Daphnin

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Daphnin
Daphnin.svg
Names
IUPAC name
7-(β-D-Glucopyranosyloxy)-8-hydroxy-2H-1-benzopyran-2-one
Preferred IUPAC name
8-Hydroxy-7-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-2H-1-benzopyran-2-one
Other names
Daphnoside; 7-(β-D-Glucopyranosyloxy)-8-hydroxycoumarin; Daphnetin 7-β-D-glucopyranoside
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C15H16O9/c16-5-8-10(18)12(20)13(21)15(23-8)22-7-3-1-6-2-4-9(17)24-14(6)11(7)19/h1-4,8,10,12-13,15-16,18-21H,5H2/t8-,10-,12+,13-,15-/m1/s1 Yes check.svgY
    Key: HOIXTKAYCMNVMY-PVOAASPHSA-N Yes check.svgY
  • O=C2\C=C/c3ccc(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)c(O)c3O2
Properties
C15H16O9
Molar mass 340.284 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Daphnin is a plant toxin with the chemical formula C15H16O9 and is one of the active compounds present in the Eurasian and North African genus Daphne of the Thymelaeaceae, a plant family with a predominantly Southern Hemisphere distribution with concentrations in Australia and tropical Africa. [1]

Contents

Origin

Daphne mezereum (sometimes called mezereon) is a plant native to Europe and western Asia and is a member of the family Thymelaeaceae. The plants have different bioactive metabolites and pharmacological active molecules like anti-inflammatory, anti-cruor effects, reduction of blood coagulation, and the increase of uric acid excretion. However, the plant's berries and twigs contain daphnin, mezerein (damages the kidneys), and daphne toxin (heavy fevers and even causing death), which are toxic to humans and some animals. Daphnin is a hydroxycoumarin compound. Coumarins are a family of benzopyrones widely distributed in nature.[ citation needed ]

Synthesis and isolation

Daphnetin is a dihydroxy coumarin and can undergo enzymatic glycosylation to yield 7-O-glucoside also called daphnin. The reaction is catalyzed by the enzyme O-dihydroxy coumarin 7-O-glucosyltransferase. [2] [3]

In Daphne odora , and possibly other Daphne species, daphnin is formed from p-glucosyl oxycinnamic acid. The formed daphnin can be converted to 8-glucoside by the enzyme transglucosidase using hydrolysis and glycosidation. The formed 8-glucoside is energetically more stable than the 7-glucoside daphnin. 

Daphnin and its precursor daphnetin have also been found in Matricaria chamomilla , also known as chamomile. [4]

Publications show different approaches for isolating daphnin, most of which focus on making an extract of Daphne mezereum followed by affinity separation. Extraction is done by using absolute ethanol, methanol, and chloroform in a mixture at different concentrations, and are often used as eluting systems for the separation procedure on silica gel columns and as mobile phases for the TLCs. Multiple fractions are taken and identified by NMR and/or mass spectroscopy. [5]

Reactions and metabolism

Hypouricemia effect

Serum uric acid levels in organisms need to be at a certain level. A high concentration causes hyperuricemia, and causes gout or in some cases kidney stones

In vitro experiments with the reaction of dapnin and serum uric acid, inhibited by potassium oxonate, cause an increase in the hyperuricemic levels in mice for several hours, after which the level decreases. The dose-dependent concentration of daphnin is 100 mg/kg for mice. However, the dose-dependent concentration for humans is not known. [6]

Human serum albumin

Most substances in the body are transported by a protein transport in the plasma. The most common transporter is the Human serum albumin (HSA) which transports endogenous molecules for ADME. The interaction between HSA and Dapnin can occur under physiological conditions in vitro. The binding can be measured by fluorescence quenching or by the tryptophan residue on the HSA.

