Sage Journals: Discover world-class research

Abstract

Gallic acid is a trihydroxybenzoic acid of plant metabolites widely spread throughout the plant kingdom. It has characteristics of the strong antioxidant and free radical scavenging activities, and can protect biological cells, tissues, and organs from damages caused by oxidative stress. This review aims to summarize the protective roles of gallic acid and the underlying pharmacological mechanisms in the pathophysiological process of the oxidative damage diseases, such as cancer, cardiovascular, degenerative, and metabolic diseases. The studies reviewed herein showed that the main therapeutic effects of gallic acid were attributed to its antioxidant properties. It modulated various signaling pathways through a wide range of inflammatory cytokines, and enzymic and nonenzymic antioxidants. However, the available data were limited to few studies assessing the treatment effects of gallic acid in human subjects to confirm its therapeutic outcomes. Therefore, the clinical trials were urgently needed to investigate the safety and efficacy of gallic acid treatment on human beings. The scientific data summarized in this review highlighted the therapeutic potentials of gallic acid for oxidative damage diseases. It could be developed as versatile adjuvant or therapeutically lead compound in future.

Keywords

gallic acid oxidative stress cancer cardiovascular disease degenerative disease metabolic disease

Oxygen- and nitrogen-based radicals are 2 types of free radicals, characterizing unstable and highly reactive in biology system.¹ Excessively high levels of free radicals could initiate lipid peroxidation; cause damage of cellular proteins, membrane lipids, and nucleic acids; and eventually result in injury.² Imbalance between the production and the elimination of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to a situation when steady-state ROS concentration is transiently or chronically enhanced with certain consequences of cell physiology, has been defined as oxidative stress.^3,4 Reactive oxygen species are oxygen-containing oxidants including hydrogen peroxide, hydroxyl radicals, superoxide, peroxyl radicals, hypochlorous acid, ozone, and singlet oxygen, while RNS include nitric oxide radicals, peoxynitrite, and nitrogen dioxide.^4,5 Oxidative stresses are categorized into acute and chronic oxidative stress, based on the ability of ROS/RNS to be rebalanced to a certain degree within a certain period of time. More or less specific physiological even pathological consequences may be induced under acute and chronic oxidative stress.⁶ Currently, the chronic oxidative stress has been exemplified to form atherosclerotic plaques and increase the risk of type 2 diabetes mellitus, cancer, atherosclerosis, and neurodegenerative diseases.^5,6

Gallic acid and its derivatives such as lauryl gallate, propyl gallate, octyl gallate, tetradecyl gallate, and hexadecyl gallate are phenolic acids of plant metabolites widely spread throughout the plant kingdom.⁷ As shown in Figure 1, gallic acid is a trihydroxybenzoic acid in which the hydroxy groups are at positions 3, 4, and 5. Its derivatives have various length of carbochains linked to the carboxyl group.⁸ Gallic acid and its derivatives have demonstrated a large number of applications in pharmaceutical, cosmetic, food, printing, and dyeing industries.^9,10 When used as an additive, gallic acid could prevent the rancidity and spoilage of fats and oils in various eatable goods such as condiment, candy, beverage, and baked and fried food.¹¹ Also, it was found that gallic acid could inhibit melanogenesis to overcome pigmentation and protect the cells from UV-B or ionizing irradiation, which is the reason for using it as an importance gradient in many cosmetics.^12,13 Besides those, there are diverse reports with regard to gallic acid on medicinal uses, such as antibacterial, anti-allergy, anti-inflammatory, and antioxidant stress. The gallic acid displayed antibacterial effects against a wide range of pathogens including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Streptococcus mutans, Chromobacterium violaceum, Campylobacter jejuni, and Listeria monocytogenes.^14
-16 It was reported that gallic acid, together with other phenolic compounds, is an effective ingredient for the treatment of allergic contact dermatitis.¹⁷ The release of the pro-inflammatory and inflammatory mediators, such as interleukin (IL)-2, IL-4, IL-5, IL-13, IL-33, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), cyclooxygenase-2 (COX-2), and nuclear factor κB (NF-κB), could be downregulated by gallic acid to prevent excessive inflammatory responses.^18
-20 Most importantly, gallic acid should be used as the strong antioxidants for the protection of human cells under acute and chronic oxidative stress, which make them significant options to be used as therapeutic agents or dietary supplements.²¹

Figure 1

Chemical structure of gallic acid and its derivatives. 1: Gallic acid; 2: propyl gallate; 3: octyl gallate; 4: lauryl gallate; 5: tetradecyl gallate; and 6: hexadecyl gallate.

As the results of its antioxidant and free radical scavenging characteristics, the protective role of gallic acid in preventing various oxidative damage diseases has attracted great interests of the scientific community toward various application potentials in recent years.²² This work summarizes the pharmacological activities and important uses of gallic acid in oxidative damage interventions which have extensively been disclosed in various research studies. This work also gives the evidences for the construction of scientific foundations toward the developments and ability of using compounds based on gallic acid in the future.

Gallic Acid in Treating Oxidative Damage Diseases

It is well-known that the oxidative damage of biomolecules, accumulated under acute and chronic oxidative stress, is involved in the pathogenesis of wide spectrum diseases, such as cancer, cardiovascular diseases, degenerative diseases, and metabolic diseases.²³ Therefore, it is important to understand the role of medicines, gallic acid in this case, in the prevention of oxidative stress and treatment of oxidative damage diseases.

Cancer

The anticancer properties of gallic acid have been related to their ability to regulate the oxidative stress and modify the oxidoreductive status of cancer cells.^24
-26 Herein, the relative studies published recently were reviewed and summarized in Table 1.

Table 1

Anticancer Mechanisms of Gallic Acid in Different Experimental Models.

