Antioxidant and Anti-Inflammatory Properties of Phytochemicals Found in the Yucca Genus

The Yucca genus encompasses about 50 species native to North America. Species within the Yucca genus have been used in traditional medicine to treat pathologies related to inflammation. Despite its historical use and the popular notion of its antioxidant and anti-inflammatory properties, there is a limited amount of research on this genus. To better understand these properties, this work aimed to analyze phytochemical composition through documentary research. This will provide a better understanding of the molecules and the mechanisms of action that confer such antioxidant and anti-inflammatory properties. About 92 phytochemicals present within the genus have reported antioxidant or anti-inflammatory effects. It has been suggested that the antioxidant and anti-inflammatory properties are mainly generated through its free radical scavenging activity, the inhibition of arachidonic acid metabolism, the decrease in TNF-α (Tumor necrosis factor-α), IL-6 (Interleukin-6), iNOS (Inducible nitric oxide synthase), and IL-1β (Interleukin 1β) concentration, the increase of GPx (Glutathione peroxidase), CAT (Catalase), and SOD (Superoxide dismutase) concentration, and the inhibition of the MAPK (Mitogen-Activated Protein Kinase), and NF-κB (Nuclear factor kappa B), and the activation of the Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway. These studies provide evidence of its use in traditional medicine against pathologies related to inflammation. However, more models and studies are needed to properly understand the activity of most plants within the genus, its potency, and the feasibility of its use to help manage or treat chronic inflammation.


