INTRODUCTION:

Phytochemicals present in the Plants have gained significant attention in medicinal world, due to the emerging problem of drug resistance associated with the available treatment regimen.

Various extracts and chemical constituents of medicinal plants have been studied in detail with potential efficacy, low cost and safety. There is a need to study these plants, there chemical composition and pharmacological activity in detail for future use in clinics and other disease models. Quercus infectoria is one such plant with varied chemical constituents and activities. It is a small shrub belonging to family-Fagaceae. It has unisexual flowers with different arrangement for male and female flowers. Plant habitat is extended to various places including turkey, Greece and is now extensively found in Asia Minor, Europe and North Africa¹. Galls of Quercus Infectoria are irregular growth of plant which arise due to the reaction between hormones of plant and chemicals produced by the insects^2,3.

Stimulated by the reaction between plant hormones and powerful growth regulating chemicals produced by insects or mites, these galls are formed due to the attack by gall wasp, Cynipsgallaetinctoriae or Adleriagallaetinctoria, which deposits its eggs there⁴. These eggs once converted to larvae are surrounded by tissues of the growing gall⁵. These galls of Quercus infectoria also known as Galla Turcica. These galls have tannins as major constituent along with syringic acid, ellagic acid, sitosterol, amentoflavone, hexamethylether, isocryptomerin, methyl betulate, methyloleanate andhexa galloyl glucose^6-8. Five major chemical constituents of Quercus infectoria galls include gallic acid, m-digallic acid, methyl gallate,1,2,3,6-tetra-O- galloyl-b-D-glucose and 1,2,3,4,6-Penta-O-galloyl-b-D-glucose. They have an array of therapeutic usage such as anti-inflammatory, antidiabetic, antifungal and many more. This review deals with the chemical constituents, medicinal properties along with their mode of action and toxicity, if any associated with Quercus infectoria galls [QG]Figure 1.

Figure 1: Graphical abstract of Quercus infectoria

Phytochemistry of Quercus Infectoria:

Phytochemical analysis of QG has shown that it contains nearly 50-70% tannic acid named as gallotannic acid. Galls also contain gallic acid, ellagic acid along with starch, sugars, essential oil, and anthocyanins. QG also consisted of beta-sitosterol, amenoflavone hexamethyl ether, isocryptomerin, calcium oxalate, methyl oleanolate^9,10. (Table1, 2).

Table 1: Various phytochemicals present in Quercus infectoria galls (QG)

Chemical Properties	Types of compound present	Percentage present
Tannin	Gallotannic acid	50-70%
Phenolic acids	Gallic acid	2-4%
Phenolic acids	Ellagic acid	-
Phytosterols	Sitosterol	-
Ester	Methyl betulate	-
Ester	Methyloleanolate	-
Carbohydrate	Starch	-
Oxalate	Calcium oxalate	-
Triterpenoid	Nyctanthic	-
Triterpenoid	Roburic	-
phenolic acids	Syringic acids	-
Polysaccharides	Gum	-
Carbohydrate	Sugar	-
Terpenes, Phenolic compound	Essential oil	-

Table 2: Various properties of Quercus infectoria

Pharmacological properties	Photochemical
Pharmacological properties	Phenols	Flavonoids	Steroids	Triterpenes	Tannins	Saponins	Alkaloids	Glycosides	Carbohydrates
Anesthetic								Х
Analgesic			Х	Х				Х
Anticancer					Х
Anti-diabetic			Х		Х			Х
Antihypertensive					Х
Anti-inflammatory			Х		Х			Х
Antimicrobial					Х			Х
Antioxidant	Х	Х			Х	Х	Х	Х	Х
Bone Metabolism					Х			Х

a) Effect of Quercus infectoria on Bones:

Skeletal system of humans has their own homeostatic maintenance. The cells involved are osteoblasts and osteoclasts which are in a perfect equilibrium in healthy individual so that degree of bone resorption is equally balanced by bone formation. Imbalance in this equilibrium can lead to pathological conditions such as osteoporosis or osteopetrosis. Most of the drugs specially Hormone replacement therapy (HRT) associated with treatment for osteoporosis results in undesirable side effects¹⁷. Natural products can be safe alternative in such scenario. It has been well established that QG galls have calcium, phosphorus, potassium, magnesium, iron, manganese, zinc and nickel¹⁸. This gall extract also induced cell proliferation as was observed by bone formation markers, ALP and osteocalcin¹⁹. Data indicates that QG extract can serve as anabolic agent by stimulating osteoblastic activity. These natural products can then be developed into clinically acceptable medications for future therapeutic use.

