Using “Avocado” and “Persea” as search descriptors with a focus for pharmacologically active metabolites, various avocado metabolites were retrieved from Combined Chemical Dictionary v23.1 (CCD) [7] and The Human Metabolite Database (HMDB) [8]. In addition to the P. americana, the search strategy also covered other Persea species such as P. mexicana, P. indica, P. gratissima, P. obovatifolia, and P. borbonia (Table 1). As per the literature, most bioactive compounds were isolated predominantly from P. americana. Other synonyms of P. americana are P. gratissima, Laurus persea, P. drymifolia, and P. nubigena [9]. The metabolite arsenal can be classified chemically into eight main classes, including fatty alcohols, furan derivatives, carotenoids, carbohydrate, diterpenoids, lignan derivatives, and miscellaneous compounds, as shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Figure 8, and Table 1. In brief, fatty alcohols isolated from avocado showed different degrees of unsaturation and alkyl chain length with several levels of hydroxylation and subsequent acetylation (Figure 1). These fatty alcohols have been reported to exhibit antiviral, cytotoxic, antifungal, trypanocidal, and antioxidant activity [10,11,12,13,14,15,16,17,18,19,20,21]. Phenolic compounds (Figure 2, and Table 1) of different chemical classes from simple organic acids such as gallic acid to larger flavonoids, anthocyanidins, and tocopherols were isolated from Persea species with significant antioxidant, neuroprotective and cardioprotective activities [22,23,24,25,26,27,28]. The antioxidant properties of avocados were also ascribed to their carotenoid content in many studies [24,28,29,30] (Figure 3). Moreover, sugar alcohol and ketoses with variable carbon chain length were isolated from avocado (Figure 4). Notable insecticidal, cytotoxic, and antifungal activities were also reported for the furan and furanone derivatives isolated from Persea species [18,31,32,33,34,35,36,37] (Figure 5), where the saturation of the furan ring was detrimental for the insecticidal activity [38]. The insecticidal activity of the furan derivatives was augmented by the diterpenoids compounds [39,40,41,42,43], especially in P. indica (Figure 6). Overall, avocado contains a vast array of secondary metabolites of different chemical classes which may attribute to its diverse biological activities.

]. Of note, the expression of p53 and its target genes (~500) regulate a wide range of cellular processes, including apoptosis, cell cycle arrest, and DNA repair [146]. Additionally, the upregulation of TIMP-2 inhibits MMP-2 expression, which consecutively leads to the reduction of cellular migration and invasion (metastasis) [147,148]. Therefore, MMP-2 upregulation has been correlated with poor prognosis and relapse in cancer patients [147]. Another study by Roberts et al. [149] also indicated synergistic interaction between the breast cancer standard drug—tamoxifen—and persin isolated from avocado leaves against MCF-7 (Michigan cancer foundation-7), T-47D, and SK-Br3 breast cancer cells in vitro. The authors reported a significant reduction of tamoxifen IC₅₀ values when it was combined with avocado persin. The synergistic interaction was Bim-dependent and mediated by the modulation of ceramide metabolism [149]. Bim is a member of the Bcl-2 (B-cell lymphoma 2) family of proteins that play a key role in the intrinsic (mitochondrial) pathway of apoptosis [150,151]. In particular, Bim is linked with microtubule-stabilizing properties, which mediate the formation of microtubule bundles with subsequent mitotic arrest and apoptosis [139,152].

Chemical synthesis of the most potent anticancer compounds found in avocado has also been carried out in a number of studies [143,145,153,154]. Similar to avocado crude extracts, chemically synthesized avocado peptide PaDef defensin was recently found to induce apoptosis via caspase 7, 8, and 9 expressions in K562 chronic myeloid leukaemia and MCF-7 breast cancer cells in two studies by the same research group [143,153]. Moreover, PaDef defensin was previously demonstrated to have antimicrobial properties [155,156]. The induction of apoptosis and abrogation of the cell cycle were also observed earlier in the human breast, lung, ovarian, and colorectal cancer cells when treated with chemically synthesized avocado β-hydroxy-α,β-unsaturated ketones by Leon et al. [145]. Although many preclinical studies were performed to elucidate the cytotoxicity of extracts derived from different parts of the avocado plant and their components, very few of them have investigated their molecular mechanisms of action. Interestingly, contradicting information regarding avocado extract-induced genotoxicity is also available. For instance, Kulkarn et al. [157] found out that avocado fruit and leaf extracts can induce chromosomal aberrations in human peripheral lymphocytes, with leaf extract being more genotoxic. The same research group later reported that avocado fruit extract can reduce cyclophosphamide-mediated chromosomal aberrations in human lymphocytes [158], which was perhaps due to the antagonistic effects of the extract on cyclophosphamide.