The binding between Daphnin and HSA changes the microenvironment of the tryptophan residue with a λmax of 215 nm for the Daphnin-HSA complex and a λmax of 314 nm for Daphnin. [6]

Interconversion

Daphnin interconversion is one of the metabolic pathways that can take place. With this metabolic pathway, the Daphnin can be converted into daphnetin by hydrolysis caused by the enzyme transglycosylase, releasing D-glucopyranose which has a major role in human metabolism. Daphnetin counteracted GSH depletion and inhibited MPO activity. Daphentin can also be metabolized back into Daphnin by the reaction with UDP-alpha-D-glucose. [7]

Biological activities

Despite the toxic effects of species in the Daphne genus, different useful bioactive and phytochemicals compounds are present in the berries.

The species of the Daphne genus have, despite the toxicity, also different bioactive effects: antioxidant, anti-inflammatory, cytotoxic, anti-ulcerogenic, absorptive, hypocholesterolemic, and hemostatic effects. [6] [8]

Like some other coumarins, daphnin also shows antimicrobial activity. [9]

Symptoms

Daphne mezereum is toxic because of the compounds daphnin, mezerein, and daphnetoxin which are partially present in the fruits and the twigs. When interacting with these parts of the plant gastrointestinal effects can occur which eventually can cause an experience of delirium, seizures, and death. [10] Some people experience only skin rash or eczema.

Earlier publications in the Lancet have shown that there is a difference in symptoms present looking at the different ages of the person when taking the fruits orally. The symptoms that are the same in all cases, were the burns and digestive tract when taken orally. [11] In young children (toddlers), the symptoms are mainly vomiting and hyper catharsis after taking one or two parts of the plant orally. When more parts are eaten it will mostly cause death.

Older children mostly experience vomiting when the fruits are taken orally, only the reaction of tympanitic distension of the abdomen will take place immediately. [12]

For adults, only 12 or more berries are needed for a death cause. After oral intake, the body immediately starts vomiting. Furthermore, narcotism signs show up like small pupils, shallow breathing, unresponsiveness, sluggishness, and confusion. [13]

Toxicity

There is not much scientific evidence of the toxicity of daphnin. However, the sap, berries, and bark of all Daphne species are toxic to humans and small animals. The sap is also a skin irritant. It has a similar structure as coumarin, which is mildly toxic to humans. It can be assumed that a similar pathway is followed by the biodegradation of daphnin. Coumarin is toxic for the liver and kidney, so it is advised to pay attention. [14] [15]

Effect on animals

Daphnin has the same toxicity for pets as for humans. Only birds have resistance against these toxic compounds, which have also a negative effect on humans and pets. Because of the nontoxicity for birds, they will spread the barriers and the twigs which leads to more spread of the plant. [15]

Medicinal application

Daphne plants

Despite the toxicity of the compound, daphnin has antibacterial activities in the low concentration rate of 200-250 µg/mL the minimum inhibitory concentrations (MIC) are defined as the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. [16]

Different species of the Thymelaeaceae family have been used for centuries in China as traditional medicine. The different parts of the plant are used for specific diseases. The toxic compounds of the Daphne mezereum. can specifically be used on P-388 lymphocytic cells for the antileukemic activities in mice. Especially mezerein can be isolated and inhibit the effect against P-388/L-1210 cells. [17]

Leaves of Daphne odora have highly bioactive compounds which can be isolated, which then can be used to make medicine to relieve headache and to lower fever. Daphne oleoides subsp. oleoides’ roots can help against diarrhea, the leaves help against skin damage and ulcers. [18] Its herbs and leaves have been reported to be used as folk medicine against rheumatism and/or edema and to treat lumbago (respectively) in the Taurus Mountains, South Turkey. [19] The flowers of Daphne genkwa is used as anti-inflammatory agent and anti-carcinogenic. [20]

Daphnetin

Daphnetin shows several neuroprotective and anti-inflammatory effects on the inhibition of the TLR4/NF-kB mediated inflammatory signaling pathway. They also could inhibit the IKKs/IkBa/NF-kB, AKT, and the Src/FAK/ERK1/2 multi-target medication signaling pathway for anti-angiogenesis and cancer. [21]

Daphnetin has been reported to be a strong sensitizer, which means that this compound and its glycosidic derivatives (e.g. daphnin) can be a cause of allergic reactions. [4]

Related Research Articles

<span class="mw-page-title-main">Glycoside</span> Molecule in which a sugar is bound to another functional group

In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications. Several species of Heliconius butterfly are capable of incorporating these plant compounds as a form of chemical defense against predators. In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body.

