Ethnopharmacology of Fruit Plants: A Literature Review on the Toxicological, Phytochemical, Cultural Aspects, and a Mechanistic Approach to the Pharmacological Effects of Four Widely Used Species

Abstract

Fruit plants have been widely used by the population as a source of food, income and in the treatment of various diseases due to their nutritional and pharmacological properties. The aim of this study was to review information from the most current research about the phytochemical composition, biological and toxicological properties of four fruit species widely used by the world population in order to support the safe medicinal use of these species and encourage further studies on their therapeutic properties. The reviewed species are: Talisia esculenta, Brosimum gaudichaudii, Genipa americana, and Bromelia antiacantha. The review presents the botanical description of these species, their geographical distribution, forms of use in popular medicine, phytochemical studies and molecules isolated from different plant organs. The description of the pharmacological mechanism of action of secondary metabolites isolated from these species was detailed and toxicity studies related to them were reviewed. The present study demonstrates the significant concentration of phenolic compounds in these species and their anti-inflammatory, anti-tumor, photosensitizing properties, among others. Such species provide important molecules with pharmacological activity that serve as raw materials for the development of new drugs, making further studies necessary to elucidate mechanisms of action not yet understood and prove the safety for use in humans.

Keywords: Bromelia antiacantha; Brosimum gaudichaudii; Genipa americana; Talisia esculenta; biological activity; natural compounds; pharmacological activity; phytochemistry; plant secondary metabolites; plant side effects.

Figure 1

Molecular mechanism of flavonoids in inflammasome regulation: (a) Studies suggest that oxidative stress is an important mediator of monosodiumurate (MSU) induced inflammation [51]. The formation of reactive oxygen species (ROS) induces nuclear translocation of Nuclear Factor-kappa B (NF-kB) via phosphorylation by IkB kinase, which binds to target DNA that regulates Pro-IL-1β and Pro-IL-8 gene expression. In addition, ROS dissociates the thioredoxin (TRX) and thioredoxin interaction protein (TXNIP) conjugation [52], and released TXNIP further recruits and binds to NLRP3 inflammasome, leading to the release of IL-1β [53] and IL-8. NLRP3 inflammasome consists of NLRP3, caspase recruitment domain (ASC), and pro-caspase-1. Mitochondrial ROS (MtROS) is also associated with NLRP3 inflammasome activation [53]. In the process of NLRP3 inflammasome activation, activated caspase-1 transforms pro-IL-1b and pro-IL-18 into mature IL-1b and IL-18, resulting in the release of inflammatory cytokines; (b) Flavonoid uptake occurs either via passive diffusion through the cell membrane, or through membrane bound transport proteins. Cut circles indicate different points of flavonoid action, inhibiting the process of inflammasome formation with subsequent inhibition of inflammatory events [54]. Phenolic compounds block the inflammatory process by inhibiting ROS formation, thereby reducing the formation of pro-inflammatory cytokines. The nature and position of substituents in relation to the hydroxyl group affect the activity of polyphenols. The easily ionizable carboxylic group contributes to the efficient hydrogen donation tendency of phenolic acids [55]. Gallic acid has high antioxidant activity rate. This is due to a beneficial influence of carboxylate on the antioxidant activity of phenolic acids [56]. The tricyclic structure of flavonoids, such as catechin, determines their antioxidant effect. Phenolic quinoid tautomerism and the localization of electrons over the aromatic system eliminate reactive oxygen species. These aromatic rings directly neutralize free radicals and increase antioxidant defense [57]; (c) DAMPs/PAMPs bind to their receptor on the cell membrane and activate a signaling cascade. As a consequence, activation and formation of NRLP3 inflammasome occur, where the formation of active caspase-1 catalyzes the cleavage and secretion of mature IL-1β and IL-18, leading to propagate inflammation [54]. ASC, caspase recruitment domain; C-JUN/JNK, c-Jun N-terminal Kinase; CARD, caspase recruitment domain; DAMPs, damage-associated molecular patterns; IκB, inhibitor of κB; IKKα, IkBkinase α; IKKβ, IkBkinase β; IL-1β, Interleukin 1-beta; IL-8, Interleukin 8; LRR, leucine-rich repeats; MAP3Ks, mitogen-activated protein 3 kinases; MEK, mitogen-activated protein kinase; MKK4, mitogen-activated protein kinasekinase 4; MKK7, mitogen-activated protein kinase kinase 7; MtROS, Mitochondrial ROS; MSU, monosodiumurate; NACHT, central nucleotide-binding and oligomerization domain; NEMO, NF-kappa-B essential modulator; NF-ΚB, Nuclear Factor-kappa B; p38a, p38 kinase α; p50, NF-ΚB, Nuclear Factor-kappa B 1 (NF-ΚB1); p65, RelA; PAMPs, pathogen-associated molecular patterns; PYD, pyrin domain; ROS, reactive oxygen species; TXNIP, thioredoxin interaction protein; TRX, thioredoxin; TXNIP, thioredoxin interaction protein.

