Aardraka-Ginger (Zingiber officinale) Part 4

Aardraka-Ginger (Zingiber officinale) Part 4

Aardraka-Ginger (Zingiber officinale) contains many bioactive phytochemicals. Here I describe in detail the pharmacology of some important phytochemicals.
Molecular Formula: C11H14O3
Structural Formula:

Zingerone, also called vanillyl acetone, is a key component of pungency of Ginger (Zingiber officinale) that imparts the “sweet”, agreeable flavor to Ginger (Zingiber officinale). Zingerone is a member of methoxyphenol family. It is a crystalline solid, sparingly soluble in water but soluble in ether. Synthetic, zingerone is not pungent. This suggests that zingerone is more likely a decomposition product of pungency rather than a direct source of pungency of Ginger (Zingiber officinale). Zingerone is the least pungent compound of Ginger (Zingiber officinale). 

Fresh Ginger (Zingiber officinale) does not contain zingerone but is produced by cooking or drying ginger rhizomes, which causes reverse aldol-reaction on gingerol.
The chemical structure of zingerone is similar to that of vanillin and eugenol. Zingerone is used as a flavor-additive in spices. It is also used in perfumery to impart spicy aromas to oils.

Zingerone was first isolated from Ginger (Zingiber officinale) in 1917 by Hiroshi Nomura. He identified the empirical formula in the laboratory of the Agicultural College where he was a professor of chemistry. [205]  

Pharmacokinetics of Zingerone

On oral or intraperitoneal administration of zingerone, its metabolites, mainly glucuronide and/ or sulphate conjugates were excreted in urine within 24 hours. [206]

Anti-inflammatory activityof Zingerone

Peroxisome proliferator-activated receptors (PPAR) have been demonstrated to be involved in the modulation of nuclear κB (NF- κB) transcription factors, which are key regulators of immune and inflammatory responses. By suppressing activities of peroxisome proliferator-activated receptors (PPAR) and nuclear factor- κB (NF- κB) zingerone displays its anti-inflammatory activity. [207]

Another study showed that by downregulating nuclear factor κB (NF- κB) activity and interleukin1β signaling pathway zingerone displays its anti-inflammatory activity. [208]
Nuclear factor κB (NF- κB) is a pro-inflammatory pathway. When activated, it induces various inflammations. A mitogen-activated protein kinase (MAPK) is a type of protein kinase that regulates cellular responses to a diverse array of stimuli such as osmotic shock, heat stroke and pro-inflammatory cytokines. Mitogen-activated protein kinases (MAPKs) regulate cell survival and apoptosis. Via inhibition of pro-inflammatory nuclear κB (NF- κB) expression and interfering with mitogen-activated protein kinase (MAPK) pathway, zingerone acts as an anti-inflammatory and antioxidant agent. [209]

Antioxidant activity of Zingerone

DPPH (2,2-diphenyl-1-picryl-hydrazyl) is a chemical compound composed of free radical molecules. DPPH is used for study on antioxidant assay. Depending upon the dose administered, zingerone displays its antioxidant activity and protects DNA. In one study, at a concentration of  500 μg/mL the DPPH radical scavenging activity of zingerone was found to be 86.7 percent. Stannus chloride (SnCl2) is another chemical used to induce oxidative stress in experimental studies. In another study zingerone at concentrations of 500 and 750 μg/mL conferred protection against Stannus chloride (SnCl2)-induced oxidative damage to DNA. Zingerone also offered protection to DNA against ultra violet (UV) rays and hydrogen peroxide (H2O2), a known reactive oxygen species (ROS) generating system. [210]

Peroxynitrite is sometimes called peroxonitrite. In the laboratory peroxynitrite can be prepared by treating acidified hydrogen peroxide with a solution of sodium nitrite. Peroxynitrite is a potent oxidizing agent.  [211]

Peroxynitrite modifies proteins by oxidizing them. These modifications of proteins can change physical and chemical properties of proteins culminating in cellular and tissue damage. Peroxynitrite is able to break DNA strand and it can react with DNA. A study revealed that zingerone has scavenging effect against peroxynitrite formed from the reaction of superoxide and nitric oxide inducing cellular and tissue damage. [212]

