Juglans regia / Notenboom

There are 15 species of Juglans ; commercially, J. regia is the most important. This deciduous tree can grow to 45 m in height. The trunk is straight and clear, with silvery-gray bark. The crown of the tree is open and round-topped. Walnut tree leaves are compound and between 15 and 30 cm long. The male flowers are long, drooping catkins, while the female flowers are short spikes. Walnut trees self-pollinate and cross-pollinate. J. regia is native to Asia but is now cultivated in France and other parts of Europe, North Africa, North America, and East Asia. 1

History
Walnuts have been found in prehistoric deposits in Europe dating from the Iron Age and are mentioned in Old Testament references to King Solomon's nut garden. The genus name Juglans comes from the Latin Jovis glans , meaning “nut of Jupiter” or “nut of the Gods.” Many legends have been associated with the walnut; the ancient Greeks and Romans regarded them as symbols of fertility. In the Middle Ages, walnuts were thought to ward off witchcraft, the evil eye, and epileptic fits because of the belief that evil spirits lurked in the walnut branches. 2

Historically, walnut oil was prescribed for colic, to soothe intestines, and to relieve diarrhea and hemorrhoids. 2 , 3 , 4 Further folk uses include treating rickets, frostbite, and glandular disturbances, and as an astringent, tonic restorative, and disinfectant. 5 , 6 Some cultures use walnut bark for cleaning the teeth, possibly improving oral hygiene because it increases the pH of saliva. 7 Walnut may possess anti-helminthic activity. 6 It is considered helpful in inflammatory conditions, including rheumatoid arthritis, and certain skin disorders. Blisters, ulcers, itchy scalp/dandruff, sunburn, and perspiration are some of the conditions treated with various walnut preparations. 5

Walnuts are a common food source and are used in cooking and baking. 2 , 8 Walnut extract is an old-fashioned hair dye and also has been used to darken (stain) the skin. 5 , 8 Walnut shell flour has been used as a carrier for insecticides, filler for building materials, and stuffing in toys. 8

Chemistry
Walnuts contain 3% to 4% water, 60% oil, and 15% to 20% protein, bearing approximately 700 calories per 100 g. 8 The mineral content includes iron and zinc (approximately 3 mg per 100 g each), sodium (2 mg per 100 g), selenium (19 mcg per 100 g), calcium, magnesium, potassium, copper, and phosphorus. 6 , 8 , 9 Vitamins E and C also are found in walnut. 4 , 10
Walnuts differ from other nuts in that they predominantly contain the polyunsaturated fatty acids alpha linolenic (n-3) acid and linoleic (n-6) acid, rather than mono-unsaturated fatty acids. 11 ,12 L-arginine (a precursor to nitric oxide) is also found in significant amounts in walnuts. 11
The chief known chemical constituent in walnut is juglone (5-hydroxy-1,4-naphthagulone). Also present are alpha-hydrojuglone (1,4,5-trihydroxynaphthalene) and its glycoside beta-hydrojuglone, along with caffeic acid, ellagic acid, hyperin, and kaempferol, and the tannins galloylglucose and ellagitannins. 5 , 8 In one report, 45 volatile compounds were isolated from whole green walnuts. 13 Gamma lactones are present in walnut oils. 14

Walnut Uses and Pharmacology
Lipid profile and cardiovascular effects
Clinical trials conducted in healthy adults 11 , 15 , 16 , 17 , 18 , 19 and in patients with type 2 diabetes 20 , 21 and metabolic syndrome 22 , 23 , 24 have been critically reviewed. 12 , 25Studies in patients with heart disease are lacking. 25
The majority of studies show a reduction of total cholesterol and low-density lipoprotein–cholesterol to cardioprotective levels. Effects on high-density lipoprotein–cholesterol are inconsistent, as are those for triglycerides. The diminishing positive effects observed may be a consequence of increased fat intake with higher dosages used (and lesser effects due to lower dosages). 12 , 25

Limited effect has been shown in patients with metabolic syndrome. 22 , 23 , 24
The role of walnut in atherosclerosis is unclear. Improved endothelial function has been demonstrated, possibly due to alpha linolenic acid or L-arginine content. 11 , 26 In another study, walnut activated the nuclear transcription factor identified in human atherosclerotic plaques in healthy men. 27
Results of studies investigating the effects of walnuts on oxidative stress and apoprotein response are variable. 22 , 25 , 27 There is general agreement that no gain in body weight results from the addition of walnuts to the diet. 16 , 20 , 25Other effects