Traditionally, an avocado leaf decoction is used for the treatment of tumours and tumour-related diseases in Nigeria [159]. Despite their health benefits highlighted in numerous reports, clinical studies examining the direct correlation between avocado consumption and the prevention and treatment of cancer are scarce. Only one case-control study involving 243 men with prostate cancer and 273 controls in Jamaica demonstrated that MUFA from avocado may reduce the risk of prostate cancer [160]. However, it should be noted that bioactive compounds that are also commonly found in avocados such as α-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin were found to have inverse associations with cancers of the mouth, larynx, pharynx, and breast in few clinical trials, as highlighted in Table 5 [161,162,163]. According to the USDA, avocados contain a significantly higher amount of glutathione per average serving compared to other fruits [61]. Glutathione is a potent tripeptide antioxidant that plays a major role in detoxification pathways and the reduction of oxidative stress and risk of cancer [62,65]. Notably, it has been linked with the reduction of chemotherapy-associated toxicity and risks of oral cancer in a few clinical studies [57,58,59,164]. Nonetheless, the molecular mechanism of how glutathione reduces the side effects of chemotherapeutic regimens remains largely speculative. In order to precisely understand the anticancer mechanisms of action of avocado extracts and their bioactive compounds, more in vitro and in vivo studies are warranted. As very few studies have identified the solitary bioactive compounds responsible for the growth inhibition of different cancer cells, more research should be undertaken to gain a comprehensive understanding of the chemical profiles of the active extracts. Notably, bioassay-guided fractionation and the subsequent isolation and characterization of biologically active compounds from different parts of the avocado plant may lead to the identification of many novel anticancer compounds. Randomized controlled trials should be designed to evaluate the efficacy of bioactive compounds derived from avocado in the prevention and treatment of different cancer types. Furthermore, the chemoprotective properties of avocado and the possibility of using its bioactive compounds as an adjunct therapy for cancer should also be explored.

Several studies have investigated the anti-inflammatory properties of avocados via modulation of inflammatory responses (Figure 9, Table 7). The aqueous extract of avocado leaves showed an anti-inflammatory effect in vivo by inhibiting carrageenan-induced rat paw oedema [185]. Persenone A, an active constituent of avocado, reduced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine macrophages [173]. Similarly, (2R)-(12Z,15Z)-2-hydroxy-4-oxoheneicosa-12,15-dien-1-yl acetate, persenone A and B isolated from the avocado fruit, decreased the generation of nitric oxide in mouse macrophages [19]. Avocado oil contains a high amount of oleic acid and essential fatty acids. A study by [186] highlighted the wound-healing properties of avocado fruit oil by increasing collagen synthesis and decreasing inflammation in Wistar rats. They also reported that oleic acid was the predominant unsaturated fatty acid (47.20%) present in the fruit oil [186].

65]. Due to their fat-soluble nature, these bioactive compounds have been shown to promote vascular health [65]. Xanthophylls suppress the damage of blood vessels by decreasing the amount of oxidized low-density lipoproteins (LDL) [75]. Additionally, lutein and zeaxanthin have been reported to slow down the progression of age-related macular degeneration, cataracts, and cartilage deterioration [74,76]. Carotenoids in general were demonstrated to protect the skin from ultraviolet radiation-associated oxidation and inflammation [62]. Furthermore, a 68 g serving of Hass avocado contains about 57 mg of phytosterols, which is significantly higher compared to other fruits (about 3 mg per serving) [65]. Avocado phytosterols have been reported to reduce the risks of coronary heart disease [65]. The American Heart Association recommends the consumption of 2–3 g of sterols and stanols per day to promote heart health [65,77]. They are the plant analogues of cholesterol and can be classified into three major groups consisting of β-sitosterol, campesterol, and stigmasterol [78]. The most abundant phytosterol present in avocado is β-sitosterol (76.4 mg/100g), followed by campesterol (5.1 mg/100g) and stigmasterol (<3 mg/100g) [79]. In addition to its cholesterol-lowering activity, β-sitosterol has been demonstrated to inhibit the production of carcinogenic compounds, alleviate symptoms associated with benign prostatic hyperplasia, and strengthen the immune system [79]. In summary, these compounds have been hypothesized to work in conjunction in the prevention of oxidative stress and age-related degenerative diseases [80].