<i>Daphne</i> (plant) Genus of flowering plants in the family Thymelaeaceae

Daphne is a genus of between 70 and 95 species of deciduous and evergreen shrubs in the family Thymelaeaceae, native to Asia, Europe and north Africa. They are noted for their scented flowers and often brightly coloured berries. Two species are used to make paper. Many species are grown in gardens as ornamental plants; the smaller species are often used in rock gardens. All parts of daphnes are poisonous, especially the berries.

<span class="mw-page-title-main">Coumarin</span> Aromatic chemical compound

Coumarin or 2H-chromen-2-one is an aromatic organic chemical compound with formula C9H6O2. Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by an unsaturated lactone ring −(CH)=(CH)−(C=O)−O−, forming a second six-membered heterocycle that shares two carbons with the benzene ring. It belongs to the benzopyrone chemical class and considered as a lactone.

<i>Calotropis</i> Genus of flowering plants

Calotropis is a genus of flowering plants in the family Apocynaceae, first described as a genus in 1810. It is native to southern Asia and North Africa.

<span class="mw-page-title-main">Human serum albumin</span> Albumin found in human blood

Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water, and it is monomeric.

<i>Daphne mezereum</i> Species of plant

Daphne mezereum, commonly known as mezereum, mezereon, February daphne, spurge laurel or spurge olive, is a species of Daphne in the flowering plant family Thymelaeaceae, native to most of Europe and Western Asia, north to northern Scandinavia and Russia. In southern Europe it is confined to medium to higher elevations and in the subalpine vegetation zone, but descends to near sea level in northern Europe. It is generally confined to soils derived from limestone.

<span class="mw-page-title-main">Phorbol</span> Chemical compound

Phorbol is a natural, plant-derived organic compound. It is a member of the tigliane family of diterpenes. Phorbol was first isolated in 1934 as the hydrolysis product of croton oil, which is derived from the seeds of the purging croton, Croton tiglium. The structure of phorbol was determined in 1967. Various esters of phorbol have important biological properties, the most notable of which is the capacity to act as tumor promoters through activation of protein kinase C. They mimic diacylglycerols, glycerol derivatives in which two hydroxyl groups have reacted with fatty acids to form esters. The most common and potent phorbol ester is 12-O-tetradecanoylphorbol-13-acetate (TPA), also called phorbol-12-myristate-13-acetate (PMA), which is used as a biomedical research tool in contexts such as models of carcinogenesis.

<span class="mw-page-title-main">Essential fatty acid interactions</span>

There are many fatty acids found in nature. Two types of fatty acids considered essential for human health are the omega-3 and omega-6 types. These two essential fatty acids are necessary for some cellular signalling pathways and are involved in mediating inflammation, protein synthesis, and metabolic pathways in the human body.

<span class="mw-page-title-main">Aesculin</span> Chemical compound

Aesculin, also called æsculin or esculin, is a coumarin glucoside that naturally occurs in the trees horse chestnut, California buckeye, prickly box, and daphnin. It is also found in dandelion coffee and olive bark. It is reported to present in olive bark, not in olive leaf, therefore, identification of aesculin in abundant in an extract indicates the extract derived from olive bark.

<span class="mw-page-title-main">Triclocarban</span> Antimicrobial agent

Triclocarban is an antibacterial chemical once common in, but now phased out of, personal care products like soaps and lotions. It was originally developed for the medical field. Although the mode of action is unknown, TCC can be effective in fighting infections by targeting the growth of bacteria such as Staphylococcus aureus. Additional research seeks to understand its potential for causing antibacterial resistance and its effects on organismal and environmental health.

<span class="mw-page-title-main">Phycocyanobilin</span> Chemical compound

Phycocyanobilin is a blue phycobilin, i.e., a tetrapyrrole chromophore found in cyanobacteria and in the chloroplasts of red algae, glaucophytes, and some cryptomonads. Phycocyanobilin is present only in the phycobiliproteins allophycocyanin and phycocyanin, of which it is the terminal acceptor of energy. It is covalently linked to these phycobiliproteins by a thioether bond.

