Genipap (Genipa americana L.): A Comprehensive Reference
1. Identity, Taxonomy, and Botanical Description
Scientific name: Genipa americana L. Family: Rubiaceae.
Genipa americana is a species of trees in the family Rubiaceae, native to the tropical forests of North and South America, as well as the Caribbean. The species is originally from the Amazon region, where it grows especially in lowland areas, and is widely distributed throughout tropical and subtropical areas in Latin America. The species is native and not endemic to Brazil, and is most prevalent in the Amazon biome.
The trees grow up to 30 m tall and up to 60 cm in diameter at breast height (dbh). Their bark is smooth with little fissures. The leaves are opposite, obovate or obovate-oblong, 10–35 cm long and 6–13 cm wide, and glossy dark green. The inflorescences are cymes up to 10 cm long, and the flowers are white to yellowish, slightly fragrant, with a bell-shaped calyx and a trumpet-shaped corolla 2–4.5 cm long, five- or six-lobed. The fruit is a thick-skinned edible greyish berry 10–12 cm long and 5–9 cm in diameter.
The fruit, known as genipap, is approximately 6 to 7 cm in diameter, with a thin yellowish-brown peel and sweet, juicy pulp; once ripe, it is used in nutritional productions as well as generating a natural blue pigment.
1.1 Common Names and Synonymy
The species is known by numerous regional names: in Colombia as jagua, caruto, or huito; in Brazil as jenipapo (formerly genipapo); in Costa Rica as guaitil or tapaculo; in Nicaragua as tapaculo or yigualtí; in Mexico as shagua, xagua, or maluco; in Peru as huito, vito, or jagua; in Argentina as ñandipá; and in Puerto Rico as jagua.
The name "jenipapo" comes from the indigenous language Tupi-Guaraní and means "fruit used for painting." The Latin nomenclature Genipa americana was derived from the Portuguese European interpretation of how the Tupi language group of South Americans pronounced yandï'pawa (yanipa).
1.2 Common Forms and Preparations
The ripe genipap fruits are used in the manufacture of liquor, jams, juices, wines, candies, and syrups. The species is also cultivated for its edible fruits, which are eaten in preserves or made into drinks, jelly, or ice cream. In traditional medicinal contexts, various parts of the plant — including the fruit pulp, leaves, bark, and roots — are used in preparations ranging from fresh juice to decoctions, macerations, and poultices. The leaf, when cooked, serves as an antidiarrheal or antisyphilitic agent and, when macerated, is used by some native tribes as an antifebrile; the fruit is considered a tonic against anemia and in infusion is used against chronic enteritis; the bark in decoction is indicated for the treatment of wounds, venereal ulcers, granular pharyngitis, and anemia; the root is purgative; and the seed emulsion is a quick-acting vomit-inducer.
The unripe fruit also yields a juice widely used as a natural dye and ink. When the unripe fruit is cut open and its interior is exposed to air, the pulp becomes gradually dark, acquiring an intense blue color, which has been widely used by Brazilian indigenous peoples in body painting and ceramics.
2. Traditional and Historical Use
2.1 Indigenous Amazonian Cultures
Indigenous groups in the Amazon, such as the Shipibo and other ethnic communities, have traditionally applied the dye derived from the unripe fruit for body decoration, camouflage during hunting, and in cultural rituals including coming-of-age ceremonies and spiritual practices to symbolize protection and identity. Genipap plays an important role in native tropical religion and medicine, and the juice of the immature fruits has been used by many indigenous tribes for body painting and hair dyeing.
In Ecuador, the plant was associated with an origin myth involving two beautiful sisters, Wituk (Genipa americana) and Manduru (Bixa orellana), who transformed the first beings into various species of plants and animals by painting them in shades of red, reddish-brown, and black. Tribes such as the Emberá Wounaán, a native tribe in Panama, use fresh jagua as a body painting agent for ceremonial purposes and because it repels insects.
2.2 Folk and Ethnopharmacological Uses
Genipa americana has been employed in traditional medicine across Latin America, particularly in Brazil and other tropical regions, for various health conditions. Indigenous and folk practices utilize leaf infusions to treat liver diseases and anemia, while the ripe fruit is consumed to alleviate asthma, jaundice, and digestive ailments such as diarrhea. Bark decoctions are applied topically for wound healing, skin infections, and ulcers due to their purported antimicrobial and anti-inflammatory effects.