Introduction
The Yucca genus belongs to the Agavoideae subfamily, a subfamily that is commonly used in traditional medicine thanks to its anti-inflammatory, antimicrobial, and antiparasitic properties [1]. It encompasses about 40 to 50 species, most of which are native to southern North America. These plants have been used for centuries to treat different ailments [2]. These benefits led to the approval by the FDA (Food and Drug Administration) of the use of Yucca species in various products, especially in dietary supplements [3]. These benefits have attracted research into the genus, which has demonstrated the presence of many biological properties [2].
One of Yucca's most notable properties is its anti-inflammatory activity. Inflammation is a physiological procedure generated by the immune system in response to tissue injury, stress, pathogens, or toxic compounds [4]. However, in some cases, inflammation can become harmful to the body, such as chronic inflammatory diseases [5], and in those cases, the inflammatory response must be suppressed. The inflammatory process generates reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can cause oxidative  The NF-kB pathway can be canonically activated by cytokines, such as TNF-α and IL-1 β, or uncanonically by the endosome complex containing NIK, AKT, and MAC. The pathway begins in the activation of IKK β, which phosphorylate IκBα. This results in the release of NF-kB dimers, translocating to the nucleus and activating the transcription of proinflammatory proteins. Yucca genus phytochemicals can interrupt this pathway by reducing the concentration of TNF-α, IL-1, and AKT, or the inhibition of IKK activation and phosphorylation IκBα. (B) There are 3 MAPK pathways, the ERK1/2, JNK, and p38 MAP kinase. The p38 MAPK pathway begins the activation of receptors, such as TNFR or the IL1R superfamily. This activation will generate the phosphorylation of TRAF 2/3/6 which in turn activates MAP3Ks, which phosphorylates MKK3 or MKK6, and those molecules will activate p38. P38 positively regulates a pro-inflammatory response. In addition, p38 partially modulates the activation of the basal transcription factors that interact with NF-κB. Yucca genus phytochemicals can reduce p38 phosphorylation, inhibiting the signaling pathway. The activation of JNK begins with the phosphorylation of MAP3Ks, which subsequently phosphorylates MKK7 or MKK4, and then phosphorylates the JNK kinases. JNK positively regulates a pro-inflammatory response. IL-6 can activate JNK pathway and STAT3 pathways by activating membrane-bound gp130, which will cause JAK enzymes to phosphorylate proteins such as STAT3. Yucca genus phytochemicals decrease the activation of this pathway. ERK1/2 signaling begins with the binding of a ligand to the RTK; this will activate the G-protein known as Ras. Ras directly binds to Raf and activates it, then Raf activates MEK, and MEK phosphorylates ERK1/2 so it can enter the nucleus and activate transcription factors. Yucca genus phytochemicals have the capacity to suppress this signaling pathway. The figure was created with BioRender.com.
There are other reports of the antioxidant activity of the Yucca genus against oxidative stress. A commercially available food additive known as Sarsaponin 30 ® has been reported to have a protective effect against nitrite-induced oxidative stress in rats [41]. Rats were pretreated with Sarsaponin 30 ® for 4 weeks prior to the nitrite intoxication in doses of 100 ppm. Said pretreatment reduced the concentrations of MDA and NO in the tissue and in glutathione ( Figure 1B).
In addition to rats, dietary supplementation with Yucca schidigera Roezl ex Ortgies a has also shown antioxidant capacity against oxidative stress in fish. In Oreochromis niloticus Biodust ® ; other food additives from Yucca schidigera Roezl ex Ortgies alleviate growth arrest, intestinal dysfunction, and oxidative damage induced by heat stress [42]. This is done by the downregulation of the ubiquitin-proteasome system, TNF-α, IL-1β, and interleukin 8 (IL-8), as well as by enhancing the Nrf2 signaling pathway. As can be seen in Section 5, the decrease of IL-1β concentration is an effect well represented through phytochemicals within the genus. IL-1 refers to two separate cytokine genes, IL-1α and IL-1β, that bind to the same receptors and stimulate similar proinflammatory signals [43]. For IL-1β to be excreted, its precursor must be processed by caspase-1 from the NALP3 inflammasome and excreted by the ATP/P2X7R influx [44]. In the same way, within the described phytochemicals of the genus, there are reports of the ability to inhibit NALP3 inflammasome formation, which would prevent the excretion of IL-1β. Once excreted, it will exert its activity by binding to the extracellular IL-1 type I receptor (IL-1RI), which will lead to the recruitment of IL-1R accessory protein (IL-1RAcP) and other adapters, and thus activate the NFκB, JNK, ERK, or MPAK signaling pathways [43], and this graphical represented in Figure 2A.
Another case with fish was with Cyprinus carpio, where they were fed an extract of Yucca schidigera Roezl ex Ortgies at doses of 200 or 400 mg/kg for 8 weeks, which improved their growth and intestinal antioxidant status [45]. This is due to an increase in the mRNA levels of GPx, CAT, SOD, and Nrf2, in addition to a reduction in the levels of IL-1β and IL-6. GPx, CAT, and SOD are known as front-line antioxidant defense systems. This is because ROS molecules are the most abundant oxidizing molecules within cells, especially molecules such as superoxide anions. Moreover, SOD can transform these superoxide anion molecules into hydrogen peroxide (H 2 O 2 ) and O 2 , so that subsequently CAT or GPx catalyzes the reduction of H 2 O 2 to water, thus eliminating the oxidative danger of these molecules [46]. It should be noted that the increase in these antioxidant enzymes is one of the most reported effects within the phytochemicals reported in Section 5, as many managed to increase the concentration of these 3 enzymes ( Figure 1B).
As it can be seen through Section 5 that the reported effect of Yucca extracts, the main pathways involved in its anti-inflammatory and antioxidant effect are the inhibition of MAPK, and NF-κB, and the activation of the Nrf2 signaling pathway.

Inhibition of NF-κB Signaling Pathway
The NF-κB is a family of transcription factors that coordinate one of the most common proinflammatory signaling pathways. Within the phytochemicals in Section 5, there is constant mention of the inhibition of this pathway ( Figure 2A). The family of NF-κB has 5 members: RelA, c-Rel, RelB, p50, and p52. RelA, RelB, and c-Rel share a transactivation domain that makes them capable of promoting transcriptional activation, while p50 and p52 act as coactivators [47]. There are 2 variations of this pathway, the canonical one where RelA and p50 are responsible for promoting the transcription of target genes, and in the non-canonical RelB and p52 [48].
The canonical NF-kB pathway is primarily a response to proinflammatory cytokines, such as TNF-α and IL-1, and it has an important role in chronic inflammatory diseases [49]. The pathway begins with the activation of receptors, such as TNFR and IL-1RI, which will generate a series of steps resulting in the activation of IKKβ [48]. The IKKβ will phosphorylation IκBα, which results in the release of the sequestered RelA-p50 dimers. Once these dimers translocate to the nucleus, they activate the transcription of receptors and proinflammatory cytokines involved in the inflammatory response [48]. As mentioned above, the inhibition of IKK activation and phosphorylation IκBα are an abundant effect between phytochemicals described in Section 5.
The non-canonical NF-kB pathway begins with the activation of the TNFR superfamily members, or the formation of an endosome complex containing NIK, AKT, and MAC, to stabilize and accumulate NIK. The NIK (NF-kB inducing kinase) with IKKα will induce the phosphorylation of the precursor of p52, resulting in the formation of RelB/p52 dimer [49].