Figure 2

Antioxidant effect of quercetin on enzyme activity, signal transduction pathways and reactive oxygen species (ROS). Several conditions and environmental factors can increase ROS production. Besides, the mitochondrial electron transport chain is an important source of intracellular ROS generation. Flavonoid uptake occurs either via passive diffusion through cell membrane, or through membrane bound transport proteins [54]. After entering the cell, quercetin acts through the regulation of the enzyme-mediated antioxidant defense system and the non-enzymatic antioxidant defense system. Nuclear factor erythroid 2–related factor 2 (NRF2), AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK) pathways induced by ROS to promote the antioxidant defense system and maintain oxidative balance can also be regulated by phenolic compounds such as quercetin [59]. Through the neutralizing effect of ROS, quercetin can develop important anti-inflammatory effect due to inhibition of the Nuclear Factor-kappa B (NF-KB) pathway, preventing the activation of NRLP3 inflammasome (shown in Figure 1B). Through the p53 pathway, ROS induce apoptotic events. Therefore, quercetin can prevent apoptosis induced by excess ROS. In addition, it enhances the production of Apurinic/apyrimidinic Endonuclease 1/ Redox Effector Factor 1 (APE1/Ref1), activation of various signaling events and the NF-E2-related factor (NRF2)-mediated activation of genes, containing antioxidant response elements (ARE) and NF-κB [60,61,62,63,64]. AMPK, AMP-activated protein kinase; AP-1, activator protein 1; APE1, Apurinic/apyrimidinic endonuclease 1; ARE, antioxidant response element; Bax, BCL2 Associated X; CAT, catalase; CREB, cAMP-response element binding protein; EGR1, Early Growth Response 1; ERK, Extracellular signal-regulated kinase; GSH, glutathione; GSHPx, Glutathione peroxidase; IκB, κB inhibitor; JNK, c-Jun N-terminal Kinase; KEAP1, Kelch-like ECH-associated protein 1; Maf, musculoaponeurotic fibrosarcoma; MAPK, mitogen-activated protein kinase; MtROS, Mitochondrial ROS; NF-ΚB, Nuclear Factor-kappa B; Nrf2, nuclear factor erythroid 2–related factor 2; PDGFR, Platelet-derived growth factor receptors; PI3K, phosphatidylinositol-3-kinase; Ref-1, redox effector factor 1; ROS, reactive oxygen species; SOD, Superoxide dismutase.

Figure 3

Use of furanocoumarins in the technique of extracorporeal photopheresis for the treatment of systemic or multifocal diseases: Leukocytes obtained by apheresis are exposed to 8-metoxipsoraleno (8-MOP), which is activated by UVA radiation and covalently binds to the DNA of these cells, causing damage and inducing apoptosis within 48 h. Pre-apoptotic leukocytes are reintroduced into the peripheral circulation, being recognized and phagocyted by antigen-presenting cells in phagolysosomes. This recognition induces tolerogenic anti-inflammatory response, which reduces the production of pro-inflammatory cytokines like IL-6, IL-12, IL-23, and TNF-α and increases the production of anti-inflammatory cytokines like IL-10, TGF-β1, and PGE2 [104]. 8-MOP, 8-metoxipsoraleno; IL-6, interleukin 6; IL-10, interleukin 10; IL-12, interleukin12; IL-23, interleukin 23; TGF-β1, Transforming growth factor beta 1; TNF-α, Tumor Necrosis Factor-Alpha. Another technique that uses furanocoumarins is extracorporeal photopheresis (ECP), which treats systemic or multifocal diseases such as Crohn’s disease, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. In this technique, the most used furanocoumarin is 8-methoxypsoralen (8-MOP), to which leukocytes, obtained by apheresis, are exposed. 8-MOP is activated by radiation and covalently binds to leukocyte DNA, leading to apoptosis within 48 h. These pre-apoptotic leukocytes are reintroduced into the peripheral circulation, where are recognized and phagocyted by antigen-presenting cells in phagolysosomes. This recognition induces a tolerogenic anti-inflammatory response that leads to a reduction in the production of pro-inflammatory cytokines IL-6, interleukin-12 (IL-12), interleukin-23 (IL-23) and TNF-α and induces the production of anti-inflammatory cytokines such as interleukin-10 (IL-10), transforming growth factor beta 1 (TGF-β1) and prostaglandin E2 (PGE2) (Figure 3) [102,104].