According to ethnobotanical and pharmacological studies, the leaves and other parts of the plant are used in the form of decoction or macerated preparations to treat inflammatory and hemostatic conditions such as pharyngitis, fever, healing, luxation, and bruises, and as a blood purifier.
In the Amazonian pharmacopeia, genipap is largely consumed and well known to treat anemia, measles, and uterine cancer. It is also used as a diuretic, digestive, healing, laxative, and antiseptic.
The plant is also used traditionally as a menstrual regulator, insect repellent, antibiotic, vermifuge, and aphrodisiac. The bark exudes a whitish, sweetish gum when cut, which is diluted and used as an eyewash and is claimed to alleviate corneal opacities.
3. Key Chemical Constituents and Phytochemistry
3.1 Iridoids — The Primary Bioactive Class
Genipap belongs to the Rubiaceae family and has a vast chemical composition, among which iridoids are the most important metabolites described. Iridoids reported from the genipap fruit include: genipin, genipic acid, genipinic acid, geniposidic acid, geniposide, genameside A, B, C, and D, genipin-gentiobioside, gardenoside, gardendiol, shanzhiside, deacetylasperulosidic methyl ester, genipacetal, genipaol, genipamide, caffeoylgeniposidic acid, p-coumaroylgeniposidic acid, feruloyl gardoside, scandoside methyl ester, gardoside, p-coumaroylgenipin gentiobioside, and feruloylgenipin gentiobioside.
The distribution of iridoids varies markedly with ripeness. Nine iridoids were identified by UPLC-DAD-ESI-QTOF-MS/MS analysis; among them, genipin (60.77 mg/g freeze-dried weight) was the most abundant iridoid in unripe genipap extract, while the ripe genipap extract mainly contained geniposide and geniposidic acid (89.48 and 25.04 mg/g freeze-dried weight, respectively).
The main iridoid compounds in the fruit are genipin (only in unripe fruits), genipin-1-O-β-D-glucoside (geniposide), and genipin-1-O-β-D-gentiobioside (only in ripe fruits).
3.2 Genipin: The Aglycone of Central Pharmacological Importance
Genipin is a non-glycosidic iridoid isolated mainly from the fruits of Gardenia jasminoides and Genipa americana. It is the active ingredient in extracts from these plants, responsible for their anti-inflammatory and hepatoprotective effects. Genipin is an important monoterpene iridoid compound and is a precursor of a blue pigment; it possesses various potential therapeutic properties such as anti-cancer, anti-diabetic, and hepatoprotective activity.
The blue pigment of the cut unripe fruit is formed from the reaction between genipin, a colorless iridoid, and primary amine sources such as amino acids and proteins. In recent years, the importance of genipin has increased due to the possibility of using this iridoid as a biocompatible and low-cytotoxicity potent crosslinking agent in the manufacture of dressings, in tissue engineering, as a component of drug carrier systems, and in the production of food packaging.
3.3 Phenolic Acids and Flavonoids
Pharmacological studies with the leaves report anti-inflammatory, antiangiogenic, antidiarrheal, and anti-syphilis activity, inhibition of larval development of gastrointestinal nematodes, antidiabetic, and anticonvulsant effects. The phytochemical composition of the leaves includes secondary metabolites such as tannins, monoterpenes, and flavonoids, with iridoids being the main secondary metabolites described.
A total of 13 compounds were identified in leaf extracts. Three flavonoids were isolated from the ethyl acetate fraction: quercetin-3-O-robinoside (GAF 1), kaempferol-3-O-robinoside (GAF 2), and isorhamnetin derivatives — a phytochemical approach that confirmed the presence of flavonoid glycosides not previously described for this species.
The plant is a rich source of cinnamic acid, with appreciable antioxidant and anti-glycant potential. Phytochemical tests in stem bark ethanolic extracts have identified flavonoid and alkaloid classes, and HPLC analysis has allowed caffeic acid quantification.
3.4 Phytosterols
Genipap fruit contains considerable concentrations of phytosterols, such as campesterol, stigmasterol, and β-sitosterol, which present anti-obesity, antioxidant, and antiproliferative functional properties.