Model	Dosage and duration	Pharmacological effects	References
HL60 cell	177 µM/72 h	ROS ↑	²⁷
HL60/VINC cell	118 µM/72 h
HL60/MX2 cell	167 µM/72 h
LNCaP cell	-	ROS ↑; mitochondrial potential loss; cytochrome c release; activation of caspases 3, 8, and 9	²⁸
Multi-drug-resistant A2780AD ovarian cancer cells	50 µM/24 h	ROS ↑; ERK phosphorylation ↓	²⁹
SCC-4 cell	300 µM/36 h	casein kinase II activation; ROS ↑; mitochondrial cytochrome c release; cytosolic Ca²⁺ ↑	³⁰
Hela cell	400 µM/24 h	ROS ↑; MMP ↓; GSH ↓	³¹
DBTRG-05MG cell	40 µM/24 h	Ca²⁺ entry; phospholipase C-dependent release; ROS ↑	³²
HCT-15 cell	740 µM/24 h	ROS ↑; MMP ↓	³³
SCC-4 cell	-	ROS ↑; MMP ↓; Ca²⁺ entry	³⁴
SMMC-7721 cell	25 µg/mL/48 h	ROS ↑; MMP ↓; caspase 3 ↑; caspase 9 ↑; Bcl-2 ↓; BAX ↑	³⁵
SCLC H446 cell	3 µg/mL/24 h	ROS ↑; MMP ↓; XIAP ↓; Bax ↑; Apaf-1 ↑; p53 ↑; DIABLO ↑	³⁶
MDA-MB-231 cell	50 µM/48 h	ROS ↑; mitochondrial dysfunction	³⁷
N-Nitrosodiethylamine induced hepatocellular carcinoma male Wistar rats	50 mg /kg bw 5 times weekly for 5 weeks	STAT3 ↓; Suppressor of cytokine signaling 3 (SOCS3) ↑; AFP ↓; GPC-3 ↓; Gamma Glutamyl Transpeptidase (GGT) ↓	³⁸
DMH-induced colon carcinogenesis male Wistar rats	50 mg/kg bw everyday for 15 weeks	lipid peroxidation levels, SOD and CAT restore; GSH ↑; GPx ↑; GR ↑	³⁹
DMBA/Croton oil-induced skin carcinogenesis Swiss albino mice	25 mg/kg bw 3 times weekly for 16 weeks	lipid peroxidation levels, SOD and CAT restore; LDH ↓; MMP-2/-9 ↓	⁴⁰

AFP, alphafetoprotein; CAT, catalase; DMBA, 7,12-dimethylbenz[a]anthracene; DMH, 1,2-dimethylhydrazine; GPC-3, glypican-3; GPx, glutathione peroxidase; GR, glutothione reductase; GSH, reduced glutothione; LDH, lactate dehydrogenase; ROS, reactive oxygen species; SOD, superoxide dismutase; STAT3, signal transducer and activator of transcription 3.

↑: Increased level of expression; ↓: decreased level of expression.

Gallic acid could exhibit both prooxidant as well as antioxidant characteristics, and its prooxidant action is responsible for its potent anticancer and apoptosis inducing properties in most of the literature reports as follows. For human promyelocytic leukemia HL60 and its resistant sublines HL60/VINC and HL60/MX2 cells, gallic acid modulated the cellular level of ROS in a dose-dependent and time-dependent manner.²⁷ Similarly, Russell et al reported that gallic acid could autoxidate to produce significant levels of H₂O₂ and O₂ in malignant cells. These increased ROS levels could cause mitochondrial potential loss, cytochrome c release, and activation of caspases 3, 8, and 9. Therefore, the treatment of gallic acid could effectively kill cancer cells through apoptosis.²⁸ Moreover, Sánchez-Carranza et al found that gallic acid sensitized paclitaxel-resistant ovarian carcinoma cells via ROS-mediated inactivation of Extracellular Signal-Regulated Kinase (ERK), therefore, it could be used as a useful co-adjuvant in ovarian carcinoma treatment.²⁹ Moreover, gallic acid could activate casein kinase II to induce the BIK-BAX/BAK-mediated endoplasmic reticulum (ER) Ca²⁺-ROS-dependent apoptosis of human oral cancer (OC) SCC-4 cells.³⁰ Gallic acid increased ROS levels including O²⁻ in Hela cells, which was accompanied by mitochondrial potential loss and reduced glutothione (GSH) depletion.³¹ In DBTRG-05MG human glioblastoma cells, gallic acid induced the enrichment of intracellular Ca²⁺ level ([Ca²⁺]i) by causing Ca²⁺ entry, and phospholipase C-dependent release from ER, and subsequently activate mitochondrial apoptotic pathways through ROS production.³² Gallic acid induced time-dependent generation of ROS and then apoptotic death in HCT-15 colon cancer cells.³³ The Ca²⁺ release, ROS generation, and Mitochondrial membrane potential (MMP) loss were also demonstrated in apoptosis of human OC cells under the treatment of gallic acid.³⁴ Compared to normal human HL-7702 hepatocytes, gallic acid was also reported to present a selective cytotoxic effect on human hepatocellular carcinoma SMMC-7721 cells. This effect was related to the ability of gallic acid to induce caspase-3, caspase-9, and ROS activities, elevate the expression of apoptosis regulator Bcl-2-like protein 4, and reduce MMP in SMMC-7721 cells.³⁵ Wang et al reported that gallic acid combined with cisplatin exhibited synergistic effects on apoptosis of human SCLC H446 cells. It induced the generation of ROS, disruption of MMP, downregulation of X-linked inhibitor of apoptosis protein (XIAP) expression, and upregulation of Bax, apoptotic protease activating factor-1 (Apaf-1), DIABLO, and p53 expression.³⁶ Also, combination of gallic acid and another phenolic compound curcumin could lead to the apoptotic death of breast cancer cells through GSH reduction, ROS generation, and mitochondrial dysfunction.³⁷ In hepatocellular carcinoma bearing rats induced by N-nitrosodiethylamine, gallic acid could significantly decline the serum levels of alphafetoprotein, glypican-3, signal transducer and activator of transcription 3, gene expression levels of hepatic gamma glutamyl transferase and heat shock protein gp96, and elevate serum suppressors of cytokine signaling 3 level.³⁸