b) Antimicrobial effect of Quercus infectoria:

Peudomonas aeruginosa is the leading cause of many hospitals acquired infections and other serious infections such as lung infection in patient with cystic fibrosis²⁰. In a study it has been found that QG extract (QGE) have an effect on Qorum sensing system of this bacteria which is important for the pathogenicity of the bacteria²¹(Kong et al., 2005). It was observed that QGE at a very low dose was able to decrease the expression of lasR gene along with inhibitory activity on bio-film formation and AHL production^22-25.It was found that the aqueous as well organic extract of the Quercus infectoria have a potential activity against the common pathogen isolated from the urine i.e, S. saprophyticus followed by E. coli and K. pneumoniae which are known resistant strains^26,27. Data shows that QGE both in water or solvent can be used for treating UTI infection²⁸.

Infections caused by Methicillin-resistant Staphylococcus aureus (MRSA) have increased. Resistant to available drugs is a major issue to kill the bacteria^29-31. Tannin, as mentioned above was supposed to be the major constituent for this activity³². Treatment with QGE caused pseudomulticellular aggregates with thick walls. This gave an insight that QGE could have interfered with the autolysins which cause cell separation^33,34.

c) Antilipidemic and Antiatherogenic effects of QG:

Cardiovascular diseases account for large number of deaths worldwide and hyperlipidemia and hyper-tension are two major risk factors associated with it. Study was designed to evaluate the effect of methanolic extract of Quercus infectoria on heart performance, lipid profile and plasma atherogenic indices in rabbits fed. Data suggested that treatment with QG attenuated plasma atherogenic indices, lowered hyperlipidaemia, and improved the cardiovascular performance in rabbits fed on hyperlipid diet^35,36. Pancreatic Lipase inhibitors used for cardiovascular disorders functions by inhibiting the activity of pancreatic lipase which helps in absorption of triglycerides in intestine^37,38. Statins have also been widely used and these inhibit HMG CoA reductase which has an important role in endogenous biosynthesis of cholesterol³⁹. Tannins present in QGE might have also shown their effect by precipitating enzymes such as pancreatic lipase and thereby improving abovesaid parameters⁴⁰.

d) Quercus infectoria in dental hygiene:

Oral hygiene is a common problem among all age groups worldwide. Bacteria and yeast responsible for most of the oral infections by causing plague include as Actinomyces, Actinobacillus, Streptococcus and Candida species⁴¹. Streptococcus species mainly Streptococcus mutant, Streptococcus Goldoni and S. sobrinus are the most oral pathogens⁴². Oral antibiotics used along with developing drug resistance, can alter the oral microbiota and cause other infections⁴³. Methanolic and acetone extracts of Quercus infectoria was found to inhibit the oral bacterial population in many studies wherein it has shown potential bactericidal activity against Gram-positive bacteria (Streptococcus mutans and Streptococcus salivarius) as well as Gram-negative bacteria (Porphyromonas gingivalis and Fusobacterium nucleatum)^44,45.

e) Quercus infectoria and diabetes:

Diabetes has become a prevalent problem worldwide with an array of complications. It affects carbohydrate, protein and fat metabolism⁴⁶. It arises due to less or no insulin secretion and sometimes impaired sensitivity of tissues to the insulin. Therefore, the main characteristic feature of diabetes is hyperglycaemia which is associated with other serious outcomes such as cardiovascular diseases, neuropathy, renal failure, chronic wounds, retinopathy amputations, blindness and coronary heart diseases^47-49. A study conducted by Saini et al., in alloxan-induced hyperglycaemic rats showed the dose-dependent efficacy of methanolic extract of Quercus infectoria in treating diabetes⁴⁵. It was found that oral administration of methanolic extract of Quercus infectoria at the doses of 250 and 500 mg/kg body weight reduced blood glucose levels in a dose-dependent manner with significant efficacy 6 hrs post treatment. It was observed that QGE significantly reduced fasting and postprandial blood glucose levels and increased the serum insulin levels⁵⁰.

f) Anti-inflammatory potential of Quercus Infectoria:

