxidative capacity; GSHPx—glutathione peroxidise; SOD—super oxide dismutase; NEP—neprilysin; MDA—malondialdehyde; NO—nitric oxide, NOS—nitric oxide synthase; PS1—presenilin 1, CAT—catalase.

    4.2.5. Alzheimer’s Disease (AD)

    AD is a common neurodegenerative disease that affects 80% of the elderly population, accounting for about half of all dementia cases and ultimately results in death [187]. Its symptoms include failure to learn, gradual memory loss, and deterioration in behavior and neuronal function [188]. Regarding treatment, only five approved treatment options are licensed in the European Union for the treatment of AD, including rivastigmine, donepezil (cholinesterase inhibitors (ChEIs), galantamine, and memantine (NMDAR antagonist) [189]. An antimitotic agent paclitaxel widely used for the treatment of lung, ovarian and breast cancer has also been investigated as a possible treatment for AD [190]. It is mainly effective in the treatment of tauopathies, which are disorders caused by mutations in the tau protein, which is abundant in central nervous system (CNS) cells and acts by stabilizing microtubules [191]. The consumption of polyphenol-rich foods or beverages has been related to the prevention of AD in distinct studies [192]. The accumulation of amyloid-(A) in brain and leptomeningeal vessels causes cerebral amyloid angiopathy (CAA), which is also a central component of neuritic plaques in AD amyloid-(A) and has been related to the pathogenesis of two of the most common forms of dementia: AD and CAA. As a result, Aβ should be a top priority in the treatment of these diseases, which currently have no effective therapies [193]. Taxifolin, an antioxidant and anti-glycation flavonoid, reduces Aβ aggregation and its accumulation in the cerebrovascular system. In vitro studies have shown that taxifolin facilitates Aβ clearance in the brain, prevents Aβ fibril formation and CAA cognitive loss, and increases cerebral blood flow [194]. The methanol extract of P. roxburghii bark contains bioactive compounds, such as quercetin and gallic acid, which play important roles in neuroprotection by reversing mitochondrial dysfunction, free radical formation, and improving memory and cognition in rats, as well as reducing oxidative stress by improving acetylcholine levels. Furthermore, anti-AD activity has been documented in Pinus species, such as P. halepensis and P. massoniana [195]. Piceatannol, a compound derived from pine bark, has proven to be effective in preventing AD [196]. Resveratrol (RV), a stilbenoid, protects neurons from oxidative damage in a variety of ways, such as lowering lipid peroxidation and increasing intracellular antioxidant levels including antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase 1 (HO-1) [197]. In this way, RV acts as an anti-AD agent by reducing neuroinflammation, inhibiting Aβ-plaque formation and tauopathy, and as a result inhibits neuronal death and improves memory [198]. Pycnogenol derived from P. pinaster bark has antioxidant, anti-inflammatory, and neuroprotective properties, including inhibition of amyloid-induced neuron apoptosis [199]. When the effect of pycnogenol was investigated in AD-related pathology in a β-amyloidosis mouse model, a decline in plaque numbers was found, while no changes were reported in the soluble β-amyloidosis levels, astrocytes, neurons, microglia, myelination pattern, morphology of axons and the gene expression of APP-processing enzymes [200]. Hence, it is suggested that pycnogenol has potential use in the prevention or in early stages of AD and mild cognitive impairment (MCI) [201]Table 5 summarizes the neuroprotective potential of different conifers’ phytochemicals in AD.

    4.2.6. Parkinson’s Disease

    PD is second to AD in terms of the most prevalent progressive ND, with an estimated global prevalence of over 10,000,000 cases [202]. The selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leads to PD. Briefly, PD occurs due to oxidative stress, dysfunction of mitochondrial complex-1, oxidative cell damage, neuronal excitotoxicity, calcium homeostasis, apoptosis, distressed energy metabolism, inflammation and protein aggregation, such as a-synuclein, apoptosis, and interaction between genetic and environmental causes [203]. Due to uncoordinated mouth and throat movements, PD causes bradykinesia, muscle rigidity, rest tremor, and the loss of postural control, as well as certain secondary symptoms, such as dementia, sialorrhea, soft voice, and trouble swallowing [204][205]. Oxidative stress generates ROS that causes oxidative damage, such as 4-hydroxynonenal (HNE), 26S proteasome and interferes with dopamine metabolism leading to PD [70]. Changes in protein ubiquitination and degradation have recently been related to dopaminergic cell death in PD [206]. Presynaptic protein α-synuclein (α-syn) influences the release of neurotransmitters from synaptic vesicles in the brain [207]. Currently, the treatment of PD includes drugs such as L-DOPA, which is catalyzed primarily by dopa decarboxylase in the brain, and some others such as ropinirole, selegiline, and rasagiline. Ropinirole has some adverse effects, including ankle oedema, vomiting, nausea, hypotension, insomnia, weight loss, hallucinations, psychosis, arrhythmia, dry mouth, nightmares, persistent diarrhea, somnolence and constipation, limiting their clinical applications [208]. As a result, the focus of rising interest in alternative treatments for ND, such as PD, has turned to natural products, which can provide alternatives due to their high effectiveness and few side effects [209]. Many plant extracts tend to stop α-syn from oligomerization and fibrillation, which is an emerging therapeutic mechanism in PD [172]. Methanol extract of J. communis at doses of 100 and 200 mg/kg was found to be effective in reducing catalepsy, enhancing locomotor activity (actophotometer), and increasing the level of reduced glutathione (GSH), protein level and muscle activity in rats [210]. In an in vitro study on Fisher F344 rats, Zhang et al. (2010) discovered that RV protect dopaminergic neurons from damage caused by MPP+, 6-OHDA, and also show efficacy against lipopolysaccharide-induced neurotoxicity by inhibiting nuclear factor kappa B (NF-κB) signaling and microglial activation [211].

    4.2.7. Insomnia

    Insomnia is a chronically debilitating disease that has become increasingly common, posing immense health and economic challenges for both individuals and the community [212]. Trouble falling asleep, staying asleep, fragmented sleep (repeatedly waking up at night or waking up early in the morning) are all symptoms of this condition [213]. While behavioral therapy, psychotherapy and light therapy have all been used to treat insomnia, the most common medications for insomnia are hypnotic drugs that target GABAA-benzodiazepine (BZD) receptors, such as diazepam and zolpidem [214]. However, several side effects have been identified, including cognitive impairment, resistance, headaches, nausea, and rebound insomnia [215][216]. Methanol extract of A. webbiana leaves showed potent synergistic effect in mice at dose of 100, 150, and 200 mg/kg, with sleep-inducing sedative drugs, diazepam (6 mg/kg), pentobarbitone sodium (50 mg/kg) and propylene glycol [144]. In addition, the major monoterpenoid components present in Pinus spp., α-pinene and 3-carene, have been reported to have hypnotic effects through GABAA-BZD receptors. 3-carene increases the length of sleep in mice given pentobarbital-induced sleep drugs by binding to the BZD site of the GABAA-BZD receptor α1 and ϒ2 [217].

    The entry is from 10.3390/molecules26103005

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