Figure 4

Proposed mechanism for inducing hemorrhage by coumarins: Coumarins act as competitive epoxide reductase inhibitors. This enzyme reduces oxidized vitamin K during its participation as co-factor in the synthesis of coagulation factors II, VII, IX, and X. With epoxide reductase inhibition, the reduction that occurs to regenerate vitamin K is blocked, depleting its levels and, consequently, inhibiting the synthesis of coagulation factors, causing hemorrhage.

Figure 5

Effects of genipin on energy metabolism: anti-tumor property: Transport mechanisms of geniposide and genipin, which are abundantly present in extracts from plants such as Genipa americana, involve converting geniposide into genipin in the intestinal lumen through bacterial enzymes β-glucosidases. Uncoupling protein 2 (UCP2) is a genipin target in the treatment of cancer. In mitochondria, the respiratory chain, formed by complexes I to IV, transfers electrons from NADH through oxidation-reduction reactions. Complexes I, II, and III contribute to the production of H+ ion gradient. The electrochemical gradient generated is coupled to the ADP phosphorylation process via ATP synthase. Oxygen is the final electron acceptor and is reduced to water by the electron transfer of complex IV. However, its early reduction into complexes I and III leads to the formation of O₂^•–. UCP2 is a protein widely expressed in tumor cells. Its function is to reduce ROS production and increase the survival of tumor cells by uncoupling the electrochemical gradient generated by the respiratory chain. For this purpose, UCP2 increases H⁺ output from the intermembrane space to the mitochondrial matrix and reduces the mitochondrial membrane potential. This mechanism, present in tumor cells as a survival factor by reducing ROS generation, is the genipin target [165]. A, adenosine; CoQ, coenzyme Q; Cyt C, cytochrome C; FAD, flavin adenine dinucleotide; NAD, Nicotinamide adenine dinucleotide; ROS, reactive oxygen species; UCP2, uncoupling protein 2.

Figure 6

Apoptosis mediated by genipin through interference with myeloid cell leukemia-1 (Mcl-1) synthesis in gastric cancer cell lines: (a) Cytokine receptors without intrinsic protein kinase domain amplify extracellular signals through signal transduction via Janus Kinase (JAK) family (JAK1 to JAK3 and tyrosine kinase 2). After receptor activation, JAK2 phosphorylates the tyrosine residue of transcription factor Signal Transducer and Activator of Transcription 3 (STAT3), which enables its binding to the promoter of target genes related to survival and apoptosis. Subsequently, Mcl-1 is synthesized; (b) Genipin absorption by tumor cells induces mitochondrial dysfunction due to decreased Mcl-1 expression through the JAK2/STAT3 pathway. Δψm, mitochondrial membrane potential; JAK2, Janus Kinase 2; Mcl-1, myeloid cell leukemia-1; STA3, Signal transducer and activator of transcription 3 [166].

Figure 7

Daucosterol mechanism on human breast adenocarcinoma cells: After treatment of tumor cells (MCF-7) with daucusterol, a phytosterol abundantly present in Bromelia antiacantha extracts, the positive regulation of Phosphatase and Tensin Homologue (PTEN) blocks Protein Kinase B (Akt) activation through PI3K. Daucusterol induces reactive oxygen species (ROS) synthesis that leads to mitochondrial oxidative stress and, subsequently, release of cytochrome C. Subsequently, the activation of caspases causes cell apoptosis [202]. Δψm, mitochondrial membrane potential; Akt, Protein Kinase B; Bax, BCL2 Associated X; Bcl2, B-cell lymphoma 2; Cyt C, cytochrome C; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue; ROS, reactive oxygen species.