3.5 Macro- and Micronutrient Profile
The fruit has great nutritional quality, with a high content of dietary fiber (4.64 g/100 g), carotenoids (874.49 mg/100 g), iron (15.94 mg/100 g), calcium (458.44 mg/100 g), and potassium (350.42 mg/100 g), with a reduced amount of antinutrients.
The unripe fruit has low energy (approximately 43–50 kcal/100 g) and high fiber content (7.88% in the mesocarp and 16.76% in the endocarp). The protein content is approximately 0.5 to 5.2%, and that of lipids is 0 to 1.6%, largely composed of saturated (52.3%) and unsaturated fatty acids (25.6%).
The plant has considerable levels of vitamins A, C, and E, as well as B-complex vitamins, and minerals including calcium, potassium, and phosphorus. It also has high levels of phenolics, flavonoids, terpenes, and iridoids.
3.6 Polysaccharides
The polysaccharide-rich extract obtained from G. americana leaves is composed of 36% carbohydrates (28% uronic acid) and 0.8% protein, showing in its structure the presence of α-L-rhamnose, α-L-arabinofuranosyl, and methoxyl and acetyl groups. An arabinogalactan-rich glycoconjugate has also been isolated from the leaves and investigated for anticoagulant and antiplatelet effects (see Section 5.4 below).
4. Established Mechanisms of Action
4.1 Anti-Inflammatory Mechanisms
The pharmacological activity of genipin has been the subject of numerous in vitro and in vivo tests, finding anti-inflammatory, antioxidant, antimicrobial, hepatoprotective, neuroprotective, cardioprotective, antiplatelet, anti-angiogenic, and anti-proliferative effects against a variety of tumour cell lines. Genipin may prove to be an effective anti-inflammatory agent both when applied topically and with systemic effects, as found in numerous in vitro and animal model studies.
In in vitro studies on RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS, 0.1 μg/μL), genipin applied at concentrations of 50–150 µM/mL produced significant inhibition of nitric oxide (NO) and PGE2 production and reduced IL-6, IL-10, and IL-1β levels; at 150 µM/mL, IL-6 levels were reduced to 4.0 pg/mL.
4.2 Antioxidant Mechanisms
The presence of total phenol content in plant extracts is associated with antioxidant activities, explained by their chemical structure and ability to donate or receive electrons, providing free radical capture. These metabolites are considered strong antioxidants and are involved in antiviral, antimicrobial, antiallergic, and immunomodulatory biological activities. There is a strong positive correlation between the phenolic constituents and antioxidant capacity, and a genipap extract was able to inhibit 50% of β-carotene oxidation.
4.3 UCP2 Inhibition and Anticancer Mechanisms
In brief, genipin inhibits uncoupling protein-2 (UCP2) to attenuate generation of reactive oxygen species (ROS), leading to ROS/c-Jun N-terminal kinase-dependent apoptosis of cancer cells. Genipin also increases the tissue inhibitors of matrix metalloprotease (MMP)-2, a tumor promoter in a variety of cancers, and induces caspase-dependent apoptosis in both in vitro and in vivo models.
Inhibition of UCP2 triggers the Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing ROS produced by mitochondrial metabolism and sustaining chemoresistance to numerous anticancer drugs.
4.4 Neuroprotective Mechanisms
A growing body of evidence shows that the neuroprotective benefit of geniposide — the glycoside form of genipin — probably arises from its agonist action on the glucagon-like peptide-1 receptor (GLP-1R). Geniposide shows several pharmacological effects (in vitro and in vivo) including neuroprotective, antidiabetic, hepatoprotective, anti-inflammatory, analgesic, antidepressant-like, cardioprotective, antioxidant, immune-regulatory, antithrombotic, and antitumoral activity. These pharmacological benefits arise through the modulating action of geniposide on proteins and genes associated with inflammatory and oxidative stress processes.
4.5 Hepatoprotective Mechanisms
The hepatoprotective effect of genipin was first noted by Jing-hua Peng. Since then, genipin was found to enhance the distribution of multidrug resistance-associated protein 2 (Mrp2) to the bile canalicular membrane. Genipin has been shown to have hepatoprotective activity, acting as an effective antioxidant and inhibitor of mitochondrial UCP2.