Inhibition of the MAPK Signaling Pathway
The MAPK superfamily is one of the major mechanisms used in signaling pathways and is characterized by its activation through the dual phosphorylation on adjacent threonine and tyrosine residues [50]. In inflammation, the activation of receptors triggers the MAPK pathways, and transcription factors are phosphorylated and activated, such as NF-κB [51]. There are 3 well-known MAPK pathways, the ERK1/2, JNK, and p38 MAP kinase, all of which activate proinflammatory stimuli [52]. ERK1/2 signaling begins with the binding of a ligand to the receptor tyrosine kinase (RTK); this activates G-protein kwon as Ras. Ras directly binds to Raf and activates it, then Raf activates MEK, and MEK phosphorylates ERK1/2 so it can enter the nucleus and activate transcription factors [53]. As can be seen in Section 5, there are molecules within the Yucca genus that have shown the capacity to suppress this signaling pathway.
The p38 MAPK pathway begins the activation of receptors, such as toll-like receptors, TNFR, or the IL1R superfamily, to inflammatory stimuli. This activation generates the phosphorylation of TRAF 2/3/6 (TNF receptor-associated factor), which in turn activates MAP3Ks, such as TAK1. Then, MAP3K phosphorylates MKK3 or MKK6, and those molecules activate p38 [54]. Many of the pro-inflammatory responses, such as TNF-α, IL-1β, IL-6, IL-8, and COX-2, are positively regulated by p38 [51]. This pathway can regulate the NF-κB-dependent gene expression because p38 partially modulates the activation of basal transcription factors that interact with NF-κB [51]. Phytochemicals within the Yucca genus can reduce p38 phosphorylation and inhibit the signaling pathway.
There are 3 types of JNK proteins JNK1 (encoded by MAPK8), JNK2 (encoded by MAPK9), and JNK3 (encoded by MAPK10), where JNK1 and JNK2 are found in almost all cells [55]. This signaling pathway, as the other two can be triggered by proinflammatory cytokines. The activation of JNK begins with the phosphorylation of MAP3Ks, which subsequently phosphorylates MKK7 or MKK4, and then phosphorylates the JNK kinases [56]. JNK regulates the activity and maturation of T cells, as well as pro-inflammatory cytokines such as IL-6 and TNF-α, and therefore this pathway is related to chronic inflammatory disorders [57]. Within the genus, there are molecules that decrease the activation of this pathway ( Figure 2B).

Activation of the Nrf2 Signaling Pathway
Nrf2 is a transcription factor that regulates the expression of antioxidant and antiinflammatory proteins, and it is considered a modulator of species longevity [58]. Its anti-inflammatory effect is due to an indirect control of NF-kB activity and a direct control of IL-6 and IL-1β expression [59]. In fact, under normal inflammatory conditions, Nrf2 expression is activated by NF-kB to initiate a slow response that can stop the NF-kB inflammatory response [60]. Nrf2 is considered the major regulator against oxidative stress, as it regulates the expression of antioxidant response element genes, such as SOD, GPx, NADP(H) quinone oxidoreductase (NQO1), and heme oxygenase (HO-1) [61]. It also regulates Phase II of xenobiotic metabolism, where it transforms carcinogenic intermediates, generated by Phase I of xenobiotic metabolism, into less toxic metabolites [62].
Nrf2 is regulated by Kelch-like ECH-associated protein 1 (Keap1) and the Cullin 3 (Cul3) ubiquitin E3 ligase complex. Keap1 sequester Nrf2 and functions as an adaptor, so the Cul3 complex ubiquitinates Nrf2 to facilitate its proteasomal degradation [63]. Nrf2 can be activated by oxidative molecules modifying the cysteine residues of Keap1, stabilizing Nrf2-Keap1 interaction, and preventing Nrf2 ubiquitination [61,64]. Therefore, new Nrf2 could be synthetized without Kaep1 being able to sequester it. Nrf2 binds to Keap1 through a high-affinity ETGE motif, so proteins with this motif can interact with Keap1 and prevent Nrf2 sequestering [64]. Once Nrf2 is free, it translocates to the nucleus, and heterodimerizes with small Maf or Jun proteins to upregulate or inhibit target genes [61]. The activation of this pathway is one of the most reported effects throughout this genus of phytochemicals, by increasing the concentration of Nrf2 or inhibiting Keap1 ( Figure 1B). One gene regulated by Nrf2 is HO-1 (Heme oxygenase 1). The main function of HO-1 is to catalyze Haem (an iron-containing porphyrin) degradation; it uses cytochrome P450 reductase to transform Haem, NADPH, and O2 to biliverdin, carbon monoxide, ferrous iron (Fe 2+ ), NADP+, and H 2 O [65]. However, it has also been shown to have anti-inflammatory properties. They have been shown to help chronic inflammation, along with Nrf2, to inhibit the adhesion of inflammatory cells by downregulating the expression of cell adhesion molecules, such as vascular cell adhesion molecule 1 (VCAM1) [60]. This could explain the ability of some reported phytochemicals to decrease the expression of VCAM1.