Moreover, their studies reported that the antioxidant action of gallic acid was also involved in the cancer elimination. In 1,2-dimethyl hydydrazine-treated colon carcinogenesis rats, gallic acid administration restored the lipid peroxidation levels, significantly normalized the superoxide dismutase (SOD) and catalase (CAT) activities, and increased the levels of GSH and the activities of glutathione peroxidase (GPx) and glutathione reductase (GR). Those effects played a key role in the prevention of malignant transformation and cancer development.³⁹ Topical application of gallic acid also reverted back the altered levels of lactate dehydrogenase (LDH)-isoenzymes, antioxidants, collagen, and MMP-2/MMP-9 activities. It was able to exhibit a significant protection for skin carcinogenesis mice induced by 7,12-dimethylbenz[a]anthracene/Croton oil.⁴⁰

Taken together, gallic acid presented extensive inhibitory effects on various cancerous models in vitro or in vivo through a dual edge sword behavior. Both of the prooxidant and antioxidant actions are responsible for the potent anticancer properties of gallic acid. As shown in Figure 2, its anticancer effects functioned through 3 key processes including causing Ca²⁺ entry, autoxidating to produce significant levels of intracellular ROS, and subsequently activating mitochondrial apoptosis on cancer cells. Reactive oxygen species generated by gallic acid have been evidenced to be responsible for the apoptotic death of cancer cell. Therefore, gallic acid behaves with the potential to be developed as a novel adjuvant or even a therapeutic agent for future use in the cancer treatment.

Figure 2

The regulation of biomolecules by gallic acid in cancer.

Cardiovascular Disease

The antioxidant potency of gallic acid was described, which is reflected in protection of the cardiovascular system.^41,42 The relative studies published recently were reviewed and summarized in Table 2.

Table 2

Protective Activities of Gallic Acid in Cardiovascular Diseases.

Model	Dosage and duration	Pharmacological effects	References
AGEs-induced H9C2 (2-1) cells	10 µM/24 h	ROS ↓; SOD ↑; CAT ↑; GSH ↑	⁴³
Male Wistar rats	7.5-30 mg/kg daily for 10 days	LDH ↑; SOD ↑; CAT ↑; GPx ↑; MDA ↓	⁴⁴
ISO-induced myocardial infarction male Wistar rats	15 mg/kg daily for 10 days	CK ↓; CK-MB ↓; AST ↓; ALT ↓; LDH ↓; SOD ↑; GPx ↑; GRx ↑; GST ↑; GSH ↑; vitamin C ↑; vitamin E ↑;	⁴⁵
ISO-induced myocardial infarction male Wistar rats	15 mg/kg daily for 10 days	CK-MB ↓; LDH ↓;β-glucuronidase ↓;β-N-acetyl glucosaminidase ↓;β-galactosidase ↓; cathepsin-B and D↓	⁴⁶
Lindane-induced myocardial damage male Wistar rats	50 mg/kg daily for 30 days	lipid peroxides (LPO) ↓; Ca²⁺ ATPase ↓; GSH ↑; SOD ↑; GPx ↑; GST ↑; Na⁺/K⁺ ATPase ↑; Mg²⁺ ATPase ↑	⁴⁷
Male SD rats	100 mg/kg daily for 14 days	GPx ↑; CAT ↑; GSSG ↓; GSH ↑; HO-1 ↑	⁴⁸
AGEs-induced cardiac fibrosis male Wistar rats	25 mg/kg daily for 30 days	TNF-a ↓; TGF-b ↓; MMP-2 ↓; MMP-9 ↓; NOX ↑; RAGE ↑; NF-jB ↑; ERK 1/2 ↑	⁴⁹
Al₂O₃ nanoparticles-induced male SD rats	100 mg/kg daily for 14 days	CPK ↓; CK-MB ↓; LDH ↓; NO ↓; TNF-α ↓; GSH ↑; SOD ↑; CAT ↑; MDA ↓	⁵⁰
l-NAME-induced hypertensive mice	100 mg/kg daily for 3 or 8 weeks	Systolic blood pressure (SBP) ↓; LV remodeling ↓; LDH ↓	⁵¹
CYP-induced cardiorenal dysfunction rats	60 and 120 mg/kg daily for 7 days	MDA ↓; H₂O₂ ↓; CAT ↑; GPx ↑; GST ↑; GSH ↑	⁵²

AGEs, advanced glycation end products; ALT, alanine transaminase; AST, aspartate transaminase; CAT, catalase; CK-MB, creatine kinase-MB; CYP, cyclophosphamide; GPx, glutathione peroxidase; GSH, reduced glutothione; GST, glutathione-S-transferase; HO-1, heme oxygenase-1; ISO, isoproterenol; LDH, lactate dehydrogenase; LV, left ventricular; MDA, malondialdehyde; l-NAME, N-nitro-l-arginine methyl ester; NOX, NADPH oxidase; ROS, reactive oxygen species; SD, Sprague-Dawley; SOD, superoxide dismutase.

↑: Increased level of expression; ↓: decreased level of expression.