Alzheimer disease
Walnut extract was demonstrated to inhibit and defibrillize amyloid beta protein—a feature of the amyloid plaque seen in the brains of patients with Alzheimer disease. 28

Antimicrobial
A study from China found borneol-walnut oil to be superior to neomycin in treating otitis media without any toxic effects. 29 The constituent juglone has been demonstrated to possess antimicrobial and antifungal effects. 7

Dosage
Daily dosages used in clinical trials range from 20 (moderate intake) to 84 g/day (4 shelled walnuts equals approximately 20 g). 25 , 30 , 31
Walnut leaves have been approved by the German Commission E for external application for excessive perspiration and skin inflammation. 32

Adverse Reactions
Allergies to nuts are common in the United States (an estimated 1%), 34 with walnut and other tree nut allergy considered to be second only to peanuts (a legume) in anaphylactic reactions. However, cross-reactivity to the proteins from tree nuts among peanut-allergic people is considered low. A co-allergy is probably the cause of allergic reactions among atopic individuals.33 , 34 Cross-reactivity between walnut and peach lipid transfer protein allergen has been noted.35 , 36 , 37
Fatalities from anaphylaxis to walnuts have been recorded. 35
Walnut allergens identified include Jug r 1 (walnut 2S albumin), Jug 3 r (vicillin-like protein), and Jug 3 r (a 9-kd lipid transfer protein). 35 , 36

Toxicology
Little data exist; however, the naphthaquinone juglone, present in all of the family Juglandaceae, is a known animal toxin. 38 The risk of contamination with aflatoxin must also be considered. 39