Immunomodulatory activity of Zingerone

Recently zingerone is reported to be immunostimulant and immunity enhancer. [213]

In an experimental study on white shrimp (Litopaenaeus vannamei juveniles), the animals were fed with diet enriched with zingerone at doses of 1, 2.5 and 5mg/kg body weight. After 56 days, shrimp (Litopaenaeus vannamei juveniles)      fed on zingerone supplement had greater weight, had higher survival rates, increased phenoloxidase levels and could resist the pathogen Vibrio alginolyticus, a Gram-negative marine bacterium. Researchers feel, in shrimp       (Litopaenaeus vannamei juveniles), the use of zingerone as appetizer and immunostimulant is promising. [214]

Antibacterial activity of Zingerone

Opportunistic pathogen Pseudomonas aeruginosa produces surface-associated communities called biofilms, which protect the pathogen by forming a complex permeability barrier for antibiotics and immune cells. Biofilm formation results in persistent chronic infection caused by Pseudomonas aeruginosa. This compels clinicians to use various antibiotics to treat this pathogen which culminated in the emergence of multiple drug-resistant strains of Pseudomonas aeruginosa. A study showed that zingerone could inhibit formation of biofilm and increase the susceptibility of the pathogen to ciprofloxacin. This suggests that zingerone can be used as an adjunct to antibiotic therapy. [215]  

Escherichia coli is the commonest organism causing diarrhea in children. Its enterotoxin is more detrimental. Enterotoxin can cause infant death. Both zingerone extracted from Ginger (Zingiber officinale) and chemically synthesized zingerone derivatives can significantly suppress enterotoxigenic Escherichia coli diarrhea. [216]

Antiviral activity of Zingerone

Anti-inflammatory and antioxidant properties of zingerone can exhibit antiviral activity

Antifungal   activity of Zingerone

Zingerone displays antifungal activity against some pathogenic fungi such as Aspergillus flavus that produces afflatoxin, Aspergillus niger that rots peanuts, pistachios, hazelnuts, walnuts, coconut and copra, cereals and oil seeds, onions, dried and smoked fish etc.; and some candida species. [217]

Actions of Zingerone on the skin

Nowadays X-rays, gamma rays, infrared rays, ultra violet rays are used for diagnostic and therapeutic purposes. Radiation therapy leads to oxidative stress in organs. Radiation causes formation of reactive oxygen species (ROS) which damages organs. Via its strong antioxidant activity zingerone has been found to neutralize radiation-induced reactive oxygen species (ROS) and free radicals. Reactive oxygen species (ROS) activates Bax protein that is responsible for radiation-induced apoptosis.    [218], [219]

Actions of Zingerone on Hematopoetic System

Zingerone displayed anti-platelet aggregation activity in mice. It reduced activated partial thromboplastin time but did not prolong bleeding time in mice. [220]

Actions of Zingerone on Nervous System

The vanilloid receptor agonist compound zingerone from Ginger (Zingiber officinale) possessed anticonvulsant and analgesic activity. [221]

The neuronal mitochondria succumb to ischemia-reperfusion injury. Ischemia-reperfusion injury of the nervous system releases huge amount of reactive oxygen species (ROS). This oxidative stress induces programmed cell death (apoptosis) of neurons. To evaluate the effect of zingerone on ischemia-reperfusion-induced oxidative stress and subsequent neuronal cell death, brain infarct was created in rats by occluding right middle cerebral artery (RMCA). The maximum infarct volume was 43.29% and maximum mitochondrial damage was 56.99%. However, oral administration of zingerone at 50 and 100mg/kg bodyweight twice a day at 5 and 12 hours from initiation of middle cerebral artery ligation showed a significant reduction in infarct volume and mitochondrial injury (<0 .001="" activity="" also="" and="" animals.="" antioxidant="" behavior="" biochemical="" by="" furthermore="" histological="" in="" mitigated="" neurons="" o:p="" of="" penumbral="" result="" salvaged="" significantly="" studies.="" subsequently="" supported="" the="" this="" was="" zingerone="" zone.="">

Anti-inflammatory and antioxidant activities of zingerone can arrest or delay Alzheimer’s disease. [223]