<span class="mw-page-title-main">Aesculetin</span> Chemical compound

Aesculetin is a derivative of coumarin. It is a natural lactone that derives from the intramolecular cyclization of a cinnamic acid derivative.

<span class="mw-page-title-main">Cucurbitacin</span> Class of biochemical compounds

Cucurbitacins are a class of biochemical compounds that some plants – notably members of the pumpkin and gourd family, Cucurbitaceae – produce and which function as a defense against herbivores. Cucurbitacins and their derivatives have also been found in many other plant families, in some mushrooms and even in some marine mollusks.

<span class="mw-page-title-main">Palmatine</span> Chemical compound

Palmatine is a protoberberine alkaloid found in several plants including Phellodendron amurense, Coptis Chinensis and Corydalis yanhusuo, Tinospora cordifolia, Tinospora sagittata, Phellodendron amurense, Stephania yunnanensis.

<span class="mw-page-title-main">Angelicin</span> Chemical compound

Angelicin is the parent compound in a family of naturally occurring organic compounds known as the angular furanocoumarins. Structurally, it can be considered as benzapyra-2-one fused with a furan moiety in the 7,8-position. Angelicin is commonly found in certain Apiaceae and Fabaceae plant species such as Bituminaria bituminosa. It has a skin permeability coefficient (LogKp) of -2.46. The maximum absorption is observed at 300 nm. The 1HNMR spectrum is available; the infrared and mass spectra of angelicin can be found in this database. The sublimation of angelicin occurs at 120 °C and the pressure of 0.13 Pa. Angelicin is a coumarin.

<span class="mw-page-title-main">Tetrahydrocannabinolic acid</span> Chemical compound

Tetrahydrocannabinolic acid is a precursor of tetrahydrocannabinol (THC), an active component of cannabis.

<span class="mw-page-title-main">Mezerein</span> Chemical compound

Mezerein is a toxic diterpene ester found in the sap of Daphne mezereum and related plants. Plants of the genera Euphorbiaceae and Thymelaeaceae possess a wide variety of different phorbol esters, which share the capacity of mimicking diacylglycerol (DAG) and thus activating different isoforms of protein kinase C. Mezerein was first isolated in 1975. It has antileukemic properties in mice, but it is also defined as a weak promoter of skin cancers in the same species. All parts of the plants contain an acrid and irritant sap that contains mezerein, thought to be the principal poison. The sap is especially prevalent in the bark and berries.

Cynaropicrin is a sesquiterpene lactone of the guaianolide type found mainly in leaves of artichoke plants. It is one of the compounds that gives the artichoke its characteristic bitterness. It is found in artichoke leaves with an abundance of approximately 87 g/kg, but can hardly be found in other parts of the plant. Cynaropicrin makes up about 0.7% of leaf extracts of the artichoke. It exhibits a large diversity of bioactivities and shows properties such as anti-inflammatory, antifeedant and activation of bitter sensory receptors, but has not yet been used in medicine. Despite its pharmacologically beneficial properties, it can be toxic in higher doses. The compound has attracted attention in recent years as a potential anticancer drug.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

<span class="mw-page-title-main">Xanthatin</span> Chemical compound

Xanthatin, or (3aR,7S,8aS)-7-methyl-3-methylidene-6-[(E)-3-oxobut-1-enyl]-4,7,8,8a-tetrahydro-3aH-cyclohepta[b]furan-2-one (C15H18O3) is a major bioactive compound found in the leaves of the Xanthium strumarium (Asteracae) plant. It is classified as a natural sesquiterpene lactone. Xanthatin is believed to have anti-inflammatory, anti-tumour, anti-microbial, and anti-parasitic properties hence it is being researched for potential use in treatment of cancer and autoimmune diseases. While it has been used in traditional medicine for decades, its mechanisms and modern use haven’t been fully understood yet.