Considering the health risks associated with synthetic antioxidants, the extraction, isolation, and identification of antioxidants from natural sources have become primary research focuses of the food, nutraceutical, and pharmaceutical industries in recent years [81,82,83]. Annually, over three million tons of avocados are produced worldwide, with only the pulp being used, while the seeds and peel are discarded [2]. Waste utilization by exploiting the phytochemical content of avocado by-products such as seeds and peels will add more value to the avocado industry and may lead to novel product development [84]. Table 3 represents the studies currently available in the literature emphasizing the role of P. Americana plant as the source of potent antioxidants. Different parts of the plant, including the leaf, fruit pulp, peel, and seed have been widely studied for their antioxidant properties using conventional spectroscopic assays such as 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid diammonium salt (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC), cupric-reducing antioxidant capacity (CUPRAC), and ferric reducing ability of plasma (FRAP) as well as more sensitive analytical techniques including high-performance liquid chromatography (HPLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), gas chromatography-mass spectrometry (GC-MS) and gas chromatography-flame ionization detector (GC-FID). Hass is the most explored avocado variety in terms of its antioxidant properties, which can perhaps be attributed to the popularity and easier availability of this variety. It is evident from the studies performed so far that phenolic compounds (including phenolic and hydroxycinnamic acids, flavonoids, and condensed tannins), carotenoids, α, β, γ, and δ-tocopherols, acetogenins, monounsaturated and polyunsaturated fatty acids are the key antioxidants found in avocado. Moreover, most of these studies have reported significant positive correlations between the phenolic compounds and antioxidant capacity of avocado extracts [84,85,86,87,88]. Phenolic compounds found in avocado were shown to reduce oxidation, inflammation, and platelet aggregation [65]. Several studies have reported that different parts of the avocado plants contain potent phenolic antioxidants such as chlorogenic-, quinic-, succinic-, pantothenic-, abscisic-, ferulic-, gallic-, sinapinic-, p-coumaric-, gentisic-, protocatechuic-, 4-hydroxybenzoic-, and benzoic- acids, quercetin, quercetin-3-glucoside, quercetin-3-rhamnoside, vanillin, p-coumaroyl-D-glucose, catechins, (−)-epicatechin, and procyanidins (Table 3) [2,28,84,89,90,91,92,93,94,95,96,97]. Among the different parts of avocado investigated in several studies, leaf, peel, and seed extracts have shown consistently greater antioxidant capacity compared to that of the pulp [84,91,94,96,97,98,99,100,101,102,103,104,105,106]. Due to the presence of higher catechin, epicatechin, leucoanthocyanidin, triterpenes, furoic acid, and proanthocyanidin contents, avocado seed extracts have been reported to display greater antioxidant capacity [62,74]. Additionally, the ripening process was also shown to influence the phenolic contents of different parts of the avocado plant [96,107,108]. For example, a study by López-Cobo et al. [96] found a higher content of phenolics in the pulp and seed extracts of overripe avocados compared to their optimally ripe counterparts. It was hypothesized that the increase in the total phenolic content in the overripe fruit was mediated by higher phenylalanine ammonia-lyase activity associated with the ripening process [96]. They also observed an increased concentration of procyanidins in the overripe parts of the avocado, which was probably a result of the hydrolysis of complex tannins after ripening. Avocado peel, seed, and leaf, as the major by-products of the avocado industry, have been demonstrated as rich sources of polyphenolics and antioxidants. More studies of developing robust, green, and economical extraction techniques are fundamental to obtain greater yields of potent antioxidants. In vivo and clinical studies to understand the bioavailability of these antioxidants and their potential toxicity are also crucial.