Progressive degeneration of dopaminergic neurons in the neurostrial system and dopamine depletion in the striatum results in the development of Parkinson’s disease (PD). The antioxidant, free radical scavenging activity of zingerone prevents the development of Parkinson’s disease. [224]

In an experimental study human neuroblstoma cell lines SH-SY5Y, BE (2) C and BE (2)-M17 were treated with zingerone for 24 to 48 hours. The results showed that the growth of BE (2)-M17 cells was significantly reduced. This suggests zingerone can be a potentially effective agent for the treatment of neuroblastoma. [225]

Actions of Zingerone on Cardiovascular System

Recently, a study on rats showed that by virtue of its antioxidant property, zingerone protects the myocardium against the isoproterenol-induced myocardial infarction. [226] 

Zingerone reduces the catalase activity, normalizes the angiotensin receptor1 expression. Zingerone protects the heart from diabetes related inflammations. Zingerone alleviates the delayed repolarization and AV conduction in diabetes. Zingerone also protects the heart from diabetes induced cardiac fibrosis. [227]

Actions of Zingerone on Respiratory System

Microparticles (MP) are phospholipid vesicles. Upon activation or at apoptosis cells shed microparticles. Monocyte-derived microparticles (MP) are involved in the synthesis of pro-inflammatory mediators (cytokines) by lung epithelial cells.  In Vitro studies showed that zingerone inhibited cytokine expression induced by lipopolysaccharide (LPS). Zingerone attenuated lipopolysaccharide (LPS) induced pulmonary inflammation. Zingerone attenuated lipopolysaccharide (LPS) induced pulmonary edema in murine acute lung injury model. [228]  

Actions of Zingerone on Gastro-intestinal System

Vomiting is the major side effect which hampers chemotherapy in cancer patients. Apart from newer synthetic antiemetics, phytochemicals from Ginger (Zingiber officinale) come for rescue. They are potent natural antiemetic agents. Zingerone is one such antiemetic agent. The anti-serotonin receptor effect of zingerone exerts antiemetic effect. It acts as a noncompetitive antagonist to 5-hydroxytryptamine-3 (5-HT-3) receptors.  [229] 

Acute diarrhea is a leading cause of mortality in pediatric patients and young adult individuals particularly during epidemics. The important organism causing enteric infection is Escherichia coli (E. coli). The organism releases enterotoxins which cause motility disturbances in the intestinal tract. The mechanisms involved in diarrhea are bacterial infection, inflammation of the intestines, abnormalities of intestinal motilities, secretory abnormalities and osmotic disturbances. Studies on mice have shown that zingerone has the ability to inhibit enterotoxins released by Escherichia coli (E. coli). Zingerone corrects motility disorders of gastro-intestinal tract caused by Escherichia coli (E. coli) infection. [230], [231]

Interstitial cells of Cajal (ICCs) are the pacemaker cells responsible for slow waves in the gastrointestinal (GI) tract. Depending upon the dose and the concentration in Ginger (Zingiber officinale) extract, zingerone inhibited pacemaker potentials of interstitial cells of Cajal (ICCs). This suggests that zingerone may have the potential for development as gastrointestinal (GI) tract regulating agent. [232]

To study the efficacy of various drugs for the treatment of colitis, by using 2, 4, 6-trinitrobenzenesulpfonic acid (TNBS) colitis is induced in mice. In one study colitis was induced in mice. Subsequently the animals were treated with Ginger (Zingiber officinale) extract and zingerone. The results showed that Ginger (Zingiber officinale) extract and zingerone regulated cytokine related pathways and ameliorated colitis. [233] 

Actions of Zingerone on Liver

Alcoholic liver disease is a direct result of hepatic insult. Moreover alcohol-induced hepatotoxicity implies the ability of the organ for regeneration. A study on rats showed that anti-inflammatory and antioxidant properties of zingerone protected the liver from alcohol-induced liver injury. Some researchers believe that zingerone can be useful for the treatment of alcoholic liver disease (ALD) [234]

In another study, researchers induced liver injury in mice by using lipopolysaccharide (LPS). The animals were treated with zingerone. The results showed that anti-inflammatory activity of zingerone was useful for the treatment of lipopolysaccharide (LPS)-induced liver damage. [235]

