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Asian Holly Oak Gall

Quercus infectoria

Family: Fagaceae

INTRODUCTION

Asian holly oak (Quercus infectoria), also referred to as Aleppo oak and Cyprus oak, is a member of the oak and beech family (Fagaceae). Quercus infectoria is a small shrub or tree that usually reaches about 3 m (9.8 ft) tall but may grow as high as 15 m (49.2 ft) and occurs in deciduous forests and agricultural landscapes. Its geographical range extends from parts of southern Europe (e.g., Greece) to western Asia (e.g., Azerbaijan, Cyprus, Iraq, Israel, Jordan, Lebanon, Palestine, Syria, and Turkey) and southern Asia (e.g., Iran). Quercus infectoria has three subspecies — subsp. infectoria (occurring in Greece, including the Aegean Islands, and northern Turkey), subsp. veneris (eastern Aegean and eastern Mediterranean to Iran), and subsp. boissieri (Turkey and surrounding Asian countries)1 — and one accepted variety: var. tenuicarpa (Iran).2

The subject of this article is the Q. infectoria gallnut (QIG), also known in commerce as Aleppo gall, Levant gall, Mecca gall, Smyrna gall, Turkey gall,3 Dead Sea apple, or oak apple.4 A gallnut is neither a nut nor a fruit, but rather an excrescence (abnormal growth or swelling) that forms in reaction to a viral infection that is caused when a female gall wasp punctures a branch or twig to oviposit (lay eggs) in the wound.5 The egg grows within the formed gall and converts into a larva, which feeds on the surrounding vegetable matter, thus forming a cavity in the center of the excrescence.6 While many species of wasps induce oak galls,7 the most frequently named species associated with Q. infectoria trees are Cynips gallae tinctoriae (syn. C. quercusfolii) and various Andricus species, as well as wasps of other genera.8,9 Host tree chemistry appears to play a role in gall-inducing wasp selection of plants, and research has shown that gall wasps can discriminate among closely related Quercus species. Cynips species gall wasps associated with Q. infectoria form one larval chamber (unichamber) per gall in the summer.10 QIGs have a nearly spherical shape, a diameter of about 12 to 20 mm, and are bluish green on the outer surface and yellowish within.4 QIGs that are still inhabited by a wasp are described as blackish- or bluish-green and heavy, while those from which the wasp has exited are generally a lighter yellowish-white color with a discernible round hole on one side.11

QIGs have not only traditional and contemporary medicinal applications but also uses for dyeing (e.g., hair, fabrics), tanning (e.g., leather), and preparing ink pigments.3,12

HISTORY AND CULTURAL SIGNIFICANCE

A cuneiform tablet of the Assyrian Empire (a Mesopotamian kingdom from about the 25th century BCE to the seventh century BCE; comprising parts of present-day Iran, Iraq, Kuwait, Syria, and Turkey) was unearthed at the site of the ancient city of Carchemish and describes the trade and use of Mesopotamian oak gallnuts, which presumably were associated with the relatively large tanning and leather production industry in the region.13 Cities in “al-Jazira” (Upper Mesopotamia), including Basra and Mosul (both in present-day Iraq) and Harran (now in Turkey), became major production and trading hubs for Mesopotamian oak gallnuts.13 As parts of the Ottoman Empire (14th to early 20th centuries CE), Iraq and Turkey were major producers and exporters of oak gallnuts.

Medicinal preparations of QIG have a long history of use and were first recorded in the writings of Greek physician Hippocrates (ca. 460–377 BCE) and later of Greek philosopher and botanist Theophrastus (ca. 371–287 BCE).3 In 1735, Swedish botanist Carl Linnaeus (1707–1778) assigned the genus name Quercus, meaning “oak tree” in Latin, in his publication Systema Naturae.14 The species Quercus infectoria was named in 1801 by French naturalist, botanist, and entomologist Guillaume-Antoine Olivier (1756–1814) in Volume I of Voyage dans l’Empire Othoman, l’Égypte et la Perse (“Voyage to the Ottoman Empire, Egypt and Persia”).15 French chemist Henri Braconnot (1780–1855) discovered an acid present in QIG and named it ellagic, derived from galle, the French name for gallnuts, by reversing the order of the letters.6