Gallic acid could protect advanced glycation end products (AGEs)-induced cardiac H9C2 (2-1) cells from the release of ROS. It prevented the cardiovascular complications through altering the antioxidant status, collagen content, and MMP of cardiac cells.⁴³ In rat models of ischemic heart, LDH, SOD, CAT, and GPx activities increased and malondialdehyde (MDA) activity decreased under the treatment of gallic acid. It provided a therapeutic approach to reduce the ischemia/reperfusion injury.⁴⁴ For male Wistar rats with isoproterenol-induced myocardial infarction, treatment of gallic acid could protect the heart. The mechanisms involve reduced activities of creatine kinase (CK), creatine kinase-MB (CK-MB), aspartate transaminase, alanine transaminase, and LDH in serum, enhanced activities of enzymic antioxidants such as SOD, CAT, GPx, glutathione reductase (GRx), and glutathione-S-transferase (GST) in the heart, and the increased levels of the nonenzymic antioxidants GSH, vitamin C and E in plasma and the heart.⁴⁵ Prince et al used the same animal model and obtained similar results. Gallic acid treatment led to decreased activities of CK-MB, LDH, β-glucuronidase, β-N-acetyl glucosaminidase, β-galactosidase, cathepsin-B and -D in serum, decreased levels of thiobarbituric acid reactive substances and lipid hydroperoxides, and increased levels of GSH in the plasma and heart.⁴⁶ Gallic acid could maintain levels of endogenous antioxidant enzymes and membrane-bound ATPase activity, inhibit the lipid peroxidation, and eventually offer the protection for male albino Wistar rats against lindane-induced myocardial damage.⁴⁷ Oral administration of gallic acid resulted in the significant induction of cardiac antioxidant enzymes SOD, GPx, and CAT in the heart of male Sprague-Dawley (SD) rats. Moreover, these enzyme expressions were accompanied by upregulating the expression of heme oxygenase-1.⁴⁸ Gallic acid presented the protective effect on the cardiac fibrosis of male Wistar rats induced by AGEs. Gallic acid treatment could effectively attenuate collagen accumulation and decrease the expression of fibrotic markers such as TNF-α, transforming growth factor b (TGF-b), and MMP-2 and -9. In addition, the increased expression of NADPH oxidase, Receptor for Advanced Glycation End Products (RAGE), NF-κB, and ERK 1/2 under AGEs infusion was normalized by gallic acid treatment.⁴⁹ Treatment with gallic acid was able to ameliorate myocardial injury of male SD rats induced by aluminum oxide (Al₂O₃) nanoparticles. The cardiac enzymes (creatine phosphokinase (CPK), CK-MB, and LDH) and myocardial oxidative stress markers (GSH, SOD, CAT, and MDA) were identified as the targets regulated by gallic acid.⁵⁰ In N-nitro-l-arginine methyl ester-induced mice, the administration of gallic acid showed a dual preventive and therapeutic effect on the left ventricular remodeling and cardiac fibrosis through the inhibition of gene expression of hypertrophy markers, GATA-binding factor 6 (GATA6) transcription factor, as well as high density lipoprotein (HDL) 1 and 2.⁵¹ Moreover, Ogunsanwo et al reported that gallic acid could decrease cardiac and renal MDA contents and H₂O₂ generation, and increase the activities of CAT, GPx, GST, and GSH through free radical scavenging activity. Therefore, gallic acid could attenuate the chronic cardiotoxicity associated with cyclophosphamide treatment.⁵²

Overall, gallic acid is able to provide the protection for cardiovascular system under oxidative stress. It can restore the series of enzymic and nonenzymic antioxidants, such as SOD, CAT, GPx, GRx, GST, and GSH, vitamin C and E, and attenuate cardiotoxic MDA contents and ROS generation through free radical scavenging activity. Therefore, gallic acid could be developed as a versatile antioxidant with promising therapeutic and industrial applications.

Degenerative Disease

The antioxidant properties of gallic acid have been exploited in the solution of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases.^53
-55 As shown in Table 3, a number of studies have demonstrated the protective effects of gallic acid on brain damage in different animal models.

Table 3

Protective Activities of Gallic Acid in Neurodegenerative Diseases.

Model	Dosage and duration	Pharmacological effects	References
Aβ-induced SD rats of Alzheimer’s disease	-	Cytosolic Ca²⁺↓; glutamate release ↓; ROS ↓	⁵⁶
Sodium fluoride induced oxidative stress rats	10 mg/kg daily for 7 days	TBARS ↓; SOD ↑; CAT ↑	⁵⁷
6-OHDA-treated Wistar rats	50, 100, and 200 mg/kg for 10 days	Passive avoidance memory ↑; total thiol and GPx ↑; MDA ↓	⁵⁸
STZ-induced sporadic Alzheimer’s Wistar rats	30 mg/kg daily for 26 days	Learning and memory impairment ↓; MDA ↓; SOD ↑; GPx ↑; CAT ↑	^59,60
SC-induced amnesic Swiss albino mice	10 mg/kg daily for 7 days	Transfer latency ↓; acetylcholinesterase (AChE) activity ↑	⁶¹
Lead-induced male Wistar rats	13.5 mg/kg daily for 3 days	ALA-D ↑; SOD ↑; GSH ↑	⁶²
Aβ-induced rat model of Alzheimer’s disease	50, 100, and 200 mg/kg for 10 days	Improved brain electrical activity and histological damage	⁶³
BV-2, Primary glial and Neuro-2A cells	-	Nuclear p65 and p65 acetylation ↓	⁶⁴
Aβ peptide-induced mice of Alzheimer’s disease	-	NF-κB and IL-1β ↓	⁶⁴
2VO-induced Wistar rats of VD	100 mg/kg daily for 10 days	Spatial memory ↑; total thiol ↑; GPx↑; MDA ↓	⁶⁵

Aβ, beta-amyloid; CAT, catalase; GPx, glutathione peroxidase; GSH, reduced glutothione; MDA, malondialdehyde; 6-OHDA, 6-hydroxydopamine; ROS, reactive oxygen species; SC, scopolamine; SD, Sprague-Dawley; SOD, superoxide dismutase; STZ, streptozotocin; TBARS, thiobarbituric acid reactive substances; VD, vascular dementia.

↑: Increased level of expression; ↓: decreased level of expression.