Currently, there is a growing interest in finding alternatives to the synthetic antimicrobial agents that are commonly used in the food and pharmaceutical industries. This is due to the concerns of the consumers regarding the safety of products containing synthetic chemicals and their associated health risks [174]. Seeds (endocarp) and peels (exocarp) being the by-products of the avocado industry are generally disposed of as wastes [175] and have been investigated for their antimicrobial properties. Most of the studies conducted thus far have noted the antimicrobial activity of the extracts derived from different avocado varieties [104,176,177,178], while only a few have reported insignificant antimicrobial activity [101,179]. The antimicrobial activity of avocado extracts might be influenced by (i) the variety of the avocado, (ii) the parts used for investigation (i.e., exocarp, endocarp, or mesocarp), (iii) the solvent type used for extraction, and iv) the bacterial species examined [104,176]. Raymond and Dykes [176] investigated the antimicrobial activity of ethanolic and aqueous extracts of seeds and peels of three different avocado varieties (Table 6). The authors reported that ethanolic extracts had antibacterial activity against both Gram-positive and Gram-negative bacteria (except for Escherichia coli) ranging from 104.2 to 416.7 μg/mL, while aqueous extracts exhibited activity against Listeria monocytogenes and Staphylococcus epidermidis. Rodriguez-Carpena et al. [104] investigated the antibacterial activity of the extracts derived from different avocado parts (peel, seed, and pulp) of a number of varieties against Bacillus cereus, S. aureus, L. monocytogenes, E. coli, Pseudomonas spp., and Yarrowia lipolytica. The highest inhibitory activity against the Gram-positive bacteria- B. cereus and L. monocytogenes was observed, while E. coli was the most sensitive among the tested Gram-negative bacterial species. The authors mentioned that all avocado parts had antimicrobial properties, with pulp (mesocarp) showing the highest activity. In addition, the authors reported that the Gram-positive bacteria were more sensitive in comparison to the Gram-negative bacteria [104]. The Gram-negative bacteria have an extra protective outer membrane, which makes them more resistant to antibacterial agents compared to the Gram-positive bacteria [104,180]. β-sitosterol in avocados was also shown to play a key role in strengthening the immune system and the suppression of human immunodeficiency virus and other infections [181]. In particular, it has been found to enhance the proliferation of lymphocytes and natural killer cell activity for invading pathogens [181]. Salinas-Salazar et al. [177] investigated the antimicrobial activity of seed extracts of avocado enriched with acetogenin against L. monocytogenes and reported growth inhibition at 37 °C and 4 °C with MIC (minimum inhibitory concentration) values of 15.6 and 7.8 mg/L, respectively. Acetogenins of avocados are fatty acid derivatives with a long unsaturated aliphatic chain (C19–C23) [182,183]. Owing to the structural similarities between acetogenins and fatty acids, authors hypothesized that acetogenins may penetrate the cell membranes of bacteria and physically disrupt their functionality [177]. Indeed, several compounds might be associated in the antimicrobial activity of avocado extracts. Polyphenols have been previously reported for their antimicrobial properties [184]. However, the contribution of the phenolic compounds toward the antimicrobial activity of avocado extracts needs to be investigated. Rodriguez-Carpena et al. [104] found that avocado pulp extract had a higher antimicrobial activity than peel and seed extracts, despite having lower polyphenol content. Future studies should be conducted to isolate individual phenolic compounds from different parts of avocado and investigate their antimicrobial properties.

Avocados have been recognized for their high nutritional value and therapeutic importance for centuries. The nutritional composition of avocado is shown in Table 2 according to the United States Department of Agriculture (USDA) [61]. A whole avocado is reported to contain 140 to 228 kcal (~585–1000 kJ) of energy depending on the size and variety [62]. The variety, grade of ripening, climate, the composition of the soil, and fertilizers are the major factors that largely influence the nutritional profiles of avocados [63].

Fiber constitutes most of its carbohydrate content (~9 g of fiber and 12 g of carbohydrate per avocado) (Table 2) and can reach up to 13.5 g in larger avocados. Higher quantities of insoluble and soluble fibers (70% and 30%, respectively) are found in the pulp [3]. A single serving can provide about 2 g protein and 2 g of fiber with a glycemic index of 1 ± 1 [64]. A high-fiber diet is often linked with a healthy digestive system. Moreover, it may help lower blood cholesterol levels and prevent constipation by improving bowel movement. In particular, avocados have been shown to improve the microflora of the intestines by working as a prebiotic [65]. In addition to fat, avocados are rich in protein (highest among fruits), sugars including sucrose and 7-carbon carbohydrates (d-mannoheptulose), antioxidants, pigments, tannins, and phytoestrogens [66].