Free Radical Scavenging Activity
Finally, there are relatively abundant reports in the literature on extracts from the Yucca genus with free radical scavenging activity in vitro. Yucca aloifolia L. leaf extracts with MeOH, CHCl3, EtOAc, nBuOH, and n-hexane solvent were tested for their radical scavenging activity [66]. Were Yucca aloifolia L. MeOH showed the highest potential by having an activity versus control of 74% in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and an inhibition of 64% in the linoleic acid peroxidation assay. Yucca schidigera Roezl ex Ortgies radical scavenging activity was tested with TEAC (Trolox Equivalent Antioxidant Capacity) assay and had trolox equivalents (TE) values of 1.78 [67,68] and 5.78 mM [69], respectively. Yucca baccata Torr. butanolic extract showed a 29.18 (µg TE/mg) in DPPH assay, 121.8 (µg TE/mg) in TEAC assay, 33.41 (µg TE/mg) in ferric reducing antioxidant power (FRAP) assay, and 156.84 in oxygen radical absorbance capacity (ORAC) assay [70]. These reports are consistent with the radical scavenging activity observed in phytochemicals observed in Section 5 ( Figure 1B).

Phytochemistry
For thousands of years, mankind has used plants to treat various ailments. This knowledge has been passed down through hundreds of generations and remains the main form of health care for more than 4 billion people today [71]. Phytochemicals naturally protect the plant from environmental hazards, pathogenic attacks, or grant characteristics, such as its aroma and flavor. Due to these functions', plants have the capability to produce a wide range of molecules, where factors such as soil pH, light, temperature, or stress will change its chemical composition [71]. Many of these molecules will have similar proprieties, especially those that are closely related.
Due to that, in recent years, there has been a trend in countries such as China where plants are being used to generate new drugs. Some phytochemicals are able to modulate inflammation and oxidative stress at the same time, since these two physiological phenomena often share the same pathways and intensify each other. An example of this is that ROS can act as an inflammatory signaling molecule, and in turn, inflammation can induce oxidative stress and reduce cellular antioxidant capacity [72].
Out of the documentary research, 365 molecules were found in the literature, of which 92 had antioxidant or anti-inflammatory reported activity. Of these molecules, 51 can be classified as Phenolic Compounds, 13 as Glycosides, 7 as Saponins, 9 as Fatty acids, 5 as Terpenes, 3 as Tocopherol, 2 as Dicarboxylic acid, 1 as Phytosterol, and Xanthones. The antioxidant and anti-inflammatory activities reported in the literature of the phytochemicals found in the Yucca genus can be seen through Sections 5.1-5.5

Phenolic Compounds
Phenolic compounds are phytochemicals that are characterized as containing an aromatic ring bonded to some hydroxyl groups in their structure. Plants can produce a wide variety of phenolic compounds [73]. These compounds play an important role in defense mechanisms against pathogens and stress conditions, such as drought, salinity, and UV [74]. This role is due, in part, to the structural capacity to capture free radicals and chelate metals, which protect the plant from oxidizing molecules [73]. These molecules maintain this antioxidant capacity when consumed, but as can be seen in Table 1, this is not the only reason behind their antioxidant or anti-inflammatory properties. Many of these molecules can downregulate inflammatory pathways, such as NF-kB, and upregulate antioxidant pathways, such as Nrf-2. A behavior that has been described similarly to non-steroidal anti-inflammatory drugs, the most commonly used drugs against inflammation [75]. Resveratrol increased the expression of SIRT1 (Sirtuin 1) and decreased ROS and p38 levels in human umbilical endothelial cells with TNF-α-induced injury. By inhibiting the MAPK/NF-κB pathway.
The cells were treated with doses of 0, 5, 10, and 20 µM. [80] Resveratrol inhibited PGE2 (Prostaglandin E2) synthesis in murine embryonic fibroblasts ex vivo. This was found to be due to resveratrol's ability to bind directly with COX-2.