QG has been used since ancient times for its anti-inflammatory property. Hot water extract of QG treats inflamed tonsils and when used topically, on the skin, helped in curing any swelling or inflammation^51,52. It has been well established that during inflammatory responses, macrophages and neutrophils produce various mediators such as eicosinoids, oxidants and cytokines⁵². These mediators initiate and help in progression of inflammation. Two most important mediators include Prostaglandins E2 (PGE2) and nitric oxide which are produced by macrophages by cyclooxygenase-2 and iNOS (inducible nitric oxide synthase) respectively^53,54. During inflammation, PEG2 at the inflammation site induces production of various proinflammatory cytokines causing vasodilatation, increased vascular permeability and oedema. Similarly, NO also causes vasodilation, and oedema formation⁵⁵. Neutrophils also release lytic enzymes playing a significant role in inflammation^56,57.

Orally administered QGE was found to treat inflammation by inhibiting histamine, serotonin and prostaglandin E2 (PGE2. Overall data suggested that QGE has a potential anti-inflammatory activity both in vitro and in vivo by inhibiting various inflammatory mediators³². It was observed that treatment with QGE reduced the expression of Set7, p65 in both the cells along with reduced expression of inflammatory cytokines. Reduced expression of IL-1β and TNF-α was also observed in the macrophages isolated from wounds of diabetic mice. These observations gave further affirmation for the anti-inflammatory potential of QGE ⁵⁸.

g) QGE treats Diabetic Nephropathy:

Diabetes has been associated with many complications; out of which diabetic nephropathy is the major reason for death in diabetic patients. QGE was used to evaluate its efficacy against experimental diabetes nephropathy in rats where type 2 diabetes was induced by feeding rats with high fat diet followed by streptozotocin injected intraperitoneally. It has been well proven that TGF-β causes accumulation of proteins such as fibronectin, collagen, of extracellular matrix in the mesangial matrix, glomerular and tubular basement membranes, and tubular epithelium during diabetes nephropathy^59-61. This causes deformation in the capillaries leading to decreased GFR. It was observed that there was significant increase in expression of TGF-β in experimental rats which decreased post-treatment with QGE along with blood glucose levels. GFR was also found to be improved in diabetic rats post-treatment indicating its nephroprotective efficacy⁶².

h) Anti-oxidant property of Quercus infectoria:

Production of reactive oxygen species and the damage they cause to the cells, is the major reason for many diseases pathogenesis such as ageing⁶³. In normal human being, there exists a balance between reactive oxygen species which are generated in the cells continuously and anti-oxidants for neutralizing them. Disturbance in this balance, is cause of various disorders such as cancer, diabetes etc⁶⁴. It has been reported that QGE has an anti-oxidant potential. This study showed that gall extract has potency to scavenge DPPH, ABTS, hydrogen peroxide and hydroxyl free radicals. Moreover, high levels of lysosomal hydrolases were observed along with attenuated phagocytosis and respiratory burst. DNA damage was also observed post-treatment with tBOOH⁶⁵. Treatment of these peritoneal macrophages with QGE had protected them against oxidative stress. Data suggested that QGE has the free radical scavenging activity³².

i) Quercus infectoria heals diabetic wounds:

Cure of diabetic wounds developed in a diabetes patient is a very tedious job. Application of antibiotics, antiseptic agents have been used but healing is a prolonged process and sometimes wound fails to heal leading to high mortality rates⁶⁶. A study was conducted to explore the wound healing potential of QGE in streptozotocin induced rat diabetic model. 20 formulations of quercus infectoria were prepared and tested for their anti-bacterial efficacy, of which the potential formulations were used in the study. It was found that wound healing process was enhanced in the groups treated with topical application of Quercus formulations with cellular infiltration, deposition of collagen and formation of epithelium⁶⁷.

Quercus infectoria was explained by various previous studies which have shown that it has strong anti-bacterial potential against S. aureus, MRSA, Pseudomonas aeruginosa, Acinetobacter baumanii, Escherichia coli⁶⁸. Diabeitc wounds are exacerbated due to increases production of inflammatory cytokines and Quercus has a known anti-inflammatory potential. These properties of Quercus infectoria have helped in wound healing.

j) Anti-cancer efficacy of Quercus infectoria galls:

Anti-cancer efficacy of QGE has been explored less. A study conducted by Tong et al., has reported in vitro efficacy of ether fraction of Quercus against human glioblastoma cell line, U251 in a dose dependent manner. Various compounds such as gallic acid isolated from QG also have potential anticancer activity. The anticancer activity of gallic acid was mediated through effect on cell cycle, inducing apoptosis, and affecting angiogenesis and metastasis⁶⁹. Reports suggest that it is involves activation of ATM kinases, inhibition of cyclooxygenase, depletion of GSH, inhibition of vascular endothelial growth factor along with inhibition of NF-кB⁷⁰.