Bibliography
1. Juglans regia L. USDA, NRCS. 2007. The PLANTS Database ( http://plants.usda.gov, 28 Oct 2007 ). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Rosengarten F. The Book of Edible Nuts . New York, NY: Walker and Company; 1984:239-262.
3. Bisset NG, trans-ed. Herbal Drugs and Phytopharmaceuticals . Boca Raton, FL: CRC Press; 1994:281-282.
4. Bruneton J. Hatton CK, trans. Pharmacognosy, Phytochemistry, Medicinal Plants . Paris; New York: Lavoisier Publishing; 1995:348.
5. D'Amelio FS. Botanicals: A Phytocosmetic Desk Reference . Boca Raton, FL: CRC Press; 1999:209-210.
6. Hocking GM. A Dictionary of Natural Products . Medford, NJ: Plexus Publishing; 1997:409-410.
7. Alkhawajah AM. Studies on the antimicrobial activity of Juglans regia . Am J Chin Med . 1997;25(2):175-180.
8. Ensminger AH, et al. Foods and Nutrition Encyclopedia . Vol. 2. 2nd ed. Boca Raton, FL: CRC Press; 1993:2277-2278.
9. Murray MT. The Healing Power of Foods . Rocklin, CA: Prima Publishing; 1993:384.
10. Zwarts L, Savage GP, McNeil DL. Fatty acid content of New Zealand-grown walnuts ( Juglans regia L.). Int J Food Sci Nutr . 1999;50(3):189-194.
11. Ros E, Nunez I, Perez-Heras A, Serra M, et al. A walnut diet improves endothelial function in hypercholesterolemic subjects: a randomized crossover trial. Circulation . 2004;109(13):1609-1614.
12. Mukuddem-Petersen J, Oosthuizen W, Jerling JC. A systematic review of the effects of nuts on blood lipid profiles in humans. J Nutr . 2005;135(9):2082-2089.
13. Buttery RG, Light DM, Nam Y, Merrill GB, Roitman JN. Volatile components of green walnut husks. J Agric Food Chem . 2000;48(7):2858-2861.
14. Ruiz Del Castillo ML, Herraiz M, Blanch GP. Determination of the enantiomeric composition of gamma-lactones in edible oils by on-line coupled high performance liquid chromatography and gas chromatography. J Agric Food Chem . 2000;48(4):1186-1190.
15. Zibaeenezhad MJ, Shamsnia SJ, Khorasani M. Walnut consumption in hyperlipidemic patients. Angiology . 2005;56(5):581-583.
16. Sabate J, Fraser GE, Burke K, Knutsen SF, Bennett H, Lindsted KD. Effects of walnuts on serum lipid levels and blood pressure in normal men. N Engl J Med . 1993;328(9):603-607.
17. Zambon D, Sabate J, Munoz S, et al. Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. A randomized crossover trial. Ann Intern Med . 2000;132(7):538-546.
18. Lavedrine F, Zmirou D, Ravel A, Balducci F, Alary J. Blood cholesterol and walnut consumption: a cross-sectional survey in France. Prev Med . 1999;28(4):333-339.
19. Chisholm A, Mann J, Skeaff M, et al. A diet rich in walnuts favourably influences plasma fatty acid profile in moderately hyperlipidaemic subjects. Eur J Clin Nutr . 1998;52(1):12-16.
20. Tapsell LC, Gillen LJ, Patch CS, et al. Including walnuts in a low-fat/modified-fat diet improves HDL cholesterol-to-total cholesterol ratios in patients with type 2 diabetes. Diabetes Care . 2004;27(12):2777-2783.
21. Gillen LJ, Tapsell LC, Patch CS, Owen A, Batterham M. Structured dietary advice incorporating walnuts achieves optimal fat and energy balance in patients with type 2 diabetes mellitus. J Am Diet Assoc . 2005;105(7):1087-1096.
22. Davis L, Stonehouse W, Loots du T, et al. The effects of high walnut and cashew nut diets on the antioxidant status of subjects with metabolic syndrome. Eur J Nutr . 2007;46(3):155-164.
23. Mukuddem-Petersen J, Stonehouse Oosthuizen W, Jerling J, Hanekorn SM, White Z. Effects of a high walnut and high cashew nut diet on selected markers of the metabolic syndrome: a controlled feeding trial. Br J Nutr . 2007;97(6):1144-1153.
24. Schutte AE, Van Rooyen JM, Huisman HW, et al. Modulation of baroreflex sensitivity by walnuts versus cashew nuts in subjects with metabolic syndrome. Am J Hypertens . 2006;19(6):629-636.
25. Feldman EB. The scientific evidence for a beneficial health relationship between walnuts and coronary heart disease. J Nutr . 2002;132(5):1062S-1101S.
26. Cortes B, Nunez I, Cofan M, et al. Acute effects of high-fat meals enriched with walnuts or olive oil on postprandial endothelial function. J Am Coll Cardiol . 2006;48(8):1666-1671.
27. Bellido C, Lopez-Miranda J, Blanco-Colio LM, et al. Butter and walnuts, but not olive oil, elicit postprandial activation of nuclear transcription factor kappa B in peripheral blood mononuclear cells from healthy men. Am J Clin Nutr . 2004;80(6):1487-1491.
28. Chauhan N, Wang KC, Wegiel J, Malik MN. Walnut extract inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils. Curr Alzheimer Res . 2004;1(3):183-188.
29. Liu SL. Therapeutic effects of borneol-walnut oil in the treatment of purulent otitis media [in Chinese]. Zhong Xi Yi Jie He Za Zhi . 1990;10(2):93-95,69.
30. Gebauer SK, Psota TL, Harris WS, Kris-Etherton PM. n-3 Fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Am J Clin Nutr . 2006;83(suppl 6):1526S-1535S.
31. Marangoni F, Colomo C, Martiello A, Poli A, Paoletti R, Galli C. Levels of the n-3 fatty acid eicosapentaenoic acid in addition to those of alpha linolenic acid are significantly raised in blood lipids by the intake of four walnuts a day in humans. Nutr Metab Cardiovasc Dis . 2007;17(6):457-461.
32. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs . Newton, MA: Integrative Medicine Communications; 2000.
33. Sicherer SH, Sampson HA. Peanut and tree nut allergy. Curr Opin Pediatr . 2000;12(6):567-573.
34. Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol . 2005;116(5):1073-1079.
35. Pastorello EA, Pompei C, Pravettoni V, et al. Lipid transfer proteins and 2S albumins as allergens. Allergy . 2001;56(suppl 67):45-47.
36. Pastorello EA, Farioli L, Pravettoni V, et al. Lipid transfer protein and vicilin are important walnut allergens in patients not allergic to pollen. J Allergy Clin Immunol . 2004;114(4):908-914.
37. Asero R, Mistrello G, Roncarolo D, et al. Immunological cross-reactivity between lipid transfer proteins from botanically unrelated plant-derived foods: a clinical study. Allergy . 2002;57(10):900-906.
38. True RG, Lowe JE. Induced juglone toxicosis in ponies and horses. Am J Vet Res . 1980;41(6):944-945.
39. Abdel-Hafez AI, Saber SM. Mycoflora and mycotoxin of hazelnut ( Corylus avellana L.) and walnut ( Juglans regia L.) seeds in Egypt. Zentralbl Mikrobiol . 1993;148(2):137-147.