Yucca periculosa Yucca schidigera Yucca gloriosa
The TEAC assay showed that 3,3',5,5'-tetrahydroxy-4methoxystilbene has the highest scavenging activity of all phenols in Yucca schidigera. It also reduced the effects of oxidative stress on blood platelets.
A concentration of 0.1 mM was used [84]  A dose of 100 mg/kg was injected intra-articular.
[85] [86,87] Gallic acid significantly inhibited inflammation in a rat model of arthritis in a dose-dependent manner. This could be due to an inhibition of PDE4 (Phosphodiesterase 4) activity, and a decrease in TNF-α concentration.

Yucca elephantipes Yucca aloifolia variegata Yucca aloifolia
Chlorogenic acid inhibited the production of TNF-α in and attenuated arthritis progression in collagen-induced arthritis mice. All of these are probably possible through the suppression of NF-κB pathways.
Doses of 30 mg/kg and 60 mg/kg for the attenuation of arthritis.

Yucca elephantipes Yucca aloifolia variegata Yucca aloifolia
Cinnamic acid reduced the concentrations of MDA, TNF-α, and increased CAT activity in cisplatin-induced splenotoxicity in rats.

Yucca elephantipes Yucca aloifolia variegata
Acacetin blocked the activation of NF-κB, decreased the activity of MPO, the expression of iNOS and COX-2, and increased the expression of SOD and HO-1 in sepsis-induced Acute lung injury mice.
Oral administration of 80 mg/kg showed the best results.

Yucca elephantipes
Epicatechin decreased the levels of TNF-a, IL-6, NO, MPO, and MDA and inhibited NF-kB activation in mice with induced ulcerative colitis.
The mean effective concentrations of antioxidant activity were 14 µM. [106] [105] Pre-treatment with eriodictyol induced the Nrf2 pathway in mice with acute lung injury. This decreased the levels of TNF-α, IL-6, IL-1β, MIP-2 (Macrophage inflammatory protein 2), H 2 O 2 , and MDA 30 mg/kg was given orally 2 days before the acute lung injury.
Results were seen at a dose of 200 mg/kg once daily for 30 days. [122] Psoralen

Yucca elephantipes
Psoralens inhibit the expression of TNF-α, IL-1β, IL-6, and IL-8, and proteins involved in the TLR4-IRAK4-NF-κb pathway in LPS-stimulated cells. The anti-inflammatory activity could be due to an agonist effect on the estrogen receptor.

4-Hydroxyphenylacetic acid
Yucca elephantipes 4-Hydroxyphenylacetic acid increased Nrf2 translocation to the nucleus, which enhanced antioxidant enzymes in mice with induced acute liver failure.
The mice were treated with 4hydroxyphenylacetic acid at doses of 6, 12, or 25 mg/kg for 3 days.

Yucca elephantipes
Chrysin treatment inhibits p65 NF-κB unit, TNF-α, IL-1β, and IL-6 levels, where 100 mg/kg had the same effect as 100 mg/kg methylprednisolone in rats with spinal cord injury. It also reduced the concentration of iNOS and NO.
Doses of 30 and 100 mg/kg/day for 26 days. [132] [79] Chrysin treatment decreased lipid peroxidation and increased the activities of SOD, CAT GPx, GSH, vitamin C, and vitamin E in hepatitis-induced rats.
Doses of 10 or 20 mg/kg were injected intraperitoneally.
[153] [79,87] Apigenin decreased LPO levels and increased SOD, CAT, GPx, vitamin C, vitamin E, and GSH levels in rats with oxidative stress caused by the carcinogen.
It also showed good radical scavenging ability in vitro.
Dose of 5 mg or 10 mg/kg/day for 10 days.
[156] Table  1 abbreviations Within the Yucca genus, there is great diversity and concentration of phenolic compounds. Specifically, unique phenolic derivatives with potent antioxidant activity have been found in Yucca gloriosa L. (gloriosaols) and Yucca schidigera Roezl ex Ortgies (yuccaols) [34,69]. Among these unique molecules of the genus, Yuccaol C stands out because it prevents NF-kB activation and inhibits iNOS expression and NO release in a dosedependent manner [34].