Another compound present in QG with anticancerous property is Ellagic acid and its activity has been proven both in vitro and in vivo. It inhibits angiogenesis and migration, invasion of cancer cells by effecting various signaling pathways which include cell-cycle signaling cascade, PKC pathway, TGF-β/Smad3 pathway⁷¹.

Methyl gallate, one of the main constituents present in the QG has shown anti-cancer property mediated by blocking of AKT, NF-кB and JAK/STAT pathways⁷². This blocking of multiple pathways leads to apoptotic death in cancer cells. Interestingly, it was observed that methyl gallate inhibited tumor infiltration of Treg cells, thereby reversing the immune milleu from suppressed state ⁷³. Amentoflavone, a bioflavonoid compound present in galls also has anti-cancer potential by stimulating the arrest of cell cycle leading to apoptosis⁷⁴. It was reported by Deiab et al., that 1,2,3,4,6-tetra-O-galloyl-β-D-glucose had shown remarkable anti-proliferative activity against human breast cancer cell line⁷⁵. The underlying molecular mechanism involves targeting overexpression of lactic acid dehydrogenase-A and other metabolic genes as observed in MDA-MB-231 cancer cell line. Overall data suggests that QGE and compounds isolated from it are potentially anti-cancerous

Toxicity of Quercus Infectori:

We have discussed in above sections, the potential activity of Quercus infectoria galls. Many medicinal plants have been used without determination of efficacy and toxicity. Therefore, inspite of vast array of natural products, few have gone to the bedside from beachside as no detailed study of their toxicity, adverse side effects are being carried out.

Iminjan et al., evaluated the toxicities associated with Quercus infectoria aqueous extract in mice model. It was found that all the mice survived even after receiving 300 times higher dose than the normal dose. Some bio-chemical and hematological parameters were initially found to be changed which resolved after a period of time. Though the data appears to be promising in animals, further evaluation of safe and effective dose need to be done before clinical trials in humans ⁷⁶.

CONCLUSION AND FUTURE PROSPECTS:

The literature cited above ensures the medicinal value of Quercus infectoria galls. It has a vast array of activities including anti-diabetic, anti-cancer, anti-inflammatory etc. The major problem associated with the medicinal plants is that although, they are in use but their complete scientific validation is lacking. Meagre information about the mechanism of action also limits the usage of medicinal plants. Quercus infectoria has shown prominent effect on various signaling pathways as well. It has affected the production of TGf-β along with many other cytokines such as IL-1β and TNF-α. This indicates that Quercus has immunomodulatory efficacy which needs to be explored more. Further bio-assay guided fractionation and isolation of pure compounds from Quercus infectoria may provide new therapeutic moelcules. Two pure compounds namely ellagic acid-4-O-[β-Dglucopyranosyl]-10-O-[β-D-glucopyranosyl] -(4 1)-β-Drhamnopyranoside (1) and 2-methyl-3-hydroxymethylene-4,5,6,7,8-pentahydroxynaphthalene were isolated from ethanolic extract of Quercus infectoria with a potential inhibitory activity against nitric oxide(NO) and superoxide (^.O2 ) free radicals, which need to be further explored for their molecular mechanism⁷⁷.

In conclusion, extended and in-depth investigation of the active components of the QGE would enhance its usage and serve as an interface for the traditional medicines and the conventional medicines. This would ease and improve the clinical usage of Quercus infectoria for patients.

ACKNOWLEDGEMENT:

Authors acknowledge the College of Applied Medical Sciences in Jubail, Imam Abdulrahman Bin Faisal University for their support to carry out this work.

FUNDING:

This work was primarily supported by grants (Grant No. 2019-165-AMSJ), from the Deanship of Scientific Research, Imam Abdulrahman Bin Faisal University Dammam, Saudi Arabia.