Phytothérapie
December 2011, Volume 9, Issue 6, pp 359–361
Juglans regia, fructus, la noix
D. Wuyts

Résumé
L’activité antiradicalaire et anti-inflammatoire des noix est particulièrement mise à profit dans la prévention des maladies neurodégénératives, cardiovasculaires et cancéreuses. Les noix diminuent aussi le risque de développer une lithiase urinaire oxalique ou une dégénérescence maculaire. Leur activité laxative est particulièrement intéressante en cas de selles sèches ou de régime amaigrissant. La consommation de noix peut cependant favoriser l’apparition d’aphtes, d’herpès, de troubles digestifs ou d’allergie parfois sévère chez certains patients. La consommation importante de noix pourrait parfois perturber la fonction thyroïdienne en cas d’apport iodé insuffisant, ou fausser les dosages de sérotonine.

Abstract
The anti-radical and anti-inflammatory activity of nuts is especially useful in the prevention of neurodegenerative and cardiovascular diseases and cancer. Nuts also reduce the risk of developing oxalic urolithiasis or macular degeneration. Their laxative properties are of particular interest in cases of dry stools or for weight loss programmes. The consumption of nuts can, however, favour the appearance of aptha, herpes, digestive problems or allergy, which in some patients can be severe. A high nut consumption may also lead to thyroid dysfunction if the food is too poor in iodine insufficiency, or interfere with serotonin test results.


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The hypoglycemic effect of Juglans regia leaves aqueous extract in diabetic patients: A first human trial
Saeed Hosseini, Hasan Fallah Huseini, Bagher Larijani, Kazem Mohammad, Alireza Najmizadeh, Keramt Nourijelyani and Leila Jamshidi
Diabetes mellitus is a major public health problem in both developed and developing countries. Among the leading causes of death, diabetes mellitus is ranked seventh and when fatal complications are taken into the account, it is ranked third [1]. Recently, there has been increasing interest in the use of medicinal plants. Frequently, however, it is mandatory to provide scientific proof in order to justify the use of a plant or its active components [2]. Several studies confirm the potential therapeutic efficacy of some medicinal plants in treatment of diabetic patients [3]. Since natural products may provide better treatments with fewer side effects than the existing artificial medications, a major focus for suitable anti-hyperglycemic agents has been on plants used in traditional medicine [4]. The probable efficiency of medicinal plants for treating diabetes and their abundance in most parts of the world facilitate their usage. J. regia belongs to the family Juglandaceae. It includes 3 species: J. nigra, J. cinerea, and J. regia although only J. regia type is found in Iran [5]. Investigations show that J. regia extract contains ellagitannins which contains anti-cancer agent and with anti-inflammatory properties [6]. The key chemical composition of walnut is Juglone (5-hydroxy-1,4-naphthoquinone), the toxic compound which is found only in green and fresh walnuts, but such property disappear in dried leaves [7]. Other several phenolic compounds with antioxidant properties have been identified in J. regia leaves [8]. In an experimental study treatment of J. regia extracts in experimental animals resulted in a significant decrease in blood glucose, glycosylated hemoglobin, LDL, triglyceride and total cholesterol and a significant increase in insulin and HDL level [9]. In another study the favorable effects of J. regia leaves on pancreatic cells in alloxan induced diabetic rat have been reported [10]. In addition, Asgary and co-authors showed that fasting blood sugar decreased meaningfully where as insulin level increased and glycosylated hemoglobin decreased significantly in diabetic groups receiving either glibenclamide or J. regia extract compared with the diabetic untreated group [11]. In the present study, we evaluated the effect of J. regia leaves aqueous extract on type II diabetic patients for the first time.