Saponins
Saponins are amphiphilic compounds that have a saccharide chain attached to a steroid or triterpenoid [157]. These compounds are involved in plant development and protection, where they are synthesized in response to pathogens, insects, or herbivores [158]. They are found in legume seeds in the human diet, and various positive effects on health are attributed to them [157]. In fact, since 1950, these molecules have been used to produce steroidal hormones and drugs [159]. As can be seen in Table 2, saponins have the capacity to decrease the levels of proinflammatory cytokines, especially steroidal saponins, due to their similarity to steroid hormones. This similarity allows some saponins to act as agonists to the glucocorticoid receptor, which generates glucocorticoid-like effects [160]. These types of molecules are found in a high content within the Yucca genus and are widely used in the food, pharmaceutical, and cosmetic industries [161]. As with the phenolic compounds, in Yucca schidigera Roezl ex Ortgies, new saponins have been found: Yucca spirostanosides [162].

Glycosides
Glycosides are a large structurally diverse group of phytochemicals; they have 2 units a small metabolite (aglycone) and a sugar (glycone) [176]. When plants add sugar to small metabolites, it improves their biodistribution, metabolism, and storage [177]. Most of its biological activities come from the "small metabolite", but the addition of sugar will change the magnitude of the activity. An example of this is that rutin (Quercetin 3-rutinoside) has higher anti-inflammatory activity than its aglycone part, quercetin [178]. This difference may be due to its absorption and metabolism, where glycosides are mostly absorbed in the small intestine after deglycosylation, which allows the metabolite to enter the liver and then be excreted to the blood [179]. As can be seen in Table 3, its antioxidant and anti-inflammatory activity is well known.

Yucca elephantipes
A treatment with poncirin showed improvement in the liver in male albino mice with Carbon tetra chloride-induced liver injury. This is done by neutralizing nitric oxide production, enhancing the concentration of GST, GSH, CAT, SOD, and attenuating the activity of lipid peroxidase, MPO, and the levels of IL-1β, IL-6 and TNF-α.
At a concentration of 30 mg/kg. [181] [86] Poncirin improved symptoms associated in mice with liver injury induced by paracetamol. This is done by decreasing the expression of NF-κB, JNK, and COX-2.    [79,87] Quercitrin decreased iNOS expression in rats with induced colitis. This was due to the inhibition of NF-κB activity.
Doses of 100 or 200 mg/kg were injected intraperitoneally for 8 weeks.
At the concentration of 0.05 mg/mL it showed an inhibition of 90.4% in DPPH and the IC50 was 24 mg/mL for the lipid peroxidation assay. [192] Naringin

Fatty Acids
Fatty acids are lipid structures composed of a long carbon chain with a carboxyl group at one end and a methyl group at the other end [201]. If this structure has a double bond, it is classified as "Unsaturated fatty acids". Plants mainly produce unsaturated fatty acids. These can be synthesized by plants as part of the various defense systems against biotic and abiotic stresses [202]. Fatty acids also function as modulators of cell membranes, as energy reserves, as extracellular barriers, and as precursors of signaling molecules [203]. As can be seen in Table 4, their anti-inflammatory and antioxidant properties are well known. This effect depends on the position of the first double bond within the carbon chain. If it occurs in the sixth (n-6), it will be considered pro-inflammatory because it is a precursor of arachidonic acid [25]. If it occurs in the third (n-3), it will be considered anti-inflammatory because it will compete as a substrate for n-6 metabolism [25]. On the other hand, these structures are susceptible to oxidize, and for the same reason, they work as antioxidants. Within the Yucca genus, it has been reported that Yucca aloifolia variegate L. contains more saturated fatty acids than unsaturated, constituted mainly by palmitic acid and palmitoleic acid [87]. Table 4. Some of the antioxidant and anti-inflammatory effects of fatty acids of the Yucca genus reported in the literature.

Effect Metabolite Screening
Gamma-Linolenic acid

Yucca elephantipes Yucca aloifolia variegata
Treatment with α-linolenic acid inhibited the production of PGE2 in on synovial membrane explant cultures with LPS-induced inflammation.
At a concentration of 100 µM [205] Caproic acid Yucca aloifolia variegata Capric acid suppressed MAPK phosphorylation and NF-kB activation in THP-1 cells treated with P. acnes.