References

  1. 1. Bates 2. Berry, 1. D.M. 2. P.E. "Malvales - Neuradacease, Thymelaeaceae, and sphaerosepalaceae". Archived from the original on March 17, 2022. Retrieved March 10, 2022.{{cite web}}: CS1 maint: numeric names: authors list (link)
  2. Ibrahim, Ragai K.; Boulay, Bernard (1980-05-01). "Purification and some properties of UDP-glucose:o-dihydroxycoumarin7-O-glucosyltransferase from tobacco cell cultures". Plant Science Letters. 18 (2): 177–184. doi:10.1016/0304-4211(80)90048-6. ISSN   0304-4211. Archived from the original on 2024-02-01. Retrieved 2022-04-03.
  3. Ueno, Katsuhiko; Sato, Mitsuhiko; Saito, Norio (1983-06-01). "The Crystal and Molecular Structure of Daphnin Dihydrate: 7-(β-D-Glucopyranosyloxy)-8-hydroxycoumarin Dihydrate". Bulletin of the Chemical Society of Japan. 56 (6): 1577–1580. doi: 10.1246/bcsj.56.1577 . ISSN   0009-2673.
  4. 1 2 Petruľová-Poracká, Veronika; Repčák, Miroslav; Vilková, Mária; Imrich, Ján (2013-11-01). "Coumarins of Matricaria chamomilla L.: Aglycones and glycosides". Food Chemistry. 141 (1): 54–59. doi:10.1016/j.foodchem.2013.03.004. ISSN   0308-8146. PMID   23768326.
  5. Frezza, Claudio; Venditti, Alessandro; De Vita, Daniela; Sciubba, Fabio; Tomai, Pierpaolo; Franceschin, Marco; Di Cecco, Mirella; Ciaschetti, Giampiero; Di Sotto, Antonella; Stringaro, Annarita; Colone, Marisa (March 2021). "Phytochemical Analysis and Biological Activities of the Ethanolic Extract of Daphne sericea Vahl Flowering Aerial Parts Collected in Central Italy". Biomolecules. 11 (3): 379. doi: 10.3390/biom11030379 . ISSN   2218-273X. PMC   8001904 . PMID   33802543.
  6. 1 2 3 Zhu, Jinhua; Wu, Liye; Zhang, Qingyou; Chen, Xingguo; Liu, Xiuhua (2012-09-01). "Investigation the interaction of Daphnin with human serum albumin using optical spectroscopy and molecular modeling methods". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 95: 252–257. Bibcode:2012AcSpA..95..252Z. doi:10.1016/j.saa.2012.04.099. ISSN   1386-1425. PMID   22634418.
  7. Brown, Stewart A. (1986-03-01). "Biosynthesis of Daphnetin in Daphne mezereum L." Zeitschrift für Naturforschung C. 41 (3): 247–252. doi: 10.1515/znc-1986-0301 . ISSN   1865-7125. S2CID   36855785.
  8. Sovrlić, Miroslav M.; Manojlović, Nedeljko T. (2017-03-01). "Plants from The Genus Daphne: A Review of its Traditional Uses, Phytochemistry, Biological and Pharmacological Activity". Serbian Journal of Experimental and Clinical Research. 18 (1): 69–80. doi: 10.1515/sjecr-2016-0024 . S2CID   51914546.
  9. Cottigli, F.; Loy, G.; Garau, D.; Floris, C.; Caus, M.; Pompei, R.; Bonsignore, L. (2001-01-01). "Antimicrobial evaluation of coumarins and flavonoids from the stems of Daphne gnidium L." Phytomedicine. 8 (4): 302–305. doi:10.1078/0944-7113-00036. ISSN   0944-7113. PMID   11515721.
  10. Spiller, Henry A.; Willias, Danetta (2008-01-01). "Daphne caucasica ingestion in a child". Clinical Toxicology. 46 (9): 912. doi:10.1080/15563650701206707. ISSN   1556-3650. PMID   19003599. S2CID   32900175. Archived from the original on 2024-02-01. Retrieved 2022-03-17.