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Plant Foods Hum Nutr. 2011 Nov;66(4):335-40. doi: 10.1007/s11130-011-0260-2. Effects of walnuts (Juglans regia) on learning and memory functions. Haider S1, Batool Z, Tabassum S, Perveen T, Saleem S, Naqvi F, Javed H, Haleem DJ.
Walnut has been regarded as a health food that is delicious and nutritious. Both preventive and therapeutic effects of walnut are well documented. Walnuts are rich in omega-3 fatty acids that are reported to have beneficial effects on brain function. The present work was designed to evaluate the effects of walnuts on learning and memory in male rats. The effect of oral intake of walnut was also monitored on food intake. Walnut was given orally to rats for a period of 28 days. Memory function in rats was assessed by elevated plus maze (EPM) and radial arm maze (RAM). A significant improvement in learning and memory of walnut treated rats compared to controls was observed. Walnut treated rats also exhibited a significant decrease in food intake while the change in growth rate (in terms of percentage) remained comparable between the two groups. Analysis of brain monoamines exhibited enhanced serotonergic levels in rat brain following oral intake of walnuts. The findings suggest that walnut may exert its hypophagic and nootropic actions via an enhancement of brain 5-HT metabolism.



Ethnobotanical data: use of Juglans folium
Assessment report on Juglans regia L., foliumEMA/HMPC/346740/2011 Page 8/26

According to ethnobotanical data, the decoction of Juglans regia leaves is still commonly used in traditional folk medicine of the Iberian Peninsula as a mouthwash, as dental antiseptic and against pharyngitis. Oral administration is used against renal stones and obesity (Agelet and Valles 2001; Blanco et al. 1999; Bonet et al. 1999).
In Bulgaria and Italy, walnut leaves are traditionally used as astringent and anti-inflammatory remedy (Leporatti and Ivancheva 2003).
The le aves of Juglans regia containing repellent and anti-parasitic substances were placed in wheat or in lentils, and in sacks containing other cereals or legumes. The leaves were placed in hen-coops to remove lice. A decoction of leaves was administered to horses as vermifuge and was used to flavour and to preserve cheese in central Italy. In southern Italy, fresh leaves were also applied topically to reduce the swelling associated with varicose veins (Quave et al. 2008). For treatment of burns and toremove warts and pimples, poultices and ointments were applied (Guarrera 1999; 2003; 2005a; 2005b).
In Sardinia Juglans regia leaves infusions are used in helminthiasis (Bruni et al. 1997).
In Turke y walnut leaves are frequently used externally for fever in sun stroke, in acne, and as an antifungal agent or to alleviate rheumatic pain (Erdemoglu et al. 2003; Kültür 2007).
Traditional use of Juglans regia as anthelmintic remedy is reported not only in Europe, but also in other parts of the world, such as the Indo-Pakistan subcontinent (Akhtar et al. 2000).
In Lebanon, Juglans regia leaves are traditionally used as a remedy in rheumatic and neuralgic complaints mainly as compresses and cataplasms (El Beyrouthy et al. 2008).
In northern and in south-eastern Morocco and in Egypt, Juglans regia leaves and bark are used in oral hygiene, on skin infections and rashes and for hypertension treatment (El-Hilaly et al. 2003; Gazi 1986; Mouhajir et al. 2001; Tahraoui et al. 2007).

In summary, the walnut tree has thousands of years of traditional medicinal use, to treat a wide range of complaints (Bruneton, 1993). Its use has been mentioned since ancient times. During the Middle Ages walnut preparations were used as a remedy for various skin ailments and were mentioned by Lonicerus (1564) and Matthiolus (1501 – 1577). Its therapeutic activity is presented by Schimpfky (1900) and in Madaus “Lehrbuch der Biologischen Heilmittel” (1938). The traditional use of Juglans regia in different diseases has been thoroughly documented in several handbooks and in folk tradition.
The leaves are contemporarily used to target skin ailments as an anti-inflammatory, astringent and depurative. However in the past they were used as anthelmintic, treatment of dyspepsia, diarrhoea, chronic coughs and asthma. The leaves are also used to treat skin disorders: acne (Magin et al. 2006; Reuter et al. 2010), eczema, herpes, scrofulous disease, in excessive perspiration of the hands and feet and slow healing wounds as a wash, compress or poultices). Its astringent activity is assigned to the tannin content (Ożarowski 1976; Ożarowski and Jaroniewski 1987; Blumenthal 2000, Wren 1975, Weiss and Fintelman 2000; Wichtl 2004, Wyk and Wink 2004, Frohne 2006). 