Actions of Zingerone on Metabolism

A study on ovariectomized (Ovx) rats showed that oral administration of 170 mg/kg bodyweight of zingerone significantly reduced bodyweight. Zingerone also increased norepinephrine-induced lypolysis in adipocytes. Zingerone also prevented fat storage. [236]

Actions of Zingerone against diabetes

I rats, zingerone normalized the elevated blood sugar in streptozotocin (STZ)-induced diabetes. [237]

Antitumor activity of Zingerone

Angiogenesis is essential for tumor survival and tumor progression. Zingerone inhibits the formation of microvessels inside tumors. In mice, by suppressing angiogenesis, zingerone suppresses tumor growth and tumor progression. This suggests that zingerone can be a potential therapeutic agent for the treatment of various human cancers. [238]

Molecular formula: C15H24
Structural formula

Bisabolenes are a group of compounds classified as sequiterpenes. They are present in essential oils of a wide variety of plants. They are produced by several fungi. The role of bisabolenes in fungi is unclear. Bisabolenes have balsamic odor. It is a natural sweetener. It is approved in Europe as a food additive. [240]

β-Bisabolene and its alcoholic analogue, α-bisabolol display cytotoxic activity for cancer cells of mouse IC50 and human breast cancer cells IC50. In vitro and in vivo β-Bisabolene and α-bisabolol induce apoptosis in breast cancer cells. [241]

During the experiments investing the effects on CNS it was found that 100 and 200 mg/kg bodyweight of β-Bisabolene showed anti-inflammatory effect both in vitro and in vivo. [242]

Molecular formula: C15H24
Structural formola:

Zingiberene is a monocyclic sesquiterpene. This compound gives Ginger (Zingiber officinale) its characteristic flavoring and causes the fragrance of the spice. [243]

The concentration of zingiberine is highest in fresh Ginger (Zingiber officinale) and decomposes on drying and storage. Hence it is preferred to use fresh rhizome than its dried form, shunthee. [244]

Zingiberene displays anti-inflammatory and antioxidant activities.
Zingiberene is a potent anti-rheumatic agent.
Zingiberene shows antibacterial activity. Zingiberene displays high virucidal activity against acyclovir resistant herpes simplex virus-1. It protects against dangers caused by radiation. For this it is used in cosmetic industry.
At 200 mg/kg bodyweight, zingiberene displayed antiemetic, analgesic and antipyretic activities.
When treated for twenty one days, zingiberene restored the elevated blood sugar to normal in diabetic rats.
After the treatment of rats for twenty one days, zingiberene lowered the total serum cholesterol levels from 136.46 to 109.46 mg/dl, elevated the levels of high density lipoproteins from 41.82 to 65.42 mg/dl and decreased low density lipoprotein and triglycerides.
Zingiberene inhibits the viability of breast cancer.
By inhibiting angiogenesis, zingiberene arrests the growth and proliferation of various cancer cells. 
Lipid peroxidation causes food spoilage. By preventing lipid peroxidation, at concentration 20 to 100 μg /ml, zingiberene can be used as a natural preservative [245] 

Molecular formula: C17H26O3
Structural formula:

[6]-paradol is a pungent vanilloid derived from the rhizome of Ginger (Zingiber officinale). This compound can be obtained from Ginger (Zingiber officinale) by dehydration and hydrogenation. Paradol is responsible for the characteristic pungent taste of Ginger (Zingiber officinale). Similar to gingerol and shogaol, paradol has many analogs.    
Pharmacology of Paradol

By inhibiting Cyclooxygenase-2 (COX-2), [8]-paradol shows anti-inflammatory activity.
Some of the paradols possess broad spectrum antibacterial and antiviral activity.
In experimental studies on mice, [6]-paradol displayed DNA protective and anti-cancer activity. Furthermore paradols show anti-inflammatory, antioxidant, free radical scavenging, immunomodulatory activities. Paradols suppress angiogenesis, inhibit growth of tumor cells, spread of tumor cells and prevent formation of metastases. Paradols are potent chemopreventive agents.