Fat contributes to most of the calories in an avocado. A 1000-kJ portion of avocado contains about 25 g of fat, most of which are healthier monounsaturated fatty acids (MUFA) [64]. The lipid content in avocados is higher than in other fruits. Most lipids found in avocados are polar lipids (glycolipids and phospholipids), which play a fundamental role in various cellular processes such as the functioning of the cell membranes as second messengers [67]. These lipids are also used to make emulsions of water and lipids, and have a wide variety of applications in food, pharmaceuticals, and cosmetics industries [68]. Compared to other vegetable oils, avocado oils are high in MUFA (oleic and palmitoleic acids) and low in polyunsaturated fatty acids (linoleic acid and linolenic acid) [3]. Oleic acid is the principal fatty acid in avocado, comprising 45% of its total fatty acids [69], and during the ripening process, palmitic acid content decreases and oleic acid content increases [70]. In terms of its total fat content and fatty acid composition, avocado oil is considered to be similar to olive oil [71]. Other fatty acids present include palmitic and palmitoleic acids with smaller [64] amounts of myristic, stearic, cinolenic, and arachidonic acids [62]. However, the compositions of these fatty acids largely depend on the cultivars, stage of maturity, and part of the fruit and geographic location of plant growth [62]. Avocado spread instead of other fatty alternatives such as butter, cream cheese, and mayonnaise on sandwiches can help significantly reduce the intake of calories, saturated fat, sodium, and cholesterol.

Avocados are notable for their potassium content (>500 mg/100 g of fresh weight), and it provides 60% more than an equal serving of banana [72]. Potassium intake helps to maintain cardiovascular health and muscle function by regulating blood pressure through the modulation of liquid retention in the body [65]. In addition, potassium regulates the electrolyte balance in the body, which is important for the conduction of electrical signals in the heart (i.e., a steady, healthy heart rate) [65]. The high potassium and low sodium contents in the diet are shown to protect against cardiovascular diseases [3]. Moreover, avocados contain a number of other minerals, including phosphorus, magnesium, calcium, sodium, iron, and zinc (<1 mg/g of fresh weight) [73].

Vitamins such as β-carotene, tocopherol, retinol, ascorbic acid, thiamine, riboflavin, niacin, pyridoxine, and folic acid are also abundantly found in avocado, which are of great importance for overall health and well-being (Table 2) [62,74]. Carotenoids, including lutein, zeaxanthin, and α- and β-carotene found in the pulp of the avocado are potent free radical scavengers [65,74]. The lutein content of avocado is higher than any other fruit, which comprises about 70% of its total carotenoid content [65]. The colour of avocado pulp is predominantly attributed to the higher content of xanthophylls (lutein and zeaxanthin). Seasonal variations in the phytochemical profile of avocado especially carotenoids, tocopherol, and fatty acid content have also been reported [