4.6 Cross-Linking Properties
The cross-linking properties of genipin are of considerable interest. Due to its low cytotoxicity, its use as a cross-linking agent for biomaterials such as casein, gelatin, and chitosan has been proposed. As a natural, water-soluble substance, genipin has been extensively studied as a non-cytotoxic crosslinking compound.
5. Scientific Evidence by Area of Activity
5.1 Antioxidant Activity
Evidence level: In vitro and animal; limited human metabolomics data.
A systematic review found that nine studies met inclusion criteria, two in humans and four in animals. The main results showed that the metabolites excreted in human urine after consumption of genipap juice were iridoids, medium-chain fatty acids, and hydroxycinnamic acids.
Purified extract from G. americana showed anti-glycant activity, reducing the formation of fructosamine by up to 53%, and recovered viability of cells under oxidative stress induced by H₂O₂. This finding is from cell culture work and has not been confirmed in human trials.
Antioxidant tests applied to stem bark ethanolic extracts have included the DPPH• method, ABTS•+ radical cation capture, Fe²⁺ chelation, Fe³⁺ reduction, and oxidative degradation of deoxyribose. These tests consistently demonstrate in vitro antioxidant activity, but direct extrapolation to human clinical outcomes requires further investigation.
5.2 Antimicrobial Activity
Evidence level: In vitro only.
A study presenting the chemical profile of the ethanolic extract of G. americana stem bark evaluated its antibacterial and antioxidant activities. The chemical prospecting consisted of qualitative analysis and quantification by HPLC-DAD, and an antibacterial evaluation was performed using broth microdilution to determine minimum inhibitory concentrations (MIC).
The results showed MICs of 256 µg/mL for Escherichia coli and Klebsiella pneumoniae, and 512 µg/mL for Shigella flexneri and Proteus vulgaris. These are in vitro findings only; no clinical antimicrobial trials in humans have been reported in the peer-reviewed literature.
5.3 Anticancer Activity
Evidence level: Predominantly in vitro and animal; no human clinical trials.
In several in vitro tests, genipin's anti-proliferative activity against tumour cell lines has been demonstrated, and due to its ability to specifically inhibit UCP2 and inhibit STAT3 activation, a significant increase in the cytotoxicity of several anticancer drugs was observed in co-treatment with genipin.
In highly invasive triple-negative breast cancer MDA-MB-231 cells, genipin induced apoptosis and repressed invasion and migration. Genipin either alone or in combination with cisplatin inhibited HCT-116 colon cancer growth by suppressing UCP2-mediated proton leaks and promoted ROS formation; genipin significantly repressed the viability of HCT116 and SW480 cells in a dose- and time-dependent manner and significantly inhibited tumor growth in vivo in animal xenograft models. The inhibition of tumor growth was combined with G0/G1 cell cycle arrest, apoptosis induction, increased ROS damage, and loss of mitochondrial membrane potential.
Genipin may prove to be an effective agent for enhancing the efficacy of some anticancer drugs. By inhibiting UCP2, it exacerbated the cytotoxic activity of cisplatin against HCT116 cells. Increased ROS production and consequent cell death were observed.
The culmination of this information positions genipin as a promising candidate for developing novel anti-cancer drugs capable of supplementing or enhancing current cancer therapies. However, all data reported on both cellular and animal models are based on extremely high doses of genipin administered, which prompts consideration of pharmacological rather than supplement-level application. A particularly important goal would be to determine appropriate therapeutic doses of genipin. No human clinical trials on genipap or isolated genipin as an anticancer agent have been completed as of the available literature.
5.4 Antiplatelet, Anticoagulant, and Antithrombotic Activity
Evidence level: In vitro and animal; no human trials.
The leaf extract of Genipa americana L. shows relevant antiplatelet, anticoagulant, and antithrombotic activity. An arabinogalactan-rich glycoconjugate of G. americana leaves, containing uronic acid, was found to have antiplatelet, anticoagulant (intrinsic/common pathway), and antithrombotic effects, with low hemorrhagic risk. These findings are from laboratory and animal models.
5.5 Anti-Inflammatory Activity
Evidence level: In vitro and animal models; one human metabolomics study; no controlled clinical trials.