In SD rats, gallic acid prevented beta-amyloid (Aβ)-induced apoptotic neuronal death by inhibiting the cytosolic Ca²⁺ entry, glutamate release, and generation of ROS.⁵⁶ The gallic acid could significantly reduce the thiobarbituric acid reactive substances level, retrieve the level of GSH, SOD, and CAT activities, and then protect the rat brain under sodium fluoride induced oxidative stress.⁵⁷ Mansouri et al reported that oral administration of gallic acid could significantly increase the passive avoidance memory, total thiol and GPx contents and also decreased MDA levels in the hippocampus and striatum of 6-hydroxydopamine-treated Wistar rats (animal model of Parkinson’s disease). The results suggested that the cerebral antioxidant defense could be enhanced by gallic acid stimulation, which is an effective approach in the treatment of Parkinson’s disease.⁵⁸ The same group also found that gallic acid could prevent streptozotocin (STZ)-induced learning and memory impairment in sporadic Alzheimer’s Wistar rats. Moreover, oral administration of gallic acid singnificantly reduced MDA levels in the brain tissues and restored the activities of antioxidant enzymes (SOD, GPx, and CAT) in the hippocampus and cerebral cortex.^59,60 In scopolamine-induced amnesic models, gallic acid was found to possess anti-amnesic activity which may be attributed to its antioxidant properties and anticholinesterase activity.⁶¹ Gallic acid also reduced the lead accumulation in brain tissue. It reversed the locomotor and exploratory activities damages, enhanced blood Aminolevulinic acid dehydratase (ALA-D) activity, and decreased brain CAT. Therefore, gallic acid played a role against the brain oxidative stress resulting from lead poisoning.⁶² In the intrahippocampal infusion of Aβ-induced rat model of Alzheimer’s disease, gallic acid treatment could improve the brain electrical activity and histological damage (removed the Alzheimer’s disease plaques in CA1 region of hippocampus) in a dose-dependent manner.⁶³ Gallic acid was also reported to inhibit NF-κB acetylation and then suppress Aβ-induced neuroinflammation and Aβ-mediated neurotoxicity on BV-2 and Neuro-2A cells in vitro. For in vivo models of Alzheimer’s disease induced by Aβ peptide, gallic acid inhibited the increase of nuclear NF-κB and IL-1β as well.⁶⁴ In animal models of vascular dementia, gallic acid treatment significantly restored the spatial memory, total thiol and GPx contents and decreased MDA levels in the hippocampus and frontal cortex. Therefore, it significantly enhanced the cerebral antioxidant defense against cognitive deficits.⁶⁵

Overall, gallic acid has exhibited great neuroprotective effects in various cellular or animal models in vitro and in vivo. As a result of regulation of antioxidant enzyme activities, neuroinflammatory cytokines, cytosolic Ca²⁺ concentration, and ROS generation, gallic acid could prevent neuronal death, and increase the learning and passive avoidance memory. Therefore, gallic acid could be introduced as a promising pharmacological agent for preventing and treating neurodegenerative diseases in future.

Metabolic Disease

It is well-known that metabolic diseases, such as diabetes mellitus and obesity, could reduce the antioxidant capacity by decreasing the level of antioxidant enzymes, leading to a progressive time-dependent cellular dysfunction, organism damage, and an increased risk of the age-related diseases and death.^23,66,67 With the great antioxidant and free radical scavenging abilities, gallic acid could reverse the metabolism to its normal condition. Therefore, it could function as an effective agent in the treatment of metabolic diseases.

In the clinic trial, it was found that gallic acid could maintain the stability of genetic materials, protect LDL against oxidative damage, and reduce the levels of C-reactive protein in the diabetic patients.⁶⁸ Similarly, gallic acid protected STZ-induced type I diabetes models from oxidative stress-induced damage. Its treatment could effectively decrease ROS levels and lipid peroxidation, and elevate activities of the antioxidant enzymes SOD, Δ-aminolevulinic acid dehydratase, CAT, and GST levels in the liver of diabetic rats⁶⁹ . Moreover, several studies reported that gallic acid could significantly decrease the levels of blood glucose, lipid peroxidation products, glycoprotein components, and lipids and significantly enhance the activities of enzymic antioxidants in STZ-induced diabetic animal models.^70
-72 It was also reported that gallic acid presented great protective effects in various experimental models of the obese state. Setayesh et al reported that gallic acid could significantly reduce the levels of glucose, insulin, and triglycerides in plasma, and oxidation of DNA bases in most organs of the obese animals.⁷³ Similarly, Hsu and Yen reported that the body and adipose tissue weights could be controlled by gallic acid in high-fat diet treated Wistar rats. The consumption of gallic acid promoted serum parameters (tumor-associated glycoprotein (TAG), phospholipid, total cholesterol, LDL-cholesterol, insulin, and leptin) and reduced oxidative stress (reduced Glutathione (GSSG) and enhanced GSH, GPx, glutathione reductase (GRd), and GST) in the obese rats.⁷⁴

Taken together, gallic acid has increasingly demonstrated ameliorative effects against various metabolic disorders in experimental models. In addition to reducing raised blood glucose and/or excessive lipid storage, gallic acid could ameliorate inflammation and oxidative stress at a cellular level through modulating the expression of relative cytokines and enzymes, mainly including SOD, Δ-aminolevulinic acid dehydratase, CAT, GST, GSH, GPx, and GRd. The available evidence would certainly create a great interest of either research or clinical community toward the therapeutic potentials of gallic acid on metabolite diseases.

Conclusive Remarks

Oxidant stress is of significant scientific interest, due to their involvement in the progressive genesis of noncommunicable diseases, such as cancer, myocardial infarction, Alzheimer’s dementia, diabetes mellitus, and obesity. The current review is an attempt to summarize the protective roles of gallic acid and the underlying pharmacological mechanisms in the pathophysiological process of these oxidative damage diseases. Studies presented herein indicate that the prooxidant as well as antioxidant actions of gallic acid are responsible for its potent anticancer and apoptosis inducing properties, while its antioxidant action is mainly responsible for the other pharmacological effects. It affects relative signaling pathways through regulation of a wide range of inflammatory cytokines, and enzymic and nonenzymic antioxidants. Therefore, gallic acid has the potentials to be developed as versatile adjuvant or even pharmaceutical agent with promising therapeutic and industrial applications. However, the major shortfalls of this development were limited to few studies assessing the treatment effects of gallic acid against oxidative damage diseases and drug metabolism in human subjects to confirm its therapeutic outcomes. This should be further complemented with properly designed clinical trials to provide meaningful data in determining the efficacy and safety of a given gallic acid treatment.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Finkel

Holbrook

. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408(6809):239-247.doi:10.1038/35041687

Maritim

AC.

Sanders

RA.

Watkins

. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17(1):24-38.doi:10.1002/jbt.10058

Lushchak

. Environmentally induced oxidative stress in aquatic animals. Aquat Toxicol. 2011;101(1):13-30.doi:10.1016/j.aquatox.2010.10.006

Ito

Sono

Ito

. Measurement and clinical significance of lipid peroxidation as a biomarker of oxidative stress: oxidative stress in diabetes, atherosclerosis, and chronic inflammation. Antioxidants. 2019;8(3):72.doi:10.3390/antiox8030072

Tan

HY.