Bode et al reported that [6]-paradol induced apoptosis in oral squamous cell carcinoma. Paradol and its derivatives are effective in controlling the gastric, colorectal, ovarian and prostate cancers. [247]

et al, Zingerone (Ginger Extract): Antioxidant Potential for Efficacy in Gastrointestinal and Liver Disease, Gastrointestinal Tissue, Chapter 21, 2017, Pages 289-297  

[207] S. W. Chung et al, Peroxisome proliferator-activated receptor activation by a short-term feeding of zingerone in aged rats, Journal of Medicinal Food, Volume 12, No. 2, pp. 345-350, 2009

[208] C. Y. Haising et al, Ginger extract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor-κB activity and interleukin-1 β signaling pathway, Food Chemistry, vol. 136, no. 1 pp. 170-177, 2013

[209] M. K. Kim et al, Modulation of age-related NF- κB activation by dietary zingerone via MAPK pathway, Experimental Gereontalogy Vol. 45, no. 6 pp. 419-426, 2010

[210] I. Rajan et al, Zingerone protects against stannous chloride-induced and hydrogen peroxide-induced oxidative DNA damage in vitro, Biological Trace Element Research, Vol. 155, no. 3, pp. 455-459, 2013 

[212] S. G. Shin et al, Zingerone as an antioxidant against peroxynitrite, Journal of Agricultural and Food Chemistry, vol. 53, no. 19, pp. 7617-7622, 2005

[213] Laura A. Svetaz, Melina G. Di Liberto, Efficient production of the flavoring agent Zingerone and both (R)- and (S)- Zingerols via Green Fungal Biocatalysis, Comparative antifungal activities between Enantiomers, Int J Mol Sci. 2014 Dec; 15(12): 22042-22058 

[214] Yueh-Ping Chang, Chun-HungLiu, Dietary administration of zingerone to enhance growth, non-specific immune response and resistance to Vibrio alginolyticus in Pacific white shrimp Litopaenaeus vannamei juveniles, Fish & Shellfish Immunology, Volume 32, Issue 2, February 2012, pages 284-290 

[215] Lokender Kumar et al, Zingerone inhibit biofilm formation and improve antibiofilm efficacy of ciprofloxacin against Pseudomonas aeruginosa PAO1, Fitoterapia, Volume 90, October 2013, Pages 73-78.

[216] Chen JC et al, Ginger and its bioactive component inhibit enterotoxigenic Escherichia coli heat-labile enterotoxin-induced diarrhea in mice, J Agric Food Chem. 2007 Oct 17; 55(21): 8390-7

[217] Laura A. Svetaz et al, Efficient production of the flaforing agent zingerone and both (R)- and (S)- Zingerols via Green Fungal Biocatalysis, Comparative Antifungal Activities between Enantiomers, Int J Mol Sci. 2014 Dec; 15 (12): 22042-22058

[218] B. N. Rao et al, Radiomodifying and anticlastogenic effect of Zingerone on Swiss albino mice exposed to whole body gamma radiation, Mutation Research/Genetic Toxicology and Environmental Mutagenesis, vol. 677, no. 1-2, pp. 33-41, 2009

[219] L. J. Buccellato et al, Reactive oxygen species are required for hyperoxia-induced Bax activation and cell death in alveolar epithelial cells, The Journal of Biological Chemistry, vol. 279, no. 8, pp6753-6760, 2004

[220] Lee W et al, Anti-factor Xa activities of zingerone with anti-platelet aggregation activity, Food Chem Toxicol. 2017 Jul; 105: 186-193    

[221] EM Awad et al, Anticonvulsant activity of some vanilloid receptor agonists, TMH El-hadiyah-Sudan Journal of Medical Sciences, Vol 8, No 4, 2013  

[222] Vaibhav K et al, Delayed administration of zingerone mitigates the behavioral and histological alteration via repression of oxidative stress and intrinsic programmed cell death in focal transient ischemic rats, Pharmacol Biochem Behav. 2013 Nov 15; 113:53-62.    