The leaves of G. americana are traditionally used to treat fever, pharyngitis, healing, luxation, and bruises. A study investigated the anti-inflammatory effect of the polysaccharide-rich extract of G. americana leaves in acute inflammation models and underlying mechanisms associated with platelet activity.
Polysaccharides obtained from medicinal plants have become an alternative for treatment of inflammatory conditions since they possess various biological activities, including immunomodulatory effects, along with low toxicity. Evidence from G. americana in this area is confined to preclinical models.
5.6 Hepatoprotective Activity
Evidence level: In vitro and animal; no completed human clinical trials.
The results of preclinical studies suggest that genipin has anti-inflammatory, antioxidant, anticancer, hepatoprotective, antidiabetic, antidepressant, and neuroprotective effects, providing therapeutic potential for inflammatory bowel disease, acute lung injury, cancer, diabetes, depressive disorder, Alzheimer's disease, and Parkinson's disease. All of these findings, as of available literature, originate from preclinical investigations.
5.7 Antidiabetic Activity
Evidence level: In vitro and animal; no human clinical trials.
The extract of the fruit pulp shows antioxidant, anticonvulsant, antiparasitic, and anti-diabetic potential. Pharmacological studies conducted on the leaves of G. americana show anti-inflammatory, antiangiogenic, antidiarrheal, antisyphilitic, and antidiabetic properties and anticonvulsant effects. These are based on in vitro and animal model data; no controlled human studies have been published.
5.8 Neuroprotective Activity
Evidence level: In vitro and animal; preliminary.
Biomedical studies show that genipin may act as a neuroprotective drug. Compared with results published from in vitro models, few in vivo studies have examined the biological activity of genipin and its mechanism of action. The GLP-1R agonist mechanism of geniposide (see Section 4.4) is under investigation in the context of neurodegenerative diseases, but human data are absent.
5.9 Human Bioavailability and Metabolomics Studies
Evidence level: Two small human studies (metabolomics only; not clinical efficacy trials).
To identify biomarkers of genipap exposure, an untargeted metabolomics approach in human urine was applied. Urine samples from 16 healthy male volunteers, before and after drinking genipap juice, were analyzed by liquid chromatography–high-resolution mass spectrometry.
The findings showed that consuming genipap juice allows large exposure of the body to iridoids, especially derivatives of genipic and genipinic acid. No data about the bioavailability of iridoids in humans had been reported until then; almost all prior investigations were in vitro or in animal models. These results demonstrated for the first time the bioavailability of some iridoids from genipap juice after human consumption.
The main metabolites excreted in human urine after consumption of genipap juice were iridoids, medium-chain fatty acids, and hydroxycinnamic acids. These bioavailability studies establish that biologically relevant iridoid compounds are absorbed and metabolized after consumption, providing a mechanistic rationale for the observed in vitro effects, but they do not constitute clinical efficacy evidence.
6. Body Systems and Health Areas of Association
Based on peer-reviewed literature, the following body systems are associated with genipap research:
- Digestive/Hepatic System: Extracts exhibit hepatoprotective and anti-diabetic effects. Traditional use for diarrhea, liver disorders, and chronic enteritis is well-documented across multiple ethnobotanical sources.
- Cardiovascular/Hematological System: Extracts exhibit antiplatelet, anticoagulant, and antioxidant effects.
- Nervous System: Genipin possesses potential therapeutic properties including neuroprotective activity, and biomedical studies indicate it may act as a neuroprotective drug.
- Immune/Inflammatory System: Anti-inflammatory activity has been demonstrated in multiple in vitro and animal studies through inhibition of nitric oxide, PGE2, and pro-inflammatory cytokines.
- Oncology: Genipin demonstrates anti-cancer properties, which it exerts at all stages of the process, from proliferation through apoptosis to inhibition of migration and metastasis. All evidence is preclinical.
- Metabolic System: Genipin possesses various potential therapeutic properties such as anti-cancer, anti-diabetic, and hepatoprotective activity.
- Dermatological/Cosmetic Applications: Commercially, the dye extracted from the fruit is employed in natural inks for temporary tattoos and as a colorant in cosmetics. Extracts of genipap seeds and peels showed antioxidant inhibition of acetylcholinesterase and tyrosinase, the latter being of relevance to skin pigmentation applications.