Cancer causes more deaths than acquired immune deficiency syndrome, tuberculosis, malaria, and diabetes combined [131]. The greatest challenges of anticancer regimens are attributed to the complex mutational landscapes of cancer, late diagnoses, expensive therapeutic options, and the development of resistance to chemo and radiation therapies [132,133]. Chemotherapy-associated side effects and toxicity also make cancer one of the most challenging diseases to treat [133]. Natural products or their derivatives comprised over 45% of the FDA-approved anticancer drugs between 1981–2010 [134]. In the United States, several plant-derived products, either alone or in conjunction with mainstream chemo and radiation therapies are used by approximately 50–60% of cancer patients [132,135]. Therefore, the search for safer alternatives to be used either as mono or adjunct therapy with the standard drugs is becoming a priority in anticancer research [136]. The in vitro cytotoxic properties of avocado against different types of cancer cell lines including breast, colon, liver, lungs, larynx, leukaemia, oesophageal, oral, ovary, and prostate have been extensively reported in the literature (Table 4). These properties have also been investigated in preclinical animal models. Interestingly, these in vitro and in vivo studies have not only explored the pulp, the most edible part of the fruit, but also the leaves, peel, and seeds of avocado. Table 4 depicts the major preclinical and clinical studies currently found in the literature emphasizing the potential anticancer activity of avocados. The chemical profiles of different parts of avocado vary among the varieties [84,137]. Therefore, rationally, depending on the chemical profiles, the bioactivities also vary accordingly. Many studies assessing the anti-proliferative activity of avocado did not report the varieties used. However, based on the limited studies that reported the varieties tested, Hass is perhaps the most explored cultivar for its anticancer properties. Molecular mechanistic studies in various cancer cell lines have reported the regulation of different signal transduction pathways, especially the induction of caspase-mediated apoptosis and the involvement of cell cycle arrest by different avocado extracts, their fractions, and isolated compounds (Figure 9, Table 4) [24,26,138,139,140,141,142,143,144,145]. For instance, Dabas et al. [140] recently found out that the methanol extract of Hass avocado seeds induced caspase 3-mediated apoptosis, poly (ADP-ribose) polymerase (PARP) cleavage, and cell cycle arrest at G₀/G₁, as well as reduced the nuclear translocation of nuclear factor kappa-B (NF-κB) and downregulated the cyclin D1 and E2 in lymph node carcinoma of the prostate (LNCaP) cells. Parallel observations were made earlier by Lee et al. [144] in MDA-MB-231 (MD Anderson metastasis breast cancer) cells using methanol extracts of avocado seeds and peel. They observed the activation of caspase-3 and its target protein- PARP, in MDA-MB-231 cells. Bonilla-Porras et al. [138] found out that ethanol extracts of avocado endocarp, seeds, whole seeds, and leaves activated transcription factor p53, caspase-3, apoptosis-inducing factor, and oxidative stress-dependent apoptosis via mitochondrial membrane depolarization in Jurkat lymphoblastic leukaemia cells. The acetone extract of avocado pulp rich in lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene, α-tocopherol, and γ-tocopherol was shown to arrest the PC-3 prostate cancer cells at the G₂/M phase and increase the expression of p27 protein [24]. The cytotoxic properties of different classes of compounds contribute to the cumulative anticancer activity of avocado. For example, the anticancer effects of the fatty alcohols, carotenoids, and phenolics were further augmented by the potential anticancer effect of norlignans/neolignans (Figure 7) from P. obovatifolia [48,49,50,51,52,53].

Scopoletin, a plant coumarin and phytoalexin found in avocado reduced the carcinogens-induced toxicity and the size of skin papilloma in vivo [26]. A mechanistic study revealed the modulation of the various key cell cycle, apoptotic and tumor invasion markers by scopoletin. Notably, the downregulation of AhR (aryl hydrocarbon receptor), CYP1A1 (cytochrome P450 1A1), PCNA (proliferating cell nuclear antigen), stat-3 (signal transducer and activator of transcription 3), survivin, MMP-2 (matrix metalloproteinase-2), cyclin D1 and c-myc (avian myelocytomatosis virus oncogene cellular homolog); and the upregulation of p53, caspase-3 and TIMP-2 (tissue inhibitor of metalloproteinases-2) by scopoletin were demonstrated [26

Inflammation in joints causes damage to the joint cartilage due to degenerative changes leading to a loss of joint function and stability [187]. Even though osteoarthritis (OA) is considered a non-inflammatory disease, recent studies have shown that inflammation is a leading cause for the initiation and continuation of the disease process [188]. Non-pharmacological agents that modulate the expression of pro-inflammatory mediators are highly promising as safe and effective ways to treat OA [189]. Avocado–soybean unsaponifiable (ASU) combination represents one of the most commonly used treatments for symptomatic OA [190]. ASU is a combination of avocado oil and soybean oil, which has been accepted as a medication/food supplement in many countries [191]. Three ratios of avocado (A) and soybean (S) unsaponifiable combinations (A:S = 1:2, 2:1, and 1:1) were studied for their anti-inflammatory properties on chondrocyte cells [192]. All the ratios showed significant inhibition compared to the individual extracts on collagenase, stromelysin, interleukin 6 (IL-6), interleukin 8 (IL-8), and prostaglandin E₂ (PGE2) release. In particular, 1:2 was found to be the most effective combination that exhibited chondroprotective effects in vivo by stimulating glycosaminoglycan and hydroxyproline synthesis and inhibiting the production of hydroxyproline in the granulomatous tissue [192]. In another study, the unsaponifiables of avocado alone indicated a significant chondroprotective effect [193]. Several preclinical and clinical studies conducted in the last few decades have revealed the modulation of different pathways and molecular targets associated with OA pathogenesis by ASU [194]. For instance, the anti-OA properties of ASU are mediated via the suppression of critical regulators of the inflammatory response such as iNOS/COX-2, and PGE-2 [195], and the reduction of catabolic enzymes (matrix metalloproteinases-3 and -13) and [190,196]. Gabay et al. [190] demonstrated the inactivation of the mitogen-activated protein kinases such as the extracellular signal-regulated kinase (ERK 1/2) and NF-κB as the molecular mechanism of action for the anti-inflammatory effects of ASU. A recent study showed the potential bone repair properties of ASU by the modulation of molecular targets Rankl and Il1β, RANKL, and TRAP using a rat model [197]. Sterols, the major bioactive components of ASU, have also shown anti-inflammatory activity in articular chondrocytes [198].