Information on traditional indications from literature
Commission E Monograph. Juglans regia L., (Bundesanzeiger No 101, published June 1, 1990): Mild, superficial inflammations of the skin; excessive perspiration, e.g. of the hands and feet.
Herbal Drugs and Phytopharmaceuticals (Wichtl, 2004): Topical route: In acne, eczema, scrophula, pyodermia, ulcers, excessive perspiration in the feet and hands.
Oral route: In folk tradition in gastrointestinal catarrhs, anthelmintic and as a “blood purifying remedy”.
Herbal Medicinals, Miller & Murray (1998): Atopic dermatitis (exudative phase)
Herbal Medicine, (Weiss & Fintelman, 2000): Dermatitis
Lehrbuch der Biologischen Heilmittel (Madaus, 1938): Scrofulosis, hyperhidrosis, acne, herpes, crusta lactea, exanthema, eczema, tinea capitis.
Medicinal Herbs: A Compendium (Gehrman et al. 2005): In mild, superficial skin inflammations; excessive perspiration, for example, of hands and feet.
M edicinal Plants of the World (Wyk & Wink, 2004):Skin ailments: acne, eczema, fungal infections, inflammations, sunburn, perspiration, itchy scalp and ulcers. Decoctions are traditionally used against bedbugs and lice.
PDR for Herbal Medicines, Gruenwald et al.(ed.) (2000): Mild, superficial inflammation of the skin, excessive perspiration.




Juglone
La juglone  est un colorant  jaune ( qui tourne rapidement  au  marron )
Les Naphtoquinones (dont la juglone) contenues dans les feuilles de noyer tombées au sol et peut-être exsudées par les racines agissent comme des herbicides sur les plantes aux alentours des noyers, limitant considérablement leur développement.Ces substances sont également toxiques pour les herbivores notamment les chevaux.
 
Propriétés médicinales :
  • Antiseptique et kératinisante  (traitement  du cuir chevelu) .
  • Antifongique, antibactérienne, mais cytotoxique vis-à-vis des kératinocytes, (donc  irritant pour la peau) [1].
  • Antitumorale sur certain type de   tumeurs ,   (La juglone  à une action  sur les polymérase  par inhibition d une ’ ARN polymérase ).
  • Activité antihypertensive et spasmolytique par blocage des canaux calciques .[2]
Cette substance ne semble pas toxique lorsqu'elle est absorbée par l'homme dans des quantités normales et raisonnables comme la consommation de vin de noix :
Formule  du vin de Noix   :  40  drupes  /1kilo de sucre / 1 litre d’ alcool blanc  /  4  litres de vin  ( idéalement un vin rouge Algérien à 13 ° ) Laisser macérer au moins  40  jours  -  filtrer   et mettre en  bouteilles – le mieux est d’ attendre  3 ans  avant la  consommation ;  la conservation peut être très longue
  1. Inbaraj JJ, Chignell CF. Cytotoxic action of juglone and plumbagin: a mechanistic study using HaCaT keratinocytes. Chem Res Toxicol. 2004 Jan;17(1):55-62. PMID 14727919
  2. Shigeyuki Sugie, Kiyohisa Okamoto, K.M.Wahidur Rahman, Takuji Tanaka, Kiyoshi Kawai, Johji Yamahara, Hideki Mori. Inhibitory effects of plumbagin and juglone on azoxymethane-induced intestinal carcinogenesis in rats. Cancer Letters, Volume 127, Issues 1–2, 15 May 1998, Pages 177–183
  3. Zhang X, Zou C, Duan Y, Wu F, Li G. Activity guided isolation and modification of juglone from Juglans regia as potent cytotoxic agent against lung cancer cell line. BMC Complementary and Alternative Medicine 2015, 15:396 (3 November 2015). Abstract texte intégral
  4. K. Neuhaus-Carlisle, W. Vierling, H. Wagner. Screening of plant extracts and plant constituents for calcium-channel blocking activity. Phytomedicine, Volume 4, Issue 1, March 1997, Pages 67–71