In Kurdistan (Upper Mesopotamia), QIGs were purported to have magical uses and strung together like beads and hung over an infant’s cradle to ward off the “Evil Eye.”4 Sanskrit names for QIGs include Máyin and Máyika, signifying magic, as QIGs also were used in India in magic rites.11 Due to their high gallotannin content, the galls traditionally are used in Iraq and Iran as a local astringent (i.e., dusted on wounds).4 In present-day Kurdistan Region, an autonomous region of Iraq, QIGs are wild collected in hill and mountain areas by climbing the tree and hand harvesting, or by using a long stick to pull branches or hit the tree to knock off the galls. For medicinal use, the galls are collected before midsummer, when their color is still dark, then ground, sieved, and applied to wounds, or mixed with egg yolk or alum (potassium aluminum sulfate), then applied to wounds, swellings, broken body parts, psoriasis, skin burns, or oral ulcers. For producing a beige dye for textiles used in traditional Kurdish clothing, the galls are collected in the autumn before rainfall.16

Even though its traditional medicinal use in India is entirely dependent on importing the raw material, QIG as a medicinal substance was incorporated into the Indian systems of medicine (Ayurveda, Siddha, and Unani) long ago and remains an important herbal drug today. The current annual trade volume of QIG within India is significant and estimated at between 100 and 200 metric tons (MT).17 Today, India imports QIG from Iran, Pakistan, and Turkey.18 During British colonial rule, QIG was exported to India mainly from Basra (Iraq) and shipped on Arabian vessels via the Persian Gulf.11 Known as Mayyaku in the Ayurvedic system of medicine, QIGs are powdered and used in formulations for therapeutic indications including hemorrhoids, diarrhea, dysentery, malabsorption syndrome, diseases of the mouth and teeth, disease of vulva or lower vaginal canal, and leucorrhea (a type of vaginal discharge).19 Known as Mazoo in the Unani system of medicine, QIGs are used in formulations for treatment of diarrhea, dysentery, and bleeding hemorrhoids.20 QIGs also are exported to Malaysia from Turkey and used in traditional Malay medicine for postpartum care.5

In traditional European medicine, QIGs in their crude state are used rarely, with the exception of topical application in ointments for treating hemorrhoids and in plasters. Tannic acid extracted from QIGs is used more often than preparations of the crude QIGs (e.g., for treating dysentery and diarrhea, or as a gargle).21

“Gallae” (Quercus cerris; Cyniphis nidus, the nest of Cynips quercusfolii wasps) was included on the primary list of materia medica of the first edition of the Pharmacopoeia of the United States of America (USP 1820). The first edition also included a monograph for Unguentum Gallae (Ointment of Galls; powdered and prepared with lard).22 However, in the first decennial revision (USP I 1830), the host tree species name was changed to Q. infectoria.23 The medicinal uses and properties of Gallae USP were described in the corresponding first edition of the Dispensatory of the United States of America (USD 1833):

As might be inferred from the quantity of tannin they contain, galls are powerfully astringent. They are little employed as an internal remedy, though occasionally prescribed in chronic diarrhea. In the form of infusion or decoction they may be advantageously used as an astringent gargle, lotion, or injection; and mixed with simple ointment, in the proportion of one part of galls, in very fine powder, to eight parts of the unguent, they are frequently applied to the anus and rectum in hemorrhoidal affections. The dose of powdered galls is from ten to twenty grains, to be repeated several times a day.6

Quality monographs for Gallae and Tinctura Gallae (Tincture of Nutgall) were included in the first edition of the German Pharmacopoeia (DAB I) in 187224 and remained official through the sixth edition (DAB VI).25 These monographs were omitted from the subsequent post-war seventh editions of the pharmacopeias of both former West Germany (DAB 7 1968) and former East Germany (DAB 7-DDR 1973), but were retained in the Austrian Pharmacopoeia (ÖAB)26 until their omission in 2014.27

A monograph for Tinctura Gallae also appeared in the eighth decennial revision of the USP in 1900.28 The Tinctura Gallae monograph was omitted from the subsequent USP IX (1916), transferred into the fourth edition of the National Formulary (NF IV 1916),29 and eventually dismissed from the seventh edition (NF VII 1942).30 The Unguentum Gallae monograph was omitted from the 12th revision of the USP in 1942.31 Also in 1942, the US War Production Board published a strategic materials conservation order that stated: “The fulfillment of requirements for the defense of the United States has created a shortage in the supply of nutgalls and tannic acid USP for the war effort.” Restrictions and reporting requirements were placed on the processing, sale, transfer, or delivery of both Gallae USP and Tannic Acid USP (made from QIG). Any person having in her/his possession or control, at any location on August 8, 1942, any stock of QIGs of five pounds or more, or any stock of Tannic Acid USP of two pounds or more, was required to file a report with the War Production Board.32