Wang

et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci. 2015;16(11):26087-26124.doi:10.3390/ijms161125942

Lushchak

. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem Biol Interact. 2014;224:164-175.doi:10.1016/j.cbi.2014.10.016

Kahkeshani

Farzaei

Fotouhi

et al. Pharmacological effects of gallic acid in health and diseases: a mechanistic review. Iran J Basic Med Sci. 2018;22(3):225-237.

Fernandes

FHA.

Salgado

HRN

. Gallic acid: review of the methods of determination and quantification. Crit Rev Anal Chem. 2016;46(3):257-265.doi:10.1080/10408347.2015.1095064

Brewer

. Natural antioxidants: sources, compounds, mechanisms of action, and potential applications. Compr Rev Food Sci Food Saf. 2011;10(4):221-247.doi:10.1111/j.1541-4337.2011.00156.x

10.

Saeed

Khan

MR.

Shabbir

. Antioxidant activity, total phenolic and total flavonoid contents of whole plant extracts Torilis leptophylla L. BMC Complement Altern Med. 2012;12(1):221.doi:10.1186/1472-6882-12-221

11.

Kosuru

RY.

Roy

Das

SK.

Bera

et al. Gallic acid and gallates in human health and disease: do mitochondria hold the key to success? Mol Nutr Food Res. 2018;62(1):1700699.doi:10.1002/mnfr.201700699

12.

T-R.

Lin

J-J.

Tsai

C-C

et al. Inhibition of melanogenesis by gallic acid: possible involvement of the PI3K/Akt, MEK/ERK and Wnt/β-catenin signaling pathways in B16F10 cells. Int J Mol Sci. 2013;14(10):20443-20458.doi:10.3390/ijms141020443

13.

Sawa

Nakao

Akaike

et al. Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds: implications for the anti-tumor-promoter effect of vegetables. J Agr Food Chem. 1999;47(2):397-402.

14.

Shao

et al. Inhibition of gallic acid on the growth and biofilm formation of Escherichia coli and Streptococcus mutans . J Food Sci. 2015;80(6):M1299-M1305.doi:10.1111/1750-3841.12902

15.

Sorrentino

Succi

Tipaldi

et al. Antimicrobial activity of gallic acid against food-related Pseudomonas strains and its use as biocontrol tool to improve the shelf life of fresh black truffles. Int J Food Microbiol. 2018;266:183-189.doi:10.1016/j.ijfoodmicro.2017.11.026

16.

Jeon

. Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds. Front Microbiol. 2015;13:1129.

17.

Zhang

YT.

Peng

Guo

Chen

. Phenolic composition and effects on allergic contact dermatitis of phenolic extracts Sapium sebiferum (L.) Roxb. leaves. J Ethnopharmacol. 2015;162:176-180.doi:10.1016/j.jep.2014.12.072

18.

Hyun

KH.

Gil

KC.

Kim

SG.

Park

S-Y.

Hwang

. Delphinidin chloride and its hydrolytic metabolite gallic acid promote differentiation of regulatory T cells and have an anti-inflammatory effect on the allograft model. J Food Sci. 2019;84(4):920-930.doi:10.1111/1750-3841.14490

19.

Radan

Dianat

Badavi

et al. In vivo and in vitro evidence for the involvement of Nrf2-antioxidant response element signaling pathway in the inflammation and oxidative stress induced by particulate matter (PM10): the effective role of gallic acid. Free Radic Res. 2019;53(2):210-225.doi:10.1080/10715762.2018.1563689

20.

Wang

Zhao

et al. Gallic acid attenuates allergic airway inflammation via suppressed interleukin-33 and group 2 innate lymphoid cells in ovalbumin-induced asthma in mice. Int Forum Allergy Rhinol. 2018;8(11):1284-1290.doi:10.1002/alr.22207

21.

Dludla

PV.

Nkambule

BB.

Jack

et al. Inflammation and oxidative stress in an obese state and the protective effects of gallic acid. Nutrients. 2018;11(1):23.doi:10.3390/nu11010023

22.

Choubey

Varughese

Kumar

Beniwal

. Medicinal importance of gallic acid and its ester derivatives: a patent review. Pharm Pat Anal. 2015;4(4):305-315.doi:10.4155/ppa.15.14

23.

Kruk

Aboul-Enein

HY.

Kładna

Bowser

et al. Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis. Free Radic Res. 2019;53(5):497-521.doi:10.1080/10715762.2019.1612059

24.

Mileo

AM.

Miccadei

. Polyphenols as modulator of oxidative stress in cancer disease: new therapeutic strategies. Oxid Med Cell Longev. 2016;17:6475624.

25.

You

BR.

Park

. Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase. Toxicology In Vitro. 2010;24(5):1356-1362.doi:10.1016/j.tiv.2010.04.009

26.

Velderrain-Rodríguez

Torres-Moreno

Villegas-Ochoa

et al. Gallic acid content and an antioxidant mechanism are responsible for the antiproliferative activity of ‘Ataulfo’ mango peel on LS180 cells. Molecules. 2018;23(3):695.doi:10.3390/molecules23030695

27.

Maruszewska

Tarasiuk

. Antitumour effects of selected plant polyphenols, gallic acid and ellagic acid, on sensitive and multidrug-resistant leukaemia HL60 cells. Phytother Res. 2019;33(4):1208-1221.doi:10.1002/ptr.6317

28.

Russell

LH.

Mazzio

Badisa

et al. Autoxidation of gallic acid induces ROS dependent death in human prostate cancer LNCaP cells. Anticancer Res. 2012;32(5):1595-1602.

29.

Sánchez-Carranza1

JN.

Díaz

JF.

Redondo-Horcajo

et al. Gallic acid sensitizes paclitaxel-resistant human ovarian carcinoma cells through an increase in reactive oxygen species and subsequent downregulation of ERK activation. Oncol Rep. 2018;39:3007-3014.

30.

Lin

ML.

Chen

. Activation of casein kinase II by gallic acid induces BIK-BAX/BAK-Mediated ER Ca⁺⁺-ROS-Dependent apoptosis of human oral cancer cells. Front Physiol. 2017;8:761.