A significant reduction of articular cartilage erosion and synovial haemorrhage compared to placebo was observed in horses using ASU extracts [199]. However, the extracts did not reduce signs of pain or lameness in horses. In humans, NSAID (nonsteroidal anti-inflammatory drugs) consumption was reduced in patients with lower limb OA after six weeks of ASU consumption [200]. Furthermore, ASU significantly reduced the progression of joint space loss in patients with hip OA [201]. Another study by Maheu et al. [202] demonstrated slow radiographic progression in hip OA using ASU treatment. They also reported that the treatment was well tolerated by patients, even though the clinical outcome did not change. Interestingly, a recent study showed that the intake of ASU extract decreased the pain symptoms and an improved the quality of life in patients with OA of the temporomandibular joint [203].

Other studies have combined ASU with bioactive compounds such as epigallocatechin gallate (EGCG), and α-lipoic acid (LA) [189,204,205]. Interestingly, contrary to previous research, Heinecke et al. [204] reported a slight inhibition of COX-2 expression and PGE₂ production in activated chondrocytes. However, when ASU was combined with EGCG, both mediators were more significantly inhibited than their mono treatments [204]. Another study by Ownby et al. demonstrated that this combination inhibited the gene expression of interleukin-1 beta (IL-1β), tumour necrosis factor- α (TNF-α), IL-6, COX-2, and IL-8 in activated chondrocytes [189]. The combination of ASU with LA showed more significant suppression of PGE₂ production in activated chondrocytes than ASU or LA alone [205].

The implementation of ASU in the treatment of other inflammatory diseases has also been explored. In particular, ASU has shown efficacy against periodontal disease by modulating the expression of transforming growth factor-beta 1 (TGF-β1), TGF-β2, and bone morphogenetic protein 2 (BMP-2) [206]. Additionally, a recent study demonstrated that ASU can repair periodontal disease within seven days [207]. These results underline the significant anti-inflammatory properties of avocado mediated via multiple signal transduction pathways and their role in the potential treatment of various inflammatory diseases.

8. Conclusions and Future Direction

Several preclinical studies performed in the last few decades lay emphasis on the unique nutritional and phytochemical composition of avocado and its potential in the treatment and prevention of different diseases. Some studies have underlined its importance as the source of lead molecules for drug discovery due to the abundance of novel chemical skeletons. The cumulative effects of avocado components in the prevention and treatment of oxidative stress and age-related degenerative diseases are also indicated in a few studies. However, more comprehensive in vitro, in vivo, and clinical investigations are fundamental to significantly expand the understanding of the molecular mechanisms of action of its phytochemicals for developing subsequent therapeutic and nutritional interventions against cancer, diabetes, inflammatory, microbial, and cardiovascular diseases. Interestingly, despite its popularity as a “superfood”, clinical studies evaluating the therapeutic potential of avocado for the prevention and management of different ailments are limited in the literature. More investigations to understand the bioavailability and pharmacokinetics of avocado phytochemicals and antioxidants are also crucial to determine their clinical efficacy and potential toxicity. Regardless of the recent food trends and marketing gimmicks of “superfoods”, variety is fundamental for a balanced healthy diet. As many studies have revealed the complex synergistic interactions among different phytochemicals present in food matrices, studies to understand the possible synergy between bioactive compounds from avocado and other fruit and vegetables will help formulate diet-based preventive strategies for many diseases. A few reports have indicated the role of avocado in improving the bioavailability of nutrients from other plant-based foods. Therefore, consuming avocados with other fruit and vegetables as a part of the diet can be beneficial to human health.