[223] Vaibhav K et al, Delayed administration of zingerone mitigates the behavioral and histological alteration via repression of oxidative stress and intrinsic programmed cell death in focal transient ischemic rats, Pharmacol Biochem Behav 2013 Nov 15; 113:53-62    

[224] Kabuto H et al, Effects of zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butenone] and eugenol [2-methoxy-4-(2-propenyl)phenol] on the pathological progress in the 6-hydroxydopamine-induced Parkin’s disease in mouse model, Neurochem Res. 2011 Dec; 36(12): 2244-2249

[225] Jae-Sun Choi et al, Zingerone Suppresses Tumor Development through Decreasing Cyclin D1 Expression and inducing Mitotic Arrest, Int J Mol Sci. 2018 Sep; 19(9): 2832 

[226] S. G. Shin et al, Zingerone as an antioxidant against peroxynitrite, Journal of Agricultural and Food Chemistry, Volume 53, No. 19, PP7617-7622, 2005

[227] Hany M. El-Bassossy et al, Zingerone alleviates the delayed repolarization and AV conduction in diabetes: Effect on cardiac fibrosis and inflammation, PLoS One December 5, 2017

[228] XianxingXie, Shicheng Sun; Zingerone attenuates lipopolysaccharide-induced acute lung injury in mice; International Immunopharmacology, Volume 19, Issue 1, March 2014, Pages 103-109

[229] Z. Jin et al, Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons, The Korean Journal of Physiology and Pharmacology, vol. 18, no. 2 pp.149-153, 2014

[230] J. C. Chen et al, Ginger and its bioactive component inhibit enterotoxigenic Escherichia coli heat-labile enterotoxin-induced diarrhea in mice, Journal of Agriculture and Food Chemistry, vol. 55, no. 21, pp. 8390-8397, 2007    

[231]  M. Iwami et al, Inhibitory effects of zingerone, a pungent component of Zingiber officinale Roscoe, on colonic motility in rats, Journal of Natural Medicines, vol. 65, no. 1, pp. 89-94, 2011.

[232] Kim J. N. et al, The Mechanism of Action of Zingerone in the Pacemaker Potentials of Interstitial Cells of Cajal Isolated from Murine Small Intestine, Cell Physiol Biochem 2018; 46: 2127-2137

[233] Hsiang CY et al, Ginger extract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor- κB activity and interleukin-1β signaling pathway, Food Chem 2013 Jan 1; 136(1): 170-7 

[234] Mani V et al, Antioxidant and anti-inflammatory role of zingerone in ethanol-induced hepatotoxicity, Mol Cell Biochem. 2016 Oct; 421(1-2):169-81; Epub 2016 Aug 20      

[235] Lokender Kumar et al, Hepatoprotective Effect of Zingerone [4-(4-Hydroxy-3-Methoxyphenyl) Butan-2-One] in Lipopolysaccharide Induced Liver Injury Mouse Model through Downregulation of Inflammatory Mediators, International Journal of Pharmacognosy and Phytochemical Research 2014; 6(2): 308-316

[236] Han LK, Effect of zingerone on fat storage in overiectomized rats, Yakugaku Zasshi; Journal of the Pharmaceutical Society of Japan 01 Aug 2008, 128(8): 1195-1201 

[237] M Arul Jothi, Hematological studies on the effect of zingerone on streptozotocin induced diabetic rats, IJPRBS, 2016; Volume 5(2): 21-26 

[238] Woom-Yee Bae, Jae-Sun Choi, Zingerone suppresses angiogenesis via inhibition of matrix metalloproteinases during tumordevelopment, Oncotarget 2016 Jul 26; 7(30): 47232-47241

[240] https://en.wikipedia.org/wiki/Bisabolene

[241] Syn Yeo, β-Bisabolene, a Sequiterpene from the Essential Oil Extract of Opponax (Commiphora guidottii), Exhibits Cytotoxicity in Breast Cancer Cell Lines, Phytotherapy Research 30 (3). December 2015

[242] Cristine Kobayashi, Tiago Oselame, Pharmacological evaluation of Copaifera multijuga oil in rats,Pharmaceutical Biology Volume 49, 2011, Issue 3

[243] https://en.wikipedia.org/wiki/Zingiberene

[244] https://www.sciencedirect.com/topics/neuroscience/zingiberene

[245] Rasna Gupta et al, Pharmacological activities of Zingiber officinale (Ginger) and its active ingredients: A Review, International Journal of Scientific and Innovative Research, 2016; 4 (1)

[247] Rasna Gupta et al, Pharmacological activities of Zingiber officinale (Ginger) and its active ingredients: A Review, International Journal of Scientific and Innovative Research, 2016; 4 (1)


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