31.

Park

. Gallic acid induces HeLa cell death via increasing GSH depletion rather than ROS levels. Oncol Rep. 2016;37(2):1277-1283.doi:10.3892/or.2016.5335

32.

Hsu

SS.

Chou

CT.

Liao

et al. The effect of gallic acid on cytotoxicity, Ca²⁺ homeostasis and ROS production in DBTRG-05MG human glioblastoma cells and CTX TNA2 rat astrocytes. Chem Biol Interact. 2016;252:61-73.doi:10.1016/j.cbi.2016.04.010

33.

Subramanian

AP.

Jaganathan

SK.

Mandal

Supriyanto

Muhamad

et al. Gallic acid induced apoptotic events in HCT-15 colon cancer cells. World J Gastroenterol. 2016;22(15):3952-3961.doi:10.3748/wjg.v22.i15.3952

34.

Lin

ML.

et al. ER-Dependent Ca++-mediated cytosolic ROS as an effector for induction of mitochondrial apoptotic and ATM-JNK signal pathways in gallic acid-treated human oral cancer cells. Anticancer Res. 2016;36(2):697-705.

35.

Sun

Zhang

Xie

Zhang

Zhao

. Gallic acid as a selective anticancer agent that induces apoptosis in SMMC-7721 human hepatocellular carcinoma cells. Oncol Lett. 2015;11(1):150-158.doi:10.3892/ol.2015.3845

36.

Wang

Weng

et al. Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway. Oncol Rep. 2016;35(5):3075-3083.doi:10.3892/or.2016.4690

37.

Moghtaderi

Sepehri

Delphi

Attari

. Gallic acid and curcumin induce cytotoxicity and apoptosis in human breast cancer cell MDA-MB-231. Bioimpacts. 2018;8(3):185-194.doi:10.15171/bi.2018.21

38.

Aglan

HA.

Ahmed

HH.

El-Toumy

SA.

Mahmoud

et al. Gallic acid against hepatocellular carcinoma: an integrated scheme of the potential mechanisms of action from in vivo study. Tumour Biol. 2017;39(6):101042831769912.doi:10.1177/1010428317699127

39.

Giftson

JS.

Jayanthi

Nalini

. Chemopreventive efficacy of gallic acid, an antioxidant and anticarcinogenic polyphenol, against 1,2-dimethyl hydrazine induced rat colon carcinogenesis. Invest New Drugs. 2009;28(3):251-259.doi:10.1007/s10637-009-9241-9

40.

Subramanian

Venkatesan

Tumala

Vellaichamy

. Topical application of gallic acid suppresses the 7,12-DMBA/Croton oil induced two-step skin carcinogenesis by modulating anti-oxidants and MMP-2/MMP-9 in Swiss albino mice. Food Chem Toxicol. 2014;66:44-55.doi:10.1016/j.fct.2014.01.017

41.

Shahrzad

Aoyagi

Winter

Koyama

Bitsch

. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr. 2001;131(4):1207-1210.doi:10.1093/jn/131.4.1207

42.

Badhani

Sharma

Kakkar

. Gallic acid: a versatile antioxidant with promising therapeutic and industrial applications. RSC Adv. 2015;5(35):27540-27557.doi:10.1039/C5RA01911G

43.

Umadevi

Gopi

Simna

et al. Studies on the cardio protective role of gallic acid against age-induced cell proliferation and oxidative stress in H9C2 (2-1) cells. Cardiovasc Toxicol. 2012;12(4):304-311.

44.

Badavi

Sadeghi

Dianat

et al. Effects of gallic acid and cyclosporine A on antioxidant capacity and cardiac markers of rat isolated heart after ischemia/reperfusion. Iran Red Crescent Med J. 2014;16(6):e16424.

45.

Priscilla

DH.

Prince

PSM

. Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chem Biol Interact. 2009;179(2-3):118-124.doi:10.1016/j.cbi.2008.12.012

46.

Stanely Mainzen Prince

Priscilla

Devika

. Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats. Eur J Pharmacol. 2009;615(1-3):139-143.doi:10.1016/j.ejphar.2009.05.003

47.

Padma

VV.

Poornima

Prakash

Bhavani

et al. Oral treatment with gallic acid and quercetin alleviates lindane-induced cardiotoxicity in rats. Can J Physiol Pharmacol. 2013;91(2):134-140.doi:10.1139/cjpp-2012-0279

48.

Yeh

CT.

Ching

LC.

Yen

. Inducing gene expression of cardiac antioxidant enzymes by dietary phenolic acids in rats. J Nutr Biochem. 2009;20(3):163-171.doi:10.1016/j.jnutbio.2008.01.005

49.

Umadevi

Gopi

Elangovan

. Regulatory mechanism of gallic acid against advanced glycation end products induced cardiac remodeling in experimental rats. Chem Biol Interact. 2014;208:28-36.doi:10.1016/j.cbi.2013.11.013

50.

El-Hussainy

Hussein

AM.

Abdel-Aziz

El-Mehasseb

et al. Effects of aluminum oxide (Al₂O₃) nanoparticles on ECG, myocardial inflammatory cytokines, redox state, and connexin and lipid profile in rats: possible cardioprotective effect of gallic acid. Can J Physiol Pharmacol. 2016;94(8):868-878.doi:10.1139/cjpp-2015-0446

51.

Jin

Lin

Piao

et al. Gallic acid attenuates hypertension, cardiac remodeling, and fibrosis in mice with NG-nitro-L-arginine methyl ester-induced hypertension via regulation of histone deacetylase 1 or histone deacetylase 2. J Hypertens. 2017;35(7):1502-1512.doi:10.1097/HJH.0000000000001327

52.

Ogunsanwo

Oyagbemi

Omobowale

Asenuga

ER.

Saba

et al. Biochemical and electrocardiographic studies on the beneficial effects of gallic acid in cyclophosphamide-induced cardiorenal dysfunction. J Complement Integr Med. 2017;14(3).doi:10.1515/jcim-2016-0161

53.