Juglon gevaarlijk?
In 2001 is het Warenwetbesluit Kruidenpreparaten vastgesteld. Juglans regia (Walnotenboom of Okkernotenboom) is, met uitzondering van de noten, opgenomenop bijlage III van dit besluit, waarvan gesteld wordt dat kruidenpreparaten geen materiaal mogen bevatten dat geheel of ten dele afkomstig is van planten opgenomen
in deze bijlage.
In  een reactie op het Warenwetbesluit Kruidenpreparaten stelt de Nederlandse Vereniging voor Fytotherapie (NVF) vast, zonder nadere onderbouwing, dat opname van Juglans regia in bijlage III van dit besluit niet terecht is, omdat daarvan niet vermeld is dat het toxisch zou zijn.
De VWA heeft het RIVM gevraagd een risicobeoordeling uit te voeren voor Juglans regia en op basis daarvan een voorstel te doen voor de verwijdering of handhaving van Juglans regia op bijlage III van het Warenwetbesluit Kruidenpreparaten.

Aanpak
De beoordeling is gebaseerd op een screening naar informatie over Juglans regia opinternet en in:
1 Besluit van 19 januari 2001, houdende vaststelling van het Warenwetbesluit Kruidenpreparaten. Staatsblad van het Koninkrijk der Nederlanden, jaargang 2001, nr. 56.
2 Van Asseldonk AGM, Kieviet OS, van der Venne I, Verdonk-Kleinjan W, en Wauters Ch (2001) Reacties op het Warenwetbesluit Kruidenpreparaten. Nederlands Tijdschrift voor Fytotherapie, 14(1), 4-16.
• de Toxicologische Informatie en Kennisbank (TIK) van het NVIC en bij de meldkamer van de VWA naar recente meldingen (laatste 5 jaar) van
intoxicaties
• het rapport van de Commissie Toetsing Fytotherapie (CTF) naar gegevens over recent gebruik
• belangrijke handboeken, monografieën
• Medline en Toxline, d.m.v. een beperkte literatuursearch naar toxicologische informatie in reviews, en waarbij vooralsnog alleen gebruik is gemaakt van de beschikbare samenvattingen.

Resultaten screening
Er zijn geen recente meldingen (laatste 5 jaar) van intoxicaties met Juglans regia (of producten waar het in zit) bekend bij het NVIC of de VWA, noch zijn gegevens over het recente gebruik van dit kruid te vinden in het rapport van de CTF.
Er is geen WHO of ESCOP monografie gewijd aan Juglans regia. In diverse van de geraadpleegde handboeken is informatie te vinden over Juglans regia. Het betreft met name informatie over de actieve stof in Juglans regia en over de geclaimde werking.

Hierover werd het volgende gevonden.
Extracten van de bast van Juglans regia worden ook wel aangeduid met Derum, Dendasa of Deirum. Juglans regia bevat juglone (5-hydroxy-1,4-naphthoquinone) in alle delen van de plant, met de hoogste concentratie in de wortel. Juglans regia vindt toepassing in kruidenpreparaten die claimen te werken als fytotherapeutisch medicijn tegen luis en schurft, als anti-verouderingsmiddel en als ontstekingsremmer. Tevens
wordt aan middelen met Juglans regia een vasorelaxerend, hypolipidemisch, hypoglycemisch en hyperinsulinemisch effect toegeschreven, en werkzaamheid bij chronische oogcatarre, abcessen en anemie. In de volksheelkunst worden middelen met Juglans regia gebruikt als ‘bloedreinigingsmiddel’ en als middel bij scrofulose, rachitis, jicht, gastroenteritis, bij onstekingen van de huid en overmatig zweten, en als
ondersteunend middel bij hoesten en bronchitis.