Yucca aloifolia variegata
Lauric acid suppressed MAPK phosphorylation and NF-kB activation in THP-1 cells treated with P. acnes.
Intraperitoneal administration of 1000 nmol/kg/day was started 2 weeks before injury and continued for 5 weeks. [211]

Other Phytochemicals
Among the phytochemicals that were found at a lower frequency, the terpenes stand out with the anti-inflammatory effect. Terpenes are the most abundant and diverse class of phytochemicals; structurally, they are made up of isoprene molecules (Table 5). They have a wide range of functions, from primarily being part of plant structures to being quinones in electron transfer [215]. On the other hand, tocopherols stand out for their antioxidant activity. These molecules are exclusively synthesized in photosynthetic organisms and consist of a chromanol head group with one, two, or three methyl groups, and an isoprenoid [216]. α-Tocopherol is the major vitamin E component and one of the most important antioxidant regulatory mechanisms [217]. Stigmasterol treatment improved clinical severity by reducing joint destruction and decreasing the expression of TNF-α, IL-6, IL-1β, iNOS and COX-2, p65 and p38 by inhibiting the activation of p-IκBα in collagen-induced arthritic rats.
200 mg/kg orally daily for 20 days [219] In rats with ischemia/reperfusion brain injury, stigmasterol treatment decreased COX-2 and p65 expressions. In addition to significantly increasing the expression of Nrf2, HO-1, SOD, CAT, and GPx.

Yucca aloifolia variegata
Phytol treatment reduced MPO activity and the concentration of TNF-α, IL-6 and COX-2. By downregulating p38 and NF-κB signaling pathways in a mouse model of arthritis induced by complete Freund's adjuvant.

Yucca carnerosana
The injection of succinic acid in Wistar rats showed a high inhibitory capacity of LPO.  [59] Nerolidol decreased the expression of TNF-α, IL-1β, IL-6, NF-kB, PGE-2, and COX-2 and increased the level of IL-10, IL-4, and serum, antioxidant activity in rats with arthritis induced.

Availability of Reported Phytochemicals
It is worth noting that the presence by itself of phytochemicals does not guarantee that it will generate the desired biological effect. As with drugs, the quantity of the phytochemical dictates its efficacy. There are many factors that could alter the quantity of phytochemicals. Phytochemicals are mostly generated in response to external stimuli [71]. Thus, all external stimuli alter the synthesis of phytochemicals. In the same way, there will be differences depending on the tissue. In addition, plant tissue may undergo postharvest changes [244]. Then, the extraction of phytochemicals will alter the availability. Here, factors such as the solvent, temperature, time, and pH, among others, will influence the type and amount of phytochemicals obtained [245]. In general, there are a small number of reports assessing the quantity of Yucca phytochemicals in the literature. The same is true regarding the difference between extraction and improvement in phytochemical concentration. Within the reports included here, the great variability caused by the factors previously described is notorious. This can be seen in Table 6. Specifically, the difference can be seen when comparing the quantity of resveratrol, 3,3',5,5'-tetrahydroxy-4-methoxystilbene, Yuccaol A, and Yuccaol C obtained between both extraction methods. Despite the differences in concentrations and types of phytochemicals, the presence of multiple phytochemicals with similar biological effects would suggest a robustness that would allow for the prevalence of their antioxidant and anti-inflammatory activity. Finally, another important factor related to the availability of phytochemicals is microbiota. The gut microbiota metabolizes most molecules consumed, including drugs or phytochemicals. In the intestine, phytochemicals are degraded by microbes and absorbed by tissues [246]. Some phytochemicals need to be metabolized by the gut microbiota in order to generate its biological effect [247]. Poorly absorptive phytochemicals can undergo structural modifications that improve their bioavailability [246,247]. This especially applies to glycosides, as mentioned above. Glycosides have low bioavailability and bioactivity until their aglycone is deglycosylated by gut microbiota [246,247]. This modification through gut microbiota has been reported to have a role in some antioxidant and anti-inflammatory effects. This is especially true through Nrf2, as the genus Lactobacillus capable of stimulating its activation through small molecules [248]. One example of this is the biotransformation of caffeic acid, a phytochemical that can be found in the Yucca, into 4-vinyl-catechol. This is an activator of Nrf2 [249]. It has also been reported that treatment with pre-fermented Angelica sinensis activates Nrf2 signaling better than treatment with non-fermented Angelica sinensis in mice [250]. It also increases the level of bacteria related to Nrf2 signaling, such as Lactobacillus. Thus, the fermentation of phytochemicals through bacteria, such as Lactobacillus, is key for the efficient activation of Nfr2. From the abundance of reports on Yucca phytochemicals activating Nrf2, it could be assumed that other phytochemicals follow the pathway of phytochemicals and are metabolized by bacteria into Nrf2 activators.