Rabiei

Solati

Amini-Khoei

. Phytotherapy in treatment of Parkinson's disease: a review. Pharm Biol. 2019;57(1):355-362.doi:10.1080/13880209.2019.1618344

54.

Ortega-Arellano

Jimenez-Del-Rio

Velez-Pardo

. Dmp53, basket and drICE gene knockdown and polyphenol gallic acid increase life span and locomotor activity in a Drosophila Parkinson's disease model. Genet Mol Biol. 2013;36(4):608-615.doi:10.1590/S1415-47572013000400020

55.

Parihar

Jat

Ghafourifar

Parihar

. Efficiency of mitochondrially targeted gallic acid in reducing brain mitochondrial oxidative damage. Cell Mol Biol. 2014;60(2):35-41.

56.

Ban

Nguyen

Lee

et al. Neuroprotective properties of gallic acid from Sanguisorbae radix on amyloid beta protein (25-35)-induced toxicity in cultured rat cortical neurons. Biol Pharm Bull. 2008;31(1):149-153.doi:10.1248/bpb.31.149

57.

Nabavi

SF.

Habtemariam

Jafari

Sureda

Nabavi

et al. Protective role of gallic acid on sodium fluoride induced oxidative stress in rat brain. Bull Environ Contam Toxicol. 2012;89(1):73-77.doi:10.1007/s00128-012-0645-4

58.

Mansouri

MT.

Farbood

Sameri

et al. Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chem. 2013;138(2-3):1028-1033.doi:10.1016/j.foodchem.2012.11.022

59.

Mansouri

MT.

Naghizadeh

Ghorbanzadeh

et al. Gallic acid prevents memory deficits and oxidative stress induced by intracerebroventricular injection of streptozotocin in rats. Pharmacol Biochem Behav. 2013;111:90-96.doi:10.1016/j.pbb.2013.09.002

60.

Naghizadeh

Mansouri

. Protective effects of gallic acid against streptozotocin-induced oxidative damage in rat striatum. Drug Res. 2014;65(10):515-520.doi:10.1055/s-0034-1377012

61.

Nagpal

Singh

SK.

Mishra

. Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for protection against scopolamine-induced amnesia. Drug Deliv. 2013;20(3-4):112-119.doi:10.3109/10717544.2013.779330

62.

Reckziegel

Dias

VT.

Benvegnú

et al. Locomotor damage and brain oxidative stress induced by lead exposure are attenuated by gallic acid treatment. Toxicol Lett. 2011;203(1):74-81.doi:10.1016/j.toxlet.2011.03.006

63.

Hajipour

Sarkaki

Farbood

et al. Effect of gallic acid on dementia type of Alzheimer disease in rats: electrophysiological and histological studies. Basic Clin Neurosci. 2016;7(2):97-106.doi:10.15412/J.BCN.03070203

64.

Kim

Seong

Yoo

et al. Gallic acid, a histone acetyltransferase inhibitor, suppresses β-amyloid neurotoxicity by inhibiting microglial-mediated neuroinflammation. Mol Nutr Food Res. 2011;55(12):1798-1808.doi:10.1002/mnfr.201100262

65.

Korani

Farbood

Sarkaki

Fathi Moghaddam

Taghi Mansouri

. Protective effects of gallic acid against chronic cerebral hypoperfusion-induced cognitive deficit and brain oxidative damage in rats. Eur J Pharmacol. 2014;733:62-67.doi:10.1016/j.ejphar.2014.03.044

66.

Ihara

Toyokuni

Uchida

et al. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Diabetes. 1999;48(4):927-932.doi:10.2337/diabetes.48.4.927

67.

Ajiboye

BO.

Ojo

OA.

Okesola

et al. In vitro antioxidant activities and inhibitory effects of phenolic extract of Senecio biafrae (Oliv and Hiern) against key enzymes linked with type II diabetes mellitus and Alzheimer's disease. Food Sci Nutr. 2018;6(7):1803-1810.doi:10.1002/fsn3.749

68.

Mainzen Prince

PS.

Kumar

MR.

Selvakumari

. Effects of gallic acid on brain lipid peroxide and lipid metabolism in streptozotocin-induced diabetic Wistar rats. J Biochem Mol Toxicol. 2010;25(2):101-107.doi:10.1002/jbt.20365

69.

Punithavathi

VR.

Stanely Mainzen Prince

Kumar

MR.

Selvakumari

. Protective effects of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic wistar rats. J Biochem Mol Toxicol. 2011;25(2):68-76.doi:10.1002/jbt.20360

70.

Ferk

Kundi

Brath

et al. Gallic acid improves Health-associated biochemical parameters and prevents oxidative damage of DNA in type 2 diabetes patients: results of a placebo-controlled pilot study. Mol Nutr Food Res. 2018;62(4):1700482.doi:10.1002/mnfr.201700482

71.

De Oliveira

LS.

Thomé

GR.

Lopes

et al. Effects of gallic acid on delta-aminolevulinic dehydratase activity and in the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Biomed Pharmacother. 2016;84:1291-1299.doi:10.1016/j.biopha.2016.10.021

72.

Kade

IJ.

Ogunbolude

Kamdem

JP.

Rocha

JBT

. Influence of gallic acid on oxidative stress-linked streptozotocin-induced pancreatic dysfunction in diabetic rats. J Basic Clin Physiol Pharmacol. 2014;25(1):35-45.doi:10.1515/jbcpp-2012-0062

73.

Setayesh

Nersesyan

Mišík

et al. Gallic acid, a common dietary phenolic protects against high fat diet induced DNA damage. Eur J Nutr. 2018;58(6):2315-2326.doi:10.1007/s00394-018-1782-2

74.

Hsu

CL.

Yen

. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br J Nutr. 2007;98(4):727-735.doi:10.1017/S000711450774686X

A Role of Gallic Acid in Oxidative Damage Diseases: A Comprehensive Review

Abstract

Keywords

Gallic Acid in Treating Oxidative Damage Diseases

Cancer

Cardiovascular Disease

Degenerative Disease

Metabolic Disease

Conclusive Remarks

Footnotes

Declaration of Conflicting Interests

Funding

References