In 1947, Gallae was dismissed from the 13th revision of the USP.33 At about the same time, two former USP monographs transferred into the eighth edition of the National Formulary (NF VIII 1946): Gallae NF and Gallae Unguentum NF.34 But both monographs were omitted from the tenth edition (NF X 1955).35 An early 1960s survey of cosmetic and drug companies listed Aleppo oak (Q. infectoria) excrescence (nutgall) among the most important active ingredients of commercial hair and scalp preparations at that time, as it was used as a brown hair dye and the tincture as an astringent in scalp diseases.36

CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES

Authorized medicinal products containing preparations of QIG are common in many Asian countries but rare in Europe and North America. The Malaysia Ministry of Health licensed pharmaceutical products database lists 147 authorized products that contain QIG and are indicated mainly for women’s conditions.37 Currently valid quality standards monographs for QIG raw material are included in The Ayurvedic Pharmacopoeia of India19 and in The Unani Pharmacopoeia of India.20 QIG-containing preparations that are dispensed in clinics, pharmacies, and hospitals in India are included in the national formularies for Ayurvedic and Unani medicines.

In the United States, the Food and Drug Administration (FDA) classifies tannic acid, obtained by solvent extraction of QIG, as a Generally Recognized as Safe (GRAS) flavoring agent and adjuvant for use in baked goods and baking mixes, nonalcoholic beverages and beverage bases, frozen dairy desserts and mixes, hard candy and cough drops, and meat products, and as a GRAS flavor enhancer of alcoholic beverages, with maximum levels of use established for each listed type of food and beverage.38 For these uses in foods, the FDA requires that the ingredient conform to the quality specifications provided in the Food Chemicals Codex (FCC) monograph.39 For the use of tannic acid obtained from QIGs as a component of pharmaceutical products, quality specifications also are provided in an official USP monograph.40 For the use of QIG as a component of dietary supplements, the FDA requires notification within 30 days of marketing if a structure-function claim is made and that product manufacturing adheres to current Good Manufacturing Practices (cGMPs).41

In Canada, while one licensed Natural Health Product (NHP) contains an extract of Q. infectoria fruit (the acorn) as a non-medicinal ingredient of a toothpaste, no NHPs containing QIG appear in the Licensed Natural Health Products Database.42 In the European Union, the defined ingredient “Quercus Infectoria Gall Extract” is authorized for use in cosmetic products for anti-sebum (helps control production of sebum, an oily, waxy substance produced by the body’s sebaceous glands), astringent, and skin-conditioning functions.43

MODERN RESEARCH

Constituents and Pharmacological Effects

The main compounds in QIGs are tannins at 50-70%. These include gallotannins and ellagitannins (the major hydrolyzable tannins).44,45 Other compounds isolated from QIGs include gallic acid (a phenolic acid) at about 2-4%, ellagic acid at about 2%, the flavonoids amentoflavone and isocryptomerin,44,46 triterpenoids, steroids (including beta-sitosterol), and various minerals.44,45,47-51

The pharmacological effects documented in current research correlate to the phytochemical constituents found in QIGs. Tannins in QIGs have astringent47,52 and antibacterial activity44 and gallic acid is researched for its antitumor activity.44,50,53-57 Studies have shown QIGs possess antibacterial42,44,45,47,50,58-64 (including anti-MRSA [methicillin-resistant Staphylococcus aureus]58,59,65,66), anti-inflammatory,47,58,67,68 antioxidant,69-71 antidiabetic,47,72 antifungal,73 antiviral,74 antitumor,44,50,53-57 and larvicidal effects.47,58,75 In a review by Elham et al (2021) of studies on QIGs, antibacterial and anti-inflammatory properties were found to be the most prominent effects.44

In Vivo and In Vitro Studies

Multiple studies have documented QIG’s antimicrobial actions. Aqueous and solvent extracts of QIGs exhibited antimicrobial properties against gram-positive and gram-negative bacteria. The extracts also performed well compared to commercial antibiotics.47,76 Research model designs have looked further at QIG’s effects against dental and wound-causing microbial pathogens. Different types of QIG extracts were evaluated against dental pathogens and showed inhibition of Streptococcus mutans, Streptococcus salivarius, Staphylococcus aureus, Lactobacillus acidophilus, and Streptococcus sanguinis.58,70,77 Basri et al (2012) evaluated antibacterial activity specifically against bacteria that induce periodontitis and dental caries (tooth decay). Results from acetone and methanol extracts of QIG powder resulted in similar antibacterial effects.78