Declaration of Competing Interest:

No potential conflict of interest was reported by the authors.

ABBREVIATIONS:

Quercus infectoria; QG, Quercus infectoria extracts; QGE, N-acyl homoserine lactone; AHL

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Received on 13.06.2021 Modified on 10.08.2022

Research J. Pharm. and Tech 2023; 16(8):3999-4006.

DOI: 10.52711/0974-360X.2023.00656

Quercus infectoria	Disease / Pathogen/condition	Mode of Action
Aqueous QG extract	Bone related problems as osteoporosis	Gall extract enhance bone formation at a very low concentration, induced cell proliferation as was observed by bone formation markers, ALP and osteocalcin. Moreover, it has many phytochemicals, which enhances osteoblastic activity, increase ALP activity, secretion of osteoclastin and deposition of calcium⁴⁴.
Aqueous QG Extract	Peudomonas aeruginosa	QG extract have an effect on Quorum sensing system of this bacteria which is important for the pathogenicity of the bacteria²⁹.
Aqueous and methanolic extract	S. saprophyticus, E. coli and K. pneumoniae (cause UTI)	The effect was possibly illustrated due to high tannin content in QGE. Tannins might have prevented bacterial binding to cells and thereby their multiplication²⁶.
Ethanolic extract	Methicillin-resistant Staphylococcus aureus (MRSA)	Treatment with QGE caused pseudomulticellular aggregates with thick walls. This gave an insight that QGE could have interfered with the autolysins which cause cell separation³¹.
Aqueous QG extract	Leptospira	QGE caused structural changes in the L. interrogans which might be due to presence of pyrogallol in QGE on outer membrane of the bacteria thereby inhibiting its growth³⁴.
Methanolic extract of QG	Cardiovascular disorders (Antilipidemic and Antiatherogenic effects)	By inhibiting the activity of enzymes, Pancreatic Lipase & HMG CoA reductase which might be responsible for the anti-lipidemic and anti-atherogenic effect. Tannins in QGE can precipitate pancreatic lipase^{73,6,49,75,12}.
Methanolic and acetone extracts of QG	Dental hygiene	Inhibit the oral bacterial population eg. Gram-positive bacteria (Streptococcus mutans and Streptococcus salivarius) & Gram-negative bacteria (Porphyromonas gingivalis and Fusobacterium nucleatum)^44,45.
Methanolic extract of QG	Diabetes	Both animal study and clinical trial was done. However detailed mechanism not explored much^35,41.
Alcoholic extract of QG	Anti-inflammatory	Orally administered QGE was found to treat inflammation by inhibiting histamine, serotonin and PGE2⁸. For inflammation associated with diabetes, anti-inflammatory potential of QGE was mediated by down-regulating Set7/NF- κB signalling pathway⁵⁸.
Ethanolic extract	Diabetic Nephropathy	In diabetic patients, due to high glucose concentration expression of renal TGF-β is induced which has an imperative function in diabetes nephropathy⁷⁶.QGE was found to decrease the expression of TGF-β, thereby protecting kidney³⁶.
Alcoholic extract	Anti-oxidant property	It showed protection to rat peritoneal macrophages against oxidative stress. Gall extract significantly scavenged DPPH, H2O2 and •OH, which establishes their anti-oxidant activity³².
Quercus extract in formulation having propylene glycol,polyethylene glycol 400, polysorbate 20, polysorbate 60, 95% ethanol, and uniphen P-23	Wound healing	QGE has already established anti-microbial property. It helped in healing of diabetic wounds. Diabetic wounds have exacerbated inflammatory cytokines, QGE has a strong anti-inflammatory property which helped in healing wounds⁵².
Ethyl acetate extract	Cancer	Inhibits Epidermal growth factor receptor, important target in various cancers⁷⁴.
Gallic acid		Causes activation of ATM kinases, inhibition of cyclooxygenase, depletion of GSH, inhibition of vascular endothelial growth factor along with inhibition of NF-кB55.
Ellagic acid		Inhibits angiogenesis and migration, invasion of cancer cells by effecting various signaling pathways which include cell-cycle signaling cascade, PKC pathway, TGF-β/Smad3 pathway.45,2,26
Methyl gallate		Anti-cancer property mediated by blocking of AKT, NF-кB and JAK/STAT pathways. Also inhibited tumor infiltration of Treg cells changing the immune milleu against cancer.24