7. Dosage Forms and Dosages Reported in Research
There is no established, standardized clinical dosage for genipap or its isolates. The following dosages and forms have been reported in specific published studies:
- Human metabolomics study (medium-term consumption): Sixteen healthy adult men were administered genipap juice (250 mL) twice a day for three weeks. Before and after the three weeks of consumption, subjects drank a control drink and consumed a standard diet. Urine was collected after 0–6 h, 6–12 h, and 12–24 h.
- Human metabolomics study (single-dose bioavailability): Urine samples from 16 healthy male volunteers were analyzed before and after drinking genipap juice. The juice was prepared by mixing genipap pulp, water, and white crystallized cane sugar (50:45:5 w/w/w).
- In vitro anti-inflammatory (cell study): Genipin applied at concentrations of 50–150 µM/mL to LPS-stimulated RAW 264.7 macrophages resulted in significant inhibition of NO and PGE2 production.
- Antimicrobial (in vitro MIC study): MICs in stem bark ethanolic extract were 256 µg/mL for E. coli and K. pneumoniae, and 512 µg/mL for S. flexneri and P. vulgaris.
- Iridoid extraction yield: Ultrasound-assisted extraction at 150 W for 7 minutes yielded maximum content of genipin (121.7 mg/g extract) and geniposide (312 mg/g extract).
No dose-ranging, pharmacokinetic, or efficacy clinical trials in humans for therapeutic purposes have been published for genipap or isolated genipin derived specifically from G. americana. The human data available are limited to biomarker/metabolomics studies and do not establish therapeutic dosages.
8. Safety Considerations
8.1 Hepatotoxicity Signal from High-Dose Animal Data
Large-dose oral administration of geniposide in rats induced hepatotoxicity, and the expression of the toxicity may be relevant to genipin generated by intestinal bacteria β-glucosidase. Due to documented cases of hepatotoxicity, genipin and the blue pigment derived from it are being investigated for effective and safe therapeutic and non-drug use. These findings come from animal studies and the clinical significance for humans consuming normal dietary quantities is not established.
8.2 Skin Staining
Intake of food or beverage containing genipin, such as genipap juice, poses a cosmetic problem in that genipin bonds to proteins in the skin around the mouth, thereby turning the skin around the mouth blue. This is a direct consequence of genipin's protein cross-linking mechanism and is well-documented.
8.3 Potential Effects on Placental Cells
Previous investigations have suggested that G. americana steroids might detrimentally affect placental cell regulation. This finding, derived from in vitro work on human trophoblast-derived cells, implies that use during pregnancy warrants caution, though no human clinical data exist to confirm or characterize this risk.
8.4 Evidence Quality and Overall Safety Assessment
All data on both cellular and animal models are based on extremely high doses of genipin administered, which prompts for pharmacological rather than supplement application of the molecule. A particularly important goal would be to determine appropriate therapeutic doses of genipin. Future experiments should also explain the broad spectrum of biological activity of genipin and may exclude it from the category of Pan-assay interference compounds (PAINS), which often give false-positive results in high-throughput screens.
Genipap juice and extract have been widely used for beverages and food and contain genipin. Foods and food additives containing geniposide or genipin have hitherto been used without major problems at typical dietary intake levels.
In vitro and in vivo studies indicate that genipin is not toxic to normal cells at the concentrations studied. However, the absence of comprehensive human safety or toxicology studies for concentrated extract or supplement forms means that the safety profile at pharmacological doses in humans remains to be established.
9. Industrial and Non-Dietary Applications
The patents registered with the World Intellectual Property Organization (WIPO) indicate its use as a colorant, insecticide, anti-inflammatory, and antioxidant, evidencing its antimicrobial and antioxidant activities.
There are currently few natural sources of iridoids, and their application as colorants is scarce. Ultrasound-assisted extraction produces extracts with blue and green colors using water and ethanol, respectively. Genipin is a substrate in the production of a blue pigment used as a food additive, fabric pigment, and in other applications.
Genipin, the aglycone after hydrolytic cleavage of geniposides by β-deglycosidases in the intestine, possesses various pharmacological effects such as protective activity against oxidative damage, inhibition of tumor promotion, and anti-inflammatory activity.
References
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