Future Perspectives
Although there is research on the anti-inflammatory and antioxidant properties of the Yucca genus, there are still many unknowns to be resolved. First, most of the research related to the anti-inflammatory and antioxidant properties has only focused on Yucca schidigera Roezl ex Ortgies and Yucca gloriosa L. [22,23,27,42]. It is worth noting that, within these 2 species, phytochemicals endemic to the genus have been found. Some of these have shown a particular effect against inflammation and oxidative stress [31]. Therefore, it could be expected to find other phytochemicals with similar structures among the other species. It has been reported that metabolomics can be used in taxonomical classifications [251]. If there are molecules that have a similar structure, it is very possible that they have a quite similar effect. This is based on the similarity principle, where similar molecules exhibit similar biological activity [252]. Thus, within the 50 species, there could be molecules with greater anti-inflammatory and antioxidant potential. Thus, there are unexplored unknowns related to most Yucca species. More specifically, to its anti-inflammatory and antioxidant properties and phytochemicals.
However, even with the favorable results of the research done with Yucca schidigera Roezl ex Ortgies and Yucca gloriosa L., further study of its use against inflammatory diseases is still needed. In particular, in vitro studies rarely cope with the complexity of human diseases [253]. From what could be found in the literature, only a few disease models have been used to study the therapeutic potential of Yucca, such as ovalbumin-induced airway hyperresponsiveness in mice [27]. Similarly, the efficacy and potency of different Yucca extracts have not been compared. Nor has its effect been compared with that of known treatments. Therefore, the study of Yucca genus against established models of inflammatory diseases is another field without much exploration. Finally, since the discovery of Yuccaol C and its mechanism of action against NO synthesis [31]. There has not been much research done on this topic. This is surprising since it is found in relatively large proportions within Yucca schidigera Roezl ex Ortgies and Yucca gloriosa L., as can be seen in Table 1. In addition to its reported efficiency, against the NF-kB pathway [31]. Thus, there is another unexplored Yucca topic. For the same reason, although there is favorable evidence on the anti-inflammatory and antioxidant capacity of Yucca genus. There is still a lot of research to be done before being able to describe the genus or its phytochemicals as an alternative to treat inflammatory diseases.

Conclusions
Yucca genus encompasses about 40 to 50 species, natives of southern North America. For centuries, it has been used to treat pathologies such as asthma, rheumatism, gonorrhea, sunburns, arthritis, etc. The ethnobotanical use led to the testing of many biological activities, where its antioxidant and anti-inflammatory excels. Unfortunately, there are a limited number of studies, so knowing its composition will provide a better understanding of the molecules responsible for these properties. This is because it is known that the medicinal use of plants is due to its phytochemicals. The documentary research found 92 phytochemicals with reported antioxidant and anti-inflammatory activities. Most of these molecules can be classified as phenolic compounds, glycosides, saponins, or fatty acids. Within these molecules, phytochemicals, such as Yuccaol C, stand out because they are original to the genus and have significant anti-inflammatory and antioxidant activity. The antioxidant and anti-inflammatory properties are mainly generated through free radical scavenging activity, the inhibition of arachidonic acid metabolism, the inhibition of MAPK and NF-κB, and the activation of Nrf2 signaling pathway. The NF-kB pathway is mainly inhibited by phytochemicals through the inhibition of IKK activation and phosphorylation IκBα, and the decrease of NF-kB concentration. The MAPK pathways are mainly inhibited by reducing p38, JNK, and ERK1/2 phosphorylation. Nrf2 is activated by increasing its concentration or inhibiting Keap1. However, there is evidence of the antioxidant and antiinflammatory activity of some species within the genus, and although it is not abundant, the fact that a great variety of the phytochemicals that compose it present the same activities allows us to assess these properties.  Data Availability Statement: All data is contained and referenced within the article.

Conflicts of Interest:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.