In a 2007 study, 191 patients’ wound sites were cultured, and microbial species were isolated and used to determine the antimicrobial effects of aqueous, methanol, and ethanol extracts of QIG. Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Enterobacter spp., and Proteus mirabilis were the most common bacterial isolates found. At concentrations of 0.781–25 mg/mL, the three QIG extracts resulted in antimicrobial activity against the isolated wound microbials. The QIG ethanol extract had a minimum inhibitory concentration (MIC) of 3.125 mg/mL on S. aureus and 6.25 mg/mL on E. coli, Klebsiella pneumoniae, and Citrobacter freundii. The aqueous extract had an MIC of 25.0 mg/mL on P. aeruginosa, the methanol extract had an MIC of 12.5 mg/mL on P. mirabilis, and the ethanol extract had an MIC of 6.25 mg/mL on K. pneumoniae.60

Furthermore, QIGs have shown promising results against drug-resistant bacteria.59,65,66,79,80 Extracts of QIGs showed inhibitory activity against MRSA (MICs from 0.02–0.4 mg/mL) and enterohemorrhagic E. coli (EHEC) (MICs from 0.05–0.1 mg/mL).59 Additionally, a combination of QIG extract with the antibiotic vancomycin found synergistic bactericidal effects.44,81,82 In summary, various types of QIG extract preparations display broad antimicrobial activity against dental and wound microbial pathogens,45,58 and methanol and aqueous extracts demonstrate anti-Candida activity against the fungal species C. albicans, C. krusei, C. glabrata, C. parapsilosis, and C. tropicalis.73

Additional studies have demonstrated anti-inflammatory and antioxidant properties. In vivo and in vitro studies documented that ethanolic extracts of QIGs were able to inhibit inflammatory responses of neutrophils and macrophages as well as inhibit inflammatory mediators.58,67,70 Ethanolic extracts of QIGs have demonstrated strong antioxidant capacity.58,69 Phenolic compounds were reported at 48.26 mg/g and flavonoid content at 29 mg/g in QIGs.70 Both phenolic compounds and flavonoids are associated with antioxidant capacity.45

Toxicity

A comprehensive review by Elham et al (2021) found limited studies on QIG extract toxicity and no known toxicity studies in humans.44 Iminjan et al (2014)46 performed an extensive preclinical toxicity animal study that evaluated an aqueous extract of QIG. An acute toxicity study using doses of 5, 7.5, and 10 g/kg body weight per rectum resulted in no behavioral or toxicity signs observed up to seven days, as the LD50 (lethal dose 50, the dose that kills 50% of a test sample) could not be established. The authors determined a maximum tolerance dose (MTD) to be greater than 10 g/kg for the acute phase of the study. Local tissue effects were also noticed during the mucosal irritation study, and daily QIG aqueous extract caused statistically insignificant intestinal epithelial hyperplasia changes.45,46 Results of the chronic toxicity portion of the study found that supplementation for 180 days (QIG aqueous extract doses from 0.2–2.0 g/kg per rectum) did not produce obvious toxicity signs. In summary, the authors concluded that acute and chronic toxicity signs were not significantly increased in the exposure group compared to the control group.46

Human Clinical Studies

QIGs are traditionally used for the treatment of gingivitis,78 but only a few current human studies on this use are available. Table 1 summarizes these preliminary studies that are informed by traditional uses, as QIG and QIG extracts are found in toothpastes and powders, such as Mājuphala powder, and other topical application medicines.45,48 The listed studies did not involve commercial branded products, but the researchers prepared the investigational products using materials procured at local markets. For human use, additional preclinical and clinical studies are needed to further investigate the pharmacology, safety, toxicity, efficacy, and quality of QIG preparations.44,45,50 More extensive studies would help inform safety and efficacy data, which may help inform possible therapeutic applications in the future.44 

ADULTERATION

Because Chinese gall (Rhus chinensis, Anacardiaceae) and QIG have similar chemical compositions and pharmacological applications, it is conceivable that one could be substituted for the other, depending on the region. For this reason, high-performance liquid chromatography–electrospray mass spectrometry (HPLC-ESI-MS/MS) methods have been developed to help prevent the adulteration or mix-up of Chinese galls and QIGs.90

SUSTAINABILITY AND FUTURE OUTLOOK

The International Union for Conservation of Nature (IUCN) assigns wild Q. infectoria to the conservation category of least concern (LC), meaning that the species is not considered to be endangered, threatened, or vulnerable according to IUCN Red List criteria.1 The subspecies veneris, however, is classified as endangered (EN) in Jordan, where it occurs only in a small area of the Mediterranean part of the country and faces threats of urban expansion and development of tourism infrastructure.91 Long-term access to QIG raw materials is dependent, in part, on the genetic diversity, geographic populations, distribution, and survival of gall-inducing wasps.

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