  11. Kingsbury, J. M. Common Poisonous Plants https://ecommons.cornell.edu/handle/1813/3497 Archived 2022-06-23 at the Wayback Machine (accessed Mar 16, 2022)
  12. Grieve, James (October 1837). "Poisoning with the Daphne mezereon". The Lancet. 29 (736): 43–45. doi:10.1016/s0140-6736(02)81176-x. ISSN   0140-6736. Archived from the original on 2024-02-01. Retrieved 2022-03-17.
  13. Narcotics Drug Poisoning - Symptoms & Treatment |St John Ambulance https://www.sja.org.uk/get-advice/first-aid-advice/poisoning/narcotics-drug-poisoning/ Archived 2022-01-19 at the Wayback Machine (accessed Mar 16, 2022).
  14. Coumarin MSDS - 822316 - Merck https://www.merckmillipore.com/NL/en/product/msds/MDA_CHEM-822316?ReferrerURL=https%3A%2F%2Fwww.google.com%2F Archived 2023-07-09 at the Wayback Machine (accessed Mar 16, 2022).
  15. 1 2 A Dangerous Garden Thug Exposed: Daphne laureola |MGABC https://www.mgabc.org/content/dangerous-garden-thug-exposed-daphne-laureola Archived 2020-01-30 at the Wayback Machine (accessed Mar 16, 2022).
  16. Shakeel-U-Rehman; Khan, Reehana; Bhat, Khursheed A.; Raja, Alsaba F.; Shawl, Abdul S.; Alam, Mohd S. (December 2010). "Isolation, characterisation and antibacterial activity studies of coumarins from Rhododendron lepidotum Wall. ex G. Don, Ericaceae". Revista Brasileira de Farmacognosia. 20 (6): 886–890. doi: 10.1590/s0102-695x2010005000037 . ISSN   0102-695X.
  17. Fisher, P. B.; Hermo Jr, H.; Solowey, W. E.; Dietrich, M. C.; Edwalds, G. M.; Weinstein, I. B.; Langer, J. A.; Pestka, S.; Giacomini, P.; Kusama, M. (1986). "Effect of recombinant human fibroblast interferon and mezerein on growth, differentiation, immune interferon binding and tumor associated antigen expression in human melanoma cells". Anticancer Research. 6 (4): 765–774. PMID   2944474.
  18. Ullah, Nisar; Ahmad, Saeed; Malik, Abdul (1999). "Phenylpropanoid Glycosides from Daphne oleoides". Chemical & Pharmaceutical Bulletin. 47 (1): 114–115. doi: 10.1248/cpb.47.114 . Archived from the original on 2022-03-17. Retrieved 2022-03-17.
  19. Yeşilada, Erdem; Honda, Gisho; Sezik, Ekrem; Tabata, Mamoru; Fujita, Tetsuro; Tanaka, Toshihiro; Takeda, Yoshio; Takaishi, Yoshihisa (1995-06-05). "Traditional medicine in Turkey. V. Folk medicine in the inner Taurus Mountains". Journal of Ethnopharmacology. 46 (3): 133–152. doi:10.1016/0378-8741(95)01241-5. ISSN   0378-8741. PMID   7564412. Archived from the original on 2024-02-01. Retrieved 2022-04-03.
  20. Yeşilada, Erdem; Taninaka, Hitomi; Takaishi, Yoshihisa; Honda, Gisho; Sezik, Ekrem; Momota, Hiroshi; Ohmoto, Yasukazu; Taki, Takao (2001-03-01). "In Vitro Inhibitory Effects of Daphne oleoides ssp. oleoides on Inflammatory Cytokines and Activity-Guided Isolation of Active Constituents". Cytokine. 13 (6): 359–364. doi:10.1006/cyto.2001.0838. ISSN   1043-4666. PMID   11292319.
  21. Liu, Jia; Chen, Qianxue; Jian, Zhihong; Xiong, Xiaoxing; Shao, Lingmin; Jin, Tong; Zhu, Xiqun; Wang, Lei (2016-12-29). "Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway". BioMed Research International. 2016: e2816056. doi: 10.1155/2016/2816056 . ISSN   2314-6133. PMC   5227117 . PMID   28119924.