De literatuur en informatie op het Internet over Juglans regia betreft met namewerking en effecten van de actieve component juglone. Voor juglone worden acute orale LD50 waarden gemeld van 2,5 mg/kg lg voor de muis en van 112 mg/kg lg voor de rat, hetgeen in het kader van Classificatie en Labeling zou resulteren in: “vergiftig bij opname door de mond”. Er zijn geen waarden voor acute dermale toxiciteit
gevonden. Aan juglone-bevattende middelen worden huid- en oogirriterende eigenschappen toegekend. Daarnaast wordt melding gemaakt van hyperpigmentatie en contactdermatitis, hetgeen heeft geleid tot het terugtrekken van juglone als zonnebrandmiddel.
Blootstelling van paarden aan schaafsel van Juglans regia resulteerde in laminitis (ontsteking in de hoef). Juglone induceerde in honden ernstig pulmonair interstitieël en alveolair oedeem, en in honden en paarden ademhalingsproblemen en gastroenteritis.
Er zijn aanwijzingen voor mutagene en carcinogene eigenschappen van Juglans regia. Juglone is positief bevonden in de Ames test, de micronucleustest, de sex-linked recessief lethaal test en de w/w+ somatische mutatie en recombinatie (SMART) test in Drosophila, en gaf in Ehrlich ascites tumor cellen mitotische afwijkingen. Er zijn geen chronische toxiciteit- of carcinogeniteitsstudies met juglone beschikbaar. Wel wordt melding gemaakt van juglone als tumorpromotor van huidtumoren in studies met muizen voorbehandeld met een initator. Huidtumoren werden niet waargenomen met juglone in muizen die niet waren voorbehandeld met een initiator. Daarnaast wordt dagelijks topicaal gebruik van juglone-bevattende preparaten bereid uit walnootschors in verband gebracht met een toename in het optreden van kanker van de tong en
leukoplakia van de lippen.

Gezien het feit dat juglone deel uitmaakt van alle delen van Juglans regia, is het opmerkelijk dat de Commissie E Monograph (door een commisie deskundigen opgestelde monografie voor de Duitse regering) onderscheid maakt tussen blad en doppen. De bladeren, voor gebruik als samentrekkend middel op de huid, worden als niet-toxisch beschouwd. De doppen daarentegen, gebruikt bij o.a. abcessen, gastroenteritis, oogontsteking, worden als toxisch beschouwd vanwege de mutagene en carcinogene eigenschappen van juglone.
Volgens VWS is het verbod op het gebruik van Juglans regia in Nederland, en dientengevolge de plaatsing ervan op bijlage III van het Warenwetbesluit Kruidenpreparaten, terug te voeren op een lijst van dr. de Smet waarop planten staan (w.o. Juglans regia) die aangemerkt zijn als risicovol voor de volksgezondheid. 
In België staat Juglans regia op de lijst van te notificeren planten indien in voorgedoseerde vorm (zgn. lijst 3 van de bijlage van het Koninklijk besluit), d.w.z. het mag niet gebruikt worden in voedingsmiddelen, in voorgedoseerde vorm, indien geen voorafgaande notificatie is uitgevoerd o.b.v. een notificatiedossier.

Beoordeling
Op basis van de beschikbare gegevens kunnen aan Juglans regia acuut toxische, huiden oogirriterende en huidsensibiliserende eigenschappen worden toegeschreven. Daarnaast zijn er aanwijzingen dat de actieve component juglone, aanwezig in alle delen van Juglans regia, mutagene en carcinogene eigenschappen bezit. Het gebruik van Juglans regia in kruidenpreparaten kan derhalve risico’s met zich meebrengen.
Dit pleit voor handhaving van Juglans regia op bijlage III van het Warenwetbesluit Kruidenpreparaten.

3 Brief VWS (d.d. 26-11-2003, onderwerp ‘warenwetbesluit kruidenpreparaten’) aan Mw. van Asseldonk van de NVF.
In adviesrapport ‘Dutch legislation on herbal remedies’ van dr. P.A.G.M. de Smet van de KNMP van mei 1991 (zoals gerefereerd in brief VWS, zie ).
5 Koninklijk besluit van 29 augustus 1997 betreffende de fabricage van en de handel in voedingsmiddelen die uit planten of uit plantenbereidingen samengesteld zijn of deze bevatten. Belgisch Staatsblad, publicatie 1997-11-21 (Ed.1).

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